the son of the late Walter and the late Mildred Harigle Kandel Paul was employed for 44 years as a millwright at Republic / WCI Steel Army and a member of Champion Presbyterian Church Champion Athletic Association and the Optimist Club of Champion He is survived by his beloved wife of 60 years Paula (Bill) Zigmont and Donna (Donald) Stevens; son McKenzie and Ryan (Katie); and great-grandchildren at Champion Presbyterian Church where Pastor Alice Phillips will officiate Interment will be in Champion Township Cemetery in Champion Arrangements have been entrusted to Carl W | https://www.tribtoday.com | 240 Franklin Street SE Stanford University The talk focused on Kandel’s work at ISFI in diagnosing what Kandel and his colleagues identify as internal existential risks for Israel and the policy ideas generated by ISFI in response to those risks Kandel began his analysis by pointing out the fact that the post-Cold War era has been one of spectacular economic success for Israel The country entered 2022 with a budget surplus Describing a deep demographic shift towards the Haredi (ultraorthodox) and religious-nationalist population as well as growing structural weaknesses in Israel’s economy and government Kandel warned that Israel could face a "run on the country" if it did not provide the most productive parts of its population with guarantees that their values would be protected Kandel outlined the three incompatible ideological groupings found in Israeli society One group believes in Jewish liberal democracy one is primarily Hasidic and believes in the Torah’s centrality and one desires a non-Jewish country for all citizens Disproportionate population growth in the Hasidic group puts liberal democracy at risk while Hasidic citizens rely heavily on social services Every Israeli citizen would be a member of one of three "Alumot"—a word meaning clusters—each with their own constitutions Changes in government would require consensus from all three Alumot Since citizens would choose their Alumot freely and could even switch between them the Alumot serving members would be motivated to improve citizens’ lives and economic conditions Magen countered that Kandel's proposals wrongly gave up on a shared Israeliness that - with all its difficulties - has proven highly successful in the past seven and a half decacdes and that the Alumot idea is politically impractical Kandel and Magen discussed how the current issues with Israeli society are the same limiting factor in adapting a new political system They also discussed how Jews outside Israel can help the Israeli government thrive and how Israel needs to address its internal conflicts if it has a realistic prospect of successfully managing its external challenges A full recording of the conversation can be viewed below Learn more about how your support makes a difference or make a gift now Our editors will review what you’ve submitted and determine whether to revise the article Kandel’s books included The Age of Insight: The Quest to Understand the Unconscious in Art and Brain: From Vienna 1900 to the Present (2012) and The Disordered Mind: What Unusual Brains Tell Us About Ourselves (2018) In Search of Memory: The Emergence of a New Science of Mind (2006) was an autobiography known affectionately to her friends as Flip and to the rest of the world as “Grandma” John Robert Paddison (Bob,1923-2021) for all but a few years of her life Phillippa is survived by her four children Paddison (Jeanne); seven cherished grandchildren along with many nieces and nephews who played significant roles in her life first on Gaston Street and later at 432 Abercorn Street on what is now known as Taylor Square Her spirit of service started early as she knit socks for the troops in WWII and taught swim lessons for the Red Cross in the creeks of Harrock Hall Phillippa attended Armstrong Junior College for two years where she met Bob Paddison in a biology class and later became life partners for 69 years She finished her BS at Georgia State College for Women where she studied math and chemistry She obtained her MPH from Columbia University After working in the mountains of North Carolina in Public Health she began a lifetime of service to her family and the community Phillippa taught Sunday School and was committed to the Social Justice and Religious Education programs at the Unitarian Universalist Church of Savannah The RE classrooms were named Phillippa’s Place in her honor She volunteered in the Savannah-Chatham public schools teaching art and tutoring math at Jenkins High School for 20 years She was a weaver and active in the Fiber Guild of the Savannahs for many years Her weaving appears in the giant oak fiber sculpture in the Oatland Island Wildlife Center Visitors center place mats and other fabric creations throughout the community creative woman who worked quietly to back up her deep belief in equity and social justice – making banners and marching in the Martin Luther King Parade preparing soup and sandwiches and serving at the Inner City Night Shelter Calculus & Statistics to many Savannah students until she was in her late 80s A graveside memorial for immediate family members will be held at a later date memorial contributions can be made in Phillippa Kandel Paddison’s honor to Hospice Savannah Donations can also be made online at [Hospice Savannah Donations](https://www.hospicesavannah.org/give-2/donations/) Oatland Island Wildlife Center at [Friends of Oatland](https://www.friendsofoatland.org/support) or Wesley Wesley Community Center Inc 1601 Drayton St GA 31401 (https://www.wesleyctrs-savh.org/How-Can-I-Help) When you think about the best parts of life the best of life is “just eating and drinking and being in love,” as he mentions on the intro to his debut album It’s talking to those you care about the most These are the moments that Theo captures on the album and they’re moments that he invites listeners to be a part of and enjoy to the fullest and blissful song with pop and folk elements throughout making it impossible not to feel happy when listening Theo mentions how he and his lover can start a life together We lean more towards reality in the middle of the album where Theo further explores the highs and lows of life He tells us that there will be times when life will get you down on “Fixer Upper,” reminding us that not everything works out in the end the warm folk feel of the track keeps it from being too downhearted On “Nothing New,” Theo’s mood picks up as he thinks about spending the rest of his life with someone he loves Accompanied by acoustic-based melodies and tender folk harmonies he figures that there will come a point in his life when he has seen and done everything there’s nothing new / If I got you.” Theo then cherishes a night with friends on the appropriately titled “One More Night (With My Friends in the City).” The wholesome full band sound moves the track along as Theo surrounds himself with good company We get the sense that his friends keep him grounded as he is able to both party and talk about “existential dread” in front of them The last few tracks on Eating & Drinking & Being in Love really drive home the essence of the stories we have heard so far, as they highlight the importance of life’s small moments. There is much to take from “On My Mind,” a striking mix of random yet specific lines Theo constructs a whole world through various feelings and memories which he imparts in lyrics like “It’s like running down the subway steps and knowing you missed the train” and “It’s like driving to the hospital where your grandma should be on the mend.” It’s so interesting to hear how everything works together and how you can still feel moved by these little vignettes After the fiery spoken word interlude of “Joshua Tree,” Theo gives us “Romanticizing Poets.” With its sweeping strings the track transports us to elegant places that would inspire the most gifted of poets “I think the best way you can help someone is just being where they are / With your head upon my shoulder / Looking out onto the sand / Oh I’m romanticizing poets again.” We realize how easy it is for Theo to take a seemingly ordinary moment and build it up to be something more He also does this on “Teeth,” which closes the album Compared to the first few songs that open the album as it contemplates the possibility of letting someone go the idea of being patient and accepting whatever happens in life also comes through Eating & Drinking & Being in Love is a simple yet moving debut from Theo Kandel The light production makes the songs straightforward allowing the focus to be on Theo’s vocals and words His sweet singer-songwriter vocals only add to the power of the words perfectly enriching the descriptions in the lyrics We then get such strong visuals from the lyrics on each track allowing us to see and feel what Theo sees and feels as he sings which is precisely what Theo aims to achieve with his music “I want people to find my moments in their lives When I find my own life in other artists’ music I’m just trying to be everyone’s best friend.” With this album Theo has given fans many opportunities to find their own moments in these songs You can listen to Eating & Drinking & Being in Love on platforms like Spotify Theo is currently on tour with Jordy Searcy until October 30. You can also find him opening up for The Script on September 30 at Brooklyn Paramount in New York. All tickets and more information can be found here Keep up with Theo Kandel: Instagram // X // Facebook // TikTok // YouTube // Substack // Website Independent and fueled by love and dedication Donate to fuel us figuratively and literally Mention "☕️" or "coffee" and $5 of your donation will go to a random staff member to keep them energized Please select what you would like included for printing: Copy the text below and then paste that into your favorite email application at Ohio’s Hospice House in New Philadelphia Clarence led a fulfilling life enriched with meaningful experiences and cherished moments leaving a lasting impact before embracing a well-deserved retirement Clarence found joy in various activities such as fishing and indulging in the soulful melodies of country music His love for sports extended to cheering for the Cleveland Indians and following exciting NASCAR races he found solace in the simple pleasure of watching these sports accompanied by his favorite snack - peanut butter One of Clarence's greatest joys was spending quality time with his grandchildren whom he adored dearly His warm personality and genuine affection created lasting memories that will be treasured by his family for generations to come He leaves behind his daughter; Erica Kandel (Chris Rhodes) of New Philadelphia and Emma Robinson of Virginia; and his two sisters he was also preceded in death by his daughter A funeral service will be held at 11:00 a.m visit the obituary link on the funeral home’s website.  Memorial contributions can be made to Ohio Hospice House Enter your phone number above to have directions sent via text This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply Service map data © OpenStreetMap contributors 2024 at 11:47 am ET.css-79elbk{position:relative;}Tyler Kandel (Borough of Metuchen)METUCHEN Councilman Tyler Kandel revealed that he had been diagnosed with multiple myeloma a form of cancer that affects the bone marrow including the physical toll and potential changes in appearance Kandel vowed to fight for their family and community The Councilman also clarified that he would continue to work for the Borough as an elected councilman In an emotional speech that lasted a little over seven minutes Kandel said he felt the need to let the community know of his diagnosis “It was discovered after I was experiencing several weeks or month of pain in my side which ultimately led me to the JFK emergency room late one night about a week and a half ago I was then given the bad news over the following few days after testing,” Kandel said The councilman said that since his diagnosis reached out to him directly to offer support Some of them were even present during the meeting on Monday “I can't put into words how much it's meant to me over the last week but I'm holding myself by a thread knowing that you took time out of your lives with what's going on in your lives to come here for me,” Kandel said Kandel is currently in the process of getting all the information about upcoming treatment and said that the road ahead will be “challenging and likely painful.” "I know the physical toll it will take on my body,” Kandel said “But the same fighter that has always been inside of me will be there the same fighter that you elected and re-elected will be there And I vow that I will not give up on that fight.” and council members for their support and reiterated his commitment to serving the community He told the community he had considered resigning at one point but decided against it after speaking with fellow council members and the Mayor “I've decided that I'm not going to resign and while you may not see me at every council meeting going forward you may not see me at every committee meeting that I'm a liaison to you may not see me at every business opening — but I will be working as hard as I can behind the scenes to contribute what I can to this borough and I will get through this difficult time and continue to contribute,” Kandel said Kandel also emphasized the importance of giving back to the community and the profound impact of the support he received A lot of my time volunteering for other people as great as it possibly could for other people and for my own family,” Kandel said “I have never expected or asked for anything in return this is what I've gotten out of it — is you guys being here for me and reaching out directly to me with your texts and calls and offers to help I can't tell you how much it means to somebody in my situation Have a correction or news tip? Email sarah.salvadore@patch.com Get more local news delivered straight to your inbox. Sign up for free Patch newsletters and alerts. Dear Reader,Unfortunately our comment platform isn\'t available at the moment due to issues with our paywall and authentication vendor who was diagnosed with multiple sclerosis late last year spoke of her journey with the disease with “MeSsy” hosts Christina Applegate and Jamie-Lynn Sigler last week On their popular podcast “MeSsy,” actors Christina Applegate and Jamie-Lynn Sigler have weekly conversations about how they each live with multiple sclerosis the pair chatted with Napa baker Rory Kandel about her journey with the disease in an episode that is making national headlines In an hourlong, eye-opening talk, Kandel, who opened Rory’s Bakehouse in 2020 selling frozen spoke frankly about how she navigates her daily life and growing business while living with MS A fan of the podcast since it launched in March, Kandel was invited onto the show after sending a letter in September to “MeSsy” producer, Allison Bresnick, giving her thanks and sharing a San Francisco Chronicle article about her own journey an incurable chronic disease in which the immune system attacks the body’s nerves after about three months of tests to determine why she was feeling pain and numbness in her feet and legs you start to search for information,” Kandel said “Christina Applegate had been pretty open about her MS diagnosis and Jamie-Lynn Sigler had come out with hers as well not too long ago.” Applegate publicly revealed her diagnosis in 2021 who has lived with the disease for 20 years who knew nothing about the disease before her diagnosis began reading everything she could about Applegate and Sigler’s experiences was the first place she found information about the disease from “real people who had it and not just from doctors.” Since the episode’s Nov. 5 release, media outlets including People have reported on the podcast conversation largely due to Applegate’s reveal that she at times lays in bed screaming from pain which she said on the show has recently traveled into her hands Kandel and the two hosts talked about living openly with MS and their struggles with being seen as an inspiration for others as well as how they cope with the fear of the disease’s inevitable progression while pushing themselves to keep going “I wake up every day and feel as if I were hit by a bus,” Kandel told The Press Democrat “I sometimes feel like my body is like Lego bricks not fitting together inside Kandel said she finds therapy in her baking “It puts me in a mental flow where I am able disengage for the pain.” Kandel has recently taken on two assistants to help in the kitchen but said she hopes to keep baking as long as physically possible which sells frozen treats for pickup in Napa and delivery in the Upvalley region of Yountville and St launched her first product available for nationwide shipping “I love everything about it,” she said of the cookie the larger size makes it the perfect chocolate chip cookie.” Kandel is also preparing to open a retail window later this year at her kitchen on 2766 Old Sonoma Road where customers will be able to stop by and get frozen products to-go as well as a few ready-to-eat treats everything from Rory’s Bakehouse is available for preorder only Kandel says people have been reaching out to her with their own MS stories and she feels “much less alone” in her battle with the disease “I had the decision to make whether I was going to hide or be open (about MS),” she said “I worried about how it was going to affect my business and all it’s done is create a sense of support I never could have imagined I would have I’m so grateful to have been on the podcast and everything it’s already done for me Listen to Kandel’s episode at messythepodcast.com and get more information her baked goods at rorysbakehouse.com of New Philadelphia passed away suddenly on Saturday he was the son of the late Dan and Alma (Sommers) Kandel.   He was also preceded in death by his brothers He dedicated over 45 years at Alsco Anaconda in Gnadenhutten before his retirement Robert found solace in the simple joys of life He had a green thumb and enjoyed tending to his garden he cherished moments spent deer hunting and fishing at Lake Erie These activities brought him immense happiness and allowed him to connect with nature.  Robert will be sadly missed by his daughters; Barb Bushong of New Philadelphia and Karen (Jeff) Miller of Lewis Center; his grandchildren Nathanael Miller (Amy Elizabeth Uebel) of Alexandria Nick Miller of Columbus; three great-grandchildren Clarence Kandel of New Philadelphia; his sisters and Nancy (Jim) Schneider of Dundee; his sister-in-law Darlene Kandel of Stone Creek; along with eight nephews A funeral service will be held at the Toland-Herzig Funeral Homes & Crematory in Dover on Tuesday at 12:00 pm with Pastor Jody Jones officiating  Friends can call at the funeral home on Tuesday one hour prior to the service  To sign an online guestbook for Robert visit the obituary link on the funeral home's website Memorial contributions can be made to the American Heart Association, https://www.heart.org  Tissue Engineering and Regenerative Medicine Volume 10 - 2022 | https://doi.org/10.3389/fbioe.2022.885369 Standard assessment of cartilage repair progression by visual arthroscopy can be subjective and may result in suboptimal evaluation Visible–near infrared (Vis-NIR) fiber optic spectroscopy of joint tissues including articular cartilage and subchondral bone provides an objective approach for quantitative assessment of tissue composition we applied this technique in the 350–2,500 nm spectral region to identify spectral markers of osteochondral tissue during repair with the overarching goal of developing a new approach to monitor repair of cartilage defects in vivo Full thickness chondral defects were created in Yucatan minipigs using a 5-mm biopsy punch and microfracture (MFx) was performed as a standard technique to facilitate repair Tissues were evaluated at 1 month (in adult pigs) and 3 months (in juvenile pigs) post-surgery by spectroscopy and histology Vis-NIR spectra were collected in situ from the defect region Additional spectroscopy experiments were carried out in vitro to aid in spectral interpretation Osteochondral tissues were dissected from the joint and evaluated using the conventional International Cartilage Repair Society (ICRS) II histological scoring system which showed lower scores for the 1-month than the 3-month repair tissues hemoglobin absorbances at 540 and 570 nm were significantly higher in spectra from 1-month repair tissue than 3-month repair tissue indicating a reduction of blood in the more mature repair tissue we observed qualitative differences between the two groups in spectra taken from the defect but differences did not reach significance spectral data also indicated that the hydrated environment of the joint tissue may interfere with evaluation of tissue water absorbances in the NIR region these data provide support for further investigation of the visible spectral region for assessment of longitudinal repair of cartilage defects which would enable assessment during routine arthroscopy progression of an injury or degradation of this tissue can result in the debilitating disease osteoarthritis (OA) this spectral region may provide information on hemoglobin which would indicate the presence of a blood clot and/or neovascularization in the repairing tissue typically present in the early stages of repair and less so at the later stages The overall aim of this study was to evaluate the potential of Vis-NIR fiber optic spectroscopy to assess molecular changes related to tissue repair in osteochondral tissues in situ in a porcine preclinical model This was carried out by collection of spectra from tissues at the defect site followed by experiments to facilitate spectral interpretation The depth of detection of diffuse reflectance spectra in the Vis-NIR spectral regions was also investigated Animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Pennsylvania and performed in the animal facility at the University of Pennsylvania Animals in the current study were part of larger studies at U Penn where the mature and immature animals comprised separate studies six skeletally mature (age 12 months at the beginning of the study) Yucatan minipigs (Sinclair Bioresources three juvenile (age 6 months at the beginning of the study) Yucatan minipigs (Sinclair Bioresources full thickness chondral defects were created bilaterally in the trochlear groove using a 5-mm biopsy punch and distal locations of the medial and lateral sides (six defects in the right hind limb per animal MFx treatments were randomized from joint to joint to enable consistency with regard to their load-bearing location Awl-based microfracture procedures (diameter: 0.8 mm; depth: 2 mm) with three marrow stimulation holes were carried out there were n = 9 microfracture-treated cartilage defects in the 1-month animal study and n = 6 microfracture-treated cartilage defects in the 3-month animal study The animals were housed and recovered under veterinary care At the end of the study period (1 or 3 months post-surgery) and the tissues were evaluated spectroscopically and histologically (in addition to other end-point tests related to the original studies A Spectralon standard underneath the tissues was used as a control for data collection Schematic of light scattering through cartilage tissue and a semi-infinite reflecting surface Full depth explants of the defect repair tissue regions were fixed in 4% paraformaldehyde for 24 h Samples were decalcified for 8 weeks by placing the samples in 50-ml conical tubes with 15–20 ml of decalcification solution (Formical-2000) with intermittent changes To account for variations in subchondral histomorphology with sectioning depth into the tissue block we obtained sections approximately from the center of each defect region observing the size of the defect region as guide to select the appropriate sections (larger defect The embedded samples were sectioned at 8 microns thickness onto the glass slides the section with the largest defect region was stained with Safranin-O (0.2%) and fast green (0.02%) and imaged under a bright field microscope One adjacent section from each block was obtained for Fourier transform infrared (FTIR) spectral imaging Four blinded independent observers previously trained in ICRS scoring of tissues reviewed and scored control and defect sections using the ICRS II Histological Assessment Scale (Mainil-Varlet et al., 2010) While all parameters that comprise the ICRS II scale were scored on a scale from 0 (poor defect repair) to 100 (normal articular cartilage) only the following parameters having significant differences between the two groups were reported: overall average score The four observer scores obtained for each parameter were averaged 10 measurements were taken and averaged to calculate the defect thickness in each sample Results of measurements were reported as means and standard deviations Comparisons of parameters between 1- and 3-month repair tissues were assessed by a Wilcoxon Rank Sum Test (ICRS II scores ad sub-scores) or Student’s t-test (defect thickness and spectral parameters) considering p < 0.05 for significance The detection depth of the NIR signal into tissue was assessed by monitoring the signal intensity of PET signature peaks at 8,865 and 6,000 cm−1 (Figure 2A). The 8,865 cm−1 peak could be detected through 4 mm of cartilage thickness as shown in Figure 2B; however, in the lower frequency range, the 6000 cm−1 absorbance was only detected through 3 mm of cartilage (Figure 2C) (A) Second-derivative spectra of harvested cartilage tissue collected on top of a semi-infinite PET block or on Spectralon standard (without PET) The depth of detection of PET signal at higher and lower frequencies was monitored by assessment of the PET signal at 8865 cm−1 and 6000 cm−1 (B) 8865 cm−1 signal intensity can be detected with a cartilage thickness of up to 4 mm (C) 6000 cm−1 PET signal intensity can be detected with a cartilage thickness of up to 3 mm only It is known that light penetration into biological tissue is greatly diminished in the visible region (Ash et al., 2017). Thus, it was not surprising that the PET signal at 375 nm was not detectable even through a cartilage thickness of 1.6 mm (Figure 3) (A) Second-derivative spectra of cartilage tissue (1.6 mm) with and without a semi-infinite PET polymer (25 mm) and the polymer alone showing the PET peak at 375 nm and cartilage peak at 420 nm (B) Second-derivative peak intensity with and without PET underneath cartilage tissue Histological staining and blinded ICRS II scoring revealed better repair after 3 months in the juvenile animals than 1 month of repair in the mature animals (Figures 4A,B). As expected, repair tissue at 3 months had higher combined total average score (Figure 4B) and better surface architecture and vascularization within the repair tissue than the 1-month repair tissues (p < 0.01) (A) Saf-O- and fast green-stained images from 1-month (n = 9) and 3-month (n = 6) animals with the defined repair tissue region (B) Mean and standard deviation of ICRS II component scores (comparisons by the Wilcoxon rank sum test (A) FTIR images based on the 1338 cm−1/Amide II areas after 1 month of repair in a mature animal (n = 9) and 3 months of repair in a juvenile animal (n = 6) The measurement lines of defect thickness are shown including both cartilage repair and subchondral remodeling regions (B) Defect thickness is significantly greater in the 3-month animals (Student’s t-test) Average (A) raw and (B) second-derivative inverted Vis-NIR spectra from 1-month (n = 9) and 3-month (n = 6) defects in situ The visible spectra clearly depict the differences in hemoglobin absorbance (540 and 570 nm) between 1-month and 3-month repair Quantified second-derivative peak intensities of hemoglobin peaks at (C) 540 nm and (D) 570 nm showing greater hemoglobin detection in the 1-month tissue (Student’s t-test) Average (A) raw and (B) second-derivative inverted NIR spectra from 1-month (n = 9) and 3-month (n = 6) defects in situ The spectra highlight qualitative differences in water absorbances at 5,200 cm−1 and 7,000 cm−1 between 1 month and 3 months of repair Quantified second-derivative peak intensities of (C) water absorbances and (D) matrix absorbances in 1- and 3-month defects no significant differences were found in intensities between 1- and 3-month defects (Student’s t-test) The subchondral bone influence on the NIR spectra of the defect can also be observed in the 8250 cm−1 region which shows the absorbance peak in both subchondral bone and in the defect while the isolated repair tissue does not have this absorbance (A) Schematic of data collection from the defect tissue (in situ) and individual components (B) Second-derivative spectra from the defect in situ and isolated repair tissue and subchondral bone ex vivo in the visible range demonstrate the hemoglobin peak intensities at 540 and 570 nm in the defect tissue are more similar to those in the repair tissue than to those in subchondral bone (C) Second-derivative spectra in the NIR region demonstrate the differences in the water absorbances in the repair tissue in ex vivo compared to in situ spectra the influence of subchondral bone on the in situ defect spectrum is apparent while absent in the isolated repair tissue spectrum those outcomes were based on artificial neural network analyses we highlight an expanded spectral range to include the visible region hemoglobin absorbances This was shown to be a valuable tool for assessment of changes in in vivo repair tissue in a Yucatan minipig chondral defect model and potentially in other animal models and clinical scenarios in which NIR spectral data from intact joints reflected subchondral bone properties this blood-rich tissue is gradually replaced by cartilaginous repair tissue over time; thus the reduction in blood content can be used as a spectral marker for the progression of cartilage repair It is important to note, however, that this relatively quick repair progression may be related to the animal model, as rabbit cartilage has been described as having high potential for spontaneous healing (Chu et al., 2010). It is thus possible that in humans and large animals, the clot phase may persist for over weeks before progressive maturation into fibrocartilage repair tissue (Fortier et al., 2012; Guermazi et al., 2015) our results indicate that the amount of blood clot and/or neovascularization in the repair tissue is greater in adult pigs after 1 month of defect creation than in juvenile animals after 3 months The more intense neovascularization is observed by the lower ICRS II scoring (indicating more presence of blood vessels) and the greater blood content (possibly in the clot and/or within blood vessels) was detected by Vis-NIR fiber optic spectroscopy we also found the influence of subchondral bone on the in situ defect spectra based on this peak to fully investigate the repair of the cartilage defects in Yucatan minipig models It is important to acknowledge limitations of this study with respect to comparing repair tissue from animals of different ages. This issue can be highlighted based on the study by Pfeifer et al. (2017) which described age-dependent differences in cartilage repair in juvenile (6 months) and skeletally mature (18 months) Yucatan minipigs Similar to the animals in the current study they evaluated tissue repair at the stifle joints after creating full thickness defects in the trochlear groove followed by treatment with MFx it was noted that the juvenile pigs had more extensive subchondral bone remodeling but overall better quality of repair tissue we analyzed tissue repair after 1 month using adult animals whereas juvenile animals were used to analyze repair after 3 months our juvenile animals had better quality repair tissue (ICRS II scores) but a more extensive subchondral bone remodeling (quantified here as a greater defect thickness) It is possible that these differences arise not only from the length of time of post-operative tissue repair but also as a difference between juvenile and adult animals This would be an important confounding factor with respect to making conclusions about the progression of MFx-based cartilage repair taken from the center region of the defect assessment of defect repair by Vis-NIR spectroscopy Differences in composition between repair tissue with better (juvenile animals 3 months of repair) or poorer (adult animals 1 month of repair) quality can be investigated using this modality this study can have a significant impact as a foundation to inform on the design of future preclinical and clinical studies for a longitudinal spectroscopic analysis of chondral and osteochondral defect healing The raw data supporting the conclusion of this article will be made available by the authors The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Pennsylvania and HZ; resources: RM and NP; supervision: RM and NP This study was supported by the NIH (R01AR056145 Additional funding was provided by the Department of Veteran’s Affairs (IK6 RX003416) and the NSF (CMMI: 15-48571) The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest 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 The author would like to thank the veterinary staff at the University of Pennsylvania’s University Laboratory Animal Resources (ULAR) for their help in the study The authors are grateful for the Penn Center for Musculoskeletal Disorder (PCMD) histology core (NIH P30AR069619) Depth Profile of Diffuse Reflectance Near-Infrared Spectroscopy for Measurement of Water Content in Skin PubMed Abstract | CrossRef Full Text | Google Scholar Effect of Wavelength and Beam Width on Penetration in Light-Tissue Interaction Using Computational 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Google Scholar Composition and Structure of Articular Cartilage CrossRef Full Text | Google Scholar Near-infrared Spectroscopy Enables Quantitative Evaluation of Human Cartilage Biomechanical Properties during Arthroscopy PubMed Abstract | CrossRef Full Text | Google Scholar Applications of Vibrational Spectroscopy for Analysis of Connective Tissues PubMed Abstract | CrossRef Full Text | Google Scholar Arthroscopic Determination of Cartilage Proteoglycan Content and Collagen Network Structure with Near-Infrared Spectroscopy PubMed Abstract | CrossRef Full Text | Google Scholar Arthroscopic Near Infrared Spectroscopy Enables Simultaneous Quantitative Evaluation of Articular Cartilage and Subchondral Bone In Vivo PubMed Abstract | CrossRef Full Text | Google Scholar Cell Origin and Differentiation in the Repair of Full-Thickness Defects of Articular Cartilage CrossRef Full Text | Google Scholar Arthroscopic Assessment of Cartilage Repair: A Validation Study of 2 Scoring Systems CrossRef 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Infrared Imaging Spectroscopy Analysis of Collagenase-Induced Cartilage Degradation PubMed Abstract | CrossRef Full Text | Google Scholar Near-Infrared Spectroscopy Predicts Compositional and Mechanical Properties of Hyaluronic Acid-Based Engineered Cartilage Constructs PubMed Abstract | CrossRef Full Text | Google Scholar Modeling Diffuse Reflectance from Semi-infinite Turbid Media: Application to the Study of Skin Optical Properties PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: visible–near infrared (Vis-NIR) Mauck RL and Pleshko N (2022) In Situ Assessment of Porcine Osteochondral Repair Tissue in the Visible–Near Infrared Spectral Region Received: 28 February 2022; Accepted: 13 June 2022;Published: 23 August 2022 Copyright © 2022 Kandel, Querido, Falcon, Zlotnick, Locke, Stoeckl, Patel, Patil, Mauck and Pleshko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use 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: Nancy Pleshko, bnBsZXNoa29AdGVtcGxlLmVkdQ== 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 − A 47-year-old Millersburg-area man died Monday one day after he was seriously hurt in a two-vehicle crash in the township The Summit County Medical Examiner's Office pronounced Rodney W A helicopter later transported him to Summa Health Systems Akron Campus Related: Man riding motorized bicycle dies following two-vehicle crash in Canton Township The patrol said Kandel and a 48-year-old female passenger were riding a 2011 Harley Davidson motorcycle south on state Route 21 (Erie Avenue NW) near Crestline Street SW around 3:15 p.m was driving a 2011 Honda CR-V north on Route 21 The Honda CR-V drove across the center line and collided head-on with the motorcycle The Honda went off the west side of the road The motorcycle ended up in the southbound lane Erie Valley EMS transported Kandel and his female passenger to Aultman She was later taken by helicopter to Cleveland Clinic Akron General Hospital The patrol said it's still trying to determine the cause of the crash The patrol does not suspect alcohol or drug use contributed to the collision Kandel and his passenger were not wearing helmets or protective equipment Phone : +977-1-4222921 Email : risingnepaldaily@gmail.com Acting Editor-in-Chief(Print) : Bhimsen Thapaliya Columbia Vagelos College of Physicians and Surgeons is dedicated to developing the next generation of leaders in medicine Read the latest news stories about CUIMC faculty University Professor Emeritus and Nobel laureate and the areas beyond Columbia and science that benefited from his work The program featured a screening of a 2018 video interview with Kandel dean of the Vagelos College of Physicians and Surgeons and remarks from Kandel’s colleagues Steven A chair of the Department of Neuroscience; Andrew Marks chair of the Department of Physiology & Cellular Biophysics; Helen Blair Simpson interim chair of the Department of Psychiatry; and Richard Axel co-director of the Zuckerman Mind Brain Behavior Institute The remarks touched on Kandel’s achievements in scientific research as well as his commitment to mentoring the next generation of scientists “Eric has shown me what it means to be a citizen of community to embody it and make it better every day,” Armstrong said “He reminds me how it is possible to live a great and rewarding life in an environment where we come together to serve others and the greater purpose of science and humanity Eric has used his platform to teach us how to elevate each other and share what science can mean He himself embodies the very appetite that he studied in his career—for embarking on new fields and crossing boundaries.” from where he and his family escaped in 1939 after the Nazi invasion Kandel’s early struggles helped inform both his lifelong commitment to Austrian culture and the people of Austria “There is a quest for truth that underlies Eric’s life,” Axel said “His science is suffused with the spirit of creativity and a deep commitment to sharing this knowledge with the world The visual exhibit honoring Kandel in the Schaefer Awards Gallery outside the Alumni Auditorium includes two wall displays one focused on his Columbia contributions and one that focuses on his contributions beyond Columbia The exhibit also includes 10 banners with more details about his life and career The wall exhibit will be on view in the gallery through June and the banners will remain in the gallery through Feb Eric Kandel and Scott Schell explore part of the visual exhibit honoring Kandel in the Schaefer Awards Gallery Kandel is the founding co-director of the Zuckerman Institute and the founding director of Columbia's Kavli Institute for Brain Science. He was awarded the Nobel Prize in 2000 for his work identifying the physiological changes that occur in the brain during the formation and storage of memories. He joined Columbia in 1974 and retired in August 2022. Learn more about Eric Kandel Columbia Psychiatry is teaching the next generation of clinicians and researchers through our residency Would you like to help support our research Learn about how to participate in clinical trials or research studies here at Columbia Psychiatry Read about the world of psychiatric research and patient care—and see what's happening here at Columbia Pyschiatry whose trailblazing studies of drug use turned scholarship about addiction on its head will retire following a distinguished career at Columbia University and the New York State Psychiatric Institute (NYSPI) that spanned more than 50 years professor of sociomedical sciences in the Department of Psychiatry and head of the Department of The Epidemiology of Substance Abuse at NYSPI has dedicated herself to understanding the risk factors and consequences of drug abuse and how it intersects with problem behaviors and psychiatric disorders in adolescents and adults The developmental sequences of first-time drug use have been a special focus of her work In a seminal paper published in Science in 1975 Kandel documented a sequence in the initiation of drug use progressing to cannabis and then to other illicit drugs These findings gave rise to the notion of “gateway drugs” and the “gateway hypothesis.” Blair Simpson, MD, PhD interim chair of the Department of Psychiatry at Columbia and executive director of NYSPI Kandel’s influence on the field cannot be overstated “How many scholars can lay claim to introducing a new term into the medical lexicon?” said Dr “The gateway theory is one of the most influential models of drug use of the 20th century Simpson added that for colleagues and friends at Columbia and NYSPI “We are excited for Denise as she embarks on her next life adventure “I am personally grateful for Denise’s generous support of me as I assumed leadership roles in the department and I will miss her razor-sharp perspective on any topic we discussed as well as her wry sense of humor.”  Denise Kandel will retire two months before her husband Eric R. Kandel, MD and professor of biochemistry and biophysics at the Vagelos College of Physicians and Surgeons won the Nobel Prize in Medicine or Physiology in 2000 for his research on the physiological basis of memory storage in neurons of the brain During their long marriage—the couple celebrated their 66th anniversary earlier this month—discussion about one another’s work has been a major part of their day but they pursued their scientific studies on separate tracks Then about 10 years ago the Kandels combined their expertise—Denise’s in epidemiology and medical sociology and Eric’s in neuroscience—to unravel the cellular and molecular mechanisms underlying the gateway effect the scientists discovered that one drug affects the circuitry of the brain in a manner that intensifies the effects of a subsequent drug The results provide a biological basis for the sequence of drug use observed in people Some of this work was done in collaboration with colleagues at the Psychiatric Institute, Amir Levine, MD, and Edmund Griffin, MD, PhD. In 2014, a review of that research was published in the New England Journal of Medicine, and in 2017, the same team collaborated on a study published in Scientific Advances that found alcohol Denise (Bystryn) Kandel’s extraordinary scholarship is matched by a personal story that makes her achievements even more remarkable one year after the German invasion of France her father was arrested and sent to a French internment camp from which he escaped before he would have been sent to Auschwitz arranged for 9-year-old Denise to be boarded in a convent in southwestern France Her younger brother was taken in by a local baker The Bystryn family made their home in New York City where Denise received her baccalaureate from the Lycée Français She graduated from Bryn Mawr College in 1952 and went on to earn a master’s degree in 1953 and PhD in 1960 both from the Department of Sociology at Columbia After post-doctoral training in mental health at the Massachusetts Mental Health Center at Harvard Medical School she worked as a research associate at the Harvard Graduate School of Education and subsequently the Department of Child Psychiatry where she eventually established her own department She joined the faculty at Columbia in 1974 in the Department of Psychiatry Vagelos College of Physicians and Surgeons and in the Department of Sociomedical Sciences at the Mailman School of Public Health Denise Kandel has published more than 200 papers and eight books She was identified as a highly cited researcher in the social sciences by the Institute for Scientific Information and served as a member of the National Advisory Council and Extramural Science Advisory Board of the National Institute of Drug Abuse including a Research Scientist Award from the National Institute on Drug Abuse; the Pacemaker Award from the Institute on Drug Abuse for her work in identifying stages of drug use; the Prevention Science Award from the Society for Prevention Research; and most recently the Rema Lapouse Award for Achievement in Epidemiology from the Public Health Association she is modest and devoted to Eric and her family,” said Myrna Weissman the Diane Goldman Kemper Family Professor of Epidemiology and Psychiatry at Columbia “Columbia and I were fortunate to have had a woman like Denise among the faculty at a time when there were so few women professors She leaves a lasting legacy as a role model and collaborator and will be greatly missed.” Denise Bystryn met her future husband in 1955 while pursuing her doctorate at Columbia Eric was working in the Columbia laboratory of renowned neuroscientist Harry Grundfest Denise and Eric married in 1956 and raised their children After living for 50 years in the same house several years ago they moved to a Columbia apartment on Riverside Drive The Kandels are looking forward to a future without the demands and deadlines of academic life But they are not abandoning their research interests One project is to collaborate on an updated review on the gateway hypothesis from both epidemiological and biological perspectives The couple also share a passion for art—museums Denise also hopes to be able to continue to collaborate with her longtime colleague and friend A few years ago in a video, Eric Kandel shared the story of how Denise and her family survived the war, speaking movingly of Denise’s strength and accomplishments.  “I have been so very lucky on both a professional and personal front,” he said. “Being married to her has been the greatest privilege of my life.”   Nobel laureate Eric Kandel, M.D., outlined his research into human memory at the recent Earl W. Sutherland Lecture. (photo by Susan Urmy) At last week's Earl W. Sutherland Lecture, Nobel laureate Eric Kandel, M.D., took the overflow crowd on a whirlwind journey through his decades of memory research. “Memory is the glue that binds our mental life together…it really makes us who we are,” said Kandel, professor of Biochemistry and Biophysics and director of the Kavli Institute for Brain Science at Columbia University in New York. “I want to address one of the most remarkable problems of memory…how memory persists, how you remember your first love experience for the rest of your life.” Kandel opted early in his career to study learning and memory in the sea slug Aplysia because of its simple nervous system and large nerve cells. “Before I became presbyopic, I could see them with my naked eye,” he quipped. His team studied a simple reflex behavior in Aplysia — the withdrawal of the gill when the animal is touched or shocked. After a single stimulus, the animal can remember and respond strongly to a subsequent stimulus for a few minutes. If the stimulus is repeated at least five times, the animal's memory will last for days. Kandel and colleagues worked out the neural circuitry of the behavior and determined the molecular mechanisms that distinguish short-term from long-term memory. They found that to establish long-term memory, genes in the nerve cell nucleus must be activated to encode for proteins involved in the growth of new synaptic connections. “It is the growth of synaptic connections that is the maintained form of long-term memory,” Kandel said. Further studies suggested that there must be a mechanism for “marking” specific synapses for lasting memory formation, and the researchers implicated a protein called CPEB in this process. They were surprised to find that the neuron-specific form of CPEB in Aplysia included a prion-like domain. Prions are self-perpetuating proteins associated with mad cow disease and variant Creutzfeldt-Jakob disease in humans. The investigators now have strong evidence in Aplysia and fruit flies and “tantalizing” evidence in mice that a CPEB-like molecule, which is capable of self-perpetuation, is involved in the maintenance of synaptic growth — the cellular mechanism for long-term memory formation, Kandel said. “This is the first time a prion mechanism has been described in which the protein in its aggregated, self-perpetuating form, is beneficial and serves a biological function,” he said. “We're now looking for other 'functional prion' candidates; we think this mechanism could be used in a number of other contexts (in addition to maintenance of memory storage).” The Department of Molecular Physiology and Biophysics established the lectureship in honor of Earl Sutherland, M.D., a former member of the department who was awarded the 1971 Nobel Prize in Physiology or Medicine for his discoveries related to cellular signaling and hormone action. 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Volume 9 - 2022 | https://doi.org/10.3389/fmolb.2022.900560 This article is part of the Research TopicGenetically Mobile Elements Repurposed by Nature and BiotechnologistsView all 10 articles Hedgehog (Hh) signaling plays pivotal roles in embryonic development Hh signaling is mostly turned off but its abnormal activation is involved in many types of cancer Hh signaling is initiated by the Hh ligand generated from the Hh precursor by a specialized autocatalytic process called Hh autoprocessing The Hh precursor consists of an N-terminal signaling domain (HhN) and a C-terminal autoprocessing domain (HhC) the precursor is cleaved between N- and C-terminal domain followed by the covalent ligation of cholesterol to the last residue of HhN which subsequently leads to the generation of Hh ligand for Hh signaling Hh autoprocessing is at the origin of canonical Hh signaling and precedes all downstream signaling events Mutations in the catalytic residues in HhC can lead to congenital defects such as holoprosencephaly (HPE) The aim of this review is to provide an in-depth summary of the progresses and challenges towards an atomic level understanding of the structural mechanisms of Hh autoprocessing We also discuss drug discovery efforts to inhibit Hh autoprocessing as a new direction in cancer therapy For a subset of Hh ligand-dependent cancer inhibitors of Hh autoprocessing have the potential of developing into a novel class of anti-cancer drugs While Hh Hint and inteins have conserved C258 and TXXH motif in common Hh Hint has unique residues not present in inteins Hedgehog autoprocessing and the generation of Hh ligand involves two key steps: N-S Acyl Shift and Transesterification Using X-ray crystallography and mutagenesis, Hall et al. solved the first crystal structure of WT Hh Hint domain from Drosophila (Figure 2, red) and identified several crucial residues in Hh autoprocessing (Hall et al., 1997). As expected, Hh Hint shares a common fold as inteins (Figure 2 The 3D structure is disc-shaped and is composed of all β-strands with a diameter of ∼ 35 Å and width of ∼ 20 Å the amino- and carboxyl-termini are close to each other with only ∼ 6 Å apart The side chains of conserved residues T326 and H329 in the conserved TXXH motif were found to be within H-bonding distance of C258 The involvement of active site residues D303 and H329 in Hh autoprocessing was assessed by alanine mutations The H329A mutant was found to be inactive in both DTT- and cholesterol-mediated reactions T326A mutant’s activity was also greatly reduced in both reactions confirming their catalytic roles D303A mutant showed active DTT-mediated N-terminal cleavage but was not able to mediate full cholesteroylation Crystal structure of Drosophila Hh Hint domain (red PDB: 2IN0; an engineered mini-intein based on Mtu RecA intein) have similar 3D structures (RMSD = 1.36 Å) The image on the right zooms in the conserved residues in the active site of Hint and intein Zn binding likely inhibits Hh autoprocessing by perturbing their active site geometry and mobility the D303 carboxyl first holds C258 thiolate in an inactive conformation supported by the pKa measurement and the finding that DTT-mediated cleavage becomes more efficient with D303 mutations D303A This prevents premature N-S acyl shift and non-productive precursor hydrolysis C258 thiolate becomes free to carry out the nucleophilic attack on C258 carbonyl for N-S acyl shift deprotonated D303 sidechain interacts with the hydroxyl of cholesterol deprotonating it and activating the cholesterol hydroxyl group to attack the thioester FIGURE 4. Coupling of pKa between D303 and C258. (A) The pKa of D303 is increased to 5.6, as determined by 13CO chemical shift titration with HB(CB)CO. (B) C1A mutation brings the pKa of D303 back to normal. (C) The structural basis of pKa shift and coupling between C258 and D303. Figure from the reference, Xie et al. (2016) with permission FIGURE 5. D303 coordinates two key steps of Hh autoprocessing. Coordination mechanism of two key steps of Hh autoprocessing by conserved D303 residue in Hint. Figure from the reference, Xie et al. (Xie et al., 2016) with permission A notable finding from this study is that the sterol recognition is influenced by mutations in the Hint sub-domain This indicates that the sterol recognition is shared between the SRR and the Hint sub-domains Crystal structures of WT Hh Hint domain (red PDB:6TYY) are almost identical (RMSD = 0.4 Å) The right image shows a magnified region of the conserved residues in the active site of WT and D303H FIGURE 7. Electrostatic stabilization mechanism by H303. Mechanism of electrostatic stabilization by H303 sidechain not available in D303. H303 promotes formation of the negatively charged tetrahedral addition intermediate through favorable electrostatic interaction with its side chain imidazolium. Figure from the reference, Zhao et al. (2019) with permission The mutant D303A lacks the key general base necessary to activate the 3-OH of cholesterol Efficient rescue of D303A by 3-HPC was described in terms of the “α-effect” where tandem electronegative atoms like the peroxy group (HO-O-R) of 3-HPC exhibit exceptionally high nucleophilicity even at low basicity Structure of native substrate: cholesterol (A) and non-native substrates: 3-hydroperoxy cholestane: 3-HPC a type of hyper nucleophilic sterol substrate (B) (2) The SRR cooperates with the Hint enabling cholesterol to access the thioester (3) Cholesterolysis proceeds followed by the generation of Hh ligand Using homology modeling based on cryptogein as a template for SRR, Banavali, N. K. derived the first structural model for SRR and cholesterol-bound Hh (Banavali, 2020) Restrained geometries and topology switches (RGATS) method was then used to derive a reaction pathway with atomic resolution no significant backbone structural changes in the Hh were observed while both cholesterol and side chains of two catalytic residues G-258 and C258 changed their conformations Almost all RGATS showed H-bonding between C258 side chain sulfur with the cholesterol O3 atom Several other polar non-catalytic residues like T326 and H329 in TXXH motif and H450 in HWY motif were also observed to interact with the cholesterol the simulation work was not carried out with lipid bilayer the native environment for Hh autoprocessing Purohit et al. (2020) carried out the first extensive experimental characterization of SRR using human Sonic Hh (hSHH) A helix-loop-helix motif was proposed for SRR based on sequence analysis Mutagenesis was carried out to identify conserved residues which are important for Hh autoprocessing using both cellular and biochemical assays and L450 located on the hydrophobic face of the 1st helix are required for cholesterolysis in cells but not in in vitro biochemical assay Deletion of the SRR 1st helix resulted in diffuse cytoplasmic distribution and loss of co-localization with Golgi organelle marker indicating that these residues likely constitute a Golgi localization motif in cells SRR not only interacts with cholesterol but also acts to direct Hh precursor to the correct cellular compartment Because Hh signaling is deregulated in prostate cancer and abiraterone is administered to treat advanced disease this off-target HhC autoprocessing observed may have therapeutic significance Although the detail mechanism of ∼ 100-fold reactivity difference among A-ring variants is not immediately clear it strongly suggests that the active site of HhC puts a spatial restriction on cholesterol analogues and their activity the starting point of the Hh signaling pathway will be of substantial merit to the drug candidate for combating abnormal Hh activation in many cancers These efforts have provided Hh autoprocessing as an alternative therapeutic target in cancer which can lead to the development of a novel class of anti-cancer agents with an IC50 of 2.2 µM and an apparent interaction constant of 0.4 µM NMR titration demonstrated that PhAsIII binds to catalytic cysteines in the Hint domain AsIII compound may inhibit Hh signaling through interactions with multiple components within this signaling pathway Structure of covalent inhibitor compounds: PhAsIII (A) an antagonist of Hh cholesterolysis; CID 72303 (B) that can attenuate cholesterol-dependent Hh autoprocessing at micromolar concentrations as identified using HTS; and ST044643 (C) reported to inactivate Hh covalently using (SNAr) mechanism as identified using FRET-based assay Both compounds inhibited cholesterol-dependent autocleavage and not the hydroxylamine-dependent N-terminal cleavage suggesting that the inhibitors targeted the nucleophilic attack by cholesterol Time dependence of the inhibition suggests that CID 72303 is a covalent inhibitor This compound has been reported to inactivate Hh covalently by a substitution nucleophilic aromatic (SNAr) mechanism Smith et al. (2020) discovered novel non-covalent modulators called HhC activator compound (HAC) which promotes the hydrolysis of Hh precursor, a side reaction of Hh autoprocessing, thereby inhibiting the cholesteroylation of Hh ligand. Using FRET-based assay, a focused library of 1187 steroid analogs were screened and identified molecules that influence HhC via an unusual and unexpected mode of action, termed paracatalytic induction (Figure 12A) a side hydrolysis reaction of HhC where the Hh precursor cleaves into HhN and HhC domains without the cholesteroylation of HhN The most effective paracatalytic activator compound HAC8 has an AC50 of 9 µM and a corresponding kmax of 9 × 10−4 s−1 Non-covalent activator and inhibitor compounds a novel class of non-covalent modulator compound with an AC50 of 9 µM (A) The best screen hit inhibitor compound with an IC50 of 2 µM (B) The thiophene analog compound of the best screen hit the first nano-molar non-covalent inhibitor of HhC cholesterolysis ∼ 10-fold improvement in IC50 from the top hit screened library yet they have dramatically different effects Establishing the structural basis of their activity difference in the future would be extremely beneficial to future drug screening efforts great progress has been made in recent years in the areas of structural mechanisms and drug discovery of Hh autoprocessing Inhibitors of Hh autoprocessing hold great promise for developing into a novel class of anti-cancer drugs for Hh ligand-dependent cancers either as a single drug or in combination with other agents There are many important issues to be addressed in future studies of Hh autoprocessing and drug discovery A key missing aspect is how Hh precursor interacts with the lipid bilayer of cell membrane and gains access to cholesterol Understanding the precise structure activity relationship of Hh in its natural membrane environment will be key to determining the mechanism of Hh autoprocessing inhibitors and for developing cellular inhibitors of Hh autoprocessing High resolution experimental structural studies of HhC and SRR are also missing due to challenges associated with the aggregation and misfolding of HhC and SRR Atomic resolution structure would be extremely valuable for understanding the precise details of how cholesterol and inhibitors interact with HhC Although many compounds are efficient in inhibiting Hh autoprocessing in vitro non-covalent compounds that are active in cellular assays are yet to be developed NK and CW wrote the original draft of the article We are grateful for support from the National Cancer Institute CA206592 (CW) We thank Shannon Faris for critical reading of the manuscript Patched Homolog 1 (PTCHI) Gene Mutations Can Predict the Outcome of Chronic Myeloid Leukemia Patients PubMed Abstract | Google Scholar PubMed Abstract | CrossRef Full Text | Google Scholar Unraveling the Therapeutic Potential of the Hedgehog Pathway in Cancer PubMed Abstract | CrossRef Full Text | Google Scholar Hedgehog Signaling in Pancreatic Fibrosis and Cancer PubMed Abstract | CrossRef Full Text | Google Scholar The Mechanism of Cholesterol Modification of Hedgehog Ligand PubMed Abstract | CrossRef Full Text | Google Scholar 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Scholar Citation: Kandel N and Wang C (2022) Hedgehog Autoprocessing: From Structural Mechanisms to Drug Discovery Received: 20 March 2022; Accepted: 21 April 2022;Published: 20 May 2022 Copyright © 2022 Kandel and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use *Correspondence: Chunyu Wang, d2FuZ2M1QHJwaS5lZHU= If there’s one thing to know about me it’s this: I write when I have something to write about I say this for reasons not too hard to imagine You should know there are those times when I try to have a constructive or productive conversation with some folk Either the other party I’m trying to engage conversationally with simply does not reciprocate/participate or totally tunes out or flat-out refuses to listen That’s tantamount to trying to squeeze blood from a turnip a scenario that could be captioned — if such were depicted in a photo or cartoon — with the words: “Hey good luck with that!” The effect being said conversation going absolutely nowhere I remember the time I phoned a photojournalist I knew (not well I was pitching a story idea to this individual He shot back with his hard-line response that he didn’t have time to deal with the matter at that particular moment He then went on to share that he was under deadline to finish a story and that he needed to focus all of his time and energies on meeting that deadline I don’t remember what my response was then If this photojournalist was under extremely tight time constraints then why the heck did he “waste the precious time that he did have” taking my call? Why he just didn’t let the call go to voicemail is beyond me Needless to say my story idea fell on deaf ears I recall a time when working in magazine advertising sales that I made a cold call and the retail establishment’s proprietor excused herself saying she would be right back She just didn’t want to deal with me apparently What she missed out on was what I could have potentially had to offer her where magazine advertising was concerned that’s when they become much more receptive and responsive The trick is to sell them on the idea that they want to advertise To convince them that doing such is in their best interest you can’t joke with people you don’t know and who don’t know you What winds up happening is you get strange looks for what they truly are and their true colors Credit or fault the thing known as human nature I have had some of my best conversations with strangers in what I would call “neutral” settings He could approach a stranger in a restaurant their appearing to have been lifelong friends Did you know he once convinced a crew on a deadhead flight going to his home town to let him get on board just so he could get back home My brother did not work for an airline or in transportation or travel if that’s what you’re thinking my boss in my first job as a magazine advertising sales rep walked into a real estate company and had all of the real-estate agents (there were at least a dozen of ‘em) give him their full and undivided attention my boss sealed the deal with many of the realtors purchasing ad space in the product we were peddling Up to that point I had never seen anything like it and I haven’t seen anything like it since If I’ve held your attention this long and you’re reading this sentence verbal communication is not one of my strong suits Not signed up for Daily Kos yet? Create a free account Today, June 20th, is World Refugee Day and escaped the country in 1939 at age 10 after the Nazi invasion The Kandel family settled in the United States Kandel would go on to have an illustrious career in neuroscience He studied at world-renowned institutions including Harvard University and the National Institutes of Health before coming to Columbia University in 1974 where he was appointed professor of physiology and psychiatry In 2000, Dr. Kandel won the Nobel Prize in Medicine for his research on the sea slug Aplysia, which helped to uncover important molecular mechanisms that drive the processes of learning and memory. To learn more about Dr. Kandel's incredible journey, and how his past life experiences influenced his work as a scientist, watch our mini-documentary above Eric Kandel, MD, is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute director of the Kavli Institute for Brain Science at Columbia University Irving Medical Center Women's soccer adds Carley Kandel to coaching staff 06/22/2023 | 10:00:00 | Women's Soccer - Women's soccer head coach Graeme Orr has announced that Carley Kandel will be joining the Southern Illinois coaching staff ahead of the 2023 season "I am delighted to make Carley my first hire at SIU," Orr said "She has a player centered coaching philosophy and I believe she will be an incredible addition to the athletic department at SIU." spent the previous two seasons at Valdosta State University in Valdosta the Blazers went 11-7-1 and made an appearance in the NCAA South Region tournament in 2021 Kandel was a four-year letter winner and two-time captain on the women's soccer team at Lake Erie College in Painesville she graduated with a degree in Early Childhood Education "The players are going to love interacting with her on a daily basis," Orr said "We are very fortunate to have her on board."  Tara McQueen - University of North Alabama Assistant Coach "Coach Carley has been someone who has pushed me every day to be the very best that I can be and that no matter what and to work hard for yourself and your teammates around you Her passion for the game along with her dedication has made a program where we feel supported and motivated to be successful on the field and in our lives!" Landon Carter - Senior Goalkeeper at Valdosta State University "Coach Carley has had a tremendous impact on not only the Valdosta State Women's Soccer program Her persistent belief in our potential on and off the field has been a massive contribution to our team's success She brings a positive light to every situation and is a true role model and someone who is dedicated to helping others."  Ansley Decenzo - Junior Forward at Valdosta State University "Words cannot express all that Coach Carley has done for the program at Valdosta State She has deep gratitude and passion for not only the game but for us as players Coach Carley's unwavering belief in the program has inspired me to be the best player and teammate we can be We are forever grateful for the countless amount of time that Coach Carley has dedicated to us." 25: The Nepali Cuisine Promotion Campaign in coordination with farmers and the hospitality industry organised a food-tasting event Bhojanlipi-Swad in Kathmandu on Monday.  The campaign aims to establish direct contact with farmers and transform their produce into delicious dishes served in major cities across the country The initiative also ensures that people can enjoy these meals either at hotels and restaurants or in the comfort of their own homes said chefs Ghanshyam Kandel and Durga Bahadur Khadka.  The event held at the Hotel Himalayan Suite in Kathmandu marked the official launching of the Campaign.  Talking to journalists after tasting the indigenous food prepared with multiple fusions Minister for Agriculture and Livestock Development expressed the government's commitment to fully supporting the marketing of Nepali produce and cuisine a variety of dishes were prepared using fresh agricultural produce sourced from districts such as Ilam The Campaign promises to bring fresh agricultural produce from almost all regions of Nepal to Kathmandu and take it to the international markets.  said that the initiative would facilitate the marketing of farmers’ produce the focus will be on the market distribution of seasonal crops with a gradual expansion towards promoting local handicrafts Journalist and agro-tourism activist Devi Prasad Sapkota explained that he had joined the campaign to support farmers and cultivate a deeper appreciation for agriculture and soil He also mentioned that he had been preparing for several years to assist in promoting government initiatives that encourage the production and consumption of domestic goods Kandel and Khadka are international chefs who have experience in preparing multiple cuisines in multiple countries including India They are also making preparations to publish a recipe book of Nepali indigenous foods called 'Bhojanlipi'.  Columbia celebrated the 80th birthday of Nobel laureate neuroscientist and University Professor Eric Kandel with a daylong symposium on November 20 Seventeen colleagues and former students gave addresses describing how Kandel’s work on brain function inspired their own research on topics ranging from the emotions of mice to the neuronal underpinning of moral thought with whom Kandel is currently cohosting a yearlong series of special episodes on the brain “One of the things that amazes me about being 80 years old is that I get as much joy out of science today as I did when I began,” says Kandel “That’s because exciting things keep on popping up.”  We celebrate this half-century milestone with a look back at some of the memorable and defining moments captured in our pages The Columbia women's basketball team scores its first-ever March Madness victory  The Board of Trustees co-chair will lead Columbia in a temporary capacity until a search for the next president is complete General Data Protection Regulation Columbia University Privacy Notice Israel Won't Make It to Its 100th BirthdayThe Israeli elite will flee the country once they see that the various 'tribes' can't agree on a social contract government-administration experts Eugene Kandel and Ron Tzur warn in a new paper 2024Israel's 76th Independence Day last week was the saddest and bleakest Independence Day since the establishment of the state Will Israel emerge from the crisis and live to celebrate its centennial Alison Abbott is a science writer based in Munich There Is Life After the Nobel Prize Eric Kandel Columbia Univ Prices may be subject to local taxes which are calculated during checkout doi: https://doi.org/10.1038/d41586-021-03623-y The author declares no competing interests Walking in two worlds: how an Indigenous computer scientist is using AI to preserve threatened languages Regulation of PV interneuron plasticity by neuropeptide-encoding genes Serotonin and neurotensin inputs in the vCA1 dictate opposing social valence Native American tribe teams up with genomicists to confirm link to iconic ancient site When a great ball of fire came crashing down Ancient DNA reveals Phoenicians’ surprising genetic ancestry HT is an interdisciplinary research institute created and supported by the Italian government whose aim is to develop innovative strategies to pr.. UNIL is a leading international teaching and research institution with over 5,000 employees and 17,000 students split between its Dorigny campus Department of Energy and Environmental Materials and advance cancer research in a leading translational institute Olivia Newton-John Cancer Research Institute We are seeking a tenure-track associate professor to promote interdisciplinary research in nanoprobe life sciences or related interdisciplinary field Sign up for the Nature Briefing newsletter — what matters in science Read the latest news stories about Mailman faculty We integrate an innovative skills-based curriculum and hands-on field experience to prepare students which focus on critical issues in public health Meet the faculty of the Mailman School of Public Health.  Learn how to apply to the Mailman School of Public Health.  Columbia scientists Eric and Denise Kandel have been married since 1956, but it took 50 years, a Nobel prize and two phone calls before they started their first scientific partnership – an effort to unravel the molecular basis behind the gateway hypothesis of drug use. The two presented their latest findings to a packed Alumni Auditorium during the Mailman School of Public Health’s Grand Rounds Series Denise and Eric Kandel in 1956 (photo courtesy of Denise and Eric Kandel) Denise Kandel answered the call from Stockholm that carried the news of Eric’s Nobel for his research in learning and memory how to convince Denise that I’m still intellectually worthy of our partnership,” Eric Kandel said during the lecture and the rest of the tag-team lecture by the Kandels recounted how the two have developed a new approach to provide new answers to the question: Why does the use of legal drugs precede the use of illegal drugs Denise Kandel has studied the use of legal and illegal drugs: who uses drugs Her groundbreaking work uncovered a remarkably common trajectory: teenagers who use marijuana almost always use cigarettes or alcohol first And adolescents who go on to harder drugs almost always use marijuana before trying cocaine or heroine The sequence from alcohol and cigarettes to cocaine is one of the most consistent findings in drug abuse research seen in every Western country regardless of legal constraints or social attitudes toward drug use Denise Kandel's research shows that the use of illegal drugs (e.g cocaine) is always preceded by alcohol or cigarette use New studies with her husband Eric suggest cigarette smoking primes the brain for addiction to other drugs The association is real, but why does the use of legal drugs always precede the use of illegal drugs? That question was hard to answer with epidemiological methods, Denise Kandel said, so in a 2003 JAMA editorial she proposed using animal models to determine if use of one drug physically changes the brain increasing the risk of using a second drug “I began looking for a collaborator,” Denise Kandel said the one she found shared her commute from home to Columbia University Medical Center I thought we were in a position to look seriously at the molecular and cellular mechanisms that might underlie the gateway trajectory,” Eric Kandel said “We had learned enough about short-term and long-term memory and others had learned that the same processes involved in memory are also involved in addiction.” Processes in the mouse brain involved in long-term memory are greatly altered when cocaine use occurs during or shortly after chronic nicotine exposure The effects on memory are not seen when either drug is used alone nor when nicotine exposure occurs after cocaine use “This gives us an insight into the molecular basis of the gateway hypothesis,” Eric Kandel said “We think that nicotine produces the perfect environment for cocaine to activate genes that turn on a long-term memory of the illegal drug One of the reasons cocaine is so addicting is that most people are smokers when they try it.” “What surprised us about the research was that it came up with new questions about drug use that we had never asked before,” Denise Kandel said “The mice findings suggest people are most likely to get addicted to cocaine if they’re active cigarette smokers Now we’re trying to see if we can test this idea in human populations using epidemiological methods.” The new findings and hypotheses generated by the collaboration between the Kandels “to my mind demonstrates the extraordinary power and extraordinary necessity of interdisciplinary science,” said DeLamar Professor Linda Fried, MD, MPH dean of the Mailman School of Public Health Article courtesy of Columbia University College of Physicians & Surgeons We are committed to the well-being and success of all community members Columbia complies with all applicable civil rights laws and does not engage in illegal preferences or discrimination.