en Morier-Genoud, Ovsienko Win 2025 AMS Robbins Prize By www.ams.org Published On :: Tue, 05 Nov 2024 00:00:00 EST Sophie Morier-Genoud of the University of Reims Champagne-Ardenne and Valentin Ovsienko of the Centre National de la Recherche Scientifique, Reims, are awarded the 2025 AMS David P. Robbins Prize for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma. Sophie Morier-Genoud Credit: Bernhard Keller Valentin Ovsienko “In this groundbreaking work .. it is shown that the new concept has striking connections and applications to a wide range of mathematical areas,” according to the prize citation. “The paper has subsequently inspired a profusion of significant further research developments.” From the citation The David P. Robbins Prize is awarded to Sophie Morier-Genoud and Valentin Ovsienko for their paper “$q$-deformed rationals and $q$-continued fractions,” published in Forum of Mathematics, Sigma, in 2020. The authors provide an entirely novel and natural definition of a $q$-analog of the rational numbers. Although a $q$-analog of the integers has been used extensively since the work of Euler, a satisfactory and meaningful $q$-analog of the rationals had remained elusive until this paper. The definition also leads to a natural $q$-analog of the real numbers and has a wide range of fascinating and far-reaching applications. A $q$-analog of a mathematical concept is a generalization of the concept which depends on a new parameter $q$ in such a way that the original concept is recovered when $q$ is set to 1, and various interesting or useful properties also arise. Response of Sophie Morier-Genoud I am thrilled and honored to receive the 2025 David P. Robbins Prize. This is a fantastic recognition and a great encouragement to keep doing what I like to do. I always had a lot of fun doing mathematics and I feel privileged to do it as a profession. I am grateful to everyone who helped me in making this path possible. I would like to thank all my collaborators and colleagues in the Math Department at the University of Reims and also everywhere in the world who show interest in the math we are doing and contribute to enrich the theory of $q$-numbers. Response of Valentin Ovsienko I am deeply moved to receive this prize, named in honor of David P. Robbins, the creator of mathematical concepts that will forever remain among the most beautiful. My scientific life has been spent trying to connect different topics in algebra, geometry, and mathematical physics. The $q$-numbers, which is a combinatorial notion, are the result of my journey with my younger and much smarter collaborator Sophie Morier-Genoud, following this route. We tried to better understand connections between cluster algebra, Coxeter friezes, Conway’s ideas, the Jones polynomial... We realized that it is impossible to $q$-deform a singular object, but only an infinite sequence of them! In order to $q$-deform rationals, one needs to count them all. We chose the way of counting determined by continued fractions and the action of the modular group. Working on this subject has been and remains the happiest part of my scientific life. I was captivated by $q$-rationals and I was completely haunted by $q$-irrationals. This happiness, enhanced by interest of other researchers, in itself is reward enough. My collaboration with Sophie produced a variety of results, including two energetic children, Lisa and Anatole; the $q$-numbers are also little kids who need to grow up! Biographical sketch of Sophie Morier-Genoud Sophie Morier-Genoud is currently full professor at the University of Reims Champagne-Ardenne in France. She completed her PhD at the University of Lyon (2006) under the supervision of Philippe Caldero. She was T.H. Hildebrandt Assistant Professor at the University of Michigan (2006-2008), postdoctoral fellow of the Fondation Sciences Mathématiques de Paris (2008-2009) and associate professor at Sorbonne Université (2009-2021). Her research work is mainly related to algebraic combinatorics and representation theory. She currently serves as an editor for the column “Gems and Curiosities” of the Mathematical Intelligencer. Biographical sketch of Valentin Ovsienko Valentin Ovsienko was born in 1964 in the Soviet Union. He received his PhD in 1989 from Moscow State University under the supervision of Alexandre Kirillov. Ovsienko is currently in Reims, Champagne, as a senior researcher at the French Centre National de la Recherche Scientifique. He worked in projective differential geometry, infinite-dimensional Lie algebras, integrable systems, octonions, and, more recently, in combinatorics. Together with Sophie Morier-Genoud, he is the editor of the column “Gems and Curiosities” of the Mathematical Intelligencer, and he invites everyone to write beautiful articles for it. About the prize The David P. Robbins Prize is awarded every three years for a paper with the following characteristics: It reports on novel research in algebra, combinatorics, or discrete mathematics and has a significant experimental component; and it is on a topic which is broadly accessible and provides a simple statement of the problem and clear exposition of the work. Papers published within the six calendar years preceding the year in which the prize is awarded are eligible for consideration. The 2025 prize will be presented at the 2025 Joint Mathematics Meetings in Seattle. Learn more about the prize and previous recipients. Contact: AMS Communications. ***** The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs. Full Article
en UC Irvine Wins 2025 AMS Award for an Exemplary Program in a Mathematics Department By www.ams.org Published On :: Tue, 12 Nov 2024 00:00:00 EST The Math Community Educational Outreach (Math CEO) program at the University of California, Irvine (UCI) will receive the 2025 AMS Award for an Exemplary Program or Achievement in a Mathematics Department. Founded in 2014, UCI’s Math CEO is an after-school math enrichment program aimed at increasing the number of talented students in STEM from diverse backgrounds by fostering mathematical exploration, mentor development, and community engagement. Participants in the Math CEO program at University of California, Irvine Credit: Jennifer Tran, Math CEO outreach assistant From the citation The University of California, Irvine (UCI) Math CEO program is recognized for its exceptional contributions to the mathematics community and society at large. Established in 2014 by professors Alessandra Pantano and Li-Sheng Tseng, Math CEO targets students from Title I middle schools, providing them with a high-quality after-school math enrichment program. This program brings middle-school students to the UCI campus to work in small groups with undergraduate mentors, many of whom are also from historically marginalized groups, to engage in challenging mathematical tasks and encourage exploration. From September 2019 to June 2024, Math CEO engaged a total of 1,221 youth, with 48.6% identifying as female. The ethnic background of the participants was predominantly Latinx (93.5%), with smaller representations of Asian, white, and multiethnic students. In the same five-year period, Math CEO engaged 553 undergraduate mentors, 62.2% of whom were female. The mentors’ ethnic backgrounds were diverse, with significant representation of Asian (52%) and Latinx (30%) students. The undergraduate mentors, many of whom pursue careers in education, receive training in culturally responsive teaching practices and equity in education, significantly impacting their professional development. In a post-survey, 52.3% of the undergraduate mentors expressed interest in teaching or working in education and 45.9% were likely to pursue professions working with children or families. Recognizing the central role of families in supporting Latinx youth, Math CEO involves parents through bilingual workshops that enhance community awareness of college pathways and financial opportunities. Math CEO has been the foundation for numerous research projects in mathematics education, supported by NSF grants, leading to publications and program growth. The program’s success is evident in its expansion to high schools and other regions in Southern California, including a new branch at California State University, Dominguez Hills. Math CEO continues to make a substantial impact on underserved youth, demonstrating a model of systemic, reproducible change that can be implemented by others. Response of Alessandra Pantano, UCI Math CEO I am deeply honored to receive the AMS Award for an Exemplary Program in a Mathematics Department on behalf of the UCI Math CEO team. This wonderful award recognizes the work of many colleagues, graduate students, and undergraduate students in developing and delivering the UCI Math Community Educational Outreach (Math CEO) program. For over a decade, Math CEO has provided creative and culturally responsive math enrichment opportunities for hundreds of underprivileged middle-school students, many of which have since “graduated” to high school or even college. Leading this exceptional and dedicated team of volunteers has been the highest pride of my professional life. A special thanks to my partners-in-crime, Prof. Li-Sheng Tseng, codirector of Math CEO, and former graduate student Andres Forero Cuervo, academic coordinator for Math CEO: We could have never done this without you. I look forward to pushing this activity forward and continuing to dedicate my energy to help kids in our county find the way to express their potential – in math and in life! A big thanks to the colleagues who nominated us and to the AMS for recognizing our efforts. History of the program The UC Irvine Math Community Educational Outreach (Math CEO) program was founded in 2014 by math faculty Alessandra Pantano and Li-Sheng Tseng in collaboration with Santa Ana Unified math teacher Jasmina Matasovic. The founders shared a belief that low standardized test scores in underserved communities do not reflect students’ interest and potential to succeed in STEM. Math CEO runs free, weekly, after-school math enrichment sessions, welcoming all youth regardless of math achievement. Starting with only 25 students from one middle school, the program has grown and engaged nearly two thousand students in all, from multiple school districts in Southern California. About the award The annual AMS Award for an Exemplary Program or Achievement in a Mathematics Department was established in 2004 and first given in 2006. This award recognizes a department which has distinguished itself by undertaking an unusual or particularly effective program of value to the mathematics community, internally or in relation to the rest of society. Departments of mathematical sciences in North America that offer at least a bachelor’s degree in mathematical sciences are eligible. The award amount is currently $5,000. The award will be presented at the 2025 Joint Mathematics Meetings in Seattle. Learn more about the award and previous recipients. Contact: AMS Communications. ***** The American Mathematical Society is dedicated to advancing research and connecting the diverse global mathematical community through our publications, meetings and conferences, MathSciNet, professional services, advocacy, and awareness programs. Full Article
en When will we see below-freezing temperatures in Milwaukee? First frost, snow forecasts By www.yahoo.com Published On :: 2024-11-11T21:45:13Z Full Article
en The Election Proved Something Painful About Gen Z. It’s Worse Than We Thought. By www.yahoo.com Published On :: 2024-11-12T20:00:00Z Full Article
en Analysis-India's middle class tightens its belt, squeezed by food inflation By finance.yahoo.com Published On :: 2024-11-13T05:35:58Z Full Article
en Woman, 23, had a 'burning sensation' in her stomach. It was the first sign of a rare cancer By www.yahoo.com Published On :: 2024-11-11T22:54:21Z Full Article
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en Scientists uncover a magnetic misunderstanding about Uranus By www.yahoo.com Published On :: 2024-11-11T16:05:33Z Full Article
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en Vybz Kartel, Shenseea nominated for Best Reggae Album Grammy By jamaica-star.com Published On :: Fri, 08 Nov 2024 12:04:07 -0500 Full Article
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en Near-death experience inspires Benzly Hype’s album By jamaica-star.com Published On :: Tue, 12 Nov 2024 05:01:17 -0500 An out-of-body experience is the inspiration behind Benzly Hype's latest album Star Its The 7th Year. Released on November 7, the entertainer said the project was done to bring back joy in music and will leave its listeners in an upbeat mood.... Full Article
en Genetic diseases of the Kennedy pathways for membrane synthesis [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 The two branches of the Kennedy pathways (CDP-choline and CDP-ethanolamine) are the predominant pathways responsible for the synthesis of the most abundant phospholipids, phosphatidylcholine and phosphatidylethanolamine, respectively, in mammalian membranes. Recently, hereditary diseases associated with single gene mutations in the Kennedy pathways have been identified. Interestingly, genetic diseases within the same pathway vary greatly, ranging from muscular dystrophy to spastic paraplegia to a childhood blinding disorder to bone deformations. Indeed, different point mutations in the same gene (PCYT1; CCTα) result in at least three distinct diseases. In this review, we will summarize and review the genetic diseases associated with mutations in genes of the Kennedy pathway for phospholipid synthesis. These single-gene disorders provide insight, indeed direct genotype-phenotype relationships, into the biological functions of specific enzymes of the Kennedy pathway. We discuss potential mechanisms of how mutations within the same pathway can cause disparate disease. Full Article
en ‘We have lost a future scientist’ - William Knibb High student gets emotional send-off By jamaica-star.com Published On :: Mon, 11 Nov 2024 05:01:16 -0500 Family, friends, and community members gathered on Saturday at the Falmouth First Assembly Church to celebrate the life of 15-year-old Jahmarie Reid, a William Knibb High student who tragically lost his life at sea on August 27 in what is believed... Full Article
en A mom’s worst nightmare - East Kingston mother mourns teen son after deadly clash with cops By jamaica-star.com Published On :: Mon, 11 Nov 2024 05:01:19 -0500 Kadian Morgan was overwhelmed with grief as she leaned against a wall outside her gate on Jackson Lane, East Kingston, yesterday, tears streaming down her face. Her 19-year-old son, Kayshan 'Bem Bem' Smith, was lying in the morgue after being... Full Article
en Gunmen shoot 18-y-o in leg By jamaica-star.com Published On :: Mon, 11 Nov 2024 11:20:08 -0500 An 18-year-old woman has been left with a gunshot wound to her left leg following a shooting incident in Central Village in St Catherine Sunday night. Full Article
en Policeman's murder won't deter fight against crime says Superintendent Nicholson By jamaica-star.com Published On :: Mon, 11 Nov 2024 12:52:26 -0500 A police sergeant who was shot and injured at his home in Portmore, St Catherine, on Thursday night succumbed to his injuries on Monday morning. Full Article
en Vaping sending youth to hospital By jamaica-star.com Published On :: Tue, 12 Nov 2024 05:01:04 -0500 Health Minister Dr Christopher Tufton is warning about the possible dangers to the health of students caused by vaping. "We have seen cases where students have been rushed to the A... Full Article
en Bridge over troubled water - Bushy Park residents construct new walkway after floodwaters sweep away old one By jamaica-star.com Published On :: Tue, 12 Nov 2024 05:01:10 -0500 After parking his taxi cab along the sidewalk, Leon Thompson exited his vehicle and held on tightly to the tiny hands of his four small passengers. They all walked towards a makeshift bridge, and Thompson lifted each child, making four trips,... Full Article
en St Thomas residents plan proper funeral for Donovan By jamaica-star.com Published On :: Tue, 12 Nov 2024 05:01:08 -0500 In a touching display of compassion and solidarity, a group of St Thomas residents has come together to organise the funeral of a a well-known and beloved man with intellectual challenges. For years, Donovan Sinclair was a familiar face in the... Full Article
en Haiti's main airport and capital frozen after a day of violence By jamaica-star.com Published On :: Tue, 12 Nov 2024 12:00:31 -0500 PORT-AU-PRINCE, Haiti (AP) — Haiti's main airport remained closed on Tuesday, a day after violence erupted as the country swore in its new prime minister in a politically tumultuous transition. Full Article
en SAS Notes for SAS®9 - 66492: FILENAME FTP(FTP/TLS) fails with "ERROR: The connection was reset by a peer" due to using implicit FTP/TLS By Published On :: Wed, 26 Aug 2020 13:59:34 EST If you connect to a FTP/TLS server that is configured to use implicit FTP/TLS, FILENAME FTP/TLS might fail with the following error: ERRO Full Article BASE+Base+SAS
en A trade-off switch of two immunological memories in Caenorhabditis elegans reinfected by bacterial pathogens [Microbiology] By www.jbc.org Published On :: 2020-12-11T00:06:21-08:00 Recent studies have suggested that innate immune responses exhibit characteristics associated with memory linked to modulations in both vertebrates and invertebrates. However, the diverse evolutionary paths taken, particularly within the invertebrate taxa, should lead to similarly diverse innate immunity memory processes. Our understanding of innate immune memory in invertebrates primarily comes from studies of the fruit fly Drosophila melanogaster, the generality of which is unclear. Caenorhabditis elegans typically inhabits soil harboring a variety of fatal microbial pathogens; for this invertebrate, the innate immune system and aversive behavior are the major defensive strategies against microbial infection. However, their characteristics of immunological memory remains infantile. Here we discovered an immunological memory that promoted avoidance and suppressed innate immunity during reinfection with bacteria, which we revealed to be specific to the previously exposed pathogens. During this trade-off switch of avoidance and innate immunity, the chemosensory neurons AWB and ADF modulated production of serotonin and dopamine, which in turn decreased expression of the innate immunity-associated genes and led to enhanced avoidance via the downstream insulin-like pathway. Therefore, our current study profiles the immune memories during C. elegans reinfected by pathogenic bacteria and further reveals that the chemosensory neurons, the neurotransmitter(s), and their associated molecular signaling pathways are responsible for a trade-off switch between the two immunological memories. Full Article
en Biochemical transformation of bacterial lipopolysaccharides by acyloxyacyl hydrolase reduces host injury and promotes recovery [Enzymology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Animals can sense the presence of microbes in their tissues and mobilize their own defenses by recognizing and responding to conserved microbial structures (often called microbe-associated molecular patterns (MAMPs)). Successful host defenses may kill the invaders, yet the host animal may fail to restore homeostasis if the stimulatory microbial structures are not silenced. Although mice have many mechanisms for limiting their responses to lipopolysaccharide (LPS), a major Gram-negative bacterial MAMP, a highly conserved host lipase is required to extinguish LPS sensing in tissues and restore homeostasis. We review recent progress in understanding how this enzyme, acyloxyacyl hydrolase (AOAH), transforms LPS from stimulus to inhibitor, reduces tissue injury and death from infection, prevents prolonged post-infection immunosuppression, and keeps stimulatory LPS from entering the bloodstream. We also discuss how AOAH may increase sensitivity to pulmonary allergens. Better appreciation of how host enzymes modify LPS and other MAMPs may help prevent tissue injury and hasten recovery from infection. Full Article
en Development of a novel mammalian display system for selection of antibodies against membrane proteins [Immunology] By www.jbc.org Published On :: 2020-12-25T00:06:31-08:00 Reliable, specific polyclonal and monoclonal antibodies are important tools in research and medicine. However, the discovery of antibodies against their targets in their native forms is difficult. Here, we present a novel method for discovery of antibodies against membrane proteins in their native configuration in mammalian cells. The method involves the co-expression of an antibody library in a population of mammalian cells that express the target polypeptide within a natural membrane environment on the cell surface. Cells that secrete a single-chain fragment variable (scFv) that binds to the target membrane protein thereby become self-labeled, enabling enrichment and isolation by magnetic sorting and FRET-based flow sorting. Library sizes of up to 109 variants can be screened, thus allowing campaigns of naïve scFv libraries to be selected against membrane protein antigens in a Chinese hamster ovary cell system. We validate this method by screening a synthetic naïve human scFv library against Chinese hamster ovary cells expressing the oncogenic target epithelial cell adhesion molecule and identify a panel of three novel binders to this membrane protein, one with a dissociation constant (KD) as low as 0.8 nm. We further demonstrate that the identified antibodies have utility for killing epithelial cell adhesion molecule–positive cells when used as a targeting domain on chimeric antigen receptor T cells. Thus, we provide a new tool for identifying novel antibodies that act against membrane proteins, which could catalyze the discovery of new candidates for antibody-based therapies. Full Article
en Quantitative phosphoproteomic analysis reveals involvement of PD-1 in multiple T cell functions [Signal Transduction] By www.jbc.org Published On :: 2020-12-25T00:06:30-08:00 Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell–mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell–mediated anti-tumor immunity, but many patients do not respond and a significant proportion develop inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization, and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed that kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1–triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1–targeting therapeutic approaches. Full Article
en Carnosine synthase deficiency is compatible with normal skeletal muscle and olfactory function but causes reduced olfactory sensitivity in aging mice [Developmental Biology] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Carnosine (β-alanyl-l-histidine) and anserine (β-alanyl-3-methyl-l-histidine) are abundant peptides in the nervous system and skeletal muscle of many vertebrates. Many in vitro and in vivo studies demonstrated that exogenously added carnosine can improve muscle contraction, has antioxidant activity, and can quench various reactive aldehydes. Some of these functions likely contribute to the proposed anti-aging activity of carnosine. However, the physiological role of carnosine and related histidine-containing dipeptides (HCDs) is not clear. In this study, we generated a mouse line deficient in carnosine synthase (Carns1). HCDs were undetectable in the primary olfactory system and skeletal muscle of Carns1-deficient mice. Skeletal muscle contraction in these mice, however, was unaltered, and there was no evidence for reduced pH-buffering capacity in the skeletal muscle. Olfactory tests did not reveal any deterioration in 8-month-old mice lacking carnosine. In contrast, aging (18–24-month-old) Carns1-deficient mice exhibited olfactory sensitivity impairments that correlated with an age-dependent reduction in the number of olfactory receptor neurons. Whereas we found no evidence for elevated levels of lipoxidation and glycation end products in the primary olfactory system, protein carbonylation was increased in the olfactory bulb of aged Carns1-deficient mice. Taken together, these results suggest that carnosine in the olfactory system is not essential for information processing in the olfactory signaling pathway but does have a role in the long-term protection of olfactory receptor neurons, possibly through its antioxidant activity. Full Article
en ARID4B is critical for mouse embryonic stem cell differentiation towards mesoderm and endoderm, linking epigenetics to pluripotency exit [Developmental Biology] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies have focused on epigenetic factors that affect embryonic stem cells (ESC) self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been as extensively studied. Using a pooled epigenetic shRNA screen strategy, we identified chromatin-related factors critical for differentiation toward mesodermal and endodermal lineages. Here we reveal a critical role for the chromatin protein, ARID4B. Arid4b-deficient mESCs are similar to WT mESCs in the expression of pluripotency factors and their self-renewal. However, ARID4B loss results in defects in up-regulation of the meso/endodermal gene expression program. It was previously shown that Arid4b resides in a complex with SIN3A and HDACS 1 and 2. We identified a physical and functional interaction of ARID4B with HDAC1 rather than HDAC2, suggesting functionally distinct Sin3a subcomplexes might regulate cell fate decisions Finally, we observed that ARID4B deficiency leads to increased H3K27me3 and a reduced H3K27Ac level in key developmental gene loci, whereas a subset of genomic regions gain H3K27Ac marks. Our results demonstrate that epigenetic control through ARID4B plays a key role in the execution of lineage-specific gene expression programs at pluripotency exit. Full Article
en Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription [Gene Regulation] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre–mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation. Full Article
en Fluctuation in O-GlcNAcylation inactivates STIM1 to reduce store-operated calcium ion entry via down-regulation of Ser621 phosphorylation [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-11T00:06:20-08:00 Stromal interaction molecule 1 (STIM1) plays a pivotal role in store-operated Ca2+ entry (SOCE), an essential mechanism in cellular calcium signaling and in maintaining cellular calcium balance. Because O-GlcNAcylation plays pivotal roles in various cellular function, we examined the effect of fluctuation in STIM1 O-GlcNAcylation on SOCE activity. We found that both increase and decrease in STIM1 O-GlcNAcylation impaired SOCE activity. To determine the molecular basis, we established STIM1-knockout HEK293 (STIM1-KO-HEK) cells using the CRISPR/Cas9 system and transfected STIM1 WT (STIM1-KO-WT-HEK), S621A (STIM1-KO-S621A-HEK), or T626A (STIM1-KO-T626A-HEK) cells. Using these cells, we examined the possible O-GlcNAcylation sites of STIM1 to determine whether the sites were O-GlcNAcylated. Co-immunoprecipitation analysis revealed that Ser621 and Thr626 were O-GlcNAcylated and that Thr626 was O-GlcNAcylated in the steady state but Ser621 was not. The SOCE activity in STIM1-KO-S621A-HEK and STIM1-KO-T626A-HEK cells was lower than that in STIM1-KO-WT-HEK cells because of reduced phosphorylation at Ser621. Treatment with the O-GlcNAcase inhibitor Thiamet G or O-GlcNAc transferase (OGT) transfection, which increases O-GlcNAcylation, reduced SOCE activity, whereas treatment with the OGT inhibitor ST045849 or siOGT transfection, which decreases O-GlcNAcylation, also reduced SOCE activity. Decrease in SOCE activity due to increase and decrease in O-GlcNAcylation was attributable to reduced phosphorylation at Ser621. These data suggest that both decrease in O-GlcNAcylation at Thr626 and increase in O-GlcNAcylation at Ser621 in STIM1 lead to impairment of SOCE activity through decrease in Ser621 phosphorylation. Targeting STIM1 O-GlcNAcylation could provide a promising treatment option for the related diseases, such as neurodegenerative diseases. Full Article
en N-acetylglucosamine drives myelination by triggering oligodendrocyte precursor cell differentiation [Molecular Bases of Disease] By www.jbc.org Published On :: 2020-12-18T00:06:18-08:00 Myelination plays an important role in cognitive development and in demyelinating diseases like multiple sclerosis (MS), where failure of remyelination promotes permanent neuro-axonal damage. Modification of cell surface receptors with branched N-glycans coordinates cell growth and differentiation by controlling glycoprotein clustering, signaling, and endocytosis. GlcNAc is a rate-limiting metabolite for N-glycan branching. Here we report that GlcNAc and N-glycan branching trigger oligodendrogenesis from precursor cells by inhibiting platelet-derived growth factor receptor-α cell endocytosis. Supplying oral GlcNAc to lactating mice drives primary myelination in newborn pups via secretion in breast milk, whereas genetically blocking N-glycan branching markedly inhibits primary myelination. In adult mice with toxin (cuprizone)-induced demyelination, oral GlcNAc prevents neuro-axonal damage by driving myelin repair. In MS patients, endogenous serum GlcNAc levels inversely correlated with imaging measures of demyelination and microstructural damage. Our data identify N-glycan branching and GlcNAc as critical regulators of primary myelination and myelin repair and suggest that oral GlcNAc may be neuroprotective in demyelinating diseases like MS. Full Article