bluuebunny/crossref_metadata_2025_split huggingface dataset:
A fibroblast-dependent TGFβ1/sFRP2 noncanonical Wnt signaling axis underlies epithelial metaplasia in idiopathic pulmonary fibrosis
Authors: Cohen Max L. , Brumwell Alexis N. , Ho Tsung Che , Montas Genevieve , Golden Jeffrey A. , Jones Kirk D. , Wolters Paul J. , Wei Ying , Chapman Harold A. , Le Saux Claude J. 
Published: August 2023

AbstractReciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate this, we administered the fibroblast-selective TGFβ1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples showed higher fibroblast TGFβ1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG significantly downregulated TGFβ1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an unrecognized TGFβ1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was essential for AEC2 trans-differentiation to basal cells. Precision cut lung slices (PCLS) from normal donors demonstrated that TGFβ1 promoted KRT17 expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin-related signaling in AEC2s were required for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGFβ1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify the TGFβ1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.
Integrated multiplexed assays of variant effect revealcis-regulatory determinants of catechol-O-methyltransferase gene expression
Authors: Hoskins Ian , Rao Shilpa , Tante Charisma , Cenik Can 
Published: August 2023

AbstractMultiplexed assays of variant effect are powerful methods to profile the consequences of rare variants on gene expression and organismal fitness. Yet, few studies have integrated several multiplexed assays to map variant effects on gene expression in coding sequences. Here, we pioneered a multiplexed assay based on polysome profiling to measure variant effects on translation at scale, uncovering single-nucleotide variants that increase and decrease ribosome load. By combining high-throughput ribosome load data with multiplexed mRNA and protein abundance readouts, we mapped thecis-regulatory landscape of thousands of catechol-O-methyltransferase (COMT) variants from RNA to protein and found numerous coding variants that alterCOMTexpression. Finally, we trained machine learning models to map signatures of variant effects onCOMTgene expression and uncovered both directional and divergent impacts across expression layers. Our analyses reveal expression phenotypes for thousands of variants inCOMTand highlight variant effects on both single and multiple layers of expression. Our findings prompt future studies that integrate several multiplexed assays for the readout of gene expression.
Direct photoreception of a pituitary endocrine cell, melanotroph, induces a hormone release
Authors: Fukuda Ayaka , Sato Keita , Fujimori Chika , Yamashita Takahiro , Takeuchi Atsuko , Ohuchi Hideyo , Umatani Chie , Kanda Shinji 
Published: August 2023

AbstractIn addition to canonical photoreception by the eye, many other organs express non-visual photoreceptors although their biological significance is mostly unknown. Here, we discovered a novel phenomenon in which the pituitary of medaka directly receives light, which induces hormone release. Ca2+imaging analysis revealed that a melanotroph, a pituitary endocrine cell secreting melanocyte-stimulating hormone (MSH), robustly increases [Ca2+]iduring short-wavelength light irradiation. Moreover, we identified Opn5m as the key molecule of this mechanism. The significance of this phenomenon was suggested to be involved in UV protection because knockout ofopn5msignificantly reduced the expression oftyrosinase, the rate-limiting enzyme for melanogenesis, in the skin. These results suggest a novel mechanism in which direct reception of short-wavelength light by pituitary endocrine cells triggers the pathway to enhance UV protection.One-Sentence SummaryAn endocrine cell of the pituitary was proven to be a photoreceptive cell that enables autonomous hormone release.
Radiation-induced rescue effect on human breast carcinoma cells is regulated by macrophages
Authors: Pathikonda Spoorthy , Tian Li , Cheng Shuk Han , Lam Yun Wah 
Published: August 2023

AbstractThe susceptibility of cancer cells to DNA damages is influenced by their microenvironment. For example, unirradiated neighbors of irradiated cells can produce signals that reduce DNA damages. This phenomenon, known as Radiation-Induced Rescue Effect (RIRE), has profound implications on the efficacy of radiotherapy. Using bystander cells cocultured with mock-irradiated cells as a control, we demonstrated, for the first time, two types of RIRE. Conditioned medium from naïve bystander cells, i.e., cells not exposed to irradiated cells, could mitigate UV-induced DNA damages in human breast carcinoma MCF7 cells, as judged by phospho-H2AX and 53BP1 immunostaining. This protective effect could be further enhanced by the prior treatment of bystander cells with factors from UV-irradiated cells. We named the former effect “basal RIRE” and the latter “active RIRE” which were cell type-dependent. As bystanders, MCF7 showed a significant active RIRE, whereas THP1-derived macrophages showed a strong basal RIRE but no active RIRE. Interestingly, RIRE of macrophages could further be modulated by polarisation. The basal RIRE of macrophages was abolished by M1 polarisation, while M2 and Tumour Associated Macrophages (TAM) demonstrated pronounced basal and active RIRE. When mixtures of MCF7 cells and polarised macrophages were used as bystanders, the overall RIRE was dictated by macrophage phenotypes: RIRE was suppressed by M1 macrophages but significantly enhanced by M2 and TAM. This study shows a previously unappreciated role of the innate immune system in RIRE. Depending on polarised phenotypes, macrophages in the tumour microenvironment can interfere with the effectiveness of radiotherapy by adjusting the RIRE magnitudes.
The effect of information content distributions on word recollection and familiarity
Authors: Wallenberg Joel C. , Fadhilah Salsabila Nadhif , Hinton Taylor D. , Smulders Tom V. , Read Jenny C.A. , Cuskley Christine 
Published: August 2023

AbstractThis study builds on work on language processing and information theory which suggests that informationally uniform, or smoother, sequences are easier to process than ones in which information arrives in clumps. Because episodic memory is a form of memory in which information is encoded within its surrounding context, we predicted that episodic memory in particular would be sensitive to information distribution. We used the “dual process” theory of recognition memory to separate the episodic memory component (recollection) from the non-episodic component (familiarity) of recognition memory. Though we find a weak effect in the predicted direction, this does not reach statistical significance and so the study does not support the hypothesis. The study does replicate a known effect from the literature where low frequency words are more easily recognized than high frequency ones when participants employ recollection-type memory. We suggest our results may be explained by linguistic processing being particularly adapted to processing linear sequences of information in a way that episodic memory is not. Episodic memory likely evolved to deal with unpredictable, sometimes clumped, information streams.
Multi-representation DeepInsight: an improvement on tabular data analysis
Authors: Sharma Alok , López Yosvany , Jia Shangru , Lysenko Artem , Boroevich Keith A. , Tsunoda Tatsuhiko 
Published: August 2023

AbstractTabular data analysis is a critical task in various domains, enabling us to uncover valuable insights from structured datasets. While traditional machine learning methods have been employed for feature engineering and dimensionality reduction, they often struggle to capture the intricate relationships and dependencies within real-world datasets. In this paper, we present Multi-representation DeepInsight (abbreviated as MRep-DeepInsight), an innovative extension of the DeepInsight method, specifically designed to enhance the analysis of tabular data. By generating multiple representations of samples using diverse feature extraction techniques, our approach aims to capture a broader range of features and reveal deeper insights. We demonstrate the effectiveness of MRep-DeepInsight on single-cell datasets, Alzheimer’s data, and artificial data, showcasing an improved accuracy over the original DeepInsight approach and machine learning methods like random forest and L2-regularized logistic regression. Our results highlight the value of incorporating multiple representations for robust and accurate tabular data analysis. By embracing the power of diverse representations, MRep-DeepInsight offers a promising avenue for advancing decision-making and scientific discovery across a wide range of fields.
A major endogenous glycosidase mediating quercetin uptake inBombyx mori
Authors: Waizumi Ryusei , Hirayama Chikara , Tomita Shuichiro , Iizuka Tetsuya , Kuwazaki Seigou , Jouraku Akiya , Tsubota Takuya , Yokoi Kakeru , Yamamoto Kimiko , Sezutsu Hideki 
Published: August 2023

AbstractQuercetin is a common plant flavonoid that is involved in herbivore–plant interactions. Mulberry silkworms (domestic silkworm,Bombyx mori, and wild silkworm,Bombyx mandarina) uptake quercetin from mulberry leaves and accumulate the metabolites in the cocoon, thereby improving its protective properties. Here we identified and characterized a glycosidase, named LPH-like quercetin glycoside hydrolase 1 (LQGH1), that initiates quercetin metabolism in the domestic silkworm. LQGH1 is expressed in the midgut where it mediates quercetin uptake by deglycosylating the three most common quercetin glycosides present in mulberry leaf: rutin, quercetin-3-O-malonyl-glucoside, quercetin-3-O-glucoside. Despite being located in an unequal crossing-over hotspot,LQGH1is conserved in some species in clade Macroheterocera, including the wild silkworm, indicating the adaptive significance of quercetin uptake.LQGH1is important also in breeding: defective mutations ofLQGH1, which result in discoloration of the cocoon and increased silk yield, are homozygously conserved in 27 of the 32 Japanese white-cocoon domestic silkworm strains and 12 of the 30 Chinese ones we investigated.
Efficacy of Centers of Biomedical Research Excellence (CoBRE) Grants to Build Research Capacity in Underrepresented States
Authors: Schaller Michael D. 
Published: August 2023

AbstractFederal funding for research has immediate and long-term economic impact. Since federal research funding is regionally concentrated and not geographically distributed, the benefits are not fully realized in some regions of the country. The Established (previously Experimental) Program to Stimulate Competitive Research (EPSCoR) programs at several agencies, e.g. the National Science Foundation, and the Institutional Development Award (IDeA) program at the National Institutes of Health were created to increase competitiveness for funding in states with historically low levels of federal funding. The Centers of Biomedical Research Excellence (CoBRE) award program is a component of the IDeA program. The CoBRE grants support research core facilities to develop research infrastructure. These grants also support the research projects of junior investigators, under the guidance of mentoring teams of senior investigators, to develop human resources at these institutions. Few studies have assessed the effectiveness of these programs. This study examines the investment and outcomes of the CoBRE grants from 2000 through 2022. The maturation of junior investigators into independently funded principal investigators is comparable to other mentoring programs supported by NIH. The investment in research cores resulted in substantial research productivity, measured by publications. Despite the successes of individual investigators and increase research infrastructure and productivity, the geographic distribution of federal and NIH research dollars has not changed. These results will be informative in consideration of policies designed to enhance the geographic distribution of federal research dollars.
Ecological Network Resilience & Extinction Proxies - Updating Projections of Ecological Networks
Authors: Kusch Erik , Ordonez Alejandro 
Published: August 2023

AbstractForecasting biodiversity and functioning changes to ecosystem composition and functioning under climate change requires using multi-species approaches that explicitly consider ecological interactions. Here, we propose a framework with which to incorporate considerations of (1) localised extinction risk proxies, (2) resilience mechanisms of ecological networks, and (3) extinction cascade directionality as a driving force of ecological change. These three aspects are seldomly considered when establishing ecosystems responses to climate change and biodiversity loss. Using this framework, we demonstrate that current practices may severely underpredict ecological change measured as loss of biodiversity and change in connectedness. Our novel framework which explicitly explores two-dimensional resilience landscapes defined by network resilience mechanisms (i.e., link loss sensitivity and realisation of rewiring potential) represents the most complete toolbox for assessment of vulnerability of ecological networks to extinction cascades. Ultimately, we propose that using localised extinction proxies, explicitly quantifying ecological network resilience through link-loss sensitivity and realisation of rewiring potential, as well as simulation of bidirectional extinction cascades will lead to improved capabilities of estimating ecosystem trajectories throughout the Anthropocene.
High-temporal resolution functional PET/MRI reveals coupling between human metabolic and hemodynamic brain response
Authors: Hahn Andreas , Reed Murray B. , Vraka Chrysoula , Godbersen Godber M. , Klug Sebastian , Komorowski Arkadiusz , Falb Pia , Nics Lukas , Traub-Weidinger Tatjana , Hacker Marcus , Lanzenberger Rupert 
Published: August 2023

ABSTRACTPositron emission tomography (PET) provides precise molecular information on physiological processes, but its low temporal resolution is a major obstacle. Consequently, we characterized the metabolic response of the human brain to working memory performance using an optimized functional PET framework at a temporal resolution of 3 seconds. Consistent with simulated kinetic modeling, we observed a constant increase in the [18F]FDG signal during task execution, followed by a rapid return to baseline after stimulation ceased. The simultaneous acquisition of BOLD fMRI revealed that the temporal coupling between hemodynamic and metabolic signals in the primary motor cortex was related to individual behavioral performance during working memory. Furthermore, task-induced BOLD deactivations in the posteromedial default mode network were accompanied by distinct temporal patterns in glucose metabolism, which depended on the task-positive network metabolic demands. In sum, the proposed approach enables the advancement from parallel to truly synchronized investigation of metabolic and hemodynamic responses during cognitive processing.
Immunoglobulin M regulates airway hyperresponsiveness independent of T helper 2 allergic inflammation
Authors: Hadebe Sabelo , Savulescu Anca Flavia , Khumalo Jermaine , Jones Katelyn , Mangali Sandisiwe , Mthembu Nontobeko , Musaigwa Fungai , Maepa Welcome , Ndlovu Hlumani , Ngomti Amkele , Scibiorek Martyna , Okendo Javan , Brombacher Frank 
Published: August 2023

AbstractAllergic asthma is a disease driven by T helper 2 (Th2) cells, eosinophilia, airway hyperresponsiveness (AHR) and IgE-secreting B cells. Asthma is largely controlled by corticosteroids and β2adregenic receptor agonists that target and relax airway smooth muscle (ASM). Immunoglobulin M (IgM) isotype secreted by naïve B cells is important for class switching but may have other undefined functions.We investigated the role of IgM in a house dust mite (HDM)-induced Th2 allergic asthma model.We sensitised wild-type (WT) and IgM-deficient (IgM-/-) mice with HDM and measured AHR, and Th2 responses. We performed RNA sequencing on the whole lung of WT and IgM-/-mice sensitised to saline or HDM. We validated our AHR data on human ASM by deleting genes using CRISPR and measuring contraction by single-cell force cytometry.We found IgM to be essential in AHR but not Th2 airway inflammation or eosinophilia. RNA sequencing of lung tissue suggested that IgM regulated AHR through modulating brain-specific angiogenesis inhibitor 1-associated protein 2-like protein 1 (Baiap2l1) and other genes. Deletion ofBAIAP2L1led to a differential reduction in human ASM contraction when stimulated with TNF-α and Acetylcholine, but not IL-13.These findings have implications for future treatment of asthma beyond current therapies.
RNA splicing modulator induces peripheral neuropathy with increased neurofilament light chain levels via p53 signaling
Authors: Krach Florian , Boerstler Tom , Reischl Stephanie , Krumm Laura , Regensburger Martin , Winkler Jürgen , Winner Beate 
Published: August 2023

AbstractRNA splicing modulators are a new class of small molecules with the potential to modify the expression levels of proteins. A recent clinical trial investigating the splicing modulator branaplam for Huntington’s disease to lower huntingtin levels was terminated due to the development of peripheral neuropathy. Here, we describe how branaplam leads to this adverse effect. On a cellular level, branaplam disrupts neurite integrity reflected by elevated neurofilament light chain levels in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN). Branaplam does not target neuropathy-associated genes. However, transcription factor binding site enrichment analysis indicates p53 activation. P53 activation upon branaplam treatment in iPSC-MN is linked to increased nucleolar stress, thereby enhanced expression of the neurotoxic p53-target gene BBC3. These findings illustrate that RNA splicing modulators may have clinically relevant off-target effects, implying the necessity of comprehensive pre-screening in human models prior to executing clinical trials.Graphical abstractOne Sentence SummaryPredicting side effects of RNA splicing modulator branaplam leading to neurotoxicity via nucleolar stress, p53 activation, and axonal degeneration.
Bioinformatics and next generation data analysis reveals the potential role of inflammation in sepsis and its associated complications
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: August 2023

AbstractSepsis is the leading systemic inflammatory response syndrome in worldwide, yet relatively little is known about the genes and signaling pathways involved in sepsis progression. The current investigation aimed to elucidate potential key candidate genes and pathways in sepsis and its associated complications. Next generation sequencing (NGS) dataset (GSE185263) was downloaded from the Gene Expression Omnibus (GEO) database, which included data from 348 sepsis samples and 44 normal control samples. Differentially expressed genes (DEGs) were identified using t-tests in the DESeq2 R package. Next, we made use of the g:Profiler to analyze gene ontology (GO) and REACTOME pathway. Then protein-protein interaction (PPI) of these DEGs was visualized by Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING). Furthermore, we constructed miRNA-hub gene regulatory network and TF-hub gene regulatory network among hub genes utilizing miRNet and NetworkAnalyst online databases tool and Cytoscape software. Finally, we performed receiver operating characteristic (ROC) curve analysis of hub genes through the pROC package in R statistical software. In total, 958 DEGs were identified, of which 479 were up regulated and 479 were down regulated. GO and REACTOME results showed that DEGs mainly enriched in regulation of cellular process, response to stimulus, extracellular matrix organization and immune system. The hub genes of PRKN, KIT, FGFR2, GATA3, ERBB3, CDK1, PPARG, H2BC5, H4C4 and CDC20 might be associated with sepsis and its associated complications. Predicted miRNAs (e.g., hsa-mir-548ad-5p and hsa-mir-2113) and TFs (e.g., YAP1 and TBX5) were found to be significantly correlated with sepsis and its associated complications. In conclusion, the DEGs, relative pathways, hub genes, miRNA and TFs identified in the current investigation might help in understanding of the molecular mechanisms underlying sepsis and its associated complications progression and provide potential molecular targets and biomarkers for sepsis and its associated complications.
Selective elimination of CD169+macrophages in lymph nodes invaded by breast cancers
Authors: Maeshima Yurina , Kataoka Tatsuki R. , Vandenbon Alexis , Hirata Masahiro , Takeuchi Yasuhide , Suzuki Yutaka , Fukui Yukiko , Ibi Yumiko , Haga Hironori , Morita Satoshi , Toi Masakazu , Kawaoka Shinpei , Kawaguchi Kosuke 
Published: August 2023

AbstractBreast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we report that metastasized breast cancer cells selectively eliminate CD169+lymph node sinus macrophages, an initiator of anti-cancer immunity, from the lymph nodes. The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+macrophages was reduced in metastatic lymph nodes, whereas the numbers of other major immune cell types were unaltered. We also detected the infiltration of CD169+macrophages into metastasized cancer tissues depending on sections, suggesting that CD169+macrophages were gradually eliminated after anti-cancer reactions. Furthermore, CD169+macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging. Collectively, we propose that metastasized breast cancer cells dispel CD169+macrophages from lymph nodes in a phased manner, disabling a critical step of anti-cancer immunity.