READ MONOGRAPH Pérez-Llorca is strengthening its litigation and arbitration capabilities in Lisbon with the appointment of Manuel de Abreu Castelo Branco (pictured) as the partner leading the practice in Portugal This move bolsters the firm’s presence in the country Castelo Branco joins from Linklaters Portugal where he served as counsel for arbitration and litigation Castelo Branco brings 20 years of experience advising national and international companies as well as private equity funds in domestic and cross-border litigation and arbitration in Portugal and various Lusophone countries His practice has focused on civil and commercial litigation particularly advising companies on a broad range of commercial disputes he has extensive experience in contentious and non-contentious matters related to restructuring and insolvency the partner responsible for Pérez-Llorca in Portugal stated that “Manuel’s appointment is key to strengthening the firm’s Litigation and Arbitration practice in Lisbon we have built a team of experts in all areas of business law in Portugal capable of providing comprehensive advice to our clients.” A graduate in Law from the Faculty of Law at the Catholic University of Lisbon with a postgraduate degree in arbitration from the Faculty of Law at Nova University of Lisbon Castelo Branco also holds postgraduate studies in economic criminal law from the Faculty of Law at the University of Coimbra He is a member of the APA – Portuguese Arbitration Association and Forum Penal – Portuguese Association of Criminal Lawyers Addleshaw Goddard Advises Hispasat on €10.5b IRIS² Project CMS advises SCPI Epsilon 360 on commercial asset… It represents the main source of information in the legal business sector in Spain and Portugal The digital magazine – and its portal – address to the protagonists of law firms and in-house lawyers The magazine is available for free on the website and on Google Play and App Store information about deals and their advisors For further information, please visit the Group’s website www.lcpublishinggroup.com About | Privacy Policy | Advertising| Editorial | Contact Us Subscribe | Login “I’m just a curious guy who is passionate about numbers and people.” Fun fact about yourself: My family is quite big (50 people +) Undergraduate School and Degree: Bachelor in Industrial Engineering Where was the last place you worked before enrolling in business school Where did you intern during the summer of 2023 Where will you be working after graduation Financial Planning Manager for France (Paris I’m very excited to join Eli Lilly in this historical moment with a pipeline filled of breakthrough medicines (e.g Cancer) that will make life better for millions of people Community Work and Leadership Roles in Business School: I engaged in a number of positions that had impact in the MBA community and helped me to strengthen my leadership skills the MBAT is the largest gathering of MBA students in the world (1,5k+ students I had a strong influence in the event planning and execution Consulting Club Leadership Team: I helped MBA students succeed in consulting interviews via organising case cracking sessions and establishing partnerships with target consulting firms The Executive Committee (TEC): TEC is an exclusive leadership program from HEC (24 students selected amongst 160+) During the program I had the opportunity to meet top executives and industry leaders about a wide range of topics (e.g I helped HEC MBA recruiting department by participating in recruiting events/panels to share my MBA experience and connect with prospective students Which academic or extracurricular achievement are you most proud of during business school The achievement I am most proud of is winning the HEC Paris Leadership Award The Leadership Award takes place in the end of the MBA program and is voted by all the students from Class of 2024 (approximately 300 students) Having the recognition of my peers on my leadership efforts and impact during our MBA journey was very special to me What achievement are you most proud of in your professional career My transition from the office of Procter & Gamble Brazil to the one in France I arrived in France in the post-pandemic context where commodities inflation was impacting considerably the profitability of the business Thanks to my Latin American experience on dealing with volatility and inflation I was quickly able to put in place actions that brought significant impact and helped to offset the inflationary pressure I was recognized by my P&G France CEO and CFO less than six months upon joining the office Doing all that while also adapting to a new country new culture and a language that I didn’t speak before was the biggest achievement of my career It was the collaborative spirit of the HEC community the structure of the MBA (16 months + specialization) and finally the outstanding strength of HEC Paris brand in Europe who was our Structured Finance professor during the Finance specialization It was a combination of strong practical experience with in-depth knowledge of the topic and a mastery in the skill of teaching in a very didactic way These made every single class unforgettable I remember discussing with some friends in the beginning of the MBA on how curious we were to understand how someone could use debt to buy a company (classic Leveraged Buyout) we not only learned perfectly how to do that but also many other “complex” finance topics I consider myself a much more well-rounded finance professional after that class what is the one thing you’d do differently and why There are a few people in my class that I would have been more intentional about connecting with The MBA has so many activities going on at the same time that eventually it’s easy to get caught up with activities that take a lot of space (especially academics) What is the biggest myth about your school it is in a small city called Jouy-en-Josas What did you love most about your business school’s town The fact that HEC is located in a small town makes the relationships between the students stronger and all the parties and events also happen there This creates a very special bond between everyone in the cohort hence the famous collaborative aspect of the HEC community What surprised you the most about business school but I would highlight the quality and the diversity of the students I’m always amazed by how inspiring HEC people are The classmate I admire the most is Nasheed Jamal As an extremely smart MIT / Georgetown graduate and fellow of the American Academy of Neurology her humility and compassion for others is what impresses me about her What are the top two items on your professional bucket list What made Arthur such an invaluable addition to the Class of 2024 on-Campus group that provides students a sounding board of trusted peers who offer them diverse perspectives to help them make better decisions in their personal and professional lives TEC is deepened by one-to-one sessions with mentors and small-group discussions with business leaders I had a series of one-on-one sessions with him as well as witnessed him working with his 12 classmates in his group on activities Arthur has above average mental abilities but more importantly he has outstanding leadership qualities He has organized several activities in which he demonstrated a great sense of organization and managed effectively a reasonably large group of MBA students His strength has been to be able to lead and manage the group by making sure they understood the common goal and agreed upon the actions to take Keep in mind that he worked with them as a peer he is a great inspiration to his peers and an exceptional organizer.” DON’T MISS: MBAS TO WATCH: CLASS OF 2024 Our Partner Sites: Poets&Quants for Execs | Poets&Quants for Undergrads | Tipping the Scales | We See Genius Website Design By: Yellowfarmstudios.com It was a thrilling weekend for the Bajas European Championship with the Baja TT Escuderia Castelo Branco The first round of the championship delivered an exhilarating weekend of racing With competitors battling across three categories – SSV and Moto – the event showcased the best of cross-country rallying and an ever-growing crowd for three days of intense competition Taking place alongside the National and World Championships the event unfolded across Vila Velha de Rodão The 2025 edition of the Baja TT Escuderia Castelo Branco featured an impressive 366.27-kilometer course The race kicked off on Friday with a 9.27-kilometer prologue followed by 188 kilometers for SS1 on Saturday and 169 kilometers for SS2 on Sunday The challenging terrain put riders and drivers to the test pushing their skills and endurance to the limit Portuguese riders dominated from the start Martim Ventura (Husqvarna) set the pace right from the prologue closely followed by David Megre (KTM) and António Maio (Yamaha) The trio maintained their strong performances throughout Saturday and Sunday ultimately finishing in the same order and cementing their supremacy in the category The Quad category saw an outstanding performance from Rodrigo Alves (Yamaha) who controlled the race with authority and secured a commanding victory His consistency and skill on the demanding course left no room for his rivals to challenge his dominance Roberto Borrego (Can-Am) claimed victory in the prologue winning both SS1 and SS2 to emerge as the overall champion in the category This opening round of the Bajas European Championship not only delivered high-octane excitement but also set the stage for the next race in September | Copyright 2025 FIM Europe | Terms of use - Privacy statement | West Creek baseball sophomore David Noriega was voted the Clarksville area boys high school athlete of the week for March 3-9 who drove in six runs in a win over Houston County Last week's winner was Houston County basketball freshman Ryan Carter Northeast: Scored four goals in a 9-0 win over Montgomery Central and again in a 9-0 win over Clarksville Academy Clarksville Christian: Went 2-for-3 and stole four bases in a 9-0 win at Oak Ridge Christian Academy (Kentucky) Northeast: Went 2-for-3 with two home runs four RBIs and three runs in a 12-7 loss to Creek Wood Kirkwood: Scored a goal in a 6-0 win at White House Heritage Had a goal and two assists in a 4-2 win over LEAD Academy six hits and a stolen base as the Hawks won three of four games to start the season Clarksville Academy: Pitched five scoreless innings Hit .357 with two doubles and two RBIs as the Cougars went 3-1 for the week MORE: Top performers in Clarksville area TSSAA basketball, baseball, softball, soccer March 3-9 Houston County: Got the decision in a 3-2 win at Santa Fe striking out 15 batters in six innings while giving up five hits and one earned run West Creek: Went 3-for-4 with a double and six RBIs in a 17-5 win at Houston County Montgomery Central: Hit a two-run walk-off home run to seal a 13-11 win over Portland and had seven RBIs in three games for the week 12 hits in 18 at-bats and had five multi-hit games as the Wildcats began the season 5-0 Rossview: Scored both of the Hawks' goals in a 2-0 win over Crockett County Kirkwood: Scored 20 points in a 58-42 win over Clarksville in the Region 7-4A semifinals two assists and four steals in a 57-51 loss to Dickson County in the title game Kirkwood: Pitched 7⅔ innings in a pair of starts had five hits in seven at-bats with a double and an RBI MORE: Who are the top TSSAA baseball players to watch in the Clarksville area for 2025 season? MORE: The TSSAA soccer season is here: Who are the top boys players in Clarksville area for 2025? 2024José Castelo Branco and Betty Grafstein photographed at their home on New York’s Upper East Side March 2024.Photograph by Max Lakner.Save this storySaveSave this storySaveJosé Castelo Branco had been wearing the same Balmain leggings for two weeks Anyone who knows knows this to be a scandal The spouse of a diamond heiress and a Kardashian-level star in Portugal José always lived for a certain level of luxury Traveling from New York to Lisbon for what was supposed to be a short trip José brought the usual 13 Louis Vuitton suitcases and paid thousands of dollars in excess baggage fees But when José and I met up this May in the Portuguese capital it was in a small apartment on a suburban street and circumstances did not allow for such standards of presentation an elderly British aristocrat and José’s wife of nearly 30 years had accused José of physical and psychological abuse The couple’s shared wardrobe and jewelry collection were now the subject of a marital dispute José was effectively couch surfing at the apartment of a loyal friend and down to a single outfit—the same one José had worn to jail when Betty ended up in the hospital after a fall According to Betty’s statement to doctors treating her for a fractured femur and an injured wrist The hospital made an official complaint to authorities José was arrested and spent the night in jail Paparazzi swarmed outside José’s cell window beauty was the one thing José and Betty always had in common per the Instagram bio and in this article) is a 61-year-old fashion model turned art dealer who has spent a lifetime breaking rules of gender and race Lady Betty Grafstein DBE (also per her bio) is a 95-year-old dame who came of age in a New York where codes of dessert fork placement made one’s standing And yet when José and Betty met in the early 1990s Betty saw it another way: “My hairdresser told me The couple’s life together consisted of galas designing gold cuff links for a Saudi prince where they lived in their exquisitely appointed Upper East Side apartment José and Betty were never seen without meticulous Over time commenters remarked that José and Betty began to look subtly alike the idea that José had abused Betty was unthinkable Their romance had already survived all manner of scandals—a labor lawsuit brought by a former maid (José claims to have been drugged the night that video was made.) What if violence had been hidden all along Commenters speculated about a murder plot to off Betty and run away with her rumored millions—or on the other hand conspiracies by hangers-on to manipulate Betty and disinherit José José was released and given an ankle monitor it was only because of José’s hard work as a caretaker that Betty was alive The couple maintained a grueling calendar: dinner parties Betty traveled to these outings sometimes precariously pushed by someone who was also filming and appeared to be managing her Instagram account ominous news leaked from the private hospital in the seaside resort of Cascais where she was being treated She had caught pneumonia and was on antibiotics would soon fly from New York to Portugal to be with her back when José’s biggest scandal was being fined for stealing perfume from the Lisbon airport (she maintains her innocence) Who were this dignified old lady and otherworldly androgynous swan madly in love with each other and drinking Champagne on all-night livestreams From what I could glean from past coverage Betty was a British American socialite who had inherited a large fortune from her second husband Although they weren’t household names in the US José and Betty had an entourage of assistants a wardrobe seemingly worth hundreds of thousands of dollars And yet their (many) TV appearances were all in Portuguese they had emerged suddenly as global icons or as social media stars acting like global icons And increasingly anyway: What’s the difference Who cares?”Photograph by Max Lakner.I emailed José and was promptly invited to an apartment uptown for tea Their home felt like a maximalist movie set Monkey sculptures knelt in prayer on gilded pedestals A living room was decorated with Louis XVI furniture Louis Vuitton should be used only for its luggage It was a disaster that the vulgar Kardashians were tastemakers—could I believe that José and Betty were only just now becoming known outside Portugal and TikTok when they could no longer travel due to Betty’s health Botox and arthritis had given Betty a limited range of motion She batted back one José interruption with a single word: “Comma!” Her age was a particular font of bons mots you never know,” she told José dryly at one point Betty’s age was the subject of much debate in comments sections Betty had been in the hospital at least three times in the past year After one health scare a rumor spread that Betty had died and José was hiding it A contingent of fans insisted the woman in the videos on Betty’s own account was a wax figure “I am scared of what could possibly happen if she does pass because her and José are giving very much like the couple where if you die I’ll kill myself,” speculated one of the hosts of Seeking Derangements including a photo of her with Hillary Clinton they sit at nursing homes waiting to die.”Photograph by Max Lakner.The newest TikTok and Instagram followers were young and international They were curious about José and Betty’s money Whether you were in search of a queer elder or a secret transphobe sugar-baby curious or an eat-the-rich type José and Betty had something to intrigue you In September 2023 designer and Knowles family favorite Luar cast José in a campaign New followers quickly became engrossed by the drama of José and Betty’s daily life: That is to say they were engrossed by the drama of watching the couple age could no longer wear many of the pieces in her collection of jewels We flew up Third Avenue into oncoming traffic José was pushing Betty in a wheelchair and galloping in stilettos (Dolce) Betty was strapped into her chair with a belt tasked with carrying their bags (Chanel and Hermès) “Should we get out of the street?” I asked warily eyeing the oncoming taxis a few blocks up I wondered if the expedition was a performance for my benefit Genuine disorganization also seemed possible By the time we reached the office of plastic surgeon Ramtin Kassir on 66th and Park It took us three minutes and one receptionist to get Betty and her chair over the half step at the office door I took out a camera to film what appeared to be a tense moment but soon felt bad and jumped in to help When we finally made it into the exam room José was exhausted and went outside for a cigarette Betty looked straight at me and got to the point: She preferred not to be jostled around to this extent It wasn’t that she wanted to stay home and do nothing—she liked seeing people the Belgian-American diamond dealer Albert Grafstein on vacation in Cannes in the 1960s.Courtesy José Castelo Branco.José with his first wife in the early 1990s in Portugal.Courtesy José Castelo Branco.José came back into the exam room and pulled out a phone The tension evaporated; now they were making content “I’m doing what I’m always doing—my very famous and favorite doctor in the whole world who I love so so much,” Betty responded “And you’re going to have what?” asked José after a mutual friend brought the recently widowed Betty to an opening at José’s art gallery in Cascais and it created in my subconscious the desire to protect her more It turned me on,” José said in his native Portuguese to an authorized biographer in 2010 José and Betty at their wedding in 1996.Abel Dias.José José found out otherwise a few days before their wedding More recently if you were to see José hosting at the NYC nightclub The Box you might assume she was a beautiful trans woman who is deeply Catholic and attends Mass every Sunday prefers not to use such labels: “I’m very well resolved José describes the decision to embrace both masculinity and femininity as a reaction to a life of hardship as well as sexual assaults starting at age 11 José!’ I was a trailblazer in this country I paved the way for people to feel free to be themselves.” became a cabinet minister in the nation’s newly independent government went on to become Portugal’s prime minister resigning last year.) A young José looked up to his iconoclastic brother who rebelled against their colonial family But even the socialist revolutionary Sérgio never accepted his sibling’s style of rule breaking José and Betty’s mainstream notoriety began in 2003 when the couple was apprehended at the Lisbon airport with 2 million euros’ worth of undeclared gems They claimed the 100-some diamond necklaces Soon José and Betty were minor celebrities with footage of José leaving jail broadcast prime time (José was eventually acquitted and the state returned the jewels.) was José’s first show—she won and became easily the most famous cast member José appeared in flashy swimsuits and took diving lessons The premise: José is sent to live in the Namibian bush Much of the storyline revolves around the “tribe” members’ confusion about whether José should integrate with its men or women and of someone cannily harnessing the spectacle of their own ostracization who calls José “my husband,” for her thoughts on gender “I never thought of those things,” she said was one of José’s many talents: “He can paint There was a fashion designer with whom José canceled a collaboration less than a week before a planned runway show The designs “would have given Betty a heart attack.” There was a security guard at an Upper East Side physical rehab facility where Betty was being treated who offended the couple by asking them to use a back entrance “One of the things I like about him is that he’s a little bit punk,” said José’s friend “He refuses to entirely be a product.” Motta recalled once helping José organize a messy part of the house Motta discovered his friend had secretly hidden thousands of pairs of false eyelashes “If the world goes into a big war and I have to fight for myself and Betty I will look my best,” José explained matter-of-factly doing sponsored posts for filler injectors at age 95 Betty was the member of the couple I observed to be more obviously performing going quiet again once they had stopped rolling She became most animated talking about her past especially lesser-known anecdotes of hardship Betty remembers going to school on England’s southern coast as bombs dropped Betty fell in love with an American GI and moved to New York to marry him “He broke my jaw when I found out he had a girlfriend,” Betty told me I was skeptical until I found his RICO conviction from 1991 and Betty went to work at a dentist’s office and at PepsiCo before marrying diamond dealer Albert Grafstein in 1959 A 1969 WWD article described Betty as a “real hidden gem” of a designer beloved by private clients who shopped for diamond-and-coral mushroom pins and emerald rings in her “sparkling east side apartment.” (Betty said Joan Crawford was among her clientele.) José and Betty on vacation on the Algarve Coast of Portugal.Abel Dias.At the couple’s joint birthday party in 2013 José turned 51 and Betty turned 85.Carlos Manuel Martins / Global Images.While a dive into genealogy sites revealed the names of colonial dons and donas among José’s ancestors Betty said she held more recent titles: According to her Instagram bio she was a dame commander of the Order of the British Empire an honor awarded for “a pre-eminent contribution in any field” in one’s lifetime by the royal family She was often credited as “Lady,” a hereditary peerage She and José told me this was a family heirloom from Betty’s adoptive grandmother in England her birth parents were of such importance that Betty would keep their names secret to the grave “We don’t want to upset the royal family,” hinted José Wasn’t she precisely the kind of woman who didn’t need to bother with indignities such as this Sketchy search results placed Betty Grafstein’s net worth between $25 million and $500 million But I couldn’t find much about the Grafstein Diamond Corporation The only website I could find mentioning the family business was a neighborhood jewelry store in New Jersey that had at one point sold its wares I couldn’t find Betty’s name on the registries of knights and dames honored by UK monarchs the couple told me Betty received her dameship in a ceremony in 2001 They had photos and a medal from the event José and Betty attend the opening of Loris Diran’s boutique in 2009 in their signature matching fur.Steve Mack / Alamy.The villa was another puzzle The 11-bedroom property was in a picturesque medieval town long the summer residence of Portuguese monarchs Betty and Albert Grafstein purchased it in the 1970s as a country home the couple hosted lavish summer parties there a former friend and fellow reality show contestant whom José and Betty now describe as a “squatter,” was advertising it for rent on Airbnb (Pico told me he’s renting legally and denied he’s a squatter.) But what of the glittering apartment on East 62nd Street A 2019 New York Supreme Court opinion revealed that the apartment that hosted parties attended by Tina Radziwill and Studio 54 promoter Carmen D’Alessio was in fact a rental—and it was rent-stabilized (The diamond heiress paid less rent than I did!) who works in the diamond business in Belgium “Albert was a normal diamond wholesaler on 47th Street,” Cohen told me of his grandfather’s upper-middle-class background “And he was not particularly successful given that he lived in Portugal half the year.” When Albert died Cohen inherited an amount that was more like a gift and less than what it would have taken to buy a condo “Have you spoken to Roger?” Cohen asked me When I was spending time at José and Betty’s apartment this spring When I tried to reach him on his mom’s urging Then the news about the domestic violence allegations broke “I’ve been silent because this has been happening for years,” Basile told me “I didn’t want to say things people didn’t already know.” Basile said he first learned of domestic abuse in the late 1990s He got a call from friends of Betty’s and flew to Portugal where José knocked her down and kept kicking her on the ground.” Basile said Betty told him José abused her he tried to extract his mom from what he describes as a violent relationship José denied ever abusing Betty and said this incident in the late 1990s never happened When I asked José why Basile would say otherwise José told me that Basile has always disliked José and has been working for 28 years to break up the marriage for his own financial gain Portugal.Abel Dias.Basile is 75 and perhaps the only person in the couple’s orbit with no social media account Basile managed the family diamond business But he flatly denied that the business was a source of great wealth for his mom “My mom is penniless!” Betty lives off Social Security Although once a woman who “lived nicely,” he said today her only possessions of value are clothes dame commander of the Order of the British Empire “My grandparents were simple people,” Basile said of his mother’s family “I visited them once at their small house in the country.” Betty’s adoptive father who the couple said owned the men’s magazine The Yachtsman Census records confirmed that and also indicated that Betty’s grandfather—the one whose wife was supposedly lady-in-waiting to Queen Mary—was a publican came not from the Queen of England but from an Irish PR adviser and diplomatic consultant named Anthony Bailey A frequent guest at José and Betty’s parties over the years Bailey helped revive the Sacred Military Constantinian Order of Saint George and the Royal Order of Francis I such as “Dame,” to individuals including Margaret Thatcher and At some point the letters changed ever so slightly it was Bailey who had explicitly told the couple that Betty’s dameship was approved by the Queen of England Grafstein’s now lapsed entry into an Italian charitable order in 2001 allowed José to claim 23 years later she was a British dame or lady are clearly the rantings of a deranged fantasist,” Bailey told me Basile argued Betty was entirely innocent in any misrepresentation “My mother never made herself out to be more than she was,” in terms of wealth or titles “José pushed these stories and they became celebrities in Portugal And she went along with it because she liked the attention.” José had a history of playing up aristocratic grandeur going by the nickname “The Count” on reality TV The couple attends New York City designer Luar’s fashion week after party in 2023.Matteo Prandoni / BFA.com.But I wondered if Basile’s interpretation—that Betty had no hand in creating the myth of her own titles—may not give Betty enough credit Many a modern-day princess had christened herself In 2024 the aristocracy is largely made-up anyway—whether by a guy 400 years ago who said God made him king And plenty of followers had happily bought into the fantasy—myself included During my time in José’s and Betty’s lives I had been enchanted by the romance: their elegant disarray their odd combination of old-world manners and American quest for celebrity Perhaps the reality was just as fascinating as the myth it meant José likely hadn’t married her for her millions—or at the very least didn’t stay by her side for nearly 30 years for them When I spoke to José about Betty’s biography she seemed stunned at what I had uncovered and denied pressuring Betty to make up stories For months after ending up in the Portuguese hospital A lawyer visited her at her hospital in Portugal leaked photos showed Betty and caregivers traveling by plane from Portugal directly to another hospital in New York and her lawyers are currently fighting a travel ban I wondered about not just the current status of her and José’s relationship Cynics may say José and Betty were never in love just using each other for beauty or status Perhaps their lifelong performance of fame was a golden cage But it also seemed possible that the artifice was the passion All romance starts with a dose of delusion: We fall in love with the idea of someone until our fantasy of the other person either buckles under the strain of reality or carries on forever eclipsing whatever reality may have once existed two months after ending up in the hospital Betty got in touch through Basile and let me know she wanted to speak with me She and her son called me on FaceTime from a beige-walled rehab room on the Upper East Side Betty was wearing blue scrubs and simple beaded bracelets tell them I’m not here!” she said at one point when the phone rang At times her memory and energy level flagged But she was most clear and confident about what she described as her longtime bullying at the hands of José “He was always throwing a punch when I least expected it,” she told me “he punched me in the head like I was a football.” The abuse started “from the beginning,” Betty said When I asked Betty about inconsistencies in her biography she first stated that she hadn’t had time to review the details Only when prompted by her son did Betty admit that José had “made up stories” about her and about her adoptive grandmother who was supposedly a lady-in-waiting to Queen Mary “José just likes to glorify everything and show off,” Betty said Betty seemed irritated by a question about the existence of her diamond fortune and avoided answering it directly “Let Roger say what he wants,” she responded with a side-eye when I told her her son said she had no assets But there was one aspect of Betty’s biography that she refused to walk back entirely When Basile prompted her to “tell the truth that you’re not a member of the British aristocracy,” Betty instead changed the subject and started talking about her home in Sintra I asked about a story she had told me months earlier she first learned she was a descendant of British royals as a teenager when her adoptive mother confessed the family secret I asked Betty to confirm this story once again In the end Betty couldn’t be sure whether her memories of her childhood were real or whether José had made them up José was adamant that she never physically abused Betty But José admitted to behavior that others may consider domineering: pressuring Betty to stand up from her wheelchair “Betty loves to look beautiful,” José said But spending time with the couple in New York I witnessed instances where José’s idea of beauty seemed more than Betty could bear Several times José tried to put a pair of Chanel flats on Betty’s swollen feet Betty grimaced and protested with a look of pain on her face People used to throw stones at me on the street because of the way I looked!” José wondered aloud if anything today could be considered abuse if definitions had changed so much to be unrecognizable According to the couple’s friend and hairstylist Alice Pires when José started passing up work opportunities to devote himself to the full-time job of Betty’s care “He wants her to be her old self: to walk normal but Betty’s not willing to do that anymore who am I to judge.” Perhaps José’s spunk was keeping Betty alive they sit at nursing homes waiting to die.” The fateful trip to Portugal that ended in the couple’s separation seemed at first like the perfect example of an adventure that was keeping Betty young “It’s so important to José,” Betty told me when we were alone The occasion was the baptism of José’s granddaughter Constança from a previous marriage before Betty.) There would be extravagant flowers In early March José called me and said they had bought tickets We scrambled to put together a photo shoot on the day before their flight Mystery boxes were stacked in an unusable shower One room looked like a Saks sample sale ravaged by raccoons I overheard the couple in tears in their bedroom I tried to calm things down then stayed for three more hours to help pack and gossiped about nonagenarian celebrities less youthful than Betty I watched the couple’s first few weeks in Portugal on social media José had a packed schedule of influencer gigs performing two shows at a drag cabaret called Glitters and making Cameo and Instagram appearances Betty tagged along and also attended events of her own Videos filmed by bystanders from the weeks surrounding the alleged domestic violence incident show José frustrated and fighting in public just days after Betty went to the hospital José waved to fans while celebrating in the streets of Lisbon for the 50-year anniversary of the Portuguese revolution Later that night José was filmed grabbing a man’s neck in a café José said the video was taken after the patron insulted Betty with the footage going online after Betty’s complaint The video shows José and a lawyer arriving outside the disputed villa in Sintra José slaps Pico in the face; Pico punches back José’s assistant Kiko recalled to me that a few minutes after the fistfight José wiped away a nosebleed and logged onto Cameo Photograph by Max Lakner.I asked José about the string of events in which she appeared to lose her temper and get physical Was it possible that José had also lost her temper with Betty “I not lose my temper with someone in their 90s,” José told me the events of that day unfolded as follows: Betty had been feeling weak and José gave her a B12 injection and brought her to a chair on the terrace of their hotel much less cross the single step that separated the terrace I’m going to fall,” José recalled her saying per José—as José struggled to get her to bed If Betty was now interpreting the incident as abuse it was because her mental faculties were failing Betty had a hallucination: “She was looking out of our window at the hotel and said she saw men in uniform cutting trees,” José said ‘Are you going senile?’” José argued that an already confused Betty fell under the influence of Basile at the hospital who manipulated her into making a domestic violence complaint When I asked Betty about the events on and after April 20 I asked Betty what words she would use to describe José’s behavior toward her When I first asked how she had ended up in the hospital “He pushed me out the window,” confirming that she meant José Betty then remembered something different: She had been outside her hotel’s entrance when José “pushed me down three flights of stairs.” I had visited the hotel in question when in Portugal It didn’t have three flights of stairs at any of its entrances I asked if perhaps Betty meant three individual stairs I asked Betty if it was possible she was confused about the specifics acknowledged his mother’s memory wasn’t particularly clear That’s why I had a hard time believing it was three floors up When I asked Betty about her and José’s love José “just needed that to build everything up,” Betty told me “I’m not going to commit suicide because I’m Catholic,” José told me when I relayed what Betty had said “The person I love for 30 years is no more the same person Like most everything about their final days together the location of the jewelry the couple once posed in for magazines is a confusing tableau of she said José admits to putting certain pieces in a bank safe days after Betty went to the hospital claiming that Basile was still holding her clothes and other possessions hostage Basile admitted to keeping the couple’s wardrobe but denied having any of their jewels The ending to this love story was not the one the couple had planned “I wish we can die at the same time,” José told me the last day we saw each other in Lisbon Everyone is dressed in black cocktail dresses And I want Betty to be beautiful,” José said “People can take everything from you but your dignity.” How Miriam Adelson Went From Big MAGA Winner to Casino Loser in Trump’s First 100 Days Trump’s Lies Are Finally Catching Up to Him The UK Has Found Another Reason to Be Mad at Meghan Markle “It’s About Him”: How Trump Is Perverting the Presidential Photo Stream The Ballad of Bill Belichick and Jordon Hudson The Truth Underlying Pete Hegseth’s Job Security Why Are Americans So Obsessed With Protein How Sebastian Stan Became Hollywood’s Most Daring Shape-Shifter Every Quentin Tarantino Movie Meet Elon Musk’s 14 Children and Their Mothers (Whom We Know of) From the Archive: Sinatra and the Mob Every year up to 1,000 Swedes develop multiple sclerosis and nearly 20,000 people are living with the lifelong disease MS is an autoimmune disease in which the body’s immune system misfires the protective sheath surrounding nerve fibers much like the insulation around electrical cables This insulation enables electrical nerve signals to travel faster This contributes to the wide range of symptoms characteristic of the disease diagnosis requires extensive investigation to rule out other potential causes of the diverse symptoms “We hope to develop technologies to identify molecular biomarkers that can reveal MS at an earlier stage these biomarkers are of a completely new type epigenetic mechanisms determine the genes that are active in a cell and those that remain silent This in turn affects which proteins are produced in the cell Castelo-Branco is developing new tools to track epigenetic changes believed to be associated with the disease Castelo-Branco hopes to move a step closer to solving the mystery of MS by combining this knowledge with mapping cells called oligodendrocytes These are one of the brain’s most common cell types and have been shown to play a unique role in the progression of multiple sclerosis we have shown that oligodendrocytes and their precursor cells can transform to acquire certain characteristics of immune cells we have developed new technologies using single-cell and spatial analysis focusing particularly on epigenetic changes.” These technologies were initially developed and applied using mouse models of the disease but the next step is to examine tissue samples from patients “We are using the techniques we developed to map epigenetic changes in MS patients We also want to combine our methods with MRI scans of the patients.” Magnetic resonance imaging (MRI) can be used to track how the disease progresses in the brain and spinal cord Castelo-Branco aims to combine the images with epigenetic methods in order to piece together the puzzle of how the disease progresses The final step is to find biomarkers for the disease but this will require further refinement of the epigenetic methods If traces of the disease processes in MS can be found in a patient’s blood Karolinska Institutet combines technological development with proximity to patients Certain cancers can leave traces in the blood in the form of minute fragments from tumor cells of altered DNA and associated proteins and techniques have been developed for detecting these traces no one has yet demonstrated the same results for multiple sclerosis In a collaborative project with Maja Jagodic and Fredrik Piehl Castelo-Branco is further developing these techniques to apply to MS “We are only just beginning a long journey but with access to clinical samples and a research environment with cutting-edge technology as we have at Karolinska Institutet we hope to create a more comprehensive picture of the progression of MS.” Castelo-Branco’s interest in multiple sclerosis was sparked during his time as a postdoc He became particularly curious about the role of oligodendrocytes in the progression of multiple sclerosis he realized he would need access to patients as well as the latest technologies “Sweden is an international leader in these areas Many of the technologies now used in the field were developed here and particularly in the Stockholm-Uppsala scientific environment which has a considerable critical mass in the field So this is naturally a good place for me to continue my work,” he says Mapping the progression of MS and ultimately stopping the disease will require a concerted multidisciplinary approach “My research team includes people from highly diverse scientific backgrounds with different ideas and perspectives on the same scientific problems The days when one person alone could make a difference are over strong teamwork is essential for scientific discovery,” says Castelo-Branco he spent most of his free time coaching his son’s football team Following the development of young players is something he remembers fondly “The role of a soccer coach has many similarities to that of a research group leader in which your role as a leader is to bring out the best in each person and then combine all the knowledge and skills into a successful team,” says Castelo-Branco New insights into multiple sclerosis Knut and Alice Wallenberg Foundation has since its establishment in 1917 awarded over SEK 39 billion in grants In 2024 the yearly grants to excellent basic research and education in Sweden was in total almost SEK 2.4 billion [email protected] Managing IP is part of Legal Benchmarking Limited Copyright © Legal Benchmarking Limited and its affiliated companies 2025 Accessibility | Terms of Use | Privacy Policy | Modern Slavery Statement The content you are trying to view is exclusive to our subscribers which you can navigate by selecting the appropriate section below ▲ Back to top of category list You have reached the limit for gifting for this month Introduction: The potential therapeutic efficacy of real-time fMRI Neurofeedback has received increasing attention in a variety of psychological and neurological disorders and as a tool to probe cognition. Despite its growing popularity, the success rate varies significantly, and the underlying neural mechanisms are still a matter of debate. The question whether an individually tailored framework positively influences neurofeedback success remains largely unexplored. Volume 14 - 2020 | https://doi.org/10.3389/fnhum.2020.578119 Introduction: The potential therapeutic efficacy of real-time fMRI Neurofeedback has received increasing attention in a variety of psychological and neurological disorders and as a tool to probe cognition and the underlying neural mechanisms are still a matter of debate The question whether an individually tailored framework positively influences neurofeedback success remains largely unexplored participants were trained to modulate the activity of a target brain region based on the performance of three imagery tasks with increasing complexity: imagery of a static dot imagery of a moving dot with two and with four opposite directions Participants received auditory feedback in the form of vocalizations with either negative The modulation thresholds were defined for each participant according to the maximum BOLD signal change of their target region during the localizer run Results: We found that 4 out of 10 participants were able to modulate brain activity in this region-of-interest during neurofeedback training This rate of success (40%) is consistent with the neurofeedback literature Whole-brain analysis revealed the recruitment of specific cortical regions involved in cognitive control and feedback processing during neurofeedback training Individually tailored feedback thresholds did not correlate with the success level We found region-dependent neuromodulation profiles associated with task complexity and feedback valence Discussion: Findings support the strategic role of task complexity and feedback valence on the modulation of the network nodes involved in monitoring and feedback control key variables in neurofeedback frameworks optimization the small sample size here tested (N = 10) impairs external validity in comparison to our previous studies our results contribute to the discussion of individually tailored solutions and justify further investigation concerning volitional control over brain activity Volitional modulation of specific brain regions was accompanied by increased activation within the striatum these findings suggest that the reward network plays a central role in neurofeedback training Individual tailoring of the self-modulation framework may be key to the success of neurofeedback training The inter-subject variability of neurofeedback success and reported inability of some participants to achieve self-modulation even after multiple sessions undermines the efficiency of neurofeedback training and limits the translation to clinical populations While neurofeedback has shown some promise there are several caveats that need to be addressed to minimize the number of “non-responders,” optimize intervention efficacy and achieve its potential as a neurorehabilitation technique follow-up on our previous work on volitional neuromodulation of the hMT+/V5 we aimed to further investigate the reward system mechanisms involved in neurofeedback and the effect of feedback valence and task complexity on the neural correlates of neurofeedback training We adopted an auditory feedback interface based on individually selected vocalizations and adaptive maximum modulation thresholds We hypothesize that neurofeedback training with explicit reward cues leads to the differential activation profiles of cognitive control and feedback monitoring areas we expect stronger task difficulty- and feedback valence-related neuroactivation in brain regions involved in neurofeedback training Ten healthy volunteers participated in this study (5 male) with ages between 19 and 35 years old (mean age = 26 The inclusion criteria allowed participants with more than 18 years old without history of neurological or psychiatric disorders Subjects were excluded in the case of any MRI contraindication The study was approved by the Ethics Commission of the Faculty of Medicine of the University of Coimbra and was conducted in accordance with the Declaration of Helsinki Each subject participated in a single neurofeedback session and was asked to volitionally modulate activity of the target brain region based on suggested visual imagery strategies (Figure 1) participants were instructed that they would receive auditory feedback to assist them in two of four imagery runs The participants were informed that the received vocalization would match the degree of success of self-modulation positive vocalization if brain activation increased in up-regulation blocks they were informed of the temporal delay of the Blood-Oxygen-Level-Dependent (BOLD) response and asked to minimize head movement during functional runs Graphical representation of the timeline of the experiment Each session started with the selection of 3 vocalizations: the most rewarding, most punishing, and a neutral, later used during neurofeedback training as auditory feedback. The identification of the vocalizations consisted of a two-stage questionnaire on a subset of 20 vocalizations from the database presented in Cowen et al. (2018) the subjects had to rate each vocalization from 1 participants were asked to only select one in case of multiple vocalizations with maximum Subjects underwent an imaging session composed by T1-weighted anatomical scan followed by five functional runs in the order: hMT+/V5 localizer Stimuli were presented on an LCD screen (70 x 39.5 cm2 60 Hz refresh rate) that the participants viewed through a mirror mounted above their eyes at an effective distance of 156 cm The visual stimuli were based on a dot size of 0.5 x 0.5 cm2 (visual angle of the dot was 0.64 deg) Scanning was performed using a 3T MRI scanner (Magnetom Prisma Germany) equipped with a 20-channel head coil Functional images of the BOLD-contrast were acquired with a gradient echo T2*-weighted echo-planar-imaging (EPI) sequence A sequence with repetition time (TR) 2 s was used (TE 30 ms flip angle 90) with 33 slices and 4 x 4 x 3 mm3 voxel resolution Anatomy was imaged with a 3D T1-weighted scan [Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) sequence The functional localizer task was designed to delineate hMT+/V5, the neurofeedback target ROI (Banca et al., 2015; Sousa et al., 2016) and to define an individually-tailored threshold for feedback presentation The localizer run consisted of three active regulation conditions: two visual motion perception conditions The visual motion perception conditions consisted of a moving white dot against a black background either oscillating along a vertical trajectory (two opposite moving stimulus−2OMS) or vertical trajectory combined with a horizontal trajectory (four opposite moving stimulus−4OMS) The visual imagery condition consisted on the imagination of a dot moving in a vertical trajectory combined with a horizontal trajectory (four opposite motion imagery−4OMI) Each active regulation condition was randomly repeated four times alternating with a stationary dot perception stimulus used as baseline—SS (13 repetitions) Participants were asked to look at a fixation cross in the center of the screen during the run the overall duration of the functional localizer was 6 min and 40 s The definition of the neurofeedback target was performed in Turbo BrainVoyager 3.2 (TBV) (Brain Innovation The contrast of interest featured the balanced test 2OMS + 4OMS > baseline A three-dimensional box was manually selected over the cluster displaying the strongest response in the statistical activation maps (defined according to t-statistic > 5) around bilateral middle temporal visual area We calculated PSC for target region activity time course during the functional localizer and applied a 3-point time-window to smooth the time course and minimize the impact of outliers The threshold τ was estimated as 50% of the maximum PSC value obtained during the 4OMI After the definition of the functional neurofeedback target mask the participants performed four imagery runs each composed by 275 volumes (lasting 9 min and 10 s each) The first and last imagery runs (control runs) were performed without feedback auditory instructions informed the participants of the condition Auditory feedback was presented in the second and third imagery runs through an interface based on three auditory cues consisting of vocalizations expressing positive The auditory cue was presented at two specific timepoints within each block if the PSC was above the threshold τ the positive vocalization was played; the negative threshold was set to 0 (the rationale was to inform the participants that the modulation was in the opposite direction); if PSC was between 0 and the τ condition the goal was to lower the BOLD signal To inform the participants of deviations (instability of the signal we set the positive and negative thresholds to τ and −τ Offline processing was performed using BrainVoyager 21.2 (BV21.2) (Brain Innovation Data processing included slice scan time correction 3D motion correction and temporal filtering including linear trend removal and temporal high pass filtering with General Linear Model (GLM) Functional data were co-registered with structural data of each participant and normalized to Talairach space functional data were smoothed using an 8 mm kernel (full width at half maximum FWHM) to account for between-subject variation in anatomical localization In the first-level analysis of the functional runs The design matrix included a constant term and six realignment parameters as well as activity spike-related predictors These parameters were obtained during motion correction and used to correct for movement-related artifacts not eliminated during realignment we analyzed the statistical significance of the differences between up-regulation conditions and baseline within the neurofeedback target region (defined individually in bilateral occipito-temporo-parietal we computed the ROI-GLM (the ROI for this analysis is the individual neurofeedback target) considering the contrast 2OMS + 4OMS > baseline The statistical significance threshold was set to p = 0.05 Second-level analysis of the functional data was performed to better understand the mechanisms involved in neurofeedback at the group level and to explore whole-brain patterns associated with the neurofeedback training within-subject 3-level ANOVA analysis considering the conditions (i) SI The p-values were adjusted based on the false discovery rate (FDR) to correct for multiple testing The resulting statistical F-map was thresholded at q(FDR) = 0.05 The clusters extracted from this analysis had a minimum of 10 voxels we computed the block-averaged response time-courses for each condition during the neurofeedback runs the time-series were converted into PSC from average activity by dividing the signal measured at each time point by the average signal during the baseline positive values represent relative increases from the mean signal intensity in the stationary condition) The block-related responses for each condition were averaged across all participants from 2 s before to 24 s after each block onset (to fully cover the 22 s of each condition/block) We also characterized the temporal activation patterns associated with feedback events in this case event-related responses for each feedback type (positive neutral and negative) were averaged across all averages from 4 s before to 16 s after the auditory cue we determined the relation between the adaptive feedback threshold computed for each participant and the success in the neurofeedback run The localizer run allowed the real-time definition of subject-specific bilateral occipito-temporo-parietal ROIs selective for hMT+/V5, considering the balanced contrast (4OMS + 2OMS > SS). Figure 2 presents the probabilistic map of the ROI selection per participant the color scale describes the probability of each voxel being selected as a neurofeedback target region Neurofeedback target probability map (color scale: % overlap) The average volume of the neurofeedback mask was 3,030 ± 416 mm3 (maximum of 4,040 and minimum of 2,474 mm3). The clusters corresponding to the neurofeedback target were delineated in bilateral occipito-temporo-parietal, in accordance with previous studies (Sousa et al., 2016) Pre-training data was used to characterize the subject's ability to modulate activity in the neurofeedback target region based on a visual imagery task Mean threshold τ across subjects was 0.52 ± 0.16 Figure 3 presents whole-brain group activation maps (N = 10) for the neurofeedback runs. Table 1 summarizes the clusters of voxels that were found with the ANOVA 3-level within-subject factor analysis (representing the three conditions) The clusters represent the brain regions involved in the participants' effort to modulate brain activity in the target region Clusters associated with the proposed neurofeedback task were found bilaterally in the middle frontal gyrus Self-regulation with neurofeedback (N = 10 3-level within-subject analysis (FDR corrected q < 0.05) increased activation in prefrontal control regions and regions involved in feedback processing (A) Statistical map projected on a participant's inflated cortex (B) Statistical map projected on an average of the individual anatomical data sets (radiological convention)—ventral striatum (Z = −5 (C) Statistical map projected on an average of the individual anatomical data sets (radiological convention)—dorsal striatum (Z = 3 considering the 3-factor ANOVA analysis (FDR corrected q < 0.05) We assessed whether subjects were able to regulate the activity of hMT+/V5 during the neurofeedback runs A repeated measure ANOVA determined that neurofeedback target ROI mean activity did not differ significantly between up-regulation conditions (2 or 4 fold motion) conditions [F(2 We also analyzed the pattern across runs. Figure 4 shows the modulation results for each run The t-tests for the contrast 4OMI + 2OMI > SI suggest a trend for a slight decrease of success (at group-level) throughout the experiment t-tests for each run considering the contrast (4OMI + 2OMI) > SI within hMT+/V5 ROI Black dots correspond to the t-statistic of each participant for the contrast of interest The white line corresponds to the mean value across participants the light gray area represents the standard error of the mean (mean ± SEM) and the dark gray regions correspond to the standard deviation (mean ± SD) An individual analysis demonstrated that 4 participants successfully modulated the target ROI during the neurofeedback runs (we used a t-test 4OMI + 2OMI > SI to determine modulation success Block-related responses averaged across the participants that successfully modulated the ROI within the neurofeedback target Figure 6 shows that there is no systematic relation between the adaptive feedback threshold computed for each participant and the success in the neurofeedback runs The threshold (y-axis) ranged from 0.34 to 0.74% The t-statistic (x-axis) from the balanced contrast 2OMI + 4OMI > SI did not vary as a function of the threshold selected the ability to modulate brain activity in the target region was not related with the selection of the threshold required to receive positive and negative feedback The Pearson correlation between neurofeedback modulation ability (as measured by the contrast of interest) and the individual threshold selected was 0.032 and 0.229 (non-significant Relation between the computed adaptive threshold and the success in the neurofeedback runs Y-axis represents the threshold (% PSC) selected for each participant and the x-axis represents the t-statistic for the ROI-GLM contrast (within the neurofeedback target) (4OMI + 2OMI < SI) (A) Represents the first neurofeedback run (B) Represents the second neurofeedback run Block-related responses averaged across all participants for different ROI involved in the neurofeedback task and identified based on ANOVA 3-level within-subject factor analysis Each plot presents the block-related curve for the conditions 2OMI and 4OMI for the following ROIs: (A) Left Striatum (Putamen); (B) Right Striatum (Putamen); (C) Left Inferior Frontal Cortex (Brodmann Area 44)/Anterior Insula (BA13); (D) Right Inferior Frontal Cortex (BA44)/Right Anterior Insula (BA13); (E) Left Middle Temporal Cortex (BA21); (F) Right Posterior Cingulate Cortex (BA23 In order to better understand the correspondence of feedback valence and the BOLD pattern in the network activated during the neurofeedback task we calculated the event-related responses for positive and negative feedback to compute PSC we considered the entire run average as baseline Event-related responses associated with the feedback events were determined as the average across all participants from 4 s (2 volumes) before to 16 s (8 volumes) after each event onset of the presentation of the vocalization Figure 8 presents a summary of the results. In general, the ventral and dorsal striatum, and anterior insula tend to present stronger activation patterns for positive feedback cues compared to negative feedback. To complement this data, we also designed GLM with feedback event-related regressors and analyzed the resulting betas per ROI of interest. Figure 9 summarizes mean beta values for each ROI (which are directly related to PSC considering a percent-transform time course normalization) Feedback valence—(positive and negative) event-related responses averaged across all participants (n = 10) for different ROIs involved in the neurofeedback task Each plot presents the positive and negative feedback event-related curve for the following ROIs: (A) Left Striatum (Putamen); (B) Right Striatum (Putamen); (C) Left Inferior Frontal Cortex (Brodmann Area The left columns for each ROI correspond to the mean bata value associated to the “positive reinforcement” events and the right columns to the “negative reinforcement” events (the whiskers represent the SEM) for the following ROIs: (A) Left Striatum (Putamen); (B) Right Striatum (Putamen); (C) Left Inferior Frontal Cortex (Brodmann Area we sought to investigate the neural correlates of feedback-related reward saliency and valence during fMRI-based neurofeedback training when feedback explicitly carried individually tailored reward signals In this study, we propose the introduction of a new feedback interface that aims to optimize current approaches based on recent findings on the neural correlates of neurofeedback (Skottnik et al., 2019) and neurofeedback learning theories (Strehl, 2014; Wood et al., 2014) the motivation for this study was (i) to test the success rate of a novel interface based on explicit positive and negative reward and (ii) to investigate the impact of such an interface on the reward system To this end, we based our paradigm on a previously validated experiment, self-modulation of the hMT+/V5 (Banca et al., 2015; Sousa et al., 2016) and adapted the feedback with individually selected vocalizations for feedback presentation (with negative we used information from the localizer run to select the participant specific threshold to determine the valence of the feedback we aimed to isolate the neural network involved in neurofeedback-driven self-modulation and characterize the responses to positive and negative reinforcement The localizer run allowed us to successfully identify bilateral hMT+/V5, our target region, in all participants; the results were in accordance with the findings presented in Sousa et al. (2016) The authors emphasize the possible role of error avoidance as a complementary mechanism to improve neurofeedback-based learning Our results do not confirm this hypothesis and warrants further investigation concerning its role in neurofeedback success Additionally, a sparser presentation of feedback and interpretability of the auditory feedback cues may also contribute to these results. In contrast to the current study, the setup in Sousa et al. (2016) presented a simpler numerical based auditory feedback each 2 TRs ultimately a more selective schedule of reward and punishment The characterization of the block-related responses within the neurofeedback target region of the successful modulators shows that the visual motion imagery strategies used by the participants evoked differential brain responses according to the number of imagined motion variations, replicating previous findings Sousa et al. (2016) The average time course per condition shows that the participants were able to elicit different patterns for the three conditions activation for the 4OMI > 2OMI as hypothesized 4OMI) had a differential impact on the activation patterns of different brain regions while performing neurofeedback training Our results also suggest that feedback valence had a different impact on specific brain nodes of the network commonly involved in neurofeedback success we found that threshold selection based on the ability of each subject to imagine the moving dot during the localizer run was not associated with the decrease of success in neurofeedback runs Additionally, our analysis showed a deactivation of several regions including the posterior cingulate cortex and middle temporal gyrus. These regions, part of the default mode network (DMN), have been previously reported to deactivate when performing cognitively demanding tasks (Emmert et al., 2016) Together, this set of regions form a network of control/regulation and reward processing, is in line with the conceptualization presented, for example in Paret et al. (2019) and Skottnik et al. (2019) the authors also found that ventral striatum activity during decision making is dynamically modulated by context Recently, Klöbl et al. (2020) also studied insula activation during regulation periods but did not report significant differences between negative and positive reward events Differences between studies may result from activation of different sub-regions of the insula these results complement the discussion on the motivation for novel interfaces and highlight the importance of reward-based feedback the lower level of success (comparing the neuromodulation scores achieved in this study with previous approaches) suggests an unbalance between informative and positive/negative reinforcement cues Future work could explore the combination of both types of feedback—e.g. informative during the conditions and reinforcement at the end of each trial probing reward-related processes and cognitive control mechanisms we hypothesize that the fine tuning of this combination may optimize neurofeedback success although we recognize that in our case this was not successful at the group level and on a subject-specific approach to explore the temporal activation pattern Even though the results only partially overlap with our previous findings as we clearly see a decrease in neurofeedback training success the activation patterns in different reward- and control- network structures are in line with previous studies this information may allow the development of individually tailored frameworks for neurofeedback providing the ground for definition of potential neural framework for neurorehabilitation success The raw data supporting the conclusions of this article will be made available by the authors The studies involving human participants were reviewed and approved by Local ethical committee of Faculty of Medicine The patients/participants provided their written informed consent to participate in this study and MC-B discussed and conceived the study and discussed the results All authors read and approved the final manuscript The authors were supported by the BRAINTRAIN grant, a Collaborative Project supported by the European Commission, under the Health Cooperation Work Programme of the 7th Framework Programme, under the Grant Agreement No. 602186 (www.braintrainproject.eu); Fundação para a Ciência e Tecnologia AS was a recipient of a PhD scholarship by Siemens Healthineers The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest Visual motion imagery neurofeedback based on the hMT+/V5 complex: evidence for a feedback-specific neural circuit involving neocortical and cerebellar regions A network engineering perspective on probing and perturbing cognition with neurofeedback The influence of feedback valence in associative learning PubMed Abstract | CrossRef Full Text | Google Scholar Mapping 24 emotions conveyed by brief human vocalization A distributional code for value in dopamine-based reinforcement learning Network neuroscience for optimizing brain–computer interfaces At the heart of the ventral attention system: the right anterior insula Meta-analysis of real-time fMRI neurofeedback studies using individual participant data: how is brain regulation mediated CrossRef Full Text | Google Scholar The reward circuit: linking primate anatomy and human imaging PubMed Abstract | CrossRef Full Text | Google Scholar Can we predict real-time fMRI neurofeedback learning success from pretraining brain activity Context dependence of the event-related brain potential associated with reward and punishment A role of right middle frontal gyrus in reorienting of attention: a case study Neurofeedback: a promising tool for the self-regulation of emotion networks Imagery of a moving object: the role of occipital cortex and human MT/V5+ A systematic review of the psychological factors that influence neurofeedback learning outcomes Reinforcement and punishment shape the learning dynamics in fMRI neurofeedback Linhartová fMRI neurofeedback in emotion regulation: a literature review Process-based framework for precise neuromodulation Functional MRI neurofeedback training on connectivity between two regions induces long-lasting changes in intrinsic functional network Error-related brain activation during a Go/NoGo response inhibition task doi: 10.1002/1097-0193(200103)12:3<131::AID-HBM1010>3.0.CO;2-C attention and control: a network model of insula function Padrón Representing the consequences of our actions trial by trial: complex and flexible encoding of feedback valence and magnitude Network-based fMRI-neurofeedback training of sustained attention Current progress in real-time functional magnetic resonance-based neurofeedback: methodological challenges and achievements Monitoring and control of amygdala neurofeedback involves distributed information processing in the human brain Self-Modulation of premotor cortex interhemispheric connectivity in a real-time functional magnetic resonance imaging neurofeedback study using an adaptive approach A deep learning framework for neuroscience Toward a comprehensive understanding of the neural mechanisms of decoded neurofeedback Mental imagery and brain regulation—new links between psychotherapy and neuroscience Success and failure of controlling the fMRI-neurofeedback signal are reflected in the striatum PubMed Abstract | CrossRef Full Text Real-time fMRI brain-computer interface : development of a “motivational feedback” subsystem for the regulation of visual cue reactivity Control of brain activity in hMT+/V5 at three response levels using fMRI-based neurofeedback/BCI A critical role for the right fronto-insular cortex in switching between central-executive and default-mode networks Differential impact of reward and punishment on functional connectivity after skill learning What learning theories can teach us in designing neurofeedback treatments PubMed Abstract | CrossRef Full Text | Google Scholar On the need to better specify the concept of “control” in brain-computer-interfaces/neurofeedback research Convergent neural representations of experimentally-induced acute pain in healthy volunteers: a large-scale fMRI meta-analysis Prefrontal Control of the amygdala during real-time fMRI neurofeedback training of emotion regulation Sousa T and Castelo-Branco M (2021) Directly Exploring the Neural Correlates of Feedback-Related Reward Saliency and Valence During Real-Time fMRI-Based Neurofeedback Received: 30 June 2020; Accepted: 28 December 2020; Published: 05 February 2021 Copyright © 2021 Direito, Ramos, Pereira, Sayal, Sousa and Castelo-Branco. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Bruno Direito, YnJ1bm8uZGlyZWl0b0B1Yy5wdA== Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish and her gender-fluid husband became celebrities who were renowned for their matching cosmetic procedures Grafstein uses the title “Lady” and is described as a diamond heiress who inherited a fortune from a previous husband is a television personality and an art dealer The couple became famous for their tales of extravagance but prosecutors claimed this week that behind the veneer of ostentatious glamour Grafstein has been the victim of domestic abuse from the day of their wedding Grafstein has accused Branco of abuseSEAN ZANNI/PATRICK MCMULLAN/GETTY IMAGESExtraordinary allegations against Branco include claims that during their marriage Grafstein was repeatedly physically and verbally abused before she was pushed playMeet the man and the grill fuelling some of football's biggest stars (2:53)Some of the most famous names in world football use one chef to help them feel a little closer to home For many of the Premier League's South American stars Nico Frangione is the man they have to thank for helping them get a little taste of home while living in England Cooking delicacies reminiscent of the best asados gaúchos from Montevideo to Buenos Aires, the barbecue chef has even won over the taste buds of some who have never played in English football, such as Lionel Messi Frangione fell in love with parrillas while preparing them for his wife to bring her closer to her homeland what used to be a ritual in the couple's free time has become a connection to home for many who missed having a barbecue to call their own "It's a way for them to get together socially with their club mates over the asado," he tells ESPN it's part of the culture and it makes them feel at home." Frangione says the first star to get to know his culinary skills was Tottenham legend Osvaldo Ardiles, who won the 1978 World Cup with host nation Argentina before spending a decade at Spurs and subsequently settling in the UK who has also produced personalised barbecue grills for each one originally imported from Argentina but now made in the UK we understand what kind of grill they want "We listen to everything and build them the best which we hope they will keep for a lifetime." Liverpool goalkeeper Alisson is one of many South Americans playing in the Premier League who have one of Frangione's personalised grills. Nico FrangioneThe success of the barbecues has been such that they've even ended up at team events helping to galvanise squads featuring players from all over the world because a happy player is a good player," Frangione says "Today it's easier to think of the clubs where we haven't done," he says I think we're the only caterers who have allowed [club chairman] Daniel Levy to cook for them They all love it and end up having a good day." Of the 11 first-team players who won the Copa América for Argentina this summer Frangione says eight are owners of one of his personalised grills who received his as a gift from former teammate Sergio Agüero he has no doubts about which players are the best when it comes down to the serious business of cooking the meat "To be honest, they're all reasonable," he says, "but there are some who stand out more. I'd have to give it to [Emiliano] 'Dibu' Martínez and Nicolás Otamendi." Race leader nabs sprint win over Kaden Groves Wout van Aert wins stage 3(Image credit: Getty Images)Wout van Aert wins stage 3(Image credit: Getty Images)Wout van Aert wins stage 3(Image credit: Getty Images)Xabier Isasa (Euskaltel-Euskadi) was the last rider from the breakaway to be caught(Image credit: Getty Images)At the start of stage 3 are Stefan Küng of Groupama-FDJ in the Polka dot Mountain Jersey Wout van Aert of Visma-Lease a Bike in the Red Leader Jersey and Mathias Vacek of Lidl-Trek in the White best young jersey(Image credit: Getty Images)(Image credit: Getty Images)(Image credit: Getty Images)(Image credit: Getty Images)(Image credit: Getty Images)(Image credit: Getty Images)(Image credit: Getty Images)Race leader Wout van Aert (Visma-Lease a Bike) soared across the slight uphill finish to win stage 3 of the Vuelta a España He had room to spare to second-placed Kaden Groves (Alpecin-Deceuninck) who could not close the gap in the final 100 metres Jon Aberasturi (Euskaltel-Euskadi) sailed past Arne Marit (Intermarché-Wanty) to grab third place two pitches of 4% made the sprinters do a little extra work and that is where Victor Campenaerts (Lotto Dstny) launched an attack He opened a small gap in the final kilometre that was closed down by Team DSM-Firmenich PostNL and Visma-Lease a Bike Alpecin-Deceuninck quickly went to the front for Groves The green jersey and the red jersey then surged to the front and were shoulder to shoulder for about a dozen pedal strokes until Van Aert took flight with 200 metres to go so I knew I had to start a bit earlier today A long sprint remains one of my strengths," Van Aert said after the victory in a team press release I came to this Vuelta with enormous motivation I was keen to win a stage and today is the day Van Aert held his acceleration to earn the stage victory going one spot better than Sunday when he was second to Groves The Belgian also took the green jersey away from Groves having finished fifth on the only intermediate sprint of the day with 50km to race and swiping 10 points to give him eight more than the Australian "The emotional release after the finish was great I missed the taste of victory," Van Aert said It was his first victory since Kuurne-Brussel-Kuurne in February and in March his spring season came to an end with a crash in Dwars door Vlaanderen With the victory Van Aert padded his advantage in the GC to 13 seconds over Brandon McNulty (UAE Team Emirates) and 15 seconds over Mathias Vacek (Lidl-Trek) There were no changes in the top 10 as all the contenders finished in the main field leaving the bonus seconds at the end to just widen the margins slightly The third and final stage in Portugal set off from the central part of the country in the Lousã Mountain range and from the watchful sight of the Arouce Castle Ahead were 191.5km with 2,471 metres of elevation gain sunshine and warm temperatures on tap for the conclusion at another castle Just minutes from the blastoff in Lousã four riders moved away across the opening 60km of rolling terrain - Kern Pharma teammates Unai Iribar and Ibon Ruiz with Euskaltel-Euskadi duo Luis Angel Maté and Xabier Isasa as Ruiz and Maté were in the breakaway on stage 2 and they allowed the foursome to stretch the gap to about 2 minutes in the opening 10km Victor Campenaerts (Lotto Dstny) and Stefan Küng (Groupama-FDJ) tried to get away they were pulled back quickly Closing on the first of two categorised climbs with 60km covered the quartet's lead had fluctuated over 3 minutes and then began to grow on the second half of the 17.5km ascent of the category 2 Alto de Teixeira (average gradient 3.2%) but Visma-Lease a Bike and Alpecin-Deceuninck paced the peloton and slowly began to trim away at the lead Across the steepest part of the climb at the crest Maté attacked for the top five points on offer at the KOM banner but surged to the three-minute mark as the four Spaniards took turns pulling across the next 58km a long descent from the high mountain plateau sprinkled with three uncategorised risers en route to the intermediate sprint at Fundão A streak of orange accelerated to the front of the four as Isasa took the 20 points up for grabs and six bonus seconds as the first rider at the sprint line which also marked the start of the final categorised climb Van Aert sailed over the intermediate sprint in the red leader's jersey to scoop the fifth and final position and earn the final 10 points on offer taking the provisional lead for the green jersey away from Kaden Groves (Alpecin-Deceuninck) Across the top of the 6.4km category 4 Alto de Alpedrinha Maté made a move to snatch two more KOM points then his Euskaltel-Euskadi teammate Isasa attacked on the descent and went away solo Isasa quickly opened a 30-second advantage to his former co-leaders who seemed to lose interest in any chase and allowed the peloton to make the catch two kilometres later He stayed away for 10km before the hard-charging progress of the peloton took over Visma's Robert Gesink at the front for Van Aert Team DSM-Firmenich PostNL moved up with EF Education-EasyPost Bahrain Victorious and Alpecin-Deceuninck as the flat roads hit the 15km to go banner the speed increasing to 53 kph from the 38 kph average posted on the stage up to this point A series of roundabouts and road furniture began to appear in the final 8km as the peloton launched into the municipality of Castelo Branco Red Bull-Bora-Hansgrohe took position at the front joining Alpecin-Deceuninck The sprint teams had plenty of room on the wide road of the finale but the punchy uphill finish gave Van Aert the edge at the end over Groves to not only take the stage win but extend his margin in the red jersey Results powered by FirstCycling a sports marketing and public relations agency which managed projects for Tour de Georgia a Georgia non-profit to promote safe cycling She is proud to have worked in professional baseball for six years - from selling advertising to pulling the tarp for several minor league teams She has climbed l'Alpe d'Huez three times (not fast) Her favorite road and gravel rides are around horse farms in north Georgia (USA) and around lavender fields in Provence (France) Located just outside the city of Castelo Branco the Quinta do Chinco gardens are a case study on how communities can grow their own food Quinta's atmosphere invites one to contemplate the importance of the environment and the implications that all this has on our quality of life Quinta do Chinco is more than a community park or a simple vegetable garden It’s a new concept called a social garden citizens of all ages and backgrounds can grow their own learn about organic farming and sustainability while interacting with other members of the community By empowering the less fortunate and engaging all citizens the Quinta do Chinco social gardens have succeeded at growing a new sense of community spirit.   The main goal of the project was to promote social development and active citizenship through family gardening By providing economically disadvantaged citizens the project aimed to help this population group learn new skills and become more involved in their communities.   the project rehabilitated the Quinta do Chinco an area just outside Castelo Branco.  The renovated gardens include 88 plots which have been intertwined within the area’s existing architectural and natural heritage With sustainability at the heart of the project meaning that no pesticides or fertilisers are used All gardeners attend a mandatory training on best practices in organic farming where they learn about topics such as communal water use and traditional soil cultivation.  they started attracting the attention of citizens of all ages and backgrounds the project expanded its scope beyond providing gardens for lower-income citizens Having now also become an ‘outdoor community centre’ or ‘living lab’ Quinta do Chinco regularly holds classes and activities on environmental protection Quinta do Chinco has far exceeded its aim of increasing community cohesion and encouraging active citizenship over 8 000 people have been involved with the social gardens This includes 3 400 people who have participated in one of the garden’s many workshops and educational activities All the available garden plots have been claimed The gardeners themselves represent a range of age groups and backgrounds: 41 % are female 58 % are between the ages of 40 and 60 they have grown over 13 tonnes of produce which has been shared with other family members Total investment for the project “Quinta do Chinco - Hortas Sociais” is EUR 1 009 479 with the EU’s European Regional Development Fund contributing EUR 680 307 through the “Regional Operational Programme Centro” for the 2014-2020 programming period The investment falls under the priority “Strengthening social and territorial cohesion” A Autoridade de gestão tem a natureza jurídica de estrutura de missão de 12 de setembro e funciona junto da Comissão de Coordenação e Desenvolvimento Regional do Centro Miranda & Associados has announced the promotion of Sara Castelo Branco (pictured) to partner Castelo Branco joined the firm in 2018 and has since focused on Public and Regulatory Law She holds a Law degree from the Faculty of Law at Universidade Católica Portuguesa and a postgraduate degree in Administrative Legal Sciences from the Faculty of Law at Universidade de Lisboa The firm has also approved promotions for over a dozen associates: Inês Frutuoso de Melo has been promoted to coordinating associate and Tânia Santos have been promoted to senior associate Camille Andrade has been promoted to associate five new lawyers have recently joined the firm: Francisco Alves Dias as coordinating associate and Filipe Moreira do Vale as junior associates “The promotion of lawyers and the reinforcement of the partner core reflect the recognition of these colleagues’ merit as well as our commitment to Miranda’s and Miranda Alliance’s organic growth We remain steadfast in implementing our strategy promoting based on the contribution and merit of our team members strengthening the Partner core is an investment in the Firm’s future and a source of great satisfaction and pride” Professor Joana Vasconcelos added to SRS team GA_P advises Etnaga on sale to SIC and… Volume 17 - 2023 | https://doi.org/10.3389/fnhum.2023.1274817 This article is part of the Research TopicBrief Research Reports in Cognitive Neuroscience: Emotional Regulation & Well BeingView all articles weight and body shape can trigger negatively loaded emotions which may prompt the use of cognitive strategies to regulate these emotional states A novel fMRI task was developed to assess the neurobehavioral correlates of cognitive strategies related to eating Fourteen healthy females were presented audio sentences referring to these conditions and instructed to repeat these internally while engaging their thoughts with the content of food or body images Participants were asked to report the elicited emotion and rate their performance All cognitive strategies recruited a network including the inferior and superior frontal gyri orbitofrontal and anterior cingulate cortex These brain regions are involved in emotional Representational similarity analysis revealed distinct patterns of neural responses for each cognitive strategy self-report measures showed that self-criticism was positively associated with superior frontal gyrus (SFG) activation Self-compassion scores were negatively correlated with activations in the insula and right putamen while self-reassurance scores were negatively associated with activity in the orbitofrontal cortex These findings identify a neural network underlying cognitive strategies related to eating where neurobehavioral correlation patterns depend on the cognitive strategy Humans have evolved with the capacity to store energy in periods of food abundance, preparing for potential periods of scarcity (Rosenbaum and Leibel, 2010). Environmental and societal changes have made calorie-rich foods that are high in fat and sugar widely available. Combined with sedentary lifestyles and stressful life experiences (Swinburn and Egger, 2004) this has contributed to overeating and weight gain indicating difficulties in emotional and reward processing when exposed to self-critical stimuli current evidence of the brain regions implicated in self-criticism and self-reassurance or self-compassion suggests a possible overlap with consistent activations observed in dorsal and ventral PFC there is a paucity of studies specifically investigating these cognitive strategies related to eating a new fMRI paradigm was designed to investigate the neural correlates of self-criticism rumination and self-reassurance related to eating psychopathology participants were presented with audio sentences related to each cognitive process with eating we aim to identify the neural circuitry underlying distinct but related cognitive strategies featuring self-criticism rumination and self-reassurance regarding eating Fourteen healthy females, with a mean age of 24.07 (SD = 3.17; ranging from 19 to 29 years) were recruited to take part in the study. The mean body mass index (BMI) was 22.44 (SD = 2.74), ranging from 19.05 to 28.08. The inclusion criteria were being female and above 18 years of age. All participants were right-handed, as confirmed by the Edinburgh Handedness Inventory (Oldfield, 1971) The exclusion criteria were having a history of a psychiatric disorder Participants were recruited through advertisements and word-of-mouth All volunteers gave their written informed consent to participate in this study The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the Faculty of Psychology and Educational Sciences of the University of Coimbra A block design fMRI experimental paradigm was used to examine participants’ neural responses to different cognitive strategies related to eating and body concerns (see Figure 1) Each trial started with a 15-s presentation of a fixation cross (baseline) to prepare the participant for the upcoming task followed by a 30-s image presentation of a body or food Those images were retrieved from public internet sources and the head was removed from each body image An audio sentence was played once for the first 4 s of the image presentation which was tailored to one of four cognitive strategies: self-criticism Each strategy was associated with specific content and tone of voice: self-criticism (“I don’t like my body!” in a harsh and hostile voice tone) avoidance (“I’ll think of good things” in an anxious and compelling voice tone) rumination (“Why I have this body?” in a worried voice tone) and self-reassurance (“It’s not my fault for having the body I have” in a warm and caring voice tone) Audio files were recorded by a professional actress participants were instructed to repeat the sentence internally Schematic representation of the fMRI task during a trial the predominant emotion they experienced during the previous block participants rated their performance in following the instruction to engage in the cognitive strategy The rating scale had four levels: “I did it without difficulty,” “I did it with little difficulty,” “I did it with great difficulty,” and “I could not do it.” Finally participants performed a 1-back distractor control task for 15 s a series of numbers were displayed on the screen one-by-one and participants pressed a button whenever the current number matched the immediately previous one The 1-back task required working memory and attentional processes which helped participants washout the previous strategy and shift the attentional focus from the prior cognitive strategy engagement task to the present one Each run contained 8 experimental trials that lasted 70 s each In order to control for the confounding effect of images the sequence of conditions and images was randomized to prevent habituation Participants were presented with images of either food or body for each condition as we assumed that under this experimental context both types of images would evoke similar reward and affective brain activity processes Our primary focus was on exploring the affective processes when participants engaged in eating and body-related self-criticism The Self-Compassion Scale (SCS; Neff, 2003) is a 26-item questionnaire that assesses self-compassion SCS is a five-point Likert scale and the responses vary from 1 (almost never) to 5 (almost always) The internal consistency obtained for the total scale in this study was excellent (α = 0.96) The Forms of Self-criticizing/Attacking and Self-reassuring Scale (FSCRS; Gilbert et al., 2004) is a 22-item measure to assess self-criticism and the ability to self-reassure when facing setbacks and failure The responses are given on a five-point Likert scale ranging from 0 (not at all like me) to 4 (extremely like me) given the low manifestation in healthy individuals the internal consistencies were good for inadequate self (α = 0.91) and reassured self (α = 0.87) The Ruminative Response Scale for Eating Disorders (RRS-ED; Cowdrey and Park, 2011) was used to assess rumination relating to food Responses ranged from 1 (almost never) to 4 (almost always) A good Cronbach’s alpha of 0.83 was obtained for the total scale in this study The Food Thought Suppression Inventory (FTSI; Barnes et al., 2010) is a 15-item measure that assesses food-related thought suppression The FTSI is scored on a five-point Likert scale ranging from 1 (strongly disagree) to 5 (strongly agree) An excellent Cronbach’s alpha of 0.96 was obtained in this study for the total scale The Eating Disorder Evaluation Questionnaire (EDE-Q; Fairburn and Beglin, 1994) is a 28-item instrument to assess eating disordered symptoms The 22 items used to calculate the global score of EDE-Q are answered using a 7-point Likert scale from 0 (no days/none of the times) to 6 (every day/every time) The Cronbach’s alpha obtained in the present sample was 0.90 for the global scale Brain images were acquired at the Institute of Nuclear Sciences Applied to Health (ICNAS) using a 3T Siemens Prismafit scanner with a 64-channel receive head coil High-resolution T1-weighted images (repetition time = 2500 ms voxel size = 1 mm × 1 mm × 1 mm) Functional data were acquired using a T2* weighted multiband Echo Planar Imaging (EPI) pulse sequence with an acceleration factor of 6 (repetition time = 1000 ms voxel size = 2 mm × 2 mm × 2 mm) a total of 570 functional volumes were obtained The first 10 volumes of each run were discarded We also acquired spin echo field maps for each participant to minimize distortions due to variations in the magnetic field with the following imaging parameters: TR = 8000 ms The nifti output of fmriPrep was converted to BrainVoyager-compatible formats using a custom script using MATLAB and NeuroElf v1.4.1 In BrainVoyager each functional dataset was high-pass filtered using a cut-off frequency of 0.007 Hz and spatially smoothed with a gaussian kernel of FWHM = 4 mm A representational similarity analysis (RSA) was computed using Pearson correlational distance to calculate the degree to which voxel patterns are similar across conditions within each ROI (Kriegeskorte, 2008) A representational dissimilarity matrix (RDM) was calculated for each ROI using the condition responses estimated in the GLM analysis trials of the same condition were grouped in the general linear model To determine the statistical significance of each measure of dissimilarity between conditions the following rationale was used: if two conditions would yield perfectly correlated spatial patterns of response (r = 1) the corresponding dissimilarity measure would be 0 (distance = 1–r) to examine whether the response pattern for each pair of conditions is statistically significantly different from 0 we tested the dissimilarity across subjects using the individual-level RDMs against 0 Data presented a normal distribution and one sample t-tests were employed Bonferroni’s-adjusted p-values were calculated to correct for multiple comparisons (uncorrected p/48) The chi-squared test was calculated to compare the proportions of emotional and performance ratings between images of food and bodies Correlation analyses between self-reported psychological measures and the beta values for brain activity in the regions of interest were calculated using the IBM SPSS Statistics for Windows Pearson correlation coefficient was used for normally distributed data and Spearman’s rank correlation coefficient when the data were non-normally distributed The ROIs were selected based on our study hypotheses which comprise superior and inferior frontal areas Participants showed low to moderate levels of self-criticism ranging from 1 to 29 (M = 13.57; SD = 9.00) Scores on the food thought suppression ranged from 15 to 57 (M = 23.07; SD = 12.37) indicating that participants presented low to medium scores weight and body shape ranged from 9 to 22 (M = 12.21; SD = 4.06) Participants’ eating psychopathology scores were low to medium ranging from 1 to 55 (M = 17.43; SD = 16.23) they exhibited moderate levels of reassured self ranging from 12 to 31 (M = 23.71; SD = 5.36) and self-compassion ranging from 51 to 115 (M = 83.79; SD = 19.34) For each trial, participants were asked to rate their performance in the task (engagement with the cognitive process). For the majority of trials in all conditions, participants reported no difficulty in performing the task, ranging from 72.14% of trials for self-reassurance to 81.43% of trials for self-criticism. There were no significant differences in the performance ratings between images of food and body (see Table 1) Frequencies of emotion and performance ratings for each condition and image type All regions with significant signal changes with the exploratory whole-brain RFX-GLM group analysis are reported in Supplementary Table 1 Regarding our hypothesized areas, significant activation clusters were found in the left superior frontal gyrus (SFG), IFG, and left OFC. We found bilaterally clusters with significant activation in the putamen and left caudate nucleus. Significant activation was also found in the left anterior insula and left supracallosal ACC (Table 2 and Figure 2) Brain regions activated in contrast self-criticism + avoidance + rumination + self-reassurance > baseline and beta weights for each condition in each cluster transversal and coronal slices showing BOLD response (FDR corrected As can be seen in Figure 3 when contrasting the four conditions against the 1-back task specifically for the areas of interest in this study this contrast revealed overlapping activation in the insula contrast 2 revealed similar results to contrast 1 When contrasting the four different conditions between them the results of the two-way repeated measures ANOVA revealed that there was a significant main effect of ROIs F(7,91) = 16.59; p < 0.001; η2p = 0.56 and a non-significant main effect of conditions on participants’ brain activity F(3,39) = 1.13; p = 0.348; η2p = 0.08 There was no significant interaction between ROIs and conditions F(21,273) = 1.15; p = 0.300; η2p = 0.08 To understand if condition related differences could be captured using representational similarity analysis (RSA), we computed the respective plots for each ROI, which are depicted in Figure 4. In general, there was a surprisingly low degree of similarity across conditions in all regions, a pattern that was not captured by standard GLM analysis. The dissimilarity was statistically significant from 0, for each pair of conditions for all ROIs (Table 3 showing statistical inference with corrections for multiple comparisons) This shows that in spite of the fact that self-relevant processing recruits the same regions across conditions Dissimilarity matrix for the conditions for each area of interest maximum of dissimilarity (the highest value of the dissimilarity matrix) Bonferroni’s adjusted p-values of dissimilarity (against zero) for pairs of conditions for each ROI Table 4 shows the exploratory correlational analyses between the signal of areas of interest and self-reported measures We found positive correlations between inadequate self scores and activation in the left SFG (self-criticism and avoidance conditions) as well as in the left insula for the rumination condition Food thought suppression scores were positively associated with activation in the left putamen during the self-reassurance condition and rumination scores were positively correlated with activation in the SFG (rumination condition) self-compassion scores correlated negatively with the activation in the left SFG (in the avoidance condition) left insula in the ruminative and self-reassurance conditions and right putamen for the self-reassurance condition Reassured self scores were negatively correlated with the posterior orbital gyrus (in the self-reassurance condition) and the left insula activation in the rumination condition scores in eating psychopathology were positively correlated with activations in the left SFG for the avoidance condition left insula (avoidance and rumination conditions) left putamen (rumination and self-reassurance conditions) and right putamen for self-reassurance condition Correlations between brain regions and self-reported psychological measures The present study aimed to investigate the neural underpinnings of cognitive strategies of self-criticism rumination and self-reassurance related to eating and body concerns using a novel fMRI task we further examined the associations between neural correlates of each condition with self-reported psychological measures avoidance and self-reassurance may be encoded differently over time in the same brain region underlying distinct mental operations or cognitive demands Contrary to our expectation, there were no significant activations when contrasting self-criticism with self-reassurance, which is different from what previous studies have shown (Longe et al., 2010; Kim et al., 2020b) It is possible that the same neural regions process these strategies along a dimensional spectrum Another possible reason for this divergence might be related to differences in experimental designs While previous studies asked participants to imagine being self-critical or self-reassuring and what those thoughts would be our task provided participants with predetermined content for these thoughts Our aim with this design choice was to reduce variability in task performance and improve the overall validity of the experimental task This attempt to correct or solve an error and difficulties in inhibiting the repetitive cycle of thoughts could also explain the association found between self-reported rumination and the increased activation of the dlPFC in the rumination condition and the role of the insula in the perception of the body’s internal state may contribute to the embodied nature of compassion We observed a distinct pattern of lateralization during the execution of the task. The activated regions were predominantly located in the left hemisphere, which is strongly associated with language processing and inner speech production (Knecht, 2000; Morin and Hamper, 2012) As we asked participants to engage in internal dialog this pattern of activation suggests that language processing plays a crucial role in the cognitive mechanisms engaged in our experimental task This finding suggests that specific brain regions have a distinct role in cognitive strategies which supports the use of this paradigm to assess eating and body-related cognitive strategies The present study may be limited by its relatively low sample size and it is essential to interpret the reported findings in consideration of this factor and in particular that replication is needed This is mitigated by the fact that fMRI studies have effect sizes which still allowed us in this case to employ random effects analysis we implemented correction for multiple comparisons we acknowledge that for generalization future studies with larger sample sizes will be needed our results are confined to a population of healthy individuals the task involves participants evaluating their emotional states implicating the monitoring of their internal states The correlation analysis was mainly exploratory further research is warranted to replicate the results observed in this study The assessment of participants’ engagement in the cognitive processes is an inherent limitation which was mitigated by online experiential debriefing where participants rated their performance in the engagement task designed to address self-criticism and shame and promote the activation of the soothing and contentment system could potentially alter the response patterns of the neural circuitry underlying those processes The present study is the first to examine the neural correlates of self-relevant cognitive processes such as self-criticism rumination and self-reassurance linked to food and body concerns The four cognitive processes activated a similar set of brain regions such as superior and inferior frontal gyri but with a differential pattern across conditions as shown by RSA Neurobehavioral correlational analyses revealed quite distinct patterns across conditions These findings contribute to a growing body of research on these regulation processes and encourage future studies to better understand how these processes differ between them The studies involving humans were approved by the Ethics Committee of the Faculty of Psychology and Educational Sciences of the University of Coimbra The studies were conducted in accordance with the local legislation and institutional requirements The participants provided their written informed consent to participate in this study The author(s) declare financial support was received for the research This work was supported by grants from FCT (Portuguese Foundation for Science and Technology): UIDB&P/4950 Research by the first author (CM) was supported by a 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(2024) A neural network underlying cognitive strategies related to eating Copyright © 2024 Marques, Sayal, Crisóstomo, Duarte, Castilho, Goss, Pereira and Castelo-Branco. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Miguel Castelo-Branco, bWNicmFuY29AZm1lZC51Yy5wdA== Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish. Background: Dementia is the one of the most common and prominent disease in the elderly person that results in the Cognitive interventions. In this study, we aim to conceptualize the cognitive intervention for older adults with and without cognitive dysfunction and to clarify the heterogeneity existing in this literature field by determining the main variables implicated. Results: We included a total of 168 studies in our review. Our findings indicated heterogeneity regarding methods, concepts, and procedures. Additionally, the values were integrated using different information existing in this field. Conclusion: In conclusion, we highlighted that this is the first review that clarify the discrepancy of various existing definitions, methods, and procedures, as well as the overlapping information in the cognitive interventions. Volume 3 - 2022 | https://doi.org/10.3389/fragi.2022.844725 A correction has been applied to this article in: Corrigendum: A conceptual view of cognitive intervention in older adults with and without cognitive decline—a systemic review Background: Dementia is the one of the most common and prominent disease in the elderly person that results in the Cognitive interventions we aim to conceptualize the cognitive intervention for older adults with and without cognitive dysfunction and to clarify the heterogeneity existing in this literature field by determining the main variables implicated Methods: We conducted a study analysis using previous literature highlighting the significant data reporting empirical results from cognitive intervention for healthy older adults and other seniors with different types of dementia Each paper was reviewed in terms of compensatory cognitive training The research analysis was performed following rigorous inclusion and exclusion criteria with the purpose of collecting relevant answers to our research questions Results: We included a total of 168 studies in our review Our findings indicated heterogeneity regarding methods the values were integrated using different information existing in this field we highlighted that this is the first review that clarify the discrepancy of various existing definitions as well as the overlapping information in the cognitive interventions The concept of healthy aging has been defined as a process of development and maintenance of functional capacity (World Health Organization, 2015) or adaptation to the physical, social, and psychological changes that allow the well-being of the elderly (Peel et al., 2004). Cognitive changes are core in this concept because of their close relationship to impairment that affects ADL and functional capacity (Yam and Marsiske, 2013) we have witnessed an increase in research on healthy aging and lifestyle associated with older adults’ cognitive functioning the development of neuropsychological interventions using new technologies capable of promoting the older adults’ quality of life (QoL) Given that cognitive intervention encompasses several distinct concepts (e.g. it is important to further analyze these concepts clarify their similarities and differences so that these can be considered in future research the main aim of this study is to define the types of cognitive intervention and corresponding methodologies usually applied in older adults and clearly distinguishing the terms usually used in the literature After reviewing the literature regarding older adults there seem to be eight different types of cognitive interventions that are most commonly used and main motivations are to focus on this work: Compensatory Cognitive Training it is important to discuss what are the most critical differences between these distinct non-pharmacological treatments We found total 168 articles (Figure 1) through database searching (Supplementary Appendix S1) in which 59 were randomized controlled studies with post-intervention follow-up of the participants 74 were randomized controlled trials without follow-up 28 used a pre and post-test design with a 3–12-month post-intervention follow-up two were descriptive and exploratory studies and one was a single-blind wait list-controlled study Literature search flow on cognitive interventions Mostly in studies investigated the sample size was approximately 97 both healthy or composed healthy older adults 26 studies were on older adults with mild cognitive impairment (MCI) or amnestic MCI (aMCI) 19 studies on older adults with dementia or mild to moderate dementia 21 studies on Parkinson’s disease (PD) and older adults with cognitive impairment HIV-associated neurocognitive disorders in older adults The studies included were thoroughly reviewed in terms of the following types of cognitive intervention: Compensatory Cognitive Training, Cognitive Remediation, Enrichment, Cognitive Activation, Brain Training, Cognitive Stimulation, Cognitive Training, and Cognitive Rehabilitation (Table 1). The criteria for determining the type of cognitive intervention used in each study are summarized in Table 2 Our review includes 35 studies on Cognitive Stimulation and 11 on Cognitive Rehabilitation intervention where most of the tasks did not include computerized tasks; 102 studies on Cognitive Training intervention where most of the tasks were presented in computerized form; three studies on Enrichment six on Cognitive Remediation and seven on Brain Training that included computer-based training or video game; and four studies on Compensatory Cognitive Training where external compensation strategies were used Types of cognitive intervention defined in the literature Criteria for type of cognitive intervention: compensatory cognitive training Cognitive Interventions (CI) is used as term to describe the variety of therapeutic approaches designed to address psychological problems at the cognitive (conscious mind) level by the activation and analysis of thoughts By using these techniques therapist helps enlist patients to develop solutions to problems going on in their mind that will be effective and permanent therapist can draw the attention of the patients to the unreasonable pictures that mind has created and then begin to create tools for dealing with those pictures The cognitive approach to psychology assumes that your emotions behaviors and psychology are controlled by the way you view the things that have happened around you and cognitive interventions are launched from this point of view they can be removed by changing the way of thinking and exercising your mind to work in different ways This type of cognitive intervention has been implemented in various populations, including older adults, namely, individuals with aMCI, using external memory compensatory strategies (Troyer et al., 2008; Greenaway et al., 2013), and individuals with psychotic disorders (Twamley et al., 2012). Velligan et al. (2000) who tested the effect of compensatory strategies on apathy and improvement of executive functions in 45 older adults with schizophrenia indicated that patients using compensatory strategies showed greater improvement in motivation and overall functioning than those under other treatments which considered empirical studies with healthy indicated that Compensatory Cognitive Training is probably most effective when the intervention specifically supports frontal mediation activity and facilitates primarily compensatory adaptation in the brain according to the direction of indigenous adjustments in the aging brain Besides the elderly, Cognitive Remediation has also been used in psychiatric populations (e.g., schizophrenia). In this case, this intervention is applied according to different theoretical perspectives, often in conjunction with psychosocial interventions or complementary to pharmacological treatment (Morimoto et al., 2012) Contrary to Cognitive Remediation, the Cognitive Activation intervention is directed to healthy individuals or individuals with MCI who are autonomous and functional. Thus, therapists are not mandatory for its administration, as computer tasks are used. Moreover, there is no group intervention, and the transfer of cognitive gains to the functioning of ADL is not expected (Lenze and Bowie, 2018) the main aim of Cognitive Activation is to maintain the users’ functioning we have emphasized very few results of this type of intervention on relevant literature single-blind design with a 3-week follow-up period and observed an improvement in reaction time and processing speed in the intervention group and achieved an improvement in processing speed and episodic memory but no differences in mental control and visuospatial processing revealing improvement in overall cognitive functioning and both found evidence of benefits in terms of memory as it is not always enough on its own for older adults Cognitive Stimulation has also been combined with physical activity. Dannhauser et al. (2014) found that this combination benefited the working memory, physical health, and fitness of older adults with MCI. Thiel et al. (2012) demonstrated that Cognitive Stimulation and physical activity might prevent age-related cognitive decline Brain Training is usually based on repeatedly using programs (“brain games”) focused on performance in cognitive tasks over a period of time to improve cognitive deficits. This type of intervention should include ADL such as video games, music, computerized training, or physical exercise (Rabipour and Raz, 2012; Heugten et al., 2016; Simons et al., 2016) and their results indicated transfer effects of the Brain Training game in the same cognitive domains Van de Ven et al. (2017) used several computerized tasks in older adults with cognitive impairment targeting executive functions, attention, reasoning, and psychomotor speed (www.braingymmer.com). Two other studies have used the Nintendo DS video games in older adults as a Brain Training method (Power et al., 2011; McDougall et al., 2012) Throughout our review, we found that the concept of Brain Training seems to be used more commercially and some researchers call it “cognitive training” (e.g., Buitenweg et al., 2017) Cognitive Rehabilitation can be focused on several cognitive domains, namely attention, concentration, memory, perception, communication, reasoning, and planning (Cicerone et al., 2000; Stuss et al., 2007). It can be computer-based or administered in a paper and pencil format (LoPresti et al., 2004; Maggio et al., 2018) Cognitive Rehabilitation has different general objectives than Cognitive Training Cognitive Rehabilitation uses a compensatory approach with an intervention aiming to improve cognitive and everyday life functioning both functional and behavioral comprised diverse Cognitive Rehabilitation activities Fasilis et al. (2018) applied a virtual environment (Main Tasks) to a group of older adults with mild dementia to train working memory, attention, problem solving, motivation, organization, impulsivity and found a relative improvement in cognitive variables. Another study by Maggio et al. (2018) used a semi-immersive therapy (virtual scenarios) system for motor and Cognitive Rehabilitation of patients with neurological diseases—BTS Nirvana—and achieved greater improvement at cognitive functioning In the healthy population, Levine et al. (2007) applied a Goal Management Training program to simulate real-life tasks in healthy older adults, and the results showed an improvement in performance and self-rated executive. Craik et al. (2007) applied a program for memory training to healthy older adults that did not include computerized tasks and there were no effects of training on working memory several studies did not include computerized tasks in the interventions involving healthy older adults and older adults with AD We also concluded that the presented studies show heterogeneity of methods regarding sample size and characteristics some studies confuse certain concepts; for example use the concept of Cognitive Stimulation or Enrichment for Cognitive Training This inconsistency does not allow a concrete definition of the most effective intervention its durability and the best format for older adults it is necessary to harmonize the methodology of intervention applied to the study population Our conclusions should be interpreted considering some limitations our research was restricted to electronic databases via EBSCO (although these are the most representative and significant in the field at hand) our attempt to contact authors and experts to access some unavailable studies was not altogether successful but we believe that this is unlikely to have determinatively influenced our findings due to rigorous research with strict inclusion/exclusion criteria we gathered a restricted pool of analyzed papers (168 studies included from 641 full-text articles assessed for eligibility) the current review allows us to find some answers to our initial research questions We also consider that our main purpose was achieved since a conceptualization of cognitive interventions for healthy and older adults with several types of cognitive impairments was possible a few questions remain for additional research to further enhance this non-pharmacological approach involving the elderly we suggest a comprehensive view to discuss the methodology of each type of intervention presented in this research and subsequently demonstrate its results and efficacy (or not) in specific older-adult populations (e.g. people with 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use *Correspondence: Liliana Mendes, bGlsaWFuYS5tZW5kZXNAaWNuYXMudWMucHQ= We analyzed the importance of fan identity and brand strength on fans’ neural reactions to different team-related stimuli. Findings indicate that brain activity in emotion regulation, memory, and cognitive control circuits is influenced by the relative level of fan identity. Volume 17 - 2023 | https://doi.org/10.3389/fnhum.2023.1235139 Introduction: We analyzed the importance of fan identity and brand strength on fans’ neural reactions to different team-related stimuli Methods: A total of 53 fMRI scans with fans of two professional sport teams were conducted Following up on a previous study we focused on the differences between fandom levels as well as the contrast between two team “brand” strength Neural responses were compared among individuals based on their levels of fan identity group comparisons between relatively high and lower identity and between weak and strong teams were made based on the notion that the latter reflects team brand strength (strong brand and weak brand) Results: Findings indicate that brain activity in emotion regulation and cognitive control circuits is influenced by the relative level of fan identity Discussion: Higher-level identified fans showed increased reactivity to positive stimuli and the under-recruitment of their cognitive appraisal circuits suggesting more vulnerability to marketers’ messages The strength of the team brand activates different neural mechanisms the posterior cingulate showed larger recruitment both for weaker brands and lower fan identification suggesting that visual memory processes are more active in these cases Neurally processed content depends on the relative brand’s strength highlighting the importance of brand-focused communications – Findings indicate that brain activity in emotion regulation and cognitive control circuits is influenced by the degree of fan identification—the stronger identification with the team the less critical the brand’s strength – Higher-level identification fans showed increased reactivity to positive stimuli and the under-recruitment of their cognitive control circuits – The strength of the team brand activates different neural mechanisms – Neurally processed content depends on the brand’s strength In the sport industry, fans are undeniably key stakeholders (García and Welford, 2015) because they invest time, money and effort in supporting the teams and are the final consumers of the services offered by teams either directly (i.e., live events) or indirectly (i.e., TV viewers and target of sponsors), while also influencing organizational decision-making (Senaux, 2008) it is vital to explore how different fans react neuronally to team brands with different levels of market prominence and on-field success the current study examined the neural correlates of sport fans in relation to two contrast levels of identity (high and very high) as well as how these neural correlates are influenced by the team brand strength (contrast between strong brand and weak brand) We conducted fMRIs in fans of two professional football teams differing in their level or competitive strength and fan identity Given the importance of consumer identification with brands and the lack of research on the neural correlates of individuals with high but distinguishable identification levels with a brand this study aims to contribute the neural and behavioral understanding about the identification and respective strength of the brand examining the neural response of fans exposed to different stimuli related to the team can be a valid contribution to better understanding the relationship between the team characteristic and the fan’s feelings The ability to remember something is linked to episodic memory and allows human beings to recall specific events about what happened, when and where (Clayton et al., 2007). Episodic memory, in this context, is not just an event, it is the fan’s own event, something personal and personalized, unique from an individual perspective (Clayton et al., 2007) Memory is a personal construction (Squire and Zola, 1996; Squire, 2009) and each sport fan builds their own memories with the behaviors he/she exhibits sport fans often have routines related to their teams (e.g. following news daily on newspapers and social media attending live games every week) and these tend to shape their identity levels and behaviors We assume that fan memories are inseparable from the fan identity level which may be reflected in neurobehavioral patterns fans’ memories help building the fan identity one could argue that fan identity is linked team-related memories and not within fan groups with differing team identity Based on previous sport consumer research and the remaining need to understand the role of fan identity on individuals’ neural responses to team stimuli H1: Fans who highly identify with their role will exhibit differential activation patterns in reward and limbic processing regions as compared to those who are very highly identified H2: Fans of a strong brand will more strongly recruit limbic and memory regions there is a dependence of neural activity on contrast levels of fan identity A final sample of 53 individuals wasincluded in the study with ages ranging from 20 to 60 years old (M = 34.9 ± 10.7 years) paying a monthly or annual fee to have discounts on club services) and the length of memberships was above 2 years All participants attended at least one live game of their teams during the season prior to data collection and 50 of them attended two or more live games Study tasks were part of a larger project related to sport and neuroscience A 3T Magnetom Trio Tim whole body scanner (Siemens A T1-weighted MPRAGE was measured for anatomical identification The acquisition parameters included a repetition time (TR) of 2530 ms field of view of 256 × 256 and a slice thickness of 1 mm Given that EPI-BOLD sequences may suffer distortions from susceptibility artifacts gradient field maps (GRE) were acquired before each Echo Planar Imaging (EPI) sequence (GRE maps acquired with the same orientation and same field of view Functional information was obtained through EPI sequences acquired parallel to the AC-PC line The acquisition parameters included a slice thickness of 3 mm and voxel size 4 mm2 matrix size 256 × 256 and FOV of 256 × 256 The visual stimulation videos were shown inside the MR scanner by means of an LCD screen (NordicNeuroLab Norway) and the participants viewed the stimuli through a mirror mounted above the participant’s eyes and was placed ∼156 cm away from the participants’ head Video audio was provided through headphones and subjects selected responses using an MR-compatible joystick (Hybridmojo EPI-BOLD images were undistorted using the GRE maps in the AnatAbacus v1.1 plugin (Breman et al., 2009) for BrainVoyager QX The pre-processing and analyses were performed in BrainVoyager QX 2.8.2 (Brain Innovation Netherlands) by using slice scanning time correction; motion correction (the second run was corrected in relation to the first volume of the first run); and filtered in the time domain (two cycles) Anatomical and functional data were co-registered automatically and manually verified and then transformed to the Talairach space A General Linear Model (GLM) random effects (RFX) analysis was conducted at group level The predictors’ model was obtained by convolution of the time course belonging to each condition with a two-gamma hemodynamic response function resulting t-maps were corrected for multiple comparisons using false discovery rate (FDR) with a fixed q-value lower than 0.01 Reported clusters included at least 25 contiguous voxels With the exception of one participant who did not answer all items the levels (SSIS) for participants of both teams varied between 2.14 and 5.00 (M = 4.09; SD = 0.76) We divided the pool of participants in two groups (equal in size) of “high” (SSIS ≤ 4.14 n = 26) and “very high” (SSIS ≥ 4.29 they were called fans with high identity (FHI) and fans with very high identity (FVHI) there were no significant differences in the fan identity levels [t-test p = 0.70] between the sample of fans of the weak brand (FWB SSIS: M = 4.04 n = 26) and the fans of the strong brand (FSB SSIS: M = 4.13 The t-map [(t102) > 3.73, p(FDR) < 0.01] of FHI vs. FVHI group comparison during the visualization of the videos (all conditions) showed activations in the visual cortex, lingual gyrus, posterior cingulate, and parahippocampus (the latter being the same regions that were revealed by the contrast weak vs. strong brands) (see Figure 1) the contrast of the groups of very high (FVHI) vs high identity (FHI) scores [t(102) > 3.73 p(FDR) < 0.01] showed activation in the inferior frontal gyrus lateral prefrontal cortex and medial frontal gyrus (regions involved in executive and emotion regulation processes) Comparison of brain activity between lower (n = 26) vs higher (n = 26) fans accordantly to the identification scores The statistical map reveals areas of significant differences during the video visualization [t(102) > 3.73 The functional results obtained of comparison of groups were projected in the brain of a single subject in Talairach space There were significant differences during the video’s visualization with activation in neural areas The FHI recruited more areas related to visual processing the FVHI focuses on more areas related to visual and spatial processing related to game viewing Concerning the contrast level defining fan identity we predicted a lower response of the cognitive and emotion control network for higher (i.e. the lower level in this study) fan identity levels These results suggest that brain networks involved in cognitive evaluations and emotional control are differentially activated as a function of the contrast level of fan identity with the team The statistical map reveals areas of significant differences during the videos visualization [t(104) > 3.61 We then performed a ROI-based analysis, using the same valence factors. Table 1 shows the mean beta values for both groups (FSB/FWB) during all conditions (positive/neutral/negative videos) in each region showing that FWB have a distinct neurobehavioral pattern which is common across different videos valences The stronger recruitment of regions in particular the posterior cingulate involved in visuospatial processing navigation and memory suggests that FWB are more focused in spatial cognitive analysis of the video scene H3 was not supported because brain activity was indeed distinct across these football fans Mean beta values for all factor-level combinations (mean condition effects averaged across FCP and AAC subjects) in the ROI-based analysis The statistical map reveals areas of significant differences during the videos visualization [t(104) >3.61 FVHI are shown in relation to their overlap The current study investigates the neural correlates of football fans according to their within-group contrast of identity as fans (high vs. very high), and the relative strength (weak vs. strong) of the team’s brand, which adds to and follows up the prior work of Duarte et al. (2017) by providing empirical evidence of different consumer reactions to brands concerning its market strength Different patterns of brain activation were shown among individual based on their identity levels Fans who are very highly identified have greater activation of the neural areas linked to memory and emotions equivalent to the fan’s feeling “to live the moment” instead of the larger posterior cingulate activation in less involved fans In sum the results indicate a brand’s pivotal role in memory and emotion regulation areas The conscious perception of remembering something means returning to past experiences and relating to the episodic memory (e.g. implicit memory processes stemming from the posterior cingulate are more prominent in less involved fans facilitating favorable reactions to the team the videos in this study seem to have been processed more in an executive logic and semantic memory for fans with very high levels of identification when compared with fans with “only” high levels Another key finding is that in the contrast between fans of strong and weak brands (Figure 2) we verified that both groups experience videos differentially at a neural level The results indicate that individuals who are attached to a weak brand are more likely to be endowed with stronger cognitive appraisal and control mechanisms during video visualization; therefore The fans of the weak brand (AAC) activate more episodic memory areas and inferior parietal lobule regions (related to emotional processing and visuospatial and attention integration) which suggest they are more likely to actively cognitive mechanism to regulate their behavior These results suggest that fans of weak brands might keep a higher level of mnemonic visual recollection control during video appraisal which might act as a protective mechanism for their frequent unsuccessful events Findings indicate that video content is processed differently depending on the level of fan identity or the strength of the brand fans are attached to Figures 3A, B A higher level of fan identity corresponds to a lower neural sensitization to the sensory information perceived in the FVHI/FHI comparison This fact may be related to the degree of exposure to this type of content we observed that fans of the strongest brand have a lower neural activation in implicit processing resulting from the brand’s overall exposition power time and space where the brand experience takes place are pivotal for consumers The findings from the current study were obtained through a study in a laboratory experimental setting It is possible that this controlled environment may not provide a good overview of the different stimuli elicited while fans attend live or broadcasted events or interact with their teams in other situations such as social media additional real-time measures such as cardiac response or eye-tracking (i.e. attention to game situations) may prove to be important to deepen the understanding of fans reactions to team brands in different occasions This study identifies neural correlates of football fans based on the contrast between identity levels (high vs very high) and the strength of the team brand (weak vs The results indicate that high fan (relatively lower) identity has a more significant impact on processing sensory information introduced by videos than very high fan identity which preferentially activate frontal executive and memory regulation regions although groups were similar in identity scores neural areas of memory and emotion were the ones that most respond to the content depending on the brand’s strength with which the fans are associated The content displayed was processed differently at a neural level depending on the fan identity level and the associated brand’s strength In such an emotional context as the one triggered by sport brands consumers less identified with a brand were more susceptible to messages as visual processing consumers associated with weaker brands activated more areas related to implicit processing The studies involving humans were approved by the work “Neural Correlates of Fanhood: The Role of Fan Identity and Team Brand Strength” complies with all the criteria defined by the Ethics Committee The work has been submitted to the Ethics Committee under reference number CES-UPT-03/01/23 Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article All authors listed have made a substantial This work was supported by the UIDB/05105/2020 Program Contract funded by national funds through the FCT I.P and also supported by the BRAINTRAIN project FP7-HEALTH-2013-INNOVATION-1–602186 Portuguese Foundation for Science and Technology (FCT) FCT-UID/NEU/04539/2013 The authors would like to thank Aaron Ahuvia and Ale Smidts for their support and feedback on earlier versions of the manuscript Crossref Full Text | Google Scholar Neuromarketing and consumer 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Ricardo Cayolla, cmNheW9sbGFAdXB0LnB0; cmljYXJkby5jYXlvbGxhQGdtYWlsLmNvbQ== West Ham United’s newest signing Luis Guilherme has all the tools required to succeed in the Premier League according to ESPN Brazil’s London correspondent Joāo Castelo-Branco It was Castelo-Branco who sat down with the 18-year-old for his debut West Ham TV interview after the Brazil Under-20 international completed his move from Palmeiras earlier this week The ESPN Brazil man was impressed with Luis Guilherme’s attitude and determined mindset which he believes will stand him in great stead for his move across the Atlantic Ocean There can be no doubting his potential on the pitch – after playing his part in helping Palmeiras complete an Under-17 quadruple consisting of the São Paulo state championship Brazilian Cup and Brazilian Super Cup – before already making his mark on the senior stage gives him the best chance of success in east London “I’d heard very highly of him before he arrived – he’s from obviously from a golden generation of the Palmeiras youth team – but I was really impressed meeting him how “He doesn’t seem fazed by the whole situation and he seems excited Being part of the Brazil U20 set-up and this hyped Palmeiras youth team will have helped with that he’s not over-confident and he’s speaking a lot about wanting to learn and he knows that he has to adapt but he’s not trying to go too fast and he seems like a really good kid.” Castelo-Branco has already seen a new generation of his countrymen impress on these shores at younger and younger ages to Joāo Gomes at Wolverhampton Wanderers and Crystal Palace’s Matheus França Brazilian talent is appearing at Premier League level younger than ever before and the ESPN reporter believes Luis Guilherme can only add to their successes “It’s something we’re seeing more and more – Brazilian players coming straight from Brazil at such a young age,” he added “They used to stop off at other clubs or be loaned out but now the Premier League clubs have clocked on that they can go to South America and get young talent “The players are much more professional perhaps than the generation before but you can see he’s a clear example of a dedicated professional who knows what he has to go through “He has a very good set-up with good people around him He has his family coming with him and he looks like a really good buy.”  Site designed & built by Other Media, powered by Clubcast this house represents a (brief) moment of “reconciliation” with Nature all of its ‘humid’ spaces emphasize a feeling of refuge and nostalgia – like an ‘elegy’ to the memory of the region’s (almost lost) thermal theme The bathroom spaces and a ‘rocky patio’ complete a simple residential program: a private bedroom secluded to the rear and the (locally called) “ribeira dos Moinhos” The idea of ​​a unified but fragmentable space An environment with its own character – although A precise design answer for a specific use – albeit ‘open’ and (almost) ambiguous not the (vulgar) principle of the ‘form that follows function’ but rather the design answer that allows for use and that can (occasionally) be freed from it ‘configuration’ and ‘functionality’ are as close a relationship as they are an unpredictable identity Álvaro Siza usually says that “Nature is Nature “we are condemned to find forms that harmonize with Nature completing it; and Nature always triumphs – but subjugated to our disturbances.” This will (always) be the role of architecture "Excavated" between the rocky cliffs a fraction of life becomes perennial – (in)finitely petrified Read today's Portuguese stories delivered to your email A fire that is burning intensely in a forest area in the municipality of Castelo Branco is being fought by 291 operators supported by 87 vehicles and eight aerial means The alert was given at 3:45 pm and the flames started in the village of Padrão According to a source from the Beira Baixa Sub-Regional Emergency and Civil Protection Command the flames were progressing towards Rochas de Baixo We appreciate that not everyone can afford to pay for our services but if you are able to we ask you to support The Portugal News by making a contribution – no matter how small You can change how much you give or cancel your contributions at any time Send us your comments or opinion on this article Reaching over 400,000 people a week with news about Portugal This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page The Vintage Tejo Train returns to the Linha da Beira Baixa with two special trips on November 23 and 30 offering a scenic experience through Ribatejo’s picturesque landscapes and riverside views along the Tagus River.  Passengers will have the opportunity to enjoy panoramic views from Schindler carriages as they travel past landmarks such as Amourol Castle The journey recreates the historic trip of King Carlos and Queen Amélia including stops at the National Railway Museum and iconic Railway Neighbourhoods Travellers are welcomed with the traditional sweet “Feijadinhas” and on-board entertainment features historical reenactments by a theatre group The first programme includes a round-trip from Lisbon to Entroncamento with a guided visit to the Railway Neighbourhoods a stop at the Railway Museum and a chance to ride a mini train Travellers can enjoy tea and a local sweet The second programme offers a full trip from Lisbon to Castelo Branco Passengers can explore Castelo Branco with a guide and benefit from a 50 percent discount on several local museums and cultural sites To celebrate Castelo Branco’s designation as a UNESCO Creative City in Crafts and Folk Art the city will present passengers with a commemorative plaque The return trip from Castelo Branco to Lisbon departs at 5.28pm The train has a capacity of 304 seats and features a bar carriage Passengers can enjoy special parking rates at Lisbon-Oriente and discounted museum entry in Castelo Branco by presenting their Vintage Tejo Train ticket a source from the National Emergency and Civil Protection Authority (ANEPC) told Lusa.  the flames have been consuming forest populations since 02:17 and are being fought by 50 vehicles around 170 operatives and five aerial resources the National Road 16 (EN16) between Carvoeiro and Poço de Santiago is closed but “there is no knowledge of homes at risk” four aircraft and more than 160 firefighters the fire that broke out in Soutelo on Friday is back on fire two aircraft and more than 150 firefighters there are no reports of houses being threatened or roads being cut off with firefighters on their way to the scene but 170 firefighters and 58 vehicles remain on site to prevent 1,250 firefighters were involved in operations related to fighting fires on the mainland assisted by almost 370 vehicles and 19 aircraft Zamalek have officially signed 19-year-old defender Djeferson Costa from Portuguese club Sport Benfica and Castelo Branco who holds dual citizenship in Portugal and Guinea-Bissau joins the Cairo giants on a permanent deal Castelo Branco retains a 10% future sell-on fee Costa will sign a four-year contract with Zamalek Having completed his medical and the necessary contract formalities He has also been included in Zamalek’s African squad Costa has previously played for several Portuguese youth clubs featuring for the full 90 minutes in their Portuguese Cup match against Académica Coimbra earlier this month Zamalek fans have more reason to celebrate as this signing comes on the heels of their club’s victory over arch-rivals Al Ahly in the CAF Super Cup and website in this browser for the next time I comment Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" This site uses Akismet to reduce spam. Learn how your comment data is processed Zamalek have been slapped with yet another transfer ban by FIFA Mohamed Elneny has been awarded the UAE Pro League’s Player of the Month for.. Mohamed Salah has credited Liverpool manager Arne Slot for unlocking his best-ever form by.. Al Ahly announced the departure of Marcel Koller on Saturday FIFA has imposed a new transfer ban on Zamalek due to the club’s ongoing.. Ceramica Cleopatra midfielder Ahmed Kendouci is set to undergo surgery following a serious injury.. Several districts on the mainland will remain under yellow and orange warnings today due to rain strong sea waves and snowfall and at least until Saturday according to the Portuguese Institute of the Sea and Atmosphere (IPMA) Coimbra and Braga have been under a yellow warning from 06:00 am today and will run until 06:00 am on Saturday due to the forecast of sometimes heavy showers which may occasionally be in the form of hail and accompanied by thunderstorms The IPMA also placed the districts of Porto Coimbra and Braga under yellow warning until 12:00 pm on Saturday due to southwest winds with gusts of up to 80 kilometers per hour (km/h) The forecast of rough seas led the IPMA to issue an orange warning for the districts of Porto Coimbra and Braga between 00:00 on Saturday and 00:00 on Sunday The IPMA has also placed the districts of Faro Setúbal and Beja on lockdown until 6:00 am on Sunday due to rough seas 17 maritime bars on the mainland are closed to all navigation and those in Aveiro Viana do Castelo and Portimão are subject to restrictions according to the National Maritime Authority The districts of Castelo Branco and Guarda are also under orange warning due to snowfall above 1,200 to 1,400 meters between 6:00 pm today and 12:00 pm on Saturday The orange warning is issued by IPMA whenever there is a moderate to high risk meteorological situation and the yellow warning when there is a risk situation for certain activities dependent on the meteorological situation caused thousands of incidents on the Portuguese mainland when orange weather warnings were in effect vehicles and energy and water services were affected particularly in the regions of Lisbon and Vale do Tejo Metrics details Probing histone modifications at a single-cell level in thousands of cells has been enabled by technologies such as single-cell CUT&Tag Here we describe nano-CUT&Tag (nano-CT) which allows simultaneous mapping of up to three epigenomic modalities at single-cell resolution using nanobody-Tn5 fusion proteins Multimodal nano-CT is compatible with starting materials as low as 25,000–200,000 cells and has significantly higher sensitivity and number of fragments per cell than single-cell CUT&Tag We use nano-CT to simultaneously profile chromatin accessibility allowing for discrimination of more cell types and states than unimodal single-cell CUT&Tag We also infer chromatin velocity between assay for transposase-accessible chromatin (ATAC) and H3K27ac in the oligodendrocyte lineage and deconvolute H3K27me3 repressive states finding two sequential waves of H3K27me3 repression at distinct gene modules during oligodendrocyte lineage progression nano-CT allows unique insights in epigenetic landscapes in complex biological systems at the single-cell level comprehensive and multimodal chromatin maps could be used to predict cell lineage or state commitment before the transcriptional program has been activated These epistatic interactions between epigenetic modalities are considered important for rapid activation and repression of gene expression but they are still not yet fully understood single-cell -omics data integration relies on correlation of features across modalities whereas direct measurement of multiple modalities in the same cell can bring more meaningful insights into chromatin functions Multi-CUT&Tag can profile various combinations of epigenetic modalities but has limited sensitivity—low number of unique fragments per cell and has only been demonstrated to work at a single-cell level in a mixture of cell lines Low sensitivity might make it difficult to deconvolute subtle epigenetic differences between related cell types and cell states within a complex tissue Although scGET-seq provides higher sensitivity than multi-CUT&Tag it lacks the flexibility of CUT&Tag to profile various modalities Even though scGET-seq could in principle be used together with pA-Tn5 profiling two out of three modalities (HP1α and ATAC-seq) would still be invariable The modular design of the nano-Tn5 makes it possible to profile a variety of different combinations of chromatin modalities and nano-CT will undoubtedly be an important addition to the spectrum of emerging multimodal single-cell epigenome profiling technologies Violin plots 1–4 from left show multimodal nano-CT performed without ATAC (1 and 3 from left) or with ATAC-seq (2 and 4 from left) and violin plot 5 depicts unimodal nano-CT experiment Individual UMAP embeddings of the single-modality scCUT&Tag (left) and nano-CT (right) data depicting the identified clusters (scCUT&Tag: 13,932 cells in 4 biological replicates; nano-CT: 6,798 cells in 1 biological replicate; 200,000 cells used as input) g UMAP co-embedding of the scCUT&Tag data (13,932 cells in 4 biological replicates) together with nano-CT data (6,798 cells in 1 biological replicate; 200,000 cells used as input) Raw matrices obtained by scCUT&Tag and nano-CT were merged together and analyzed without integration Cartoon depicting the strategy used to profile multiple epigenomic modalities Individual Tn5 and nano-Tn5 are loaded with barcoded oligonucleotides that are used in the analysis to identify the source of tagmentation and demultiplex the modalities Violin plots depicting the number of unique fragments per cell per replicate and modality Violin plots depicting FrIP per cell per replicate and modality UMAP embeddings of the multimodal nano-CT data for ATAC-seq The lines connect representations of the same cells in the individual modalities (4,434 cells in two biological replicates which passed quality control for all three modalities individually and originate from the three-modal datasets; 200,000 cells used as input for all replicates) UMAP embedding of the individual modalities with cluster labels n = 2 biological replicates—each biological replicate was profiled both by nano-CT with ATAC (3-modal) and nano-CT without ATAC (2-modal): 4,960 cells ATAC-seq 12,763 cells H3K27me3; 200,000 cells were used as input for all replicates Cell is shown in modality UMAP if it passes quality control in its respective modality regardless of the other modalities Nano-CT also vastly outperforms previously reported multimodal histone profiling method-multi-CUT&Tag in terms of number of fragments per cell with median 95 and 428 reads per cell in multi-CUT&Tag and 9,135 and 3,201 median reads per cell in nano-CT in H3K27ac and H3K27me3, respectively (Extended Data Fig. 3e) Genome browser tracks of the multimodal data for several clusters showing marker peak regions Markers: Mag for ATAC/H3K27ac in mature oligodendrocytes and Dmkn for H3K27me3 in microglia Venn diagram showing the genomic overlap of significant H3K27ac and H3K27me3 peaks in cluster AST-TE single-cell nano-CT can be used to simultaneously obtain robust and specific multimodal epigenetic profiles of several histone modifications and open chromatin from single cells UMAP embedding of the individual modalities with cluster labels identified through WNN analysis Embedding is based on individual modalities whereas cluster identities are assigned from WNN dimensionality reduction Venn diagram showing the overlap of peaks identified from the individual modalities H3K27ac and H3K27me3 signal intensity in single cells at the Foxg1 (c) and Irx2 loci (d) Gray lines connect the cells with same the single-cell barcodes across the different modalities Clusters for telencephalon astrocytes (AST_TE) and non-telencephalon astrocytes (AST_NT) were selected for the visualization Aggregated pseudo-bulk tracks for all modalities together with genomic annotations are shown to the right UMAP embedding showing pseudo-time calculated by slingshot on the basis of WNN dimensionality reduction and cluster identities Scatter plot depicting meta-region score for all modalities (y-axis) and pseudo-time (x-axis) The score was calculated as a sum of normalized score across all regions The regions were selected on the basis of P value (P < 0.05 Wilcoxon test) and log fold change > 0 at the marker regions of the ATAC modality The line depicts local polynomial regression fit (loess) of the data and shaded regions depict 95% confidence intervals Heat map representation of the H3K27me3 signal intensity at the regions the marker regions that are gaining H3K27me3 during oligodendrocytes differentiation (P < 0.05 Each column depicts one single cell and row single genomic region (peak) Cells are ordered by pseudo-time calculated as shown in a The order of the regions is based on k-means clustering of the matrix with k = 2 Scatter plots depicting meta-region score for all modalities (y-axis) and pseudo-time (x-axis) Wilcoxon test) and log fold change > 0 at the marker regions of the H3K27ac modality The regions were further stratified to wave 1 and wave 2 regions on the basis of k-means clustering as shown in c our analysis indicates that the chromatin opening precedes deposition of H3K27ac at loci that are marked for gene expression oligodendrocyte lineage progression encompasses two sequential H3K27me3 repressive states which would not be possible to discriminate using transcriptomic data multimodal nano-CT analysis allows unique insights into the epigenomic processes driving biological processes such as oligodendrocyte differentiation clustered by similarity and columns depict single cells ordered in pseudo-time Violin plot showing normalized expression of set of marker genes identified in scRNA-seq dataset and normalized expression of a set of genes identified as the key driver genes by scvelo UMAP projection and velocity vectors projection of chromatin velocity calculated using H3K27ac gene-by-cell matrix used as input into unspliced layer and H3K27me3 gene-by-cell matrix used as input into the spliced layer and then running the scvelo algorithm using default parameters suggesting that the set of genes identified through chromatin velocity comprised non-canonical oligodendrocyte differentiation genes This indicates the potential of multimodal chromatin profiling and chromatin velocity modeling in identification of genes which might be dynamically regulated through changes in the chromatin landscape but difficult to pick up through gene expression profiling anti-correlated active and repressive chromatin marks might require other modeling or data pre-processing strategies to correctly predict chromatin velocity We applied nano-CT to the mouse juvenile brain demonstrating that the simultaneous detection of ATAC repressive and active histone marks can provide further deconvolution of cell heterogeneity we found that individual modalities are not equally effective in the identification of cell identity and that histone marks can be more informative than we show that nano-CT could provide direct measurement of time-resolved dynamics of chromatin enhancer activation resolve distinct waves of repressive H3K27me3 and define chromatin velocity in single cells When profiling open chromatin together with histone post-translational modifications open chromatin tagmentation is performed before nano-CT antibody incubations and thus an increased number of centrifugation and washing steps pushes the input requirements to roughly 200,000 nuclei nano-CT can with similar input requirements to scCUT&Tag profile up to three chromatin modalities at the same time Previous scCUT&Tag library construction protocols rely on two tagmentation events in close proximity and correct orientation for amplification of single fragment This results in very high specificity of scCUT&Tag but also restricts the number of fragments per cell the nano-CT tagmentation strategy uses MeA-only-loaded Tn5 to deterministically tagment the chromatin Linear amplification of the tagmented chromatin ensures that also events with single integration (orphan tagmentation) are pre-amplified and used for library construction This increases the number of fragments per cell by more than tenfold but also reduces slightly the specificity of the assay resulting in a lower fraction of reads in peak regions Despite higher levels of background tagmentation nano-CT provides superior single-cell data quality for one-modality profiling compared to scCUT&Tag and enables multimodal chromatin profiling Here we show that multimodal nano-CT permits deconvolution of H3K27me3 states in a continuous and dynamic biological process such as oligodendrocyte differentiation Sequential waves of H3K27me3 occur in pseudo-time at distinct loci regulating distinct modules necessary for efficient oligodendrocyte lineage progression and differentiation the functional relationships between chromatin modalities differ from unspliced/spliced RNA and therefore other modeling approaches with different assumptions should be specifically tailored to chromatin velocities defined by their specific modalities Development of novel computational methods that can tackle these relationships will undoubtedly be necessary to capture the full predictive potential of multimodal datasets measurements of more than three chromatin modalities or chromatin and gene expression from single cells by expanding our fusion nanobody approach to other species or using primary nanobodies will provide data that can drive more accurate predictive algorithms and models to more reliably assign functional genomic elements to their target genes nano-CT and NTT-Seq are the latest of a new series of multimodal single-cell epigenomic technologies that also includes Multi-CUT&Tag and scGET-seq. These technologies have specific advantages and disadvantages which include fragments per cell, input material, and throughput, among other parameters (Supplementary Table 3) which might make them more amenable for application in specific biological contexts then others the use of fusion proteins of Tn5 with single-chain nanobodies recognizing mouse and rabbit antibodies confers a unique versatility to nano-CT The modular design of the presented nano-Tn5 fusions permit adopting this strategy to virtually any combination of histone marks or chromatin-binding proteins Tn5 fusion with other single-chain nanobodies might allow analyzing more than three epigenomic modalities in the same cell which is bound to provide further insights into chromatin dynamics We anticipate that measurement of levels of other histone marks or chromatin-binding factors (transcription factors RNA polymerase etc.) with nano-CT can provide mechanistic insights into multitude of processes such as activation of enhancers A detailed step by step protocol for nano-CT is available on protocols.io (https://www.protocols.io/view/nano-cut-amp-tag-for-multimodal-profiling-of-the-c-8epv59o8dg1b/v2). A detailed list of required reagents is in Supplementary table 4 Females with a hemizygous Cre allele were mated with males lacking the Cre allele while the reporter allele was kept in hemizygosity or homozygosity in both females and males In the resulting Sox10:Cre-RCE:LoxP (EGFP) animals the entire oligodendrocyte lineage was labeled with EGFP Breeding with males containing a hemizygous Cre allele in combination with the reporter allele to non-Cre carrier females resulted in offspring where all cells were labeled with EGFP and was therefore avoided All animals were free from mouse viral pathogens Mice were kept with the following light/dark cycle: dawn 6:00–7:00 night 19:00–6:00 and housed to a maximum number of five per cage in individually ventilated cages (IVC sealsafe GM500 General housing parameters such as relative humidity and ventilation follow the European convention for the protection of vertebrate animals used for experimental and other scientific purposes treaty ETS 123 consistent relative air humidity of 55 ± 10% 22 °C and the air quality is controlled with the use of standalone air-handling units supplemented with HEPA-filtrated air Monitoring of husbandry parameters is done using ScanClime (Scanbur) units The mice received regular chow diet (either R70 diet or R34 Water was provided by using a water bottle All cage changes were done in a laminar air-flow cabinet Respiratory masks were used when working outside of the laminar air-flow cabinet Animals were sacrificed at juvenile stages (P19) and both sexes were included in the study All experimental procedures on animals were performed following the European directive 2010/63/EU Saknr L150 and Karolinska Institutet complementary guidelines for procurement and use of laboratory animals The procedures described were approved by the local committee for ethical experiments on laboratory animals in Sweden (Stockholms Norra Djurförsöksetiska nämnd) The following antibodies were used in the multimodal nano-CT experiments: mouse anti-H3K27me3 (Abcam 9733T) was used in the single-modality nano-CT experiment The full-length fusion protein sequences were ordered from Twist Bioscience cloned into twist expression vector The constructs were transformed into BL21 (DE3) Star Escherichia coli inoculated into an overnight culture and grown in TB medium supplemented with 8 g l−1 glycerol at 30 °C with 175 r.p.m The next day the cultures were grown in the LEX system starting in the morning with cultivation at 37 °C The optical density was measured at different times and the temperature was switched to 18 °C when the culture reached an optical density of 2 The protein expression was induced at an approximate optical density of 3 (isopropyl β-d-1-thiogalactopyranoside Protein expression continued overnight before the cells were collected by centrifugation (10 min at 4,500g) IMAC lysis buffer (1.5 ml buffer per gram cell pellet) and the complete stock solution (1 tablet Complete EDTA-free (protease inhibitor cocktail Roche) and 50 μl benzonase nuclease cell resuspension (PSF) per 1 ml; 1 ml per 1.5 l culture) were added and the cell pellets were resuspended on a shaker table (cold room) The resuspended cell pellets were stored at −80 °C extra benzonase was added and the cells were disrupted by pulsed sonication (4 s/4 s 4 min The sonicated lysates were centrifuged (20 min at 49,000g) and the soluble fractions were decanted and filtered through 0.45-μm filters The samples were loaded onto the ÄKTA Xpress and purified overnight The following buffers were used: lysis buffer (100 mM HEPES pH 7.2); gel filtration buffer (50 mM HEPES pH 7.2); IMAC column (5 ml HisTrap HP (GE Healthcare)); gel filtration column (HiLoad 16/60 Superdex 200 (GE Healthcare)) Selected fractions were examined on SDS-PAGE gels before pooling Fractions containing the target proteins were pooled and concentrated with Vivaspin concentration filters (Vivascience The samples were then diluted with buffer containing 60% glycerol to get 50% in the final buffer The final concentration was measured by absorbance at 280 nm (Nanodrop) the protein was flash frozen in aliquots of 200 μl in liquid nitrogen and stored at −80 °C Nanobody-Tn5 fusion protein was loaded with barcoded oligonucleotides. First, an equimolar mixture of 100 μM forward oligonucleotides (Tn5_P5_MeA_BcdX_0N, Tn5_P5_MeA_BcdX_1N, Tn5_P5_MeA_BcdX_2N, Tn5_P5_MeA_BcdX_3N; Supplementary Table 1) was mixed (5 μl each) with an equimolar amount of 100 μM of Tn5_Rev oligonucleotide (20 μl) The oligonucleotide mixture was denatured for 5 min at 95 °C and annealed by slowly ramping down the temperature at 0.1 °C s−1 in a thermocycler The nano-Tn5 was loaded by mixing the following: 8 μl annealed (P5) oligonucleotides 44.1 μl 2× dialysis buffer (100 mM HEPES-KOH pH 7.2 20% glycerol) 5.9 μl anti-mouse-nano-Tn5 (5 mg ml−1 67.6 μM) or 8 μl annealed oligonucleotides 45.7 μl 2× dialysis buffer (100 mM HEPES-KOH pH 7.2 20% glycerol) 4.3 μl anti-rabbit-nano-Tn5 (6.8 mg ml−1 93 μM) to get final 2 μM loaded nano-Tn5 dimer Non-fused Tn5 (as in ATAC-seq) was loaded using Tn5_P7_MeB standard oligonucleotides (referred to as P7 Tn5) the 100 μM Tn5_P7_MeB oligonucleotides was mixed with an equimolar amount of 100 μM Tn5_Rev The oligonucleotide mixture was denatured for 5 min at 95 °C and annealed by slowly ramping down the temperature at 0.1 °C per second in a thermocycler The Tn5 was loaded by mixing the following: 8 μl annealed oligonucleotides (P7); 43.12 μl glycerol; 42.6 μl 2× dialysis buffer (100 mM HEPES-KOH pH 7.2 20% glycerol); and 6.28 μl Tn5 (3.5 mg ml−1 The brain was dissociated into a single-cell suspension using the Neural Tissue Dissociation Kit P (Miltenyi Biotec 130-092-628) according to the manufacturer’s protocol myelin was removed using debris removal solution (Miltenyi Biotec 130-109-398) according to the manufacturer’s instructions The single-cell suspension was filtered through a 50-μm cell strainer Two-hundred thousand cells (nano-CT without ATAC-seq) were centrifuged for 5 min at 500g resuspended in 200 μl antibody buffer (20 mM HEPES pH 7.5 and 2% bovine serum albumin (BSA)) and incubated for 3 min on ice to extract nuclei Nuclei were then centrifuged at 600g for 3 min and resuspended in 100 μl antibody buffer pre-mixed with 1:100 diluted primary mouse antibody 1:100 diluted anti-rabbit-nano-Tn5 loaded with barcoded P5 oligonucleotide (2μM stock) and 1:100 diluted anti-mouse-nano-Tn5 (2μM stock) loaded with a different barcoded P5 oligonucleotide The sample was then incubated at 4 °C on a roller overnight the nuclei were centrifuged at 600g for 3 min and washed twice with Dig-300 buffer (20 mM HEPES pH 7.5 the nuclei were resuspended by pipetting in 200 μl tagmentation buffer (20 mM HEPES pH 7.5 and 10 mM MgCl2) and incubated for 1 h at 37 °C The sample was mixed by pipetting after 30 min of the incubation to prevent sedimentation The reaction was stopped by addition of 200 μl 1× diluted nuclei buffer (Chromium Next GEM Single Cell ATAC Library and Gel Bead Kit v1.1; 10x Genomics) supplemented with 2% BSA (1× DNB/BSA) and 12.5 mM EDTA The nuclei were sedimented by centrifugation at 600g for 3 min and washed twice with 200 μl 1× DNB supplemented with 2% BSA around 180 μl 1× DNB/BSA supernatant was removed from the sample The nuclei were resuspended in the remaining 20 μl 1× DNB/BSA 2 μl were mixed with 8 μl trypan blue and counted manually using a counting chamber Sixteen thousand nuclei were used to load the 10x chromium chip Nano-CT without ATAC was performed in two biological replicates and nano-CT with ATAC was performed on the same biological sample as a technical replicate The number of cells used as input was 200,000 resuspended at 4 °C in 200 μl ATAC resuspension buffer (ARB pipetted up and down three times and incubated on ice for 3 min and mixed by inverting the tube three times Nuclei were pelleted by centrifugation at 500g for 10 min at 4 °C on swinging bucket rotor centrifuge with appropriate adapters for microtubes Supernatant was aspirated and cell pellet as resuspended in 200 μl transposition mix (100 μl 1× TD buffer 10 μl of 2μM Tn5 transposase loaded with barcoded MeA/Rev (P5) oligonucleotides pipetted up and down five times gently to mix and incubated at 37 °C for 30 min with 1,000 r.p.m the nuclei were centrifuged at 500g for 10 min and nuclei were washed with 200 μl CT antibody buffer (20 mM HEPES pH 7.5 The nuclei were then pelleted by centrifugation for 3 min at 600g the washed again with 200 μl antibody buffer and centrifuged for 3 min at 600g The pellet was then resuspended in 100 μl antibody buffer pre-mixed with 1:100 diluted primary mouse antibody 1:100 diluted anti-rabbit-nano-Tn5 (2μM stock) loaded with barcoded P5 oligonucleotide and 1:100 diluted anti-mouse-nano-Tn5 (2μM stock) loaded with a different barcoded P5 oligonucleotide The reaction was stopped by addition of 200 μl 1× diluted nuclei buffer (Chromium Next GEM Single Cell ATAC Library & Gel Bead Kit v1.1; 10x Genomics) supplemented with 2% BSA (1× DNB/BSA) and 12.5 mM EDTA The nuclei were sedimented by centrifugation at 300g for 3 min and washed twice with 200 μl 1× DNB supplemented with 2% BSA around 180 μl the 1× DNB/BSA supernatant was removed from the sample Single-cell indexing was performed using Chromium Next GEM Single Cell ATAC Library & Gel Bead Kit v1.1 (10x Genomics) Up to 8 μl nuclei suspension (filled up to 8 μl with 1× DNB/BSA) was mixed with 7 μl 10x ATAC buffer B 1.5 μl reducing agent B and 1 μl barcoding enzyme Seventy microliters of the master mixture was loaded on Chromium Next GEM Chip H together with 50 μl gel beads and 40 μl partitioning oil according to the manufacturer’s instructions followed by single-cell partitioning using the chromium controller and GEM incubation according to the manufacturer’s instructions (Chromium Next GEM Single Cell ATAC Reagent Kits v1.1 (Steps 2.0–2.5)) the sample was recovered by post-GEM incubation cleanup with Dynabeads MyOne SILANE and SPRIselect beads according to Chromium Next GEM Single Cell ATAC Reagent Kits v1.1 (Steps 3.0–3.2) 40 μl sample was recovered and 2 μl were used to measure the concentration using Qubit dsDNA HS Assay kit (ThermoFisher) The rest of the sample was used for P7 tagmentation by mixing the following reaction: 38 μl template DNA 1 μl MeB-only loaded standard Tn5 (P7 Tn5; typically 0.5–1 μl P7 Tn5 in single-cell experiment; see above for details on loading conditions) per 10 ng template DNA and dH2O up to 100 μl and incubation for 30 min at 37 °C in a thermocycler the sample was purified with DNA Clean and concentrator-5 (Zymo) using 500 μl binding buffer and eluted in 40 μl Zymo elution buffer The purified DNA was used as a template for the final PCR amplification according to Chromium Next GEM Single Cell ATAC Reagent Kits v1.1 (Step 4.1) (40 μl template 7.5 μl SI-PCR primer B and 2.5 μl individual Single index N Set A primer) and amplified using standard 10x scATAC-seq PCR amplification program (1 The amplified product was purified with SPRIselect reagent (Beckman-Coulter) using 0.4× and 1.2× two-sided purification according to the Chromium Next GEM Single Cell ATAC Reagent Kits v1.1 (Step 4.2) The size distribution and concentration of the library was assessed using Qubit dsDNA HS Assay kit (ThermoFisher) and bioanalyzer high-sensitivity DNA kit The sequencing library structure is shown in Supplementary data figure 2 The size distribution should be equal across 200-1000 bp range Peak at cca 200bp or cca 1500bp means the sample has been overtagmented or undertagmented The libraries were sequenced on Illumina Novaseq v1.5 using custom read1 (R1_seq GCGATCGAGGACGGCAGATGTGTATAAGAGACAG) and index2 (I2_seq CTGTCTCTTATACACATCTGCCGTCCTCGATCGC) primers (Supplementary Table 1) with custom read lengths 36-8-48-36 (R1-I1-I2-R2) A Seurat object was then created for each modality and replicate separately using R function FeatureMatrix and peaks called previously Seurat objects were then merged per modality (ATAC Bigwig files per cell cluster were constructing by filtering the possorted_bam.bam file using single-cell barcodes by custom script creating bam file per cluster and bamCoverage script from deeptools Integration with scCUT&Tag and scRNA-seq was performed using CCA implemented in Seurat package v.4.0.5 Pseudo-time analysis was performed using Slingshot v2.2.0 Gene annotations from Ensembl release v79 were used in the analysis (EnsDb.Mmusculus.79) Metagene plots were generated using deeptools package v.3.5.1 using computeMatrix and plotHeatmap scripts Scores for individual peak regions were generated using deeptools multiBigwigSummary script GO analysis was performed using R package clusterProfiler v.4.2.2 Correlation scatter plots were created using deepTools multiBigWigSummary script Pseudo-time in the oligodendrocyte lineage was calculated using R package slingshot v.2.2.044 Chromatin velocity was performed using Python package scvelo v.0.2.4 by directly using ATAC-seq and H3K27ac matrix gene-by-cell matrix into unspliced and spliced layers scvelo analysis was performed using default parameters Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article The plasmids used for purification of nanobody-Tn5 fusions are available through Addgene (#183637 and #183638) All code, scripts, analysis pipeline and instructions for reproducibility can be found on Github https://github.com/mardzix/bcd_nano_CUTnTag Transcription factors: from enhancer binding to developmental control Regulation of chromatin by histone modifications Mechanisms of action and regulation of ATP-dependent chromatin-remodelling complexes The diverse roles of DNA methylation in mammalian development and disease Organizational principles of 3D genome architecture Gene regulation by long non-coding RNAs and its biological functions Epigenomic priming of immune genes implicates oligodendroglia in multiple sclerosis susceptibility Chromatin potential identified by shared single-cell profiling of RNA and chromatin A unique chromatin signature uncovers early developmental enhancers in humans Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells Co-ChIP enables genome-wide mapping of histone mark co-occurrence at single-molecule resolution A bivalent chromatin structure marks key developmental genes in embryonic stem cells Single-cell chromatin accessibility reveals principles of regulatory variation CUT&Tag for efficient epigenomic profiling of small samples and single cells Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression Single-cell chromatin immunocleavage sequencing (scChIC-seq) to profile histone modification Profiling single-cell histone modifications using indexing chromatin immunocleavage sequencing A chromatin integration labelling method enables epigenomic profiling with lower input CoBATCH for high-throughput single-cell epigenomic profiling Mapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq) Simultaneous quantification of protein–DNA contacts and transcriptomes in single cells Joint profiling of histone modifications and transcriptome in single cells from mouse brain High-throughput single-cell epigenomic profiling by targeted insertion of promoters (TIP-seq) Comprehensive integration of single-cell data Single-cell multi-omic integration compares and contrasts features of brain cell identity An ultra high-throughput method for single-cell joint analysis of open chromatin and transcriptome Simultaneous profiling of multiple chromatin proteins in the same cells Chromatin velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin A toolbox of anti-mouse and anti-rabbit IgG secondary nanobodies Characterizing cellular heterogeneity in chromatin state with scCUT&Tag-pro Stuart, T. et al. Nanobody-tethered transposition enables multifactorial chromatin profiling at single-cell resolution. Nat. Biotechnol. https://doi.org/10.1038/s41587-022-01588-5 (2023) Expanded encyclopaedias of DNA elements in the human and mouse genomes Molecular architecture of the mouse nervous system Integrated analysis of multimodal single-cell data Emx2 and Foxg1 inhibit gliogenesis and promote neuronogenesis Foxg1 antagonizes neocortical stem cell progression to astrogenesis Generalizing RNA velocity to transient cell states through dynamical modeling Oligodendrocyte heterogeneity in the mouse juvenile and adult central nervous system Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression An improved ATAC-seq protocol reduces background and enables interrogation of frozen tissues Slingshot: cell lineage and pseudotime inference for single-cell transcriptomics Single-cell ATAC by Cellranger ATAC v2.1.0 New developments on the Encyclopedia of DNA Elements (ENCODE) data portal Download references Open access funding provided by Karolinska Institute Present address: Department of Biochemistry and Biophysics Department of Medical Biochemistry and Biophysics Marek Bartosovic & Gonçalo Castelo-Branco Ming Wai Lau Centre for Reparative Medicine optimized and performed the nano-CUT&Tag experiments and analyzed the data Both authors contributed and approved the manuscript have filed a patent application on the basis of this work (European patent application number EP22160860.7) reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations qPCR amplification curve for libraries generated using the same amount of input material using scCUT&Tag method scCUT&Tag combined with linear pre-amplification and nano-CT protocol with two-step tagmentation Bioanalyser plot showing the size distribution of libraries generated using scCUT&Tag and nano-CT Typical nucleosome profile can only be seen in the scCUT&Tag library UMAP co-embedding of the scCUT&Tag and nano-CT dataset (single modality) and dimensionality reduction was done on both datasets together Violin plot showing fraction of reads in peak regions (FrIP) for data collected by scCUT&Tag and nano-CT Heatmap showing the cell by marker matrix for scCUT&Tag dataset Top markers were selected based on adjusted p-value calculated using Seurat’s FindAllMarkers function (two-sided Wilcoxon rank sum test and corrected for multiple hypothesis testing by Bonferroni correction) Heatmap showing the cell by marker matrix for nano-CT dataset Boxplot depicting fraction of cells with any signal (counts >1) in the most significantly enriched marker regions (top 100) for the respective cluster Markers are selected based on adjusted p-value calculated using Seurat’s FindAllMarkers function (two-sided Wilcoxon rank sum test and corrected for multiple hypothesis testing by Bonferroni correction) Lower and upper bounds of boxplot specify 25th and 75th percentile and lower and upper whiskers specify minimum and maximum Violin jitter plot showing the p-value determined by two-sided Wilcoxon rank sum test (Seurat FindAllMarkers function) distribution for the top 50 marker bins for each cluster of nano-CT and scCUT&Tag dataset *** p value = 1.3×10−34 (Two sided wilcoxon rank sum test) e Volcano plot showing p-value determined by two sided wilcoxon rank sum test (Seurat FindAllMarkers function) and average log2 fold change for top 50 marker bins in nano-CT and scCUT&Tag Genome browser snapshot showing pseudobulk scCUT&Tag midbrain and hindbrain) for H3K27me3 histone mark Fingerprint analysis of H3K27me3 pseudobulk scCUT&Tag result of linear amplification duplicates or result of PCR duplicates in nano-CT and multimodal nano-CT experiments UMAP co-embedding of CCA-integrated H3K27ac nano-CT together with scRNA-seq dataset Gene body and promoters were used as gene activity scores for the integration UMAP co-embedding of CCA-integrated nano-CT ATAC-seq together with scRNA-seq dataset UMAP embedding and visualization of marker peak activities for H3K27ac nano-CT Exact genomic region together with the closest gene is shown in the plot title Violin plot visualization the of peak scores for the same peak regions as in a) Genome browser tracks for all modalities profiled by multimodal nano-CT (ATAC Scatter plot showing the signal of scATAC-seq (single modality profiled from 10x Genomics) and multimodal ATAC-seq performed with nano-CT in cluster astrocytes and in astrocyte-specific peaks The same scatter plot as in a.,but stratified by H3K27ac signal H3K27ac low represents peaks with the 20% lowest quantile of H3K27ac signal and H3K27ac high represents peaks with 20% highest quantile of H3K27ac signal Metagene heatmaps showing the genomic distribution of the ATAC-seq signal in the same regions as in b Scatter plot showing the cluster astrocytes H3K27ac signal profiled either together with H3K27me3 (without_ATAC) or together with ATAC-seq and H3K27me3 (with ATAC) within the astrocyte-specific peaks The scatter plot of H3K27ac astrocytic signal within peak regions stratified by ATAC-seq signal ATAC low represents peaks with the 20% lowest quantile of ATAC-seq signal and ATAC high represents peaks with the 20% highest quantile of ATAC-seq signal Metagene heatmaps showing the genomic distribution of H3K27ac signal in the same regions as in e Confusion matrix of broad cell identities between a Confusion matrices for fine cluster identities across the different modalities for d ATAC and H3K27ac e.ATAC and H3K27me3 and f Alluvial diagram of corresponding cell identities between the ATAC H3K27ac and H3K27me3 signal intensity in single cells at the Lhx2 (b) and Foxb1 (c) locus Gray lines connect the cells with same single-cell barcodes across the different modalities Clusters telencephalon astrocytes (AST_TE) and non-telencephalon astrocytes (AST_NT) were selected for the visualization Gene ontology enrichment analysis of genes which are repressed in the wave 2 of H3K27me3-mediated repression P value was calculated using R package enrichGO using one sided Fischer’s test with Benjamini-Hochberg correction for multiple hypothesis testing Rows depict individual top velocity driver genes sorted by time of value with maximum intensity and columns depict individual cells sorted by latent time Gene ontology enrichment analysis of the most important velocity driver genes Supplementary Sequences 1 and 2 and Supplementary Figs 1 and 2 list of genes identified as the most important velocity driver genes by scvelo summary of single-cell epigenome profiling technologies Download citation DOI: https://doi.org/10.1038/s41587-022-01535-4 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science Cherry blossoms symbolise the beauty of new life and renewal in spring. However, their lifespan is very short (usually only around 10 days); and for this reason, they also also represent the brief, fleeting nature of life. The cherry blossom season typically occurs in late March to early April, when the trees produce a stunning display of pink and white flowers, although this largely depends on the weather and other conditions. The exact start of the blooming season in 2025 is yet to be determined, however, it is expected that the prime time to witness the cherry blossoms in Portugal will be near the end of March 2025, meaning you still have time to plan your trip to see this natural wonder.  Fundão is known as the Portuguese “cherry town”, with a production that reaches more than 20 million euros, and attracting more than 130,000 tourists a year. and explores every single business opportunity involved with this fruit. Apart from its picturesque landscapes, Fundão town boasts numerous other attractions worth exploring. Be sure to take a stroll through the historic center and visit landmarks like the Capela de Nossa Senhora da Conceição, dating back to the 16th century, or the Capela da Nossa Senhora do Miradouro ou de Seixo, which dates from the 14th century and is associated with a legendary apparition of the Virgin Mary. Carnation Revolution: Portugal's Freedom Day On 25th April Portugal underwent a fundamental transformation known as the Carnation Revolution This pivotal event marked the end of the Estado Novo dictatorship and the start of Portugal's path to democracy The day is celebrated annually as Freedom Day to honour this peaceful transition and the newfound era of freedom and democracy Daniel Castelo Branco Ramos describes his day to day as “overwhelming.” With the number of cases per judge always in the thousands one of the highest on average in the world Judge Ramos is lucky if he has any down time at all “Many of my cases involve a lot of litigation I dedicate myself to studying the most complex cases both the intellectual tasks and the personal contact with lawyers and litigants.” and civil procedure law at the Milton Campos Law School “Learning has always been of interest to me and in turn I graduated with a degree in law from the Federal University of Minas Gerais 1998 which is one of the most traditional and respected universities in Brazil I later received a master’s degree in public law in 2009 from the same University.” It was Judge Ramos’s interest in both learning and environmental law that led him to pursue his SJD at Haub Law “I knew Haub Law’s strong reputation and decided to apply for the doctoral program in environmental law the differences between the legal systems in the United States and Brazil motivated me to do more in-depth comparative law research.” While he was a student at Pace Judge Ramos had what he describes as many outstanding professors While Judge Ramos describes the SJD program at Haub Law as one of the toughest intellectual and personal tasks of his life he is very cognizant of the importance of the end result “I work with environmental litigation and teach environmental law The knowledge that I acquired during my SJD studies was crucial both in solving practical day-to-day issues and in deepening my legal thinking and research being immersed in a learning environment with a social and legal culture so different from the one I was used to was invaluable.” When he isn’t behind the bench or in the classroom Judge Ramos enjoys immersing himself in the nature of his home state After spending the last 35 years pursuing a career in finance Todd Jacobson ’27 decided to switch gears and pursue a law degree the potentially negative longer lasting consequences became abundantly clear – from educational outcomes to healthcare access I would like to pursue a career in public policy to work on these issues.” Elisabeth Haub School of Law Professor Josh Galperin speaks with Bloomberg Law about proposed changes to the federal civil service system highlighting how the plan strategically favors the current administration.  Haub Law Professor Bennett Gershman continues to offer insightful commentary on the Trump administration’s immigration crackdown He warns that the president is "using every weapon at his disposal" and stresses the consequences of undermining judicial independence.  Copyright © 2024 Pace University Privacy Policy Architect and pop-surrealist painter Tiago Azevedo launched a new YouTube series with art dealer and TV personality José Castelo Branco the two artists talk about cultural differences in etiquette and discuss the concepts of starving artist and abundant artist fashion icon and jewelry designer pioneer Betty Grafstein are prominent figures in New York City’s high society The couple hosts regular dinner parties with a Studio 54-like atmosphere: a bohemian environment and an exquisite circle of celebrity friends shape these social gatherings where the art scene is as vibrant as ever – with Baccarat crystal champagne flutes saluting the original Picasso and Albrech Durer paintings on the walls Tiago Azevedo is a leading figure of contemporary art movement Pop-Surrealism and his most recent series of oil paintings was displayed at Castelo Branco and Grafstein’s 25th wedding anniversary Some of the subjects Azevedo and Castelo Branco address in their new video series include what conversation topics to avoid at a formal dinner and why to ask guests about their allergies and food restrictions ahead of time They also explain how the setting of the cutlery should follow the menu and why guests should never refuse dessert the two artists discuss what made painters like Andy Warhol and Pablo Picasso so successful and how relevant the work of art dealers and curators still is Azevedo said that “this series is an extension of another YouTube series that I have been working on for some time now José Castelo Branco is a very prominent art dealer and he has a lot of precious tips to share with my audience The idea is to create as much awareness as possible on how the art business and industry works “We also talk about how fabulous and prosperous an artist’s life can be,” Azevedo continued “One of my personal goals in life is to change the conversation from the so-called starving artist mentality to the abundant artist philosophy José and I discuss how people can prepare for success with tips about body language One of our objectives is to ensure that success – however each person chooses to define it – happens for as many people as possible That is the intention for this video series I believe it will help open the eyes of many people on how successful your life can be if you follow your passion” Check out Storytime with José Castelo Branco & Tiago Azevedo on YouTube to find out more etiquette rules such as the right posture to have at the table and how to politely let your guests know that it is time to go home document.getElementById("comment").setAttribute( "id" "a566fb60dd324d5b71fc38be43ee1bec" );document.getElementById("d628b68082").setAttribute( "id" GET OUR HAUTEST STORIES DELIVERED TO YOUR INBOX Ricardo Resende on Unsplash Editorial Team 4 February 2025 10:00Although February is considered a winter month it’s an ideal time for more affordable travel allowing you to explore cities and natural landscapes without the intense summer heat or large crowds of tourists February is the month when Valentine’s Day is celebrated making Portugal a perfect destination for couples Find out where to go on holiday in Portugal this February From medieval castles and boat trips to vineyards and fairy-tale palaces there are countless places that capture the hearts of couples These destinations offer the perfect blend of culture Singa Hitam, CC BY 2.0 Creative commonsSintra, located in the Lisbon region, is a true romantic paradise. The town offers a variety of experiences that combine history, culture, and natural beauty. Strolling hand in hand through the gardens of Quinta da Regaleira exploring the opulent halls of the Pena Palace enjoying the panoramic views from the Moorish Castle and having picnics at Lagoa Azul are activities sure to enchant couples don’t miss visiting the Monserrate Palace and its exotic gardens a romantic dinner in the historic centre of the town is essential such as Negrais roast suckling pig and Mercês-style pork indulge in Sintra’s famous queijadas and travesseiros Feliciano Guimarães, CC BY 2.0 Creative commonsThe Douro Valley with terraced vineyards stretching as far as the eye can see create an incredible backdrop for a weekend getaway for two where you can admire the riverbanks dotted with centuries-old wine estates a train journey along the Douro Line is also a fantastic option where you can taste award-winning wines and learn about the production process Some of these estates offer outdoor dining experiences allowing visitors to savour regional cuisine while enjoying the sunset over the vineyards Spend the weekend soaking up the city’s architecture, characterised by its Art Nouveau style. Another must-see in Aveiro is the Friendship Ribbon Bridge, located in the city centre. Don’t miss the chance to savour the local cuisine, from the lagoon eels to the famous ovos moles for a sweet finish. Portugal is home to an archipelago of islands that offer a more direct connection with nature. Three of these pieces of land surrounded by water stand out for their unparalleled beauty. Even in February, these islands retain a special charm with their mild climate, providing visitors with a chance to escape the continental winter. Alberto-g-rovi, CC BY 3.0 Creative commonsMadeira Island is a delightful destination for a February weekend, offering mild weather and a variety of activities to enjoy. Daily average temperatures hover around 17°C, with highs reaching up to 20°C, particularly in coastal areas like Funchal. This pleasant climate allows you to take the Monte Cable Car and enjoy breathtaking views of the island. You can also hike the Levada do Caldeirão Verde, following trails through dense forests that lead to a spectacular waterfall. Don’t miss the chance to savour Madeira’s famous dishes, including espetadas, grilled limpets, poncha, bolo do caco, and honey cakes. São Miguel’s cuisine is rich and varied, with highlights including the traditional Furnas stew, slowly cooked using the geothermal heat of the ground. For fish lovers, fresh tuna and chicharro are popular choices in local restaurants. Be sure to try the island’s artisanal cheeses and traditional sweets, such as the Vila Franca do Campo queijadas. The island’s cuisine is simple yet delicious. Be sure to try stewed octopus, fish stew, the local island cheese, and incense honey. In February, daily high temperatures average around 16°C, with lows of about 13°C, providing comfortable conditions for exploring the island's natural beauty. In February, Portugal offers a variety of cities that stand out for their affordability. During this period, prices tend to be lower due to the off-season, giving visitors the chance to explore cultural destinations at reduced costs. Whether it's to admire historic monuments, enjoy local cuisine, or simply relax in natural settings, these cities excel at providing authentic experiences. Turismo En Portugal, CC BY 2.0 Creative commonsLocated on the northern coast of Portugal, Póvoa de Varzim stands out as one of the most affordable cities to visit in February. During this month, accommodation prices tend to be lower, with reductions of up to 33% compared to peak months, making it an economical choice for a weekend getaway. During your stay, you can explore the local beaches, which, although less inviting for swimming due to the cold water temperatures, offer peaceful landscapes perfect for seaside walks. The Municipal Museum of Ethnography and History provides an in-depth view of the city’s maritime heritage. GualdimG, CC BY-SA 4.0 Creative commonsDuring February, Palmela stands out as an economical option, with accommodation prices starting from €37. The average temperatures range between 10°C and 19°C, offering a mild climate for exploring the town. A must-visit is the Palmela Castle, which provides panoramic views of the region and an immersion in the local history. The Casa Mãe da Rota dos Vinhos offers tastings of local wines, allowing visitors to savour the typical flavours of the area. Be sure to sweeten your visit with the famous tortas de Azeitão. Vitor Oliveira CC BY-SA 2.0 Creative commonsFor a weekend in Castelo Branco, it is recommended to visit the Jardim do Paço Episcopal, a green space filled with history and beauty. The Manuel Cargaleiro Museum, dedicated to the artist Manuel Cargaleiro, showcases an impressive collection of contemporary art. Another option in Castelo Branco is the Centre for the Interpretation of Castelo Branco Embroidery. In terms of cuisine, the city offers traditional dishes such as maranhos, a local delicacy made with goat meat, ham, rice, and various aromatic herbs, and for dessert, don’t miss the famous tigeladas. Unprecedented power outage in Spain and Portugal: everything we know so far and what to do if it happens again No electricity no running water – that was the situation from around 11:30am yesterday in Portugal and Spain countless businesses were forced to close due to the lack of power and internet public transport and road traffic ground to a halt and long queues formed at petrol stations and supermarkets Power began to be restored in the early evening on both sides of the Iberian Peninsula The Tejo Vintage Train is back on the rails and Those embarking on this experience will have the opportunity to watch a historical re-enactment of the journey of King Carlos and Queen Amélia on the Beira Baixa Line visit the National Railway Museum and the Railway Neighbourhoods or see various places of interest such as the emblematic Almourol Castle Belver Castle or the Portas de Ródão Natural Monument The journey will take place on Schindler carriages with panoramic windows that allow passengers take advantage of the landscapes of the Ribatejo marshland and the riverside route along the River Tagus especially the stretch between Entroncamento and Vila Velha de Ródão showing the tourist potential of the Beira Baixa Line Among the novelties are the offer of a typical sweet to welcome passengers; a historical re-enactment on board by a theatre group and visits to the Railway Neighbourhoods where travellers can choose between two different programmes The first includes the journey between Lisbon and Entroncamento (round trip) After being welcomed by a guide at Entroncamento Station where the history of this important railway heritage will be explained to have lunch on board the restaurant carriages that are part of the Museum's collection participants will also have the opportunity to visit the National Railway Museum see more than 160 years of railway history in Portugal and travel on a mini-train the Municipality of Entroncamento will offer everyone tea and a traditional sweet - ‘o Ferroviário’ The second programme covers the route between Lisbon and Castelo Branco allowing passengers to enjoy beautiful landscapes and monuments Passengers will be greeted by a guide and a musical group at the train station to have lunch and visit the city of Castelo Branco They will get half-price access to various points of interest if they show their Vintage Train ticket from the Cargaleiro Museum to the Castelo Branco Embroidery Interpretation Centre the Textile Museum in the parishes of Cebolais de Cima and Retaxo the Francisco Tavares Proença Júnior Museum the Silk Museum and the Stonemason's Museum in Alcains To mark Castelo Branco's nomination as a ‘UNESCO Creative City’ in the category of ‘Crafts and Popular Arts’ the town council will present a plaque alluding to the date which will be another memory of a day well spent The train leaves Castelo Branco station for Lisbon at 17.28 The Tejo Vintage Train is scheduled to arrive at Lisbon-Santa Apolónia Station at 20:32 This tourist product is the result of a partnership between CP - Comboios de Portugal the National Railway Museum and Castelo Branco City Council with the collaboration of Entroncamento City Council Timetable: Outward journey - Reception in Lisbon-Santa Apolónia at 8:30 and departure at 8.55; stops in Lisbon-Oriente (9:03) Vila Franca de Xira (9:18) and Entroncamento (10:08) arriving in Castelo Branco at 12:12; Return journey - Departure from Castelo Branco at 17:28; stops in Entroncamento at 19:17 arriving in Lisbon-Santa Apolónia at 20:32; Programmes: Two to choose from - Programme 1 - Between Lisbon-Santa Apolónia and Entroncamento (round trip); Programme 2 - Between Lisbon-Santa Apolónia and Castelo Branco (round trip); €16 per Child (4 to 12 years) | Programme 2 - €43 per Adult €22 per Child (4 to 12 years); there are special prices for groups; On sale from: ticket offices or online at www.cp.pt Benefits: The train has a bar service available in its own carriage; those who leave their car in the Lisboa-Oriente car park will be able to enjoy preferential fares simply by showing their train ticket; in Castelo Branco passengers will have 50% off access to various museums by showing their Tagus Vintage Train ticket All the information can be found at www.cp.pt. Our Standards: The Thomson Reuters Trust Principles., opens new tab , opens new tab Browse an unrivalled portfolio of real-time and historical market data and insights from worldwide sources and experts. , opens new tabScreen for heightened risk individual and entities globally to help uncover hidden risks in business relationships and human networks. © 2025 Reuters. All rights reserved Gerson Castelo Branco is a self-taught architect from the state of Piauí in Brazil His architecture is a collection of references and experiences that he describes as "an expression of freedom," the Paraqueira often use the term international to describe what in reality is just another renowned way of building The architecture of Gerson Castelo Branco is not: it is original and fits anywhere on the planet without losing its essence Paraqueira In Natura (1984). Image courtesy of Gerson Castelo Branco.A self-taught architect We were very modern in our behavior, I don't know if this is the right word, but we were the reference of different people in that conservative city of Fortaleza, I looked at all that, and I could not live there anymore. So he decides to go on a trip to the Andean countries, in which he acknowledges that, despite his Christian upbringing, he was having his values put to the test. This experience carried him into a new phase in his life and work. My grandmother's recipe for high ceilings, with half walls and ventilation circulating in all rooms. He did a renovation in several stages, knocking down a wall and lifting a roof to make room for a mezzanine. Casa do Pescador (Fishermen's house). Image courtesy of Gerson Castelo Branco.Carnaúba - a material that was being discarded in the demolition of warehouses in Parnaíba and therefore very cheap - was picked for structural purposes and also for panels and revolving doors, in order to create integrated spaces and to dialogue with other local textures such as the cattail and monkey vine mats, also used to make walls that provide natural light. The staircase was inspired by Lina Bo Bardi's iconic stairs at Solar do Unhão, and this design becomes an element that he will incorporate in most of his future projects, as well as the permeability between the interior space and the surroundings. This hut, in particular, had a bathroom with a large window facing a pathway for the fishermen, who interacted with Gerson while he was taking a bath. And so was created what would become the first Paraqueira - the name he calls his architectural works. The inspiration for this title comes from the nickname he received in his teenage years, Paraca, because they say he "looked like a parachute, always opening up to life." "Since I was the Paraca, feeling good about life, these architectures could be the Paraqueiras, that's where this expression came from," he explains. Gerson was asked to design a house to be built on Praia do Futuro where "there was nothing but flying objects at that time." The project consisted of a regular brick house in the shape of a sail the city government did not allow the construction which he considers a boycott of his work at the time one of his neighbors requested a project which allowed him to adapt the design for a new plot of land Finally, the house was built on another beach and was included, amongst forty projects selected by Oscar Niemeyer, in the book Art in Brazil, organized by Pietro Maria Bardi. When asked about his creative process, Gerson states: "I am absolutely sure that it is nature. For me, creating is a stone, it is a tree, it is the very definition of terrain, which can change, bringing whatever reference, literally a process of transmission of nature through thought, imagination, from the electric field to the magnetic." Paraqueira Loiba (2010) © Gerson Castelo BrancoAs an example of creation, he cites his own house, in Viçosa do Ceará: These spaces are literally integrated, open, with no concern for anything established by the concepts of morality and behavior. There was no promiscuity, but the human being living in freedom with nature itself. For me that was the fundamental point. Paraqueira In Natura (1984). Image courtesy of Gerson Castelo Branco.Architecture today Paraqueira Cumbuco. Image courtesy of Gerson Castelo Branco. When giving lectures in several Brazilian universities, I felt bothered by the old-fashioned nature of architecture schools, by the constraints they impose on the minds of young people in Brazil. A lack of self-direction, a subordination to the market, to materials. Paraqueira Almendra (2017). Image courtesy of Gerson Castelo Branco.In general one can say that Gerson expresses his dissatisfaction with the current scenario of architecture just as he was unable to see himself inside the city the non-subordination to the ruling market the societal castrations opposed to the freedom and proximity to nature he experienced together with the way he appropriates the climates are some of the main factors that helped to shape his character and way of thinking the spaces it is a unique way of approaching architecture and has a lot to teach us You'll now receive updates based on what you follow Personalize your stream and start following your favorite authors If you have done all of this and still can't find the email Alzheimer's Disease and Related Dementias Volume 15 - 2023 | https://doi.org/10.3389/fnagi.2023.1161847 Corrigendum: Normative mice retinal thickness: 16-month longitudinal characterization of wild-type mice and changes in a model of Alzheimer's disease Animal models of disease are paramount to understand retinal development and to study neurodegeneration using optical coherence tomography (OCT) data we present a comprehensive normative database of retinal thickness in C57BL6/129S mice using spectral-domain OCT data The database covers a longitudinal period of 16 months and provides valuable insights into retinal development and changes over time Our findings reveal that total retinal thickness decreases with age while the thickness of individual retinal layers and layer aggregates changes in different ways and retinal pigment epithelium (RPE) thickened over time whereas other retinal layers and layer aggregates became thinner we compare the retinal thickness of wild-type (WT) mice with an animal model of Alzheimer's disease (3×Tg-AD) and show that the transgenic mice exhibit a decrease in total retinal thickness compared to age-matched WT mice with statistically significant differences observed at all evaluated ages This normative database of retinal thickness in mice will serve as a reference for future studies on retinal changes in neurodegenerative and eye diseases and will further our understanding of the pathophysiology of these conditions Optical coherence tomography (OCT), first demonstrated in 1991, is a non-contact imaging modality based on interferometry. It was first used to image the human retina in vivo in 1993 (Swanson et al., 1993) OCT has transformed medical retinal imaging non-invasive modality with fast scan times are just a few of the features that have facilitated the introduction and expansion of OCT into clinical practice Currently, OCT devices are available in most clinics and are widely used to evaluate the retina in healthy and diseased conditions. It is used to aid in the diagnosis of ophthalmological complications, such as diabetic retinopathy, macular edema, and age-related macular degeneration. Moreover, OCT has been at the forefront of retinal biomarkers of neurodegeneration research (Doustar et al., 2017; Vujosevic et al., 2023) together with the fact that the retina is part of the central nervous system and inexpensive method to image neurodegeneration Magnetic resonance imaging (MRI) and positron emission tomography (PET) remain the gold standard in diagnosing neurodegeneration characterization of the retina over a longer period of time is paramount we characterize the total retinal thickness and the thickness of individual layers for WT and 3×Tg-AD animals aged up to 16 months The same animals were monitored longitudinally over time The thickness of the retina and retinal layers are discussed as a function of age and the relative distance to the optic disc 3×Tg-AD induced changes in retinal thickness are reported Total number of OCT data volumes included in this study for wild-type (WT) mice and the triple transgenic Alzheimer's disease (3×Tg-AD) mice model A significant increase in animal body weight with age was observed for both groups (p-values < 0.001 for both groups) No statistical differences were observed between the weights of WT and 3×Tg-AD mice up to 4 months of age WT mice had significantly higher body weights than 3×Tg-AD mice Statistical differences were assessed by independent samples t-test Longitudinal average weight distribution of wild-type (WT) and the triple transgenic Alzheimer's disease (3×Tg-AD) mice animals were anesthetized with a mixture of 80 mg/kg of ketamine (Nimatek; Dechra) and 5 mg/kg xylazine (Sedaxylan; Dechra) A solution of 0.5% tropicamide (Tropicil; Edol) and 2.5% phenylephrine (Davinefrina; Dávi) was used for pupil dilation and oxibuprocaine (Anestocil; Edol) was used for topical anesthesia the eyes were regularly lubricated with eye drops [1% carmellose (Celluvisc; Allergan)] This study was approved by the Animal Welfare Committee of iCBR All experiments were conducted in accordance with the Association for Research in Vision and Ophthalmology statement for animal use in research applications and in agreement with the European Community Directive Guidelines for the care and use of non-human animals for scientific purposes (2010/63/EU) transposed into the Portuguese law in 2013 (DL113/2013) Retinal OCT data were acquired with a Micron IV OCT System (Phoenix Technology Group each composed by 512 A-scans of 1024 discrete samples B-scans were saved as non-compressed TIFF image files The system uses a superluminescent diode emitting at a central wavelength of 830 nm with a bandwidth of 160 nm all OCT data acquisitions were performed by the same operator The optic disc was used as a landmark to select the imaged retinal region which was horizontally aligned with and directly above it are used to achieve finer-grain information and increase the accuracy of classification prediction A total of eight distinct structures (layers and layer aggregates) were considered in the classification (Figure 1): retinal nerve fiber layer and ganglion cell layer complex (RNFL-GCL) Volumetric segmentation is obtained by combining the 512 segmented B-scans Representative B-scan with overlayed segmentation retinal nerve fiber layer and ganglion cell layer complex; IPL Retinal thickness maps were computed from the volumetric segmented OCT data The thickness of each segmented structure and the total retinal thickness (TRT) were calculated as the distance between the respective segmented boundaries For each volume, nine regions-of-interest (ROIs) were considered to assess thickness variations within the imaged area. These consisted of 3× 3 non-overlapping blocks of 170 × 170 points. The blocks, organized from temporal to nasal and superior to inferior directions, were labeled B1–B9, as described in Ferreira et al. (2021) The original data was cropped centrally into a 510 × 510 volume for ROI size consistency Average thickness values were calculated as the average of the 510 × 510 and 170 × 170 thickness values for the entire imaged area and each ROI Data acquired from left and right eyes show nasal-temporal asymmetry For a straightforward comparison between them OCT scans from the left eyes were mirrored left-hand-side/right-hand-side thickness maps correspond to the temporal/nasal region Statistical analysis was performed with Matlab R2020a (The MathWorks Inc. The normal distribution of the data was assessed using the Kolmogorov-Smirnov normality test Over 93% of all thickness distributions were normal Statistical differences between the WT and 3×Tg-AD groups were assessed using the independent samples t-test when normal distribution was confirmed The alternative non-parametric Mann–Whitney U-test was used when the data did not follow a Gaussian distribution Because multiple layers were compared at each time point the Bonferroni correction was applied to correct for multiple comparisons For the analysis of statistical differences over time one-way repeated measures ANOVA (RANOVA) or the non-parametric Friedman test were used depending on the normality of the data distribution Only eyes that could be measured at all ages were included in this analysis (WT OS N = 27; WT OD N = 22; 3×Tg-AD OS N = 33; 3×Tg-AD OD N = 36) Two-way RANOVA was used to test the influence of each group on thickness values over time Pairwise comparisons were evaluated and corrected for multiple comparisons using the Tukey–Kramer test From the volumetric segmented OCT data of each subject, detailed thickness maps over the imaged area were computed for each retinal layer/layer aggregate. Figure 2 shows the average TRT maps defined as the distance between the vitreous-RNFL and RPE-choroid interfaces The range of thickness values is similar for both eyes within the same group Detailed analysis of the mean TRT values obtained for each eye at each time point showed no statistically significant differences in retinal thickness between the right and left eyes except for 3×Tg-AD mice at 1 month of age (p-value = 0.02) Average total retinal thickness maps of wild-type (WT) and the triple transgenic mouse model of Alzheimer's disease (3×Tg-AD) retinas separated by left (OS) and right (OD) eyes of animals aged 1 Color represents the retinal thickness in μm as indicated by the color bar Detailed TRT maps indicate a decrease in overall retinal thickness with age in both groups This decrease appears to be more pronounced between 1 and 2 months of age Higher thickness values are observed in WT mice compared to 3×Tg-AD mice for all ages An increase in TRT can also be seen in both eyes with the proximity to the optic disc (superior to inferior) an apparent temporal-nasal asymmetry was observed in both groups for both eyes of wild-type (WT) and the triple transgenic Alzheimer's disease (3xTg-AD) mice Kernel density estimates of the total retinal thickness (TRT) for the left eye (OS) and right eye (OD) of wild-type (blue) and the triple transgenic Alzheimer's disease (3xTg-AD) mice (red) Median (dashed) and first and third quartiles (dotted) are shown p-values < 0.01 (■) and < 0.001 (*) Kernel density estimates of retinal thickness per layer for the left (A) and right (B) eyes of wild-type (blue) and the triple transgenic Alzheimer's disease (3xTg-AD) mice (red) Bonferroni correction was applied per time point to correct for multiple comparisons Consistent statistically significant differences were found between WT and 3×Tg-AD mice retinal layer thicknesses at all ages. Overall, the retina of 3×Tg-AD mice is thinner than that of WT mice. Both eyes show significantly lower TRT values in 3×Tg-AD mice than in WT mice at all time points (Figure 3) Statistical differences between groups in the thickness of the RNFL-GCL complex and the ONL were observed primarily in mice aged 8 months or older Longitudinal total retinal thickness of wild-type (A B) and the triple transgenic Alzheimer's disease (C D) mice for left (OS; blue) and right (OD; red) eyes Color coded p-values for pairwise comparisons are shown in (B) and (D) The color indicates the level of the p-value Normalized longitudinal mean retinal thickness variations for wild-type mice differentiated by layer and block (B1–B9) Data were normalized for each retinal layer/layer aggregates Normalized thickness is indicated by the color bar Normative thickness maps can also be used to compute the probability that the retina of a given mouse has thickness values outside the normal range. Examples of these applications can be found in our previous publications (Ferreira et al., 2021; Bernardes et al., 2022) the human tau mutant harbored by this mouse model causes frontotemporal dementia or other tauopathies in humans tau protein is not mutated in Alzheimer's disease and the distribution of tau pathology differs between Alzheimer's disease and frontotemporal dementia Comparison of mean thickness of retinal layers/layer aggregates reported in the literature Considering AD-induced changes to individual layer/layer aggregate thickness, Chidlow et al. (2017) investigated changes in IPL, INL, OPL, and ONL thickness in the APP/PS1 mouse model of AD at 9–10 (N = 25) and 11–12 months of age (N = 10) using immunohistochemistry. However, unlike what we observed using retinal thicknesses based on OCT imaging of the ocular fundus, the authors did not find significant differences (Chidlow et al., 2017) The apparent contradictions with our results may be due to the different mouse model of AD used in the two studies The APP/PS1 mouse model is a double transgenic mouse model with genes expressing mutant amyloid precursor protein and presenilin 1 we resorted to the triple transgenic mouse model in addition to the mutant genes mentioned above also expresses the mutant microtubule-associated protein tau The different methods used to quantify retinal thickness may also help justify the differences observed Similar to our findings, Chiquita et al. (2019a) found significantly lower thicknesses in the GCL-IPL and ILS-OLS aggregates of male 3×Tg-AD mice 4 and 16 months of age when compared to age-matched WT mice This study provides a comprehensive normative database of retinal thickness in WT C57BL6/129S mice using OCT imaging Our results demonstrate that retinal thickness is influenced by both age and imaging position relative to the optic disc we report thickness changes in eight different layers/layer aggregates 3×Tg-AD transgenic mice had lower overall retinal thickness and in multiple layers Our findings are consistent with previous reports in the literature for animals up to 4 months of age and provide valuable information for future studies on retinal changes in animal models of neurodegenerative diseases such as AD and 16 months of age can serve as a reference for evaluating the effects of disease progression over extended periods of time The animal study was reviewed and approved by Animal Welfare Committee of Coimbra Institute for Clinical and Biomedical Research and PS contributed to the conceptualization and study design RB and PS contributed to the project administration AB and PS contributed to statistical analysis and RB performed the analysis and interpretation of data and RB completed an initial review and provided significant edits and additional content before review and approval by the other authors The authors would like to acknowledge the support by the Portuguese Foundation for Science and Technology (FCT) through PTDC/EMD-EMD/28039/2017 FCT/UIDB/4950/Base/2020 and FCT/UIDP/4950/Programatico/2020 and by FEDER-COMPETE through POCI-01-0145-FEDER-028039 The authors acknowledge the contribution of Hugo Ferreira to the segmentation of OCT volumes The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnagi.2023.1161847/full#supplementary-material Spectral-domain optical coherence tomography of the rodent eye: highlighting layers of the outer retina using signal averaging and comparison with histology Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice Neural mechanisms of ageing and cognitive decline PubMed Abstract | CrossRef Full Text | Google Scholar Investigations into retinal pathology in the early stages of a mouse model of Alzheimer's disease Retinal thinning of inner sub-layers is associated with cortical atrophy in a mouse model of Alzheimer's disease: a longitudinal multimodal in vivo study A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss The role of optical coherence tomography in Alzheimer's disease CrossRef Full Text | Google Scholar Optical coherence tomography in Alzheimer's disease and other neurodegenerative diseases PubMed Abstract | CrossRef Full Text | Google Scholar Age-related retinal changes in wild-type C57BL/6J mice between 2 and 32 months 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Evaluation of retinal nerve fiber layer and ganglion cell layer thickness in Alzheimer's disease using spectral-domain optical coherence tomography Animal models of aging research: implications for human aging and age-related diseases Retinal texture biomarkers may help to discriminate between Alzheimer's Triple-transgenic model of Alzheimer's disease with plaques and tangles CrossRef Full Text | Google Scholar Impact of aging on hippocampal function: plasticity Salobrar-García Retinal thickness changes over time in a murine AD model APPNL-F/NL-F Sánchez Usefulness of peripapillary nerve fiber layer thickness assessed by optical coherence tomography as a biomarker for Alzheimer's disease Multimodal coherent imaging of retinal biomarkers of Alzheimer's disease in a mouse model Characterization of the 3xTg-AD mouse model of Alzheimer's disease: part 2 Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease In vivo retinal imaging by optical coherence 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Ana Batista, YW5hLmJhdGlzdGFAdWMucHQ=; Rui Bernardes, cm1iZXJuYXJkZXNAZm1lZC51Yy5wdA== Your Ads Privacy ChoicesIMDb and a 35-year age gap — Lady Betty Grafstein and Jose Castelo Branco are living the millionaire lifestyle With Betty previously having been married to Albert Grafstein, of the Grafstein Diamond Corporation, and José having been previously married as well, the two have blended their family. Now situated in the swanky Upper East Side of Manhattan, the spark between the two clearly hasn't dimmed after 27 years of marriage. Surrounded by finery, from leopard skin rugs to commissioned artwork, each with a unique backstory, the couple exclusively sat down with The U.S. Sun in their luxury apartment - to recount their love story. Betty, 95, had her royal title from birth, under the wing of the Windsors. Escaping the horrors of World War II and coming to the United States at age 18, Betty learned that she was adopted by the Lady in Waiting. "I only found out when I came to America in 1947, when I went to get my birth certificate and it said on there that I was adopted, National Adoption Society," she said. "I didn't want anybody to know because my mother and father were so fantastic to me and I loved them so much, so I never did want to change [my name]," Betty said. "I never, ever to this day worried about it ever." The pair are so recognizable for their opulent look, they cannot walk the streets without fans stopping them for a photograph. "I love people as well," Betty chimed in Betty's high profile has led to people speculating her personal life Many websites circulating the internet cite a billionaire status for the diamond heiress "They always exaggerate everything," she said of the rumors keeping tight-lipped about the actual size of her fortune the synchronicity between the two is a testament to their love formally met at a dinner hosted by artist and mutual friend José and Betty found themselves the only ones seated at the table and we started to have a lot of chemistry right away," he said Betty invited José to the 50th anniversary of the United Nations for lunch, which nearly didn't happen due to overbooked hotels in New York City The situation was mitigated when Betty made a quick call to a friend — the Sultan of Brunei — who owned a hotel in the city and found a room for José "That was the beginning of the end," he said After visiting one another between Portugal and the United States the lovebirds realized their profound connection Betty told me: 'We can't be separate anymore,'" José added The age gap between the two was not revealed until they tied the knot in 1996 let's be married.' And we got married," José said "And I just discovered [Betty's] age on the day of the wedding I didn't remember I didn't tell him and he said he was in shock when he found out," Betty said Betty and José both appear decades younger than their age Both José and Betty said they don't go to the gym but Betty often does physiotherapy to stay in her best shape "I'm pretty faithful to it," she added "I know all the exercises I have under my chair all the rubber bands and the weights." José said the pair focus on beauty from the inside out, using skincare, vitamins, and health foods from Portuguese wellness brand Prozis on a daily basis "Betty is a very young spirit," José added "She was 87 the first time she told her age publicly "We were walking in Park Avenue and there were men doing construction and she had difficulty walking "There was an open space for her to pass and the men said: ‘How old are you?’ — it was rude — and she told them: ‘I'm 87.’ I said: ‘Why did you tell them your age?’ Because I was hiding our age and I was calling myself older to not look so crazy," he added they look at their love story with optimism "One of the things I pray for the most is to have Betty for more years," José said the lovebirds are even mistaken for mother and son with José recounting when strangers asked if Betty was his mom "They asked: 'Is that your mom?' I said: 'Yes,'" José added we walk along the street and people stop us who say: ‘Do you mind if we photograph you?’" Betty chimed in "Because you get annoyed when people stop because it means you look so terrible,” she added Betty was previously in another age gap marriage with her late ex-husband who by contrast was nearly 20 years her senior "I was married 38 years," she said The age difference sometimes comes with issues ranging from misunderstandings to flat out cruelty from strangers accusing of José of mistreating Betty "They say: 'I'm living on her money I can't wait for her to die.' I get the most and real bullying," José said "Oh [it's] terrible," Betty added regarding the cruel comments "It makes me feel really furious," José said of haters who say he is using Betty for nefarious purposes a descendant of European aristocracy from Mozambique said he takes the criticism from strangers in stride “I don't mind if someone is bullying me for my sexuality "Someone told me: ‘I must address you as a she.’ I told him: ‘As you prefer.’ For me And that is my inspiration," he added the two have the life experience that many may never see in several lifetimes "I was given an Egyptian head by John Harjes for breakfast one day," Betty said "I still have the papers on it and the pictures of it "People wanted to buy it and I said: 'No "And then I gave it to the Brooklyn Museum," she added Betty noted a memorable fruit of her generous donation — a child marveling at the artifact "I went to the Brooklyn Museum and I see a little boy with his class The children were standing there with a whole class of children and he was drawing my head in the case," she said "I thought it was because I donated it anonymously to see that little child standing there drawing this Egyptian head," she added Unlike past representations of boozy Y2K-era socialites You could never point a finger at me anywhere and say a thing regarding a scandal And I was always proud of that," Betty said their passion and servitude for one another has not dimmed "I'm still happy to have Betty every day next to me "I wake up in the middle of the night [for Betty] to go to the bathroom "He wakes up and says: 'Where are you Do you need my help?'" Betty said "And she always needs my help," José said where their kingsize bed is surrounded by old photographs of family and fond memories "Tatiana survived for a very short time Then I met my first wife and I discovered my sexuality," he said Truly ahead of his time in terms of social commentary José naturally made his mark in haute couture and fine arts — passions they both share in more ways than one I'm wearing Betty's clothes," José said "Betty let me be myself," he added looked on smiling as her husband recounted their love story "The love is so big between the two of us "The most important three people I have in my life are Betty Across the world some 2.5 million people live with multiple sclerosis – MS The disease causes the body’s white blood cells to attack the myelin that sheaths the nerve cell axons in the brain Myelin is a lipid-rich substance that insulates the nerve fibers very much like the insulation surrounding electrical wiring The insulation enables the electric nerve signals to travel at a faster speed causing the symptoms suffered by MS patients The cells that synthesize myelin – oligodendrocytes- can be replenished periodically by their precursor cells Oligodendrocytes are not any longer regenerated as effectively and their precursors might also disappear in some lesions,” says Gonçalo Castelo Branco The researchers want to find out why this is happening The answer may lie in recently discovered interplay between oligodendroglia and immune cells Oligodendroglia are one of the commonest cell types in the brain and spinal cord In 2016 Castelo Branco’s research team published a study revealing a greater diversity of oligodendroglia than had previously been realized Two years later they were able to show that some oligodendroglia had the ability to change upon interaction with immune cells Genes that were activated in the immune cells were also switched on by those cells.” The change gave them the ability to acquire some of the properties of immune cells they could clear away damaged myelin and also communicate with the immune cells The researchers hope that the new project will give them a better understanding of why this happens and what the implications are for the disease Clues include a molecule that immune cells secrete that has been found to impact oligodendroglia which has also demonstrated that the secretion compromises the ability to synthesize myelin “But we don’t know for sure whether altered functions of the “immune” oligodendroglia increase the pace at which the disease progresses The researchers have several opposing theories: either the cells attempt to mimic immune system cells to get them to cease their attack or they join in the attack rendering the disease more aggressive as they do so “The discovery that oligodendroglia mimic immune cells opened up a new field We’re now examining this issue in collaboration with another research team Together we will be able to improve our understanding,” comments Castelo Branco which is being supported by Knut and Alice Wallenberg Foundation also involves Tomas Olsson’s research team whose expertise lies in clinical and experimental neuroimmunology One of the most important tools used by the researchers is single-cell sequencing The technique enables them to analyze the RNA of individual cells to see which genes are active in the cell One of those first developing this technology is Sten Linnarsson and a collaborator of the Castelo Branco’s team “The technologies needed to carry out this research have only recently become available They provide us with large quantities of information So the team needs to have members with expertise in bioinformatics.” Another challenge is the difficulty of performing studies on human subjects So far the research team has concentrated on mouse models Some experiments have also been performed on archived tissue from deceased MS sufferers “If we are to understand the mechanisms involved but we must constantly bear in mind that there are differences Performing studies of this kind on living human subjects is virtually impossible Over the past few decades scientists have learnt a lot more about how the brain works One example of this is how neurodegenerative diseases such as Parkinson’s Alzheimer’s and MS impact not only one but various distinct cell types “In recent years several articles have been published on the part played by oligodendroglia in Parkinson’s and Alzheimer’s but they seem to be more important than was previously believed that may be more involved than we thought.” New knowledge may lead to new therapies for MS but the future may see therapies that target oligodendroglia “Our long-term goal is for our findings to help in the development of better drugs that are capable of slowing or even halting the progress of multiple sclerosis but a highly stimulating one,” says Castelo Branco New methods to map the progression of MS [email protected]