bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structure based virtual screening identifies novel competitive inhibitors for the sialoglycan binding protein Hsa
Authors: Agarwal Rupesh , Bensing Barbara A. , Mi Dehui , Vinson Paige N. , Baudry Jerome , Iverson Tina M. , Smith Jeremy C. 
Published: March 2020

AbstractInfective endocarditis (IE) is a cardiovascular disease often caused by bacteria of theviridansgroup of streptococci, which includesStreptococcus gordoniiandStreptococcus sanguinis. Previous research has found that a serine-rich repeat (SRR) proteins on theS. gordoniibacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialyated glycans displayed on human platelets. Despite its important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel inhibitors against the sialoglycan binding domain of the SRR adhesin protein Hsa from theS. gordoniistrain DL1.In silicocross screening against the glycan binding domains of closely related SRR proteins from five otherS. gordoniiorS. sanguinisstrains was also performed to further reduce false positives. Using ourin silicoscreening strategy we successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in anin vitroassay and bind competitively to adhesin protein Hsa (∼20% hit rate).
Immunological cross-reactions with paramyxovirus nucleoproteins may explain sporadic apparent ebolavirus seropositivity in European populations
Authors: Bishop Lisa A. , Müllner Marcell , Bjurhult-Kennedy Amalie , Lauder Robert M. , Gatherer Derek 
Published: March 2020

AbstractAlthough confirmed outbreaks of Ebola Virus Disease (EVD) have been confined to central and west Africa, seropositivity to Zaire ebolavirus (EBOV) has been reported in other parts of Africa and even in one study from the early 1990s in Germany. The possible reasons for the discrepancy between serological studies and clinical evidence, remain uncertain. Here, we report anonymous serum donors sampled in Lancaster (UK) with seropositivity by ELISA to EBOV nucleoprotein at a frequency of approximately 2%. In one serum donor, we confirm the result using Western blot. This is only the second report of seropositivity for EBOV outside of Africa. Our samples are negative to EBOV glycoprotein, suggesting that the seropositivity is specific to the nucleoprotein and may be due to cross-reaction with antibodies produced by exposure to another virus. To investigate potential candidates for this cross-reacting virus, we perform bioinformatics analysis that suggests that EBOV nucleoprotein has structural similarity to paramyxovirus nucleoproteins at a candidate immunological epitope. Cross-reaction of antibodies against paramyxovirus nucleoproteins, with EBOV nucleoprotein antigens used in serological testing, may be the cause of the rare instances of ebolavirus seropositivity in Europe, and may also be a confounding factor in African serosurveys.
“DOCK3 is a dosage-sensitive regulator of skeletal muscle and Duchenne muscular dystrophy-associated pathologies”
Authors: Reid Andrea L. , Wang Yimin , Samani Adrienne , Hightower Rylie M. , Lopez Michael A. , Gilbert Shawn R. , Ianov Lara , Crossman David K. , Dell’Italia Louis J. , Millay Douglas P. , van Groen Thomas , Halade Ganesh V. , Alexander Matthew S. 
Published: March 2020

AbstractDOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression ofDOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. By utilizingDock3global knockout (Dock3KO) mice, we found reducingDock3gene via haploinsufficiency in DMD mice improved dystrophic muscle histology, however complete loss ofDock3worsened overall muscle function on a dystrophin-deficient background. Consistent with this,Dock3KO mice have impaired muscle architecture and myogenic differentiation defects. Moreover, transcriptomic analyses ofDock3knockout muscles reveal a decrease in factors known for myogenesis, suggesting a possible mechanism of action. These studies identifyDOCK3as a novel modulator of muscle fusion and muscle health and may yield additional therapeutic targets for treating dystrophic muscle symptoms.
A Comprehensive Multi-Center Cross-platform Benchmarking Study of Single-cell RNA Sequencing Using Reference Samples
Authors: Chen Wanqiu , Zhao Yongmei , Chen Xin , Xu Xiaojiang , Yang Zhaowei , Bi Yingtao , Chen Vicky , Li Jing , Choi Hannah , Ernest Ben , Tran Bao , Mehta Monika , Moos Malcolm , Farmer Andrew , Mir Alain , Kumar Parimal , Mehra Urvashi , Li Jian-Liang , Xiao Wenming , Wang Charles 
Published: March 2020

AbstractSingle-cell RNA sequencing (scRNA-seq) has become a very powerful technology for biomedical research and is becoming much more affordable as methods continue to evolve, but it is unknown how reproducible different platforms are using different bioinformatics pipelines, particularly the recently developed scRNA-seq batch correction algorithms. We carried out a comprehensive multi-center cross-platform comparison on different scRNA-seq platforms using standard reference samples. We compared six pre-processing pipelines, seven bioinformatics normalization procedures, and seven batch effect correction methods including CCA, MNN, Scanorama, BBKNN, Harmony, limma and ComBat to evaluate the performance and reproducibility of 20 scRNA-seq data sets derived from four different platforms and centers. We benchmarked scRNA-seq performance across different platforms and testing sites using global gene expression profiles as well as some cell-type specific marker genes. We showed that there were large batch effects; and the reproducibility of scRNA-seq across platforms was dictated both by the expression level of genes selected and the batch correction methods used. We found that CCA, MNN, and BBKNN all corrected the batch variations fairly well for the scRNA-seq data derived from biologically similar samples across platforms/sites. However, for the scRNA-seq data derived from or consisting of biologically distinct samples, limma and ComBat failed to correct batch effects, whereas CCA over-corrected the batch effect and misclassified the cell types and samples. In contrast, MNN, Harmony and BBKNN separated biologically different samples/cell types into correspondingly distinct dimensional subspaces; however, consistent with this algorithm’s logic, MNN required that the samples evaluated each contain a shared portion of highly similar cells. In summary, we found a great cross-platform consistency in separating two distinct samples when an appropriate batch correction method was used. We hope this large cross-platform/site scRNA-seq data set will provide a valuable resource, and that our findings will offer useful advice for the single-cell sequencing community.
On Inferring Additive and Replacing Horizontal Gene Transfers Through Phylogenetic Reconciliation
Authors: Kordi Misagh , Kundu Soumya , Bansal Mukul S. 
Published: March 2020

AbstractHorizontal gene transfer is one of the most important mechanisms for microbial evolution and adaptation. It is well known that horizontal gene transfer can be eitheradditiveorreplacingdepending on whether the transferred gene adds itself as a new gene in the recipient genome or replaces an existing homologous gene. Yet, all existing phylogenetic techniques for the inference of horizontal gene transfer assume either that all transfers are additive or that all transfers are replacing. This limitation not only affects the applicability and accuracy of these methods but also makes it difficult to distinguish between additive and replacing transfers.Here, we address this important problem by formalizing a phylogenetic reconciliation framework that simultaneously models both additive and replacing transfer events. Specifically, we (1) introduce theDTRLreconciliation framework that explicitly models both additive and replacing transfer events, along with gene duplications and losses, (2) prove that the underlying computational problem is NP-hard, (3) perform the first experimental study to assess the impact of replacing transfer events on the accuracy of the traditional DTL reconciliation model (which assumes that all transfers are additive) and demonstrate that traditional DTL reconciliation remains highly robust to the presence of replacing transfers, (4) propose a simple heuristic algorithm for DTRL reconciliation based on classifying transfer events inferred through DTL reconciliation as being replacing or additive, and (5) evaluate the classification accuracy of the heuristic under a range of evolutionary conditions. Thus, this work lays the methodological and algorithmic foundations for estimating DTRL reconciliations and distinguishing between additive and replacing transfers.An implementation of our heuristic for DTRL reconciliation is freely available open-source as part of the RANGER-DTL software package fromhttps://compbio.engr.uconn.edu/software/ranger-dtl/.
A Self-Immobilizing NIR Probe for Non-invasive Imaging of Senescence
Authors: Liu Jun , Ma Xiaowei , Cui Chao , Wang Ying , Deenik Philip R. , Cui Lina 
Published: March 2020

AbstractCellular senescence, a process that arrests the cell cycle, is a cellular stress response to various stimuli and is implicated in aging and age-related diseases. However, the understanding of senescence in living organisms is insufficient, largely due to the scarcity of sensitive tools for the detection of cellular senescencein vivo. Herein, we describe the development of a self-immobilizing near-infrared (NIR) probe that can be activated by senescence-associatedβ-Galactosidase (SA-β-Gal), a widely accepted senescence marker. The NIR fluorophore is turned on in the presence of SA-β-Gal, and the self-immobilizing group, based on quinone methide chemistry, retains the fluorescence signal to the site of activation. This strategy significantly improves the sensitivity of the probe from the one we developed before. We demonstrate the non-invasive imaging of drug-induced senescence in mice models.
CyclinD1 controls development of cerebellar granule cell progenitors through phosphorylation and stabilization of ATOH1
Authors: Miyashita Satoshi , Owa Tomoo , Seto Yusuke , Yamashita Mariko , Aida Shogo , Nishioka Tomoki , Kaibuchi Kozo , Kawaguchi Yoshiya , Taya Shinichiro , Hoshino Mikio 
Published: March 2020

AbstractHere we report that CyclinD1 (CCND1) directly regulates both the proliferative and immature states of cerebellar granule cell progenitors (GCPs). CCND1 not only accelerates cell cycle but also upregulates ATOH1 protein, an essential transcription factor that maintains GCPs in an immature state. In cooperation with CDK4, CCND1 directly phosphorylates Ser309 of ATOH1, which inhibits additional phosphorylation at S328, consequently preventing Ser328 phosphorylation-dependent ATOH1 degradation. PROX1 downregulates Ccnd1 expression by histone-deacetylation of Ccnd1 promoter in GCPs, leading to cell cycle exit and differentiation. WNT signaling upregulates PROX1 expression in GCPs. These findings suggest that WNT-PROX1-CCND1-ATOH1 signaling cascade cooperatively controls proliferation and immaturity of GCPs. We revealed that the expression and phosphorylation levels of these molecules dynamically change during cerebellar development, which was suggested to determine appropriate differentiation rates from GCPs to GCs at distinct developmental stages. This study contributes to understanding the regulatory mechanism of GCPs as well as neural progenitors.
The forensic landscape and the population genetic analyses of Hainan Li based on massively parallel sequencing DNA profiling
Authors: Fan Haoliang , Du Zhengming , Wang Fenfen , Wang Xiao , Wen Shao-Qing , Wang Lingxiang , Du Panxin , Liu Hai , Cao Shengping , Luo Zhenming , Han Bingbing , Huang Peiyu , Zhu Bofeng , Qiu Pingming 
Published: March 2020

AbstractDue to the formation of the Qiongzhou Strait by climate change and marine transition, Hainan island isolated from the mainland southern China during the Last Glacial Maximum. Hainan island, located at the southernmost part of China and separated from the Leizhou Peninsula by the Qiongzhou Strait, laid on one of the modern human northward migration routes from Southeast Asia to East Asia. The Hlai-language speaking Li minority, the second largest population after Han Chinese in Hainan island, is the direct descendants of the initial migrants in Hainan island and has unique ethnic properties and derived characteristics, however, the forensic associated studies on Hainan Li population are still insufficient.Hence, 136 Hainan Li individuals were genotyped in this study using the MPS-based ForenSeq™DNA Signature Prep Kit (DNA Primer Set A) to characterize the forensic genetic polymorphism landscape, and DNA profiles were obtained from 152 different molecular genetic markers (27 autosomal STRs, 24 Y-STRs, 7 X-STRs, and 94 iiSNPs). A total of 419 distinct length variants and 586 repeat sequence sub-variants, with 31 novel alleles (at 17 loci), were identified across the 58 STR loci from the DNA profiles of Hainan Li population. We evaluated the forensic characteristics and efficiencies of DAPA, it demonstrated that the STRs and iiSNPs in DAPA were highly polymorphic in Hainan Li population and could be employed in forensic applications. In addition, we set up three Datasets, which included the genetic data of (I). iiSNPs (27 populations, 2640 individuals), (II). Y-STRs (42 populations, 8281 individuals), and (III). Y-haplogroups (123 populations, 4837 individuals) along with the population ancestries and language families, to perform population genetic analyses separately from different perspectives.In conclusion, the phylogenetic analyses indicated that Hainan Li, with a southern East Asia origin and Tai-Kadai language-speaking language, is an isolated population relatively. But the genetic pool of Hainan Li influenced by the limited gene flows from other Tai-Kadai populations and Hainan populations. Furthermore, the establishment of isolated population models will be beneficial to clarify the exquisite population structures and develop specific genetic markers for subpopulations in forensic genetic fields.
A NanoFE Simulation-based Surrogate Machine Learning Model to Predict Mechanical Functionality of Protein Networks from Live Confocal Imaging
Authors: Asgharzadeh Pouyan , Birkhold Annette I. , Triverdi Zubin , Özdemir Bugra , Reski Ralf , Röhrle Oliver 
Published: March 2020

AbstractSub-cellular mechanics plays a crucial role in a variety of biological functions and dysfunctions. Due to the strong structure-function relationship in cytoskeletal protein networks, light can be shed on their mechanical functionality by investigating their structures. Here, we present a data-driven approach employing a combination of confocal live imaging of fluorescent tagged protein networks, in-silico mechanical experiments and machine learning to investigate this relationship. Our designed image processing and nanoFE mechanical simulation framework resolves the structure and mechanical behaviour of cytoskeletal networks and the developed gradient boosting surrogate models link network structure to its functionality. In this study, for the first time, we perform mechanical simulations of Filamentous Temperature Sensitive Z (FtsZ) complex protein networks with close-to-reality network geometry depicting its skeletal functionality inside organelles (here, chloroplasts) of the mossPhyscomitrella patens. Training on synthetically produced simulation data enables predicting the mechanical characteristics of FtsZ network mechanics purely based on its structural features (R2≥ 0.93), therefore allowing to extract structural principles enabling specific mechanical traits of FtsZ, such as load bearing and resistance to buckling failure in case of large network deformation. The presented method and the specific in silico findings from its application may allow in the future to reproduce mechanical cell responses in engineered environments.
Comprehensive proteomics analyses identify PIM kinases as key regulators of IL-15 driven activation of intestinal intraepithelial lymphocytes
Authors: James Olivia J. , Vanderyken Maud , Marchingo Julia M. , Singh Francois , Love Andrew G. , Swamy Mahima 
Published: March 2020

SUMMARYIntestinal intraepithelial lymphocytes (IEL) are an abundant population of tissue-resident T cells that protect the gut from pathogens and maintain intestinal homeostasis. The cytokine IL-15 is transpresented by epithelial cells to IEL in complex with the IL-15 receptor α chain (IL-15Rα). It plays essential roles both in maintaining IEL homeostasis, and in inducing IEL activation in response to epithelial stress. IL-15 overexpression also drives the gluten-induced enteropathy Coeliac disease, through cytotoxic activation of IEL. In order to better understand how IL-15 directly regulates both homeostatic and inflammatory functions of IEL, we set up quantitative proteomics of IL-15/Rα stimulated IEL. We reveal that high IL-15/Rα stimulation licenses cell cycle activation, upregulates the biosynthetic machinery in IEL, increases mitochondrial respiratory capacity and induces expression of cell surface immune receptors and adhesion proteins that potentially drive IEL activation. We find that high IL-15/Rα selectively upregulated the Ser/Thr kinases PIM1 and PIM2 and demonstrate that PIM1/2 are essential for IEL to proliferate, grow, and upregulate Granzyme B in response to high IL-15. Significantly, IEL from Coeliac disease patients express high levels of PIM kinases. These unexpected findings reveal PIM kinases to be key determinants of IEL responses to elevated levels of IL-15.
Chromatin-based mechanisms to coordinate convergent overlapping transcription
Authors: Inagaki Soichi , Takahashi Mayumi , Takashima Kazuya , Oya Satoyo , Kakutani Tetsuji 
Published: March 2020

AbstractIn eukaryotic genomes, transcription units of genes often overlap with other protein-coding and/or noncoding transcription units1,2. In such intertwined genomes, coordinated transcription of nearby or overlapping genes would be important to ensure integrity of genome function; however, the mechanisms underlying this coordination are largely unknown3-6. Here, we show inArabidopsis thalianathat genes with convergent orientation of transcription are major sources of overlapping bidirectional transcripts and that these bidirectionally transcribed genes are regulated by a putative LSD1 family histone demethylase, FLD7,8. Our genome-wide chromatin profiling revealed that FLD downregulated histone H3K4me1 in regions with convergent overlapping transcription. FLD localizes to actively transcribed genes where it colocalizes with elongating RNA polymerase II phosphorylated at Ser-2 or Ser-5 sites. Genome-wide transcription analyses suggest that FLD-mediated H3K4me1 removal negatively regulates bidirectional transcription by retaining the elongating transcription machinery. Furthermore, this effect of FLD on transcription dynamics is mediated by DNA topoisomerase I. Our study has revealed chromatin-based mechanisms to cope with overlapping bidirectional transcription, likely by modulating DNA topology. This global mechanism to cope with bidirectional transcription could be co-opted for specific epigenetic processes, such as cellular memory of responses to environment9.
Loss of Activating Transcription Factor 3 prevents KRAS-mediated pancreatic cancer
Authors: Azizi Nawab , Toma Jelena , Martin Mickenzie , Khalid Muhammad Faran , Steele Nina , Shi Jiaqi , Pasca di Magliano Marina , Pin Christopher L. 
Published: March 2020

AbstractThe unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, wxe examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation ofAtf3(Atf3-/-) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D).Atf3-/-mice with (termedAPK) and without KRASG12Dwere exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis,Atf3-/-mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC inPtf1acreERT/+KrasLSL-G12Dmice. In response to injury, KRASG12Dbipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlikePtf1acreERT/+KrasLSL-G12Dmice,APKmice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.
Abiotic drivers of protein abundance variation among natural populations
Authors: Ebner Joshua Niklas , Ritz Danilo , Fumetti Stefanie von 
Published: March 2020

AbstractIdentifying when and where environmental change induces molecular responses in natural populations is an important goal in contemporary ecology. It can aid in identifying molecular signatures of populations experiencing stressful conditions and potentially inform if species are approaching the limits of their tolerance niches. Achieving this goal is hampered by our limited understanding of the influence of environmental variation on the molecular systems of most ecologically relevant species as the pathways underlying fitness-affecting plastic responses have primarily been studied in model organisms under controlled laboratory conditions. In this study, we establish relationships between protein abundance patterns and the abiotic environment by profiling the proteomes of 24 natural populations of the caddisflyCrunoecia irrorata.We subsequently relate these profiles to natural variations in the abiotic characteristics of their freshwater spring habitats which shows that protein abundances and networks respond to abiotic variation according to the functional roles these proteins have. We provide evidence that geographic and past and present environmental differences between sites affect protein abundances and identifications, and that baseline reaction norms are ubiquitous and can be used as information rather than noise in comparative field studies. Taking this natural variation into account is a prerequisite if we are to identify the effects environmental change has on natural populations.