tbuckley/cabot-search huggingface dataset:
Domain-Specific Physical Activity and Stroke in Sweden
Authors: Adam Viktorisson, Annie Palstam, Fredrik Nyberg, Christina Berg, Lauren Lissner, Katharina S. Sunnerhagen
Journal: JAMA Network Open (2024)

Importance Associations of domain-specific physical activity with stroke incidence and poststroke outcomes have not been extensively studied using long-term, population-based data. Objective To investigate associations of leisure time, work time, transport, and household physical activity with stroke incidence and death or dependency in activities of daily living (ADL) 3 months after stroke. Design, Setting, and Participants The prospective, population-based Interplay Between Genetic Susceptibility and External Factors (INTERGENE) cohort study was conducted among a random sample of individuals from an urban-rural area covering western Sweden; 3614 individuals aged 24 to 77 years were examined in 2001 to 2004, and 1394 individuals were reexamined in 2014 to 2016. The median (range) follow-up was 20.0 years (56 days to 21.9 years). Data were analyzed from September through October 2023. Exposure Physical activity levels were self-reported for leisure time, work time, transportation, and household domains. The mean number of steps taken over a 6-day period was collected in a subgroup of participants using a sealed pedometer. Main Outcomes and Measures Follow-up for stroke incidence and mortality rates continued until December 31, 2022. The composite outcome of death or ADL dependency was assessed at 3 months after stroke. Results Among 3614 individuals (mean [SD] age, 51.4 [13.1] years; 1910 female [52.9%]); 269 individuals (7.4%) developed stroke, of whom 120 individuals (44.6%) were dead or ADL dependent at 3 months. Intermediate (adjusted hazard ratio [aHR], 0.54; 95% CI, 0.38-0.77) and high (aHR, 0.47; 95% CI, 0.31-0.73) levels of leisure time physical activity were associated with a reduced incidence of stroke compared with low levels, as was an intermediate level of physical activity in transportation (aHR, 0.69; 95% CI, 0.52-0.93). High levels of leisure time physical activity were also associated with a reduced risk of poststroke death or ADL dependency (adjusted odds ratio, 0.34; 95% CI, 0.16-0.71) compared with low levels. Work time and household physical activity were not associated with stroke incidence or stroke outcomes. In exploratory subgroup analyses, there were interactions between physical activity and smoking (current smoking or smoking in the past year associated with stroke risk only in participants with low or intermediate physical activity: aHR, 2.33; 95% CI, 1.72-3.15) and family history of stroke (first-degree relative with a history of stroke associated with stroke risk only in participants with low or intermediate physical activity: aHR, 1.73; 95% CI, 1.27-2.38). Conclusions and Relevance In this study, leisure time and transport-related physical activities were associated with a reduced risk of stroke. A high level of leisure time physical activity was also associated with a lower risk of death or ADL dependency 3 months after stroke.
New Liver Allocation Policy and National Liver Transplant Volume
Authors: Daniela P. Ladner, Charles F. Manski, Sanjay Mehrotra
Journal: JAMA Surgery (2024)

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An IFNγ-dependent immune–endocrine circuit lowers blood glucose to potentiate the innate antiviral immune response
Authors: Marko Šestan, Sanja Mikašinović, Ante Benić, Stephan Wueest, Christoforos Dimitropoulos, Karlo Mladenić, Mia Krapić, Lea Hiršl, Yossef Glantzspiegel, Ana Rasteiro, Maria Aliseychik, Đurđica Cekinović Grbeša, Tamara Turk Wensveen, Marina Babić, Irit Gat-Viks, Henrique Veiga-Fernandes, Daniel Konrad, Felix M. Wensveen, Bojan Polić
Journal: Nature Immunology (2024)
High-resolution genome-wide mapping of chromosome-arm-scale truncations induced by CRISPR–Cas9 editing
Authors: Nathan H. Lazar, Safiye Celik, Lu Chen, Marta M. Fay, Jonathan C. Irish, James Jensen, Conor A. Tillinghast, John Urbanik, William P. Bone, Christopher C. Gibson, Imran S. Haque
Journal: Nature Genetics (2024)

Abstract Clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) is a powerful tool for introducing targeted mutations in DNA, but recent studies have shown that it can have unintended effects such as structural changes. However, these studies have not yet looked genome wide or across data types. Here we performed a phenotypic CRISPR–Cas9 scan targeting 17,065 genes in primary human cells, revealing a ‘proximity bias’ in which CRISPR knockouts show unexpected similarities to unrelated genes on the same chromosome arm. This bias was found to be consistent across cell types, laboratories, Cas9 delivery methods and assay modalities, and the data suggest that it is caused by telomeric truncations of chromosome arms, with cell cycle and apoptotic pathways playing a mediating role. Additionally, a simple correction is demonstrated to mitigate this pervasive bias while preserving biological relationships. This previously uncharacterized effect has implications for functional genomic studies using CRISPR–Cas9, with applications in discovery biology, drug-target identification, cell therapies and genetic therapeutics.
Non-invasive stimulation of the human striatum disrupts reinforcement learning of motor skills
Authors: Pierre Vassiliadis, Elena Beanato, Traian Popa, Fabienne Windel, Takuya Morishita, Esra Neufeld, Julie Duque, Gerard Derosiere, Maximilian J. Wessel, Friedhelm C. Hummel
Journal: Nature Human Behaviour (2024)

Abstract Reinforcement feedback can improve motor learning, but the underlying brain mechanisms remain underexplored. In particular, the causal contribution of specific patterns of oscillatory activity within the human striatum is unknown. To address this question, we exploited a recently developed non-invasive deep brain stimulation technique called transcranial temporal interference stimulation (tTIS) during reinforcement motor learning with concurrent neuroimaging, in a randomized, sham-controlled, double-blind study. Striatal tTIS applied at 80 Hz, but not at 20 Hz, abolished the benefits of reinforcement on motor learning. This effect was related to a selective modulation of neural activity within the striatum. Moreover, 80 Hz, but not 20 Hz, tTIS increased the neuromodulatory influence of the striatum on frontal areas involved in reinforcement motor learning. These results show that tTIS can non-invasively and selectively modulate a striatal mechanism involved in reinforcement learning, expanding our tools for the study of causal relationships between deep brain structures and human behaviour.
Cross-ancestry genome-wide association studies of brain imaging phenotypes
Authors: Jilian Fu, Quan Zhang, Jianhua Wang, Meiyun Wang, Bing Zhang, Wenzhen Zhu, Shijun Qiu, Zuojun Geng, Guangbin Cui, Yongqiang Yu, Weihua Liao, Hui Zhang, Bo Gao, Xiaojun Xu, Tong Han, Zhenwei Yao, Wen Qin, Feng Liu, Meng Liang, Sijia Wang, Qiang Xu, Jiayuan Xu, Peng Zhang, Wei Li, Dapeng Shi, Caihong Wang, Su Lui, Zhihan Yan, Feng Chen, Jing Zhang, Jiance Li, Wen Shen, Yanwei Miao, Dawei Wang, Junfang Xian, Jia-Hong Gao, Xiaochu Zhang, Kai Xu, Xi-Nian Zuo, Longjiang Zhang, Zhaoxiang Ye, Jingliang Cheng, Mulin Jun Li, Chunshui Yu, Quan Zhang, Junping Wang, Xue Zhang, Xinjun Suo, Congcong Yuan, Yuan Ji, Hui Xue, Tianying Gao, Junpeng Liu, Yanjun Li, Xi Guo, Lixue Xu, Jiajia Zhu, Huaigui Liu, Fangshi Zhao, Jie Sun, Yongjie Xu, Huanhuan Cai, Jie Tang, Yaodan Zhang, Yongqin Xiong, Xianting Sun, Nannan Pan, Xue Zhang, Jiayang Yang, Nana Liu, Ya Wen, Dan Zhu, Bingjie Wu, Wenshuang Zhu, Qingqing Diao, Yujuan Cao, Bingbing Yang, Lining Guo, Yingying Xie, Jiahui Lin, Zhimin Li, Yan Zhang, Kaizhong Xue, Zirui Wang, Junlin Shen, Xuejun Zhang, Hao Ding, Qian Su, Shijie Zhang, Lun Ma, Yan Bai, Min Guan, Wei Wei, Peifang Miao, Fuhong Duan, Yafei Guo, Weijian Wang, Lijuan Zheng, Li Lin, Yunfei Wang, Han Zhang, Xinyuan Zhang, Zhao Qing, Sichu Wu, Junxia Wang, Yi Sun, Yang He, Zhe Zhang, Yin-Shan Wang, Quan Zhou, Tian Tian, Yi Liang, Yujie Liu, Hui Zeng, Jingxian Chen, Haitao Ge, Peng Xu, Cailuan Lu, Chen Wu, Xiaoying Yang, Yuzhao Wang, Yankai Wu, Xuran Feng, Ling Li, Duo Gao, Rujing Zha, Ying Li, Lizhuang Yang, Ying Chen, Ling Zuo, Jianqiao Ge, Guoyuan Yang, Wen Wang, Linfeng Yan, Yang Yang, Jin Zhang, Qian Wang, Xiaoxia Qu, Ying Wang, Fei Yuan, Li Hu, Jizhen Li, Weiwei Wang, Yujing Zhou, Miaomiao Long, Lihua Liu, Xiaohu Li, Xiaoshu Li, Yunjun Yang, Nengzhi Xia, Shuai Yang, Youming Zhang, Guangyao Liu, Laiyang Ma, Xiaochun Wang, Ying Lei, Gang Zhang, Kang Yuan, Jingjing Xu, Xiaojun Guan, Yuankai Lin, Huijuan Chen, Yuchuan Fu, Yi Lu, Jun Guo, Hao Lu, Yue Wu
Journal: Nature Genetics (2024)
Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells
Authors: Cody T. Mowery, Jacob W. Freimer, Zeyu Chen, Salvador Casaní-Galdón, Jennifer M. Umhoefer, Maya M. Arce, Ketrin Gjoni, Bence Daniel, Katalin Sandor, Benjamin G. Gowen, Vinh Nguyen, Dimitre R. Simeonov, Christian M. Garrido, Gemma L. Curie, Ralf Schmidt, Zachary Steinhart, Ansuman T. Satpathy, Katherine S. Pollard, Jacob E. Corn, Bradley E. Bernstein, Chun Jimmie Ye, Alexander Marson
Journal: Nature Genetics (2024)

Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.
Impact of malnutrition in patients with severe heart failure
Authors: Matteo Pagnesi, Lisa Serafini, Mauro Chiarito, Davide Stolfo, Luca Baldetti, Riccardo M. Inciardi, Daniela Tomasoni, Marianna Adamo, Carlo M. Lombardi, Antonio M. Sammartino, Ferdinando Loiacono, Marta Maccallini, Alessandro Villaschi, Gaia Gasparini, Marco Montella, Stefano Contessi, Daniele Cocianni, Maria Perotto, Giuseppe Barone, Stefan D. Anker, Marco Merlo, Alberto M. Cappelletti, Gianfranco Sinagra, Daniela Pini, Marco Metra
Journal: European Journal of Heart Failure (2024)
Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer
Authors: Bingqi Dong, Yanlun Gu, Xiaojiao Sun, Xin Wang, Ying Zhou, Zhuona Rong, Jixin Zhang, Xuedong Shi, Zhuo Zhang, Xu He, Lin Chen, Qingqing Xiong, Xiaocong Pang, Yimin Cui
Journal: Advanced Healthcare Materials (2024)

Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment-induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis-related prognostic risk model of PCa, this study identifies TUBB3 as a key anoikis-related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis-resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis-resistance-induced PCa cell invasion and migration as well as epithelial-mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvβ3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, this work develops bone-targeting lipid nanoparticles (BT-LNP) based on bisphosphonate-modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT-LNP-delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT-LNP-mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease.
Injectable PEG Hydrogels with Tissue‐Like Viscoelasticity Formed through Reversible Alendronate–Calcium Phosphate Crosslinking for Cell–Material Interactions
Authors: Hongqiang Yu, Ziqian Yan, Cecile A. Dreiss, Gustavo G. Gaitano, James A. Jarvis, Eileen Gentleman, Ricardo M. P. da Silva, Agamemnon E. Grigoriadis
Journal: Advanced Healthcare Materials (2024)

Synthetic hydrogels provide controllable 3D environments, which can be used to study fundamental biological phenomena. The growing body of evidence that cell behavior depends upon hydrogel stress relaxation creates a high demand for hydrogels with tissue-like viscoelastic properties. Here, a unique platform of synthetic polyethylene glycol (PEG) hydrogels in which star-shaped PEG molecules are conjugated with alendronate and/or RGD peptides, attaining modifiable degradability as well as flexible cell adhesion, is created. Novel reversible ionic interactions between alendronate and calcium phosphate nanoparticles, leading to versatile viscoelastic properties with varying initial elastic modulus and stress relaxation time, are identified. This new crosslinking mechanism provides shear-thinning properties resulting in differential cellular responses between cancer cells and stem cells. The novel hydrogel system is an improved design to the other ionic crosslink platforms and opens new avenues for the development of pathologically relevant cancer models, as well as minimally invasive approaches for cell delivery for potential regenerative therapies.
Exceptional Genetics, Generalizable Therapeutics, and Coronary Artery Disease
Authors: Pradeep Natarajan
Journal: New England Journal of Medicine (2024)

The increasingly widespread availability of genomic sequencing has enabled the identification of persons and families with uniquely favorable traits, including a very low incidence of clinical events. Such exceptional persons across diverse communities are playing an important role in the genesis of medicines for common cardiovascular diseases. The discovery of proprotein convertase subtilisin–kexin type 9 (PCSK9) as a therapeutic target for coronary artery disease established a playbook. Approximately 20 years ago, positional cloning of a novel candidate locus of families with familial hypercholesterolemia living in France and Utah identified gain-of-function variants in PCSK9. In short course, targeted sequencing of PCSK9 . . .
Granular Biomaterials as Bioactive Sponges for the Sequestration and Release of Signaling Molecules
Authors: Dilara Börte Emiroglu, Apoorv Singh, Bruno Marco‐Dufort, Noël Speck, Pier Giuseppe Rivano, John S. Oakey, Nako Nakatsuka, Andrew J. deMello, Céline Labouesse, Mark W. Tibbitt
Journal: Advanced Healthcare Materials (2024)

A major challenge for the regeneration of chronic wounds is an underlying dysregulation of signaling molecules, including inflammatory cytokines and growth factors. To address this, it is proposed to use granular biomaterials composed of jammed microgels, to enable the rapid uptake and delivery of biomolecules, and provide a strategy to locally sequester and release biomolecules. Sequestration assays on model biomolecules of different sizes demonstrate that granular hydrogels exhibit faster transport than comparable bulk hydrogels due to enhanced surface area and decreased diffusion lengths. To demonstrate the potential of modular granular hydrogels to modulate local biomolecule concentrations, microgel scaffolds are engineered that can simultaneously sequester excess pro-inflammatory factors and release pro-healing factors. To target specific biomolecules, microgels are functionalized with affinity ligands that bind either to interleukin 6 (IL-6) or to vascular endothelial growth factor A (VEGF-A). Finally, disparate microgels are combined into a single granular biomaterial for simultaneous sequestration of IL-6 and release of VEGF-A. Overall, the potential of modular granular hydrogels is demonstrated to locally tailor the relative concentrations of pro- and anti-inflammatory factors.
Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications
Authors: Miaodan Huang, Yong U. Liu, Xiaoli Yao, Dajiang Qin, Huanxing Su
Journal: Translational Neurodegeneration (2024)

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1 , the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1 -associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.
JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression
Authors: Torben Redmer, Martin Raigel, Christina Sternberg, Roman Ziegler, Clara Probst, Desiree Lindner, Astrid Aufinger, Tanja Limberger, Karolina Trachtova, Petra Kodajova, Sandra Högler, Michaela Schlederer, Stefan Stoiber, Monika Oberhuber, Marco Bolis, Heidi A. Neubauer, Sara Miranda, Martina Tomberger, Nora S. Harbusch, Ines Garces de los Fayos Alonso, Felix Sternberg, Richard Moriggl, Jean-Philippe Theurillat, Boris Tichy, Vojtech Bystry, Jenny L. Persson, Stephan Mathas, Fritz Aberger, Birgit Strobl, Sarka Pospisilova, Olaf Merkel, Gerda Egger, Sabine Lagger, Lukas Kenner
Journal: Molecular Cancer (2024)

Abstract Background Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. Methods We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten -deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. Results Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten -deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten -deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten -deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten -deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. Conclusions Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes. Graphical Abstract
Early Injury Landscape in Vein Harvest by Single-Cell and Spatial Transcriptomics
Authors: Marina E. Michaud, Lucas Mota, Mojtaba Bakhtiari, Beena E. Thomas, John Tomeo, William Pilcher, Mauricio Contreras, Christiane Ferran, Swati S. Bhasin, Leena Pradhan-Nabzdyk, Frank W. LoGerfo, Patric Liang, Manoj K. Bhasin
Journal: Circulation Research (2024)

Vein graft failure following cardiovascular bypass surgery results in significant patient morbidity and cost to the healthcare system. Vein graft injury can occur during autogenous vein harvest and preparation, as well as after implantation into the arterial system, leading to the development of intimal hyperplasia, vein graft stenosis, and, ultimately, bypass graft failure. Although previous studies have identified maladaptive pathways that occur shortly after implantation, the specific signaling pathways that occur during vein graft preparation are not well defined and may result in a cumulative impact on vein graft failure. We, therefore, aimed to elucidate the response of the vein conduit wall during harvest and following implantation, probing the key maladaptive pathways driving graft failure with the overarching goal of identifying therapeutic targets for biologic intervention to minimize these natural responses to surgical vein graft injury.