bluuebunny/crossref_metadata_2025_split huggingface dataset:
FDX1 regulates cellular protein lipoylation through direct binding to LIAS
Authors: Dreishpoon Margaret B. , Bick Nolan R. , Petrova Boryana , Warui Douglas M. , Cameron Alison , Booker Squire J. , Kanarek Naama , Golub Todd R. , Tsvetkov Peter 
Published: February 2023

AbstractFerredoxins are a family of iron-sulfur (Fe-S) cluster proteins that serve as essential electron donors in numerous cellular processes that are conserved through evolution. The promiscuous nature of ferredoxins as electron donors enables them to participate in many metabolic processes including steroid, heme, vitamin D and Fe-S cluster biosynthesis in different organisms. However, the unique natural function(s) of each of the two human ferredoxins (FDX1 and FDX2) are still poorly characterized. We recently reported that FDX1 is both a crucial regulator of copper ionophore induced cell death and serves as an upstream regulator of cellular protein lipoylation, a mitochondrial lipid-based post translational modification naturally occurring on four mitochondrial enzymes that are crucial for TCA cycle function. Here we show that FDX1 regulates protein lipoylation by directly binding to the lipoyl synthase (LIAS) enzyme and not through indirect regulation of cellular Fe-S cluster biosynthesis. Metabolite profiling revealed that the predominant cellular metabolic outcome of FDX1 loss-of-function is manifested through the regulation of the four lipoylation-dependent enzymes ultimately resulting in loss of cellular respiration and sensitivity to mild glucose starvation. Transcriptional profiling of cells growing in either normal or low glucose conditions established that FDX1 loss-of-function results in the induction of both compensatory metabolism related genes and the integrated stress response, consistent with our findings that FDX1 loss-of-functions is conditionally lethal. Together, our findings establish that FDX1 directly engages with LIAS, promoting cellular protein lipoylation, a process essential in maintaining cell viability under low glucose conditions.
Cardiac Troponin I Directly Binds and Inhibits Mitochondrial ATP Synthase: a Noncanonical Role in the Post-Ischemic Heart
Authors: Elezaby Aly , Lin Amanda J , Vijayan Vijith , Pokhrel Suman , Bechara Luiz RG , Ostberg Nicolai P , Queliconi Bruno B , Campos Juliane C , Ferreira Julio CB , Haileselassie Bereketeab , Mochly-Rosen Daria 
Published: February 2023

AbstractCardiac troponin I (cTnI) is a sarcomeric protein critical to myocyte contraction. Unexpectedly, we found that some cTnI localized to the mitochondrial matrix in the heart, inhibited mitochondrial functions when stably expressed in non-cardiac cells and increased opening of the mitochondrial permeability transition pore under oxidative stress. Direct, specific, and saturable binding of cTnI to ATP synthase was demonstratedin vitro, using immune-captured ATP synthase, and in cells using proximity ligation assay. cTnI binding doubled F1F0ATPase activity, whereas skeletal troponin I and several human mutant cTnI variants associated with familial hypertrophic cardiomyopathy did not. A rationally-designed ten amino acid peptide, P888, inhibited cTnI binding to ATP synthase, inhibited cTnI-induced increase in ATPase activityin vitro, and reduced cardiac injury following transient ischemiain vivo. We therefore suggest that mitochondria-associated cTnI may inhibit cardiac ATP synthase under basal conditions; pharmacological agents that release this inactivating effect of cTnI and thus preventing ATP hydrolysis during cardiac ischemia may increase the reservoir of functional mitochondria to reduce cardiac injury.Significance StatementCardiac troponin I (cTnI) is a key sarcomeric protein involved in the regulation of myocardial contractility. We found that some cTnI is present in the mitochondrial matrix where it binds to ATP synthase, disrupting mitochondrial function; inhibition of the cTnI-ATP synthase interaction with a selective peptide inhibitor reduces cardiac dysfunction following ischemia and reperfusion injury. Several pathogenic cTnI mutations associated with hypertrophic cardiomyopathy do not affect ATP synthase activity, suggesting a potential mechanism that contributes to the diverse pathologies associated with these mutations.
IQMMA: an efficient MS1 intensity extraction using multiple feature detection algorithms for DDA proteomics
Authors: Postoenko Valeriy I. , Garibova Leyla A. , Levitsky Lev I. , Bubis Julia A. , Gorshkov Mikhail V. , Ivanov Mark V. 
Published: February 2023

AbstractOne of the key steps in data dependent acquisition (DDA) proteomics is detection of peptide isotopic clusters, also called «features», in MS1 spectra and matching them to MS/MS-based peptide identifications. A number of peptide feature detection tools became available in recent years each relying on its own matching algorithm. Here, we provide an integrated solution, Intensity-based Quantitative Mix and Match Approach (IQMMA), which integrates a number of peptide feature detection algorithms and returns the most probable intensity values for the MS/MS-based identifications. IQMMA was tested using available proteomic data acquired for both well-characterized (ground truth) and real-world biological samples, including a mix ofE. Colidigest spiked at different concentrations into the HeLa digest used as a background and a set of glioblastoma cell lines. Three open-source feature detection algorithms were integrated: Dinosaur, biosaur2 and OpenMS FeatureFinder. Neither of them was found optimal when applied individually to all the datasets employed in this work, however, their combined use in IQMMA improved efficiency of subsequent protein quantitation. The software implementing IQMMA is freely available athttps://github.com/PostoenkoVI/IQMMAunder Apache 2.0 license.
Virus-host dynamics in archaeal groundwater biofilms and the associated bacterial community composition
Authors: Turzynski Victoria , Griesdorn Lea , Moraru Cristina , Soares André , Simon Sophie A. , Stach Tom L. , Rahlff Janina , Esser Sarah P. , Probst Alexander J. 
Published: February 2023

ABSTRACTLytic viruses can be prevalent in deep groundwater, yet their spatial and temporal distribution in such an ecosystem remains unexplored. Here, we tackle this gap of knowledge by studying viral infections in individual, archaea-dominated biofilm flocks sampled from deep anoxic groundwater over a period of three years. Using virusFISH whose detection efficiency for individual viral particles was 15%, we show a significant and steady increase of virus infections between the years 2019 and 2022. Based on various fluorescence micrographs of individual biofilm flocks, we determined different stages of viral infections in biofilms for single sampling events, demonstrating the progression of infection of biofilms in deep groundwater. Biofilms associated with many host cells undergoing lysis showed a substantial accumulation of filamentous microbes around infected cells probably feeding off host cell debris. Using 16S rRNA gene sequencing across ten individual biofilm flocks from one sampling event, we determined that the associated bacterial community remains relatively constant and was dominated byDesulfobacterota. Given the stability of the virus-host interaction in these deep groundwater samples, we postulate that the virus-host dynamics ofCa. Altiarchaeum hamiconexum and its abundant virus Altivir_l_MSI described herein represent a suitable model system for studying deep biosphere virus-host interactions in future research endeavors.
Widespread reductions in body size are paired with stable assemblage biomass
Authors: Martins Inês S. , Schrodt Franziska , Blowes Shane A. , Bates Amanda E. , Bjorkman Anne D. , Brambilla Viviana , Carvajal-Quintero Juan , Chow Cher F. Y. , Daskalova Gergana N. , Edwards Kyle , Eisenhauer Nico , Field Richard , Fontrodona-Eslava Ada , Henn Jonathan J , van Klink Roel , Madin Joshua S. , Magurran Anne E. , McWilliam Michael , Moyes Faye , Pugh Brittany , Sagouis Alban , Trindade-Santos Isaac , McGill Brian , Chase Jonathan M. , Dornelas Maria 
Published: February 2023

AbstractBiotic responses to global change include directional shifts in organismal traits. Body size, an integrative trait that determines demographic rates and ecosystem functions, is often thought to be shrinking in the Anthropocene. Here, we assess the prevalence of body size change in six taxon groups across 5,032 assemblage time-series spanning 1960-2020. Using the Price equation to partition this change into within-species body size versus compositional changes, we detect prevailing decreases in body size through time. Change in assemblage composition contributes more to body size changes than within-species trends, but both components show substantial variation in magnitude and direction. The biomass of assemblages remains remarkably stable as decreases in body size trade-off with increases in abundance.One-Sentence SummaryVariable within-species and compositional trends combine into shrinking body size, abundance increases and stable biomass.
RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension
Authors: Piper Bryce , Bogamuwa Srimathi , Hossain Tanvir , Farkas Daniela , Rosas Lorena , Green Adam , Newcomb Geoffrey , Sun Nuo , Horowitz Jeffrey C. , Bhagwani Aneel R , Yang Hu , Kudryashova Tatiana V. , Rojas Mauricio , Mora Ana L. , Yan Pearlly , Mallampalli Rama K. , Goncharova Elena A. , Eckmann David M. , Farkas Laszlo 
Published: February 2023

ABSTRACTPulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from PAH patients. Endothelial haploinsufficiency of RAB7 caused spontaneous PH in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA sequencing and RAB7 silenced ECs showed impaired angiogenesis, expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, which suggests inhibition of autophagy at the pre-degradation level. Further, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in chronic hypoxia/SU5416 rats. In conclusion, we demonstrate here for the first time the fundamental impairment of EC function by loss of RAB7 that leads to PH and show RAB7 activation as a potential therapeutic strategy in a preclinical model of PH.
Structure-informed Language Models Are Protein Designers
Authors: Zheng Zaixiang , Deng Yifan , Xue Dongyu , Zhou Yi , Ye Fei , Gu Quanquan 
Published: February 2023

AbstractThis paper demonstrates that language models are strong structure-based protein designers. We present LM-Design, a generic approach to reprogramming sequence-based protein language models (pLMs), that have learned massive sequential evolutionary knowledge from the universe of natural protein sequences, to acquire an immediate capability to design preferable protein sequences for given folds. We conduct astructural surgeryonpLMs, where a lightweight structural adapter is implanted intopLMs and endows it with structural awareness. During inference, iterative refinement is performed to effectively optimize the generated protein sequences. Experiments show that LM-Designimproves the state-of-the-art results by a large margin, leading to 4% to 12% accuracy gains in sequence recovery (e.g., 55.65%/56.63% on CATH 4.2/4.3 single-chain benchmarks, and>60% when designing protein complexes). We provide extensive and in-depth analyses, which verify that LM-Designcan (1) indeed leverage both structural and sequential knowledge to accurately handle structurally non-deterministic regions, (2) benefit from scaling data and model size, and (3) generalize to other proteins (e.g., antibodies andde novoproteins).
BCR-ABL promotes hematopoietic stem and progenitor cell formation in embryonic stem cells
Authors: Artus Jérôme , Zenych Alina , Simanic Isidora , Desterke Christophe , Clay Denis , Saïm Sonia , Ijjeh Yousef , de Souza Lucas Eduardo Botelho , Coignard Sabrina , Bennaceur-Griscelli Annelise , Turhan Ali G. , Foudi Adlen 
Published: February 2023

ABSTRACTGenerating Hematopoietic Stem Cells (HSCs) from Pluripotent Stem Cells (PSCs) has been a long-lasting quest in the field of hematopoiesis. Previous studies suggested that enforced expression of BCR-ABL, the unique oncogenic driver of Chronic Myelogeneous Leukemia (CML), in Embryonic Stem Cells (ESCs)-derived hematopoietic cells is sufficient to confer long-termin vivorepopulating potential. To precisely uncover the molecular events regulated by the Tyrosine-kinase activity of BCR-ABL1 (p210) during the course of hematopoietic differentiation, we engineered a Tet-ON inducible system to modulate its expression in murine ESC. We showed in unique site-directed knock-in ESC model, thatBCR-ABLexpression tightly regulated by doxycycline (dox) controls the formation and the maintenance of immature hematopoietic progenitors. Interestingly, these progenitors can be expandedin vitrofor several passages in the presence of dox. Our analysis of cell surface markers and transcriptome compared to wild-type fetal and adult HSCs unraveled a similar molecular signature. LTC-IC assay confirmed their self-renewal capacities albeit with a differentiation bias towards erythroid and myeloid cells. Collectively, our novel Tet-ON system represents a uniquein vitromodel to shed lights on ESC-derived hematopoiesis, CML initiation and maintenance.KEY POINTSWe report a unique BCR-ABL-induced-embryonic stem cell -derived hematopoiesis model in murine embryonic stem cellsThis BCR-ABL-induced self-renewal and differentiation model can be of major interest to uncover molecular events required for ESC-derived hematopoiesis
Label-free tumor cells classification using deep learning and high-content imaging
Authors: Piansaddhayanon Chawan , Koracharkornradt Chonnuttida , Laosaengpha Napat , Tao Qingyi , Ingrungruanglert Praewphan , Israsena Nipan , Chuangsuwanich Ekapol , Sriswasdi Sira 
Published: February 2023

AbstractMany studies have shown that cellular morphology can be used to distinguish spiked-in tumor cells in blood sample background. However, most validation experiments included only homogeneous cell lines and inadequately captured the broad morphological heterogeneity of cancer cells. Further-more, normal, non-blood cells could be erroneously classified as cancer because their morphology differ from blood cells. Here, we constructed a database of microscopic images of organoid-derived cancer and normal cell with diverse morphology and developed a proof-of-concept deep learning model that can distinguish cancer cells from normal cells within an unlabeled microscopy image. In total, more than 75,000 organoid-drived cells from 3 cholangiocarcinoma patients were collected. The model achieved an area under the receiver operating characteristics curve (AUROC) of 0.78 and can generalize to cell images from an unseen patient. These resources serve as a foundation for an automated, robust platform for circulating tumor cell detection.
Low dimensionality of phenotypic space as an emergent property of coordinated teams in biological regulatory networks
Authors: Hari Kishore , Harlapur Pradyumna , Saxena Aashna , Haldar Kushal , Girish Aishwarya , Malpani Tanisha , Levine Herbert , Jolly Mohit Kumar 
Published: February 2023

AbstractBiological networks driving cell-fate decisions involve complex interactions, but they often give rise to only a few phenotypes, thus exhibiting low-dimensional dynamics. The network design principles that govern such cell-fate canalization remain unclear. Here, we investigate networks across diverse biological contexts– Epithelial-Mesenchymal Transition, Small Cell Lung Cancer, and Gonadal cell-fate determination – to reveal that the presence of two mutually antagonistic, well-coordinated teams of nodes leads to low-dimensional phenotypic space such that the first principal component (PC1) axis can capture most of the variance. Further analysis of artificial team-based networks and random counterparts of biological networks reveals that the principal component decomposition is determined by the team strength within these networks, demonstrating how the underlying network structure governs PC1 variance. The presence of low dimensionality in corresponding transcriptomic data confirms the applicability of our observations. We propose that team-based topology in biological networks are critical for generating a cell-fate canalization landscape.
Common synaptic inputs and persistent inward currents of vastus lateralis motor units are reduced in older age
Authors: Guo Yuxiao , Jones Eleanor J. , Škarabot Jakob , Inns Thomas B. , Phillips Bethan E. , Atherton Philip J. , Piasecki Mathew 
Published: February 2023

AbstractAlthough muscle atrophy may partially account for age-related strength decline, it is further influenced by alterations of neural input to muscle. Persistent inward currents and the level of common synaptic inputs to motoneurons influence neuromuscular function. However, these have not yet been described in aged human quadriceps.High density surface electromyography (HDsEMG) signals were collected from the vastus lateralis of 15 young (mean±SD, 23 ± 5 y) and 15 older (67 ± 9 y) men during submaximal sustained and 20-s ramped contractions. HDsEMG signals were decomposed to identify individual motor unit discharges, from which delta F and intramuscular coherence were estimated.Older participants produced significantly lower knee extensor torque (p<0.001) and poorer force tracking ability (p<0.001) than young. Older participants also had lower delta F (p=0.001) and coherence estimates in the alpha frequency band (p<0.001) during ramp contractions when compared to young.Persistent inward currents and common synaptic inputs are lower in the vastus lateralis of older males when compared to young. These data highlight altered neural input to the clinically and functionally important quadriceps, further underpinning age-related loss of function which may occur independently of the loss of muscle mass.Key PointsThe age-related loss of muscle mass is exceeded by the loss of function, which is influenced by structural and functional alterations of the nervous system.Motoneuronal persistent inward currents and common synaptic inputs play an important role in the activation of motor units and subsequent force generation and control ability.Here we show reduced estimates of persistent inward currents and lower common synaptic inputs to older vastus lateralis, potentially contributing to observed lower strength and poorer force tracking.These findings highlight decrements of the aged human motor system, accompanied by muscle atrophy in functionally relevant muscle groups, which should be considered in the application of interventions targeting aged human muscle.
Towards Universal Cell Embeddings: Integrating Single-cell RNA-seq Datasets across Species with SATURN
Authors: Rosen Yanay , Brbić Maria , Roohani Yusuf , Swanson Kyle , Li Ziang , Leskovec Jure 
Published: February 2023

AbstractAnalysis of single-cell datasets generated from diverse organisms offers unprecedented opportunities to unravel fundamental evolutionary processes of conservation and diversification of cell types. However, inter-species genomic differences limit the joint analysis of cross-species datasets to homologous genes. Here, we present SATURN, a deep learning method for learning universal cell embeddings that encodes genes’ biological properties using protein language models. By coupling protein embeddings from language models with RNA expression, SATURN integrates datasets profiled from different species regardless of their genomic similarity. SATURN has a unique ability to detect functionally related genes co-expressed across species, redefining differential expression for cross-species analysis. We apply SATURN to three species whole-organism atlases and frog and zebrafish embryogenesis datasets. We show that cell embeddings learnt in SATURN can be effectively used to transfer annotations across species and identify both homologous and species-specific cell types, even across evolutionarily remote species. Finally, we use SATURN to reannotate the five species Cell Atlas of Human Trabecular Meshwork and Aqueous Outflow Structures and find evidence of potentially divergent functions between glaucoma associated genes in humans and other species.
UVB modifies skin immune-stroma cross-talk and promotes effector T cell recruitment during crypticLeishmania donovaniinfection
Authors: de Oca Marcela Montes , Dey Shoumit , Van Bocxlaer Katrien , Ashwin Helen , Brown Najmeeyah , Myburgh Elmarie , Dey Nidhi S , Rani Gulab Fatima , Muscutt Edward , Osman Mohamed , Perez-Mazliah Damian , James Sally , Gilbert Lesley , Chatterjee Mitali , Kaye Paul M 
Published: February 2023

SUMMARYMany parasites of significant public health importance assume skin residency without causing overt pathlogy. How immune and stromal cells respond to such “cryptic” infections and how exposure to UVB alters such responses in poorly understood. We combined scRNA-seq, spatial transcriptomics and inferential network analysis to address these questions in a model of cryptic skin infection byLeishmania donovani. In infected C57BL/6 mice, p-selectin and CXCL12 interactions dominate intercellular communication between leucocytes, fibroblast and endothelial cells, but effector T cell function remains muted. Following UVB exposure, increased numbers of IFNγ+CD4+Th1 cells and NK cells enter the skin, communicating with stromal cells via CCL5-CCR5 and LFA-1-ICAM1/2. However, spatial mapping indicated that Th1 cells and macrophages occupied distinct niches after UVB exposure, likely limiting effector function. Our data provide the first holistic view of the immune landscape during crypticL. donovaniinfection and demonstrate how UVB exposure fundamentally reshapes this response.GRAPHICAL ABSTRACT
The organotypic culture of mouse seminiferous tubules as a reliable methodology for the study of meiosisin vitro
Authors: López-Jiménez P , Berenguer I , Pérez-Moreno I , de Aledo J.G. , Parra MT , Page J , Gómez R 
Published: February 2023

AbstractMale mouse meiosis has been traditionally studied using descriptive methods like histological sections, spreading or squashing techniques, which allow the observation of fixed meiocytes in either wildtype or genetically modified mice. For these studies, the sacrifice of the males and the extraction of the testicles are required to obtain the material of study. Other functionalin vivostudies include the administration of intravenous or intraperitoneal drugs, or the exposure to mutagenic agents or generators of DNA damage, in order to study their impact on meiosis progression. However, in these studies, the exposure times or drug concentration are important limitations to consider when acknowledging animal welfare. Recently, several approaches have been proposed to offer alternative methodologies that allow thein vitrostudy of spermatocytes with a considerable reduction in the use of animals. Here we revisit and validate an optimal technique of organotypic culture of fragments of seminiferous tubules for meiotic studies. This technique is a trustable methodology to develop functional studies that preserve the histological configuration of the seminiferous tubule, aim homogeneity of the procedures (the use of the same animal for different study conditions), and allow procedures that would compromise the animal welfare. Therefore, this methodology is highly recommendable for the study of meiosis and spermatogenesis, while it supports the principle of 3R′s for animal research.