bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide variability in recombination activity is associated with meiotic chromatin organization
Authors: Jin Xiaofan , Fudenberg Geoff , Pollard Katherine S. 
Published: January 2021

AbstractBackgroundRecombination enables reciprocal exchange of genomic information between parental chromosomes and successful segregation of homologous chromosomes during meiosis. Errors in this process lead to negative health outcomes, while variability in recombination rate affects genome evolution. In mammals, most crossovers occur in hotspots defined by PRDM9 motifs, though PRDM9 binding sites are not all equally hot. We hypothesize that dynamic patterns of meiotic genome folding are linked to recombination activity.ResultsWe apply an integrative bioinformatics approach to analyze how three-dimensional (3D) chromosomal organization during meiosis relates to rates of double-strandbreak (DSB) and crossover formation at PRDM9 hotspots. We show that active, spatially accessible genomic regions during meiotic prophase are associated with DSB-favoured hotspots, which further adopt a transient locally active configuration in early prophase. Conversely, crossover formation is depleted among DSBs in spatially accessible regions during meiotic prophase, particularly within gene bodies. We also find evidence that active chromatin regions have smaller average loop sizes in mammalian meiosis. Collectively, these findings establish that differences in chromatin architecture along chromosomal axes are associated with variable recombination activity.ConclusionsWe propose an updated framework describing how 3D organization of brush-loop chromosomes during meiosis may modulate recombination.
Human B cell lineages engaged by germinal centers following influenza vaccination are measurably evolving
Authors: Hoehn Kenneth B. , Turner Jackson S. , Miller Frederick I. , Jiang Ruoyi , Pybus Oliver G. , Ellebedy Ali H. , Kleinstein Steven H. 
Published: January 2021

AbstractPoor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses.1Consistent with this notion, no significant increase in somatic hypermutation (SHM) among circulating influenza-binding lineages was detected following seasonal vaccination in humans.2A more recent study showed that at least a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages can occur.3Crucially, however, it has not been demonstrated whether these GC-engaged lineages actually accumulate additional SHM. Here, we address this point using a phylogenetic test of measurable evolution. We first validate this test through simulations and demonstrate measurable B cell evolution in known examples of affinity maturation such as the response to HIV infection. We then show that lineages in the blood are rarely measurably evolving following influenza vaccination, but that GC-engaged lineages - likely derived from memory B cells - are frequently measurably evolving. These findings confirm that seasonal influenza virus vaccination can stimulate additional SHM among responding B cell lineages.
Association between resting-state functional brain connectivity and gene expression is altered in autism spectrum disorder
Authors: Berto Stefano , Treacher Alex , Caglayan Emre , Luo Danni , Haney Jillian R. , Gandal Michael J. , Geschwind Daniel H. , Montillo Albert , Konopka Genevieve 
Published: January 2021

AbstractGene expression covaries with brain activity as measured by resting state functional MRI. However, it is unclear how genomic differences driven by disease state can affect this relationship. Here, we integrate brain gene expression datasets of neurotypical controls and autistic (ASD) patients with regionally matched brain activity measurements from fMRI datasets. We identify genes linked with brain activity whose association is disrupted in ASD patients. We identified a subset of genes that showed a differential developmental trajectory in ASD patients compared with controls. These genes are enriched in voltage-gated ion channels and inhibitory neurons, pointing to excitation-inhibition imbalance in ASD. We further assessed differences at the regional level showing that the primary visual cortex is the most affected region in ASD patients. Our results link disrupted brain expression patterns of individuals with ASD to brain activity and show developmental, cell type, and regional enrichment of activity linked genes.
Inherent random fluctuations in COVID-19 outbreaks may explain rapid growth of new mutated virus variants
Authors: Bodin Kenneth , Rocklöv Joacim 
Published: January 2021

AbstractA new virus variant of SARS-COV-2 has had a profound impact on society while governments have taken action to limit its impacts by enforcing lockdowns and limiting spread from the UK to other countries. Variants with mutations in the virus genome are likely to occur, but do not always associate to significant changes in the biology of the virus, or the disease. For the variant VOC 202012/01 (also referred to as B.1.1.7), however, preliminary reports indicate it may be more transmissible. Here we use a simulation model calibrated to the inherent random fluctuating transmission pattern of COVID-19 to investigate what the probability may be for detecting more transmissible virus variants post facto. We find that post facto identification of successful virus variants of SARS-COV-2 are likely to exhibit growth rates that are substantially larger than the average growth rate. This finding has implications for interpreting growth rate and transmissibility of new virus variants.
MinION™, a portable long-read sequencer, enables rapid vaginal microbiota analysis in a clinical setting
Authors: Komiya Shinnosuke , Matsuo Yoshiyuki , Nakagawa So , Morimoto Yoshiharu , Kryukov Kirill , Okada Hidetaka , Hirota Kiichi 
Published: January 2021

AbstractIt has been suggested that the local microbiota in the reproductive organs is relevant to women’s health and may also affect pregnancy outcomes. Analysis of partial 16S ribosomal RNA (rRNA) gene sequences generated by short-read sequencers has been used to identify vaginal and endometrial microbiota, but it requires a long time to obtain the results, making it unsuitable for the rapid analysis of small samples in a clinical context. We demonstrated a simple workflow using the nanopore sequencer MinION™ that allows high-resolution and rapid differentiation of vaginal microbiota. Vaginal samples collected from 18 participants were subjected to DNA extraction and full-length 16S rRNA gene sequencing with MinION™. The principal coordinate analysis showed no differences in the bacterial compositions regardless of the sample collection method. The vaginal microbiota results could be reported within 2 days of specimen receipt. Although bacterial vaginosis (BV) was not diagnosed by the Nugent score in any cases, groups with both healthy and BV-like vaginal microbiota were clearly characterized by MinION™ sequencing. We conclude that full-length 16S rRNA gene sequencing analysis with MinION™ provides a rapid means for identifying vaginal bacteria with higher resolution. Species-level profiling of human vaginal microbiota by MinION™ sequencing can allow the analysis of associations with conditions such as genital infections, endometritis, and threatened miscarriage.
CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge
Authors: Lien Chia-En , Lin Yi-Jiun , Chen Charles , Lian Wei-Cheng , Kuo Tsun-Yung , Campbell John D , Traquina Paula , Lin Meei-Yun , Liu Luke Tzu-Chi , Chuang Ya-Shan , Ko Hui-Ying , Liao Chun-Che , Chen Yen-Hui , Jan Jia-Tsrong , Sun Cheng-Pu , Lin Yin-Shiou , Wu Ping-Yi , Wang Yu-Chiuan , Tao Mi-Hua , Lin Yi-Ling 
Published: January 2021

AbstractThe COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 μg or 5 μg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.
Assessing the Involvement of Platelet Degranulation in the Therapeutic Properties of Exosome Derived from Amniotic Epithelial Cells through Enrichment and Interaction Network Analysis
Authors: Valizadeh M. , Bangash A. Haider , Hayati D. , Jafari A. , Rajabi-Maham H. 
Published: January 2021

AbstractPlatelet degranulation allows the release of large secretable pools of biologically active proteins which are critical in wound healing initiation and angiogenesis. Exosomes, which can transport a diverse suite of macromolecules, derived from amniotic epithelial cells (AEC-Exo) improve wound healing and angiogenesis. However, the underlying mechanisms are still unclear. In this investigation, we performed a user-friendly bioinformatics analysis system to identify association among the angiogenic and wound healing effects of AEC-Exo treatments. To this end, FunRich software was used, and linked to the Universal Protein Resource (UniProt) as a background database. Several enrichment analyses, including biological process, cellular component, molecular function, and protein domains were conducted on AEC-Exo proteome. Furthermore, to identify the proteins involved in platelet degranulation and evaluate protein–protein association information, comparative analyses and interaction network analyses were illustrated using the NCBI BioSystems, ExoCarta, and STRING databases. Our results indicated the statistically significant association between the proteome in AEC-Exo, platelet degranulation, and their corresponding processes. Therefore, the involvement of platelet degranulation in AEC-Exo proteins may elucidate the angiogenic and wound-healing effects of AEC-Exo treatments.
Capsule network for protein ubiquitination site prediction
Authors: Huang Qiyi , Jiang Jiulei , Luo Yin , Li Weimin , Wang Ying 
Published: January 2021

AbstractUbiquitination modification is one of the most important protein posttranslational modifications used in many biological processes. Traditional ubiquitination site determination methods are expensive and time-consuming, whereas calculation-based prediction methods can accurately and efficiently predict ubiquitination sites. This study used a convolutional neural network and a capsule network in deep learning to design a deep learning model, “Caps-Ubi,” for multispecies ubiquitination site prediction. Two encoding methods, one-of-K and the amino acid continuous type were used to characterize the sequence pattern of ubiquitination sites. The proposed Caps-Ubi predictor achieved an accuracy of 0.91, a sensitivity of 0.93, a specificity of 0.89, a measure-correlate-prediction of 0.83, and an area under receiver operating characteristic curve value of 0.96, which outperformed the other tested predictors.
The intensity of the immune response to LPS andE. coliregulates the induction of preterm labor in Rhesus Macaques
Authors: Cappelletti Monica , Presicce Pietro , Ma Feyaing , Senthamaraikannan Paranthaman , Miller Lisa A. , Pellegrini Matteo , Jobe Alan H. , Divanovic Senad , Way Sing Sing , Chougnet Claire A. , Kallapur Suhas G. 
Published: January 2021

ABSTRACTIntrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed Rhesus macaque models of IUI driven by lipopolysaccharyde (LPS) or liveE. coli. PTL did not occur in LPS challenged Rhesus macaque whileE. coliinfected animals frequently delivered preterm. Although LPS and liveE. coliboth caused immune cell infiltration,E. coliinfected animals showed higher levels of inflammatory mediators, particularly IL6 and prostaglandins, in the chorioamnion decidua and amniotic fluid. Neutrophil infiltration in the chorion was a common feature to both LPS andE. coli. However, neutrophilic infiltration andIL6andPTGS2expression in the amnion was specifically induced by liveE. coli. RNASeq analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon response, chemotaxis, sumoylation and iron homeostasis were upregulated in theE. coligroup compared to the LPS group. Our data suggest that intensity of the host immune response to IUI may determine susceptibility to PTL.
Phosphorylation of the selective autophagy receptor TAX1BP1 by canonical and noncanonical IκB kinases promotes its lysosomal localization and clearance of MAVS aggregates
Authors: Choi Young Bong , Zhang Jiawen , Vo Mai Tram , White Jesse , He Chaoxia , Harhaj Edward W. 
Published: January 2021

AbstractTAX1BP1 is a selective autophagy receptor which inhibits NF-κB and RIG-I-like receptor (RLR) signaling to prevent excessive inflammation and maintain homeostasis. Selective autophagy receptors such as p62/SQSTM1 and OPTN are phosphorylated by the noncanonical IκB kinase TBK1 to stimulate their selective autophagy function. However, it is unknown if TAX1BP1 is regulated by TBK1 or other kinases under basal conditions or during RNA virus infection. Here, we found that the noncanonical IκB kinases TBK1 and IKKi phosphorylate TAX1BP1 to regulate its basal turnover, whereas the canonical IκB kinase IKKα and the core autophagy factor ATG9 play essential roles in RNA virus-mediated TAX1BP1 autophagosomal degradation. TAX1BP1 phosphorylation by canonical and noncanonical IκB kinases promotes its localization to lysosomes resulting in its degradation. Furthermore, TAX1BP1 plays a critical role in the clearance of MAVS aggregates, and phosphorylation of TAX1BP1 augments its MAVS aggrephagy function. Together, our data support a model whereby IκB kinases license TAX1BP1 selective autophagy function to inhibit MAVS and RLR signaling.Author SummaryThe RIG-I-like receptor (RLR) pathway induces type I interferon (IFN) and proinflammatory cytokines in response to RNA virus infection. MAVS is a mitochondrial adaptor protein in the RLR pathway that forms prion-like aggregates upon activation; however, how MAVS aggregates are cleared to restore homeostasis is unclear. Autophagy is a lysosomal degradation pathway important for the clearance of potentially cytotoxic protein aggregates that could induce inflammation and/or cell death. TAX1BP1 is a selective autophagy receptor that inhibits RLR signaling, but the precise mechanisms remain unknown. Here, we found that TAX1BP1 is a substrate for multi-site phosphorylation by canonical and noncanonical IκB kinases which triggered its lysosomal localization and degradation. We also found that TAX1BP1 was critical for the clearance of MAVS aggregates in a phosphorylation-dependent manner. Overall, our data suggest that phosphorylation serves a key regulatory function for TAX1BP1 to inhibit RLR signaling.
Potential biomarker of human papillomavirus 16 L1 methylation for prediction of anal intraepithelial neoplasia in men who have sex with men (MSM)
Authors: Chaiwongkot Arkom , Phanuphak Nittaya , Pankam Tippawan , Bhattarakosol Parvapan 
Published: January 2021

AbstractQuantitative measurement of human papillomavirus (HPV) 16 early promoter and L1 genes methylation were analyzed in anal cells collected from men who have sex with men (MSM) to determine the potential biomarker for screening of HPV related anal cancer. The methylation patterns of the HPV16 genes including early promoter (CpG 31, 37, 43, 52 and 58) and L1 gene (CpG 5600, 5606, 5609, 5615, 7136 and 7145) were analyzed in 178 anal samples with histology diagnosed as normal, anal intraepithelial neoplasia (AIN) 1, AIN2 and AIN3 by pyrosequencing assay. Low methylation levels of early promoter (<10%) and L1 genes (<20%) were found in all detected normal anal cells, while medium to high methylation (>20-60%) in early promoter was found 1.5% (1/67) and 5% (2/40) in AIN1 and AIN2-3 samples, respectively. Interestingly, slightly increased L1 gene methylation level (>20-60%) especially at HPV16 5’L1 regions CpGs 5600 and 5609 from normal to AIN3 were demonstrated. Moreover, negative correlation between high HPV16 L1 gene methylation at CpGs 5600, 5609, 5615 and 7145 and low percentage of CD4+ was found in AIN3 HIV positive cases. When compared methylation status of AIN2-3 to those of the normal/AIN1 lesion, the results indicated potential of using HPV16 L1 gene methylation as a biomarker for HPV related cancer screening.
Milieu matters: Anin vitrowound milieu to recapitulate key features of, and probe new insights into, polymicrobial biofilms
Authors: Kadam Snehal , Madhusoodhanan Vandana , Bhide Devyani , Ugale Rutuja , Tikhole Utkarsha , Kaushik Karishma S 
Published: January 2021

AbstractBacterial biofilms are a major cause of delayed wound healing. Consequently, the study of wound biofilms, particularly in host-relevant conditions, has gained importance. Mostin vitrobiofilm studies employ refined laboratory media to study biofilms, conditions that are not relevant to the infection state. To mimic the wound milieu,in vitrobiofilm studies often incorporate serum or plasma in growth conditions, or employ clot or matrix-based biofilm models. While incorporating serum or plasma alone is a minimalistic approach, the more complexin vitrowound models are technically demanding, and poorly compatible with standard biofilm assays. Based on previous reports of clinical wound fluid composition, we have developed anin vitrowound milieu (IVWM) that includes, in addition to serum (to recapitulate wound fluid), matrix elements and biochemical factors. In comparison with Luria-Bertani broth and Fetal Bovine Serum (FBS), the IVWM was used to study planktonic growth and biofilm features, including interspecies interactions, of common wound pathogens,Staphylococcus aureusandPseudomonas aeruginosa. We demonstrate that the IVWM recapitulates widely reportedin vivobiofilm features such as metabolic activity, increased antibiotic tolerance, 3D structure, and interspecies interactions for single- and co-species biofilms. Further, the IVWM is simple to formulate, uses laboratory-grade components, and is compatible with standard biofilm assays. Given this, it holds potential as a tractable approach to study wound biofilms under host-relevant conditions.
New targets for drug design: Importance of nsp14/nsp10 complex formation for the 3’-5’ exoribonucleolytic activity on SARS-CoV-2
Authors: Saramago Margarida , Bárria Cátia , Costa Vanessa , Souza Caio S. , Viegas Sandra C. , Domingues Susana , Lousa Diana , Soares Cláudio M , Arraiano Cecília M , Matos Rute G. 
Published: January 2021

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has triggered a global pandemic with devastating consequences for health-care and social-economic systems. Thus, the understanding of fundamental aspects of SARS-CoV-2 is of extreme importance.In this work, we have focused our attention on the viral ribonuclease (RNase) nsp14, since this protein was considered one of the most interferon antagonists from SARS-CoV-2, and affects viral replication. This RNase is a multifunctional protein that harbors two distinct activities, an N-terminal 3’-to-5’ exoribonuclease (ExoN) and a C-terminal N7-methyltransferase (N7-MTase), both with critical roles in coronaviruses life cycle. Namely, SARS-CoV-2 nsp14 ExoN knockout mutants are non-viable, indicating nsp14 as a prominent target for the development of antiviral drugs.Nsp14 ExoN activity is stimulated through the interaction with the nsp10 protein, which has a pleiotropic function during viral replication. In this study, we have performed the first biochemical characterization of the complex nsp14-nsp10 from SARS-CoV-2. Here we confirm the 3’-5’ exoribonuclease and MTase activities of nsp14 in this new Coronavirus, and the critical role of nsp10 in upregulating the nsp14 ExoN activityin vitro. Furthermore, we demonstrate that SARS-CoV-2 nsp14 N7-MTase activity is functionally independent of the ExoN activity. The nsp14 MTase activity also seems to be independent of the presence of nsp10 cofactor, contrarily to nsp14 ExoN.Until now, there is no available structure for the SARS-CoV-2 nsp14-nsp10 complex. As such, we have modelled the SARS-CoV-2 nsp14-nsp10 complex based on the 3D structure of the complex from SARS-CoV (PDB ID 5C8S). We also have managed to map key nsp10 residues involved in its interaction with nsp14, all of which are also shown to be essential for stimulation of the nsp14 ExoN activity. This reinforces the idea that a stable interaction between nsp10 and nsp14 is strictly required for the nsp14-mediated ExoN activity of SARS-CoV-2, as observed for SARS-CoV.We have studied the role of conserved DEDD catalytic residues of SARS-CoV-2 nsp14 ExoN. Our results show that motif I of ExoN domain is essential for the nsp14 function contrasting to the functionality of these conserved catalytic residues in SARS-CoV, and in the Middle East respiratory syndrome coronavírus (MERS). The differences here revealed can have important implications regarding the specific pathogenesis of SARS-CoV-2.The nsp10-nsp14 interface is a recognized attractive target for antivirals against SARS-CoV-2 and other coronaviruses. This work has unravelled a basis for discovering inhibitors targeting the specific amino acids here reported, in order to disrupt the assembly of this complex and interfere with coronaviruses replication.