tbuckley/cabot-search huggingface dataset:
Disruption of gut barrier integrity and host–microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus
Authors: R. Forlano, L. Martinez-Gili, P. Takis, J. Miguens-Blanco, T. Liu, E. Triantafyllou, C. Skinner, R Loomba, M. Thursz, J. R. Marchesi, B.H. Mullish, P. Manousou
Journal: Gut Microbes (2024)

Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.
Facts and Hopes in Using Omics to Advance Combined Immunotherapy Strategies
Authors: Ryan C. Augustin, Wesley L. Cai, Jason J. Luke, Riyue Bao
Journal: Clinical Cancer Research (2024)

Abstract The field of oncology has been transformed by immune checkpoint inhibitors (ICI) and other immune-based agents; however, many patients do not receive a durable benefit. While biomarker assessments from pivotal ICI trials have uncovered certain mechanisms of resistance, results thus far have only scraped the surface. Mechanisms of resistance are as complex as the tumor microenvironment (TME) itself, and the development of effective therapeutic strategies will only be possible by building accurate models of the tumor-immune interface. With advancement of multi-omic technologies, high-resolution characterization of the TME is now possible. In addition to sequencing of bulk tumor, single-cell transcriptomic, proteomic, and epigenomic data as well as T-cell receptor profiling can now be simultaneously measured and compared between responders and nonresponders to ICI. Spatial sequencing and imaging platforms have further expanded the dimensionality of existing technologies. Rapid advancements in computation and data sharing strategies enable development of biologically interpretable machine learning models to integrate data from high-resolution, multi-omic platforms. These models catalyze the identification of resistance mechanisms and predictors of benefit in ICI-treated patients, providing scientific foundation for novel clinical trials. Moving forward, we propose a framework by which in silico screening, functional validation, and clinical trial biomarker assessment can be used for the advancement of combined immunotherapy strategies.
Enhanced Mechanical Properties, Corrosion Resistance, Cytocompatibility, Osteogenesis, and Antibacterial Performance of Biodegradable Mg–2Zn–0.5Ca–0.5Sr/Zr Alloys for Bone‐Implant Application
Authors: Xian Tong, Yilong Dong, Runqi Zhou, Xinkun Shen, Yuncang Li, Yue Jiang, Huiyuan Wang, Jinguo Wang, Jixing Lin, Cuie Wen
Journal: Advanced Healthcare Materials (2024)

Abstract Magnesium (Mg) alloys are widely used in bone fixation and bone repair as biodegradable bone‐implant materials. However, their clinical application is limited due to their fast corrosion rate and poor mechanical stability. Here, the development of Mg–2Zn–0.5Ca–0.5Sr (MZCS) and Mg–2Zn–0.5Ca–0.5Zr (MZCZ) alloys with improved mechanical properties, corrosion resistance, cytocompatibility, osteogenesis performance, and antibacterial capability is reported. The hot‐extruded (HE) MZCZ sample exhibits the highest ultimate tensile strength of 255.8 ± 2.4 MPa and the highest yield strength of 208.4 ± 2.8 MPa and an elongation of 15.7 ± 0.5%. The HE MZCS sample shows the highest corrosion resistance, with the lowest corrosion current density of 0.2 ± 0.1 µA cm −2 and the lowest corrosion rate of 4 ± 2 µm per year obtained from electrochemical testing, and a degradation rate of 368 µm per year and hydrogen evolution rate of 0.83 ± 0.03 mL cm −2 per day obtained from immersion testing. The MZCZ sample shows the highest cell viability in relation to MC3T3‐E1 cells among all alloy extracts, indicating good cytocompatibility except at 25% concentration. Furthermore, the MZCZ alloy shows good antibacterial capability against Staphylococcus aureus .
Cancer Mutations Converge on a Collection of Protein Assemblies to Predict Resistance to Replication Stress
Authors: Xiaoyu Zhao, Akshat Singhal, Sungjoon Park, JungHo Kong, Robin Bachelder, Trey Ideker
Journal: Cancer Discovery (2024)

Rapid proliferation is a hallmark of cancer associated with sensitivity to therapeutics that cause DNA replication stress (RS). Many tumors exhibit drug resistance, however, via molecular pathways that are incompletely understood. Here, we develop an ensemble of predictive models that elucidate how cancer mutations impact the response to common RS-inducing (RSi) agents. The models implement recent advances in deep learning to facilitate multidrug prediction and mechanistic interpretation. Initial studies in tumor cells identify 41 molecular assemblies that integrate alterations in hundreds of genes for accurate drug response prediction. These cover roles in transcription, repair, cell-cycle checkpoints, and growth signaling, of which 30 are shown by loss-of-function genetic screens to regulate drug sensitivity or replication restart. The model translates to cisplatin-treated cervical cancer patients, highlighting an RTK-JAK-STAT assembly governing resistance. This study defines a compendium of mechanisms by which mutations affect therapeutic responses, with implications for precision medicine.
The ZmWAKL–ZmWIK–ZmBLK1–ZmRBOH4 module provides quantitative resistance to gray leaf spot in maize
Authors: Tao Zhong, Mang Zhu, Qianqian Zhang, Yan Zhang, Suining Deng, Chenyu Guo, Ling Xu, Tingting Liu, Yancong Li, Yaqi Bi, Xingming Fan, Peter Balint-Kurti, Mingliang Xu
Journal: Nature Genetics (2024)

Gray leaf spot (GLS), caused by the fungal pathogens Cercospora zeae-maydis and Cercospora zeina, is a major foliar disease of maize worldwide (Zea mays L.). Here we demonstrate that ZmWAKL encoding cell-wall-associated receptor kinase-like protein is the causative gene at the major quantitative disease resistance locus against GLS. The ZmWAKL
Gpcpd1–GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism
Authors: Domagoj Cikes, Michael Leutner, Shane J. F. Cronin, Maria Novatchkova, Lorenz Pfleger, Radka Klepochová, Benjamin Lair, Marlène Lac, Camille Bergoglio, Nathalie Viguerie, Gerhard Dürnberger, Elisabeth Roitinger, Mihaela Grivej, Eric Rullman, Thomas Gustafsson, Astrid Hagelkruys, Geneviève Tavernier, Virginie Bourlier, Claude Knauf, Michael Krebs, Alexandra Kautzky-Willer, Cedric Moro, Martin Krssak, Michael Orthofer, Josef M. Penninger
Journal: Nature Aging (2024)
Spatial multi-omics: novel tools to study the complexity of cardiovascular diseases
Authors: Paul Kiessling, Christoph Kuppe
Journal: Genome Medicine (2024)

Abstract Spatial multi-omic studies have emerged as a promising approach to comprehensively analyze cells in tissues, enabling the joint analysis of multiple data modalities like transcriptome, epigenome, proteome, and metabolome in parallel or even the same tissue section. This review focuses on the recent advancements in spatial multi-omics technologies, including novel data modalities and computational approaches. We discuss the advancements in low-resolution and high-resolution spatial multi-omics methods which can resolve up to 10,000 of individual molecules at subcellular level. By applying and integrating these techniques, researchers have recently gained valuable insights into the molecular circuits and mechanisms which govern cell biology along the cardiovascular disease spectrum. We provide an overview of current data analysis approaches, with a focus on data integration of multi-omic datasets, highlighting strengths and weaknesses of various computational pipelines. These tools play a crucial role in analyzing and interpreting spatial multi-omics datasets, facilitating the discovery of new findings, and enhancing translational cardiovascular research. Despite nontrivial challenges, such as the need for standardization of experimental setups, data analysis, and improved computational tools, the application of spatial multi-omics holds tremendous potential in revolutionizing our understanding of human disease processes and the identification of novel biomarkers and therapeutic targets. Exciting opportunities lie ahead for the spatial multi-omics field and will likely contribute to the advancement of personalized medicine for cardiovascular diseases.
Tunable control of <i>B. infantis</i> abundance and gut metabolites by co-administration of human milk oligosaccharides
Authors: Abigail L. Reens, Casey M. Cosetta, Russell Saur, Olivia Trofimuk, Sarah L. Brooker, Martin L. Lee, Adam K. Sun, Gregory J. McKenzie, Julie E. Button
Journal: Gut Microbes (2024)

Precision engineering of the gut microbiome holds promise as an effective therapeutic approach for diseases associated with a disruption in this microbial community. Engrafting a live biotherapeutic product (LBP) in a predictable, controllable manner is key to the consistent success of this approach and has remained a challenge for most LBPs under development. We recently demonstrated high-level engraftment of Bifidobacterium longum subsp. infantis (B. infantis) in adults when co-dosed with a specific prebiotic, human milk oligosaccharides (HMO). Here, we present a cellular kinetic-pharmacodynamic approach, analogous to pharmacokinetic-pharmacodynamic-based analyses of small molecule- and biologic-based drugs, to establish how HMO controls expansion, abundance, and metabolic output of B. infantis in a human microbiota-based model in gnotobiotic mice. Our data demonstrate that the HMO dose controls steady-state abundance of B. infantis in the microbiome, and that B. infantis together with HMO impacts gut metabolite levels in a targeted, HMO-dependent manner. We also found that HMO creates a privileged niche for B. infantis expansion across a 5-log range of bacterial inocula. These results demonstrate remarkable control of both B. infantis levels and the microbiome community metabolic outputs using this synbiotic approach, and pave the way for precision engineering of desirable microbes and metabolites to treat a range of diseases.
Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial
Authors: David Marin, Ye Li, Rafet Basar, Hind Rafei, May Daher, Jinzhuang Dou, Vakul Mohanty, Merve Dede, Yago Nieto, Nadima Uprety, Sunil Acharya, Enli Liu, Jeffrey Wilson, Pinaki Banerjee, Homer A. Macapinlac, Christina Ganesh, Peter F. Thall, Roland Bassett, Mariam Ammari, Sheetal Rao, Kai Cao, Mayra Shanley, Mecit Kaplan, Chitra Hosing, Partow Kebriaei, Loretta J. Nastoupil, Christopher R. Flowers, Sadie Mae Moseley, Paul Lin, Sonny Ang, Uday R. Popat, Muzaffar H. Qazilbash, Richard E. Champlin, Ken Chen, Elizabeth J. Shpall, Katayoun Rezvani
Journal: Nature Medicine (2024)

Abstract There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19 + B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10 7 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .
A ubiquitous spectrolaminar motif of local field potential power across the primate cortex
Authors: Diego Mendoza-Halliday, Alex James Major, Noah Lee, Maxwell J. Lichtenfeld, Brock Carlson, Blake Mitchell, Patrick D. Meng, Yihan Xiong, Jacob A. Westerberg, Xiaoxuan Jia, Kevin D. Johnston, Janahan Selvanayagam, Stefan Everling, Alexander Maier, Robert Desimone, Earl K. Miller, André M. Bastos
Journal: Nature Neuroscience (2024)

Abstract The mammalian cerebral cortex is anatomically organized into a six-layer motif. It is currently unknown whether a corresponding laminar motif of neuronal activity patterns exists across the cortex. Here we report such a motif in the power of local field potentials (LFPs). Using laminar probes, we recorded LFPs from 14 cortical areas across the cortical hierarchy in five macaque monkeys. The laminar locations of recordings were histologically identified by electrolytic lesions. Across all areas, we found a ubiquitous spectrolaminar pattern characterized by an increasing deep-to-superficial layer gradient of high-frequency power peaking in layers 2/3 and an increasing superficial-to-deep gradient of alpha-beta power peaking in layers 5/6. Laminar recordings from additional species showed that the spectrolaminar pattern is highly preserved among primates—macaque, marmoset and human—but more dissimilar in mouse. Our results suggest the existence of a canonical layer-based and frequency-based mechanism for cortical computation.
Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission
Authors: Chenyan Ma, Bing Li, Daniel Silverman, Xinlu Ding, Anan Li, Chi Xiao, Ganghua Huang, Kurtresha Worden, Sandra Muroy, Wei Chen, Zhengchao Xu, Chak Foon Tso, Yixuan Huang, Yufan Zhang, Qingming Luo, Kaoru Saijo, Yang Dan
Journal: Nature Neuroscience (2024)

Abstract Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia—the resident immune cells in the brain—remains poorly understood. Here, we show in mice that microglia can regulate sleep through a mechanism involving G i -coupled GPCRs, intracellular Ca 2+ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia G i signaling strongly promoted sleep, whereas pharmacological blockade of G i -coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12–G i activation elevated microglia intracellular Ca 2+ , and blockade of this Ca 2+ elevation largely abolished the G i -induced sleep increase. Microglia Ca 2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12–G i activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.
The transcriptional cofactor Tle3 reciprocally controls effector and central memory CD8+ T cell fates
Authors: Xin Zhao, Wei Hu, Sung Rye Park, Shaoqi Zhu, Shengen Shawn Hu, Chongzhi Zang, Weiqun Peng, Qiang Shan, Hai-Hui Xue
Journal: Nature Immunology (2024)
Lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH): a scoping review unveils clinical and diagnostic patterns of a lymphoma subgroup with poor prognosis
Authors: Johanna Knauft, Thomas Schenk, Thomas Ernst, Ulf Schnetzke, Andreas Hochhaus, Paul La Rosée, Sebastian Birndt
Journal: Leukemia (2024)

Abstract Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome driven by pathologic activation of cytotoxic T-lymphocytes and macrophages. Despite advances in diagnostics and management, adult patients with lymphoma-associated HLH (LA-HLH) harbor particularly poor prognosis and optimal treatment remains challenging. As systematic data on LA-HLH are scarce, we aimed to synthesize research evidence by thorough analysis of the published literature in PubMed (MEDLINE-database) within the context of a scoping review. Of 595 search results, 132 articles providing information on 542 patients were reviewed and analyzed. Median patient age was 60 years (range, 18–98) with male predominance (62.7%). B- and T-NHL were equally represented (45.6% and 45.2%), Hodgkin’s lymphoma was reported in 8.9% of the cases. The majority of patients (91.6%) presented in Ann-Arbor-Stages III and IV, and bone marrow infiltration was observed in a significant proportion of patients (61.5%). Soluble CD25 levels were markedly elevated (median 10,000 U/ml), with levels beyond 10,000 U/ml indicating unfavorable prognosis for 30-day and overall survival. 66.8% of the patients died after median 5.1 months. LA-HLH remains a clinical challenge requiring specialized management. Timely diagnosis and appropriate lymphoma-specific treatment are of utmost importance to enhance patient outcomes.
SARS-CoV-2 immunity in animal models
Authors: Zhao Chen, Yaochang Yuan, Qingtao Hu, Airu Zhu, Fenghua Chen, Shu Li, Xin Guan, Chao Lv, Tian Tang, Yiyun He, Jinling Cheng, Jie Zheng, Xiaoyu Hu, Jingxian Zhao, Jincun Zhao, Jing Sun
Journal: Cellular and Molecular Immunology (2024)

The COVID-19 pandemic, which was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide health crisis due to its transmissibility. SARS-CoV-2 infection results in severe respiratory illness and can lead to significant complications in affected individuals. These complications encompass symptoms such as coughing, respiratory distress, fever, infectious shock, acute respiratory distress syndrome (ARDS), and even multiple-organ failure. Animal models serve as crucial tools for investigating pathogenic mechanisms, immune responses, immune escape mechanisms, antiviral drug development, and vaccines against SARS-CoV-2. Currently, various animal models for SARS-CoV-2 infection, such as nonhuman primates (NHPs), ferrets, hamsters, and many different mouse models, have been developed. Each model possesses distinctive features and applications. In this review, we elucidate the immune response elicited by SARS-CoV-2 infection in patients and provide an overview of the characteristics of various animal models mainly used for SARS-CoV-2 infection, as well as the corresponding immune responses and applications of these models. A comparative analysis of transcriptomic alterations in the lungs from different animal models revealed that the K18-hACE2 and mouse-adapted virus mouse models exhibited the highest similarity with the deceased COVID-19 patients. Finally, we highlighted the current gaps in related research between animal model studies and clinical investigations, underscoring lingering scientific questions that demand further clarification.
The constitutive activation of STAT3 gene and its mutations are at the crossroad between LGL leukemia and autoimmune disorders
Authors: Gianpietro Semenzato, Giulia Calabretto, Antonella Teramo, Vanessa Rebecca Gasparini, Elisa Rampazzo, Gregorio Barilà, Renato Zambello
Journal: Blood Cancer Journal (2024)

Type T Large Granular Lymphocyte Leukemia (T-LGLL) is a chronic disorder characterized by the abnormal proliferation of clonal cytotoxic T cells. The intriguing association of T-LGLL with autoimmune and inflammatory diseases, the most prominent example being rheumatoid arthritis, raises questions about the underlying pathophysiologic relationships between these disorders which share several biological and clinical features, most notably neutropenia, which is considered as a clinical hallmark. Recent progress in molecular genetics has contributed to a better understanding of pathogenetic mechanisms, thus moving our knowledge in the field of LGL leukemias forward. Focusing on the constitutive activation of STAT3 pathway and the well-established role of STAT3 mutations in T-LGLL, we herein discuss whether the T cell clones occurring in comorbid conditions are the cause or the consequence of the immune-inflammatory associated events. Overall, this review sheds light on the intricate relationships between inflammation and cancer, emphasizing the importance of the STAT3 gene and its activation in the pathophysiology of these conditions. Gaining a deeper understanding of these underlying mechanisms seeks to pave the way for the development of novel targeted therapies for patients affected by inflammation-related cancers.
Evaluation of gut microbiota predictive potential associated with phenotypic characteristics to identify multifactorial diseases
Authors: Danielle Cristina Fonseca, Ilanna Marques Gomes da Rocha, Bianca Depieri Balmant, Leticia Callado, Ana Paula Aguiar Prudêncio, Juliana Tepedino Martins Alves, Raquel Susana Torrinhas, Gabriel da Rocha Fernandes, Dan Linetzky Waitzberg
Journal: Gut Microbes (2024)

Gut microbiota has been implicated in various clinical conditions, yet the substantial heterogeneity in gut microbiota research results necessitates a more sophisticated approach than merely identifying statistically different microbial taxa between healthy and unhealthy individuals. Our study seeks to not only select microbial taxa but also explore their synergy with phenotypic host variables to develop novel predictive models for specific clinical conditions. Design: We assessed 50 healthy and 152 unhealthy individuals for phenotypic variables (PV) and gut microbiota (GM) composition by 16S rRNA gene sequencing. The entire modeling process was conducted in the R environment using the Random Forest algorithm. Model performance was assessed through ROC curve construction. Results: We evaluated 52 bacterial taxa and pre-selected PV (p < 0.05) for their contribution to the final models. Across all diseases, the models achieved their best performance when GM and PV data were integrated. Notably, the integrated predictive models demonstrated exceptional performance for rheumatoid arthritis (AUC = 88.03%), type 2 diabetes (AUC = 96.96%), systemic lupus erythematosus (AUC = 98.4%), and type 1 diabetes (AUC = 86.19%). Conclusion: Our findings underscore that the selection of bacterial taxa based solely on differences in relative abundance between groups is insufficient to serve as clinical markers. Machine learning techniques are essential for mitigating the considerable variability observed within gut microbiota. In our study, the use of microbial taxa alone exhibited limited predictive power for health outcomes, while the integration of phenotypic variables into predictive models substantially enhanced their predictive capabilities.