bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial stiffening induced by CD36-mediated lipid uptake leads to endothelial barrier disruption and contributes to atherosclerotic lesions
Authors: Aguilar Victor , Master Elizabeth Le , Paul Amit , Ahn Sang Joon , Lazarko Dana , Febbraio Maria , Lee James , Levitan Irena 
Published: November 2023

ABSTRACTBackgroundTo determine the impact of endothelial stiffening induced by CD36-mediated lipid uptake in the disruption of aortic endothelial barrier and development of atherosclerosis in mouse models of obesity and hypercholesterolemia.Approach and ResultsEndothelial-specific inducible downregulation of CD36 results in abrogating the stiffening of aortic endothelium induced by a short-term (6-8 weeks) high-fat Western diet in intact freshly isolated mouse aortas of Cdh5.CreERT2CD36fl/flmice, as assessed by atomic force microscopy. No effect was observed on the stiffness of aortic vascular wall assessed in the same groups of mice by echocardiography. Prevention of WD-induced endothelial stiffening by the downregulation of endothelial CD36 was associated with a protective effect against endothelial barrier disruption, assessed by morphological analysis of VE-cadherin junctions and penetration of Evans blue dye into the aortic wall. These protective effects were independent of the changes in the serum lipid profiles. Furthermore, endothelial specific downregulation of CD36 in hypercholesterolemic Cdh5.CreERT2CD36fl/flLDLR-/-mice also led to significant decrease in endothelial stiffening after 4-5 months of high fat diet and a significant decrease in the areas of atherosclerotic lesion. In both models, significant endothelial stiffening was observed specifically in male mice, while female mice exhibited less endothelial stiffening and less severe atherosclerosic phenotype, consistent with endothelial stiffening playing an important role in aortic vascular disease in a sex-dependent way. Mechanistically, we showin vitrothat CD36-mdiated uptake of long chain saturated fatty acids, particularly palmitic acid, induces endothelial stiffening via activation of RhoA/ROCK pathway. Moreover, palmitic acid-induced endothelial stiffening critically depends on the expression of a RhoA inhibitory protein, Rho-GDI-1.ConclusionsWe conclude that stiffening of the aortic endothelium by CD36-mediated uptake of fatty acids contributes significantly to WD-induced vascular dysfunction and atherosclerosis. We further propose that fatty acids may activate RhoA by inducing its dissociation from Rho-GDI-1.
Mem-GAN: A Pseudo Membrane Generator for Single-cell Imaging in Fluorescent Microscopy
Authors: Wang Yixin , Ding Jiayuan , Wu Lidan , Wardhani Aster , Danaher Patrick , Lu Qiaolin , Wen Hongzhi , Tang Wenzhuo , Chang Yi , Lei Yu Leo , Tang Jiliang , Xie Yuying 
Published: November 2023

AbstractMotivationFluorescent microscopy imaging is vital to capturing single-cell spatial data, characterizing tissue organization and facilitating comprehensive analysis of cellular state. Advancements in fluorescent microscopy imaging technologies have enabled precise downstream cellular analysis, particularly in cell segmentation. Accurate segmentation of individual cells allows better profiling and understanding of cell properties and behaviors. The majority of existing segmentation methods predominantly concentrate on enhancing segmentation algorithms, and their effectiveness strongly relies on the input stained image quality. Factors such as high cellular density, indistinct cell boundaries, and staining artifacts can result in uneven and low-quality staining, particularly causing missing or unclear membrane staining. These artifacts adversely impact the efficacy of the subsequent cell segmentation methods.ResultsTo tackle this insufficient membrane staining, we propose a novel approach, Mem-GAN, to generate high-quality membranes for cells with missing or weak membranes. Inspired by advanced style transfer techniques in computer vision, Mem-GAN styles the content of the cells with missing or weak membranes into cells with integrated membrane staining. Considering the differences in membrane morphology between epithelial/tumor cells and immune cells, Mem-GAN deals with tumor and immune cells separately, not only enhancing membrane staining for cells with partially weak membrane signals but also generating membranes for cells with only nuclear channels. The proposed Mem-GAN is evaluated using the publicly available CosMx dataset. Experimental results demonstrate significant improvements in image staining quality, more accurate representation of membrane morphology characteristics, and better performance in downstream segmentation tasks. Mem-GAN is flexibly adapted and applied to other spatially resolved transcriptomics datasets, such as MERFISH and FISHseq. Our work provides a new perspective on tackling the challenges in cell segmentation from fluorescent microscopy image restoration.Availability and implementationThe implementation of Mem-GAN is open-source and available at the github repositoryhttps://github.com/OmicsML/Mem-GAN. The interactive webserver-based demo of Mem-GAN can be accessed athttps://omicsml.ai/memgan.
An encyclopedia of enhancer-gene regulatory interactions in the human genome
Authors: Gschwind Andreas R. , Mualim Kristy S. , Karbalayghareh Alireza , Sheth Maya U. , Dey Kushal K. , Jagoda Evelyn , Nurtdinov Ramil N. , Xi Wang , Tan Anthony S. , Jones Hank , Ma X. Rosa , Yao David , Nasser Joseph , Avsec Žiga , James Benjamin T. , Shamim Muhammad S. , Durand Neva C. , Rao Suhas S. P. , Mahajan Ragini , Doughty Benjamin R. , Andreeva Kalina , Ulirsch Jacob C. , Fan Kaili , Perez Elizabeth M. , Nguyen Tri C. , Kelley David R. , Finucane Hilary K. , Moore Jill E. , Weng Zhiping , Kellis Manolis , Bassik Michael C. , Price Alkes L. , Beer Michael A. , Guigó Roderic , Stamatoyannopoulos John A. , Aiden Erez Lieberman , Greenleaf William J. , Leslie Christina S. , Steinmetz Lars M. , Kundaje Anshul , Engreitz Jesse M. 
Published: November 2023

AbstractIdentifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the impact of human genetic variation on disease1–6. Here we create and evaluate a resource of >13 million enhancer-gene regulatory interactions across 352 cell types and tissues, by integrating predictive models, measurements of chromatin state and 3D contacts, and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,411 element-gene pairs measured in CRISPR perturbation experiments, >30,000 fine-mapped eQTLs, and 569 fine-mapped GWAS variants linked to a likely causal gene. Using this framework, we develop a new predictive model, ENCODE-rE2G, that achieves state-of-the-art performance across multiple prediction tasks, demonstrating a strategy involving iterative perturbations and supervised machine learning to build increasingly accurate predictive models of enhancer regulation. Using the ENCODE-rE2G model, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, which reveals global properties of enhancer networks, identifies differences in the functions of genes that have more or less complex regulatory landscapes, and improves analyses to link noncoding variants to target genes and cell types for common, complex diseases. By interpreting the model, we find evidence that, beyond enhancer activity and 3D enhancer-promoter contacts, additional features guide enhancer-promoter communication including promoter class and enhancer-enhancer synergy. Altogether, these genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models, and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
Evaluating diversionary feeding as a method to resolve conservation conflicts in a recovering ecosystem
Authors: Bamber Jack A. , Kortland Kenny , Sutherland Chris , Payo-Payo Ana , Lambin Xavier 
Published: November 2023

Abstract1. The recovery of mammalian predators of conservation concern in Europe is a success story, but their impact on some prey species of conservation concern may cause conservation dilemmas. This calls for effective intervention strategies that mitigate predator impacts without compromising their recovery.2. We evaluated diversionary feeding as a management intervention tool to reduce depredation on nests of rapidly declining Western capercaillies in Scotland. We studied the influence of diversionary feeding provision on the fates of artificial nests deployed using a replicated and representative randomised landscape-scale experiment. This comprised 30 paired control (no diversionary feeding) and treatment (diversionary feeding applied) sites, 60 in total, each containing six artificial nests distributed across 600 km2. The experiment was replicated over two years, and in the second year, the control-treatment pairs were reversed, yielding 60 treatment and 60 control sites and 720 artificial nests.3. Diversionary feeding substantially reduced depredation of artificial nests, translating into an 83% increase in predicted nest survival over 28 days of incubation. The increase in survival was mostly accounted for by a reduction in the probability that a pine marten, the main nest predator, consumed or cached eggs. Diversionary food also significantly reduced nest predation by badgers, although the magnitude of this effect varied by year.4. Diversionary feeding is an easily employable method shown in this study to reduce predator impact (functional) without lethal (numerical) intervention. Managers should proceed with its application for conserving capercaillie in Scotland without delay.
Cis- andtrans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia
Authors: Head S. Taylor , Dezem Felipe , Todor Andrei , Yang Jingjing , Plummer Jasmine , Gayther Simon , Kar Siddhartha , Schildkraut Joellen , Epstein Michael P. 
Published: November 2023

ABSTRACTTranscriptome-wide association studies (TWAS) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have only considered regulatory effects of risk associated SNPs thought to act incison a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWAS of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of bothcis- andtrans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such asACAP3, whose associations are predominantly driven bytrans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents a first look into the role oftrans-eQTLs in the complex molecular mechanisms underlying these diseases.
Spatial distribution of insular cliff vegetation and future scenarios in a climate change perspective
Authors: Capó Miquel , Cortés-Fernández Iván , Borràs Joshua 
Published: November 2023

ABSTRACTCliff ecology has been studied for decades, providing good information about its high biodiversity values and their vulnerability to climate change. At the same time, literature shows how insular ecosystems are evolutionarily enhanced to present biodiversity hotspots with high endemicity rates, but they are also severely affected by anthropogenic effects. Together, insular cliff communities combine both biodiversity uniqueness and high vulnerability to global change, but few studies have evaluated these particular ecosystems. In this study, our aim was to provide novel information on the spatial distribution of insular cliff vegetation, taking the Balearic islands as a study case, assessing which environmental and climatic variables contribute to the definition of habitat conditions. Also, we used the predictions found in the WorldClim database to predict how the spatial distribution model vary. The map obtained showed that the mountains and coast were the most suitable habitats, especially the mountain ranges of the island of Mallorca. In particular, the high peaks of Serra de Tramuntana englobe the most fitted conditions for rupicolous species. Regarding the future climatic scenarios, in both the pessimistic and optimistic models, the spatial distribution of cliff vegetation remain intact in the mountain ranges where the habitat suitability was high, but disappear or reduce in other less favorable zones for the period 2021-2040. However, the extension of the distribution will be reduced in mid- and long-term periods, until 2081-2100, when the well-suited areas are only predicted to be in high-elevation mountains from the north of Mallorca island. These results emphasize the high vulnerability of these habitats to climate change due to their vulnerability to aridity and the strict requirements for habitat suitability (e.g., high slopes). From this, future studies should focus on single-species analysis to evaluate if any cliff specialist species can be at risk of extinction due to climate change.
Impact of Evolutionary Relatedness on Species Diversification and Tree Shape
Authors: Qin Tianjian , Valente Luis , Etienne Rampal 
Published: November 2023

AbstractSlowdowns in lineage accumulation are often observed in phylogenies of extant species. One explanation is the presence of ecological limits to diversity and hence to diversification. Previous research has examined whether and how species richness (SR) impacts diversification rates, but rarely considered the evolutionary relatedness (ER) between species, although ER can affect the degree of interaction between species, which likely sets these limits. To understand the influences of ER on species diversification and the interplay between SR and ER, we present a simple birth-death model in which the speciation rate depends on the ER. We use different metrics of ER that operate at different scales, ranging from branch/lineage-specific to clade-wide scales. We find that the scales at which an effect of ER operates yield distinct patterns in various tree statistics. When ER operates across the whole tree, we observe smaller and more balanced trees, with speciation rates distributed more evenly across the tips than in scenarios with lineage-specific ER effects. Importantly, we find that negative SR dependence of speciation masks the impact of ER on some of the tree statistics. Our model allows diverse evolutionary trajectories for producing imbalanced trees, which are commonly observed in empirical phylogenies but have been challenging to replicate with earlier models.
Disrupted sleep-wake regulation in the MCI-Park mouse model of Parkinson’s disease
Authors: Summa K.C. , Jiang P. , González-Rodríguez P. , Huang X. , Lin X. , Vitaterna M.H. , Dan Y. , Surmeier D.J. , Turek F.W. 
Published: November 2023

AbstractDisrupted sleep has a profound adverse impact on lives of Parkinson’s disease (PD) patients and their caregivers. Sleep disturbances are exceedingly common in PD, with substantial heterogeneity in type, timing, and severity. Among the most common sleep-related symptoms reported by PD patients are insomnia, excessive daytime sleepiness, and sleep fragmentation, characterized by interruptions and decreased continuity of sleep. Alterations in brain wave activity, as measured on the electroencephalogram (EEG), also occur in PD, with changes in the pattern and relative contributions of different frequency bands of the EEG spectrum to overall EEG activity in different vigilance states consistently observed. The mechanisms underlying these PD-associated sleep-wake abnormalities are poorly understood, and they are ineffectively treated by conventional PD therapies. To help fill this gap in knowledge, a new progressive model of PD – the MCI-Park mouse – was studied. Near the transition to the parkinsonian state, these mice exhibited significantly altered sleep-wake regulation, including increased wakefulness, decreased non-rapid eye movement (NREM) sleep, increased sleep fragmentation, reduced rapid eye movement (REM) sleep, and altered EEG activity patterns. These sleep-wake abnormalities mirror those identified in PD patients. Thus, this model may help elucidate the circuit mechanisms underlying sleep disruption in PD and identify targets for novel therapeutic approaches.
RPPA survey of cancer hotspot panel proteins and cell markers in matched tumor-normal human breast and kidney samples reveals a weak correlation between proteins expression and public transcriptome repositories
Authors: Paal Krisztina , Konrad Csaba , Karnok Noemi , Bui David , Chinopoulos Christos 
Published: November 2023

ABSTRACTDespite the tremendous global effort in discovering and cataloguing somatic mutations in cancer-related genes and the impact they exert on human cancers, the effects of these mutations on the levels of protein expression are inadequately addressed. Here, we semi-quantitated the expression of 48 (out of 50) proteins represented by the most widely used cancer hotspot panel, the Ion AmpliSeq™ Cancer Hotspot Panel v2, and 14 cell markers commonly used as ‘house-keeping’ proteins, using reverse phase protein array (RPPA) technology in 586 human breast- and 192 kidney matched tumor-normal samples. We further correlated our RPPA data with gene chip data from the Gene Expression Omnibus repository fetched through the TNMplot portal. Nearly half of proteins expression exhibited a negative correlation from their gene expression, while several of the remaining were only moderately correlated. Our data complement the vast information obtained elsewhere by transcriptomic analysis of the respective genes and gene products, potentially assisting in harmonizing proteomic with NGS outputs.
Structural and biochemical requirements for secretory component interactions with dimeric Immunoglobulin A
Authors: Kumar Bharathkar Sonya , Stadtmueller Beth M. 
Published: November 2023

ABSTRACTSecretory (S) Immunoglobulin (Ig) A is the predominant mucosal antibody that protects host epithelial barriers and promotes microbial homeostasis. SIgA production occurs when plasma cells assemble two copies of monomeric IgA and one joining-chain (JC) to form dimeric (d) IgA, which is bound by the polymeric Ig receptor (pIgR) on the basolateral surface of epithelial cells and transcytosed to the apical surface. There, pIgR is proteolytically cleaved, releasing SIgA, a complex of the dIgA and the pIgR ectodomain, called secretory component (SC). The pIgR’s five Ig-like domains (D1-D5) undergo a conformational change upon binding dIgA, ultimately contacting four IgA heavy chains and the JC in SIgA. Here we report structure-based mutational analysis combined with surface plasmon resonance binding assays that identify key residues in mouse SC D1 and D3 that mediate SC binding to dIgA. Residues in D1 CDR3 are likely to initiate binding whereas residues that stabilize the D1-D3 interface are likely to promote the conformation change and stabilize the final SIgA structure. Additionally, we find that the JC’s three C-terminal residues play a limited role in dIgA assembly but a significant role in pIgR/SC binding to dIgA. Together results inform new models for the intricate mechanisms underlying IgA transport across epithelia and functions in the mucosa.KEY POINTSThe secretory component D1 CDR3 loop plays an important role in binding to dIgA.The formation of SC D1-D3 interface stabilizes SIgA.JC C-terminal residues influence dIgA assembly and mediate pIgR binding to dIgA.
PCDH15 Dual-AAV Gene Therapy for Deafness and Blindness in Usher Syndrome Type 1F
Authors: Ivanchenko Maryna V. , Hathaway Daniel M. , Mulhall Eric M. , Booth Kevin T. , Wang Mantian , Peters Cole W. , Klein Alex J. , Chen Xinlan , Li Yaqiao , György Bence , Corey David P. 
Published: November 2023

AbstractUsher syndrome type 1F (USH1F), resulting from mutations in the protocadherin-15 (PCDH15) gene, is characterized by congenital lack of hearing and balance, and progressive blindness in the form of retinitis pigmentosa. In this study, we explore a novel approach for USH1F gene therapy, exceeding the single AAV packaging limit by employing a dual adeno-associated virus (AAV) strategy to deliver the full-length PCDH15 coding sequence. We demonstrate the efficacy of this strategy in mouse USH1F models, effectively restoring hearing and balance in these mice. Importantly, our approach also proves successful in expressing PCDH15 in clinically relevant retinal models, including human retinal organoids and non-human primate retina, showing efficient targeting of photoreceptors and proper protein expression in the calyceal processes. This research represents a major step toward advancing gene therapy for USH1F and the multiple challenges of hearing, balance, and vision impairment.
Proximity Labeling Expansion Microscopy (PL-ExM) resolves structure of the interactome
Authors: Park Sohyeon , Wang Xiaorong , Li Xiangpeng , Huang Xiao , Fong Katie C. , Yu Clinton , Tran Arthur A. , Scipioni Lorenzo , Dai Zhipeng , Huang Lan , Shi Xiaoyu 
Published: November 2023

AbstractElucidating the spatial relationships within the protein interactome is pivotal to understanding the organization and regulation of protein-protein interactions. However, capturing the 3D architecture of the interactome presents a dual challenge: precise interactome labeling and super-resolution imaging. To bridge this gap, we present the Proximity Labeling Expansion Microscopy (PL-ExM). This innovation combines proximity labeling (PL) to spatially biotinylate interacting proteins with expansion microscopy (ExM) to increase imaging resolution by physically enlarging cells. PL-ExM unveils intricate details of the 3D interactome’s spatial layout in cells using standard microscopes, including confocal and Airyscan. Multiplexing PL-ExM imaging was achieved by pairing the PL with immunofluorescence staining. These multicolor images directly visualize how interactome structures position specific proteins in the protein-protein interaction network. Furthermore, PL-ExM stands out as an assessment method to gauge the labeling radius and efficiency of different PL techniques. The accuracy of PL-ExM is validated by our proteomic results from PL mass spectrometry. Thus, PL-ExM is an accessible solution for 3D mapping of the interactome structure and an accurate tool to access PL quality.