bluuebunny/crossref_metadata_2025_split huggingface dataset:
A human brain vascular atlas reveals diverse cell mediators of Alzheimer’s disease risk
Authors: Yang Andrew C. , Vest Ryan T. , Kern Fabian , Lee Davis P. , Maat Christina A. , Losada Patricia M. , Chen Michelle B. , Agam Maayan , Schaum Nicholas , Khoury Nathalie , Calcuttawala Kruti , Pálovics Róbert , Shin Andrew , Wang Elizabeth Y. , Luo Jian , Gate David , Siegenthaler Julie A. , McNerney M. Windy , Keller Andreas , Wyss-Coray Tony 
Published: April 2021

AbstractThe human brain vasculature is of vast medical importance: its dysfunction causes disability and death, and the specialized structure it forms—the blood-brain barrier—impedes treatment of nearly all brain disorders. Yet, no molecular atlas of the human brain vasculature exists. Here, we develop Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to profile the major human brain vascular and perivascular cell types through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 17 control and Alzheimer’s disease (AD) patients. We identify brain region-enriched pathways and genes divergent between humans and mice, including those involved in disease. We describe the principles of human arteriovenous organization, recapitulating a gradual endothelial and punctuated mural cell continuum; but discover that many zonation and cell-type markers differ between species. We discover two subtypes of human pericytes, marked by solute transport and extracellular matrix (ECM) organization; and define perivascular versus meningeal fibroblast specialization. In AD, we observe a selective vulnerability of ECM-maintaining pericytes and gene expression patterns implicating dysregulated blood flow. With an expanded survey of brain cell types, we find that 30 of the top 45 AD GWAS genes are expressed in the human brain vasculature, confirmedin situ. Vascular GWAS genes map to endothelial protein transport, adaptive immune, and ECM pathways. Many are microglia-specific in mice, suggesting an evolutionary transfer of AD risk to human vascular cells. Our work unravels the molecular basis of the human brain vasculature, informing our understanding of overall brain health, disease, and therapy.
Woody species do not differ in dormancy progression: differences in time to budbreak due to forcing and cold hardiness
Authors: Kovaleski Al 
Published: April 2021

AbstractBudbreak is one of the most observed and studied phenological phases in perennial plants. Two dimensions of exposure to temperature are generally used to model budbreak: accumulation of time spent at low temperatures (chilling); and accumulation of heat units (forcing). These two effects have a well-established negative correlation: the more chilling, the less forcing required for budbreak. Furthermore, temperate plant species are assumed to vary in amount of chilling required to complete endodormancy and begin the transition to breaking bud. Still, prediction of budbreak remains a challenge. The present work demonstrates across a wide range of species how bud cold hardiness must be accounted for to study dormancy and accurately predict time to budbreak. Cold hardiness defines the path length to budbreak, meaning the difference between the cold hardiness buds attain during the winter, and the cold hardiness at which deacclimated buds are predicted to open. This distance varies among species and throughout winter within a species. Increases in rate of cold hardiness loss (deacclimation) measured throughout winter show that chilling controls deacclimation potential – the proportion of the maximum rate response attained at high chill accumulation – which has a sigmoid relationship to chilling accumulation. For forcing, rates of deacclimation increase non-linearly in response to temperature. Comparisons of deacclimation potential show a dormancy progresses similarly for all species. This observation suggests that comparisons of physiologic and genetic control of dormancy requires an understanding of cold hardiness dynamics and the necessity for an update of the framework for studying dormancy and its effects on spring phenology.
The maize hexokinase geneZmHXK7confers salt resistance in transgenicArabidopsisplants
Authors: Liu Qianqian , Tian Zengyuan , Guo Yuqi 
Published: April 2021

AbstractThe hexokinase (HXK) gene family, whose members play vital roles in sugar induction signals and glycolysis in organisms, is widely found in plants. Although some hexokinase genes have been studied in maize, a systematic report of the gene family and its role in plant resistance is lacking. In this study, 10 hexokinase genes were systematically identified in maize based on the maize genome-wide database. Phylogenetic analysis divides the maize HXK protein family into four clusters. Prediction of cis-regulatory elements showed that a number of elements responding to abiotic stress exist in the promoter of hexokinase genes. The expression profile of these genes, originated from B73, showed that different members of hexokinase genes are highly expressed in roots and leaves of maize under salt or drought stress, which is similar to that of Mo17.The coding sequence ofZmHXK7gene, isolated from maize B73, was constructed into plant expression vector pMDC45 and then transformed intoathxk3(Salk_022188C). By hyg resistance detection, PCR analysis, and western blot confirmation, the homozygous progenies of transgenic Arabidopsis lines were identified. Subcellular localization analysis showed that theZmHXK7gene was located in cytosol. Seedling growth and salt stress inhibition in complementary mutant plants ofZmHXK7gene were significantly improved, and enhanced salt tolerance was displayed. Our study provides insights into the evolution and expression patterns of the hexokinase gene and show that maize ZmHXK7 proteins play an important role in resisting salt stress, which will be useful in plant breeding for abiotic stress resistance.
A general theory for temperature-dependence in biology
Authors: Arroyo José Ignacio , Díez Beatriz , Kempes Christopher P. , West Geoffrey B. , Marquet Pablo A. 
Published: April 2021

AbstractAt present, there is no simple, complete, and first principles-based model for quantitatively describing the full range of observed biological temperature responses. Here, we derive a theory exhibiting these features based on the Eyring-Evans-Polanyi theory governing chemical reaction rates, and which is applicable across all scales from the micro to the macro. Assuming only that the conformational entropy of molecules changes with temperature, we derive a theory for the temperature dependence which takes the form of an exponential function modified by a power-law. Our framework leads to six deductions applicable to any biological trait that depends on temperature, and elucidates novel aspects of universal temperature responses across the tree of life, from quantum to classical scales. All predictions are well supported by data for a wide variety of biological rates and steady states, from molecular to ecological scales and across multiple taxonomic groups. In addition, we provide novel explanations of several empirical relationships including optimal values in temperature response curves.One-Sentence SummaryWe derive a simple and universal formulae to characterize temperature responses of biological processes across the tree of life.
Spatial transcriptome sequencing revealed spatial trajectory in the Non-Small Cell Lung Carcinoma
Authors: Zhang Li , Mao Shengqiang , Yao Menglin , Chao Ningning , Yang Ying , Ni Yinyun , Song Tingting , Liu Zhiqiang , Yang Yongfeng , Li Weimin 
Published: April 2021

ABSTRACTDeepening understanding in the heterogeneity of tumors is critical for clinical treatment. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal lung cancer using the spatial transcriptomics (ST) technology. We identified gene expression gradients in stroma adjacent to tumor regions that allow for re-understanding of the tumor micro-environment. The establishment of these profiles was the first step towards an unbiased view of lung cancer and can serve as a dictionary for future studies. Tumor subclones were detected by ST technology in our research, while we contrast the EMT ability among in subclones which inferred the possible trajectory of tumor metastasis and invasion, which was confirmed by constructing the pseudo-time model of spatial transition within subclones. Together, these results uncovered lung cancer spatial heterogeneity, highlight potential tumor micro-environment differences and spatial evolution trajectory, and served as a resource for further investigation of tumor microenvironment.
Improving the understanding of cytoneme-mediated morphogen gradients byin silicomodeling
Authors: Aguirre-Tamaral Adrián , Guerrero Isabel 
Published: April 2021

AbstractMorphogen gradients are crucial for the development of organisms. The biochemical properties of many morphogens prevent their extracellular free diffusion, indicating the need of an active mechanism for transport. The involvement of filopodial structures (cytonemes) has been proposed for morphogen signaling. Here, we describe anin silicomodel based on the main general features of cytoneme-meditated gradient formation and its implementation into Cytomorph, an open software tool. We have tested the spatial and temporal adaptability of our model quantifying Hedgehog (Hh) gradient formation in twoDrosophilatissues. Cytomorph is able to reproduce the gradient and explain the different scaling between the two epithelia. After experimental validation, we studied the predicted impact of a range of features such as length, size, density, dynamics and contact behavior of cytonemes on Hh morphogen distribution. Our results illustrate Cytomorph as an adaptive tool to test different morphogens gradients and to generate hypotheses that are difficult to study experimentally.
Affordable and Effective Optokinetic Response Methods to Assess Visual Acuity and Contrast Sensitivity in Larval to Juvenile Zebrafish
Authors: Sánchez Alicia Gómez , Álvarez Yolanda , Colligris Basilio , Kennedy Breandán N. 
Published: April 2021

AbstractBackgroundThe optokinetic response (OKR) is an effective behavioural assay to investigate functional vision in zebrafish. The rapid and widespread use of gene editing, drug screening and environmental modulation technologies have resulted in a broader need for visual neuroscience researchers to access affordable and more sensitive OKR, contrast sensitivity (CS) and visual acuity (VA) assays. Here, we demonstrate how 2D- and 3D-printed, striped patterns or drums coupled with a motorised base and microscope provide a simple, cost-effective but efficient means to assay OKR, CS and VA in larval-juvenile zebrafish.ResultsIn wild-type, 5 days post-fertilisation (dpf) zebrafish, the 2D or 3D drums printed with the standard OKR stimulus of 0.02 cycles per degree (cpd), 100% black-white contrast evoked equivalent responses of 24.2 or 21.8 saccades per minute, respectively. Furthermore, although the OKR number was significantly reduced compared to the 0.02 cpd drum (p<0.0001), the 2D and 3D drums evoked respectively equivalent responses with the 0.06 and 0.2 cpd drums. Notably, standard OKR responses varied with time of day; peak responses of 29.8 saccades per minute occurred in the early afternoon with significantly reduced responses occurring in the early morning or late afternoon, (18.5 and 18.4 saccades per minute, respectively). A customised series of 2D printed drums enabled analysis of visual acuity and contrast sensitivity in 5-21 dpf zebrafish. The saccadic frequency in visual acuity and contrast sensitivity assays, was inversely proportional to age, spatial frequency and contrast of the stimulus.ConclusionsOKR, VA and CS of zebrafish larvae can be efficiently measured using 2D- or 3D-printed striped drums. For data consistency the luminance of the OKR light source, the time of day when the analysis performed, and the order of presentation of VA and CS drums must be considered. These simple methods allow effective and more sensitive analysis of functional vision in zebrafish.
RIF1 acts in DNA repair through phosphopeptide recognition of 53BP1
Authors: Setiaputra Dheva , Escribano-Diaz Cristina , Reinert Julia K. , Sadana Pooja , Zong Dali , Callen Elsa , Seebacher Jan , Nussenzweig Andre , Thomä Nicolas H. , Durocher Daniel 
Published: April 2021

SummaryThe chromatin-binding protein 53BP1 promotes DNA repair by orchestrating the recruitment of downstream effectors including PTIP, RIF1 and shieldin to DNA double-strand break sites. While how PTIP recognizes 53BP1 is known, the molecular details of RIF1 recruitment to DNA damage sites remains undefined. Here, we report that RIF1 is a phosphopeptide-binding protein that directly interacts with three phosphorylated 53BP1 epitopes. The RIF1-binding sites on 53BP1 share an essential LxL motif followed by two closely apposed phosphorylated residues. Simultaneous mutation of these sites on 53BP1 abrogates RIF1 accumulation into ionizing radiation-induced foci, but surprisingly only fully compromises 53BP1-dependent DNA repair when an alternative mode of shieldin recruitment to DNA damage sites is also disabled. Intriguingly, this alternative mode of recruitment still depends on RIF1 but does not require its interaction with 53BP1. RIF1 therefore employs phosphopeptide recognition to promote DNA repair but also modifies shieldin action independently of 53BP1 binding.
Refining the genomic location of SNP variation affecting Atlantic salmon maturation timing at a key large-effect locus
Authors: Sinclair-Waters Marion , Piavchenko Nikolai , Ruokolainen Annukka , Aykanat Tutku , Erkinaro Jaakko , Primmer Craig R. 
Published: April 2021

ABSTRACTEfforts to understand the genetic underpinnings of phenotypic variation are becoming more and more frequent in molecular ecology. Such efforts often lead to the identification of candidate regions showing signals of association and/or selection. These regions may contain multiple genes and therefore validation of which genes are actually responsible for the signal is required. In Atlantic salmon (Salmo salar), a large-effect locus for maturation timing, an ecologically important trait, occurs in a genomic region including two genes,vgll3andakap11, but data for clearly determining which of the genes (or both) contribute to the association have been lacking. Here, we take advantage of natural recombination events detected between the two candidate genes in a salmon broodstock to reduce linkage disequilibrium at the locus, and thus enabling delineation of the influence of variation at these two genes on maturation timing. By rearing 5895 males to maturation age, of which 81% had recombinantvgll3/akap11allelic combinations, we found thatvgll3SNP variation was strongly associated with maturation timing, whereas there was little or no association betweenakap11SNP variation and maturation timing. These findings provide strong evidence supportingvgll3as the primary candidate gene in the chromosome 25 locus for influencing maturation timing. This will help guide future research for understanding the genetic processes controlling maturation timing. This also exemplifies the utility of natural recombinants to more precisely map causal variation underlying ecologically important phenotypic diversity.
The TPLATE complex mediates membrane bending during plant clathrin-mediated endocytosis
Authors: Johnson Alexander , Dahhan Dana A , Gnyliukh Nataliia , Kaufmann Walter A , Zheden Vanessa , Costanzo Tommaso , Mahou Pierre , Hrtyan Mónika , Wang Jie , Aguilera-Servin Juan , van Damme Daniël , Beaurepaire Emmanuel , Loose Martin , Bednarek Sebastian Y , Friml Jiri 
Published: April 2021

AbstractClathrin-mediated endocytosis in plants is an essential process but the underlying mechanisms are poorly understood, not least because of the extreme intracellular turgor pressure acting against the formation of endocytic vesicles. In contrast to other models, plant endocytosis is independent of actin, indicating a mechanistically distinct solution. Here, by using biochemical and advanced microscopy approaches, we show that the plant-specific TPLATE complex acts outside of endocytic vesicles as a mediator of membrane bending. Cells with disrupted TPLATE fail to generate spherical vesicles, andin vitrobiophysical assays identified protein domains with membrane bending capability. These results redefine the role of the TPLATE complex as a key component of the evolutionarily distinct mechanism mediating membrane bending against high turgor pressure to drive endocytosis in plant cells.One Sentence SummaryWhile plant CME is actin independent, we identify that the evolutionarily ancient octameric TPLATE complex mediates membrane bending against high turgor pressure in plant clathrin-mediated endocytosis.
Bacteroidalesspecies are a reservoir of phase-variable antibiotic resistance genes in the human gut microbiome
Authors: Yan Wei , Hall A. Brantley , Jiang Xiangfang 
Published: April 2021

ABSTRACTPhase-variable antibiotic resistance genes (ARGs) can mitigate the fitness cost of maintaining ARGs in the absence of antibiotics and could potentially prolong the persistence of ARGs in bacterial populations. However, the origin, prevalence, and distribution of phase-variable ARGs remains poorly understood. Here, we sought to assess the threat posed by phase-variable ARGs by systematically searching for phase-variable ARGs in the human gut microbiome and examining their origin, prevalence, and distribution. Through metagenomic assembly of 2227 human gut metagenomes and genomic analysis of the Unified Human Gastrointestinal Genome (UHGG) collection, we identified phase-variable ARGs and categorized them into three classes based on the invertase regulating phase variation. In the human gut microbiome, phase-variable ARGs are commonly and exclusively distributed inBacteroidalesspecies. Through genomic analysis, we observed that phase-variable ARGs have convergently originated from ARG insertions into phase-variable capsule polysaccharide biosynthesis (CPS) loci at least three times. Moreover, all identified phase-variable ARGs are located within integrative conjugative elements (ICEs). Therefore, horizontal transfer via ICEs could explain the wide taxonomic distribution of phase-variable ARGs. Overall, these findings reveal that phase-variable CPS loci inBacteroidalesspecies are an important hotspot for the emergence of clinically-relevant phase-variable ARGs.
Toward comprehensive functional analysis of gene lists weighted by gene essentiality scores
Authors: Fan Rui , Cui Qinghua 
Published: April 2021

ABSTRACTGene functional enrichment analysis represents one of the most popular bioinformatics methods for annotating the pathways and function categories of a given gene list. Current algorithms for enrichment computation such as Fisher’s exact test and hypergeometric test totally depend on the category count numbers of the gene list and one gene set. In this case, whatever the genes are, they were treated equally. However, actually genes show different scores in their essentiality in a gene list and in a gene set. It is thus hypothesized that the essentiality scores could be important and should be considered in gene functional analysis. For this purpose, here we proposed WEAT (https://www.cuilab.cn/weat/), a weighted gene set enrichment algorithm and online tool by weighting genes using essentiality scores. We confirmed the usefulness of WEAT using two case studies, the functional analysis of one aging-related gene list and one gene list involved in Lung Squamous Cell Carcinoma (LUSC). Finally, we believe that the WEAT method and tool could provide more possibilities for further exploring the functions of given gene lists.
Autophagy modulation enhances enzyme replacement therapy response in Fabry disease
Authors: Abily-Donval Lénaig , Barbey Frédéric , Torre Stéphanie , Lesueur Céline , Chevrier Marc , Pereira Tony , Pilon Carine , Marret Stéphane , Tebani Abdellah , Bekri Soumeya 
Published: April 2021

AbstractSummaryFabry disease is a lysosomal disease due to α-galactosidase A (a-GalA) deficiency. Since 2001, Enzyme replacement therapy (ERT) has been used as specific treatment of Fabry disease, with variable effects depending on patient gender and affected organs. In Fabry cells, the endososomal/lysosomal system is highly altered. Consequently, the exogenous enzyme may be mistargeted and trapped into intracellular vesicles instead of reaching the lysosomes. In this study, we aimed to investigate the mechanisms underlying the processing of the exogenous enzyme. We used Fabry cells (cultured fibroblasts and podocyte cell line) to study the enzyme internalization and its effects on the catabolism of the main a-Gal A substrate, globotriaosylceramide (Gb3), upon autophagy inhibition. The exogenous enzyme reaches the early endosome in a similar timeframe in Fabry and control cells, while its targeting to lysosomes is delayed in Fabry cells. Gb3 concentration is lowered upon therapeutic enzyme addition or wortmannin treatment with a synergetic effect. These findings illustrate the positive impact of autophagy inhibition on enzyme trafficking and processing, allowing the increase of functional enzyme rate within the lysosome. Given the high cost of ERT, a better understanding of the cellular fate of the exogenous enzyme may lead to improve its targeting to the lysosome.
Interferon-γ-producing CD4+T cells drive monocyte activation in the bone marrow during experimentalLeishmania donovaniinfection
Authors: Romano Audrey , Brown Najmeeyah , Ashwin Helen , Doehl Johannes S.P. , Hamp Jonathan , Osman Mohamed , Dey Nidhi , Rani Gulab Fatima , Ferreira Tiago Rodrigues , Kaye Paul M. 
Published: April 2021

ABSTRACTLy6Chiinflammatory monocytes develop in the bone marrow and migrate to the site of infection during inflammation. Upon recruitment, Ly6Chimonocytes can differentiate into dendritic cells or macrophages. According to the tissue environment they can also acquire different functions. Several studies have described pre-activation of Ly6Chimonocytes in the bone marrow during parasitic infection, but whether this process occurs during experimental visceral leishmaniasis and, if so, the mechanisms contributing to their activation are yet to be established. In wild type C57BL/6 (B6) mice infected withLeishmania donovani, the number of bone marrow Ly6Chimonocytes increased over time. Ly6Chimonocytes displayed a highly activated phenotype from 28 days to 5 months post infection (p.i), with >90% expressing MHCII and >20% expressing iNOS. In comparison, in B6.Rag2-/-mice <10% of bone marrow monocytes were MHCII+at day 28 p.i., an activation deficiency that was reversed by adoptive transfer of CD4+T cells. Depletion of CD4+T cells in B6 mice and the use of mixed bone marrow chimeras further indicated that monocyte activation was driven by IFN-γ produced by CD4+T cells. In B6.Il10-/-mice,L. donovaniinfection induced a faster but transient activation of bone marrow monocytes, which correlated with the magnitude of CD4+T cell production of IFN-γ and resolution of the infection. Under all of the above conditions, monocyte activation was associated with greater control of parasite load in the bone marrow. Through reinfection studies in B6.Il10-/-mice and drug (AmBisome) treatment of B6 mice, we also show the dependence of monocyte activation on parasite load. In summary, these data demonstrate that duringL. donovaniinfection, Ly6Chimonocytes are primed in the bone marrow in a process driven by CD4+T cells and whereby IFN-γ promotes and IL-10 limits monocyte activation and that the presence of parasites/parasite antigen plays a crucial role in maintaining bone marrow monocyte activation.