bluuebunny/crossref_metadata_2025_split huggingface dataset:
The lncRNAAPOLOinteracts with the transcription factor WRKY42 to trigger root hair cell expansion in response to cold
Authors: Moison Michaël , Martínez Pacheco Javier , Lucero Leandro , Fonouni-Farde Camille , Rodríguez-Melo Johan , Mansilla Natanael , Christ Aurélie , Bazin Jérémie , Benhamed Moussa , Ibañez Fernando , Crespi Martin , Estevez José M. , Ariel Federico 
Published: July 2020

ABSTRACTPlant long noncoding RNAs (lncRNAs) have emerged as important regulators of chromatin dynamics, impacting on transcriptional programs leading to different developmental outputs. The lncRNAAUXIN REGULATED PROMOTER LOOP(APOLO) directly recognizes multiple independent loci across theArabidopsisgenome and modulates their three-dimensional chromatin conformation, leading to transcriptional shifts. Here, we show thatAPOLOrecognizes the locus encoding the root hair (RH) master regulator ROOT HAIR DEFECTIVE 6 (RHD6) and controlsRHD6transcriptional activity leading to cold-enhanced RH elongation through the consequent activation of the transcription factor gene RHD6-likeRSL4. Furthermore, we demonstrate thatAPOLOinteracts with the transcription factor WRKY42 and modulates its binding to theRHD6promoter. WRKY42 is required for the activation ofRHD6by low temperatures andWRKY42deregulation impairs cold-induced RH expansion. Collectively, our results indicate that a novel ribonucleoprotein complex involvingAPOLOand WRKY42 forms a regulatory hub which activatesRHD6by shaping its epigenetic environment and integrates signals governing RH growth and development.SUMMARYThe lncRNAAPOLOdirectly regulates the transcription of the root hair-master geneRHD6. In response to cold,APOLOis induced and it decoys the H3K27me3-binding protein LHP1 away fromRHD6. In addition,APOLOmodulates the binding of the transcription factor WRKY42 to theRHD6promoter at low temperatures.
A Meta-analysis of the known Global Distribution and Host Range of theRalstoniaSpecies Complex
Authors: Lowe-Power Tiffany M. , Avalos Jason , Bai Yali , Munoz Maria Charco , Chipman Kyle , Elmgreen Vienna N. , Prasad Neha , Ramirez Benjamin , Sandhar Ajay , Tom Cloe E. , Williams Darrielle 
Published: July 2020

AbstractTheRalstoniaspecies complex is a group of genetically diverse plant wilt pathogens. Our goal is to create a database that contains the reported global distribution and host range ofRalstoniaclades (e.g. phylotypes and sequevars). In this fifth release, we have cataloged information from 304 sources that report one or moreRalstoniastrains isolated from 107 geographic regions. Metadata for nearly 10,000 strains are available as a supplemental table. The aggregated data suggest that the pandemic brown rot lineage (IIB-1) is the most widely dispersed lineage, and the phylotype I and IIB-4 lineages have the broadest natural host range. Although phylotype III is largely restricted to Africa, one strain collection reports a phylotype III strain isolated from Jamaica in the mid-1900s. In the previous release, we included reported presence of phylotype III strains in Brazil, but closer inspection of those results reveals that the strains were actually phylotype I strains that were mis-identified. Similarly, although phylotype IV is mostly found in East and Southeast Asia, phylotype IV strains are reported to be present in Kenya.Additionally, we have created an open science resource for phylogenomics of the RSSC. We associated strain metadata (host of isolation, location of isolation, and clade) with almost 700 genomes in a public KBase narrative. Our colleagues can use this narrative to identify the phylogenetic position of newly sequenced strains. We further curate a set of 601 high quality genomes based on low contamination and high completeness by CheckM. Our colleagues can use the curated dataset for comparative genomics studies.
Active synthesis of type I collagen homotrimer in Dupuytren’s fibrosis is unaffected by anti-TNF-α treatment
Authors: Williamson Kate , Lee Katie J. , Beamish Emma L. , Carter Alan , Gumbs Jade A. , Cooper Gabriella , Cheung Graham , Brown Daniel , Pettitt Rob , Comerford Eithne J. , Clegg Peter D. , Canty-Laird Elizabeth G. 
Published: July 2020

AbstractDupuytren’s disease is a common fibroproliferative disease of the palmar fascia of the hand with advanced cases treated surgically. Anti-tumour necrosis factor (TNF) injection has undergone phase 2 trials and may be effective in slowing early-stage disease progression. Here we sought to determine how new synthesis of type I collagen in Dupuytren’s differs from normal palmar fascia samples and to analyse the role of TNF in aberrant collagen synthesis. Model non-fibrotic, but fibrous connective tissues, were used to analyse active type I collagen protein synthesis in development, ageing and degenerative disease, where it was restricted to early development and ruptured tissue. Dupuytren’s tissue was shown to actively synthesise type I collagen, including abnormal type I collagen homotrimer. TNF-α reducedCOL1A2gene expression only in the presence of serum in 2D cell culture and had opposing effects on collagen protein production in the presence or absence of serum. TNF-α had only limited effects in 3D tendon-like constructs. Anti-TNF did not reduce type I collagen synthesis in 3D tendon-like constructs or prevent type I collagen homotrimer synthesis in Dupuytren’s tissue. Hence, modulation of the TNF-α pathway in Dupuytren’s disease is unlikely to prevent the pathological collagen accumulation that is characteristic of fibrosis.
DHX30 coordinates cytoplasmic translation and mitochondrial function contributing to cancer cell survival
Authors: Bosco Bartolomeo , Rossi Annalisa , Rizzotto Dario , Giorgetta Sebastiano , Perzolli Alicia , Bonollo Francesco , Gaucherot Angeline , Catez Frédéric , Diaz Jean-Jacques , Dassi Erik , Inga Alberto 
Published: July 2020

AbstractDHX30 was recently implicated in the translation control of mRNAs involved in p53-dependent apoptosis. Here we show that DHX30 exhibits a more general function by integrating the activities of its cytoplasmic isoform and of the more abundant mitochondrial one. The depletion of both DHX30 isoforms in HCT116 cells leads to constitutive changes in polysome-associated mRNAs, enhancing the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing the translational efficiency of the nuclear-encoded mitoribosome mRNAs. Furthermore, depletion of both DHX30 isoforms exhibits higher global translation but slower proliferation, and reduced mitochondrial energy metabolism. Isoform-specific silencing established a role for cytoplasmic DHX30 in modulating global translation. The impact on global translation and proliferation were confirmed in U2OS and MCF7 cells, although the effect of DHX30 depletion on mitochondrial gene expression was observed only in MCF7 cells. Exploiting RIP, eCLIP, and gene expression data, we identified a gene signature comprising DHX30 and fourteen mitoribosome transcripts that we candidate as direct targets: this signature shows prognostic value in several TCGA cancer types, with higher expression associated with reduced overall survival. We propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Targeting DHX30 could, thus, expose a vulnerability in cancer cells.Author summaryTranslation occurs in the cell both through cytoplasmic and mitochondrial ribosomes, respectively translating mRNAs encoded by the nuclear and the mitochondrial genome. Here we found that DHX30, an RNA-binding protein implicated in p53-dependent apoptosis, enhances the translation of mRNAs coding for cytoplasmic ribosomal proteins while reducing that of the mitoribosome mRNAs when silenced. This coordination of the cytoplasmic and mitochondrial translation machineries affected both cell proliferation and energy metabolism, suggesting an important role for this mechanism in determining the fitness of cancer cells. Indeed, the analysis of publicly available cancer datasets led us to define a 15-genes signature that is able to affect the prognosis of a subset of cancer types. In this subset, we found that higher expression of the genes composing the signature is associated with a worse prognosis. We thus propose DHX30 as a potential vulnerability in cancer cells, that could be targeted to develop novel therapeutic strategies.
Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2
Authors: Schmidt Sven H. , Weng Jui-Hung , Aoto Phillip C. , Boassa Daniela , Mathea Sebastian , Silletti Steven , Hu Junru , Wallbott Maximilian , Komives Elizabeth A , Knapp Stefan , Herberg Friedrich W. , Taylor Susan S. 
Published: July 2020

AbstractIn a multi-tiered approach, we explored how Parkinson’s Disease-related mutations hijack the finely tuned activation process of Leucine-Rich Repeat Kinase 2 (LRRK2) using a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We hypothesized that the N-terminal domains shield the catalytic domains in an inactive state. PD mutations, type-I LRRK2 inhibitors, or physiological Rab GTPases can unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules. Mapping solvent accessible regions of LRRK2RCKWemploying hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed how inhibitor binding is sensed by the entire protein. Molecular Dynamics simulations of the kinase domain elucidated differences in conformational dynamics between wt and mutants of the DYGψ motif. While all domains contribute to regulating kinase activity and spatial distribution, the kinase domain, driven by the DYGψ motif, coordinates domain crosstalk and serves as an intrinsic hub for LRRK2 regulation.
Vascular Endothelial Growth Factor as an Immediate-Early Activator of UV-induced Skin Injury
Authors: Hartono Stella P. , Bedell Victoria M. , Alam Sk. Kayum , O’Gorman Madelyn , Serres MaKayla , Hall Stephanie R. , Pal Krishnendu , Kudgus Rachel A. , Mukherjee Priyabrata , Seelig Davis M. , Meves Alexander , Mukhopadhyay Debabrata , Ekker Stephen C. , Hoeppner Luke H. 
Published: July 2020

ABSTRACTThe negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. Acute effects of sunburn include erythema, edema, and severe pain, and chronic overexposure to UV radiation can lead to skin cancer. While the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for the initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. Collectively, these findings suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, which reveals a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin.
Identifying Key Determinants of SARS-CoV-2/ACE2 Tight Interaction
Authors: Ngo Van A. , Jha Ramesh K. 
Published: July 2020

ABSTRACTSARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS- CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in reduced dissociation rate of SARS-CoV-2 from human recep- tor protein compared to SARS-CoV. This phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study shed light on the key residues and their dynamics at the virus spike and human receptor binding interface and advance our knowledge for the development of diagnostics and therapeutics to combat the pandemic efficiently.
A highly expressing, soluble, and stable plant-made IgG fusion vaccine strategy enhances antigen immunogenicity in mice without adjuvant
Authors: Diamos Andrew G. , Pardhe Mary D. , Sun Haiyan , Hunter Joseph G. L. , Kilbourne Jacquelyn , Chen Qiang , Mason Hugh S. 
Published: July 2020

SummaryTherapeutics based on fusing a protein of interest to the IgG Fc domain have been enormously successful, though fewer studies have investigated the vaccine potential of IgG fusions. In this study, we systematically compared the key properties of seven different plant-made human IgG1 fusion vaccine candidates using Zika virus (ZIKV) envelope domain III (ZE3) as a model antigen. Complement protein C1q binding of the IgG fusions was enhanced by: 1) antigen fusion to the IgG N-terminus; 2) removal of the IgG light chain or Fab regions; 3) addition of hexamer-inducing mutations in the IgG Fc; 4) adding a self-binding epitope tag to create recombinant immune complexes (RIC); or 5) producing IgG fusions in plants that lack plant-specific β1,2-linked xylose and α1,3-linked fucose N-linked glycans. We also characterized the expression, solubility, and stability of the IgG fusions. By optimizing immune complex formation, a potently immunogenic vaccine candidate with improved solubility and high stability was produced at 1.5 mg IgG fusion per g leaf fresh weight. In mice, the IgG fusions elicited high titers of Zika-specific antibodies which neutralized ZIKV using only two doses without adjuvant, reaching up to 150-fold higher antibody titers than ZE3 antigen alone. We anticipate these findings will be broadly applicable to the creation of other vaccines and antibody-based therapeutics.HighlightsA modified immune complex has high expression, solubility, stability, and immunogenicity.Antigen immunogenicity is improved up to 150-fold by fusion to plant-made IgGs.High serum IgG titers >1:500,000 were achieved with only two doses without adjuvant.
PARG inhibition induces replication catastrophe in ovarian cancer cells with down-regulated DNA replication genes
Authors: Coulson-Gilmer C. , Morgan R.D. , Nelson L. , Barnes B. , McGrail J.C. , Taylor S.S. 
Published: July 2020

SummaryThe discovery that PARP1/2 inhibitors selectively killBRCAmutant cells has led to a paradigm shift in the treatment of women with homologous recombination (HR)-deficient high-grade serous ovarian cancer (HGSOC), driving unprecedented improvements in progression-free and, more recently, overall survival. However, because most HGSOC cases are not HR-defective, and are therefore unlikely to benefit from PARPi-based therapies, additional strategies will be required to improve outcomes for women with HR-proficient disease. To develop novel therapeutic strategies, considerable attention is now being focused on inhibitors targeting PARG, the poly(ADP ribose) glycohydrolase that counterbalances PARP1/2 activity. Here we characterise ten ovarian cancer cell lines in response to the PARG inhibitor PDD00017273, hereafter PARGi. We demonstrate that six lines are resistant while four are sensitive, and that sensitivity correlates with several markers of persistent DNA replication stress, DNA damage and replication catastrophe, namely the accumulation of asymmetric DNA replication fibres, γH2AX and RPA foci, KAP1 and Chk1 phosphorylation, a pre-mitotic cell cycle block and, following prolonged exposure, a pan-nuclear γH2AX phenotype that indicates RPA exhaustion. We demonstrate that PARGi-sensitive cell lines have down-regulated DNA replication genes, including components of the fork protection complex, namelyTIMELESS,TIPINandCLASPIN. These observations suggest that a subset of HGSOC may respond to PARG inhibitors and that “replication stress” gene expression signature could serve as a predictive biomarker to guide the design of clinical trials.
Oxidations and amino acid substitutions in urinary proteins are the distinguishing characteristics of aging
Authors: Liu Yongtao , Pan Xuanzhen , Hua Yuanrui , Wang Yunlong , Gao Youhe 
Published: July 2020

AbstractAging is an inevitable course of life. Additionally, the risk of chronic diseases or cancer increases with age. The comprehensive identification of signs related to aging can be beneficial for the prevention and early diagnosis of geriatric diseases. The comparison of global modifications in the urine proteome is a means of multidimensional information mining. This approach is based on urine, in which changes from whole-body metabolism can accumulate. This study used the urine of healthy people at different ages (22 children, 10 young people, 6 senior people) as the research object and using high-resolution tandem mass spectrometry, label-free quantitation combined with non-limiting modification identification algorithms and random group test, compared the differences in protein chemical modifications among three groups. The results show that multi-sites oxidative modifications and amino acid substitutions are noticeable features that distinguish these three age groups of people. The proportion of multi-site oxidations in urine proteins of senior (29.76%) is significantly higher than the young group (13.71% and 12.97%), which affect the biological processes of various proteins. This study could provide a reference for studies of aging mechanisms and biomarkers of age-related disease.
Dynamics of residual malaria transmission in Central Western Senegal: Mapping the breeding sites ofAnopheles gambiaes. l
Authors: Ndiaye A. , Niang E.A , Niang-Diène A. , Nourdine M. A. , Sarr P C , Konaté L. , Faye O. , Gaye O. , Sy O. 
Published: July 2020

AbstractDespite the use of several effective control interventions in the central western Senegal, residual malaria transmission still occurring in some hotspots. In order to better understand the factors associated with this situation to better tailor targeted control actions, it is critical to unravel environmental and geographical factors underlying the persistence of the disease in study hotspot villages. Hotspots villages were defined as those reporting more than six indigenous malaria cases during the previous year. A total of ten villages, including seven hotspots and three non-hotspots, were surveyed. All potential mosquito breeding sites identified in and around the tenth study villages were regularly monitored between 2013 and 2017. This monitoring concerned the presence of anophelines larvae and the collection of epidemiological, hydrogeological, topographical and biogeographical data. Throughout the study area, the number of larval breeding sites inventoried and monitored over the study period ranged from 50 to 62. They were higher, with no significant difference, in hotspot sites than in non-hotspot sites for each year of monitoring with 62.3% (56/62) in 2013, 90.9% (50/55) in 2014, 90.3% (56/62) in 2015 and 86% (43/50) in 2017 (Fisher’s exact test; p = 1). The Hotspot villages were mostly characterized by saline or moderately saline hydro-morphic and halomorphic soils allowing water retention and a suitable presence of potential larval breeding sites. Whereas non-hotspot villages are characterized mainly by a high proportion of extremely permeable sandy-textured soils due to their porosity, which reduces water retention. The annual number of confirmed malaria cases was corelated relatively with the frequency and extent of breeding sites. Malaria cases were much more higher in the hamlets located near to the breeding sites ofAn. gambiaes.l then gradually decreases with their remoteness. This study has shown that the dynamics of larval breeding sites by their longevity, stability, proximity to houses and their positiveness rate for the presence ofAnopheleslarvae could be a determining factor in the persistence of malaria hotspots in central western Senegal. The results of this study shed more light on the environmental factors underlying the residual transmission and should make it possible to better organize vector control interventions for malaria elimination in west-central Senegal.
Development of a humanized mouse model to analyze antibodies specific for human leukocyte antigen (HLA)
Authors: Yanagawa Senichiro , Tahara Hiroyuki , Shirouzu Takayuki , Kawai Shintaro , Tanaka Yuka , Ide Kentaro , Akimoto Shuji , Ohdan Hideki 
Published: July 2020

AbstractIn organ transplantation, human leukocyte antigen (HLA)-mismatch grafts not only induce the activation of cellular mediated immune response but also the development of chronic antibody-mediated rejection due to the donor-specific anti-HLA antibody (DSA) produced by B cells and plasma cells interacting with the graft endothelium.Significant improvement in long-term survival after transplantation can be expected if antibody-mediated rejection due to the DSA can be overcome. However, the mechanism of producing or controlling the DSA remains to be elucidated.In recent decades, “humanized mouse model” have been widely used for the basic research of human immune systems, but a humanized mouse model to analyze the mechanism of DSA production has not been established yet. Thus, we aimed to create a humanized mouse using a severe immunodeficiency mouse (NSG mouse) administered with human peripheral blood mononuclear cells (PBMCs). Initially, we detected very low level of human total-IgG and no anti-HLA antibodies (Abs) in these mice. The responder PBMCs with antibody-producing B cell activating factors added or regulatory T cells depleted were subsequently co-cultured with the irradiated stimulator PBMCsin vitro, and these whole cells were administered into naïve NSG mice. The humanized model with sufficient human total-IgG and anti-HLA antibody production was consequently established. Interestingly, in all these mouse models, allo-specific anti-HLA Abs production was prominently suppressed, whereas non-allo-specific anti-HLA Abs were sufficiently detectable.Therefore, this novel humanized mouse model might be useful for analyzing the mechanism of anti-allogeneic human B cell tolerance induction.