tbuckley/cabot-search huggingface dataset:
An overview of magnesium-based implants in orthopaedics and a prospect of its application in spine fusion
Authors: Xuan He, Ye Li, Da Zou, Haiyue Zu, Weishi Li, Yufeng Zheng
Journal: Bioactive Materials (2024)

Due to matching biomechanical properties and significant biological activity, Mg-based implants present great potential in orthopedic applications. In recent years, the biocompatibility and therapeutic effect of magnesium-based implants have been widely investigated in trauma repair. In contrast, the R&D work of Mg-based implants in spinal fusion is still limited. This review firstly introduced the general background for Mg-based implants. Secondly, the mechanical properties and degradation behaviors of Mg and its traditional and novel alloys were reviewed. Then, different surface modification techniques of Mg-based implants were described. Thirdly, this review comprehensively summarized the biological pathways of Mg degradation to promote bone formation in neuro-musculoskeletal circuit, angiogenesis with H-type vessel formation, osteogenesis with osteoblasts activation and chondrocyte ossification as an integrated system. Fourthly, this review followed the translation process of Mg-based implants via updating the preclinical studies in fracture fixation, sports trauma repair and reconstruction, and bone distraction for large bone defect. Furthermore, the pilot clinical studies were involved to demonstrate the reliable clinical safety and satisfactory bioactive effects of Mg-based implants in bone formation. Finally, this review introduced the background of spine fusion surgeryand the challenges of biological matching cage development. At last, this review prospected the translation potential of a hybrid Mg-PEEK spine fusion cage design.
Advances and applications of biomimetic biomaterials for endogenous skin regeneration
Authors: Mengyang Wang, Yiyue Hong, Xiaobing Fu, Xiaoyan Sun
Journal: Bioactive Materials (2024)

Endogenous regeneration is becoming an increasingly important strategy for wound healing as it facilitates skin's own regenerative potential for self-healing, thereby avoiding the risks of immune rejection and exogenous infection. However, currently applied biomaterials for inducing endogenous skin regeneration are simplistic in their structure and function, lacking the ability to accurately mimic the intricate tissue structure and regulate the disordered microenvironment. Novel biomimetic biomaterials with precise structure, chemical composition, and biophysical properties offer a promising avenue for achieving perfect endogenous skin regeneration. Here, we outline the recent advances in biomimetic materials induced endogenous skin regeneration from the aspects of structural and functional mimicry, physiological process regulation, and biophysical property design. Furthermore, novel techniques including in situ reprograming, flexible electronic skin, artificial intelligence, single-cell sequencing, and spatial transcriptomics, which have potential to contribute to the development of biomimetic biomaterials are highlighted. Finally, the prospects and challenges of further research and application of biomimetic biomaterials are discussed. This review provides reference to address the clinical problems of rapid and high-quality skin regeneration.
Neuroendocrine gut–brain signaling in obesity
Authors: Tim Gruber, Franziska Lechner, Jean-Philippe Krieger, Cristina García-Cáceres
Journal: Trends in Endocrinology and Metabolism (2024)

The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate behavior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called 'gut-brain axis' and to explore novel concepts, cutting-edge technologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut-brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics.
Nf1 mutation disrupts activity-dependent oligodendroglial plasticity and motor learning in mice
Authors: Yuan Pan, Jared D. Hysinger, Belgin Yalçın, James J. Lennon, Youkyeong Gloria Byun, Preethi Raghavan, Nicole F. Schindler, Corina Anastasaki, Jit Chatterjee, Lijun Ni, Haojun Xu, Karen Malacon, Samin M. Jahan, Alexis E. Ivec, Benjamin E. Aghoghovwia, Christopher W. Mount, Surya Nagaraja, Suzanne Scheaffer, Laura D. Attardi, David H. Gutmann, Michelle Monje
Journal: Nature Neuroscience (2024)

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects in activity-dependent oligodendrogenesis and harbor focal OPC hyperdensities with disrupted homeostatic OPC territorial boundaries. These OPC hyperdensities develop in a cell-intrinsic Nf1 mutation-specific manner due to differential PI3K/AKT activation. OPC-specific Nf1 loss impairs oligodendroglial differentiation and abrogates the normal oligodendroglial response to neuronal activity, leading to impaired motor learning performance. Collectively, these findings show that Nf1 mutation delays oligodendroglial development and disrupts activity-dependent OPC function essential for normal motor learning in mice.
Aging atlas reveals cell-type-specific effects of pro-longevity strategies
Authors: Shihong Max Gao, Yanyan Qi, Qinghao Zhang, Youchen Guan, Yi-Tang Lee, Lang Ding, Lihua Wang, Aaron S. Mohammed, Hongjie Li, Yusi Fu, Meng C. Wang
Journal: Nature Aging (2024)

Abstract Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms.
Affinity gaps among B cells in germinal centers drive the selection of MPER precursors
Authors: Rashmi Ray, Torben Schiffner, Xuesong Wang, Yu Yan, Kimmo Rantalainen, Chang-Chun David Lee, Shivang Parikh, Raphael A. Reyes, Gordon A. Dale, Ying-Cing Lin, Simone Pecetta, Sophie Giguere, Olivia Swanson, Sven Kratochvil, Eleonora Melzi, Ivy Phung, Lisa Madungwe, Oleksandr Kalyuzhniy, John Warner, Stephanie R. Weldon, Ryan Tingle, Edward Lamperti, Kathrin H. Kirsch, Nicole Phelps, Erik Georgeson, Yumiko Adachi, Michael Kubitz, Usha Nair, Shane Crotty, Ian A. Wilson, William R. Schief, Facundo D. Batista
Journal: Nature Immunology (2024)

Abstract Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor–competitor affinity gap.
Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement
Authors: Xin Lan, Tian Mi, Shanta Alli, Cliff Guy, Mohamed Nadhir Djekidel, Xueyan Liu, Shannon Boi, Partha Chowdhury, Minghong He, Dietmar Zehn, Yongqiang Feng, Ben Youngblood
Journal: Nature Immunology (2024)
Three-year outcomes of post-acute sequelae of COVID-19
Authors: Miao Cai, Yan Xie, Eric J. Topol, Ziyad Al-Aly
Journal: Nature Medicine (2024)

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC) in many organ systems. Risks of these sequelae have been characterized up to 2 years after infection, but longer-term follow-up is limited. Here we built a cohort of 135,161 people with SARS-CoV-2 infection and 5,206,835 controls from the US Department of Veterans Affairs who were followed for 3 years to estimate risks of death and PASC. Among non-hospitalized individuals, the increased risk of death was no longer present after the first year of infection, and risk of incident PASC declined over the 3 years but still contributed 9.6 (95% confidence interval (CI): 0.4–18.7) disability-adjusted life years (DALYs) per 1,000 persons in the third year. Among hospitalized individuals, risk of death declined but remained significantly elevated in the third year after infection (incidence rate ratio: 1.29 (95% CI: 1.19–1.40)). Risk of incident PASC declined over the 3 years, but substantial residual risk remained in the third year, leading to 90.0 (95% CI: 55.2–124.8) DALYs per 1,000 persons. Altogether, our findings show reduction of risks over time, but the burden of mortality and health loss remains in the third year among hospitalized individuals.
Systematic assessment of ISWI subunits shows that NURF creates local accessibility for CTCF
Authors: Mario Iurlaro, Francesca Masoni, Ilya M. Flyamer, Christiane Wirbelauer, Murat Iskar, Lukas Burger, Luca Giorgetti, Dirk Schübeler
Journal: Nature Genetics (2024)

Abstract Catalytic activity of the imitation switch (ISWI) family of remodelers is critical for nucleosomal organization and DNA binding of certain transcription factors, including the insulator protein CTCF. Here we define the contribution of individual subcomplexes by deriving a panel of isogenic mouse stem cell lines, each lacking one of six ISWI accessory subunits. Individual deletions of subunits of either CERF, RSF, ACF, WICH or NoRC subcomplexes only moderately affect the chromatin landscape, while removal of the NURF-specific subunit BPTF leads to a strong reduction in chromatin accessibility and SNF2H ATPase localization around CTCF sites. This affects adjacent nucleosome occupancy and CTCF binding. At a group of sites with reduced chromatin accessibility, CTCF binding persists but cohesin occupancy is reduced, resulting in decreased insulation. These results suggest that CTCF binding can be separated from its function as an insulator in nuclear organization and identify a specific role for NURF in mediating SNF2H localization and chromatin opening at bound CTCF sites.
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
Authors: Goro Katsuumi, Ippei Shimizu, Masayoshi Suda, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Chieh-Lun Hsiao, Liang Jiaqi, Shinya Fujiki, Manabu Abe, Masataka Sugimoto, Tomoyoshi Soga, Tohru Minamino
Journal: Nature Aging (2024)

Abstract It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium–glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β- d -ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.
Vaccination induces broadly neutralizing antibody precursors to HIV gp41
Authors: Torben Schiffner, Ivy Phung, Rashmi Ray, Adriana Irimia, Ming Tian, Olivia Swanson, Jeong Hyun Lee, Chang-Chun D. Lee, Ester Marina-Zárate, So Yeon Cho, Jiachen Huang, Gabriel Ozorowski, Patrick D. Skog, Andreia M. Serra, Kimmo Rantalainen, Joel D. Allen, Sabyasachi Baboo, Oscar L. Rodriguez, Sunny Himansu, Jianfu Zhou, Jonathan Hurtado, Claudia T. Flynn, Katherine McKenney, Colin Havenar-Daughton, Swati Saha, Kaitlyn Shields, Steven Schultze, Melissa L. Smith, Chi-Hui Liang, Laura Toy, Simone Pecetta, Ying-Cing Lin, Jordan R. Willis, Fabian Sesterhenn, Daniel W. Kulp, Xiaozhen Hu, Christopher A. Cottrell, Xiaoya Zhou, Jennifer Ruiz, Xuesong Wang, Usha Nair, Kathrin H. Kirsch, Hwei-Ling Cheng, Jillian Davis, Oleksandr Kalyuzhniy, Alessia Liguori, Jolene K. Diedrich, Julia T. Ngo, Vanessa Lewis, Nicole Phelps, Ryan D. Tingle, Skye Spencer, Erik Georgeson, Yumiko Adachi, Michael Kubitz, Saman Eskandarzadeh, Marc A. Elsliger, Rama R. Amara, Elise Landais, Bryan Briney, Dennis R. Burton, Diane G. Carnathan, Guido Silvestri, Corey T. Watson, John R. Yates, James C. Paulson, Max Crispin, Gevorg Grigoryan, Andrew B. Ward, Devin Sok, Frederick W. Alt, Ian A. Wilson, Facundo D. Batista, Shane Crotty, William R. Schief
Journal: Nature Immunology (2024)

Abstract A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
Point-of-care testing for sepsis in remote Australia and for First Nations peoples
Authors: Brooke Spaeth, Sean Taylor, Mark Shephard, Richard L. Reed, Rodney Omond, Jonathan Karnon, Billie Bonevski, Chris Rissel, Shahid Ullah, Tina Noutsos, Jacqueline H. Stephens, James A. Smith, Annabelle Wilson, Brett Abbenbroek, Emma de Courcy-Ireland, Simon Finfer
Journal: Nature Medicine (2024)
Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury
Authors: B. Rohaut, C. Calligaris, B. Hermann, P. Perez, F. Faugeras, F. Raimondo, J-.R. King, D. Engemann, C. Marois, L. Le Guennec, L. Di Meglio, A. Sangaré, E. Munoz Musat, M. Valente, A. Ben Salah, A. Demertzi, L. Belloli, D. Manasova, L. Jodaitis, M. O. Habert, V. Lambrecq, N. Pyatigorskaya, D. Galanaud, L. Puybasset, N. Weiss, S. Demeret, F. X. Lejeune, J. D. Sitt, L. Naccache
Journal: Nature Medicine (2024)

Abstract Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale–Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70–40.32), P &lt; 0.001; and 2.9 (1.56–5.45), P &lt; 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21–0.59), P &lt; 0.001) and improved prognostic accuracy (OR = 2.72 (1.18–6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .
High-throughput functional mapping of variants in an arrhythmia gene, KCNE1, reveals novel biology
Authors: Ayesha Muhammad, Maria E. Calandranis, Bian Li, Tao Yang, Daniel J. Blackwell, M. Lorena Harvey, Jeremy E. Smith, Zerubabell A. Daniel, Ashli E. Chew, John A. Capra, Kenneth A. Matreyek, Douglas M. Fowler, Dan M. Roden, Andrew M. Glazer
Journal: Genome Medicine (2024)

KCNE1 encodes a 129-residue cardiac potassium channel (IKs) subunit. KCNE1 variants are associated with long QT syndrome and atrial fibrillation. However, most variants have insufficient evidence of clinical consequences and thus limited clinical utility. In this study, we leveraged the power of variant effect mapping, which couples saturation mutagenesis with high-throughput sequencing, to ascertain the function of thousands of protein-coding KCNE1 variants. We comprehensively assayed KCNE1 variant cell surface expression (2554/2709 possible single-amino-acid variants) and function (2534 variants). Our study identified 470 loss- or partial loss-of-surface expression and 574 loss- or partial loss-of-function variants. Of the 574 loss- or partial loss-of-function variants, 152 (26.5%) had reduced cell surface expression, indicating that most functionally deleterious variants affect channel gating. Nonsense variants at residues 56-104 generally had WT-like trafficking scores but decreased functional scores, indicating that the latter half of the protein is dispensable for protein trafficking but essential for channel function. 22 of the 30 KCNE1 residues (73%) highly intolerant of variation (with > 70% loss-of-function variants) were in predicted close contact with binding partners KCNQ1 or calmodulin. Our functional assay data were consistent with gold standard electrophysiological data (ρ = - 0.64), population and patient cohorts (32/38 presumed benign or pathogenic variants with consistent scores), and computational predictors (ρ = - 0.62). Our data provide moderate-strength evidence for the American College of Medical Genetics/Association of Molecular Pathology functional criteria for benign and pathogenic variants. Comprehensive variant effect maps of KCNE1 can both provide insight into I Ks channel biology and help reclassify variants of uncertain significance.
Residual tricuspid regurgitation after tricuspid transcatheter edge‐to‐edge repair: Insights into the <scp>EuroTR</scp> registry
Authors: Lukas Stolz, Karl‐Patrik Kresoja, Jennifer von Stein, Vera Fortmeier, Benedikt Koell, Wolfgang Rottbauer, Mohammad Kassar, Bjoern Goebel, Paolo Denti, Paul Achouh, Tienush Rassaf, Manuel Barreiro‐Perez, Peter Boekstegers, Andreas Rück, Philipp M. Doldi, Julia Novotny, Monika Zdanyte, Marianna Adamo, Flavien Vincent, Philipp Schlegel, Ralph‐Stephan von Bardeleben, Thomas J. Stocker, Ludwig T. Weckbach, Mirjam G. Wild, Stephanie Brunner, Stefan Toggweiler, Julia Grapsa, Tiffany Patterson, Holger Thiele, Tobias Kister, Mathias H. Konstandin, Eric Van Belle, Marco Metra, Tobias Geisler, Rodrigo Estévez‐Loureiro, Peter Luedike, Nicole Karam, Francesco Maisano, Philipp Lauten, Fabien Praz, Mirjam Kessler, Daniel Kalbacher, Volker Rudolph, Christos Iliadis, Philipp Lurz, Jörg Hausleiter
Journal: European Journal of Heart Failure (2024)

Aims Data on the prognostic impact of residual tricuspid regurgitation (TR) after tricuspid transcatheter edge‐to‐edge repair (T‐TEER) are scarce. The aim of this analysis was to evaluate 2‐year survival and symptomatic outcomes of patients in relation to residual TR after T‐TEER. Methods and results Using the large European Registry of Transcatheter Repair for Tricuspid Regurgitation (EuroTR registry) we investigated the impact of residual TR on 2‐year all‐cause mortality and New York Heart Association (NYHA) functional class at follow‐up. The study further identified predictors for residual TR ≥3+ using a logistic regression model. The study included a total of 1286 T‐TEER patients (mean age 78.0 ± 8.9 years, 53.6% female). TR was successfully reduced to ≤1+ in 42.4%, 2+ in 40.0% and 3+ in 14.9% of patients at discharge, while 2.8% remained with TR ≥4+ after the procedure. Residual TR ≥3+ was an independent multivariable predictor of 2‐year all‐cause mortality (hazard ratio 2.06, 95% confidence interval 1.30–3.26, p = 0.002). The prevalence of residual TR ≥3+ was four times higher in patients with higher baseline TR (vena contracta &gt;11.1 mm) and more severe tricuspid valve tenting (tenting area &gt;1.92 cm 2 ). Of note, no survival difference was observed in patients with residual TR ≤1+ versus 2+ (76.2% vs. 73.1%, p = 0.461). The rate of NYHA functional class ≥III at follow‐up was significantly higher in patients with residual TR ≥3+ (52.4% vs. 40.5%, p &lt; 0.001). Of note, the degree of TR reduction significantly correlated with the extent of symptomatic improvement ( p = 0.012). Conclusions T‐TEER effectively reduced TR severity in the majority of patients. While residual TR ≥3+ was associated with worse outcomes, no differences were observed for residual TR 1+ versus 2+. Symptomatic improvement correlated with the degree of TR reduction.