bluuebunny/crossref_metadata_2025_split huggingface dataset:
How Images of Food Become Cravingly Salient in Obesity
Authors: Devoto F. , Ferrulli A. , Banfi G. , Luzi L. , Zapparoli L. , Paulesu E. 
Published: March 2023

AbstractBackgroundObesity is characterized by neurofunctional alterations within the mesocorticolimbic reward system, a brain network that originates from the midbrain ventral tegmental area (VTA). Here we tested the hypothesis that this system might be misconfigured in obesity, reflecting a bias for food-related visual stimuli and a predisposition for craving.MethodsA group of normal weight and a group of obese patients underwent a resting-state fMRI scan and the assessment of impulsivity, food craving, appetite, and implicit bias for food and non-food pictures. The VTA was used as a seed to map, for each participant, the strength of its functional connections with the rest of the brain. We then computed the difference of such maps between the groups and performed brain-behavior correlations.ResultsObese patients showed hyper-connectivity of the VTA with part of ventral occipitotemporal cortices (vOTC) recently found to be specialized for food images; there was also a hypo-connectivity with the left inferior frontal gyrus (IFG), devoted to cognitive control. The VTA-left vOTC connectivity was positively associated with food craving and bias for high-calories food; a reversed such correlation was seen for the IFG.InterpretationThese findings reveal that, in obesity, food-related visual stimuli become cravingly salient through an imbalanced connectivity of the reward system with sensory-specific regions and the frontal cortex involved in cognitive control.
Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme
Authors: Wu Cheng-Guo , Balakrishnan Vijaya K. , Parihar Pankaj S. , Konovolov Kirill , Chen Yu-Chia , Merrill Ronald A , Wei Hui , Carragher Bridget , Sundaresan Ramya , Cui Qiang , Wadzinski Brian E. , Swingle Mark R. , Musiyenko Alla , Honkanen Richard , Chung Wendy K. , Suzuki Aussie , Strack Stefan , Huang Xuhui , Xing Yongna 
Published: March 2023

AbstractAn increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrentde novomissense mutations have been discovered in B56δ (encoded byPPP2R5D), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56δ holoenzyme possesses closed latent and open active forms. In the closed form, the long, disordered arms of B56δ termini fold against each other and the holoenzyme core, establishing dual autoinhibition of the phosphatase active site and the substrate-binding protein groove. The resulting interface spans over 190 Å and harbors unfavorable contacts, activation phosphorylation sites, and nearly all residues with ID-associated mutations. Our studies suggest that this dynamic interface is close to an allosteric network responsive to activation phosphorylation and altered globally by mutations. Furthermore, we found that ID mutations perturb the activation phosphorylation rates, and the severe variants significantly increase the mitotic duration and error rates compared to the wild variant.
Epigenetic then genetic variations underpin rapid adaptation of oyster populations (Crassostrea gigas) to Pacific Oyster Mortality Syndrome (POMS)
Authors: Gawra Janan , Valdivieso Alejandro , Roux Fabrice , Laporte Martin , de Lorgeril Julien , Gueguen Yannick , Saccas Mathilde , Escoubas Jean-Michel , Montagnani Caroline , Destoumieux-Garzón Delphine , Lagarde Franck , Leroy Marc A. , Haffner Philippe , Petton Bruno , Cosseau Céline , Morga Benjamin , Dégremont Lionel , Mitta Guillaume , Grunau Christoph , Vidal-Dupiol Jeremie 
Published: March 2023

AbstractDisease emergence is accelerating in response to human activity-induced global changes. Understanding the mechanisms by which host populations can rapidly adapt to this threat will be crucial for developing future management practices. Pacific Oyster Mortality Syndrome (POMS) imposes a substantial and recurrent selective pressure on oyster populations (Crassostrea gigas). Rapid adaptation to this disease may arise through both genetic and epigenetic mechanisms. In this study, we used a combination of whole exome capture of bisulfite-converted DNA, next-generation sequencing, and (epi)genome-wide association mapping, to show that natural oyster populations differentially exposed to POMS displayed signatures of selection both in their genome (single nucleotide polymorphisms) and epigenome (CG-context DNA methylation). Consistent with higher resistance to POMS, the genes targeted by genetic and epigenetic variations were mainly related to host immunity. By combining correlation analyses, DNA methylation quantitative trait loci, and variance partitioning, we revealed that a third of the observed phenotypic variation was explained by interactions between the genetic sequence and epigenetic information, ∼14% by the genetic sequence, and up to 25% by the epigenome alone. Thus, as well as genetic adaptation, epigenetic mechanisms governing immune responses contribute significantly to the rapid adaptation of hosts to emerging infectious diseases.
Genetic analysis ofrab7mutants in zebrafish
Authors: Heutschi Daniel , Schmelzer Etienne , Aydogan Vahap , Schmidt Alexander , Belting Heinz-Georg , Spang Anne , Affolter Markus , Kotini Maria P. 
Published: March 2023

AbstractVascular network formation requires the fusion of newly formed blood vessels and the emergence of a patent lumen between the newly established connections so that blood flow can start. Lumen formation has been shown to depend on the late endosomal/lysosomal pathway in various organs of animal tubular systems. Here, we identified a late endosomal/lysosomal vesicular fraction (Rab7/Lamp2) in early zebrafish angiogenic sprouts, which appears to contribute to apical membrane growth during lumen formation. To study the effect of the late endocytic pathway on vascular development, we generated mutant alleles for all threerab7genes in zebrafish (rab7a, rab7ba, rab7bb). Allrab7genes are expressed in wild-type zebrafish and we did not detect any compensatory effects by the otherrab7isoforms in single knockout mutants, which were all viable. Only the triple mutant was lethal suggesting some functional redundancy. However, the differentrab7isoforms fulfil also at least partially independent functions because eggs laid from mothers lacking tworab7(rab7a and/or rab7bb). showed reduced survival and contained enlarged yolk granules, suggesting maternal contribution of these tworab7. Finally, we observed minor effects on lumen formation in embryos which still express one copy ofrab7. Our results support the notion that the late endocytic/lysosomal compartment contributes to lumen expansion.
Topography modulates climate sensitivity of multidecadal trends of holm oak decline
Authors: López-Ballesteros Ana , Rodríguez-Caballero Emilio , Moreno Gerardo , Escribano Paula , Hereş Ana María , Curiel-Yuste Jorge 
Published: March 2023

AbstractForest decline events have increased worldwide over the last decades, being holm oak one of the tree species with the most worrying trends across Europe. Previous research identified drought and soil pathogens as the main causes behind holm oak decline. However, despite tree health loss is a multifactorial phenomenon where abiotic and biotic factors interact in time and space, there are some abiotic factors whose influence has been commonly overlooked. Here, we evaluate how land use (forests versus savannas), topography, and climate extremes jointly relate to spatiotemporal patterns of holm oak defoliation over almost three decades (1987-2014) in Spain, where holm oak represents the 25% of the national forested area. We found an increasing defoliation trend in 119 of the total 134 holm oak plots evaluated, being this increase rate significantly higher in forests compared to savannas. Moreover, we have detected that the interaction between topography and summer drought can explain trends of holm oak decline across the Mediterranean region. While a higher occurrence of dry summers increases defoliation trends in complex terrains where forests dominate, an inverse relationship was found at flatter terrains where savannas are located. Our results contribute to growing evidence of the influence of local topography, tightly linked to potential soil water availability, on forest functioning, as it can shape forest vulnerability against climate extremes. The present work could assist the identification of potential tree decline hotspots over the Mediterranean region. Moreover, our findings suggest that forest adaptive management will be key to guarantee the health and future stability of Mediterranean oak ecosystems, especially in the topographically more complex areas where tree vulnerability to climate extremes may be greater.
Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy
Authors: McFaline-Figueroa José L. , Srivatsan Sanjay , Hill Andrew J. , Gasperini Molly , Jackson Dana L. , Saunders Lauren , Domcke Silvia , Regalado Samuel G. , Lazarchuck Paul , Alvarez Sarai , Monnat Raymond J. , Shendure Jay , Trapnell Cole 
Published: March 2023

SummaryChemical genetic screens are a powerful tool for exploring how cancer cells’ response to drugs is shaped by their mutations, yet they lack a molecular view of the contribution of individual genes to the response to exposure. Here, we present sci-Plex-Gene-by-Environment (sci-Plex-GxE), a platform for combined single-cell genetic and chemical screening at scale. We highlight the advantages of large-scale, unbiased screening by defining the contribution of each of 522 human kinases to the response of glioblastoma to different drugs designed to abrogate signaling from the receptor tyrosine kinase pathway. In total, we probed 14,121 gene-by-environment combinations across 1,052,205 single-cell transcriptomes. We identify an expression signature characteristic of compensatory adaptive signaling regulated in a MEK/MAPK-dependent manner. Further analyses aimed at preventing adaptation revealed promising combination therapies, including dual MEK and CDC7/CDK9 or NF-kB inhibitors, as potent means of preventing transcriptional adaptation of glioblastoma to targeted therapy.
vcfdist: Accurately benchmarking phased small variant calls in human genomes
Authors: Dunn Tim , Narayanasamy Satish 
Published: March 2023

AbstractAccurately benchmarking small variant calling accuracy is critical for the continued improvement of human whole genome sequencing. In this work, we show that current variant calling evaluations are biased towards certain variant representations and may misrepresent the relative performance of different variant calling pipelines. We propose solutions, first exploring the affine gap parameter design space for complex variant representation and suggesting a standard. Next, we present our tool “vcfdist” and demonstrate the importance of enforcing local phasing for evaluation accuracy. We then introduce the notion of partial credit for mostly-correct calls and present an algorithm for clustering dependent variants. Lastly, we motivate using alignment distance metrics to supplement precision-recall curves for understanding variant calling performance. We evaluate the performance of 64 phased “Truth Challenge V2” submissions and show that vcfdist improves measured (SNP, INDEL) performance consistency across variant representations fromR2= (0.14542, 0.97243)for baseline vcfeval to(0.99999, 0.99996)for vcfdist.
Methodological Considerations When Using Polygenic Scores to Explore Parent-Offspring Genetic Nurturing Effects
Authors: Chuong M. , Adams M.J. , Kwong A.S.F. , Haley C.S. , Amador C. , McIntosh A.M. 
Published: March 2023

ABSTRACTBackgroundResearch has begun to explore the effects of parental genetic nurturing on offspring outcomes using polygenic scores (PGSs). However, there are concerns regarding potential biases due to confounding when mediating parental phenotypes are included.MethodsDepression, educational attainment and height PGSs were generated for 2680 biological parent-offspring trios using genome-wide association study (GWAS) meta-analysis summary statistics in a large population study: Generation Scotland. Regression and pathway models were estimated incorporating PGSs for both parents and offspring to explore direct (offspring PGS) and genetic nurturing (parental PGS) effects on psychological distress, educational attainment and height. Genetic nurturing via parental phenotypes were incorporated into the models. To explore sources of bias we conducted simulation analyses of 10,000 trios using combinations of PGS predictive accuracy and accounted variance.ResultsModels incorporating both offspring and parental PGSs suggested positive parental genetic nurturing effects on offspring educational attainment, but not psychological distress or height. In contrast, models additionally incorporating parental phenotypic information suggested positive parent phenotype mediated genetic nurturing effects were at play for all phenotypes explored as well as negative residual genetic nurturing effects for height. 10,000 parent-offspring trio effects (without genetic nurturing effects) were simulated. Simulations demonstrated that models incorporating parent and offspring PGSs resulted in genetic nurturing effects that were unbiased. However, adding parental phenotypes as mediating variables results in biased positive estimates of parent phenotype mediated genetic nurturing effects and negative estimates of residual genetic nurturing effects. Biased effects increased in magnitude as PGS accuracy and accounted variance decreased. These biases were only eliminated when PGSs were simulated to capture the entirety of trait genetic variance.ConclusionResults suggest that in the absence of PGSs that capture all genetic variance, parental phenotypes act as colliders in the same way as heritable environments. Relatively simple models combining parental and offspring PGSs can be used to detect genetic nurturing effects in complex traits. However, our findings suggest alternative methods should be utilised when aiming to identify mediating phenotypes and potentially modifiable parental nurturing effects.
Phylogenetic relatedness of plant species co-occurring with an invasive alien plant species (Anthemis cotulaL.) varies with elevation
Authors: Afshana  , Pinto-Ledezma Jesús N. , Reshi Zafar A. 
Published: March 2023

AbstractDarwin’s naturalization conundrum, which posits that the alien species either succeed in the introduced region because being phylogenetically related to the native species hence being pre-adapted, or are phylogenetically dissimilar to native species and thus occupy unfilled niches, has received a lot of attention but the results have been contradictory. Instead of the usual phylogenetic comparison between native and introduced species to address this conundrum, we followed a novel approach of studying the phylogenetic relationship of a highly widespread and invasive species, Anthemis cotula L. (focal species) separately with the native species and all its co-occurring species (including native and non-native species) along an elevation gradient. The abundance of A. cotula declined continuously with an increase in elevation and species richness. The phylogenetic relationship between the focal species and all the co-occurring species using abundance-weighted mean pair-wise distance (MPDaw) showed an increase with an increase in elevation and species richness. A similar but slightly weaker relationship was noticed when the non-abundance weighted mean pair-wise distance (MPDpa) was used. Interestingly, the phylogenetic distance between the focal species and the native species based on MPDaw declined with elevation as well as species richness, but such a decline was seen when MPDpa was used. Our study also revealed that soil nutrients influence the abundance of A. cotula and the phylogenetic distance between the focal and other species, thereby indicating the role of micro-ecological factors and spatial heterogeneity in community assembly.
DANGER ANALYSIS: RISK-AVERSE ON/OFF-TARGET ASSESSMENT FOR CRISPR EDITING WITHOUT A REFERENCE GENOME
Authors: Nakamae Kazuki , Bono Hidemasa 
Published: March 2023

ABSTRACTThe CRISPR-Cas9 system has successfully achieved site-specific gene editing in organisms ranging from humans to bacteria. The technology efficiently generates mutants, allowing for phenotypic analysis of the on-target gene. However, some conventional studies did not investigate whether deleterious off-target effects partially affect the phenotype. Herein, we present a novel phenotypic assessment of CRISPR-mediated gene editing: Deleterious and ANticipatable Guides Evaluated by RNA-sequencing (DANGER) analysis. Using RNA-seq data, this bioinformatics pipeline can elucidate genomic on/off-target sites on mRNA-transcribed regions related to expression changes and then quantify phenotypic risk at the gene ontology (GO) term level. We demonstrated the risk-averse on/off-target assessment in RNA-seq data from gene-edited samples of human cells and zebrafish brains. Our DANGER analysis successfully detected off-target sites, and it quantitatively evaluated the potential contribution of deleterious off-targets to the transcriptome phenotypes of the edited mutants. Notably, DANGER analysis harnessedde novotranscriptome assembly to perform risk-averse on/off-target assessments without a reference genome. Thus, our resources would help assess genome editing in non-model organisms, individual human genomes, and atypical genomes from diseases and viruses. In conclusion, DANGER analysis facilitates the safer design of genome editing in all organisms with a transcriptome.
A systematic search for RNA structural switches across the human transcriptome
Authors: Khoroshkin Matvei , Asarnow Daniel , Navickas Albertas , Winters Aidan , Yu Johnny , Zhou Simon K. , Zhou Shaopu , Palka Christina , Fish Lisa , Ansel K. Mark , Cheng Yifan , Gilbert Luke A. , Goodarzi Hani 
Published: March 2023

ABSTRACTRNA structural switches are key regulators of gene expression in bacteria, yet their characterization in Metazoa remains limited. Here we present SwitchSeeker, a comprehensive computational and experimental approach for systematic identification of functional RNA structural switches. We applied SwitchSeeker to the human transcriptome and identified 245 putative RNA switches. To validate our approach, we characterized a previously unknown RNA switch in the 3’UTR of the RORC transcript.In vivoDMS-MaPseq, coupled with cryogenic electron microscopy, confirmed its existence as two alternative structural conformations. Furthermore, we used genome-scale CRISPR screens to identifytransfactors that regulate gene expression through this RNA structural switch. We found that nonsense-mediated mRNA decay acts on this element in a conformation-specific manner. SwitchSeeker provides an unbiased, experimentally-driven method for discovering RNA structural switches that shape the eukaryotic gene expression landscape.
Towards bone-remodeling-on-a-chip: self-assembling 3D osteoblast-osteoclast coculture in a microfluidic chip
Authors: Vis M.A.M. , Zhao F. , Bodelier E.S.R. , Bood C.M. , Bulsink J. , van Doeselaar M. , Amirabadi H. Eslami , Ito K. , Hofmann S. 
Published: March 2023

AbstractHealthy bone is maintained by the process of bone remodeling. An unbalance in this process can lead to pathologies such as osteoporosis which are often studied with animal models. However, data from animals have limited power in predicting the results that will be obtained in human clinical trials. In search for alternatives to animal models, humanin vitromodels are emerging as they address the principle of reduction, refinement, and replacement of animal experiments (3Rs). At the moment, no completein vitromodel for bone-remodeling exists. Microfluidic chips offer great possibilities, particularly because of the dynamic culture options, which are crucial forin vitrobone formation. In this study, a scaffold free, fully human, 3D microfluidic coculture model of bone remodeling is presented. A bone-on-a-chip coculture system was developed in which human mesenchymal stromal cells differentiated into osteoblasts and self-assembled into scaffold free bone-like tissues with the shape and dimensions of human trabeculae. Human monocytes were able to attach to these tissues and to fuse into multinucleated osteoclast-like cells, establishing the coculture. Furthermore, a set-up was developed allowing for long-term (35 days) on-chip cell culture with benefits including continuous fluid-flow, low bubble formation risk, easy culture medium exchange inside the incubator and live cell imaging options. This on-chip coculture is a crucial advance towards developingin vitrobone remodeling models to facilitate drug testing.
In-silico Discovery of Genetic Diversity inCucumis sativusvar. hardwickii: A Wild Relative of Cultivated Cucumber
Authors: Rawat Suniti , Kaushik Prashant 
Published: March 2023

AbstractGenome-wide sequencing data play an important role in evaluating the genomic level differences between superior and poor-quality crop plants and improving our understanding of molecular association with desired traits. We analyzed the obtained 92,921,066 raw reads from genome-wide resequencing ofCucumis sativusvar. hardwickii through in-silico approaches and mapped to the reference genome of Cucumis sativus to identify the genome-wide single nucleotide polymorphisms (SNPs) and Single nucleotide variations (SNV). Here, we report 19, 74,213 candidate SNPs including 1,33,468 insertions and 1,43,237 deletions and 75 Indels genome-wide. A total of 2228224 identified variants were classified into four classes including 0.01% sequence alteration, 5.94% insertion, 6.37% deletion and 87.66% SNV respectively. These variations can be a major source of phenotypic diversity and sequence variation within the species. Overall, the discovery of SNPs and genomic variants may help predict the plant response to certain environmental factors and can be utilized to improve crop plants’ economically important traits.
Finite Sample Corrections for Average Equivalence Testing
Authors: Boulaguiem Younes , Quartier Julie , Lapteva Maria , Kalia Yogeshvar N , Victoria-Feser Maria-Pia , Guerrier Stéphane , Couturier Dominique-Laurent 
Published: March 2023

AbstractAverage (bio)equivalence tests are used to assess if a parameter, like the mean difference in treatment response between two conditions for example, lies within a given equivalence interval, hence allowing to conclude that the conditions have ‘equivalent’ means. TheTwo One-Sided Tests(TOST) procedure, consisting in testing whether the target parameter is respectively significantly greater and lower than some pre-defined lower and upper equivalence limits, is typically used in this context, usually by checking whether the confidence interval for the target parameter lies within these limits. This intuitive and visual procedure is however known to be conservative, especially in the case of highly variable drugs, where it shows a rapid power loss, often reaching zero, hence making it impossible to conclude for equivalence when it is actually true. Here, we propose a finite sample correction of the TOST procedure, theα-TOST, which consists in a correction of the significance level of the TOST allowing to guarantee a test size (or type-I error rate) ofα. This new procedure essentially corresponds to a finite sample and variability correction of the TOST procedure. We show that this procedure is uniformly more powerful than the TOST, easy to compute, and that its operating characteristics outperform the ones of its competitors. A case study about econazole nitrate deposition in porcine skin is used to illustrate the benefits of the proposed method and its advantages compared to other available procedures.