bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2
Authors: Wang Yinfang , Fan Yingzhe , Huang Yitong , Du Tao , Liu Zongjun , Huang Dekui , Wang Ying , Wang Nanping , Zhang Peng 
Published: August 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)-induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. Importantly, the upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells but not PAEpiCs. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.
KSHV-encoded vCyclin can modulate HIF1α levels to promote DNA replication in hypoxia
Authors: Singh Rajnish Kumar , Pei Yonggang , Lamplugh Zachary L , Sun Kunfeng , Yuan Yan , Lieberman Paul , You Jianxin , Robertson Erle S 
Published: August 2020

AbstractThe cellular adaptive response to hypoxia, mediated by high HIF1α levels includes metabolic reprogramming, restricted DNA replication and cell division. In contrast to healthy cells, the genome of cancer cells, and Kaposi’s sarcoma associated herpesvirus (KSHV) infected cells maintains replication in hypoxia. We show that KSHV infection, despite promoting expression of HIF1α in normoxia, can also restricts transcriptional activity, and promoted its degradation in hypoxia. KSHV-encoded vCyclin, expressed in hypoxia, mediated HIF1a cytosolic translocation, and its degradation through a non-canonical lysosomal pathway. Attenuation of HIF1α levels by vCyclin allowed cells to bypass the block to DNA replication and cell proliferation in the hypoxia. These results demonstrated that KSHV utilizes a unique strategy to balance HIF1α levels to overcome replication arrest and induction of the oncogenic phenotype, which are dependent on the levels of oxygen in the microenvironment.
Midkine in chick and mouse retinas: neuroprotection, glial reactivity and the formation of Müller glia-derived progenitor cells
Authors: Campbell Warren A. , Fritsch-Kelleher Amanda , Palazzo Isabella , Hoang Thanh , Blackshaw Seth , Fischer Andy J. 
Published: August 2020

AbstractRecent studies have shown that midkine (MDK), a basic heparin-binding growth factor, is involved in the development and regeneration of the zebrafish retina. However, very little is known about MDK in the retinas of warm-blooded vertebrates. We investigate the expression patterns of MDK and related factors, roles in neuronal survival, and influence upon the formation of Müller glia-derived progenitor cells (MGPCs) in chick and mouse model systems. By using single-cell RNA-sequencing, we find thatMDKis upregulated during Müller glia (MG) maturation in chick development and when stimulated to reprogram into MGPCs after NMDA damage or FGF2/Insulin treatment. Interestingly,MDKis significantly up-regulated by MG in damaged chick retinas, but down-regulated by MG in damaged mouse retinas. In both chick and mouse retinas, exogenous MDK selectively up-regulates cFOS and pS6 (a readout of mTOR-signaling) in MG. In the chick, intraocular injections of MDK before injury is neuroprotective with an observed decrease in dying neurons and microglial reactivity, inducing fewer proliferating MGPCs. Blocking MDK signaling with Na3VO4following blocks neuroprotective effects with an increase the number of dying cells and negates the pro-proliferative effects on MGPCs. Inhibitors of PP2A and Pak1 associated with MDK integrin β1 signaling had MG specific inhibitory effects on MGPC formation. In mice, MDK administration with NMDA damage drives a small but significant increase in MGPCs. We conclude thatMDKexpression is dynamically regulated in reactive Müller glia and during reprogramming into MGPCs. MDK acts to coordinate glial activity, neuronal survival, and may act in an autocrine manner to influence the re-programming of Müller glia into proliferating MGPCs.
A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation
Authors: Kiritsy Michael C. , Ankley Laurisa M. , Trombley Justin D. , Huizinga Gabrielle P. , Lord Audrey E. , Orning Pontus , Elling Roland , Fitzgerald Katherine A. , Olive Andrew J. 
Published: August 2020

AbstractCytokine-mediated activation of host immunity is central to the control of pathogens. A key cytokine in protective immunity is interferon-gamma (IFNγ), which is a potent activator of antimicrobial and immunomodulatory effectors within the host. A major role of IFNγ is to induce major histocompatibility complex class II molecules (MHCII) on the surface of cells, which is required for CD4+T cell activation. Despite its central role in host immunity, the complex and dynamic regulation of IFNγ-induced MHCII is not well understood. Here, we integrated functional genomics and transcriptomics to comprehensively define the genetic control of IFNγ-mediated MHCII surface expression in macrophages. Using a genome-wide CRISPR-Cas9 library we identified genes that control MHCII surface expression, many of which have yet to be associated with MHCII. Mechanistic studies uncovered two parallel pathways of IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase 3 beta (GSK3β) or the mediator complex subunit MED16. Both pathways are necessary for IFNγ-mediated induction of the MHCII transactivator CIITA, MHCII expression, and CD4+T cell activation. Using transcriptomic analysis, we defined the regulons controlled by GSK3β and MED16 in the presence and absence of IFNγ and identified unique networks of the IFNγ-mediated transcriptional landscape that are controlled by each gene. Our analysis suggests GSK3β and MED16 control distinct aspects of the IFNγ-response and are critical for macrophages to respond appropriately to IFNγ. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+T cell responses by macrophages. These discoveries will aid in our basic understanding of macrophage-mediated immunity and will shed light on mechanisms of failed adaptive responses pervasive in infectious disease, autoimmunity, and cancer.
Gene expression associated with disease resistance and long-term growth in a reef-building coral
Authors: Kelley Emma R. , Sleith Robin S. , Matz Mikhail V. , Wright Rachel M. 
Published: August 2020

ABSTRACTRampant coral disease, exacerbated by climate change and other anthropogenic stressors, threatens reefs worldwide, especially in the Caribbean. Physically isolated yet genetically connected reefs such as Flower Garden Banks National Marine Sanctuary (FGBNMS) may serve as potential refugia for degraded Caribbean reefs. However, little is known about the mechanisms and trade-offs of pathogen resistance in reef-building corals. Here we measure pathogen resistance inMontastraea cavernosafrom FGBNMS. We identified individual colonies that demonstrated resistance or susceptibility toVibrio spp. in a controlled laboratory environment. Long-term growth patterns suggest no trade-off between disease resistance and calcification. Predictive (pre-exposure) gene expression highlights subtle differences between resistant and susceptible genets, encouraging future coral disease studies to investigate associations between resistance and replicative age and immune cell populations. Predictive gene expression associated with long-term growth underscores the role of cation transporters and extracellular matrix remodelers, contributing to the growing body of knowledge surrounding genes that influence calcification in reef-building corals. Together these results demonstrate that coral genets from isolated sanctuaries such as FGBNMS can withstand pathogen challenges and potentially aid restoration efforts in degraded reefs. Furthermore, gene expression signatures associated with resistance and long-term growth help inform strategic assessment of coral health parameters.
Increased copy number couples the evolution of plasmid horizontal transmission and antibiotic resistance
Authors: Dimitriu Tatiana , Matthews Andrew , Buckling Angus 
Published: August 2020

AbstractAntimicrobial resistance (AMR) in bacteria is commonly encoded on conjugative plasmids, mobile elements which can spread horizontally between hosts. Conjugative transfer disseminates AMR in communities but it remains unclear when and how high transfer rates evolve, and with which consequences. Here we studied experimentally the evolution of two antibiotic resistance encoding plasmids when confronted to different immigration rates of susceptible, plasmid-free hosts. While plasmid RP4 did not evolve detectably, plasmid R1 rapidly evolved up to 1000-fold increased transfer rates in the presence of susceptible hosts, at a cost to its host. Unexpectedly, most evolved plasmids also conferred to their hosts the ability to grow at high concentrations of antibiotics. The most common mutations in evolved plasmids were contained within thecopAgene which controls plasmid replication and copy number. EvolvedcopAvariants had elevated copy number, leading to both higher transfer rates and AMR. Due to these pleiotropic effects, host availability and antibiotics were each sufficient to select for highly transmissible plasmids conferring high levels of antibiotic resistance.
Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease
Authors: Malkov Anton , Popova Irina , Ivanov Anton , Jang Sung-Soo , Yoon Seo Yeon , Osypov Alexander , Huang Yadong , Zilberter Yuri , Zilberter Misha 
Published: August 2020

AbstractA predominant trigger and driver of sporadic Alzheimer’s disease (AD) is the synergy of brain oxidative stress and glucose hypometabolism starting at early preclinical stages. Oxidative stress damages macromolecules, while glucose hypometabolism impairs cellular energy supply and antioxidant defense. However, the exact cause of AD-associated glucose hypometabolism and its network consequences has remained unknown. Here we report NADPH oxidase 2 (NOX2) activation as the main initiating mechanism behind Aβ1-42-related glucose hypometabolism and network dysfunction. We utilize a combination of electrophysiology with real-time recordings of metabolic transients bothex- andin-vivoto show that Aβ1-42induces oxidative stress and acutely reduces cellular glucose consumption followed by long-lasting network hyperactivity and abnormalities in the animal behavioral profile. Critically, all of these pathological changes were prevented by the novel bioavailable NOX2 antagonist GSK2795039. Our data provide the first direct experimental evidence for causes and consequences of AD-related brain glucose hypometabolism, and suggest that targeting NOX2-mediated oxidative stress is a promising approach to both the prevention and treatment of AD.Single sentence summaryBeta-amyloid induces brain hypometabolism, network hyperactivity, and behavioral changes via NADPH oxidase-mediated oxidative stress, suggesting a novel therapeutic target for Alzheimer’s disease treatment.
Structural basis for transcription complex disruption by the Mfd translocase
Authors: Kang Jin Young , Llewellyn Eliza , Chen James , Olinares Paul Dominic B. , Brewer Joshua , Chait Brian T. , Campbell Elizabeth A. , Darst Seth A. 
Published: August 2020

SummaryTranscription-coupled repair (TCR) is a sub-pathway of nucleotide excision repair (NER) that preferentially removes lesions from the template-strand (t-strand) that stall RNA polymerase (RNAP) elongation complexes (EC). Mfd mediates TCR in bacteria by removing the stalled RNAP concealing the lesion and recruiting Uvr(A)BC. We used cryo-electron microscopy to visualize Mfd engaging with a stalled EC and attempting to dislodge the RNAP. We visualized seven distinct Mfd-EC complexes in both ATP and ADP-bound states. The structures explain how Mfd is remodeled from its repressed conformation, how the UvrA-interacting surface of Mfd is hidden during most of the remodeling process to prevent premature engagement with the NER pathway, how Mfd alters the RNAP conformation to facilitate disassembly, and how Mfd forms a processive translocation complex after dislodging the RNAP. Our results reveal an elaborate mechanism for how Mfd kinetically discriminates paused from stalled ECs and disassembles stalled ECs to initiate TCR.
ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells
Authors: Constantin Daniel , Widmann Christian 
Published: August 2020

AbstractIt is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that non-responders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Using a whole genome CRISPR/Cas9 gene knockout approach we have identified that low levels of ASH2L cause resistance to genotoxins. ASH2L is a core component of the H3K4 methyl transferase complex. We show that ASH2L absence decreases cell proliferation and favors DNA repair upon genotoxin exposure. The cell models we have used are derived from cancers currently treated either partially (Hodgkin’s lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. Our data also indicate that patients with low ASH2L expressing tumors do not develop resistance to ATR inhibitors. In these patients, such inhibitors may represent an alternative treatment to DNA damaging drugs.
Creb5 establishes the competence forPrg4expression in articular cartilage
Authors: Zhang Cheng-Hai , Gao Yao , Jadhav Unmesh , Hung Han-Hwa , Holton Kristina M , Grodzinsky Alan J. , Shivdasani Ramesh A. , Lassar Andrew B. 
Published: August 2020

AbstractA hallmark of cells comprising the superficial zone of articular cartilage is their expression of lubricin, encoded by thePrg4gene, that lubricates the joint and protects against the development of arthritis. Here, we identify Creb5 as a transcription factor that is specifically expressed in superficial zone articular chondrocytes and is required for TGF-β and EGFR signaling to inducePrg4expression. Notably, forced expression of Creb5 in chondrocytes derived from the deep zone of the articular cartilage confers the competence for TGF-β and EGFR signals to inducePrg4expression. Chromatin-IP and ATAC-Seq analyses have revealed that Creb5 directly binds to twoPrg4promoter-proximal regulatory elements, that display an open chromatin conformation specifically in superficial zone articular chondrocytes; and which work in combination with a more distal regulatory element to drive induction ofPrg4by TGF-β. Our results indicate that Creb5 is a critical regulator ofPrg4/lubricin expression in the articular cartilage.
Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase
Authors: Seitz Christian , Casalino Lorenzo , Konecny Robert , Huber Gary , Amaro Rommie E. , McCammon J. Andrew 
Published: August 2020

AbstractInfluenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atomin silicosystems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase.Statement of SignificanceThe influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.
DeepCSO: a deep-learning network approach to predicting Cysteine S-sulphenylation sites
Authors: Lyu Xiaru , He Ningning , Chen Zhen , Zou Yang , Li Lei 
Published: August 2020

AbstractCysteine S-sulphenylation (CSO), as a novel post-translational modification (PTM), has emerged as a potential mechanism to regulate protein functions and affect signal networks. Because of its functional significance, several prediction approaches have been developed. Nevertheless, they are based on a limited dataset fromHomo sapiensand there is a lack of prediction tools for the CSO sites of other species. Recently, this modification has been investigated at the proteomics scale for a few species and the number of identified CSO sites has significantly increased. Thus, it is essential to explore the characteristics of this modification across different species and construct prediction models with better performances based on the enlarged dataset. In this study, we constructed a few classifiers and fond that the long short-term memory model with the word-embedding encoding approach, dubbed LSTMWE, performs favorably to the traditional machine-learning models and other deep-learning models across different species, in terms of cross-validation and independent test. The area under the ROC curve values for LSTMWEranged from 0.82 to 0.85 for different organisms, which is superior to the reposted CSO predictors. Moreover, we developed the general model based on the integrated data from different species and it showed great universality and effectiveness. We provided the on-line prediction service called DeepCSO that included both species-specific and general models, which is accessible throughhttp://www.bioinfogo.org/DeepCSO.
MSImpute: Imputation of label-free mass spectrometry peptides by low-rank approximation
Authors: Hediyeh-zadeh Soroor , Webb Andrew I. , Davis Melissa J. 
Published: August 2020

AbstractRecent developments in mass spectrometry (MS) instruments and data acquisition modes have aided multiplexed, fast, reproducible and quantitative analysis of proteome profiles, yet missing values remain a formidable challenge for proteomics data analysis. The stochastic nature of sampling in Data Dependent Acquisition (DDA), suboptimal preprocessing of Data Independent Acquisition (DIA) runs and dynamic range limitation of MS instruments impedes the reproducibility and accuracy of peptide quantification and can introduce systematic patterns of missingness that impact downstream analyses. Thus, imputation of missing values becomes an important element of data analysis. We introducemsImpute, an imputation method based on low-rank approximation, and compare it to six alternative imputation methods using public DDA and DIA datasets. We evaluate the performance of methods by determining the error of imputed values and accuracy of detection of differential expression. We also measure the post-imputation preservation of structures in the data at different levels of granularity. We develop a visual diagnostic to determine the nature of missingness in datasets based on peptides with high biological dropout rate and introduce a method to identify such peptides. Our findings demonstrate thatmsImputeperforms well when data are missing at random and highlights the importance of prior knowledge about nature of missing values in a dataset when selecting an imputation technique.
Integrative Spatial Single-cell Analysis with Graph-based Feature Learning
Authors: Zhu Junjie , Sabatti Chiara 
Published: August 2020

AbstractWe proposeGLISS, a strategy to discover spatially-varying genes by integrating two data sources: (1) spatial gene expression data such as image-based fluorescencein situhybridization techniques, and (2) dissociated whole-transcriptome single-cell RNA-sequencing (scRNA-seq) data.GLISSutilizes a graph-based association measure to select and link genes that are spatially-dependent in both data sources.GLISScan discover new spatial genes and recover cell locations in scRNA-seq data from landmark genes determined from SGE data.GLISSalso offers a new dimension reduction technique to cluster the genes, while accounting for the inferred spatial structure of the cells. We demonstrate the utility ofGLISSon simulated and real datasets, including datasets on the mouse olfactory bulb and breast cancer biopsies, and two spatial studies of the mammalian liver and intestine.
Pleiotropy inFOXC1-attributable phenotypes involves altered ciliation and cilia-dependent signaling
Authors: Havrylov Serhiy , Chrystal Paul , van Baarle Suey , French Curtis R , MacDonald Ian M , Avasarala Jagannadha R , Rogers R Curtis , Berry Fred B , Kume Tsutomu , Waskiewicz Andrew J , Lehmann Ordan J 
Published: August 2020

AbstractAlterations to cilia are responsible for a wide range of severe disease; however, understanding of the transcriptional control of ciliogenesis remains incomplete. We evaluated whether ciliary dysfunction contributed to the pleiotropic phenotypes caused by theForkheadtranscription factorFOXC1. Here, we show that patients withFOXC1-attributable Axenfeld-Rieger Syndrome (ARS) have a prevalence of ciliopathy-associated phenotypes comparable to syndromic ciliopathies. We demonstrate that altering the level of Foxc1, via shRNA mediated inhibition and mRNA overexpression, modifies cilia lengthin vitro. These structural changes were associated with substantially perturbed cilia-dependent signaling [Hedgehog (Hh) and PDGFRα] and the altered ciliary compartmentalization of a major Hh pathway transcription factor, Gli2. Analyses of twoFoxc1murine mutant strains demonstrated altered axonemal length in the choroid plexus with the increased expression of an essential regulator of multi-ciliation,Foxj1. The novel complexity revealed in ciliation of the choroid plexus indicates a partitioning of function between theseForkheadtranscription factors. Collectively, these results support a contribution from ciliary dysfunction to someFOXC1-induced phenotypes.