Trinity Episcopal Cathedral100 W Roosevelt St venue website View on Google Maps They head into their second decade of the Peel Memorial Organ concert with Adam Brakel James Cathedral and the Diocese of Orlando National Public Radio hailed him as "an absolute organ prodigy with the technique and virtuosity that most concert pianists could only dream of...he is the Franz Liszt of the organ." Mr and Meyerbeer on the cathedral's IV/71 Schantz organ event website Sign Up For Emails Emailinfo@dtphx.org and contribute to the growth and vitality of our community more inclusive city core that generates positive perceptions © 2025 Downtown Phoenix Accessibility Kiralyn Brakel ’15 has joined the biology department as an assistant professor of Biology and will direct the cadaver labs in Anatomy and Physiology classes this fall Brakel has worked at Hillsdale for the past four years as a lab technician “My husband and I decided to move closer to our family,” Brakel said for somebody who could do a lot of work with the technical side of the lab a position as a lab manager at Hillsdale opened up.”  Brakel graduated with a degree in biology from Hillsdale in 2015 and earned her Ph.D in neuroscience from Texas A&M University in 2020 I didn’t know what I wanted to do and I was afraid of the future,” Brakel said “And then I figured out that what I loved about my Ph.D program was a lot of the technical troubleshooting that I had to do Chair of Biology David Houghton said Brakel’s previous work at the college made her a good candidate for the role Brakel has been in the biology department for several years working as our core lab manager so we already know that she’s a hard worker and a very good mentor to our students,” he said which involves the courses Anatomy and Physiology I and II and overseeing the cadaver lab Houghton said Brakel will provide students with an excellent resource in these fields “She has specific expertise in neuroscience and histology the latter of which is a rare and unique subdiscipline of anatomy that isn’t found at most institutions,” he said “So our students have the opportunity to learn valuable skills from Brakel that aren’t even available at most other schools.”  Among these skills is Brakel’s experience in cadaver dissections “It’s been cool being able to have that opportunity and help the students develop both their anatomy skills and this perspective about what it means to work with a human being who has donated their body has been a really valuable experience for everybody,” Brakel said said she has worked with Brakel since her freshman year but she patiently taught me everything from the ground up,” Suganuma said Brakel has been an influential and supportive figure in her college career she even came to Jackson to visit me,” she said “She always makes time for me when I need to talk and never dismisses my questions Houghton said it is lucky that Brakel will join the biology department as it is hard to find qualified individuals at schools as small as Hillsdale “Most people who are qualified to teach cadaver-based Anatomy and Physiology are probably already teaching at a medical school somewhere,” Houghton said “We are very fortunate to have found someone who not only has the technical skills and training to teach Anatomy and Physiology but who also understands liberal arts education and the mission of the college.” Courtesy | Avedis Maljanian My family’s phones screamed with alerts at about 6:30 p.m... When I nannied for millennial parents who raised their kids with the “gentle parenting” philosophy After 40 hours of work and two tons of ice blocks four men from Simpson Residence constructed an igloo outside.. Home / Features / Meet The Scientist podcast: An interview with Dr In the latest episode of Meet the Scientist to discuss her work at IAVI in support of our TB vaccine program we explore IAVI’s diverse engagement in the development of the MTBVAC TB vaccine candidate and learn about how Elana and IAVI’s TB team are preparing for the Phase 2b clinical trial of MTBVAC in adolescents and adults in sub-Saharan Africa Tune in to learn more about Elana’s work and IAVI’s TB vaccine program See below for a full transcription of the podcast Hello and welcome to the latest episode of IAVI’s Meet Scientist podcast series a communications and advocacy specialist at IAVI’s Europe hub in Amsterdam and I am pleased to be here today to speak with Elana Van Brakel to discuss her work at IAVI in support of our TB vaccine portfolio TB vaccine research and development is a core pillar of IAVI’s portfolio with TB remaining the deadliest infectious disease and much of the world Now to meet the World Health Organization’s End TB targets by 2030 we urgently need multiple new TB vaccines that are equitably and affordably accessible around the world We find ourselves in a historic moment in TB vaccine development this year following last year’s United Nations High-Level Meeting on TB which included commitments to develop and roll out new TB vaccines this decade The enthusiasm and anticipation in the field is palpable with a growing and advancing TB vaccine pipeline and a number of exciting initiatives and events in 2024 including the WHO TB Vaccine Accelerator Council as well as the 7th Global Forum on TB vaccines which will take place in Rio de Janeiro in Brazil in October and is co-organised by the Stop TB Partnership Working Group on New TB Vaccines this is truly a momentous year for TB vaccine development we’re proud to be contributing to this effort it’s a pleasure to speak with you today about IAVI’s work in this space and about the role of you and your team in particular I was wondering if you could tell us a little about the focus of your work and role here at IAVI It really is a privilege to be here to talk to you about TB in this exciting time that we’re in And so I’ve just started my third year at IAVI feels like I’ve been part of the IAVI family for a very long time My role is that of medical director in the clinical development team I’m specifically working on TB projects and what this role involves is basically being the medical lead for a cross-departmental team that is responsible for the design the analysis and the eventual reporting of candidate vaccines for TB And it also involves design of clinical development plans and eventually also preparing for vaccine access and delivery So there my role is that of oversight of the conduct of the trial and specifically focused on the safety data I’m part of a cross-departmental team We have amazing colleagues and also collaborators from across the world that help us do this it’s clear that you and your team are engaged in the full breadth of our TB vaccine development and the planning and preparations for our clinical trials I was wondering if you could just tell us a bit more broadly how IAVI is engaged in the TB vaccine development space so at IAVI we collaborate with partners from around the world and our aim is to develop safe and effective and accessible TB vaccines And together we work across the global hubs with a diverse network of partners to advance the most promising TB vaccine candidates from discovery through clinical trials to post-licensure access And we also lead policy and advocacy initiatives engaging with international partners to support TB vaccine development and access We’re currently partnering with the Spanish biopharmaceutical company Biofabri in the advanced development of the MTBVAC vaccine candidate to see if it prevents TB disease in infants and adolescents and adults And we’re also partnering with Moderna to assess a series of mRNA candidates So that is basically a measure of the ability and the strength and the type of immune response that a specific vaccine can elicit constructs can be protective in preclinical studies So this is still very early on in the development but we’ll watch this space to see what happens but also some really promising late stage development going on And you mentioned here the MTBVAC vaccine candidate one of the more advanced TB vaccine candidates But what is unique about MTBVAC as a TB vaccine I’m very excited to talk to you about MTBVAC This really is a very promising vaccine candidate for TB It was designed by Professor Carlos Martín at the University of Zaragoza and basically this is the only live attenuated TB vaccine candidate that was derived from an actual mycobacterium tuberculosis sample So from a human sample and not like not from bovine TB as is the case for the other live attenuated vaccine that we know So basically what happened was they took this Mtb and deleted some of the genes in the original organism that really makes Mtb a very infective organism harmless form of the pathogen that can still elicit an immune response in humans So it still contains the full range of antigenic targets of the original pathogen So that means that it has the full range of targets on the pathogen that may be involved in generating an immune response against TB And the MTBVAC development plan has been running over a number of years I think about at least 25 years since MTBVAC has been tested in a range of preclinical animal models studies And all of these demonstrated that compared to BCG MTBVAC is really as safe as BCG and even more immunogenic and protective we’ve had four clinical trials completed successfully and these have been conducted in infants and adults that was the very first time the vaccine was given to humans occurred in Switzerland And all these trials have been conducted by leveraging the expertise of a global network of partners So these earlier stage trials have really helped us to define the dose of MTBVAC to be used in adults and in infants and all these trials have also demonstrated really a favorable immunogenicity and safety profile so wonderful to hear about the exciting history of the development for MTBVAC over what is now And great to see that it’s finally in late stage development but as a candidate you know how may MTBVAC help control the TB pandemic if it is found to be effective in these late stage clinical trials Thank you for sharing all of these details about MTBVAC It’s clear the amount of work going into developing this candidate to make sure that it will be affordably accessible if it is shown to be effective I think the excitement is clearly quite apparent in your own household as well So looking at IAVI’s involvement more specifically could you tell us a little bit about how IAVI is advancing the development of the MTBVAC candidate So IAVI is more directly involved with the adult and adolescent development program for MTBVAC IAVI sponsored an earlier phase 1b/2 clinical trial that was conducted in adults and that took place at the South African TB Vaccines Initiative here in South Africa And a publication on the results of this trial is expected later this year But what this trial did result in is a dose that was selected for later phased trials and it also showed that it was compared to BCG in this trial and it did show that MTBVAC was at least as safe as BCG which is quite a comfort when you have to think about developing this vaccine further we are currently preparing for a phase 2b clinical trial and this is anticipated to start later this year [2024] And we will investigate whether MTBVAC can prevent disease in adolescents and adults So essentially this is a what we call a proof of concept study So this is the first time that we’re going to look at the effectiveness or the efficacy of MTBVAC to be able to prevent TB disease So we aim to enrol over 4000 people who have latent TB infection means that these are people who have been infected with TB And so you can be infected with Mtb but not be sick or actually have TB disease So we aim to enroll these people with latent TB infection and all of them will be living in South Africa and several other countries in East Africa And these are all areas where there is a high TB burden We’re not enrolling people living with HIV in this trial We need to first determine whether the vaccine is safe in people living with HIV a trial is actually currently running here in South Africa that is specifically looking at the safety and immunogenicity of MTBVAC in people living with HIV And this is being run by the HIV Vaccine Trials Network we are enrolling HIV negative participants with latent TB infection in high TB burden countries and participants will receive a single dose of MTBVAC or a placebo which is essentially a saltwater injection And they will then be observed for the occurrence of TB disease over 2 to 3 years So quite a lengthy trial and requires quite quite some expertise that I’ll tell you a little bit about later there’s so much work going on in this space you mentioned the HVTN trial here in people living with HIV the earlier work that IAVI has been involved in leading up to this really critically important phase 2b trial to test the efficacy of MTBVAC in preventing TB disease in adolescents and adults And before we discuss a little bit further about the work that you and the team in South Africa are doing for MTBVAC development at IAVI you’ve mentioned how one of the key indications of MTBVAC is to prevent TB disease in adolescents and adults But why is a TB vaccine for adolescents and adults so important BCG offers important but incomplete protection against the most severe forms of TB such as TB meningitis in infants and young children it is almost ineffective in adolescents and adults And adults and adolescents are really the ones most at risk of developing and also spreading TB almost 90% of TB cases occur among adolescents and adults we urgently need multiple new TB vaccines that work across all age groups but particularly among adults and adolescents and that are available in all geographies if we are to meet the WHO 2030 End TB targets and to eliminate TB it’s critically important that we have vaccines that work among adolescents and adults to finally end TB to contribute to this shared mission to end TB as a global health threat going back to you and your team in Cape Town and elsewhere in South Africa could you tell the listeners a little bit about how you and your team are contributing specifically to the late-stage development of MTBVAC What we’ve done so far since we’ve received the funding for this project we’ve developed the clinical trial protocols the design and the actual plan on how we’re going to conduct this trial We initiated and conducted quite a lengthy process for selecting clinical research centers to partner with it’s a combination of our clinical operations team which is mostly based here in South Africa and in Cape Town and also working closely with our epidemiology team it really is a team effort and it’s not just us here in Cape Town We really are reliant on contributions from our regulatory people So just in terms of selecting the or the Clinical Research Centers really need to make may make sure that we bring on board centers that have experience in these types of trials or in TB trials in general that are strong operationally and that are also situated in areas of high TB incidence So that is why working with our epidemiology team has been crucial in selecting these centers And a very important part of our planning for any trial is community engagement And at IAVI we really feel very passionate about engaging the communities where we want to do our trials and really partnering with communities partly to inform them about clinical trials in general informing them about the specific trial protocol and that we want to implement getting their feedback and then just generally training them on clinical trials and making sure that they come on board they can share our vision and they can then translate to other members in their community So that is really an important part of the success of any trial Elana for such a thorough overview of how you and the team and the global team as well are engaged in this effort it’s really the collaboration between a group of individuals bringing all of their experience and expertise to the table to ensure the successful conduct of a late-stage clinical trial IAVI’s first late-stage clinical trials once it gets up and running you bring a lot of experience from the field to IAVI as well And for the final part of the episode today could you tell us a little bit about your own career working in TB clinical trials to date and what has this work involved and how is this now informing your work at IAVI I’ve completed my master’s of science in Medicine because I wanted to explore this field of clinical research I was fortunate to be employed by a clinical research center here in Cape Town called TASK TASK is very well known and a respected research center in the field of TB drug trials over many years And that is also where I learned about TB and TB clinical research and TB clinical trials and that has really laid a strong foundation for the work that I’m doing now because working as an investigator on the ground really is proving to be very helpful knowledge to have now where we are planning to conduct a trial it’s also useful when engaging with the staff at the clinical research centers because I’ve been there I was also very fortunate to be an investigator on the actually the very first TB vaccine trial that TASK conducted That was the other vaccine candidate that is now entering a late-stage efficacy trial and was actually the first vaccine for TB that showed 50% efficacy I learned basically what I know about TB vaccine trials I learned there and it was such a rewarding experience to be part of that and to eventually see when we got the results and they were positive to really be part of that And I was also fortunate to be part of the co-writing team that developed the publications that were published in the New England Journal of Medicine So those two pivotal publications about that And that was an amazing honor and a learning experience for me personally I’m sort of at the other end of the spectrum approaching this from a sponsor perspective but definitely my experience as a clinical trial investigator is really proving to be very helpful in my role what would work practically at a site level and at a trial level I’m very happy that I had this journey through task and I’m very happy to be at IAVI where I am now as we’ve reached the end of today’s interview and thank you Elana for joining me today and sharing your insights and reflections on your work here at IAVI and earlier in your career and especially on the promising MTBVAC candidate would you be able to share with us today one thing that you would like the listeners to remember or walk away with from this interview just to have an appreciation for the complexity of Mtb as a pathogen or an organism and how much we still have to learn and understand about the organism And then just the complexity of designing these trials and then also when it gets to the implementation stage really making sure we partner with the right people I think we’ve already seen earlier in our chat 25 years of clinical pre-clinical development and then starting in 2013 with the first in human trial for MTBVAC you know just I think an appreciation for this very long journey that we have to go on to get to an eventual new TB vaccine or at least to a promising TB vaccine candidate So that and then on the other side of that it’s such an exciting time for the field of TB vaccine development And for the first time it feels like we’re moving forward since we’ve had BCG for over 100 years and in all this time we haven’t been able to get another TB vaccine we’re now for the first time close due to hopefully having these effective TB vaccines and to have two candidates… You know I think it’s such a promising vaccine candidate So I think just to get that from this podcast is that excitement and the promise that is as is here at the moment And you know that what lies ahead might be really groundbreaking change for the field of TB I would love people do to take away from this conversation for joining us today and for sharing those really motivating words to end on it’s such an exciting moment for TB vaccine development work alongside yourself and the rest of the team on this effort And I think I speak for all of us in the fact that we’re really looking forward to what’s to come throughout this phase 2b trial and the years ahead for what we hope will be a groundbreaking new tool for trying to address the TB pandemic So thanks again for your time and we’ll continue to share updates and news on IAVI’s involvement in MTBVAC development as the program continues to evolve The state of vaccine science now is far more powerful and sophisticated than it has ever been And I am confident that many of these challenges that we face will be solved by vaccine development We are a nonprofit scientific research organization that develops vaccines and antibodies for HIV Careers HIV Vaccines HIV Antibodies Tuberculosis Emerging Infectious Diseases NY 10004T: +1.212.847.1111F: +1.212.847.1112 ©2025 International AIDS Vaccine Initiative and the IAVI logo® are registered trademarks of the International AIDS Vaccine Initiative Use this form to receive updates on IAVI‘s work and the latest news from the field Royal Poinciana Chapel to celebrate Bach with service performance organ recital SundayPalm Beach Daily NewsWhen Adam Brakel was a young musician in Pittsburgh he worked at a church that had a 1962 Von Beckerath organ an instrument that highlighted the works of Johann Sebastian Bach “In my teenage years I really became obsessed with his music,” said Brakel director of music and organist for Royal Poinciana Chapel Brakel has won international acclaim playing works by many classical music greats But he remains dedicated to Bach and on Sunday will lead two musical events at the chapel in honor of the 275th anniversary of the composer’s death the Chapel Chorale and Chamber Orchestra will perform Bach’s Cantata 106 His time is ever best.” One of Bach’s early works the piece was written for Lent and highlights eternal life Brakel will perform an all-Bach organ recital featuring six distinct works and the various compositional styles he used “The program that I’m playing is actually the recital program that Felix Mendelsohn played to revitalize the music of Bach,” Brakel said “Bach wasn’t as popular when he was alive.” Bach has become a major influence for countless artists around the world Musicians often have used Bach's compositional techniques harmonic progression and structures in their compositions and improvisations Many listeners may be unaware of the composer’s presence in those forms “I think everybody’s been in some ways inspired by Bach and has utilized some essence of his music,” Brakel said Bach’s music is timeless because of his genius who calls the composer’s “Mass in B Minor” a textbook of musical knowledge and musical history So much was done in Leipzig where he spent that last 21 years of his life He was director of the city and doing a lot of violin work Playing the complete works of Bach for organ would take about 21 hours “It’s my first recital since I started as musical director in October and I can think of no better way to do it than with Bach,” Brakel said Royal Poinciana Chapel is located at 60 Cocoanut Row It is with heavy hearts that we announce the passing of Valerie Brakel on January 25 and friend who brought warmth and laughter to all who knew her She is survived by her husband of 32 years She was predeceased by her beloved parents She cherished summers spent at the trailer in Seven Sisters where she found peace and happiness among family and friends Valerie also had a deep passion for hockey spending some of her most cherished years working for the Winnipeg Jets—though she remained a dedicated Toronto Maple Leafs fan and unwavering love for her family will be deeply missed but never forgotten A celebration of Valerie’s life will be held at a later date the family asks that you honour her memory by spending time with loved ones or enjoying a peaceful summer evening by the lake I’ve played hockey with Rick for years Always heart breaking to hear the loss of someone We are so very sorry for you Rick and your family’s loss Rick and family so sad to hear of Valerie’s passing Please know your in my thoughts and prayers It’s hard to find the right words to say at such a difficult time but please know that our hearts and thoughts are with you Val’s warmth and love will continue to live on through your memories and your love for each other May the comfort of her memories help you find the strength to get through this Δdocument.getElementById( "ak_js_1" ).setAttribute( "value" This site uses Akismet to reduce spam. 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Email UsMap & Directions Email UsMap & Directions Email UsMap & Directions Email UsMap & Directions Email UsMap & Directions Made with ❤ by Ashlean Sep 10, 2024 | Entertainment | 0 comments Brakel will kick off the Musical Arts Series’ new season with an Oct 13 performance at Immaculate Conception Church the Musical Arts Series (MAS) has been bringing the beauty of music to Port Clinton kicks off the 2024-2025 series with a concert by famed concert organist Adam J “He’s one of the top organists in the country We’re very excited to have him,” said MAS Coordinating Committee President Peggy Debien The MAS season will feature seven concerts: Thanks to Paul Moon and other MAS members who seek out talent the MAS season offers an exceptional variety of musicians who merge their own skills and influences into classical pieces creating unique performances for their audiences The Westbound Situation Quartet describe their music as chamber grass “They take classical music and interpret it their own way with a folk twist,” Debien said Burning River Brass features musicians from around the country Their Christmas concert will feature holiday The concert is held in honor of the late Earl a popular Port Clinton High School band director Mark Kosower is the principal cellist for the Cleveland Orchestra We’re lucky to have him back,” Debien said who serves as the talented organist for St the Cleveland Institute of Music chooses its top nine students for The Trio of Trios concert “This is always their first professional performance and the audience is so appreciative,” Debien said “They excite people because they’re so young and so talented.” The Verona Quartet is the Oberlin Conservatory’s Quartet-in-Residence This will be their first performance for MAS The Cleveland Burning River Brass performance is free Pick 6 tickets can be used to admit one person to each of the six performances “The reason the tickets are so inexpensive is because of our sponsors and donors We have a lot of patrons and donors who help because they love music.” Among MAS’s generous sponsors are the Harry Stensen Memorial Trust Foundation and former Lakesider the organization hosts concerts at area nursing homes which are funded by the Ottawa County Community Foundation which brings a taste of the opera to area schools Tickets can be purchased at the door or ordered online at www.musicalartsportclinton.com Apr 29, 2025 | Featured, Entertainment BY SHERI TRUSTY OTTAWA COUNTY - Two years ago local organizations collaborated to create Ottawa County Community Day Apr 29, 2025 | Entertainment Have your events listed in our Calendar through Paid Advertising or https://info.thebeacon.net/eandesubmission THURSDAY MAY 1 74th Annual National.. PORT CLINTON - Advance ride tickets for the 2025 David W Leonard Fraternal Order of Eagles #2295 Walleye Festival are now available Lake Erie Marine Forecast ODNR Fishing Reports Powered by Webify ​CategoriesCategoriesEnglishPOLITICS, ELECTIONSElections 2024: Outgoing prime minister to become mayor of East Flemish municipality22 October 2024 Outgoing prime minister Alexander De Croo will become the new mayor of his hometown of Brakel in East Flanders Open VLD had secured 43.2 per cent of the votes in Brakel “I received the right of initiative and respected to the maximum the voters’ choice to form a coalition with the second-largest party which gained 6 seats,” De Croo wrote on Facebook the parties have a comfortable majority of 19 out of 25 seats “I’m very much looking forward to working with our strong team to make a difference for all Brakelaars in the coming years,” added De Croo “Our team combines experience with fresh ideas The agreement we have reached really puts our residents at the centre Together we will build a Brakel that is ready for the future #FlandersNewsService | Prime minister Alexander De Croo sits underneath a television screen showing electoral news at cafe 't Bierpotje after he went voting earlier in Brakel 09 June 2024 © BELGA PHOTO NICOLAS MAETERLINCK Copy linkGet updates in your mailboxYour email addressSubscribeBy clicking "Subscribe" I confirm I have read and agree to the Privacy Policy rapid and high-quality information 24 hours a day from Belgium and abroad to all Belgian media not to mention entertainment and lifestyle our journalists and press photographers produce hundreds of photos and news stories Since the end of March 2022 English has been added as a language businesses and various organisations that need reliable information Belga News Agency also offers a comprehensive range of corporate services to meet all their communication needs www.belganewsagency.eu PDF of paper Canada urgently needs a new trade policy and a strategy to work with President Donald Trump This is the worst possible time for Canada to be adrift suffering as it is from a complete absence of federal leadership As Trump ratchets up his tariff threats (first 10 percent executive orders for an America First Trade Policy Prime Minister Justin Trudeau has already resigned and is awaiting his replacement while Canada’s Parliament is closed down until March 24 so the Prime Minister is not able to confront a tariff crisis with significant new spending deliver speeches (lamenting Kamala Harris’s loss and declaring himself a “feminist” (Tasker 2024) His government will be fortunate to last more than a few weeks after the reopening of Parliament: his party trails the Conservatives by 25 percent there are at least two confidence votes imminent and the opposition parties are all promising to bring down the government at the earliest opportunity The crisis can only get worse in the months ahead with a rudderless Canada unable to respond and a trade-focused U.S The most likely scenario is that when a new government takes office in May it will have to move swiftly to develop a new trade policy and a strategy to work productively with Trump Canada currently has a tremendous opportunity to overhaul its trade policy improve economic and border security (things it should be doing anyway) Canada could benefit from a closer economic union with the world’s most dynamic advanced economy – a tighter relationship that could yield improved trade and investment the economic consequences could be devastating imposing 25 percent tariffs on Canada will be a loss of $275 billion in Canada’s real GDP from 2025 to 2030 with 222,000 fewer jobs on average over the period (Deloitte 2024) A 21st century Canadian trade policy must be based around three principles: secure “Fortress North America.” Canada and the U.S should move from a trade agreement to a broader and closer economic union (the free movement of goods people) that includes mutual regulatory recognition as well as reciprocal treatment of tax incentives and procurement It should also include a security and military co-operation agreement recognizing that economic security and the overall relationship is vastly more important than trade grievances has always prioritized security above trade and every G-7 statement reinforces that economic security is now a paramount global concern Make Canada the best place in the world in which to invest and build a business This will require dramatically reduced taxes and the development of an industrial policy for strategic industries Industrial policy should not be seen as a bunch of subsidies for favored industries Canada’s industrial policy should include a major overhaul of its patchwork of regulations and tax policies that are now making it hard to do business there: Canada must lower taxes and lower energy costs make real investments in the supply chain and infrastructure The Trump administration will cut taxes and regulation drastically so Canada must move aggressively to avoid being left at worsening competitive disadvantage The global trade system cannot function with countries that flout global trade rules and abuse the system – China’s trade surplus reached a record high of $1 trillion in 2024 and the growing imbalances are stressing manufacturers in countries around the world It’s time to forge alliances to crack down on China or see the collapse of the global system as other countries retreat into protectionism This report contains specific policies and recommendations to achieve these objectives The final issue is how to package all of this in the immediate term so that no president would want to impose tariffs on a critical ally like Canada Canada must offer these policies from a position of strength via a credible government that will deliver on its promises (no more vague assurances that have no follow-through) and they must include real tangible benefits that are a win-win for Canada and the United States Here the biggest challenge is Canada’s federal leadership A lame duck prime minister and a paralyzed Parliament is a recipe for disaster Only a new Canadian prime minister with a new mandate can completely change the narrative and perceptions of Canada in Washington but it requires bold new policies and a change at the top Support the Macdonald-Laurier Institute to help ensure that Canada is one of the best governed countries in the world Click below to learn more or become a sponsor Support Us It is with a heavy heart we say goodbye to our beloved husband and grandfather who went home to be with the Lord on July 31 He attended grade school at a rural school near Hurdsfield ND where Marvin grew up working with his dad on the family farm and graduated from Heaton High School as part of the class of 1956 Marvin was involved in basketball and played on one of the schools last teams Marvin married Sharon Grindhiem from Bowdon After they were married the couple moved to Minneapolis MN where Marvin was enrolled in Telegraphy school In  1959 the couple moved to Fessenden ND where Marvin ran the Foremost cream station and drove school bus followed by their daughter Gwen who was born on August 19th where Marvin worked for a short period of time at General Mills before moving to Minot where he worked for Cass Clay and Coca Cola In 1964 they moved back to rural Heaton where Marvin farmed until 2003 Marvin also worked as a crop hail adjuster for RCIS for over 20 years and truly enjoyed his newfound passion continuing to work with farmers establishing many new friends over the course of his career while also mentoring many new adjusters for the company.  Marvin retired from adjusting in 2019 Marvin also served on numerous boards including the school board the local coop board and had a true servant’s heart always willing to help out wherever he could.  and a born-again Christian with a heart for the Lord.  He was everyone’s friend had a generous heart,  and never had a harsh word to say about anyone Marvin went home to be with his Heavenly Father on Saturday July 31st after a 3-year battle with Alzheimer’s surrounded by his loving family in the comfort of his own home He was a hero and Godly example to his children and grandchildren and will be dearly missed Marvin is survived by his devoted wife and love of his life for 63 years Sharon his daughter Gwen and her husband Tim and his granddaughter Mandy Anderson and her husband Nate and his grandson Taylor and his fiancée Ashlee and his sister Jean Fossen Memorial Service:     2:00 PM West Funeral Home & Life Tribute Center Donald Trump’s tariffs on Canadian imports will ultimately fail But they’ll do a lot of economic damage before that happens That’s the conclusion of economist and public policy advisor Hendrik Brakel in a report published last week by the Macdonald-Laurier Institute and the Center for North American Prosperity and Security Titled From Trade Wars to Trade Wins: Securing Canada’s Economic Security in the Trump Era the paper lays out a comprehensive road map to shield Canada’s economy and position it for long-term success Brakel describes Canada as “rudderless” as the Liberal Party chooses a new leader and Parliament has been prorogued until March 24 “The Prime Minister is not able to confront a tariff crisis with significant new spending or added security measures,” the report says deliver speeches (lamenting Kamala Harris’s loss and declaring himself a “feminist”)…The crisis can only get worse in the months ahead with a rudderless Canada unable to respond and a trade-focused US president sensing weakness Tariffs are paid by the importer (despite what Trump says) which means the financial burden will fall on U.S Tariffs will lead to massive inflationary pressure The Bank of Canada confirmed last week that would be the case in this country but the higher costs of imported goods would also be felt in the U.S gas prices could increase by as much as $0.75 a gallon if oil is not exempted Trump’s assumption that businesses can easily repatriate to the U.S It’s not easy to simply pick up a billion-dollar manufacturing facility and plunk it down in the middle of Ohio competitiveness by increasing the cost of inputs Tariffs are a poor source of revenue because of the broader distortion and dampening of markets and productivity they cause But no one knows how long it will take for all these effects to filter through to the U.S economy and for the administration to realize the plan has failed and climb down tariff on Canadian exports could cost the economy $275-billion in GDP by 2030 “Canada’s current approach is inadequate in the face of these challenges,” he writes strategic vision to secure our economic future.” He sets out three policy goals Canada should follow to get through the current situation and prevent a future repetition Fortress North America: Strengthen economic and security ties with the U.S freer movement of goods and services and enhanced military co-operation “These measures would solidify Canada’s place in the North American economic and security architecture,” he says something we’re not seeing from Washington right now Brakel says we need to “make Canada the best place in the world in which to invest and build a business” This would involve dramatically reduced taxes and the development of an industrial policy for strategic industries “Industrial policy should not be seen as a bunch of subsidies for favoured industries,” he writes make real investments in the supply chain and infrastructure and improve competitiveness so Canada must move aggressively to avoid being left at worsening competitive disadvantage” Combat global trade abuses: We must lead efforts to counter unfair trade practices while championing a rules-based global trade system to ensure fair competition for Canadian industries “This is a once-in-a-generation opportunity for Canada to transform its trade policy,” Mr we can secure our economic sovereignty and ensure a prosperous future for all Canadians.” Gordon Pape is editor and publisher of the Internet Wealth Builder and Income Investor newsletters Be smart with your money. 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For more information on our commenting policies and how our community-based moderation works, please read our Community Guidelines and our Terms and Conditions Artificial Intelligence has the potential to upend and rewrite so many industries and aspects of our daily lives VML Intelligence reached out to Marcel van Brakel founder of the interdisciplinary Dutch experience design collective called Polymorf for his expert insight into what this evolving tool means for technology We're a Dutch art collective and design studio and we create immersive experiences and speculative designs of all kinds We like to work with new technologies: sometimes we build our own technology A lot of our work is centered around the human body or the body itself and raises questions about the consciousness of a multi-sensory system We started off as a theatre group reading operas and now we’re into this kind of cross section between our technology So we look work a lot with stable diffusion and mid journey just to make visualizations or prototypes or test that kind of stuff and we're preparing more projects that involve artificial intelligence and that's kind of a spinoff project of Symbiosis in which people experience the world not as a human and we think about how a non human-centric new world will change perspectives and change society we are not the main artist; the audience will be the artist to create these narratives and to create these worlds by making gardens that we're going to plant in real gardens [The project directs a] discussion between the possible future nature and ecosystems and the current nature and ecosystems and the audience will work with AI to create these narratives and 3D models that we can plant in this world we speculate on the future city and ecology We're trying to design an AI for world governance in a sense that is more inclusive and not human centric at all [This AI functions] as something that can negotiate power and politics between humans and non-humans The aim for that project is to create an AI system that is as free of the human bias as possible We previously did a project with Polymorf called Algorithmic Perfumery created together with lead designer Frederik Duerinck a musician who works with algorithms and generative music patterns It was an art piece shown in New York that created perfumes in collaboration with a perfumer from IFF (International Flavors and Fragrances) We created a space where visitors could hear samples of music from Hecker you could push a button and we would have a machine learning system create a perfume based on your musical choice we would create the perfume on the spot [for the visitor to bring home] I cannot imagine a field where it's not applied I think we will use this for world governance there's still a lot of friction [introducing it] It challenges [us to consider] what it means to be human and to be creative: what is creativity and what is intelligence AI is a very powerful tool to take over or optimize our processes but I think AI can still step into fields where there's a lot of uncertainty It's a bit like predicting: what is the impact of the Internet It has a huge implication on almost everything So in a sense that it can be both good and bad we can transform it to help us to solve problems or make processes more efficient and even to make [a stronger] connection to nature or to other people by translating what we don't understand But I think the most interesting thing about AI is that it introduces a fundamentally different consciousness Maybe it's not at the level that it is self-conscious of course most of the AI is a collection of the human thinking but as soon as we step away and can make more neutral AI systems or systems that are trained on different datasets and on different rules I think that's huge: to encounter another consciousness that will see reality in a completely and fundamentally different way that gives us an opening to understand [the world] in a different manner we see each other as the most important measurement of everything and as the most important reference in understanding reality because of our sensory system that gives us access to reality But having a system that is completely Interested in other stuff I'm quite optimistic that it could be a huge beautiful opportunity if we can surrender to the idea that we have to be more humble as a species Before submitting your information, please read our Privacy Policy as it contains detailed information on the processing of your personal data and how we use it Associate Professor Ingar Haaland underlines the importance of earning coding skills before entering the world of business This semester NHH students have been able to take a full course in artificial intelligence (AI) Associate Professor Haaland´aim is to provide a comprehensive overview of how recent developments within AI and large language models (LLMs) ‘Although there is great demand from the business world there are few courses in artificial intelligence (AI) at Norwegian institutions’ This course is the best one I’ve had here at NHH and one of the most interesting courses I’ve ever had in my life’ says German exchange student Konstantin Fuss (24) and adds: Haaland is very enthusiastic and a great lecturer ‘This is something totally new and I’ve never done anything like it’ the master students have developed a research question in groups of three or four which after being shaped and reshaped through coding in Python has been analyzed using OpenAI AOI Platform allowing the students to use Chat GPT at scale.  The results have then been analyzed and presented for the class for input The course finishes with a paper on their findings ‘There are many reasons for holding such AI courses at NHH it is about understanding the possibilities and limitations of various AI tools several of our guest lectures from the business world also show us that AI is the future of business whilde highlighting both opportunities and limitations of todays' models’ The course is called Transforming business with AI: The power of large language models and is credted 7,5 points as a part of the MSc in Economics and Business administration the students will learn how to explain the foundational concepts of AI and LLMs identify applications and implications of AI in business and research Fuss and Wasem have together with Steyn van Brakel (24) from the Netherlands and Anne Hohner (26) from Germany looked at the sentiment in US congressional hearing speeches regarding nuclear energy over a span of more than 40 years ‘Based on our interest and ideas we happened to look at the nuclear energy topic and saw that there was a lot of material to work with’ but we had a lot of help from Chat GPT itself – so AI helped us to use AI ‘I think the biggest challenge for us was that we were all new to Python We had one obstacle with the huge dataset and had to identify it and finetune the course back and forward to get it right The students all agree upon the notion that “there always was a new problem they had to try to fix” during the process especially during the final week before the presentation But if you get a result or if the coding works it’s such a nice feeling It finally works and it feels as if you’ve solved a riddle’ the master students wholeheartedly recommend it to others: Van Brakel also praise the guest lecturers from the business world that visited the class: ‘It was great that top level executives from companies came here and told us how they are currently using and implementing AI-tools in their businesses In that way wo got a great understanding of how you may encounter AI later in our careers’ van Brakel joined RSF Social Finance as its president and CEO in March 2018 He is convinced that innovative approaches are needed to address the significant social and guides RSF as it builds on its success in transforming the way individuals and organizations work with money Canada will face “devastating” economic consequences unless it urgently develops new trade policies and strategy A new paper, From Trade Wars to Trade Wins: Securing Canada’s Economic Security in the Trump Era by leading economist and public policy advisor Hendrik Brakel lays out a comprehensive roadmap to shield Canada’s economy and position it for long-term success published by the Macdonald-Laurier Institute and the Center for North American Prosperity and Security argues that Trump’s tariff threats need to be taken seriously The old bi-partisan economic orthodoxy that the U.S was the biggest beneficiary of free markets is long gone and Trump and his top advisors aren’t swaying from their belief that tariffs will energize the economy But Brakel explains that Trump’s tariffs will fizzle for five reasons (1) tariffs are paid by the importer (no matter what Trump says) (2) tariffs will lead to massive inflationary pressure (3) Trump’s assumption that businesses can easily repatriate to the U.S and (5) tariffs are a poor source of revenue because of the broader distortion and dampening of markets and productivity they cause tariffs on Canada will fall away when they fail to produce the desired result and as they ultimately hurt the American consumer but they may still do a lot of damage along the way tariff on Canadian exports could cost the economy $275 billion in GDP by 2030 “Canada’s current approach is inadequate in the face of these challenges strategic vision to secure our economic future,” writes Brakel the report offers three core policy recommendations: These measures would solidify Canada’s place in the North American economic and security architecture Global Competitiveness: Reform Canada’s tax and regulatory frameworks to attract investment These steps are essential to making Canada a top-tier destination for global business Combat Global Trade Abuses: Lead efforts to counter unfair trade practices “This is a once-in-a-generation opportunity for Canada to transform its trade policy,” argues Brakel Hendrik Brakel is a director in the Federal Practice at Sussex Strategy Group first as the Chief Economic Advisor to the Leader of the Official Opposition and later he was promoted to Director of Policy and Parliamentary Affairs Hendrik served as the Chief Economist at the Canadian Chamber of Commerce Hendrik holds a Master of Public Policy and International Affairs as well as a Master of Business Administration from the University of Ottawa Stay informed on developments in the Canada-US policy space by visiting: https://cnaps.org By continuing to browse the site you are agreeing to our use of cookies is a graduate of the University of Chicago Law School (1968) a former Research Fellow at the American Bar Foundation Professor and Director of Research of the Health Law Institute at DePaul University College of Law Legal Affairs and Project Development at the Isaac Ray Center and CEO and Director of Education of the Isaac Ray Forensic Group – all in Chicago His specialties are in the areas of Mental Health Law Tort Law reform and Legal Aid for low income people Professor Brakel has published widely in each of these areas multiple book chapters and over 70 articles in journals ranging from the American Bar Foundation Research Journal The New England Journal of Criminal and Civil Confinement the Journal of The American Academy of Psychiatry and Law the Australian and New Zealand Journal of Psychiatry and many others Brakel has testified before Congress and the Board of Directors of the Legal Services Corporation and has published op-eds in The Wall Street Journal and the Chicago Tribune He currently teaches part-time in the forensic psychiatry fellowship program at Northwestern University Feinberg School of Medicine The Heartland Institute offers free email subscriptions to all of its newsletters and monthly public policy newspapers Your Support of Heartland will allow us to continue to educate others about our work director of music at the Diocese of Orlando The choir at the Basilica of the National Shrine of Mary Queen of the Universe prepares for the Rite of Election March 6 The Florida Catholic Media attended The Basilica of the National Shrine of Mary Bishop John Noonan of the Diocese of Orlando performed the Rite of Election The footage is of choir performing and interviews with members of the choir and the pipe organist ORLANDO  |   Adam Brakel is the director of music at the Diocese of Orlando and a walking database of musical information “The greatest living musician was Johann Sebastian Bach,” Adam Brakel said when asked which composer influenced him the most Brakel possesses an enthusiasm for the artform along with a dedication to the diocese he serves He played an excerpt of “Presto” from Concerto in G Major BWV 592 The majesty of the notes from the organ complemented the massive interior of the catedral Brakel’s parents recognized a talent for music in their son Along with enjoying soccer and baseball in his youth “I was lucky to be supported by my parents,” for the encouragement towards music Yet after studying music for nine years in college he discovered he wanted to master the pipe organ “Mozart called the pipe organ the king of instruments “It truly can play anything from jazz transcriptions to the works of Bach And my goal is to showcase the diversity of it Pope Benedict had the best quote: ‘The pipe organ is the best representation of God from the soft and serene to the loud and bombastic.’ And that is the perfect description of what the organ can do.” A major part of Brakel’s success as a musician is his devotion to the faith and having it all tied together in wonderful diocesan each week” serve as expressions of his faith “Prayer helps me with everything,” he added Whether playing on the pipe organ or conducting a choir both the ones in the pews and also among his faithful choir you’re only giving the best to God,” he said “For myself to hear it and to play it and to direct it giving the high quality of music back — not just to the Catholic Church but to faith and to God in general — I think is extremely enriching By only doing and promoting the best here in the Diocese and at the Cathedral I think we can also educate people For any youths hoping to follow in Brakel’s footsteps he wants them to know “it’s a tough profession but it’s very rewarding.” Each time he performs he hopes the young people in the pews take note of the magnificent ambience his concerts produce that could give them a nudge to learn music for themselves “I try to showcase with the youth to give them an exposure of this type of music and classical music but also organ repertoire,” he said And if playing musical instruments or singing in a church choir doesn’t come naturally Brakel urged people to take the opportunity and go for it There needs to be a commitment and a dedication But I think it needs to be nurtured,” he said “I just want to encourage people to get involved Singing and playing instruments in a church setting is very rewarding.” Don’t expect Brakel to change anything in his department too drastically He’s proud “having been able to grow the program for the Diocese and the Cathedral to what it is We’re hosting all of the Cathedral musicians from all over the country next year in 2023 Then the following year we’re hosting all the rectors and bishops To touch one person each week is as good as an accomplishment as one can get.” “I think (music) is one of the more rewarding things one can do for the Church,” Brakel said “Each time you’re singing or playing an instrument you’re participating in the Liturgy There’s a mindset that goes with it that you really have to have.” “I have such a wonderful group of musicians the hard work of the diocese” inspires Brakel “to be able to spread the message of the Catholic faith and to spread God’s word to the Orlando community At 25, Brakel was appointed director of music at St. James Cathedral, making him one of the youngest directors in the United States. https://www.adambrakel.com/about Brakel has won many awards, including the Albert Schweitzer Organ Competition, André Marchal Award for Excellence in Performance as well as the Oundle Award https://www.adambrakel.com/about Email notifications are only sent once a day Your browser is out of date and potentially vulnerable to security risks.We recommend switching to one of the following browsers: CARLETON — Lisa Brakel, longtime school librarian with Airport Community Schools, has been selected as this year’s recipient of the 2023 President’s Award by the Michigan Association of School Librarians (MASL) MASL is a professional organization with a membership of approximately 400 school librarians and educators representing hundreds of Michigan school districts universities and educational programs across the state Brakel received the award at the organization’s annual state conference on Nov The award is given at the discretion of the group’s president and serves to honor outstanding individuals or organizations who have made a truly unique contribution to the profession President Carma Roesch nominated Brakel to highlight the incredible support she has provided to the world of school librarianship Brakel’s long-standing commitment to library leadership within her district, MASL and the American Association of School Librarians (AASL) were key reasons the past president of MASL and a longtime school librarian within Airport Schools was recognized “She has worked on numerous state committees as an advocate for school libraries,” said Bethany Bratney MASL awards co-chair and citations committee said in a written statement “Brakel is also an incredible mentor within MASL creating partnerships and friendships throughout the organization and providing support to other librarians with less experience in the field Lisa Brakel is truly deserving of recognition for her unwavering commitment to the school library community.” “I’ve been a librarian since 1999,” Brakel said “I had been a band director as a certified teacher Then you add a library information and science degree on top of your bachelor’s degree and get certified to be a school librarian She started her career with Airport Community Schools in 2008 after working as a librarian in Monroe Public Schools Airport is one of two districts that have school libraries being managed by a licensed Brakel manages six libraries for Airport's district and is assisted by three aides “I was one of two people presented with this award and I always feel very honored to be recognized,” Brakel said “This award is different from the many awards that MASL presents annually This one is selected specifically by the president and you’re to give it to someone you feel needs the recognition for the work they’ve done in supporting the organization “I was surprised when I found out I was going to receive it … It was mind boggling to me but I appreciate it a lot.” Brakel said she plans to retire at the end of the school year and although she doesn’t have any future plans she mentioned there is a shortage of school librarians in Michigan “We’re on the official shortage list that comes out from the Michigan Department of Education,” she said you can come back to work and still draw your pension — Contact reporter Lisa Vidaurri-Bowling at lvidaurribowling@gannett.com He got an assistant video production job for the Pittsburgh Steelers and achieved a super bowl ring with the team One summer during his tenure at Pittsburgh he went to Germany and worked for the NFL Europe and championed a ring for the team he worked for He moved to Phoenix and was promoted to the director position of the video department  In 2017 Rob moved to Denver and worked as an instant replay technician  He never passed up an opportunity to give a shout out to his Alma Mater Robert Morris We wish to raise at least $1,500 so that we can have a memorial tree planted at the RMU Memorial Garden with a special plaque in Robert's memory Contact | Campus Map DeepDives is a bi-weekly essay series exploring key issues related to the economy The goal of the series is to provide Hub readers with original analysis of the economic trends and ideas that are shaping this high-stakes moment for Canadian productivity The series features the writing of leading academics The DeepDives series is made possible thanks to the ongoing support of Centre for Civic Engagement The burning issue right now in Canada is the cost of living—and it’s not going away anytime soon. Despite the inflation rate slowing to 2.9 percent in March, Canadians remain anxious, and recent polls show that sentiment is only worsening A big reason for Canadians’ discontent is that while inflation (year-over-year price growth) may have slowed price levels are still far higher than in mid-2021 when they first began to take off have risen overall by a crushing 21 percent There’s no sign that either will retreat to lower levels anytime soon (see Table 1).1This DeepDive was written prior to last week’s release of Statistics Canada’s April CPI data the data in this table are reflective of March 2024 If policymakers want to address price levels themselves it prompts the question: what can they do about them?  Any pro-affordability agenda needs to address the different factors that have contributed to higher prices and rising costs for Canadians.  There are five forces that have driven inflation in Canada and around the world: This DeepDive aims to outline various causes of Canadian price inflation and offer some substantive ideas as to what governments can do to make the lives of Canadians more affordable.  and Eurozone was caused by supply problems that made it impossible for producers to meet resurgent demand This is not limited to the Russia-Ukraine war but also growing disruption in the Middle East the potential for Donald Trump to further upend the trade order We must consider how to protect our economy from such shocks in the future It is important to be realistic—we cannot divorce ourselves from global supply chains but we can improve our resilience to shocks The fact that inflation hit 8.1 percent in June 2022 while interest rates were rising faster than at any point in Canadian history has demonstrated that the Bank of Canada like many central banks throughout the advanced economies held interest rates too low for too long and continued quantitative easing when it was no longer needed.   central banks initially declared it “transitory,” a temporary phenomenon that would take care of itself They then found themselves behind the curve offering too little too late and in need of unprecedented interest rate hikes from 0.25 percent to 5 percent in a little over a year.  In the U.S., the Federal Reserve has come under considerable criticism for policy mistakes. As Larry Summers put it: I do think there needs to be considerable soul searching at the Fed as to how they missed this as badly as they did They were declaring that inflation would be transitory through most of 2021 even as it was becoming clearer and clearer to a growing number of observers that inflation was not a path to being purely transitory To his credit, the Bank of Canada governor did some of the soul-searching recommended by Summers. Tiff Macklem wrote in February 2024 that he and his team had underestimated the strength and persistence of inflation in 2021 and 2022 in the midst of a series of shocks the Bank’s models weren’t properly calibrated to measure price pressures throughout the economy and Bank officials were “not sufficiently attentive to the risk that inflation could rise sharply.” To be fair, it would also have been impossible for the Bank of Canada to foresee how serious the COVID crisis would be. A shutdown of the Canadian economy could have lasted years and been far more devastating. As then-governor Stephen Poloz explained “A firefighter has never been criticized for using too much water.”  It’s not at all clear that the performance of the Bank of Canada has been worse than other central banks It is entirely possible to argue that the Bank did well in engineering a “soft landing.” Nevertheless the inflation crisis precipitated by the pandemic has proven the need to reinforce the Bank’s inflation mandate and improve Parliamentary oversight without harming the Bank’s independence while the more moderate spenders have had lower inflation rates to contend with federal program expenditures almost doubled from $349 billion to $623 billion an increase amounting to 14 percent of GDP And the spending kept on coming: an additional $130 billion or 6 percent of GDP in 2021-22 and another $100 billion or 4.5 percent of GDP in 2022-23 This pushed an explosion of demand (almost 20 percent of GDP) into our economy of diminished supply and created shortages that drove prices sky-high excessive government spending forced the Bank to raise interest rates by an additional 2 percent.  Overall federal program spending remains well above pre-crisis levels at 16 percent of GDP compared to the 13.2 percent average before the crisis Budget 2024 just added another $5 billion of annual spending annually and it’s no doubt to head even higher as we get closer to an election in 2025 Some left-wing politicians in Canada who believe that inflation is caused by corporate greed alone have been summoning grocery store CEOs to various Parliamentary committees to yell at them. Instead, they should listen to economist Brian Albrecht who says: “Blaming inflation on greed is like blaming plane crashes on gravity.”  It may be literally true that planes crash because of gravity but gravity is a pre-existing condition that has always been with us corporations have always sought to maximize profit but they can provide low prices in spite of their desire to make money by ensuring competition.  Nevertheless, we can’t be too dismissive about firm behaviour and competition. Isabella Weber has written some fascinating work on sellers’ inflation defined as “when the corporate sector manages to pass on a major cost shock to consumers by increasing prices to protect or enhance its profit margins.” In a normal competitive market economy firms are extremely reluctant to hike prices across the board even when they’re under pressure from rising costs because they fear losing out to competitors.  But imagine there is a supply chain crisis that affects all retailers and they know for certain that all of their competitors will have to raise prices Then they’d be a fool not to raise prices concurrently with their competitors In fact, IMF research showed that in Europe rising corporate profits account for almost half of the increase in inflation in 2021 and 2022 The Bank of Canada has done some great research comparing inflation rates and corporate profit margins While changes in markups may have contributed to the initial rise of inflation in 2021 their contribution dissipated by the end of 2021 and growth in marginal costs was the driving force of peak inflation […] during 2021 the contribution of markup growth to inflation was positive but mild—inflation during 2021 was 5.1 percent whereas markup growth was only 0.44 percent over the same period (less than one-tenth the rate of inflation) The evidence for sellers’ inflation is somewhat mixed and the concept may be more theoretical than practical the only way to ensure that profits are not excessive is to foster a real competitive policy environment to bring down prices One critical point is that competition law by itself cannot create competition Competition laws in Canada have been strengthened with increased penalties at least three times without having much of a noticeable effect on prices The second is to provide incentives to encourage investment in concentrated sectors (e.g airlines) or in regions (rural areas where there are one or few grocery stores) by making Canada a more attractive place to invest with tax incentives or bringing down the high cost of doing business in Canada through regulatory reforms and tax reductions.  The ultimate goal is to push down prices by having multiple companies investing and competing aggressively to steal customers from one another This cannot be achieved by having the industry minister cold-calling foreign grocery stores to ask them to come to Canada who would respond to Canada’s invitation to invest hundreds of millions in order to be constantly threatened with excess profit taxes on top of high costs It’s time to make Canada an exciting place to invest and build a business the fastest-growing parts of inflation are in housing the sector that is driving the greatest unhappiness among young people rents grew by 8.5 percent compared to a year ago while mortgage interest costs were up 25 percent and owned accommodation costs rose 7 percent.  the problem is not going to get better—in fact the housing shortage will get worse this year and will be even worse next year—because Canada’s construction industry cannot keep pace with the growth in population.  Canada certainly does not have the workers to double the rate of home construction with an estimated $1 trillion required to build the additional homes.  Canada is building homes much faster than the Americans is currently building 1.5 million homes annually which is the equivalent of Canada building just 150,000 If the government’s strategy to accelerate construction were able to build 280,000 or 290,000 per year The CMHC projection that we’ll have a shortage of 3.5 million homes by 2030 is based on Canada having a population of 43 million by 2030 Canada’s population is already at 40.8 million and will hit 43 million in just over two years (The reduction in international students will slow Canada’s population growth from 1.2 million per year to 900,000-1 million per year.) This means that Canada is on track to face CMHC’s 3.5 million housing gap sometime as early as 2026 rather than 2030 The government and the official opposition have proposed a series of thoughtful and effective policies to accelerate home construction but there are limits to how much supply can be increased The point is that even if you build 250,000 or 300,000 homes per year while the population is growing by 1 million per year then the housing shortage will continue to worsen as demand will far outstrip supply.  addressing inflation in Canada requires a decisive approach that covers all the five forces behind the rise in prices over the past few years Canada can pave the way toward a more stable economic future fostering greater market competition and adjusting immigration targets to align with housing capabilities are essential steps.  we can do even better: improving productivity capital investment and innovation will drive up the wages of Canadian workers with better jobs a future DeepDive will cover how to raise Canadian wages The ultimate goal is to not only stabilize prices but also support sustainable growth and improve the quality of life for all Canadians Hendrik Brakel is a Director in the Federal Practice at Sussex Strategy Group PLATINUM Corporate & Industry Council Members: You are using an outdated browser. Please upgrade your browser or activate Google Chrome Frame to improve your experience Jeff Kirkwood announce the engagement of their daughter Madalyn Marie Kirkwood to Benjamin Joseph Brakel The bride to be is a graduate of Cathedral High School in Natchez and a graduate of Louisiana State University in Baton Rouge and the University of Louisiana College of Pharmacy where she received her Doctor of Pharmacy degree She completed her PGY1 Pharmacy residency at University Medical Center in New Orleans She will complete her PGY2 Critical Care Pharmacy residency in Baton Rouge at Our Lady of the Lake Regional Medical Center where she will begin work as the Critical Care Pharmacist in July of this year The groom to be is a graduate of Slidell High School in Slidell LA and a graduate of Louisiana State University in Baton Rouge LA where he received a Bachelor of Science degree in Renewable Natural Resources He is the Operations Manager for Guice Offshore of Lafayette A reception will immediately follow the ceremony Monday’s SWAC college basketball lineup has lots in store Among those contests is the Southern Jaguars squaring off… Ranked squads are on the Monday college basketball schedule in two games including the Wake Forest Demon Deacons… Monday’s college basketball schedule has several interesting games including the matchup between the McNeese Cowboys and the Stephen… which includes the Tampa Bay Lightning taking on the Florida Panthers Top-25 teams will take the court across two games on Monday’s college basketball slate Adams County residents: Could you live with once-a-week garbage pick up if it would save you significantly on your monthly garbage collection bill View Results Volume 15 - 2021 | https://doi.org/10.3389/fnhum.2021.786133 This article is part of the Research TopicFrontiers in Psychodynamic NeuroscienceView all 18 articles Given that disparate mind/body views have interfered with interdisciplinary research in psychoanalysis and neuroscience the mind/body problem itself is explored here problems for both dualists and physicalists are presented along with essential concepts including: independent mental causation To address some of these issues in a new light this article advances an original mind/body account—Diachronic Conjunctive Token Physicalism (DiCoToP) and some empirical evidence accrued for views consistent with DiCoToP are presented this piece challenges/appeals for neuroscience research to gain evidence for (or against) the DiCoToP view calls for a deepening dialogue between neuroscience and psychoanalysis could offer much toward addressing the conflicting mind/body views inhibiting progress both in psychoanalysis and neuroscience It is within this added discipline that I attempt a contribution to this collection Section One explores essential problems embedded within the mind/body problem, arriving in Section Two at the view I devised (Brakel, 2013) and now advocate—Diachronic Conjunctive Token Physicalism (DiCoToP)1 Although the DiCoToP account resolves some of the issues associated with the mind/body problem Section Three grapples with new puzzles that this particular mind/body account reveals and entails I aver that DiCoToP can go some distance in explaining two matters endemic to clinical psychoanalytic work but heretofore quite vexing These are: (a) working through; and (b) the mechanism of therapeutic action after patients gain new knowledge through interpretation acknowledges that even if I am correct about these and more general aspects of DiCoToP’s explanatory power much more than such coarse correlations are needed after providing a brief account of some existing empirical studies whose findings can be taken to clearly support DiCoTop the close of Part Two is essentially an appeal (and a challenge) to neuroscientists Can neuroscientists apply cutting edge neuroscientific methods to explore in humans whether or not features of DiCoToP could obtain I would hope that this sort of empirical investigation would be a thoroughly interdisciplinary adventure ‘‘Why physicalism?’’ is the first question every physicalist2 must consider—this especially when dualism seems so appealing Dualism’s appeal owes to its rather elegant solution to some basic and difficult mind/body problems for physicalists (especially physicalists of the reductive variety)—that of independent mental downward causation (a) there is nothing over and above the physical (and the laws thereof) and (b) everything mental is at base physical; how then can mental goings-on—familiar processes of the mind desires—be genuine causes of behavior unproblematic grasp of such important concepts and phenomena as the Self dualism presents its own insurmountable problem: If one embraces the most prevalent scientific view of a physical-only universe the very nature of the mental—ontologically as well as epistemologically—has not been there are two famous and compelling arguments for dualism I will discuss them both in the section below The Knowledge Argument was advanced by Frank Jackson in 1982. The main character is Mary, the color scientist. Jackson (1982 p.130) describes Mary as “…a brilliant scientist who is…forced to investigate the world from a black and white room via a black and white television monitor She specializes in the neurophysiology of [color] vision and acquires…all the physical information there is to obtain about what goes on when we see ripe tomatoes and use terms like ‘red,’ ‘blue,’ and so on.” Jackson (p.130) then asks two pivotal questions: What will happen when Mary is released from her room and sees colors for the first time in her life “Will she learn anything or not?” He concludes (p.130): “It seems just obvious that she will learn something about the world and our visual experience of it But then it is inescapable that her previous knowledge was incomplete one can assume Mary did not know what it’s like to experience color one must also assume that knowing-what-it-is like type knowledge—so called acquaintance knowledge (or know-how knowledge)—is not part of physical knowledge exactly what it is trying to prove: namely that there exists knowledge that is non-physical The Zombie/Conceivability Argument is presented concisely by Chalmers (2010 Here he paraphrases his earlier work (and that of others) setting up the Zombie Case as follows: “…It is conceivable that there be a system that is physically identical to a conscious being but lacks…that being’s conscious states Such a system might be a zombie: a system that is physically identical to a conscious being but that lacks consciousness entirely.” He continues (p.107) …will look identical to a normal conscious being from the third-person perspective In particular…brain processes will be molecule-for-molecule identical with the original and their behavior will be indistinguishable But things will be different from the first-person point of view What it is like to be…a…zombie will differ from what it is like to be the original being [For] there is nothing it is like to be a zombie is to acknowledge that since such zombie systems/beings are coherently imaginable with “no contradiction,” it can be inferred that they are a metaphysical possibility: “From here it is inferred that consciousness must be non-physical If there is a metaphysically possible universe that is physically identical to ours but that lacks consciousness non-physical component of our universe.” Again (1) It is conceivable that there are zombies (2) If it is conceivable that there are zombies it is metaphysically possible that there are zombies (3) If it is metaphysically possible that there are zombies This argument for dualism too, is very appealing. And yet, there are serious problems embedded within its structure. Several authors, including Jackson (2003, pp.9, 30) and (Nagel, 1998, p.346), suggest that the Zombie Argument, turning on the conceptual conceivability of conscious-less human physical duplicates, is paradoxically a function of our own human concepts, and the limitations therewith (See also Hill, 1997) our powers of conceiving may outstrip both metaphysical reality and epistemological possibility A physicalist can then mount a simple 6 step counter argument (1) Person-X and Zombie-X are molecule-for-molecule/neuron-for-neuron identical; (2) Person-X’s consciousness is no more than a physical arrangement of these molecules/neurons; (3) Zombie-X has the same arrangement of these same molecules/neurons; this must be due to some consciousness-blocker (5) Any blocker must itself be physical, subject to physical laws (since there is nothing over-and-above the physical)3 (6) The upshot: Either Zombie-X is not a zombie and is conscious; or Zombie-X is not conscious With the hope that these refutations of two great dualist arguments have had some sway let’s move on to some physicalist views and yet holds (as its name signals) that the mental is not reducible to the physical It follows that non-reductive physicalism holds many of the advantages of dualism while avoiding dualism’s biggest challenge—the ontologic nature of the mind and its mental goings-on the mind is strictly material/physical ontologically; but mental properties non-reductive physicalism allows such mental entities as Self conscious attitudes and their contents (like beliefs and desires) to have real and independent downward causative powers Emergentism might help the non-reductive physicalist emergentism holds that “macroproperties” arising from a number of “microproperties” conjoined many H2O molecules combined constitute a macroproperty emerging from a combination of many single H2O molecules—the microproperties from the underlying microproperties—the single H2O molecules and water is causally autonomous and independent from those of the underlying single H2O molecule microproperties Applying this to the mind/body puzzle—emergentists aver that mental macroproperties emerge from physical microproperties. Searle (1992 …consciousness is a causally emergent property of systems It is an emergent feature of certain systems in the same way that solidity and liquidity are emergent features of systems of molecules The existence of consciousness can be explained by the causal interactions between elements of the brain at the micro level but consciousness cannot itself be deduced or calculated from the sheer physical structure of the neurons without some additional account of the causal relations between them But Searle’s important discussion of emergentism has not actually solved the problem Searle acknowledges that the existence of consciousness is reductively accounted for physically but to repeat the last clause of his last quoted sentence just above: “…but consciousness cannot itself be deduced [reduced to] or calculated from the sheer physical structure of the neurons without some additional account of the relations between them.” This is true but Searle does not answer two questions that immediately follow: What are these accounts can consciousness indeed be deduced or calculated from additional accounts of the relation of neurons physicalism is rescued; but is its cost too high with respect to autonomous mental causal powers the notion of independent mental causation seems vindicated; but do these autonomous mental powers arise in the forbidden emergent2 fashion which features mental goings-on as emergent1 phenomena along with the sort of independent causal powers seen with other emergent1 macroproperties such as the familiar example of water’s liquidity and H2O molecules holds that both type and token physicalists “…maintain that we obtain a simpler and more straightforward picture of the universe if we assume that sensory [mental] events are identical with physical events.” Elaborating this further Hill (p.22) discusses reductive physicalists as having the scientific advantage of “the best explanation principle” whereby “If a theory provides a good explanation of a set of facts and the explanation is [as good as or] better than any provided by a competing theory there is good and sufficient reason for believing that the theory is true.” Hill (p.11) explains: “Type materialism is like token materialism in claiming that sensory [mental] events are identical with physical events it also claims that there is a set of physical characteristics with which qualitative [mental] characteristics are universally and lawfully correlated…” Continuing Hill (p.35) goes on to assert that “…type materialism is simpler than dualism because it postulates fewer events…[and] type materialism is simpler than double aspect theory because it postulates fewer facts [Hill’s italics throughout].” And as far as type materialism over token becoming the more popular view it is understandable because type materialism brought a universal lawful regularity to the vexing mind/body problem: predictable mappings of mental state types of a certain character onto brain states types of a certain character First articulated in a seminal article by Putnam (1967/1975), the Multiple Realization Argument (MR), and its consequences for type physicalism is described in some detail by Kim (1993) According to Kim (p.179) The MR argument advances the idea that given that “…any mental state…can be ‘physically realized’ in many diverse types of organisms and physical structures (e.g. it is extremely unlikely that some uniform physical state exists to serve as…physical correlate [to that mental state].” What follows then … [Since] any psychological event-type can be “physically realized” or “instantiated” or “implemented” in endlessly diverse ways depending on the physical-biological nature of the organism or system…it [is] highly implausible to expect the event[-type] to correlate uniformly with and thus be identical with [or reducible to] some “single” type of neural or physical state This conclusion from the MR argument made a deep impact upon those working on the mind/body question. Kim (1993) characterizes its effect as profound and devastating to type materialism (p.309): “‘[T]ype materialism’ is standardly thought to have been definitively dispatched by MR to the heap of obsolete theories of mind.” Indeed as talk of type materialism narrowed to type materialism within a species Thus there would be human type pain (Mental-H–P) and human type brain circuits (Physical-H–BC); these not necessarily similar to mollusk type pain (Mental-Mol–P) and mollusk nervous tissue (Physical-Mol-NT); and Martian type pain (Mental-Mar–P) and Martian type physical type pain realizer (Physical-Mar–PR); all of these also not necessarily similar to one another Undoubtedly the brain’s degeneracy and its plasticity are of great import for survival and for evolutionary success these current scientific developments severely compromise any type physicalist view of the mind/body question It becomes increasingly apparent that even the more limited local species-specific type physicalist cannot rely on type-type identity or type-type reduction even within the brain of a single individual much less across the brains of an entire species No one-to-one physical type to mental type correlation can be found to exist The usual reaction among philosophers to this daunting challenge to type materialism has been to turn back to a non-reductive version of physicalism which in my view deserves much further investigation in the next subsection another issue will be presented also admits of possible solutions offering potential advantages for token physicalism p.14464) characterize neuronal assemblies in general as “…large populations of neurons believed to imprint [particular] memories and other cognitive information.” They further describe these as “randomly connected,” demonstrating plasticity Given this mismatch, how can token physicalism—which essentially holds that one particular mental event is identical with a physical event—hold up? Stephen Yablo (1992, p.256, 271) proposes a view of the relation between mental and physical properties and events, which can be helpfully applied to token physicalism. Yablo (1992 p.256) briefly outlines his account of determinable/determinate relations as follows: “Necessarily something has a mental property iff [if and only if] it has also a physical determination of that property.” This “…is an instance of the standard equation for determinable and determinates that something has a determinable property if it has some determinate falling thereunder.” The color blue for example is a determinable with various shades of blue—navy blue royal blue—being among its determinates a particular belief (and its content) would be the determinable while several different neuronal assemblies would be its various determinates the New York Yankees are a conjunction (not a composite) of all of the New York Yankee teams during those years all of the players playing for a specific Yankee team comprise a composite—the 1960 New York Yankees the 1960 New York Yankees would still have been the 1960 New York Yankees the question here is how do these matters apply to the mind/body problem and token physicalism I will attempt to answer this in the next subsection I have posited (Brakel, 2013, Chapter 3) a novel token physicalist view of the mind/body problem—Diachronic Conjunctive Token Physicalism (DiCoToP). It features a brain-based view of mental content in which each singular mental event (i.e., a particular belief with a specific mental content7) occurring at time-t along with whatever neurochemical processes facilitate their connection This is a reductive token physicalist view there is nothing over and above these brain goings-on as far as the specific mental event is concerned each additional singular instance of the same mental content (each token)—take for example “My dog is fun”—is populated by a different network of neurons Sometimes the neural assemblies at times-t and t + 1 or t + 20 vary only slightly; sometimes they are quite different the sum of all of these instances of this content all of their variable neuronal assemblies—neurons On this account, the mental event/process would be the determinable and its various neuronal ensemble instantiations would be the determinates. Following Yablo (1992 this understanding admits of at least a partial resolution of the mental causation problem: “…determinates and their determinable…are not causal rivals…” And Yablo adds (p.272) “…rather than competing for causal honors determinable and their determinates seem likelier to share in one another’s successes.” But even if these determinables—the mental goings-on—do have autonomous causal powers, there remains the still vexing question of the relation of the physical to the mental, namely how is it that mental goings-on, like consciousness, arise from its physical-only base?8 micro-based upon Ps; and their relation can therefore be explained in the usual way by normal science But, to be fair, this account of Ms and Ps is not a universally endorsed. Kim (1998, p.98), for one, does not consider an M to be a macroproperty micro-based on Ps; and even Searle (1992) contests the emergent1 solution as explanatory for first person ontology let’s consider what is different in the relation of Ps to Ms and H2O molecules to the wet fluid we know as water is that physical chemists know how the multiple molecules of H2O They can understand the organization of the many molecules within a structure the Brownian movements of the molecules under temperature and pressure conditions we would still have no good understanding of the “how” relation between mental contents as a macroproperty and the myriad neuronal assemblies that are its microproperties the final subsection of this work will essentially be a mixture of plea and challenge to neuroscience colleagues to work on the “how” within the DiCoToP account in the section just to follow are some new puzzles the DiCoToP view brings to light With Diachronic Conjunctive Token Physicalism in place let’s start with a thought experiment Suppose that water’s liquidity/wetness which seemingly owes to a very large collection of H2O molecules “really” owes to the perceptual capacity of the subject experiencing the wetness suppose that for a very different sort of experiencer (one that is microscopically small) only two or three H2O molecules would suffice as a sufficient microproperty base for the emergent1 macroproperty The parallel question immediately presents itself: Would a small number of neural assemblies allow this imagined tiny experiencing subject to experience consciousness and allow mental independent (not epiphenomenal) causal efficacy Both of these problems might lead one to the panpsychism family of materialist mind/body views, in which (a) physicalism holds; (b) conscious experience is the only thing we really know for sure; and (c) even the most basic physical particles (including their subatomic constituents) can be mental/conscious (Again, see especially Strawson, 1994, 2009) But as I’ve outlined earlier (footnote 4) Here are two: (1) Either there must be an accounting for whatever aspects are non-conscious/non-experiential if any such parts are posited; or (2) If there is nothing that is non-conscious the panpsychist needs to explain why it is that our human conscious experience is not experienced until these fundamental “conscious” particles undergo much combinatory work the nature of these combinatory processes ought to be outlined it is these somewhat esoteric philosophical puzzles revealed by DiCoTop that can return us to something potentially more solvable—although still very difficult Given (a) that many H2O molecules are needed for the emergent1 property of liquidity and the subjective experience thereof; and (b) that the “how” of liquidity/fluidity can be understood in terms of the principles of physics and physical chemistry Q: Can a similar understanding about how the myriad neural assemblies align/combine in emergent 1 fashion to yield consciousness couldn’t the answer evolve: first to “not yet” and later to “yes!” the Diachronic Conjunctive Token Physicalist view does now allow some explanation for some heretofore perplexing aspects of psychoanalysis could go some distance in explaining what the working-through mechanism might actually entail and therefore how working-through might actually work The sum of all of these instances of this content all of their slightly variable neuronal networks (the conjunction) let’s take a neurotic belief with a clear and simple mental content “All spiders are dangerous and should be avoided.” How would the working-through process actually occur according to the DiCoToP model of mental events It seems clear that dealing with the phobic pathology that this specific mental content represents would require much re-aligning over a great number of neuronal assemblies considerable experiential re-workings of the particular mental content would be needed—this in most of the myriad contexts in which the neurotic belief appeared Working-through more complex neurotic symptoms composed as they are of diverse and variegated neurotic beliefs much of it taking place after gaining new knowledge from even the most successful interpretations Diachronic Conjunctive Token Physicalism is then a mind/body view that can help explain not only working-through and the post-interpretative mechanism of therapeutic action and why post analytic self-analysis is rarely optional these research findings have included degenerate neuronal arrays at the level of disparate circuits reflecting an even greater degree of plasticity all of the optogenetic imaging and their encouraging results were of necessity gathered on non-human animal subjects What are the implications for human consciousness were directly applied to human mental goings-on the subjects were clearly conscious in their responses to perceptual stimuli and various learning tasks This means that the fine-grained (neuronal assembly and even synapse-level) imaging results do reflect mental activity which should be generalizable to human animals Here is one possibility offered by this author (a not-even-neophyte neuroscientist; but a psychoanalyst/philosopher) in order to test DiCoToP more specifically Could the research methods described above (optogenetic imaging) be employed to study particular mental contents more directly in appropriate non-human animals two simple belief-like attitudes for a mouse might be selected: (1) “that is frightening;” and (2) “that is appealing.” Then many versions of each of those content-rich beliefs would be delivered to each mouse-subject (e.g. 10 different mouse-subjects) in many iterations (20) during a single session and then in succeeding sessions over some duration of time (e.g. Would imaging results compared within subjects and between subjects—both with regard to trials at-a-time and those over-time—prove revealing really of this whole article: I wrote it in the hopes of providing a challenge and registering a plea to neuroscience colleagues to devise human experiments offering empirical brain-based (perhaps neuronal assembly and neuron level) evidence for or against DiCoToP (as well as other competing mind/body views) Any investigation of the perpetually vexing mind/body problem should not exclude a philosophical exploration especially in light of the claim that neuroscientists and psychoanalysts hold clashing positions inhibiting their interdisciplinary collaboration this article adds the philosophy of mind to the endeavor set forth as the “Frontiers Research Topic: Psychodynamic Neuroscience.” This piece begins with a series of questions: Why should one be a physicalist when non-reductive physicalism has the appeal of dualism when type physicalism has been much more popular Asking and answering these questions provides a review of some of the most important aspects of the mind/body dilemma Among the issues taken up was the matter of independent causation If the mind and the mental are properly reduced to the physical how can mental goings-on have real autonomous Emergence as a possible solution was discussed along with the problems it does not resolve a concept that is truly pivotal for neuroscience and mind/body physicalists and found to be particularly relevant as it has become a central feature in the mind/body view I developed in 2013 Termed Diachronic Conjunctive Token Physicalism (DiCoToP) this account can resolve many of the outstanding mind/body problems the DiCoTop account also brought to the fore a few new vexing philosophical puzzles of two sorts—statistic modeling of neurological phenomena at the level of the neuron and neuronal assembly; and imaging studies on non-human animal subjects on fine-grained brain processes—were seen to provide evidence for essential aspects advanced by the DiCoToP account This article ends with a challenge that is at the same time an appeal: Can neuroscientists devise empirical experiments with human subjects in order to gain evidence for (or against) the Diachronic Conjunctive Token Physicalist mind/body account The original contributions presented in the study are included in the article/supplementary material further inquiries can be directed to the corresponding author/s The author confirms being the sole contributor of this work and has approved it for publication The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest 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 Multiple realizability revisited: linking cognitive and neural states CrossRef Full Text | Google Scholar Unconscious Knowing and Other Essays in Psycho-Philosophical Analysis Google Scholar The Ontology of Psychology: Questioning Foundations in the Philosophy of Mind Google Scholar The emergence of a stable neuronal ensemble from a wider pool of activated neurons in the dorsal medial prefrontal cortex during appetitive learning in mice doi: 10.1093/acrefore/9780190264086.013.298 CrossRef Full Text | Google Scholar (2021) Identification of pattern completion neurons in neuronal ensembles using probabilistic graphic models Google Scholar Neuronal assemblies evidence distributed interactions within a tactile discrimination task in rats Degeneracy and complexity in biological systems Google Scholar Neuroscience and the multiple realization of cognitive functions CrossRef Full Text | Google Scholar Google Scholar Degeneracy and redundancy in cognitive anatomy CrossRef Full Text | Google Scholar Google Scholar Google Scholar Redundancy in synaptic connections enables neurons to learn optimally PubMed Abstract | CrossRef Full Text | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar “Mind and illusion,” in Minds and Persons Google Scholar Google Scholar Google Scholar Google Scholar Formation and maintenance of neuronal assemblies through synaptic plasticity Visual stimuli recruit intrinsically generatedcortical ensembles Google Scholar Conceiving the impossible and the mind-body problem CrossRef Full Text | Google Scholar Redundancy and synergy of neuronal ensembles in motor cortex Degenerate neuronal systems sustaining cognitive functions Brain computation by assemblies of neurons Google Scholar Cognitive conjunction; a new approach to brain activation experiments Google Scholar CrossRef Full Text | Google Scholar “The nature of mental states,” in Mind CrossRef Full Text | Google Scholar Google Scholar Google Scholar Google Scholar Google Scholar Google Scholar Google Scholar Citation: Brakel LAW (2021) Can Neuroscientists Test a New Physicalist Mind/Body View: DiCoToP (Diachronic Conjunctive Token Physicalism) Copyright © 2021 Brakel. 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: Linda A. W. Brakel, YnJha2VsQG1lZC51bWljaC5lZHU= 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. So when Dore called me in spring this year and said, “What about commemorating the Munich Agreement?” and built a conference around that event to reassess appeasement and draw some lessons for the future, I said “sure.” I thought a little bit about it and said, “Yeah, this will be interesting but it will be very complicated because it’s a very sophisticated task.” Dore said, “Yeah, that’s what we here for, so okay, then let’s do that.” Beit Milken, 13 Tel Hai St., Jerusalem, 9210717, Israel A pipe organ concert originally scheduled to get listeners into the mood for Christmas will be presented Wednesday evening to maintain the holiday spirit. Grace Cathedral, as part of its Great Spaces Music & Arts Series, will present organ virtuoso Adam J. Brakel’s “Noel! Great Organ Works” at 7 p.m. Wednesday in the cathedral, 701 S.W. 8th. Admission is free, but a freewill offering will be gathered. Brakel’s concert was initially planned for Dec. 4, but delays in upgrades to the cathedral’s heating system didn’t allow enough time for the venue’s 63-rank Schantz pipe organ to acclimate to the new conditions, so the event was postponed but the repertoire unchanged. The spell-binding performances of Brakel had led to his being compared to Franz Liszt, Glenn Gould, Leonard Bernstein and Niccolo Paganini and proving that true musical prodigies continue to exist in the 21st century. Brakel began his musical studies at age 4, and the American Guild of Organists, the Topeka chapter of which is co-sponsoring his concert, awarded him a scholarship as a high school junior. As a student at Duquesne University, he was appointed associate organist at St. Paul Roman Catholic Church in Pittsburgh where he was featured weekly on television broadcasts throughout western Pennsylvania. After graduated magna cum laude from Duquesne in 2006, he enrolled at the Juilliard School in New York where he served as assistant organist of the Church of St. Ignatius Loyola on Park Avenue and was featured in solo recitals at St. Patrick’s Cathedral and Central Synagogue among other notable Manhattan venues. In autumn 2007, Brakel enrolled at the Peabody Conservatory in Baltimore where he completed his master’s degree and then was awarded a graduate performance diploma in 2011. During this time, Brakel also served as guest assisting organist at the Basilica of the National Shrine of the Immaculate Conception in Washington, D.C., and studied in Toulouse, France. His other positions include director of music and organist at St. Ignatius Roman Catholic Cathedral in Palm Beach Gardens, Fla. That appointment at age 25 made him at the time one of the youngest directors at a United States cathedral. Brakel, 32, currently serves as music director at St. Francis Xavier Cabrini Parish in the Diocese of St. Petersburg, Fla. A winner of numerous organ competitions, Brakel performs recitals around the world. National Public Radio in Florida hailed him as “an absolute organ prodigy, with the technique and virtuosity that most concert pianists could only dream of, and having the potential to be the leading organist of his generation … the Franz Liszt of the organ.” The Chicago Tribune called Brakel “one of the most talented organists in the world.” He will open his “Noel!” concert with Gaston Marie Dethier’s “Christmas,” which contains variations on the tune “Adeste Fidelis” hidden throughout the work, as well as Pietro Yon’s “Jesu Bambino.” Brakel, whose repertoire includes the complete organ works of Johann Sebastian Bach, will follow with “Canonic Variations on ‘Vom Himmel Hoch’ (‘From Heaven Above to Earth I Come’),” which Brakel said in his program notes “utilize canons in various intervals as well as ornamentation and counterpoint as only Bach can do.” The last two measures of the final variation even includes Bach’s own name in the work: B-A-C-H with H representing B-natural. The organist also will play English composer Ralph Vaughan Williams’ “Rhosymedre,” also known as “Lovely,” and “Variations sur un Noel,” French composer Marcel Dupre’s variations on the French Renaissance carol “Noel Nouvelet, which concludes with an exciting fugue and grand French toccata representing the pealing bells of St. Sulpice where Dupre was organist. The concert will conclude with American composer Garth Edmundson’s “Toccata on ‘Vom Himmel Hoch,” which Brakel wrote “utilizes the tune in a grand toccata style with fast figurations and exciting scale passages with the tune played in almost a hymn-like fashion.” Video and audio samples of Brakel’s playing can be found on his website at www.adambrakel.com. You can turn to OPB for stories about the people and places that make our region unique thanks to member support. Join in now! It was created by the Dutch design collective Polymorf Oregon Art Beat producer Eric Slade spoke with Symbiosis co-directors Marcel van Brakel and Mark Meeuwenoord about the role of art in environmental crises their love/hate relationship with technology and a future where you might be able to experience your dog’s happiness creators of the extended reality experience Symbiosis Eric Slade: What do you hope people take away from Symbiosis Marcel van Brakel: I think within Symbiosis people have to let go of their human body position not only in a mental or philosophical way but also in a physical way And what I noticed during the early experiments in the studio is that it not only changes how you experience your body but also how you experience reality It opens up new space for new perspectives We are of course very worried about what’s happening to the world now And I think that the current state where everything is built and created only to serve humans and their human needs is not sustainable anymore Something needs to be done fundamentally differently Mark Meeuwenoord: I think as artists you have this opportunity to explore the possibilities of rethinking with the tools and the knowledge you can actually do we really noticed VR is supposed to be the “empathy machine.” It’s the thing that can actually put you in this other perspective So I think that’s the concept we tried to challenge Symbiosis is an extended reality experience at the Portland Art Museum's Center for an Untold Tomorrow Slade: Tell me more about how you approach complex social issues from your perspective as artists van Brakel: I think by playing around in this virtual reality of what might be you train yourself for future scenarios And I think that’s the biggest importance of being a storyteller is that you offer that to humanity And if you do that well some things will stick and will be transferred to other people If the thing is really powerful it will be copied into other brains like a virus And it will spread itself and people will help it grow As an artist sometimes you feel like calling in the desert and nobody’s hearing you If you make powerful stories you actually have power to change stuff Symbiosis takes guests on an immersive journey 200 years in the future where they must confront a collapsing ecosystem Participants will see environments such as this Slade: It looks like some very complicated technology you use to create Symbiosis Meeuwenoord: I really like and hate (laughs) the complexity of all the facets of this there’s the hardware part and I try to explore it all But I think that the starting point is to always challenge ourselves they have to serve all sorts of pneumatic systems that are connected to the VR itself We have to write our own software to be able to make that all interactive and you see yourself being connected to it Slade: What do you see as the future of this kind of technology or this kind of experience van Brakel: I don’t know about the future of XR (extended reality) because that’s the fun thing about it -— it will change all the time It should be changing in places where we don’t expect it to be Meeuwenoord: A lot of technologies actually being developed right now are about predicting what’s going to happen next And I think maybe we should not know some stuff and be surprised sometimes and not be in control Because all these technologies are about control control and predict and predict and predict I would like to see more surprising forms of technologies in the future van Brakel: With Polymorf we did an experiment with hormonal storytelling with hormones influencing the brain directly instead of with something outside of the body It’s way too hard to predict what happens if we kind of mix up hormones to create an emotional journey But I think maybe in the future we will be able to kind of make an emotional transplant with you and your dog I’m waiting for that kind of stuff (laughs) but we definitely think that the future of technology will be more feminine Symbiosis is sold out through the end of its PAM CUT run Tags: Culture, Arts And Culture, Arts, Portland Art Museum Stand with OPB and protect independent journalism for everyone Listen to the OPB News live stream (opens new window)Streaming Now Augustine will host a Blessing and Dedication Concert at 7 p.m The concert will highlight the new Colby/Walker Gallery Organ that has joined the Cathedral's Chancel Casavant Pipe Organ in the renovated and restored church The 87 rank Colby/Walker and the 57 Rank Casavant will lead worship for the Cathedral Parish and Diocese of St Augustine and will enhance future organ concerts as well The new organ was made possible by a gift from a generous donor The two organs are playable from either organ console the Colby/Walker in the new choir gallery has full capability of the pipe organ in the chancel of the Cathedral and the Casavant has limited accessibility to the Colby/Walker To inaugurate the new organ and the restoration of the Casavant Pipe Organ Brakel will perform a concert on the two organs proving that true musical prodigies continue to exist in the 21st century National Public Radio in Florida hailed him as "An absolute organ prodigy with the technique and virtuosity that most concert pianists could only dream of and having the potential to be the leading organist of his generation.. The Chicago Tribune recognized Brakel as "One of the most talented organists in the world." A recent graduate of the Peabody Conservatory Brakel has already embarked on a successful concert career playing from coast to coast in the United States and concert tours have taken him to England "He is to be commended for his devotion to the art of performance and to music itself," said Dame Gillian Weir one of the foremost organists in the world Brakel's repertoire of organ literature is extensive and includes the entire spectrum of styles including the complete organ works of Bach Mendelssohn and others - laudable for a performer who is only in his 20s Recent highlights include performances of the complete works of César Franck and the fiendishly difficult Six Etudes of Jeanne Demessieux one of very few performers in the world to perform and record the entire set Brakel has also made an intentional study of jazz music for the pipe organ and has worked with leading jazz composers in the development of new works in this genre Brakel will include the works of Marco Enrico Bossi He will conclude his concert with the renowned "Sonata on the 94th Psalm" of Julius Reubke call Bernie Sans at 824-2806 or email cathstaugmusic@gmail.com it appeared as though Devin Brakel had more fun this season the forward on the West Windsor-Plainsboro North High field hockey team appeared to take everything so seriously Brakel let her hair down and her personality shine through and it became obvious why her teammates speak so highly of her that is so true,” head coach Shannon Maruca said she’s got one of the funniest personalities I’ve ever seen “She’s always taking pictures and sending them to me on my phone She really has loosened up a lot this year Those who played against her probably didn’t laugh too much Brakel had one of those rare seasons where she finished in the Top 5 in the area in goals and assists Brakel is The Times’ Colonial Valley Conference Player of the Year “I think she definitely deserves it; she’s had a great career,” Maruca said “She’s just been an outstanding player and team leader She’s just been an amazing player to have.” Brakel finished the season second in the CVC in goals with 28 but led the league in assists with 21 while playing with a completely new frontline as the Knights went 13-5 with another CVC Colonial Division banner to hang “We talked about it at the beginning of the season,” Maruca said “She has always been playing with older girls and really good players We pulled her aside and said she’s got a lot of responsibility this year “She exceeded our expectations as far as being a leader and helping out the younger girls And she did it in a way where she never made anyone feel they weren’t as good as she was “She took them under her wing and made them better players I don’t think there are too many high school girls who can do that I think that is one thing that was special about Devin She has a way of teaching girls and making them better players We were worried about that because she had played with so many good players in the past She’s an unselfish player and unselfish person.” Vermont and Lebanon Valley as colleges to play at next season (with Ursinus in the lead) leaves as the program’s all-time leading scorer with 87 goals and 59 assists in three varsity seasons She tallied 30 goals in her sophomore season with 29 coming in her junior campaign “That’s another thing with Devin: the bigger the challenge “Sometimes you worry about her being double-teamed and triple-teamed There were a lot of good players (in the CVC) Contact Anthony Coleman at acoleman@njtimes.com Follow the Times of Trenton on Twitter. 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All rights reserved (About Us) The material on this site may not be reproduced except with the prior written permission of Advance Local Community Rules apply to all content you upload or otherwise submit to this site YouTube's privacy policy is available here and YouTube's terms of service is available here Ad Choices Volume 10 - 2022 | https://doi.org/10.3389/fchem.2022.798006 This article is part of the Research TopicEditors’ Showcase: Chemical BiologyView all 13 articles The antimicrobial peptide (AMP) ARV-1502 was designed based on naturally occurring short proline-rich AMPs Identification of chaperone DnaK as a therapeutic target in Escherichia coli triggered intense research on the ligand-DnaK-interactions using fluorescence polarization and X-ray crystallography to reveal the binding motif and characterize the influence of the chaperone on protein refolding activity 182 analogs of ARV-1502 were designed by substituting residues involved in antimicrobial activity against Gram-negative pathogens The peptides synthesized on solid-phase were examined for their binding to E aureus DnaK providing 15 analogs with improved binding characteristics for at least one DnaK These 15 analogs were distinguished from the original sequence by their increased hydrophobicity parameters the influence of the entire DnaK chaperone system including co-chaperones DnaJ and GrpE on refolding and ATPase activity The increasingly hydrophobic peptides showed a stronger inhibitory effect on the refolding activity of E these more hydrophobic peptides had only a minor effect on the ATPase activity The most dramatic changes on the ATPase activity involved peptides with aspartate substitutions these peptides resulted in a 59% reduction of the ATPase activity in the E coli chaperone system whereas they stimulated the ATPase activity in the S Of particular note is the improvement of the antimicrobial activity against S aureus from originally >128 µg/mL to as low as 16 µg/mL Only a single analog exhibited improved activity over the original value of 8 µg/mL against E the various moderate-throughput screenings established here allowed identifying (un)favored substitutions on 1) DnaK binding 3) the refolding activity of DnaK alone or together with co-chaperones and 4) the antimicrobial activity against both E Molecular insights into the substrate-target interactions are very useful for a rational inhibitor design PrAMPs are excellent DnaK substrates and are additionally interesting drug options due to their good antimicrobial and host defense activities This study describes the influence of PrAMP ARV-1502 and 182 substituted analogs on the chaperone system of the Gram-negative bacterium E aureus to identify amino acid substitutions affecting the functional properties of different DnaK alleles the relationship between the influence on the protein refolding activity and the antimicrobial activity of the novel peptides was thoroughly examined Ammonium heptamolybdate tetrahydrate (>99%) sodium chloride (>99.5%) and sodium dodecyl sulfate (SDS >99.5%) were purchased from Carl Roth GmbH and Co Adenosine 5′-triphosphate disodium salt hydrate (ATP disodium hydrogen phosphate (>98%) magnesium acetate tetrahydrate (>99%) potassium dihydrogen phosphate (>98%) sulfuric acid (>95%) and thiazolyl blue tetrazolium bromide (MTT; ≥97.5%) were obtained from Sigma Aldrich Chemie GmbH (Taufkirchen cOmplete™ Mini EDTA-free protease inhibitor cocktail and DNase I (from bovine pancreas) were purchased from Roche Deutschland Holding GmbH (Mannheim Magnesium chloride hexahydrate (>99%) and β-mercaptoethanol were obtained from Fluka (Buchs and Tris ultrapure (>99.9%) were purchased from AppliChem GmbH (Darmstadt Casein (from bovine milk) and guanidinium hydrochloride (>99.9%) were obtained from CalbioChem™ (San Diego and TEV protease (10 U/µl) were purchased from SERVA electrophoresis GmbH (Heidelberg Gibco® Penicillin-Streptomycin (10,000 U/mL) and Gibco® Trypsin-EDTA (0.5%) were obtained from Life Technologies GmbH (Darmstadt >99.97%) and formic acid (ULC-MS grade >99%) were purchased from Biosolve B.V Water (resistance R > 18 mΩ/cm; total organic content <10 ppb) was purified by a PureLab Ultra Analytic system (ELGA Lab Water ARV-1502 acetate was obtained from PolyPeptide Laboratories (SanDiego United States) as white powder with a purity of 97.3% according to RP-HPLC The identity was further confirmed by amino acid analysis (Asx The 182 substituted analogs of ARV-1502 were obtained from ABclonal These peptides were purified by RP-HPLC using an acetonitrile gradient in the presence of 0.1% TFA Masses were confirmed by ESI-MS and the purities (>80%) were determined by RP-HPLC recording the absorbance at 214 nm Peptides containing a N-terminal 5 (6)-carboxyfluorescein-label were synthesized in-house by Fmoc/tBu-chemistry on Rink amide resin and purified by RP-HPLC using an acetonitrile gradient in the presence of 0.1% TFA Masses were confirmed by ESI-MS and the purities (>95%) were determined by RP-HPLC recording the absorbance at 214 nm DnaK (UniProt-ID P0A6Y8 and P99110), DnaJ (UniProt-ID P08622 and P63971), and GrpE (UniProt-ID P09372 and P99086, downloaded on 26.08.2021), from Escherichia coli and Staphylococcus aureus were overexpressed in E. coli (DE3) Rosetta pLysS after induction with IPTG (Zahn et al., 2013) the coding sequences were cloned into a pET 15b vector (GeneScript Biotech BV Netherlands) using restriction enzymes NdeI and NcoI coli (DE3) Rosetta pLysS was grown in LB broth containing ampicillin (0.1 g/L) and 0.0075% (v/v) Antifoam Y-30 to reach an optical density of 0.6 recorded at 600 nm on an orbital shaker (180 rpm Expression was induced with IPTG (1 mmol/L) resuspended in lysis buffer (20 mmol/L KH2PO4/Na2HPO4 5% (v/v) glycerol) containing 2 mmol/L DTT for DnaK or 3 mmol/L DTT for DnaJ expression (pH 8.0) and disrupted by FastPrep-24™ 5G (60 s Proteins were purified using immobilized metal affinity chromatography (IMAC The N-terminal sequence MGSSHHHHHHSSGENLYFQ was cleaved with TEV protease overnight at room temperature leaving only the sequence GGTHT at the N-terminus of all six proteins and proteins with the remaining His-tag were removed by IMAC Proteins were stored at −80°C in Tris-HCl (20 mmol/L) v/v) containing 2 mmol/L DTT (only DnaK) or 3 mmol/L DTT (only DnaJ) at pH 7.5 The purity of all proteins was verified with SDS-PAGE and the protein confirmed by identifying the tryptic peptides by LC-MS Dissociation (Kd) and inhibitory constants (Ki) were measured using a previously reported protocol with slight modifications (Krizsan et al., 2015; Kolano et al., 2020) Germany) were blocked with 0.5% (w/v) casein in phosphate buffered saline (PBS; 10 mmol/L Na2HPO4 pH 7.4) containing 0.05% (w/v) Tween® 20 (PBST) at 4°C overnight and washed three times with PBST Kd values were measured by dissolving the proteins in FP-buffer (20 mmol/L Tris-HCl pH 7.5) and serially diluting them twofold in 23 steps on the plate (20 µL/well) The 5 (6)-carboxyfluorescein-labeled peptide was added (20 μL/well and the fluorescence polarization recorded at an excitation wavelength (λex) of 485 nm and an emission wavelength (λem) of 535 nm using a PARADIGM™ microplate reader (Beckman Coulter Ki values were determined using a twofold dilution series of unlabeled peptide (20 µL/well) and DnaK (10 µL/well) The plate was incubated at 28°C in the dark for 90 min before the Cf-labeled peptides were added (10 µL/well the fluorescence polarization was recorded (λex = 485 nm Dissociation and inhibitory constants were calculated by fitting the data with a variable slope parameter [y = min + (max- min)/(1+(x/Kd) −Hill slope)] using SigmaPlot 13 (Systat Software Inc. aureus DnaK used unlabeled peptide (10 µmol/L for E aureus; 20 µL/well) pipetted into a 384-well plate and DnaK solutions of 20 µmol/L (E dark) and Cf-ARV-1502 (80 nmol/L; 10 µL/well) added λem = 535 nm) on the PARADIGM™ microplate reader Control samples either lacked the unlabeled peptide (maximum) or contained Cf-ARV-1502 in buffer (minimum) ATPase activity of E. coli and S. aureus chaperones was studied in the presence of an AMP using a 384-well plate colorimetric assay (Chang et al., 2008; Zahn et al., 2013) The peptide screening used a chaperone mix of DnaK respectively) dissolved in assay buffer (20 mmol/L Tris-HCl The chaperone mix (13.5 µL) was incubated with an aqueous peptide solution (1.5 µL; final concentration 0.3 mmol/L) at 37°C for 30 min in a non-binding 384-well plate (flat bottom Each sample was prepared in triplicates on the same plate The reaction was started by addition of ATP dissolved in assay buffer (5 µL 4 mmol/L) and the plate centrifuged (500 × g The released phosphate was quantified using an external phosphate dilution series (10–200 µmol/L KH2PO4 in assay buffer) prepared on each plate and treated equally as the samples The reaction was stopped by adding assay buffer (80 µL) to all samples except the phosphate dilution series Aliquots of all samples (10 µL) were transferred to a clear 384-well plate (flat bottom Greiner Bio-One GmbH) and malachite green reagent added (90 µL; mixture of malachite green in water (0.04% w/w) in aqueous sulfuric acid (3.5 mol/L) the absorbance was recorded at 620 nm on the PARADIGM™ microplate reader The phosphate standard curve was fitted by a hyperbolic equation y = (ax)/(b + x) + c Recombinant firefly luciferase (0.5 g/L) was denatured in luciferase buffer (25 mmol/L HEPES (pH 7.2), 50 mmol/L potassium acetate, 5 mmol/L DTT) containing guanidine hydrochloride (6 mol/L) at room temperature for 1 h (Wisén and Gestwicki, 2008) The denatured luciferase was 100fold diluted in luciferase buffer and incubated on ice for 20 min in the dark Peptides (4 µL; final concentration 150 µmol/L) were incubated in a non-binding 384-well plate (flat bottom Greiner Bio-One GmbH) with chaperone mix (41 µL; final concentrations: 240 nmol/L DnaK 48 nmol/L DnaJ and 24 nmol/L GrpE) in refolding buffer [28 mmol/L HEPES (pH 7.6) 35 U/mL creatine kinase) at 37°C for 30 min The reaction was started by addition of denatured luciferase (5 µL) dark) before 10 µL of each sample were transferred to a white 384-well plate (Greiner Bio-One GmbH) and diluted with detection buffer (20 µL; 25 mmol/L HEPES (pH 7.8) 10 min) in the PARADIGM™ microplate reader the luminescence was recorded using an integration time of 0.5 s Minimal inhibitory concentrations (MICs) were determined using a liquid broth micro dilution assay in sterile 96-well plates (polystyrene F-bottom Greiner Bio-One GmbH) and a total volume of 100 μL per well Aqueous peptide solutions (10 g/L) were serially twofold diluted in 25% Mueller-Hinton broth 2 (25% MBH2) starting at a peptide concentration of 128–1 µg/mL (50 μL per well) grown in 25% MHB2 were diluted 30-fold in 25% MHB2 After an incubation period of 4 h (37°C cells were diluted to 1.5 × 107 cfu/mL and 50 μL were added to each well (final concentration of 7.5 × 106 cfu/mL per well) 20 h) and the optical density was determined at 595 nm using the PARADIGM™ microplate reader The MIC was defined as the lowest peptide concentration preventing visible bacterial growth Human embryonic kidney (HEK293) and human hepatoma (HepG2) cells were cultured in Dulbecco’s modified Eagle’s/Ham’s F-12 medium (DMEM/F-12) containing 10% (v/v) fetal bovine serum and 1% (v/v) penicillin/streptomycin Cells (20,000/well; 200 µL) were seeded into a 96-well plate (polystyrene F-bottom Greiner Bio-One GmbH) and incubated for 24 h (37°C Cells were washed with PBS (100 µL) and peptide solutions (0.6 g/L in DMEM/F-12) were added The positive control consisted of a dilution series from 12 to 1.5% (v/v) DMSO and the negative control was 12% (v/v) PBS fresh medium (90 µL/well) and MTT (10 µL/well 5 g/L in PBS) were added and the plate was incubated for 4 h (37°C A solution (100 µL) of sodium lauryl sulfate [10% (v/v)] in hydrochloric acid (10 mmol/L) was added and the plate was incubated again for 24 h (37°C The absorbance was recorded at 570 nm relative to the reference at 650 nm (PARADIGM™ microplate reader) All samples were corrected for background extinction of the medium The relative cell viability was calculated using the ratio of the absorbance between treated and untreated cells Graphical representation of the studied chaperone system In total 183 peptides were designed and synthesized by substituting seven different positions in lead structure ARV-1502 (marked in red) by Asp Leu or Phe in different combinations (top) All peptides were studied for their effect on the DnaK/DnaJ/GrpE-chaperone systems of E and protein refolding activity as well as the antibacterial activity against one strain of each bacterium Fluorescence polarization measurements to study the interaction between ARV-1502 or substituted analogs and E Based on the dissociation constants (Kd) determined for Cf-ARV-1502 (A) the inhibitory constant (Ki) was measured for ARV-1502 (B) and six randomly chosen screening peptides (C) confirming a suitable dynamic range for the screening assay Dissociation constants (Kd) measured for ARV-1502 and the analog 102 Kd were determined with Cf-labeled peptides and recombinant proteins DnaK For the measurement with full chaperone system DnaK DnaJ and GrpE (ratio 0.6:1.0:0.9) were pre-incubated for 30 min at room temperature Fluorescence polarization of samples marked with * did not reach the upper plateau In addition to the elevated hydrophobicity the substituted position was also important for binding as eight of the ten best binding peptides were modified at residue 3 or 4 (mostly Phe or Lys; e.g or 97) and the other two peptides at residue eight or 10 (e.g while substitutions at residues 9 and 12 weakened the interactions Effect of amino acid substitutions on the binding of ARV-1502 analogs to E aureus DnaK using fluorescence polarization (FP) values normalized to ARV-1502 Comparison of the normalized FP values for E aureus DnaK with the hydrophobicity of each peptide represented by the GRAVY index score indicated by the spot color blue indicating a high hydrophobicity and red a low hydrophobicity (A) The FP curves of Cf-labeled peptide 102 as the most promising screening peptide indicated a much better binding than the original ARV-1502 sequence for both DnaK variants (B) Twelve peptides binding better or equal to E aureus DnaK than ARV-1502 (normalized FP ≤ 1) shared common features in the substitution patterns and the enrichment of certain amino acids in distinct positions [pie diagram; (C)] the Kd of Cf-ARV-1502 was lower for GrpE than for DnaJ the Kd of Cf-102 was 20-fold higher for the E coli DnaJ/DnaJ/GrpE-system than for DnaK alone 17 peptides affected the ATPase activities of E aureus DnaK and additional five peptides (54 The Phe3-Phe4 motif appeared to be very important as it was present in twelve of the 17 peptides (e.g. Peptides showing the strongest effects of the ATPase activities of E aureus (>160%) contained typically the original Asp3 or Lys4 although Asp was also frequently present at position 4 Asp substitutions occurred quite often in these sequences 58% of the peptides decreasing the ATPase activity of E coli DnaK by at least 40% and contained at least two Asp residues (e.g. while 41% of the peptides increasing the ATPase activity of S aureus DnaK by 60% or more had at least two Asp spread on the substituted positions (e.g. Dark grey letters indicate unmodified positions and light grey letters the common presence of the original amino acid while the color code indicates the property of the substitution The pie diagrams indicate the number of the sequences with no which improved DnaK-binding without affecting the ATPase activity was present in 10 of the 20 peptides (e.g. hydrophobic amino acids phenylalanine and leucine were favored at position 9 A substitution of Tyr8 did neither increase nor reduce the inhibitory effect the overall peptide hydrophobicity appeared to be more important than the substituted position for the refolding activity Impact of ARV-1502 or its substituted analogs on the refolding activity of the E aureus chaperone systems using a denatured luciferase refolding assay aureus (▲) chaperone systems in the presence of a substituted ARV-1502 analog relative to the chaperone system in the absence of a peptide (100%) The peptides were sorted by their hydrophobicity based on the GRAVY index score (A) Sequence alignment of 18 peptides inhibiting the refolding activity of the E Substituted positions are marked in darker grey (B) The MIC-values obtained for the Gram-negative strain E coli BW25113 ranged from 4 µg/mL to >128 µg/mL with only peptide 2 being more active than the lead structure ARV-1502 with an MIC of 8 µg/mL determined in parallel ARV-1502 was inactive against the Gram-positive strain S but this strain was susceptible to several substituted peptides with the lowest MIC-values at 16 µg/mL In total 68 and 76% of the tested peptides were inactive (MIC ≥128 µg/mL) against E which might relate to changes in the physicochemical properties as a result of some substitutions such as peptide 105 (Chex-RPFFPRPYLPRKRPPRPVR-NH2) and 103 (Chex-RPFFPRPYLPFPRPPRPVR-NH2) resulting in a minimum viability of 39% (±5%) in HepG2 and 61% (±6%) in HEK293 cells a relative viability of 78% (±4%) was achieved for HepG2 and 91% (±5%) for HEK293 cells Violin plot of the MIC-values determined for 179 substituted ARV-1501 peptides against E aureus (below) versus the peptide net charge expressed as difference of basic and acidic residues in each peptide sequence aureus DSM 6247 and the knock-out mutant E a) Sequences with a single Asp or Ser substitution showed significantly lower antimicrobial activities in E b) Peptides with similar antibacterial activities against both strains These peptides were chosen due to their behavior in the other screening (peptide 10: insufficient binding; 45: insufficient binding but high impact on ATPase activity; 102: best binding) inhibition of DnaK activity correlated well with the antibacterial activity Graphical representation of the influence strength of the studied peptides grouped by substituted amino acids x represents one of the five substituted amino acids Asp Peptides with high impact or good DnaK binding are shown in green and those with low efficacy or poor binding are shown in red the results of the respective tests were divided into five equal groups corresponding to the five color groups used The screening of 182 analogs derived from the lead PrAMP ARV-1502 provided interesting results allowing a better understanding of their effect on the functional activity of E Similarities and differences between the Gram-negative and Gram-positive chaperone systems could be identified which could help to develop antibacterials targeting the bacterial chaperone system or to target the human Hsp70 chaperones to treat chaperone-related diseases including cancer Substitutions with phenylalanine in ARV-1502 improved the binding to DnaK A stronger influence on the functionality of the chaperone system did not necessarily increase the antimicrobial activity which confirms that inhibition of the DnaK chaperone system does not kill the bacteria at least when using the favorable growth conditions applied for determining the MIC-values in vitro The dataset presented in this study can be found in the Supplementary Material (Table S3) AB and RH conceived and designed the experiments aureus and has cultivated the cells for cytotoxicity assay All authors critically revised the manuscript and agreed to be accountable for all aspects of the work Support from the National Institutes of Health (grant R41AI142829-01 to CK) and a PhD stipend from Universität Leipzig to AB is gratefully acknowledged The remaining authors declare that the research were conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest We thank Susanne Moschütz and Norbert Sträter for providing the E We acknowledge support from the German Research Foundation (DFG) and Universität Leipzig within the program of Open Access Publishing The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2022.798006/full#supplementary-material Differential Stability of Therapeutic Peptides with Different Proteolytic Cleavage Sites in Blood PubMed Abstract | CrossRef Full Text | Google Scholar Quantitation of a Novel Engineered Anti-infective Host Defense Peptide ARV-1502: Pharmacokinetic Study of Different Doses in Rats and Dogs PubMed Abstract | CrossRef Full Text | Google Scholar Tuning of Chaperone Activity of Hsp70 Proteins by Modulation of Nucleotide Exchange PubMed Abstract | CrossRef Full Text | Google Scholar Multistep Mechanism of Substrate Binding Determines Chaperone Activity of Hsp70 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Functional Effects of ARV-1502 Analogs Against Bacterial Hsp70 and Implications for Antimicrobial Activity Received: 19 October 2021; Accepted: 11 January 2022;Published: 09 February 2022 Copyright © 2022 Brakel, Kolano, Kraus, Otvos and Hoffmann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use *Correspondence: Alexandra Brakel, YmlvYW5hbHlAcnoudW5pLWxlaXB6aWcuZGU=; Ralf Hoffmann, YmlvYW5hbHlAcnoudW5pLWxlaXB6aWcuZGU= 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 Authorities are searching for a 16-year-old Cheyenne girl who ran away from home early this morning ran away from their home in Sun Valley with her dog who is an Australian Shepherd with a merle coat and two different colored eyes is Kassidy's "achilles heel" and will likely be with her Anyone who knows Kassidy's whereabouts is asked to call the Cheyenne Police Department or the Laramie County Sheriff's Department Authorities are searching for a 16-year-old Cheyenne girl who ran away from home early this morning.\nRead More Anyone who knows Kassidy's whereabouts is asked to call the Cheyenne Police Department or the Laramie County Sheriff's Department Residents from Lismore to the Lower Macleay in northern New South Wales under evacuation orders Residents from Lismore to the Lower Macleay in northern New South Wales are under evacuation orders after a body believed to be that of a missing nurse was found The State Emergency Services received 652 calls for help and performed 23 rescues in the past 24 hours Already drenched areas could see flash flooding with saturated soil increasing the risk of falling trees NSW police believe they have found the body of aged care nurse Anita Brakel who went missing in flood waters south of Lismore almost three days ago The body of a 55-year-old woman was found on Thursday evening in North Lismore While the body is yet to be formally identified who became trapped in her white station wagon at Monaltrie about 10pm on Tuesday heavy surf and high tides are expected in southern NSW on Friday as flood waters in the north of the state recede 1:14NSW floods: drone footage shows scale of devastation in Lismore – videoGusts nearing 100km/h have been recorded across the state with the Bureau of Meteorology warning of possible 9m waves along coastal areas Heavy swells forced Sydney transport authorities to shut down the Manly to Circular Quay ferry on Friday The rain that has battered the north for most of the week is now easing as Lismore and Byron Bay reel from another round of flooding although that was below expectations of 12m The BoM said the waters were now below the 10.6m height of the city’s levee But evacuation orders are in place from North Lismore to as far south as the Lower Macleay the Rapid Relief Team charity was donating tonnes of hay to flood-affected farmers to help them feed stock after two floods very devastating to come through Lismore and see what they’ve been through,” charity director Lester Sharples said Thirty truckloads of hay were driven north from NSW’s Cowra and Griffith regions with flooded roads adding hours to drivers’ journeys The charity has set up at Lismore’s airport where it is doling out food while other agencies offer mental health and financial support “It’s important to get these farmers back online,” Sharples said With two low pressure systems colliding over the state’s south-east rainfall is hitting Newcastle and Sydney on Friday and is expected to extend down to the Victorian border into the weekend before easing on Sunday which has been criticised for its flood response by the opposition and Lismore and Byron Bay residents has partnered with the national non-profit GIVIT to encourage the public to donate to flood victims The government said the arrangement would allow councils local charities and community groups to tell authorities what they need GIVIT works to meet these needs through an online warehouse or by purchasing requested items locally using donations We couldn't find the page you were looking for here are some ways to continue your journey: Notices are posted by 10 am Monday through Saturday Adjust Text Size: A+ A- uncle and friend left this world to continue on with his journey he leaves to mourn his wife Louise; his daughter Melissa who was his ray of sunshine (her mother Rita); Jeffrey and Jennifer his step-children whom he loved as his own; his sisters and brothers Frank was predeceased some years before (1968) by his mother and father Frank and Helen Brakel A small private service will be held at Green Acres Special thanks to his nephew Rick for his concern and support over the last few months De Rocquigny and the staff at the Victoria Hospital may God hold you in the hollow of his hand I hope you are walking free and without pain along the white beaches of the Caribbean somewhere GREEN ACRES Funeral Home and Cemetery Hwy As published in Winnipeg Free Press on Jan 12 Share your memories and/or express your condolences below Unfortunately with the need to moderate tributes for inappropriate content your comments may take up to 48 hours to appear