bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population
Authors: Neitzel Julia , Malik Rainer , Muetzel Ryan , Knol Maria J , Zonneveld Hazel , Georgakis Marios K , Franzmeier Nicolai , Rubinski Anna , Dichgans Martin , Ikram M Arfan , Vernooij Meike W , Ewers Michael 
Published: August 2021

AbstractThe functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic basis and risk factors of system segregation are largely unknown. Here, we present the first genome-wide association study of fMRI-assessed system segregation in 16,635 UK Biobank participants, identifying nine independent genomic loci. The 66 implicated genes were significantly downregulated in brain tissue and upregulated in vascular tissue. Of major vascular risk factors (Life’s Simple 7), blood pressure showed a robust genetic correlation with system segregation. Observational and Mendelian randomization analyses confirmed a unfavourable effect of higher blood pressure on system segregation and of lower system segregation on cognition. Replication analyses in 2,414 Rotterdam Study participants supported these conclusions.
Transmission dynamics and epidemiological characteristics of Delta variant infections in China
Authors: Kang Min , Xin Hualei , Yuan Jun , Ali Sheikh Taslim , Liang Zimian , Zhang Jiayi , Hu Ting , Lau Eric H. Y. , Zhang Yingtao , Zhang Meng , Cowling Benjamin J. , Li Yan , Wu Peng 
Published: August 2021

ABSTRACTBackgroundThe Delta variant of SARS-CoV-2 has become predominant globally. We evaluated the transmission dynamics and epidemiological characteristics of the Delta variant in an outbreak in southern China.MethodsData on confirmed cases and their close contacts were retrospectively collected from the outbreak that occurred in Guangdong, China in May-June 2021. Key epidemiological parameters, temporal trend of viral loads and secondary attack rates were estimated and compared between the Delta variant and the wild-type SARS-CoV-2 virus. We also evaluated the association of vaccination with viral load and transmission.ResultsWe identified 167 patients infected with the Delta variant in the Guangdong outbreak. The mean estimates of the latent period and the incubation period were 4.0 days and 5.8 days, respectively. A relatively higher viral load was observed in Delta cases than in wild-type infections. The secondary attack rate among close contacts of Delta cases was 1.4%, and 73.9% (95% confidence interval: 67.2%, 81.3%) of the transmissions occurred before onset. Index cases without vaccination (OR: 2.84, 95% confidence interval: 1.19, 8.45) or with one dose of vaccination (OR: 6.02, 95% confidence interval: 2.45, 18.16) were more likely to transmit infection to their contacts than those who had received 2 doses of vaccination.DiscussionPatients infected with the Delta variant had more rapid symptom onset. The shorter and time-varying serial interval should be accounted in estimation of reproductive numbers. The higher viral load and higher risk of pre-symptomatic transmission indicated the challenges in control of infections with the Delta variant.
The longitudinal dynamics and natural history of clonal haematopoiesis
Authors: Fabre Margarete A. , Almeida José Guilherme de , Fiorillo Edoardo , Mitchell Emily , Damaskou Aristi , Rak Justyna , Orrù Valeria , Marongiu Michele , Vijayabaskar MS , Baxter Joanna , Hardy Claire , Abascal Federico , Chapman Michael Spencer , Williams Nicholas , Nangalia Jyoti , Martincorena Iñigo , Campbell Peter J. , McKinney Eoin F. , Cucca Francesco , Gerstung Moritz , Vassiliou. George S. 
Published: August 2021

SummaryHuman cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system of healthy individuals and have been termed clonal haematopoiesis (CH). While CH predisposes to myeloid neoplasia and other diseases, we have limited understanding of how and when CH develops, what factors govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression. Here, we track 697 CH clones from 385 individuals aged 55 or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A,TP53) to over 50%/yr (SRSF2-P95H). Growth rates of clones with the same mutation differed by approximately +/−5%/yr, proportionately impacting “slow” drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole genome-sequenced haematopoietic colonies from 7 older individuals, we reveal distinct patterns of lifelong clonal behaviour.DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations only drove expansion later in life, while growth ofTET2-mutant clones showed minimal age-dependency. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterise the lifelong natural history of CH and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
An efficient method to identify, date and describe admixture events using haplotype information
Authors: Wangkumhang Pongsakorn , Greenfield Matthew , Hellenthal Garrett 
Published: August 2021

AbstractWe present fastGLOBETROTTER, an efficient new haplotype-based technique to identify, date and describe admixture events using genome-wide autosomal data. With simulations, we demonstrate how fastGLOBETROTTER reduces computation time by 4-20 fold relative to the haplotype-based technique GLOBETROTTER without suffering loss of accuracy. We apply fastGLOBETROTTER to a cohort of >6000 Europeans from ten countries, revealing previously unreported admixture signals. In particular we infer multiple periods of admixture related to East Asian or Siberian-like sources, starting >2000 years ago, in people living in countries north of the Baltic Sea. In contrast, we infer admixture related to West Asian, North African and/or Southern European sources in populations south of the Baltic Sea, including admixture dated to ≈300-700CE, overlapping the fall of the Roman Empire, in people from Belgium, France and parts of Germany. Our new approach scales to analysing hundreds to thousands of individuals from a putatively admixed populations and hence is applicable to emerging large-scale cohorts of genetically homogeneous populations.
Large-scale integration of DNA methylation and gene expression array platforms
Authors: Lancaster Eva E. , Vladimirov Vladimir I. , Riley Brien P. , Landry Joseph W. , Roberson-Nay Roxann , York Timothy P. 
Published: August 2021

AbstractEpigenome-wide association studies (EWAS) aim to provide evidence that marks of DNA methylation (DNAm) have downstream consequences that can result in the development of human diseases. Although these methods have been successful in identifying DNAm patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE inciswere enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated withtransGE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonicalcisDNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented.
Phase transition specified by a binary code patterns the vertebrate eye cup
Authors: Balasubramanian Revathi , Min Xuanyu , Quinn Peter M.J. , Giudice Quentin Lo , Tao Chenqi , Polanco Karina , Makrides Neoklis , Peregrin John , Bouaziz Michael , Mao Yingyu , Wang Qian , Costa Bruna L , Buenaventura Diego , Wang Fen , Ma Liang , Tsang Stephen H , Fabre Pierre J. , Zhang Xin 
Published: August 2021

ABSTRACTThe developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE) and the ciliary margin (CM). By single cell analysis, we showed that a gradient of FGF signaling regulates demarcation and subdivision of the CM and controls its stem cell-like property of self-renewal, differentiation and survival. This regulation by FGF is balanced by an evolutionarily conserved Wnt signaling gradient induced by the lens ectoderm and the periocular mesenchyme, which specifies the CM and the distal RPE. These two morphogen gradients converge in the CM where FGF signaling promotes Wnt signaling by stabilizing β-catenin in a GSK3β-independent manner. We further showed that activation of Wnt signaling converts the NR to either the CM or the RPE depending on the level of FGF signaling. Conversely, activation of FGF transforms the RPE to the NR or CM dependent on Wnt activity. We demonstrated that the default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in retinal organoid culture of human iPS cells. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.
Cancer cell hyper-proliferation disrupts the topological invariance of epithelial monolayers
Authors: Roshal Daria S. , Martin Marianne , Fedorenko Kirill , Molle Virginie , Baghdiguian Stephen , Rochal Sergei B. 
Published: August 2021

AbstractAlthough the polygonal shape of epithelial cells has drawn the attention of scientists for several centuries, only recently, it has been demonstrated that distributions of polygon types (DOPTs) are similar in proliferative epithelia of many different plant and animal species. In this study we show that hyper-proliferation of cancer cells disrupts this universality paradigm and results in random epithelial structures. Examining non-synchronized and synchronized HeLa cervix cells, we suppose that the cell size spread is the single parameter controlling the DOPT in these monolayers. We test this hypothesis by considering morphologically similar random polygonal packings. By analyzing the differences between tumoral and non-tumoral epithelial monolayers, we uncover that the latter have more ordered structures and argue that the relaxation of mechanical stresses associated with cell division induces more effective ordering in the epithelia with lower proliferation rates. The proposed theory also explains the specific highly ordered structures of some post-mitotic unconventional epithelia.
Mapping the peptide binding groove of MHC class I
Authors: Kopicki Janine-Denise , Saikia Ankur , Niebling Stephan , Günther Christian , Garcia-Alai Maria , Springer Sebastian , Uetrecht Charlotte 
Published: August 2021

ABSTRACTAn essential element of adaptive immunity is the selective binding of peptide antigens by major histocompatibility complex (MHC) class I proteins and their presentation to cytotoxic T lymphocytes on the cell surface. Using native mass spectrometry, we here analyze the binding of peptides to an empty disulfide-stabilized HLA-A*02:01 molecule. This novel approach allows us to examine the binding properties of diverse peptides. The unique stability of our MHC class I even enables us to determine the binding affinity of complexes, which are suboptimally loaded with truncated or charge-reduced peptides. Notably, a unique erucamide adduct decouples affinity analysis from peptide identity alleviating issues usually attributed to clustering during electrospray ionization. We discovered that two anchor positions at the binding surface between MHC and peptide can be stabilized independently and further identify the contribution of other peptidic amino acids on the binding. We propose this as an alternative, likely universally applicable method to artificial prediction tools to estimate the binding strength of peptides to MHC class I complexes quickly and efficiently. This newly described MHC class I-peptide binding affinity quantitation represents a much needed orthogonal, independent approach to existing computational affinity predictions and has the potential to eliminate binding affinity biases and thus accelerate drug discovery in infectious diseases, autoimmunity, vaccine design, and cancer immunotherapy.
Simultaneous infection with porcine reproductive and respiratory syndrome and influenza viruses abrogates clinical protection induced by live attenuated porcine reproductive and respiratory syndrome vaccination
Authors: Chrun Tiphany , Maze Emmanuel A. , Vatzia Eleni , Martini Veronica , Paudyal Basu , Edmans Matthew , McNee Adam , Manjegowda Tanuja , Salguero Francisco J. , Wanasen Nanchaya , Koonpaew Surapong , Graham Simon P. , Tchilian Elma 
Published: August 2021

AbstractThe porcine respiratory disease complex (PRDC) is responsible for significant economic losses in the pig industry worldwide. Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus are major viral contributors to PRDC. Vaccines are cost-effective measures for controlling PRRS, however, their efficacy in the context of co-infections has been poorly investigated. In this study, we aimed to determine the effect of PRRSV-2 and swine influenza H3N2 virus co-infection on the efficacy of PRRSV modified live virus (MLV) vaccination, which is widely used in the field. Following simultaneous challenge with contemporary PRRSV-2 and H3N2 field isolates, we found that the protective effect of PRRS MLV vaccination on clinical disease and pathology was abrogated, although viral load was unaffected and antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and H3N2 virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and H3N2 in the lung. Further analysis suggested that an upregulation of inhibitory cytokines gene expression in the lungs of vaccinated pigs may have influenced responses to H3N2 and PRRSV-2. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identity more effective vaccination strategies against PRDC in the field.
Immunoglobulin heavy constant gamma gene evolution is modulated by both the divergent and birth-and-death evolutionary models
Authors: Garzón-Ospina Diego , Buitrago Sindy P. 
Published: August 2021

AbstractImmunoglobulin G (IgG) is one of the five antibody classes produced in mammals as part of the humoral responses. This high-affinity antibody produced late in a primary immune response is responsible for protecting the organisms from infection. This protein’s heavy chain constant region is encoded by the Ig gamma gene (Igγ). In Humans, IgG has evolved into four subclasses with specialized effector functions. However, in Platyrrhini, IgG has been reported to be encoded by a single-copy gene. Here, we analyzed data from 38 primate genome sequences to identify Igγ genes and describe the evolution of this immunoglobulin in this group. Igγ belongs to a multigene family that evolves by the birth-death evolutionary model in primates. Whereas Strepsirrhini and Platyrrhini have a single-copy gene, in Catarrhini species it has expanded to having several paralogs in their genomes; some have been deleted or have become pseudogenes. Furthermore, episodic positive selection might promote a specialized species-specific IgG effector function. A hypothesis for the Igγ evolution has been proposed, suggesting that IgG has evolved to reach an optimal number of copies per genome to adapt their humoral immune responses to different environmental conditions.Graphical abstract
Long reads and Hi-C sequencing illuminate the two compartment genome of the model arbuscular mycorrhizal symbiont Rhizophagus irregularis
Authors: Yildirir Gokalp , Sperschneider Jana , Mathu Malar C , Chen Eric CH , Iwasaki Wataru , Cornell Calvin , Corradi Nicolas 
Published: August 2021

AbstractChromosome folding links genome structure with gene function by generating distinct nuclear compartments and topologically associating domains (TADs). In mammals, these undergo preferential interactions and regulate gene expression. However, their role in fungal genome biology is unclear. Here, we combine Nanopore (ONT) sequencing with chromatin conformation capture sequencing (Hi-C) to reveal chromosome and epigenetic diversity in a group of obligate plant symbionts; the arbuscular mycorrhizal fungi (AMF). We find that five phylogenetically distinct strains of the model AMF Rhizophagus irregularis carry 33 chromosomes with substantial within species variability in size, as well as in gene and repeat content. Strain-specific Hi-C contact maps all reveal a ‘checkerboard’ pattern that underline two dominant euchromatin (A) and heterochromatin (B) compartments. Each compartment differs in the level of gene transcription, regulation of candidate effectors and methylation frequencies. The A-compartment is more gene-dense and contains most core genes, while the B-compartment is more repeat-rich and has higher rates of chromosomal rearrangement. While the B-compartment is transcriptionally repressed, it has significantly more secreted proteins and in planta up-regulated candidate effectors, suggesting a possible host-induced change in chromosome conformation. Overall, this study provides a fine-scale view into the genome biology and evolution of prominent plant symbionts, and opens avenues to study the epigenetic mechanisms that modify chromosome folding during host-microbe interactions.
Proteomic analysis reveals different sets of proteins expressed during high temperature stress in two thermotolerant isolates ofTrichoderma
Authors: Poosapati Sowmya , Kumar Viswanathaswamy Dinesh , Prasad Ravulapalli Durga , Kannan Monica 
Published: August 2021

AbstractSeveral species of the soil borne fungus of the genusTrichodermaare known to be versatile, opportunistic plant symbionts, and are the most successful biocontrol agents used in today’s agriculture. To be successful in the field conditions, the fungus must endure varying climatic conditions. Studies have indicated that high atmospheric temperature coupled with low humidity is a major limitation for the inconsistent performance ofTrichodermaunder field conditions. Understanding the molecular modulation associated with suchTrichodermathat persist and deliver under abiotic stress condition will aid in exploiting the worth of these organisms for such use. In this study, comparative proteomic analysis using two-dimensional gel electrophoresis (2DE) and matrix-assisted laser desorption/time-of-flight (MALDI-TOF-TOF) mass spectrometry was used to identify proteins associated with thermotolerance in two thermotolerant isolates ofTrichoderma—T. longibrachiatum673, TaDOR673 andT. asperellum7316, TaDOR7316—and 32 differentially expressed proteins were identified. Sequence homology and conserved domains were used to identify these proteins and to assign probable function to them. Thermotolerant isolate, TaDOR673, seemed to employ the stress signaling MAPK pathways and heat shock response pathways to combat the stress condition whereas the moderately tolerant isolate, TaDOR7316, seemed to adapt to high temperature conditions by reducing the accumulation of mis-folded proteins through unfolded protein response pathway and autophagy. Also, there were unique as well as common proteins that were differentially expressed in the two isolates studied.
MetaLogo: a heterogeneity-aware sequence logo generator and aligner
Authors: Chen Yaowen , He Zhen , Men Yahui , Dong Guohua , Hu Shuofeng , Ying Xiaomin 
Published: August 2021

AbstractSequence logos are used to visually display conservations and variations in short sequences. They can indicate the fixed patterns or conserved motifs in a batch of DNA or protein sequences. However, most of the popular sequence logo generators are based on the assumption that all the input sequences are from the same homologous group, which will lead to an overlook of the heterogeneity among the sequences during the sequence logo making process. Heterogeneous groups of sequences may represent clades of different evolutionary origins, or genes families with different functions. Therefore, it is essential to divide the sequences into different phylogenetic or functional groups to reveal their specific sequence motifs and conservation patterns. To solve these problems, we developed MetaLogo, which can automatically cluster the input sequences after multiple sequence alignment and phylogenetic tree construction, and then output sequence logos for multiple groups and aligned them in one figure. User-defined grouping is also supported by MetaLogo to allow users to investigate functional motifs in a more delicate and dynamic perspective. MetaLogo can highlight both the homologous and nonhomologous sites among sequences. MetaLogo can also be used to annotate the evolutionary positions and gene functions of unknown sequences, together with their local sequence characteristics. We provide users a public MetaLogo web server (http://metalogo.omicsnet.org), a standalone Python package (https://github.com/labomics/MetaLogo), and also a built-in web server available for local deployment. Using MetaLogo, users can draw informative, customized and publishable sequence logos without any programming experience to present and investigate new knowledge on specific sequence sets.