bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor cell heterogeneity drives spatial organization of the intratumoral immune response in squamous cell skin carcinoma
Authors: Tanaka Miho , Lum Lotus , Hu Kenneth , Ledezma-Soto Cecilia , Samad Bushra , Superville Daphne , Ng Kenneth , Adams Zoe , Kersten Kelly , Fong Lawrence , Combes Alexis J. , Krummel Matthew , Reeves Melissa 
Published: April 2023

AbstractIntratumoral heterogeneity (ITH)—defined as genetic and cellular diversity within a tumor—is linked to failure of immunotherapy and an inferior anti-tumor immune response. The underlying mechanism of this association is unknown. To address this question, we modeled heterogeneous tumors comprised of a pro-inflammatory (“hot”) and an immunosuppressive (“cold”) tumor population, labeled with YFP and RFP tags respectively to enable precise spatial tracking. The resulting mixed-population tumors exhibited distinct regions comprised of YFP+(hot) cells, RFP+(cold) cells, or a mixture. We found that tumor regions occupied by hot tumor cells (YFP+) harbored more total T cells and a higher frequency of Th1 cells and IFNγ+CD8 T cells compared to regions occupied by cold tumor cells (RFP+), whereas immunosuppressive macrophages showed the opposite spatial pattern. We identified the chemokine CX3CL1, produced at higher levels by our cold tumors, as a mediator of intratumoral macrophage accumulation, particularly immunosuppressive CD206Himacrophages. Furthermore, we examined the response of heterogeneous tumors to a therapeutic combination of PD-1 blockade and CD40 agonist on a region-by-region basis. While the combination successfully increases Th1 abundance in “cold” tumor regions, it fails to bring overall T cell activity to the same level as seen in “hot” regions. The presence of the “cold” cells thus ultimately leads to a failure of the therapy to induce tumor rejection. Collectively, our results demonstrate that the organization of heterogeneous tumor cells has a profound impact on directing the spatial organization and function of tumor-infiltrating immune cells as well as on responses to immunotherapy.
COP9 signalosome complex subunit-7-mediated regulation of cAMP levels contributes to autophagic degradation and pathogenesis of rice blast fungusMagnaporthe oryzae
Authors: Lin Lili , Guo Hengyuan , Batool Wajjiha , Lin Lianyu , Cao Jiayin , An Qiuli , Aliyu Sami Rukaiya , Bao Jiandong , Wang Zonghua , Norvienyeku Justice 
Published: May 2023

SummaryPhoto-dependent processes, including circadian rhythm, autophagy, ubiquitination, neddylation/deneddylation, and metabolite biosynthesis, profoundly influence microbial pathogenesis. Although a photomorphogenesis signalosome (COP9/CSN) has been identified, the mechanism by which this large complex contributes to pathophysiological processes in filamentous fungi remains unclear.Here, we identified eight CSN complex subunits in the rice blast fungusMagnaporthe oryzaeand functionally characterized the translocon subunits containing a nuclear export or localization signal (NES/NLS).Targeted gene replacement of these CSN subunits, includingMoCSN3,MoCSN5,MoCSN6,MoCSN7, andMoCSN12, attenuated vegetative growth and conidiation inM. oryzaeand rendered non-pathogenic deletion strains.MoCSN7deletion significantly suppressed arachidonic acid catabolism, compromised cell wall integrity, subverted photo-dependent ubiquitination, and abolished photo-responsiveness. Surprisingly, we also discovered that MoCSN subunits, particularly MoCsn7, are required for the cAMP-dependent regulation of autophagic flux.Therefore, MoCSN significantly contributes to morphological, physiological, and pathogenic differentiation inM. oryzaeby fostering cross-talk between multiple pathways.
The mechanics of correlated variability in segregated cortical excitatory subnetworks
Authors: Negrón Alex , Getz Matthew P. , Handy Gregory , Doiron Brent 
Published: April 2023

AbstractUnderstanding the genesis of shared trial-to-trial variability in neural activity within sensory cortex is critical to uncovering the biological basis of information processing in the brain. Shared variability is often a reflection of the structure of cortical connectivity since this variability likely arises, in part, from local circuit inputs. A series of experiments from segregated networks of (excitatory) pyramidal neurons in mouse primary visual cortex challenge this view. Specifically, the across-network correlations were found to be larger than predicted given the known weak cross-network connectivity. We aim to uncover the circuit mechanisms responsible for these enhanced correlations through biologically motivated cortical circuit models. Our central finding is that coupling each excitatory subpopulation with a specific inhibitory subpopulation provides the most robust network-intrinsic solution in shaping these enhanced correlations. This result argues for the existence of excitatory-inhibitory functional assemblies in early sensory areas which mirror not just response properties but also connectivity between pyramidal cells.
Self-regulatory function of bacterial small heat shock protein IbpA through mRNA binding is conferred by a conserved arginine
Authors: Cheng Yajie , Miwa Tsukumi , Taguchi Hideki 
Published: April 2023

AbstractBacterial small heat shock proteins, IbpA and IbpB, co-aggregate with denatured proteins and recruit other chaperones for the processing of aggregates, thereby assisting in their refolding. In addition, as a recently revealed uncommon feature,Escherichia coliIbpA self-represses its own translation through interaction with the 5’ untranslated region (UTR) of theibpAmRNA, enabling IbpA to act as a mediator of negative feedback regulation. Although IbpA also suppresses the expression of IbpB, IbpB does not have the self-repression activity despite the two Ibps being highly homologous. This study demonstrates that the self-repression function of IbpA is conserved in other bacterial IbpAs. Moreover, a cationic residue-rich region in the α-crystallin domain (ACD) of IbpA, which is not conserved in IbpB, is critical for the self-suppression activity. Notably, arginine 93 (R93) located within the ACD is an essential residue that cannot be replaced by the other 19 amino acids, including lysine. IbpA-R93 mutants completely lost the interaction with the 5’ UTR of theibpAmRNA but retained almost all of the chaperone activity to sequester denatured proteins. Taken together, the conserved Arg93-mediated translational control of IbpA through RNA binding would be beneficial for a rapid and massive supply of the chaperone on demand.
Inositol hexakisphosphate kinase 1 is essential for cell junction integrity in the mouse seminiferous epithelium
Authors: Bhat Sameer Ahmed , Malla Aushaq Bashir , Oddi Vineesha , Sen Jayraj , Bhandari Rashna 
Published: April 2023

AbstractInositol hexakisphosphate kinases (IP6Ks) are enzymes that catalyse the synthesis of the inositol pyrophosphate 5-IP7 which is involved in the regulation of many physiological processes in mammals. The IP6K paralog IP6K1 is expressed at high levels in the mammalian testis, and its deletion leads to sterility in male mice. Here, we show that the loss of IP6K1 in mice causes a delay in the first wave of spermatogenesis. Testes from juvenileIp6k1knockout mice show downregulation of transcripts that are involved in cell adhesion and formation of the testis-specific inter-Sertoli cell impermeable junction complex known as the blood-testis barrier (BTB). We demonstrate that loss of IP6K1 in the mouse testis causes BTB disruption associated with transcriptional misregulation of the tight junction protein claudin 3, and subcellular mislocalization of the gap junction protein connexin 43. In addition to BTB disruption, we also observe loss of germ cell adhesion in the seminiferous epithelium ofIp6k1knockout mice, ultimately resulting in premature sloughing of round spermatids into the epididymis. Mechanistically, we show that loss of IP6K1 in the testis enhances cofilin activity due to increased AKT/ERK and integrin signalling, resulting in destabilization of the actin-based cytoskeleton in Sertoli cells and germ cell loss.
GraphComm: A Graph-based Deep Learning Method to Predict Cell-Cell Communication in single-cell RNAseq data
Authors: So Emily , Hayat Sikander , Nair Sisira Kadambat , Wang Bo , Haibe-Kains Benjamin 
Published: April 2023

AbstractInteractions between cells coordinate various functions across cell-types in health and disease states. Novel single-cell techniques enable deep investigation of cellular crosstalk at single-cell resolution. Cell-cell communication (CCC) is mediated by underlying gene-gene networks, however most current methods are unable to account for complex interactions within the cell as well as incorporate the effect of pathway and protein complexes on interactions. This results in the inability to infer overarching signalling patterns within a dataset as well as limit the ability to successfully explore other data types such as spatial cell dimension. Therefore, to represent transcriptomic data as intricate networks, complementing gene expression with information from cells to ligands and receptors for relevant cell-cell communication inference, we present GraphComm - a new graph-based deep learning method for predicting cell-cell communication in single-cell RNAseq datasets. GraphComm improves CCC inference by capturing detailed information such as cell location and intracellular signalling patterns from a database of more than 30,000 protein interaction pairs. With this framework, GraphComm is able to predict biologically relevant results in datasets previously validated for CCC, datasets that have undergone chemical or genetic perturbations and datasets with spatial cell information.
Analysis of single-cell CRISPR perturbations indicates that enhancers act multiplicatively and provides limited evidence for epistatic-like interactions
Authors: Zhou Jessica , Guruvayurappan Karthik , Toneyan Shushan , Chen Hsiuyi V. , Chen Aaron R. , Koo Peter , McVicker Graham 
Published: April 2023

SummaryA single gene may have multiple enhancers, but how they work in concert to regulate transcription is poorly understood. To analyze enhancer interactions throughout the genome, we developed a generalized linear modeling framework, GLiMMIRS, for interrogating enhancer effects from single-cell CRISPR experiments. We applied GLiMMIRS to a published dataset and tested for interactions between 46,166 enhancer pairs and corresponding genes, including 264 ’high-confidence’ enhancer pairs. We found that enhancer effects combine multiplicatively but with limited evidence for further interactions. Only 31 enhancer pairs exhibited significant interactions (FDR < 0.1), of which none came from the high confidence subset and 20 were driven by outlier expression values. Additional analyses of a second CRISPR dataset and in silico enhancer perturbations with Enformer both support a multiplicative model of enhancer effects without interactions. Altogether, our results indicate that enhancer interactions are uncommon or have small effects that are difficult to detect.HighlightsAnalysis of a large single-cell CRISPRi screen finds limited evidence for synergistic or redundant interactions between enhancersThe collective action of multiple enhancers on a common target gene follows a multiplicative model of activityA new statistical framework for simulating and modeling data from single-cell CRISPRi screens
Detection of dynamic lung hyperinflation using cardiopulmonary exercise testing and respiratory function in patients with stable cardiac disease: a multicenter cross-sectional study
Authors: Kominami Kazuyuki , Noda Kazuki , Minagawa Nanaho , Yonezawa Kazuya , Ueda Masanori , Kobayashi Yasuyuki , Murata Makoto , Akino Masatoshi 
Published: May 2023

AbstractBackgroundMany patients with heart disease potentially have comorbid COPD, however there are not enough opportunities for screening and the qualitative differentiation of shortness of breath (SOB) has not been well established. We investigated the detection rate of SOB based on a visual and qualitative dynamic lung hyperinflation (DLH) detection index during cardiopulmonary exercise testing (CPET) and whether there was a difference in respiratory function between the two groups.MethodsWe recruited 534 patients with heart disease and to scrutinize physical functions (369 males, 67.0±12.9 years) who underwent CPET and spirometry simultaneously. The difference between inspiratory and expiratory tidal volume was calculated (TV E-I) from the breath-by-breath data. A TV E-I decrease after the start of exercise comprised the convex group, and a TV E-I that remained unchanged or increased comprised the non-convex group.Results129 patients (24.2%) were in the convex; there was no difference in clinical characteristics between groups. The Borg scale scores at the end of the CPET showed no difference. VE/VCO2 slope, its Y-intercept and minimum VE/VCO2 showed no significant difference. In the convex group, FEV1.0% was significantly lower (69.4±13.1 vs. 75.0±9.0%), and FEV1.0% and Y-intercept and the difference between minimum VE/VCO2 and VE/VCO2 slope were significantly correlated (r=−0.343 and r=−0.478).ConclusionsThe convex group showed decreased respiratory function, suggesting potential airway obstruction during exercise. A combined assessment of the TV E-I and Y-intercept of the VE/VCO2 slope or the difference between the minimum VE/VCO2 and VE/VCO2 slopes could potentially detect COPD or airway obstruction.
Analyzing bivariate cross-trait genetic architecture in GWAS summary statistics with the BIGA cloud computing platform
Authors: Li Yujue , Xue Fei , Li Bingxuan , Yang Yilin , Fan Zirui , Shu Juan , Yang Xiaochen , Wang Xiyao , Lin Jinjie , Copana Carlos , Zhao Bingxin 
Published: May 2023

AbstractAs large-scale biobanks provide increasing access to deep phenotyping and genomic data, genome-wide association studies (GWAS) are rapidly uncovering the genetic architecture behind various complex traits and diseases. GWAS publications typically make their summary-level data (GWAS summary statistics) publicly available, enabling further exploration of genetic overlaps between phenotypes gathered from different studies and cohorts. However, systematically analyzing high-dimensional GWAS summary statistics for thousands of phenotypes can be both logistically challenging and computationally demanding. In this paper, we introduce BIGA (https://bigagwas.org/), a website that aims to offer unified data analysis pipelines and processed data resources for cross-trait genetic architecture analyses using GWAS summary statistics. We have developed a framework to implement statistical genetics tools on a cloud computing platform, combined with extensive curated GWAS data resources. Through BIGA, users can upload data, submit jobs, and share results, providing the research community with a convenient tool for consolidating GWAS data and generating new insights.
SimpliPyTEM: An open-source Python library and app to simplify Transmission Electron Microscopy andin situ-TEM image analysis
Authors: Ing Gabriel , Stewart Andrew , Battaglia Guiseppe , Ruiz-Perez Lorena 
Published: May 2023

AbstractIntroducing SimpliPyTEM, a Python library and accompanying GUI that simplifies the post-acquisition evaluation of transmission electron microscopy (TEM) images, helping streamline the workflow. After an imaging session, a folder of image and/or video files, typically containing low contrast and large file size 32-bit images, can be quickly processed via SimpliPyTEM into high-quality, high-contrast .jpg images with suitably sized scale-bars. The app can also generate HTML or PDF files containing the processed images for easy viewing and sharing. Additionally, SimpliPyTEM has a specific focus on in situ TEM videos, an emerging field of EM, allowing for fast data processing into preview movies, averages, image series, or motion corrected averages using MotionCor2. The accompanying Python library offers many standard image processing methods, all simplified to a single command, plus a module to analyse particle morphology and population. This latter application is particularly useful for life sciences investigations. User-friendly tutorials and clear documentation are included to help guide users through the processing and analysis. We invite the EM community to contribute to and further develop this open-source package.
Molecular and morphological characterisation of four new ancyromonad genera and proposal for an updated taxonomy of the Ancyromonadida
Authors: Yubuki Naoji , Torruella Guifré , Galindo Luis Javier , Heiss Aaron A. , Ciobanu Maria Cristina , Shiratori Takashi , Ishida Ken-ichiro , Blaz Jazmin , Kim Eunsoo , Moreira David , López-García Purificación , Eme Laura 
Published: May 2023

ABSTRACTAncyromonads are small biflagellated protists with a bean-shaped morphology. They are cosmopolitan in marine, freshwater and soil environments, where they attach to surfaces while feeding on bacteria. These poorly known grazers stand out by their uncertain phylogenetic position in the tree of eukaryotes, forming a deep-branching ‘orphan’ lineage that is considered key to better understanding the early evolution of eukaryotes. Despite their ecological and evolutionary interest, only limited knowledge exists about their true diversity. Here, we aimed to better characterise ancyromonads by integrating environmental surveys with behavioural observation and description of cell morphology, for which sample isolation and culturing is indispensable. We studied 18 ancyromonad strains, including 14 new isolates and 7 new species. Most of them belong to three new and genetically divergent genera:Caraotamonas,Nyramonas, andOlneymonas(encompassing 4 species). The remaining three new species belong to the already known generaFabomonasandAncyromonas. We also raisedStriomonas, formerly a subgenus ofNutomonas, to full genus status, based on morphological and phylogenetic grounds. For all these new species, we studied their morphology under light and electron microscopy and carried out molecular phylogenetic analyses, including as well 18S rRNA gene sequences from several environmental surveys. Based on these analyses, we have updated the taxonomy of Ancyromonadida.
ISRES+: An improved evolutionary strategy for function minimization to estimate the free parameters of Systems Biology models
Authors: Bandodkar Prasad U. , Shaikh Razeen R. , Reeves Gregory T. 
Published: May 2023

AbstractModel development is essential to gain a mathematical understanding of the underlying phenomena in systems biology. In most models, it is typically hard to estimate the values of the biophysical/phenomenological parameters that characterize the model. The parameters are estimated by minimizing a function that reduces a measure of the error between model predictions and experimental data. In this work, we build on an algorithm for function minimization proposed by Runnarson and Yao, named Improved Evolutionary Strategy by Stochastic Ranking (ISRES), that finds a best-fit individual by evolving a population in the direction of minimizing error by using information at most from a pair of individuals in any generation to create a new population. Our algorithm, named ISRES+, builds on it by combining information from all individuals across the population and across all generations to gain a better sense of direction to evolve the population. ISRES+ makes use of the additional information generated by the creation of a large population in the evolutionary methods to approximate the local neighborhood around the best-fit individual using linear least squares fit in one and two dimensions. We compared the performance of the two algorithms on three systems biology models with varying complexities and found that not only does the ISRES+ lead to fitter individuals, but it also leads to a tighter distribution of fittest individuals over successive runs.
FET fusion oncoproteins disrupt physiologic DNA repair networks in cancer
Authors: Menon Shruti , Gracilla Daniel , Breese Marcus R. , Lin Yone Phar , Cruz Filemon Dela , Feinberg Tamar , de Stanchina Elisa , Galic Ana-Florina , Allegakoen Hannah , Perati Shruthi , Wen Nicholas , Heslin Ann , Horlbeck Max A. , Weissman Jonathan , Sweet-Cordero E. Alejandro , Bivona Trever G. , Tulpule Asmin 
Published: May 2023

AbstractWhile oncogenes promote cancer cell growth, unrestrained proliferation represents a significant stressor to cellular homeostasis networks such as the DNA damage response (DDR). To enable oncogene tolerance, many cancers disable tumor suppressive DDR signaling through genetic loss of DDR pathways and downstream effectors (e.g., ATM or p53 tumor suppressor mutations). Whether and how oncogenes can help “self-tolerize” by creating analogous functional defects in physiologic DDR networks is not known. Here we focus on Ewing sarcoma, a FET fusion oncoprotein (EWSR1-FLI1) driven pediatric bone tumor, as a model for the class of FET rearranged cancers. Native FET family members are among the earliest factors recruited to DNA double-strand breaks (DSBs), though the function of both native FET proteins and FET fusion oncoproteins in DNA repair remains to be defined. We discover that the EWSR1-FLI1 fusion oncoprotein is recruited to DNA DSBs and interferes with native FET (EWSR1) protein function in activating the DNA damage sensor ATM. In multiple FET rearranged cancers, FET fusion oncoproteins induce functional ATM defects, rendering the compensatory ATR signaling axis as a collateral dependency and therapeutic target. More generally, we find that aberrant recruitment of a fusion oncoprotein to sites of DNA damage can disrupt physiologic DSB repair, revealing a mechanism for how growth-promoting oncogenes can also create functional defects within tumor suppressive DDR networks.
Camouflaging Endovascular Stents with an Endothelial Coat Using CD31 Domain 1-mimetic Peptides
Authors: Sénémaud J. , Skarbek C. , Song R. , Pan Z. , Lefevre I , Bianchi E. , Castier Y. , Nicoletti A. , Bureau C. , Caligiuri G. 
Published: May 2023

AbstractBackgroundEndovascular stents and flow diverters have become widely used for the treatment of vascular diseases; however, their effectiveness is often limited by the deposition and activation of blood platelets and leukocytes. The foreignness of these devices often triggers pathologic local reactions that impede their integration and compromise their efficacy. In this study, we developed a method to camouflage endovascular stents and flow diverters by coating them with a surface that mimics healthy endothelium, in order to promote more effective device integration and prevent the activation of blood cells.MethodsWe designed peptides using domain 1 and/or domain 2 of human CD31 and synthesized the chosen peptide to coat clinical-grade nitinol flow diverters and cobalt chromium balloon expandable stents. The coated stents were implanted in adult rabbits and included control groups of uncoated devices and drug-eluting CoCr stents. The rabbits were monitored for 60 days, during which we assessed the integration of the devices under a physiologic confluence of endothelial cells.ResultsOur results demonstrated that the stents coated with the CD31-Domain 1 mimicking peptide promoted a smooth integration of the devices under a physiologic confluence of endothelial cells. By day 7, the coated stents were entirely covered by a smooth endothelium, unlike bare-metal and drug-eluting stents which remained largely exposed to the flowing blood. By day 60, the coated stents demonstrated superiority over both bare-metal and drug-eluting stents, as they resulted in the formation of a “neo-arterial” wall at the entrance of the aneurysmal sac.ConclusionOur method provides a promising step towards the development of more effective and biocompatible endovascular devices. The CD31 domain 1 coating prevented the pathologic local reaction at the site of stent implantation and promoted faster and more effective device integration. Further studies are necessary to investigate the efficacy and safety of CD31 domain 1 coatings on a larger scale, as well as their long-term durability and potential clinical applications.