tbuckley/cabot-search huggingface dataset:
A molecular mechanism for environmental sex determination
Authors: Xiaojing Li, John K. Colbourne
Journal: Trends in Genetics (2024)

Daphnia produce genetically identical males and females; their sex is determined by environmental conditions. Recently, Kato et al. identified isoform switching events in Daphnia as a gene regulatory mechanism for sex-specific development. This finding uncovers the impact of alternative usage of gene isoforms on this extreme phenotypic plasticity trait.
'Living drugs' target CD70 in advanced renal tumors
Authors: Kilian Wagner, Peter J. Siska
Journal: Trends in Pharmacological Sciences (2024)

Cellular therapies against solid tumors face three major barriers: low persistence, insufficient specificity, and high costs. In a recent study, Pal et al. tackle these challenges in kidney cancer by using novel, 'persistence-tuned' allogeneic chimeric antigen receptor (CAR) T cells directed against a stable antigen.
Maternal age enhances purifying selection on pathogenic mutations in complex I genes of mammalian mtDNA
Authors: Yanfei Ru, Xiaoling Deng, Jiatong Chen, Leping Zhang, Zhe Xu, Qunyu Lv, Shiyun Long, Zijian Huang, Minghua Kong, Jing Guo, Min Jiang
Journal: Nature Aging (2024)
Phospholipase-mediated phosphate recycling during plant leaf senescence
Authors: Bao Yang, Zengdong Tan, Jiayu Yan, Ke Zhang, Zhewen Ouyang, Ruyi Fan, Yefei Lu, Yuting Zhang, Xuan Yao, Hu Zhao, Xuemin Wang, Shaoping Lu, Liang Guo
Journal: Genome biology (2024)

Phosphorus is a macronutrient necessary for plant growth and development and its availability and efficient use affect crop yields. Leaves are the largest tissue that uses phosphorus in plants, and membrane phospholipids are the main source of cellular phosphorus usage. Here we identify a key process for plant cellular phosphorus recycling mediated by membrane phospholipid hydrolysis during leaf senescence. Our results indicate that over 90% of lipid phosphorus, accounting for more than one-third of total cellular phosphorus, is recycled from senescent leaves before falling off the plants. Nonspecific phospholipase C4 (NPC4) and phospholipase Dζ2 (PLDζ2) are highly induced during leaf senescence, and knockouts of PLDζ2 and NPC4 decrease the loss of membrane phospholipids and delay leaf senescence. Conversely, overexpression of PLDζ2 and NPC4 accelerates the loss of phospholipids and leaf senescence, promoting phosphorus remobilization from senescent leaves to young tissues and plant growth. We also show that this phosphorus recycling process in senescent leaves mediated by membrane phospholipid hydrolysis is conserved in plants. These results indicate that PLDζ2- and NPC4-mediated membrane phospholipid hydrolysis promotes phosphorus remobilization from senescent leaves to growing tissues and that the phospholipid hydrolysis-mediated phosphorus recycling improves phosphorus use efficiency in plants.
Population-level coding of avoidance learning in medial prefrontal cortex
Authors: Benjamin Ehret, Roman Boehringer, Elizabeth A. Amadei, Maria R. Cervera, Christian Henning, Aniruddh R. Galgali, Valerio Mante, Benjamin F. Grewe
Journal: Nature Neuroscience (2024)

Abstract The medial prefrontal cortex (mPFC) has been proposed to link sensory inputs and behavioral outputs to mediate the execution of learned behaviors. However, how such a link is implemented has remained unclear. To measure prefrontal neural correlates of sensory stimuli and learned behaviors, we performed population calcium imaging during a new tone-signaled active avoidance paradigm in mice. We developed an analysis approach based on dimensionality reduction and decoding that allowed us to identify interpretable task-related population activity patterns. While a large fraction of tone-evoked activity was not informative about behavior execution, we identified an activity pattern that was predictive of tone-induced avoidance actions and did not occur for spontaneous actions with similar motion kinematics. Moreover, this avoidance-specific activity differed between distinct avoidance actions learned in two consecutive tasks. Overall, our results are consistent with a model in which mPFC contributes to the selection of goal-directed actions by transforming sensory inputs into specific behavioral outputs through distributed population-level computations.
Genetic factors associated with reasons for clinical trial stoppage
Authors: Olesya Razuvayevskaya, Irene Lopez, Ian Dunham, David Ochoa
Journal: Nature Genetics (2024)

Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to evaluate targets for drug discovery programs.
Mining alternative splicing patterns in scRNA-seq data using scASfind
Authors: Yuyao Song, Guillermo Parada, Jimmy Tsz Hang Lee, Martin Hemberg
Journal: Genome biology (2024)

Single-cell RNA-seq (scRNA-seq) is widely used for transcriptome profiling, but most analyses focus on gene-level events, with less attention devoted to alternative splicing. Here, we present scASfind, a novel computational method to allow for quantitative analysis of cell type-specific splicing events using full-length scRNA-seq data. ScASfind utilizes an efficient data structure to store the percent spliced-in value for each splicing event. This makes it possible to exhaustively search for patterns among all differential splicing events, allowing us to identify marker events, mutually exclusive events, and events involving large blocks of exons that are specific to one or more cell types.
scCross: a deep generative model for unifying single-cell multi-omics with seamless integration, cross-modal generation, and in silico exploration
Authors: Xiuhui Yang, Koren K. Mann, Hao Wu, Jun Ding
Journal: Genome biology (2024)

Single-cell multi-omics data reveal complex cellular states, providing significant insights into cellular dynamics and disease. Yet, integration of multi-omics data presents challenges. Some modalities have not reached the robustness or clarity of established transcriptomics. Coupled with data scarcity for less established modalities and integration intricacies, these challenges limit our ability to maximize single-cell omics benefits. We introduce scCross, a tool leveraging variational autoencoders, generative adversarial networks, and the mutual nearest neighbors (MNN) technique for modality alignment. By enabling single-cell cross-modal data generation, multi-omics data simulation, and in silico cellular perturbations, scCross enhances the utility of single-cell multi-omics studies.
Guideline on positioning and early mobilisation in the critically ill by an expert panel
Authors: Stefan J. Schaller, Flora T. Scheffenbichler, Thomas Bein, Manfred Blobner, Julius J. Grunow, Uwe Hamsen, Carsten Hermes, Arnold Kaltwasser, Heidrun Lewald, Peter Nydahl, Anett Reißhauer, Leonie Renzewitz, Karsten Siemon, Thomas Staudinger, Roman Ullrich, Steffen Weber-Carstens, Hermann Wrigge, Dominik Zergiebel, Sina M. Coldewey
Journal: Intensive Care Medicine (2024)

A scientific panel was created consisting of 23 interdisciplinary and interprofessional experts in intensive care medicine, physiotherapy, nursing care, surgery, rehabilitative medicine, and pneumology delegated from scientific societies together with a patient representative and a delegate from the Association of the Scientific Medical Societies who advised methodological implementation. The guideline was created according to the German Association of the Scientific Medical Societies (AWMF), based on The Appraisal of Guidelines for Research and Evaluation (AGREE) II. The topics of (early) mobilisation, neuromuscular electrical stimulation, assist devices for mobilisation, and positioning, including prone positioning, were identified as areas to be addressed and assigned to specialist expert groups, taking conflicts of interest into account. The panel formulated PICO questions (addressing the population, intervention, comparison or control group as well as the resulting outcomes), conducted a systematic literature review with abstract screening and full-text analysis and created summary tables. This was followed by grading the evidence according to the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence and a risk of bias assessment. The recommendations were finalized according to GRADE and voted using an online Delphi process followed by a final hybrid consensus conference. The German long version of the guideline was approved by the professional associations. For this English version an update of the systematic review was conducted until April 2024 and recommendation adapted based on new evidence in systematic reviews and randomized controlled trials. In total, 46 recommendations were developed and research gaps addressed.
The promise and challenges of genomics‐informed periodontal disease diagnoses
Authors: Luigi Nibali, Kimon Divaris, Emily Ming‐Chieh Lu
Journal: Periodontology 2000 (2024)

Abstract Recent advances in human genomics and the advent of molecular medicine have catapulted our ability to characterize human and health and disease. Scientists and healthcare practitioners can now leverage information on genetic variation and gene expression at the tissue or even individual cell level, and an enormous potential exists to refine diagnostic categories, assess risk in unaffected individuals, and optimize disease management among those affected. This review investigates the progress made in the domains of molecular medicine and genomics as they relate to periodontology. The review summarizes the current evidence of association between genomics and periodontal diseases, including the current state of knowledge that approximately a third of the population variance of periodontitis may be attributable to genetic variation and the management of several monogenic forms of the disease can be augmented by knowledge of the underlying genetic cause. Finally, the paper discusses the potential utility of polygenic risk scores and genetic testing for periodontitis diagnosis now and in the future, in light of applications that currently exist in other areas of medicine and healthcare.
Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study
Authors: Khaled Z. Abd-Elmoniem, Jehad H. Edwan, Katrina B. Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N. Qaddumi, Sydney A. Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M. Gharib, Stephanie T. Chung
Journal: Circulation Research (2024)

Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.
Enhancing recovery from gut microbiome dysbiosis and alleviating DSS-induced colitis in mice with a consortium of rare short-chain fatty acid-producing bacteria
Authors: Achuthan Ambat, Linto Antony, Abhijit Maji, Sudeep Ghimire, Samara Mattiello, Purna C. Kashyap, Sunil More, Vanessa Sebastian, Joy Scaria
Journal: Gut Microbes (2024)

The human gut microbiota is a complex community comprising hundreds of species, with a few present in high abundance and the vast majority in low abundance. The biological functions and effects of these low-abundant species on their hosts are not yet fully understood. In this study, we assembled a bacterial consortium (SC-4) consisting of B. paravirosa, C. comes, M. indica, and A. butyriciproducens, which are low-abundant, short-chain fatty acid (SCFA)-producing bacteria isolated from healthy human gut, and tested its effect on host health using germ-free and human microbiota-associated colitis mouse models. The selection also favored these four bacteria being reduced in abundance in either Ulcerative Colitis (UC) or Crohn's disease (CD) metagenome samples. Our findings demonstrate that SC-4 can colonize germ-free (GF) mice, increasing mucin thickness by activating MUC-1 and MUC-2 genes, thereby protecting GF mice from Dextran Sodium Sulfate (DSS)-induced colitis. Moreover, SC-4 aided in the recovery of human microbiota-associated mice from DSS-induced colitis, and intriguingly, its administration enhanced the alpha diversity of the gut microbiome, shifting the community composition closer to control levels. The results showed enhanced phenotypes across all measures when the mice were supplemented with inulin as a dietary fiber source alongside SC-4 administration. We also showed a functional redundancy existing in the gut microbiome, resulting in the low abundant SCFA producers acting as a form of insurance, which in turn accelerates recovery from the dysbiotic state upon the administration of SC-4. SC-4 colonization also upregulated iNOS gene expression, further supporting its ability to produce an increasing number of goblet cells. Collectively, our results provide evidence that low-abundant SCFA-producing species in the gut may offer a novel therapeutic approach to IBD.
AIEC-dependent pathogenic Th17 cell transdifferentiation in Crohn’s disease is suppressed by <i>rfaP</i> and <i>ybaT</i> deletion
Authors: G. Leccese, M. Chiara, I. Dusetti, D. Noviello, E. Billard, A. Bibi, G. Conte, C. Consolandi, M. Vecchi, MP Conte, N. Barnich, F. Caprioli, F. Facciotti, M. Paroni
Journal: Gut Microbes (2024)

Mucosal enrichment of the Adherent-Invasive E. coli (AIEC) pathotype and the expansion of pathogenic IFNγ-producing Th17 (pTh17) cells have been linked to Crohn's Disease (CD) pathogenesis. However, the molecular pathways underlying the AIEC-dependent pTh17 cell transdifferentiation in CD patients remain elusive. To this aim, we created and functionally screened a transposon AIEC mutant library of 10.058 mutants to identify the virulence determinants directly implicated in triggering IL-23 production and pTh17 cell generation. pTh17 cell transdifferentiation was assessed in functional assays by co-culturing AIEC-infected human dendritic cells (DCs) with autologous conventional Th17 (cTh17) cells isolated from blood of Healthy Donors (HD) or CD patients. AIEC triggered IL-23 hypersecretion and transdifferentiation of cTh17 into pTh17 cells selectively through the interaction with CD-derived DCs. Moreover, the chronic release of IL-23 by AIEC-colonized DCs required a continuous IL-23 neutralization to significantly reduce the AIEC-dependent pTh17 cell differentiation. The multi-step screenings of the AIEC mutant's library revealed that deletion of ybaT or rfaP efficiently hinder the IL-23 hypersecretion and hampered the AIEC-dependent skewing of protective cTh17 into pathogenic IFNγ-producing pTh17 cells. Overall, our findings indicate that ybaT (inner membrane transport protein) and rfaP (LPS-core heptose kinase) represent novel and attractive candidate targets to prevent chronic intestinal inflammation in CD.
Know your orientation: A viewpoint-aware framework for polyp segmentation
Authors: Linghan Cai, Lijiang Chen, Jianhao Huang, Yifeng Wang, Yongbing Zhang
Journal: Medical Image Analysis (2024)

Automatic polyp segmentation in endoscopic images is critical for the early diagnosis of colorectal cancer. Despite the availability of powerful segmentation models, two challenges still impede the accuracy of polyp segmentation algorithms. Firstly, during a colonoscopy, physicians frequently adjust the orientation of the colonoscope tip to capture underlying lesions, resulting in viewpoint changes in the colonoscopy images. These variations increase the diversity of polyp visual appearance, posing a challenge for learning robust polyp features. Secondly, polyps often exhibit properties similar to the surrounding tissues, leading to indistinct polyp boundaries. To address these problems, we propose a viewpoint-aware framework named VANet for precise polyp segmentation. In VANet, polyps are emphasized as a discriminative feature and thus can be localized by class activation maps in a viewpoint classification process. With these polyp locations, we design a viewpoint-aware Transformer (VAFormer) to alleviate the erosion of attention by the surrounding tissues, thereby inducing better polyp representations. Additionally, to enhance the polyp boundary perception of the network, we develop a boundary-aware Transformer (BAFormer) to encourage self-attention towards uncertain regions. As a consequence, the combination of the two modules is capable of calibrating predictions and significantly improving polyp segmentation performance. Extensive experiments on seven public datasets across six metrics demonstrate the state-of-the-art results of our method, and VANet can handle colonoscopy images in real-world scenarios effectively. The source code is available at https://github.com/1024803482/Viewpoint-Aware-Network.
Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy
Authors: Hsien-Chen Mon, Pei-Chang Lee, Yi-Ping Hung, Ya-Wen Hung, Chi-Jung Wu, Chieh-Ju Lee, Chen-Ta Chi, I-Cheng Lee, Ming-Chih Hou, Yi-Hsiang Huang
Journal: Journal of Hepatology (2024)

Background & AimsImmune checkpoint inhibitors (ICIs) can restore exhausted T cell immunity not only for cancer treatment but also potentially for curing chronic hepatitis B (CHB). The impact of ICIs on Hepatitis B surface antigen (HBsAg) seroclearance in cancer patients was unclear.MethodsConsecutive cancer patients from 2016 to 2020 (Cohort 1, n=118), and hepatocellular carcinoma (HCC) patients from 2020 to 2022 (Cohort 2, n=44, as validation) receiving ICIs and positive for HBsAg were retrospectively recruited. An additional hepatitis B virus (HBV)-HCC cohort (Cohort 3, n=85) without ICI served as a control group. Factors associated with HBsAg loss or combining HBsAg decline >1 log were analyzed.ResultsWith median follow-up of 17.5 months, 8 (6.8%) in cohort 1 and 4 (9.1%) in cohort 2 achieved HBsAg seroclearance, and additional 4 in cohort 1 and 1 in cohort 2 had HBsAg decline >1 log. In multivariate analysis, HBsAg <100 IU/mL was associated with HBsAg seroclearance (HR=6.274, p=0.028). In the validation cohort, the cumulative incidence of HBsAg loss at months 12 and 24 was 13.0% and 38.4% for baseline HBsAg <100 IU/ml, which were significantly higher than those in the control group (p=0.0267). While no case in cohort 3 achieved HBsAg within 24 months. Of the 17 cases achieved HBsAg loss and decline >1 log, 16 (94.1%) had nucleos(t)ide analogs treatment. The median time to HBsAg loss or HBsAg decline was 16.5 months (ranged 9.6 to 27.5).ConclusionsICIs may accelerate HBsAg seroclearance in cancer patients with baseline HBsAg <100 IU/ml. This finding provides important information for the design of future ICI trials to achieve functional cure in patients with CHB.
Pulmonary delivery of silver nanoparticles prevents influenza infection by recruiting and activating lymphoid cells.
Authors: Lydie Martín-Faivre, Lisa Prince, Clémentine Cornu, Bérengère Villeret, Daniel Sanchez-Guzman, François Rouzet, Jean-Michel Sallenave, Ignacio Garcia-Verdugo
Journal: Biomaterials (2024)
Dynamic change of metabolic dysfunction-associated steatotic liver disease in chronic hepatitis C patients after viral eradication: A nationwide registry study in Taiwan
Authors: Chung-Feng Huang, Chia-Yen Dai, Yi-Hung Lin, Chih-Wen Wang, Tyng-Yuan Jang, Po-Cheng Liang, Tzu-Chun Lin, Pei-Chien Tsai, Yu-Ju Wei, Ming-Lun Yeh, Ming-Yen Hsieh, Chao-Kuan Huang, Jee-Fu Huang, Wan-Long Chuang, Ming-Lung Yu
Journal: Clinical and Molecular Hepatology (2024)

Steatotic liver disease (SLD) is a common manifestation in chronic hepatitis C (CHC). Metabolic alterations in CHC are associated with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to elucidate whether hepatitis C virus (HCV) eradication mitigates MASLD occurrence or resolution. We enrolled 5,840 CHC patients whose HCV was eradicated by direct-acting antivirals in a nationwide HCV registry. MASLD and the associated cardiometabolic risk factors (CMRFs) were evaluated at baseline and 6 months after HCV cure. There were 2,147 (36.8%) patients with SLD, and 1,986 (34.0%) of them met the MASLD criteria before treatment. After treatment, HbA1c (6.0% vs. 5.9%, P<0.001) and BMI (24.8 kg/m2 vs. 24.7 kg/m2, P<0.001) decreased, whereas HDL-C (49.1 mg/dL vs. 51.9 mg/dL, P<0.001) and triglycerides (102.8 mg/dL vs. 111.9 mg/dL, P<0.001) increased significantly. The proportion of patients with SLD was 37.5% after HCV eradication, which did not change significantly compared with the pretreatment status. The percentage of the patients who had post-treatment MASLD was 34.8%, which did not differ significantly from the pretreatment status (P=0.17). Body mass index (BMI) (odds ratio [OR] 0.89; 95% confidence intervals [CI] 0.85-0.92; P<0.001) was the only factor associated with MASLD resolution. In contrast, unfavorable CMRFs, including BMI (OR 1.10; 95% CI 1.06-1.14; P<0.001) and HbA1c (OR 1.19; 95% CI 1.04-1.35; P=0.01), were independently associated with MASLD development after HCV cure. HCV eradication mitigates MASLD in CHC patients. CMRF surveillance is mandatory for CHC patients with metabolic alterations, which are altered after HCV eradication and predict the evolution of MASLD.