bluuebunny/crossref_metadata_2025_split huggingface dataset:
From complete cross-docking to partners identification and binding sites predictions
Authors: Dequeker Choé , Behbahani Yasser Mohseni , David Laurent , Laine Elodie , Carbone Alessandra 
Published: August 2021

AbstractProteins ensure their biological functions by interacting with each other. Hence, characterising protein interactions is fundamental for our understanding of the cellular machinery, and for improving medicine and bioengineering. Over the past years, a large body of experimental data has been accumulated on who interacts with whom and in what manner. However, these data are highly heterogeneous and sometimes contradictory, noisy, and biased.Ab initiomethods provide a means to a “blind” protein-protein interaction network reconstruction. Here, we report on a molecular cross-docking-based approach for the identification of protein partners. We applied it to a few hundred of proteins, and we systematically investigated the influence of several key ingredients, such as the size and quality of the interfaces and the scoring function. We achieved some significant improvement compared to previous works, and a very high discriminative power on some specific functional classes. In addition, we assessed the ability of the approach to account for protein surface multiple usages, and we compared it with a sequence-based deep learning method. This work may contribute to guiding the exploitation of the large amounts of protein structural models now available toward the discovery of unexpected partners and their complex structure characterisation.
Intra-host SARS-CoV-2 evolution in the gut of mucosally-infected Chlorocebus aethiops (African green monkeys)
Authors: Rowe Lori A. , Beddingfield Brandon J. , Goff Kelly , Killeen Stephanie Z. , Chirichella Nicole R. , Melton Alexandra , Roy Chad J. , Maness Nicholas J. 
Published: August 2021

AbstractIn recent months, several SARS-CoV-2 variants have emerged that enhance transmissibility and escape host humoral immunity. Hence, the tracking of viral evolutionary trajectories is clearly of great importance. Little is known about SARS-CoV-2 evolution in nonhuman primate models used to test vaccines and therapies and to model human disease. Viral RNA was sequenced from rectal swabs from Chlorocebus aethiops (African green monkeys) after experimental respiratory SARS-CoV-2 infection. Two distinct patterns of viral evolution were identified that were shared between all collected samples. First, mutations in the furin cleavage site that were initially present in the virus as a consequence of VeroE6 cell culture adaptation were subsequently lost in virus recovered in rectal swabs, confirming the necessity of this motif for viral infection in vivo. Three amino acid changes were also identified; ORF 1a S2103F, and spike D215G and H655Y, that were detected in rectal swabs from all sampled animals. These findings are demonstrative of intra-host SARS-CoV-2 evolution unique to this nonhuman primate species and may identify a host-adapted variant of SARS-CoV-2 that would be useful in future development of primate disease models.
Insights from the genomes of four diploid Camelina spp.
Authors: Martin Sara L. , Toro Beatriz Lujan , James Tracey , Sauder Connie A. , Laforest Martin 
Published: August 2021

AbstractPlant evolution has been a complex process involving hybridization and polyploidization making understanding the origin and evolution of a plant’s genome challenging even once a published genome is available. The oilseed crop, Camelina sativa (Brassicaceae), has a fully sequenced allohexaploid genome with three unknown ancestors. To better understand which extant species best represent the ancestral genomes that contributed to C. sativa’s formation, we sequenced and assembled chromosome level draft genomes for four diploid members of Camelina: C. neglecta C. hispida var. hispida, C. hispida var. grandiflora and C. laxa using long and short read data scaffolded with proximity data. We then conducted phylogenetic analyses on regions of synteny and on genes described for Arabidopsis thaliana, from across each nuclear genome and the chloroplasts to examine evolutionary relationships within Camelina and Camelineae. We conclude that C. neglecta is closely related to C. sativa’s sub-genome 1 and that C. hispida var. hispida and C. hispida var. grandiflora are most closely related to C. sativa’s sub-genome 3. Further, the abundance and density of transposable elements, specifically Helitrons, suggest that the progenitor genome that contributed C. sativa’s sub-genome 3 maybe more similar to the genome of C. hispida var. hispida than that of C. hispida var. grandiflora. These diploid genomes show few structural differences when compared to C. sativa’s genome indicating little change to chromosome structure following allopolyploidization. This work also indicates that C. neglecta and C. hispida are important resources for understanding the genetics of C. sativa and potential resources for crop improvement.
Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height
Authors: Hattori Atsushi , Seki Atsuhito , Inaba Naoto , Nakabayashi Kazuhiko , Takeda Kazue , Tatsusmi Kuniko , Naiki Yasuhiro , Nakamura Akie , Ishiwata Keisuke , Matsumoto Kenji , Nasu Michiyo , Okamura Kohji , Michigami Toshimi , Katoh-Fukui Yuko , Umezawa Akihiro , Ogata Tsutomu , Kagami Masayo , Fukami Maki 
Published: August 2021

AbstractAdult men are, on average, ∼13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.
A universal approach for integrating super large-scale single-cell transcriptomes by exploring gene rankings
Authors: Shen Hongru , Shen Xilin , Feng Mengyao , Wu Dan , Zhang Chao , Yang Yichen , Yang Meng , Hu Jiani , Liu Jilei , Wang Wei , Li Yang , Zhang Qiang , Yang Jilong , Chen Kexin , Li Xiangchun 
Published: August 2021

AbstractAdvancement in single-cell RNA sequencing leads to exponential accumulation of single-cell expression data. However, there is still lack of tools that could integrate these unlimited accumulation of single-cell expression data. Here, we presented a universal approachiSEEEKfor integrating super large-scale single-cell expression via exploring expression rankings of top-expressing genes. We developediSEEEKwith 13.7 million single-cells. We demonstrated the efficiency ofiSEEEKwith canonical single-cell downstream tasks on five heterogenous datasets encompassing human and mouse samples.iSEEEKachieved good clustering performance benchmarked against well-annotated cell labels. In addition,iSEEEKcould transfer its knowledge learned from large-scale expression data on new dataset that was not involved in its development.iSEEEKenables identification of gene-gene interaction networks that are characteristic of specific cell types. Our study presents a simple and yet effective method to integrate super large-scale single-cell transcriptomes and would facilitate translational single-cell research from bench to bedside.
Influence of condensation domains on activity and specificity of adenylation domains
Authors: Kranz Janik , Wenski Sebastian L. , Dichter Alexander A. , Bode Helge B. , Bozhüyük Kenan A. J. 
Published: August 2021

AbstractMany clinically used natural products are produced by non-ribosomal peptide synthetases (NRPSs), which due to their modular nature should be accessible to modification and engineering approaches. While the adenylation domain (A) plays the key role in substrate recognition and activation, the condensation domain (C) which is responsible for substrate linkage and stereochemical filtering recently became the subject of debate - with its attributed role as a “gatekeeper” being called into question. Since we have thoroughly investigated different combinations of C-A didomains in a series of in vitro, in vivo, and in situ experiments suggesting an important role to the C-A interface for the activity and specificity of the downstream A domain and not the C domain as such, we would like to contribute to this discussion. The role of the C-A interface, termed ‘extended gatekeeping’, due to structural features of the C domains, can also be transferred to other NRPSs by engineering, was finally investigated and characterised in an in silico approach on 30 wild-type and recombinant C-A interfaces. With these data, we not only would like to offer a new perspective on the specificity of C domains, but also to revise our previously established NRPS engineering and construction rules.
Divergent effect of central incretin receptors inhibition in a rat model of sporadic Alzheimer’s disease
Authors: Barilar Jelena Osmanovic , Knezovic Ana , Homolak Jan , Perhoc Ana Babic , Salkovic-Petrisic Melita 
Published: August 2021

SummaryThe incretin system is an emerging new field that might provide valuable contributions to the research of both pathophysiology and therapeutic strategies in the treatment of diabetes, obesity, and neurodegenerative disorders. This study aimed to explore the role of central glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) on cell metabolism and energy in the brain as well as on the levels of these incretins, insulin and glucose, by inhibiting the central incretins’ receptors following intracerebroventricular administration of the respective antagonists in healthy rats and a streptozotocin-induced rat model of sporadic Alzheimer’s disease (sAD). Chemical ablation of the central GIP receptor (GIPR) or GLP-1 receptor (GLP-1R) in healthy and diseased animals indicated a region-dependent role of incretins in the brain cell energy and metabolism and central incretin-dependent modulation of peripheral hormone secretion, markedly after GIPR inhibition, as well as a dysregulation of the GLP-1 system in experimental sAD.
Comprehensive Analysis of Co-Mutations Identifies Cooperating Mechanisms of Tumorigenesis
Authors: Jiang Limin , Yu Hui , Ness Scott , Mao Peng , Guo Fei , Tang Jijun , Guo Yan 
Published: August 2021

AbstractSomatic mutations are one of the most important factors in tumorigenesis and are the focus of most cancer sequencing efforts. The co-occurrence of multiple mutations in one tumor has gained increasing attention as a means of identifying cooperating mutations or pathways that contribute to cancer.Using multi-omics, phenotypical, and clinical data from 29,559 cancer subjects and 1,747 cancer cell lines covering 78 distinct cancer types, we show that co-mutations are associated with prognosis, drug sensitivity, and disparities in sex, age, and race. Some co-mutation combinations displayed stronger effects than their corresponding single mutations. For example, co-mutation TP53:KRAS in pancreatic adenocarcinoma is significantly associated with disease specific survival (hazard ratio = 2.87, adjusted p-value = 0.0003) and its prognostic predictive power is greater than either TP53 or KRAS as individually mutated genes. Functional analyses revealed that co-mutations with higher prognostic values have higher potential impact and cause greater dysregulation of gene expression. Furthermore, many of the prognostically significant co-mutations caused gains or losses of binding sequences of RNA binding proteins or micro RNAs with known cancer associations. Thus, detailed analyses of co-mutations can identify mechanisms that cooperate in tumorigenesis.
Differential gene expression reveals host factors for viral shedding variation in mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza virus
Authors: Dolinski Amanda C. , Homola Jared J. , Jankowski Mark D. , Robinson John D. , Owen Jennifer C. 
Published: August 2021

AbstractIntraspecific variation in pathogen shedding impacts disease transmission dynamics; therefore, understanding the host factors associated with individual variation in pathogen shedding is key to controlling and preventing outbreaks. In this study, ileum and bursa of Fabricius tissues of mallards (Anas platyrhynchos) infected with low-pathogenic avian influenza (LPAIV) were evaluated at various post-infection time points to determine genetic host factors associated with intraspecific variation in viral shedding. By analyzing transcriptome sequencing data (RNA-seq), we found that LPAIV-infected mallards do not exhibit differential gene expression compared to uninfected birds, but that gene expression was associated with viral shedding quantity early in the infection. In both tissues, immune genes were mostly up-regulated in higher shedding birds and had significant positive relationships with viral shedding. In the ileum, host genes involved in viral cell entry were down-regulated in low shedders one day post-infection (DPI), and host genes promoting viral replication were up-regulated in high shedders on two DPI. Our findings indicate that viral shedding is a key factor for gene expression differences in LPAIV-infected mallards, and the genes identified in this study could be important for understanding the molecular mechanisms driving intraspecific variation in pathogen shedding.
Dandelion pappus morphing is actuated by radially patterned material swelling
Authors: Seale Madeleine , Kiss Annamaria , Bovio Simone , Viola Ignazio Maria , Mastropaolo Enrico , Boudaoud Arezki , Nakayama Naomi 
Published: August 2021

AbstractPlants can generate motion by absorbing and releasing water. Such motion often facilitates reproductive success through the dispersal of seeds and fruits or their self-burial into the soil. Asteraceae plants, such as the dandelion, often have a hairy pappus attached to their fruits to allow them to fly and in many cases, these can open and close depending on moisture levels to modify dispersal. Here we demonstrate the relationship between structure, composition and function of the underlying hygroscopic actuator. By investigating the structure and properties of the actuator cell walls we have identified the mechanism by which the dandelion pappus closes and developed a structural computational model that can capture observed pappus closing. This model was used to explore the contribution of differential material domains in the actuator function and the critical design features. We find that the actuator relies on the radial arrangement of vascular bundles and surrounding tissues including cortex and the floral podium around a central cavity. This allows heterogeneous swelling in a radially symmetric manner to co-ordinate precise movements of the pappus hairs attached at the upper flank. This actuator is a derivative of bilayer structures, but is radial and can synchronise the movement of a planar or lateral attachment. The simple, material-based mechanism presents a promising biomimetic potential in robotics and functional materials.
Extreme purifying selection against point mutations in the human genome
Authors: Dukler Noah , Mughal Mehreen R. , Ramani Ritika , Huang Yi-Fei , Siepel Adam 
Published: August 2021

AbstractGenome sequencing of tens of thousands of humans has enabled the measurement of large selective effects for mutations to protein-coding genes. Here we describe a new method, called ExtRaINSIGHT, for measuring similar selective effects in noncoding as well as in coding regions of the human genome. ExtRaINSIGHT estimates the prevalance of strong purifying selection, or “ultraselection” (λs), as the fractional depletion of rare single-nucleotide variants in target genomic sites relative to matched sites that are putatively free from selection, after controlling for local variation and neighbor-dependence in mutation rate. We show using simulations that λs is closely related to the average site-specific selection coefficient against heterozygous point mutations, as predicted at mutation-selection balance. Applying ExtRaINSIGHT to 71,702 whole genome sequences from gnomAD v3, we find strong evidence of ultraselection in evolutionarily ancient miRNAs and neuronal protein-coding genes, as well as at splice sites. By contrast, we find weak evidence in other noncoding RNAs and transcription factor binding sites, and only modest evidence in ultraconserved elements and human accelerated regions. We estimate that ~0.3–0.5% of the human genome is ultraselected, implying ~0.3–0.4 lethal or nearly lethal de novo mutations per potential human zygote. Overall, our study sheds new light on the genome-wide distribution of fitness effects for new point mutations by combining deep new sequencing data sets and classical theory from population genetics.
Yersinia pseudotuberculosis YopE prevents uptake by M cells and instigates M cell extrusion in human ileal enteroid-derived monolayers
Authors: Fasciano Alyssa C. , Dasanayake Gaya S. , Estes Mary K. , Zachos Nicholas C. , Breault David T. , Isberg Ralph R. , Tan Shumin , Mecsas Joan 
Published: August 2021

AbstractMany pathogens use M cells to access the underlying Peyer’s patches and spread to systemic sites via the lymph as demonstrated by ligated loop murine intestinal models. However, the study of interactions between M cells and microbial pathogens has stalled due to the lack of cell culture systems. To overcome this obstacle, we use human ileal enteroid-derived monolayers containing five intestinal cell types including M cells to study the interactions between the enteric pathogen, Yersinia pseudotuberculosis (Yptb) and M cells. The Yptb type three secretion system (T3SS) effector Yops inhibit host defenses including phagocytosis and are critical for colonization of the intestine and Peyer’s patches. Therefore, it is not understood how Yptb traverses through M cells to breach the epithelium. By growing Yptb under two physiological conditions that mimic the early infectious stage (low T3SS-expression) or host-adapted stage (high T3SS-expression), we found that large numbers of Yptb specifically associated with M cells, recapitulating murine studies. Transcytosis through M cells was significantly higher by Yptb expressing low levels of T3SS, because YopE and YopH prevented Yptb uptake. YopE also caused M cells to extrude from the epithelium without inducing cell-death or disrupting monolayer integrity. Sequential infection with early infectious stage Yptb reduced host-adapted Yptb association with M cells. These data underscore the strength of enteroids as a model by discovering that Yops impede M cell function, indicating that early infectious stage Yptb more effectively penetrates M cells while the host may defend against M cell penetration of host-adapted Yptb.
Tunable Cellular Localization and Extensive Cytoskeleton-Interplay of Reflectins
Authors: Song Junyi , Liu Chuanyang , Li Baoshan , Liu Liangcheng , Zeng Ling , Ye Zonghuang , Mao Ting , Wu Wenjian , Hu Biru 
Published: August 2021

AbstractReflectin proteins are nature copolymers consist of repeated canonical domains, locating in a biophotonic system called Bragg lamellae and manipulating the dynamic structural coloration of iridocytes. Their biological functions are intriguing, but the underlying mechanism is not fully understood. In this study, reflectin A1, A2, B1 and C were found to present distinguished cyto-/nucleoplasmic localization preferences. Comparable intracellular localization can be reproduced by truncated reflectin variants, suggesting a conceivable evolutionary order among reflectin proteins. Secondly, the size-dependent access of reflectin variants into nucleus demonstrate a potential model of how reflectins get into Bragg lamellae. Thirdly, RfA1 was found to extensively interact with cytoskeleton, including its binding to actin and microtubule minus-end-directed movement. This implies cytoskeleton system plays fundamental role during the organization and transportation of reflectin proteins. Findings presented here recommend reflectins as programmable biomaterials which can be used to decipher their evolution processes, to delineate their biological mechanism, and to achieve tunable intracellular targeting as editable tags.
Viral spillover risk increases with climate change in High Arctic lake sediments
Authors: Lemieux Audrée , Colby Graham A. , Poulain Alexandre J. , Aris-Brosou Stéphane 
Published: August 2021

AbstractThe host spectrum of viruses is quite diverse, as they can sustainedly infect a few species to several phyla. When confronted with a new host, a virus may even infect it and transmit sustainably in this new host, a process called “viral spillover.” However, the risk of such events is difficult to quantify. As climate change is rapidly transforming environments, it is becoming critical to quantify the potential for spillovers. To address this issue, we resorted to a metagenomics approach and focused on two environments, soil and lake sediments from Lake Hazen, the largest High Arctic freshwater lake in the world. We used DNA and RNA sequencing to reconstruct the lake’s virosphere in both its sediments and soils, as well as its range of eukaryotic hosts. We then estimated the spillover risk by measuring the congruence between the viral and the eukaryotic host phylogenetic trees, and show that spillover risk is higher in lake sediments than in soil, and increases with runoff from glacier melt, a proxy for climate change. Should climate change also shift species range of potential viral vectors and reservoirs northwards, the High Arctic could become fertile ground for emerging pandemics.
Isolation and Genomics of multidrug-resistant Brevundimonas diminuta collected from patients with pertussis-like symptoms
Authors: Safarchi Azadeh , Nikbin Vajihe Sadat , Saedi Samaneh , Dinarvand Mojdeh , Sedaghatpour Mahdi , Lotfi Masoumeh Nakhost , Tay Chin Yen , Lamichhane Binit , Shahcheraghi Fereshteh 
Published: August 2021

AbstractBrevundinomas diminuta is known as an opportunistic pathogen and is rarely associated with invasive infections in humans causing infection in the different parts of the body. In this study, we identified three B. diminuta isolates from three patients with an initial diagnosis of pertussis. Isolates were confirmed using biochemical tests and 16s rRNA sequencing. All isolates were resistant to three different classes of antimicrobial drugs including ceftazidime and ciprofloxacin. We performed Illumina whole-genome sequencing for two isolates. The results showed an average genome size of 3.25 Mbp with the G+C content 67% with multiple predicted virulence factors and genes leading to antibiotic resistance. We found an open pan-genome with 1502 core genes by analysing 13 available global B. diminuta isolated from different environments such as water, soil, or gentamicin fermentation residue. In the phylogenetic analysis, our isolates were grouped with B. diminuta isolate collected from an oral cavity of a patient in the USA.