bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide association study reveals genetic risk factors for trigeminal neuralgia
Authors: Hale Andrew T. , He Jing , Akinnusotu Oluwatoyin , Sale Rebecca L. , Wang Janey , Bastarache Lisa , Gamazon Eric R. 
Published: February 2021

AbstractBackgroundWhile many clinical risk factors of trigeminal neuralgia (TN) have been identified, the genetic basis of TN is largely unknown. Here, we perform the first genome-wide association study (GWAS) for TN using three independent DNA biobanks – BioVU, the UK Biobank, and Finngen.ObjectiveTo elucidate the genetic basis of TN.MethodsUsing GWAS summary statistics generated from BioVU, the UK Biobank, and Finngen, we performed fixed-effect meta-analysis across 490,912 individuals (1,188 TN cases and 489,724 controls) to identify genetic risk factors for TN. Genome-wide significance was defined as p < 5.0×10−8.ResultsWe identify an intergenic locus on chromosome 1p22.2 flanked byZNF326andSNORD3Gcontaining 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10−8), where rs77449572 is the sentinel variant (p = 1.72 x 10−9). The SNP rs77449572 overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 are located in enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10−8).ConclusionsTo our knowledge, we perform the first GWAS of TN. Future studies should be aimed at understanding the extent to which genetic variation stratifies response to neuropathic pain medication and whether genetic information may be used to identify patients who are likely to benefit (or not) from surgical intervention.
pyconsFold: A fast and easy tool for modelling and docking using distance predictions
Authors: Lamb J , Elofsson A 
Published: February 2021

AbstractMotivationContact predictions within a protein has recently become a viable method for accurate prediction of protein structure. Using predicted distance distributions has been shown in many cases to be superior to only using a binary contact annotation. Using predicted inter-protein distances has also been shown to be able to dock some protein dimers.ResultsHere we present pyconsFold. Using CNS as its underlying folding mechanism and predicted contact distance it outperforms regular contact prediction based modelling on our dataset of 210 proteins. It performs marginally worse than the state of the art pyRosetta folding pipeline but is on average about 20 times faster per model. More importantly pyconsFold can also be used as a fold-and-dock protocol by using predicted inter-protein contacts to simultaneously fold and dock two protein chains.Availability and implementationpyconsFold is implemented in Python 3 with a strong focus on using as few dependencies as possible for longevity. It is available both as a pip package in Python 3 and as source code onGitHuband is published under the GPLv3 license.Contactarne@bioinfo.seSupplemental materialInstall instructions, examples and parameters can be found in the supplemental notes.Availability of dataThe data underlying this article together with source code are available on github, athttps://github.com/johnlamb/pyconsfold.
Living apart if you can – how genetically and developmentally controlled sex has shaped the evolution of liverworts
Authors: He Xiaolan , Flores Jorge R. , Sun Yu , Bowman John L. 
Published: February 2021

AbstractSexual differentiation in bryophytes occurs in the dominant gametophytic generation. Over half of bryophytes are dioicous, and this pattern in liverworts is even more profound as over 70% of species are dioicous. However, the evolutionary mechanisms leading to the prevalence of dioicy and the shifts of sexual systems between dioicy and monoicy have remained poorly known. These essential factors in reproductive biology are explored here in light of phylogenetics combined with evidence of genomic characterization of sex chromosomes and sex-determination, as well as cytology. Our analyses and discussions on liverworts are focused on: (1) ancestry and shifts in sexuality, (2) evolution of sex chromosomes and maintenance of haploid dioicy, and (3) environmental impact on the evolution of monoicism. We show that the dioicous condition is ancestral in liverworts, and the evolution of sexual systems is both conserved and stable with an ancient origin, but also highly dynamic in certain more recently diverged lineages. We assume that the haploid dioicy maintained in the course of evolution must be linked to the genetically controlled sex-determination, and transition from genetically to developmentally controlled sex determination, the evolution of monoicism, is driven by ephemeral and unstable environments. Monoicy is less stable in the long-term than dioicy, and thus, ultimately, dioicy is selected in liverworts. It is concluded that sexual dimorphism is maintained through a highly dynamic evolutionary process, sex chromosomes bearing distinct set of evolutionary forces that can have large impacts on genome evolution and may also promote speciation.
Biomechanical control of meiotic chromosomal bouquet and germ cell morphogenesis by the zygotene cilium
Authors: Mytlis Avishag , Kumar Vineet , Tao Qiu , Deis Rachael , Hart Neta , Levy Karine , Masek Markus , Shawahny Amal , Ahmad Adam , Eitan Hagai , Nather Farouq , Adar-Levor Shai , Birnbaum Ramon Y. , Elia Natalie , Bachmann-Gagescu Ruxandra , Roy Sudipto , Elkouby Yaniv M. 
Published: February 2021

AbstractThe hallmark of meiosis is chromosomal pairing and synapsis via synaptonemal complexes, but chromosomal pairing also depends on cytoplasmic counterparts that tether and rotate telomeres on the nuclear envelope. Telomeres slide on perinuclear microtubules, shuffling chromosomes and mechanically driving their homology searches. Pull of telomeres towards the centrosome drives formation of the “zygotene chromosomal bouquet”. These telomere dynamics are essential for pairing and fertility, and the bouquet, discovered in 1900, is universally conserved. Nevertheless, how cytoplasmic counterparts of bouquet formation are mechanically regulated has remained enigmatic. Here, we report the “zygotene cilium” - a previously unrecognized cilium, in oocytes. We show in zebrafish that this cilium specifically connects to the bouquet centrosome, constituting a cable system of the cytoplasmic bouquet machinery. Furthermore, zygotene cilia extend throughout the germline cyst, a conserved germ cell organization. Using multiple ciliary mutants and laser-induced excision, we demonstrate that the zygotene cilium is essential for chromosomal bouquet and synaptonemal complex formation, germ cell morphogenesis, ovarian development and fertility. Mechanistically, we provide evidence that the cilium functions at least partly via anchoring the bouquet centrosome in order to counterbalance telomere rotation and pulling. We also show that the zygotene cilium is conserved in both male and female meiosis in zebrafish, as well as in mammals. Our work uncovers the novel concept of a cilium as a critical player in meiosis and sheds new light on reproduction phenotypes in ciliopathies. We propose a cellular paradigm that cilia can control chromosomal dynamics.
Scalable Bias-corrected Linkage Disequilibrium Estimation Under Genotype Uncertainty
Authors: Gerard David 
Published: February 2021

AbstractLinkage disequilibrium (LD) estimates are often calculated genome-wide for use in many tasks, such as SNP pruning and LD decay estimation. However, in the presence of genotype uncertainty, naive approaches to calculating LD have extreme attenuation biases, incorrectly suggesting that SNPs are less dependent than in reality. These biases are particularly strong in polyploid organisms, which often exhibit greater levels of genotype uncertainty than diploids. A principled approach using maximum likelihood estimation with genotype likelihoods can reduce this bias, but is prohibitively slow for genome-wide applications. Here, we present scalable moment-based adjustments to LD estimates based on the marginal posterior distributions of the genotypes. We demonstrate, on both simulated and real data, that these moment-based estimators are as accurate as maximum likelihood estimators, and are almost as fast as naive approaches based only on posterior mean genotypes. This opens up bias-corrected LD estimation to genome-wide applications. Additionally, we provide standard errors for these moment-based estimators. All methods are implemented in theldseppackage on the Comprehensive R Archive Networkhttps://cran.r-project.org/package=ldsep.
A unified model of amino acid homeostasis in mammalian cells
Authors: Gauthier-Coles Gregory , Vennitti Jade , Zhang Zhiduo , Comb William C. , Javed Kiran , Broer Angelika , Broer Stefan 
Published: February 2021

AbstractHomeostasis is one of the fundamental concepts in physiology. Despite remarkable progress in our molecular understanding of amino acid transport, metabolism and signalling, it remains unclear by what mechanisms cytosolic amino acid concentrations are maintained. We propose that amino acid transporters are the primary determinants of intracellular amino acid levels. We show that a cell’s endowment with amino acid transporters can be deconvoluted by a logical series of experiments. This was used to computationally simulate amino acid translocation across the plasma membrane. For two different cancer cell lines and human myotubes, transport simulation generates cytosolic amino acid concentrations that are close to those observedin vitro. Perturbations of the system were replicatedin silicoand could be applied to systems where only transcriptomic data are available. The methodology developed in this study is widely applicable to other transport processes and explain amino acid homeostasis at the systems-level.
Energetic and structural features of SARS-CoV-2 N-protein co-assemblies with nucleic acids
Authors: Zhao Huaying , Wu Di , Nguyen Ai , Li Yan , Adão Regina C. , Valkov Eugene , Patterson George H. , Piszczek Grzegorz , Schuck Peter 
Published: February 2021

SummaryNucleocapsid (N) protein of the SARS-CoV-2 virus packages the viral genome into well-defined ribonucleoprotein particles, but the molecular pathway is still unclear. N-protein is dimeric and consists of two folded domains with nucleic acid (NA) binding sites, surrounded by intrinsically disordered regions that promote liquid-liquid phase separation. Here we use biophysical tools to study N-protein interactions with oligonucleotides of different length, examining the size, composition, secondary structure, and energetics of the resulting states. We observe formation of supramolecular clusters or nuclei preceding growth into phase-separated droplets. Short hexanucleotide NA forms compact 2:2 N-protein/NA complexes with reduced disorder. Longer oligonucleotides expose additional N-protein interactions and multi-valent protein-NA interactions, which generate higher-order mixed oligomers and simultaneously promote growth of droplets. Phase separation is accompanied by a significant increase in protein secondary structure, different from that caused by initial NA binding, which may contribute to the assembly of ribonucleoprotein particles within molecular condensates.
Thinopyrum intermediumTiAP1 interacts with a chitin deacetylase fromBlumeria graminisf. sp.triticiand increases the resistance toBgtin wheat
Authors: Yang Yanlin , Fan Pan , Liu Jingxia , Xie Wenjun , Liu Na , Niu Zubiao , Li Quanquan , Song Jing , Tian Qiuju , Bao Yinguang , Wang Honggang , Feng Deshun 
Published: February 2021

SummaryThe biotrophic fungal pathogenBlumeria graminisf. sp.tritici(Bgt) is a crucial factor causing reduction of global wheat production. Wild wheat relatives, e.g.Thinopyrum intermedium,is one of the wild-used parents in wheat disease-resistant breeding. FromT.intermediumline, we identified the aspartic acid protein gene,TiAP1, which involved in resistance againstBgt. TiAP1 is a secreted protein that accumulates in large amounts at the infection sites of powdery mildew and extends to the intercellular space. Yeast two-hybrid showed that it interacted with the chitin deacetylase (BgtCDA1) ofBgt. The yeast expression, purification, andinvitrotest confirmed the chitin deacetylase activity of BgtCDA1. The bombardment and VIGS mediated host-induced gene silencing showedBgtCDA1promotes the invasion ofBgt. Transcriptome analysis showed the cell wall xylan metabolism, lignin biosynthesis-related, and defence genes involved in the signal transduction were upregulated in the transgenicTiAP1wheat induced byBgt. The TiAP1 in wheat may inactivate the deacetylation function of BgtCDA1, cause chitin oligomers expose to wheat chitin receptor, then trigger the wheat immune response to inhibit the growth and penetration ofBgt, and thereby enhance the tolerance of wheat to pathogens.
Oncogenic alterations in the p53 pathway abolish oscillatory competence
Authors: Xiong Lingyun , Garfinkel Alan 
Published: February 2021

AbstractThe tumor suppressor p53 displays concentration oscillations in response to DNA damage, a behavior that has been suggested to be essential to its anti-cancer function. Many genetic alterations in the p53 pathway have been shown to be oncogenic, whether by experiment or by clinical associations with various cancers. These oncogenic alterations include somatic mutations, copy number variations and inherited polymorphisms. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that all of the oncogenic perturbations have a common effect, to abolish the oscillatory competence of p53, thereby impairing its tumor suppressor function. In this analysis, these diverse genetic alterations, widely observed in human cancers, have a unified mechanistic explanation.SignificanceIn human cancers, the p53 tumor suppressor pathway is frequently altered by diverse genetic changes. An integrated understanding of these oncogenic alterations is currently lacking. We show that all oncogenic alterations in the p53 pathway abolish the oscillatory competence of p53, a property that is essential for cell cycle arrest upon stress, for effective DNA damage response and for maintaining genome integrity. This unified dynamical explanation of distinct cancer driver events that converge on a key cancer hallmark pathway has practical implications for anti-cancer therapies.
The 3-D structure of fibrous material is fully restorable from its X-ray diffraction pattern
Authors: Iwamoto Hiroyuki 
Published: February 2021

AbstractX-ray fiber diffraction is potentially a powerful technique to study the structure of fibrous materials, such as DNA and synthetic polymers. However, only rotationally averaged diffraction patterns can be recorded, and it is difficult to correctly interpret them without the knowledge of esoteric diffraction theories. Here we demonstrate that, in principle, the non-rotationally averaged 3-D structure of the material can be restored from its fiber diffraction pattern. The method is a simple puzzle-solving process, and in ideal cases, it does not require any prior knowledge about the structure, such as helical symmetry. We believe that the proposed method has a potential to transform the fiber diffraction to a 3-D imaging technique, and will be useful for a wide field of life and materials sciences.
Comparative analysis of mammal genomes unveils key genomic variability for human lifespan
Authors: Farré X. , Molina R. , Barteri F. , Timmers P.R.H.J. , Joshi P.K. , Oliva B. , Acosta S. , Esteve-Altava B. , Navarro A. , Muntané G. 
Published: February 2021

AbstractMammals vary 100-fold in their maximum lifespan. This enormous variation is the result of the adaptations of each species to their own biological trade-offs and ecological conditions. Comparative genomics studies have demonstrated that the genomic factors underlying the lifespans of species and the longevity of individuals are shared across the tree of life. Here, we set out to compare protein-coding regions across the mammalian phylogeny, aiming to detect individual amino acid changes shared by the most long-lived mammal species and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 amino acid changes in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p=0.003). The detected genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 amino acids, located in 996 different genes, showed a significant association with maximum lifespan in a phylogenetically controlled test. Interestingly, most of the detected amino acids positions do not vary in extant human populations (>81.2%) or have allele frequencies below 1% (99.78%), Consequently, almost none could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected by chance, successfully demonstrating for the first time that comparative genomics can be used to enhance the interpretation of human GWAS. Finally, we show that the human longevity-associated proteins coded by the detected genes are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.
Reconciling Inherent Interfacial Compatibility Conflict Enhances Adhesive Infiltration and Resolves Dentin Bonding Durability
Authors: Luo Qiaojie , Chen Yadong , Xu Jiajia , Shu Chang , Li Zimeng , Zhu Weipu , Shen Youqing , Li Xiaodong 
Published: February 2021

AbstractWet bonding is a basic technique used daily in clinics for tooth-restoration fixation. However, only 50% of the bonding lasts more than 5 years and thus patients must visit the dentists repeatedly. This is attributed to the limited infiltration of adhesives into the demineralized dentin (DD) matrix during wet-bonding. Herein, we show that reconciling interfacial compatibility conflict between the DD matrix and the critical hydrophobic adhesive molecules via hydrophobizing the DD matrix enables the adhesives to thoroughly infiltrate and uniformly distribute within the DD matrix. Thus, the bonding of the hydrophobic DD matrix using commercial dentin adhesives achieves the bonding strength 2-6 times higher than that of the non-treated DD matrix. When a hydrophobic adhesive is applied on the hydrophobic DD matrix, a flawless hybrid layer is produced as observed by nanoleakage investigation. A long-term bonding strength comes up to 7.3 fold that of the control group and very importantly, with no attenuation after 12 months. This study clarifies the basic cause of poor wet-bonding durability and demonstrates a paradigm in adhesive dentistry to overcome the long-existing bonding durability problem associated with inadequate adhesive infiltration into the DD matrix. This provides a new angle of view to resolve clinical dentin bonding durability problem and will significantly promote adhesive dentistry.HighlightsInherent interfacial compatibility conflict between demineralized dentin matrix and hydrophobic molecules of dentin adhesives is the basic cause for the dentin bonding durability problem.Reconciling the interfacial compatibility conflict markedly facilitates adhesive infiltration in the demineralized dentin matrix and greatly enhances bonding effectiveness.High interfacial compatibility produces a flawless hybrid layer and ideal bonding effectiveness and durability.Graphical AbstractFor wet bonding, poor infiltration of adhesives within the DD matrix inevitably produces numerous defects throughout the hybrid layer, which always leads to the failure of restoration. Via hydrophobizing the DD matrix, reconciling interfacial compatibility conflict between the DD matrix and the hydrophobic adhesive monomers overcomes durability problems associated with the infiltration of adhesives into the DD matrix producing a flawless hybrid layer and providing ideal bonding effectiveness and durability.
Checkpoint proteins in patients with precancer and cervical cancer
Authors: Kayukova Elena , Sholokhov Leonid , Belokrinitskaya Tatiana , Tereshkov Pavel 
Published: February 2021

AbstractThe efficiency of immuno-oncological drugs in treatment cervical cancer is not high. The research of new immunological targets in cervical cancer is actual.The aim was to study the local level of checkpoint proteins of immune cycle in patients with cervical cancer of different stages (sCD25, 4-1BB, B7.2, TGF-b1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9, sCD27, PD-L2).Materials and research methods. The objects of study were the patients with precancer (n=13) and cervical cancer (n=49). The control group consisted of 13 gynecologically healthy women. The material of study was cervical epithelium obtained by cervical brush. The research method was flow cytometry. Test parameters: sCD25, 4-1BB, B7.2, TGF-b1, CTLA-4, PD-L1, PD-1, Tim-3, LAG-3, Galectin-9, sCD27, PD-L2. Statistical analysis of the data was carried out using nonparametric statistics using the Mann – Whitney U-test. The results of the study.The levels of sCD25, B7.2, PDL1, Tim-3, sCD27, PD-L2 were increased in the comparison groups relation to the control (p <0.05). The differential criterion for invasive cervical cancer may be an increase in the level of LAG-3 in the cervical epithelium by 43% (p <0.05).The levels of PD-L1, PD-1, sCD27 and PD-L2 were increased opposite the levels LAG-3 and Galectin-9 were decreased in patients with metastatic cervical cancer(p <0.05).
A Safe and Effective Mucosal RSV Vaccine Consisting of RSV Phosphoprotein and Flagellin Variant
Authors: Zhao Bali , Yang Jingyi , He Bing , Li Xian , Yan Hu , Liu Shuning , Yang Yi , Zhou Dihan , Liu Bowen , Fan Xuxu , Zhong Maohua , Zhang Ejuan , Zhang Fan , Zhang Yue , Chen Yao-Qing , Jiang Shibo , Yan Huimin 
Published: February 2021

SUMMARYRespiratory syncytial virus (RSV) is a major cause of serious acute lower respiratory tract infection in infants and the elderly. No licensed RSV vaccine available thus far calls for the development of vaccines with new target(s) and vaccination strategies. Here, we constructed a recombinant protein, designated P-KFD1, comprised of RSV phosphoprotein (P) andE. coliK12 strain-derived flagellin variant KFD1. Intranasal (i.n.) immunization with P-KFD1 inhibits RSV replication in both upper and lower respiratory tract, and protects mice against lung disease without vaccine-enhanced disease (VED). The P-specific CD4+T cells provoked by P-KFD1 i.n. immunization, either reside in or migrate to respiratory tract, mediate protection against RSV infection. Sc-RNA seq and carboxyfluorescein succinimidyl ester (CFSE) labeled cell transfer further characterized the Th1 and Th17 responses induced by P-KFD1. Finally, we found the anti-viral protection depends on either IFN-γ or IL-17A. Collectively, P-KFD1 is promising as a safe and effective mucosal vaccine candidate to prevent RSV infection.HIGHLIGHTSA new subunit RSV vaccine candidate with new target and vaccination strategy, P-KFD1, is designed and generatedIntranasal immunization with P-KFD1 protects mice against RSV infection and averts vaccine-enhanced diseaseSc-RNA seq and CFSE-labelled cell transfer identified characteristics of the protective CD4+T cellsLocal and peripheral CD4+T cells provide protection against RSV infection dependent on either IFN-γ or IL-17A