Ahyeon Hwang, Mario Skarica, Siwei Xu, Jensine Coudriet, Che Yu Lee, Lin Lin, Rosemarie Terwilliger, Alexa-Nicole Sliby, Jiawei Wang, Tuan Nguyen, Hongyu Li, Min Wu, Yi Dai, Ziheng Duan, Shushrruth Sai Srinivasan, Xiangyu Zhang, Yingxin Lin, Dianne Cruz, P J Michael Deans, Traumatic Stress Brain Research Group, Bertrand R Huber, Daniel Levey, Jill R Glausier, David A Lewis, Joel Gelernter, Paul E Holtzheimer, Matthew J Friedman, Mark Gerstein, Nenad Sestan, Kristen J Brennand, Ke Xu, Hongyu Zhao, John H Krystal, Keith A Young, Douglas E Williamson, Alicia Che, Jing Zhang, Matthew J Girgenti <<<

Post-traumatic stress disorder (PTSD) is a polygenic disorder occurring after extreme trauma exposure. Recent studies have begun to detail the molecular biology of PTSD. However, given the array of PTSD-perturbed molecular pathways identified so far, it is implausible that a single cell type is responsible. Here we profile the molecular responses in over two million nuclei from the dorsolateral prefrontal cortex of 111 human brains, collected post-mortem from individuals with and without PTSD and major depressive disorder. We identify neuronal and non-neuronal cell-type clusters, gene expression changes and transcriptional regulators, and map the epigenomic regulome of PTSD in a cell-type-specific manner. Our analysis revealed PTSD-associated gene alterations in inhibitory neurons, endothelial cells and microglia and uncovered genes and pathways associated with glucocorticoid signalling, GABAergic transmission and neuroinflammation. We further validated these findings using cell-type-specific spatial transcriptomics, confirming disruption of key genes such as SST and FKBP5. By integrating genetic, transcriptomic and epigenetic data, we uncovered the regulatory mechanisms of credible variants that disrupt PTSD genes, including ELFN1, MAD1L1 and KCNIP4, in a cell-type-specific context. Together, these findings provide a comprehensive characterization of the cell-specific molecular regulatory mechanisms that underlie the persisting effects of traumatic stress response on the human prefrontal cortex. <<<

Gustaw Eriksson, Congru Li, Tina Gorsek Sparovec, Anja Dekanski, Sara Torstensson, Sanjiv Risal, Claes Ohlsson, Angelica Lindén Hirschberg, Sophie Petropoulos, Qiaolin Deng, Elisabet Stener-Victorin <<<

Abstract Polycystic ovary syndrome (PCOS) has a negative effect on the receptivity of the endometrium to embryo implantation and increases the risk of miscarriage and endometrial cancer. The cellular and molecular heterogeneity of the endometrium in women with PCOS has not been well studied. Our study presents a comprehensive cellular atlas of the endometrium during the proliferative phase in women with PCOS characterized by overweight and obesity, hyperandrogenism and insulin resistance compared with controls of similar age, weight and body mass index. Analysis of 247,791 isolated endometrial nuclei from 27 biopsies (5 controls and 12 PCOS cases at baseline and 7 after 16 weeks of metformin and 3 after lifestyle intervention) revealed cell-type-specific disease signatures and variations in cellular composition and localization. Samples taken after 16 weeks of metformin treatment and lifestyle management showed extensive recovery of disease-specific endometrial signatures. We linked the specific role of each cell type to clinical features such as hyperandrogenism and insulin resistance, and specific cell types to risk of endometrial and metabolic disease. In addition, potential therapeutic targets such as integrin inhibitors were identified and the role of metformin in restoring endometrial health in patients with PCOS was highlighted. Our findings lay the groundwork to significantly advance the understanding of PCOS-specific endometrial dysfunction for future targeted therapies. <<<

Matthias Diebold, Patrick T. Gauthier, Katharina A. Mayer, Martina Mackova, Christian Hinze, Jessica Chang, Uptal D. Patel, Ekkehard Schütz, Bernd Jilma, Eva Schrezenmeier, Klemens Budde, Georg A. Böhmig, Philip F. Halloran <<<

Abstract A recent randomized controlled trial demonstrated that treatment with anti-CD38 monoclonal antibody felzartamab suppressed antibody-mediated rejection (ABMR) in kidney transplant patients but with recurrence after treatment in some patients. Here we examined the molecular effects of 6 months of felzartamab treatment on biopsies from the trial using genome-wide microarray analysis, comparing pretreatment, end-of-treatment (week 24) and posttreatment (week 52) biopsies from ten patients treated with felzartamab and ten patients in the placebo group. Felzartamab reduced molecular ABMR activity scores in all nine patients with baseline ABMR activity, selectively suppressing interferon gamma-inducible and natural killer cell transcripts, with minimal effect on ABMR stage-related endothelial transcripts. Suppression was often incomplete when ABMR activity was intense, and molecular recurrence was nearly universal by week 52. However, we also found that felzartamab had parenchymal benefits at week 52, slowing the trajectories of molecular injury scores beyond the treatment period, suggesting that suppression of ABMR activity could potentially slow future progression to kidney failure. These data provide preliminary molecular insights into the effects of CD38-directed treatment for ABMR, which have the potential to inform future therapeutic strategies. <<<

Anne-Julie Tessier, Fenglei Wang, Andres Ardisson Korat, A. Heather Eliassen, Jorge Chavarro, Francine Grodstein, Jun Li, Liming Liang, Walter C. Willett, Qi Sun, Meir J. Stampfer, Frank B. Hu, Marta Guasch-Ferré <<<

Areeba Patel, Kirsten Göbel, Sebastian Ille, Felix Hinz, Natalie Schoebe, Henri Bogumil, Jochen Meyer, Michelle Brehm, Helin Kardo, Daniel Schrimpf, Artem Lomakin, Michael Ritter, Pauline Göller, Paul Kerbs, Lisa Pfeifer, Stefan Hamelmann, Christina Blume, Franziska M. Ippen, Natalie Berghaus, Philipp Euskirchen, Leonille Schweizer, Claus Hultschig, Nadine Van Roy, Jo Van Dorpe, Joni Van der Meulen, Siebe Loontiens, Franceska Dedeurwaerdere, Henning Leske, Skarphéðinn Halldórsson, Graeme Fox, Simon Deacon, Inswasti Cahyani, Nadine Holmes, Satrio Wibowo, Rory Munro, Dan Martin, Abid Sharif, Mark Housley, Robert Goldspring, Sebastian Brandner, Somak Roy, Jürgen Hench, Stephan Frank, Andreas Unterberg, Violaine Goidts, Natalie Jäger, Simon Paine, Stuart Smith, Christel Herold-Mende, Wolfgang Wick, Stefan M. Pfister, Einar O. Vik-Mo, Andreas von Deimling, Sandro Krieg, David TW Jones, Matthew Loose, Matthias Schlesner, Martin Sill, Felix Sahm <<<

Hesham ElAbd, Mitchell Pesesky, Gabriel Innocenti, Brian K. Chung, Aya K. H. Mahdy, Valeriia Kriukova, Laila Kulsvehagen, Dennis Strobbe, Claudia Stühler, Gabriele Mayr, Damon H. May, Melanie Prinzensteiner, Tim A. Steiert, Florian Tran, Michel V. Hadjihannas, Rainer Günther, Elisa Rosati, Sören Mucha, Wolfgang Lieb, Malte Ziemann, Astrid Dempfle, Felix Braun, Trine Folseraas, Johannes R. Hov, Espen Melum, Petra Bacher, Martina Sterneck, Tobias J. Weismüller, Henrike Lenzen, Bernd Bokemeyer, Bryan Howie, Harlan S. Robins, Christoph Röcken, Stefan Schreiber, Nina Khanna, Anne-Katrin Pröbstel, Christoph Schramm, Thomas Vogl, Tom H. Karlsen, Andre Franke <<<

Abstract Primary sclerosing cholangitis (PSC) is an idiopathic, progressive and incurable liver disease. Here, we aimed for systematic analyses of adaptive immune responses in PSC. By profiling the T cell repertoires of 504 individuals with PSC and 904 healthy controls, we identified 1,008 clonotypes associated with PSC. A substantial fraction of these clonotypes was restricted to known PSC human leukocyte antigen susceptibility alleles and known to target Epstein–Barr virus (EBV) epitopes. We further utilized phage-immunoprecipitation sequencing to determine antibody epitope repertoires of 120 individuals with PSC and 202 healthy controls, which showed a higher burden of anti-EBV responses in PSC than controls. EBV-specific monoclonal antibodies isolated from B cells in PSC livers corroborated convergent B and T cell responses against EBV. By analyzing electronic health records of >116 million people, we identified an association between infectious mononucleosis and PSC (odds ratio, 12; 95% confidence interval, 6.3–22.9), suggesting a link between EBV and PSC. <<<

Rajappa S. Kenchappa, Laszlo Radnai, Erica J. Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T. Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K.H. Nagaiah, Gavin Rumbaugh, Michael D. Cameron, Theodore M. Kamenecka, Patrick R. Griffin, Courtney A. Miller, Steven S. Rosenfeld <<<

Ensuring that large language models (LLMs) generate outputs aligned withhuman preferences is important for safe and effective AI interactions. WhileDirect Preference Optimization (DPO) employs an implicit reward function tooptimize the policy model, however, it and its related variants overlook thedifferential importance of individual tokens and are sensitive to judgmentnoise in preference datasets during generation. Although recent methods attemptto assess the important weight of tokens via probability prediction orsimplistic weighting schemes, these evaluation methods are prone to biases andstill cannot fully address these issues. To solve this problem, we propose theToken-Importance Guided Direct Preference Optimization (TI-DPO), whichintroduces two key innovations: the gradient-based token-importance weightsthat dynamically prioritize critical tokens, and a triple loss that explicitlyguides model outputs to approach human-preferred responses and stay away fromnon-preferred responses. Experimental results show that TI-DPO achieves higheraccuracy and stronger generative diversity, providing more stable andcomputationally efficient solutions compared with DPO and other RLHF methods. <<<

William M. Schultz, Heval M. Kelli, John C. Lisko, Tina Varghese, Jia Shen, Pratik Sandesara, Arshed A. Quyyumi, Herman A. Taylor, Martha Gulati, John G. Harold, Jennifer H. Mieres, Keith C. Ferdinand, George A Mensah, Laurence S. Sperling <<<

Socioeconomic status (SES) has a measurable and significant effect on cardiovascular health. Biological, behavioral, and psychosocial risk factors prevalent in disadvantaged individuals accentuate the link between SES and cardiovascular disease (CVD). Four measures have been consistently associated with CVD in high-income countries: income level, educational attainment, employment status, and neighborhood socioeconomic factors. In addition, disparities based on sex have been shown in several studies. Interventions targeting patients with low SES have predominantly focused on modification of traditional CVD risk factors. Promising approaches are emerging that can be implemented on an individual, community, or population basis to reduce disparities in outcomes. Structured physical activity has demonstrated effectiveness in low-SES populations, and geomapping may be used to identify targets for large-scale programs. Task shifting, the redistribution of healthcare management from physician to nonphysician providers in an effort to improve access to health care, may have a role in select areas. Integration of SES into the traditional CVD risk prediction models may allow improved management of individuals with high risk, but cultural and regional differences in SES make generalized implementation challenging. Future research is required to better understand the underlying mechanisms of CVD risk that affect individuals of low SES and to determine effective interventions for patients with high risk. We review the current state of knowledge on the impact of SES on the incidence, treatment, and outcomes of CVD in high-income societies and suggest future research directions aimed at the elimination of these adverse factors, and the integration of measures of SES into the customization of cardiovascular treatment. <<<

Binjie Guo, Hanyu Zheng, Guowei Su, Ru Zhang, Haohan Jiang, Xurong Lin, Hongyan Wei, Aisheng Mo, Jie Li, Zhiyuan Qian, Zhuhao Zhang, Xiaoyuan Cheng <<<

Recent years have witnessed significant progress in reinforcement learning,especially with Zero-like paradigms, which have greatly boosted thegeneralization and reasoning abilities of large-scale language models.Nevertheless, existing frameworks are often plagued by high implementationcomplexity and poor reproducibility. To tackle these challenges, we presentAlphaZero-Edu, a lightweight, education-focused implementation built upon themathematical framework of AlphaZero. It boasts a modular architecture thatdisentangles key components, enabling transparent visualization of thealgorithmic processes. Additionally, it is optimized for resource-efficienttraining on a single NVIDIA RTX 3090 GPU and features highly parallelizedself-play data generation, achieving a 3.2-fold speedup with 8 processes. InGomoku matches, the framework has demonstrated exceptional performance,achieving a consistently high win rate against human opponents. AlphaZero-Eduhas been open-sourced at https://github.com/StarLight1212/AlphaZero_Edu,providing an accessible and practical benchmark for both academic research andindustrial applications. <<<

Progressive age-induced deterioration in the structure and function of the cardiovascular system involves cardiac hypertrophy, diastolic dysfunction, myocardial fibrosis, arterial stiffness, and endothelial dysfunction. These changes are driven by complex processes that are interconnected, such as oxidative stress, mitochondrial dysfunction, autophagy, inflammation, fibrosis, and telomere dysfunction. In recent years, the advances in research of cardiovascular aging, including the wide use of animal models of cardiovascular aging, elucidated an abundance of cell signaling pathways involved in these processes and brought into sight possible interventions, which span from pharmacological agents, such as metformin, sodium-glucose cotransporter 2-inhibitors, rapamycin, dasatinib and quercetin, to lifestyle changes. <<<

AbstractDirectional tongue movements are crucial for feeding and speech, ensuring proper food positioning for chewing and swallowing, as well as accurate sound production. While directional tuning in the arm region of the sensorimotor cortex during reaching tasks is well-studied, little is known about how 3D tongue direction is encoded in the orofacial sensorimotor cortex (OSMCx) during natural behaviors. Understanding this neural representation has important implications for rehabilitating individuals with orolingual dysfunctions. This study examines the directional tuning and population dynamics in OSMCx during naturalistic feeding and drinking, and how these are affected by sensory loss. Using biplanar videoradiography, we tracked implanted tongue markers in behaving rhesus macaques (Macaca mulatta) and simultaneously recorded 3D positional data with spiking activity from chronically implanted microelectrode arrays in primary motor (MIo) and somatosensory (SIo) areas of the orofacial cortex. In some sessions, tasks were preceded by bilateral nerve block injections to the sensory branches of the trigeminal nerve. Modulation to 3D tongue direction during feeding and drinking was found in most MIo and SIo neurons. Directional information in both individual- and population-level was higher in feeding and was more robust in MIo. Following sensory loss, alterations in tongue kinematics were accompanied by changes in directional information in MIo and SIo, manifesting as modifications in both individual neuron tuning characteristics and the broader dynamics of population-level neural activity. Overall, this study advances our understanding of how OSMCx contributes to complex, coordinated control of naturalistic tongue movements. It expands our current knowledge of orofacial control to three dimensions and demonstrates the specificity and adaptability of population activity in MIo and SIo in response to different behavioral contexts. <<<

Ana Mikolic, Tasha Klotz, Penelope Brasher, Keith Yeates, Ana-Maria Vranceanu, Karen D Kendall, Deborah L Snell, Chantel T Debert, Mark Bayley, William Panenka, Molly Cairncross, Cindy Hunt, Matthew Burke, Maria Carmela Tartaglia, Noah Silverberg <<<

IntroductionPersistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic disability after mTBI. This study will evaluate the efficacy of graded exposure therapy (GET) for reducing persistent symptoms following mTBI, with two primary aims: (1) To determine whether GET is more effective than usual care; (2) to identify for whom GET is the most effective treatment option, by evaluating whether baseline fear avoidance moderates differences between GET and an active comparator (prescribed aerobic exercise). Our findings will guide evidence-based care after mTBI and enable better matching of mTBI patients to treatments.Methods and analysisWe will conduct a multisite randomised controlled trial with three arms. Participants (n=220) will be recruited from concussion clinics and emergency departments in three Canadian provinces and randomly assigned (1:2:2 ratio) to receive enhanced usual care, GET or prescribed aerobic exercise. The outcome assessment will occur remotely 14–18 weeks following baseline assessment, after completing the 12-week treatment phase. The primary outcome will be symptom severity (Rivermead Post-concussion Symptoms Questionnaire).Ethics and disseminationInformed consent will be obtained from all participants. All study procedures were approved by the local research ethics boards (University of British Columbia Clinical Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, University Health Network Research Ethics Board—Panel D). Operational approvals were obtained for Vancouver Coastal Health Research Institute and Provincial Health Services Authority. If GET proves effective, we will disseminate the GET treatment manual and present instructional workshops for clinicians.Trial registration numberClinicalTrials.gov #NCT05365776 <<<

Abstract Background Noninvasive prenatal testing (NIPT) is increasingly used to screen for fetal chromosomal aneuploidy by analyzing cell-free DNA (cfDNA) in peripheral maternal blood. The method provides an opportunity for early detection of large genetic abnormalities without an increased risk of miscarriage due to invasive procedures. Commercial applications for use at clinical laboratories often take advantage of DNA sequencing technologies and include the bioinformatic workup of the sequence data. The interpretation of the test results and the clinical report writing, however, remains the responsibility of the diagnostic laboratory. In order to facilitate this step, we developed NIPTviewer, a web-based application to visualize and guide the interpretation of NIPT data results. Results NIPTviewer has a database functionality to store the NIPT results and a web interface for user interaction and visualization. The application has been implemented as part of a novel analysis pipeline for NIPT in a diagnostic laboratory at Uppsala University Hospital. The validation data set included 84 previously analyzed plasma samples with known results regarding chromosomes 13, 18, 21, X and Y. They were sequenced in six different experiments, uploaded to NIPTviewer and assigned to a clinical laboratory geneticist for interpretation. The results of all previously analyzed samples were replicated. Conclusion NIPTviewer facilitates NIPT results interpretation and has been implemented as part of a NIPT analysis routine that was accredited by the national accreditation body for Sweden (Swedac). <<<

Vision-language-action (VLA) models have emerged as the next generation ofmodels in robotics. However, despite leveraging powerful pre-trainedVision-Language Models (VLMs), existing end-to-end VLA systems often lose keycapabilities during fine-tuning as the model adapts to specific robotic tasks.We argue that a generalizable VLA model should retain and expand upon the VLM'score competencies: 1) Open-world embodied reasoning - the VLA should inheritthe knowledge from VLM, i.e., recognize anything that the VLM can recognize,capable of solving math problems, possessing visual-spatial intelligence, 2)Reasoning following - effectively translating the open-world reasoning intoactionable steps for the robot. In this work, we introduce ChatVLA-2, a novelmixture-of-expert VLA model coupled with a specialized three-stage trainingpipeline designed to preserve the VLM's original strengths while enablingactionable reasoning. To validate our approach, we design a math-matching taskwherein a robot interprets math problems written on a whiteboard and pickscorresponding number cards from a table to solve equations. Remarkably, ourmethod exhibits exceptional mathematical reasoning and OCR capabilities,despite these abilities not being explicitly trained within the VLA.Furthermore, we demonstrate that the VLA possesses strong spatial reasoningskills, enabling it to interpret novel directional instructions involvingpreviously unseen objects. Overall, our method showcases reasoning andcomprehension abilities that significantly surpass state-of-the-art imitationlearning methods such as OpenVLA, DexVLA, and pi-zero. This work represents asubstantial advancement toward developing truly generalizable roboticfoundation models endowed with robust reasoning capacities. <<<

Yihan Jiang, Yuanyuan Chen, Lijiang Wei, Farui Liu, Zeqing Zheng, Zong Zhang, Zheng Li, Yingying Tang, Jijun Wang, Qing Xie, Chuanxin M. Niu, Chaozhe Zhu <<<

Despite recent progress in general purpose robotics, robot policies still lagfar behind basic human capabilities in the real world. Humans interactconstantly with the physical world, yet this rich data resource remains largelyuntapped in robot learning. We propose EgoZero, a minimal system that learnsrobust manipulation policies from human demonstrations captured with ProjectAria smart glasses, $\textbf{and zero robot data}$. EgoZero enables: (1)extraction of complete, robot-executable actions from in-the-wild, egocentric,human demonstrations, (2) compression of human visual observations intomorphology-agnostic state representations, and (3) closed-loop policy learningthat generalizes morphologically, spatially, and semantically. We deployEgoZero policies on a gripper Franka Panda robot and demonstrate zero-shottransfer with 70% success rate over 7 manipulation tasks and only 20 minutes ofdata collection per task. Our results suggest that in-the-wild human data canserve as a scalable foundation for real-world robot learning - paving the waytoward a future of abundant, diverse, and naturalistic training data forrobots. Code and videos are available at https://egozero-robot.github.io. <<<