bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting human Plasmacytoid dendritic cells through BDCA2 prevents inflammation and fibrosis in xenotransplant mouse model of Scleroderma
Authors: Ross Rebecca L. , Corinaldesi Clarissa , Migneco Gemma , Carr Ian , Antanaviciute Agne , Carriero Antonio , Wasson Christopher , Georgiou Ioanna , Distler Jörg H. W. , Holmes Steve , El-Sherbiny Yasser M. , McKimmie Clive S. , Del Galdo Francesco 
Published: January 2020

AbstractPlasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of Scleroderma (SSc) through their ability to infiltrate the skin and secrete interferons (IFN) and proinflammatory chemokines. Blood Dendritic Cells Antigen 2 (BDCA2) is an inhibitory type II C-type lectin expressed by human pDC. Here we determined the effects of BDCA2 internalisation on pDC mediated skin inflammation and fibrosis in human preclinical models of skin inflammation and fibrosis in vitro and in vivo. BDCA2 targeting reversed TLR-signalling induced transcriptome and differentiation of pDC and suppressed their ability to induce IFN response in organotypic 3D human skin culturesin vitro.In vivo, xenotransplantation of human pDC into immunocompromised mice (XenoSCID) significantly increased IFN induced responses to topical TLR7/9 agonist and separately enhanced the fibrotic response to bleomycin. Targeting of BDCA2 strongly suppressed both of these pathological responses ameliorating skin inflammation and fibrosis. Together, these preclinical data strongly support the notion that human pDC play a key role in immune driven skin fibrosis, which can be effectively blocked by targeting BDCA2.
Microglia in the developing retina couple phagocytosis with the progression of apoptosis via P2RY12 signaling
Authors: Blume Zachary I. , Lambert Jared M. , Lovel Anna G. , Mitchell Diana M. 
Published: January 2020

AbstractBackgroundMicroglia colonize the developing vertebrate central nervous system coincident with detection of developmental apoptosis. Our understanding of apoptosis in intact tissue in relation to microglial clearance of dying cells is largely based on fixed samples, which is limiting given that microglia are highly motile and mobile phagocytes. Here, we used a system of microglial depletion andin vivoreal-time imaging in zebrafish to directly address microglial phagocytosis of apoptotic cells during normal retinal development, the relative timing of phagocytosis in relation to apoptotic progression, and the contribution of P2RY12 signaling to this process.ResultsDepletion of microglia resulted in accumulation of numerous apoptotic cells in the retina. Real-time imaging revealed precise timing of microglial engulfment with the progression of apoptosis, and dynamic movement and displacement of engulfed apoptotic cells. Inhibition of P2RY12 signaling delayed microglial clearance of apoptotic cells.ConclusionsMicroglial engulfment of dying cells is coincident with apoptotic progression and requires P2RY12 signaling, indicating that microglial P2RY12 signaling is shared between development and injury response. Our work provides importantin vivoinsight into the dynamics of apoptotic cell clearance in the developing vertebrate retina and provides a basis to understand microglial phagocytic behavior in health and disease.Bullet PointsLevels and location of developmental apoptosis in the zebrafish retina are elusive due to rapid and efficient clearance by microgliaMicroglial clearance of apoptotic cells is timed with the progression of apoptosis of the engulfed cell so that many cells are cleared in relatively early apoptotic stagesP2RY12 signaling is involved in microglial sensing and clearance of cells undergoing normal developmental apoptosis, indicating shared signals in microglial responses to cell death in both healthy and injured tissueGrant SponsorsNIH NIGMS Grant No. P20 GM103408
Lnc-ECAL-1controls cerebrovascular homeostasis by targeting endothelium-specific tight junction proteinCldn5b
Authors: Li Fang-Fang , Liang Yu-Lai , Zhang Jing-Jing , Jing Qing 
Published: January 2020

AbstractCerebrovascular disorder-induced brain blood flow interruption or intracranial hemorrhage pose a great threaten to health. Emerging roles of long-noncoding RNAs (lncRNAs) in diagnosis and treatment of cardiovascular diseases have been recognized. However, whether and how lncRNAs modulate vascular homeostasis, especially network formation remain largely unknown. Here, we identifiedECAL-1, a long non-coding RNA, as an important determinant for cerebrovascular homeostasis. Using the morpholino- and CRISPR /Cas9-based genetic modifications in combination within vivoconfocal imaging in zebrafish, we claimed that inactivation ofECAL-1induced the apparent distortion of cerebral vascular pattern accompanied by intracranial hemorrhage. These cerebrovascular abnormalities were associated with decreased proliferation and anomalous interconnection of endothelial cells. Importantly, overexpression of Cldn5b, an endothelial cell-specific tight junction protein-encoding gene, could partially rescued the phenotype induced byECAL-1deficiency. Furthermore, bioinformatic analysis and experimental validation revealed thatECAL-1sponged miR-23a, which targeted Cldn5b 3’UTR and modulated Cldn5b expression, to maintain cerebrovascular pattern formation and integrity. Our results presented here revealed thatECAL-1specifically controls cerebrovascular network formation and integrity through targeting miR-23a-Cldn5baxis. These findings provide a new regulation modality for cerebrovascular patterning and the potential neurovascular disorders, andECAL-1-miR-23a axis represents as an attractive therapeutic target for cerebrovascular diseases.
Differentiation genes were governed by DNA methylation during hair follicle morphogenesis in Cashmere goat
Authors: Wang Shanhe , Li Fang , Liu Jinwang , Zhang Yuelang , Zheng Yujie , Ge Wei , Qu Lei , Wang Xin 
Published: January 2020

AbstractDNA methylation plays a critical role in early embryonic skin development by controlling gene expression. Act as an indirect regulator, long non-coding RNA (lncRNA) recruit DNA methyltransferases to specific genomic sites to methylate DNA. However, the molecular regulation mechanisms underlying hair follicle morphogenesis is unclear in cashmere goat. In this study, RNA-seq and Whole-genome bisulfite sequencing (WGBS) in embryonic day 65 (E65) and E120 skin tissues of cashmere goat were used to reveal this complex regulatory process. RNA-seq, qRT-PCR and immunohistochemistry results showed that Wnt signaling played an important role in both hair follicle induction and differentiation stage, transcriptional factors (TFs) including Hoxc13, Sox9, Sox21, Junb, Lhx2, Vdr and Gata3 participated in hair follicle differentiation via specific expression at E120. Subsequently, combination of WGBS and RNA-seq analysis showed that the expression of hair follicle differentiation genes and TFs genes was negatively correlated with DNA methylation level generally. A portion of hair follicle differentiation genes were methylated and repressed in hair follicle induction stage but were subsequently demethylated and expressed during hair follicle differentiation stage, suggesting DNA methylation play an important role in hair morphogenesis through regulating associated gene expression. Furthermore, the potential differentially expressed lncRNAs associated with DNA methylation on target gene were revealed. LncRNA XR_001918556 may affect the DNA methylation of TFs geneGata3, lnc-003786 may affect the DNA methylation of signaling geneFgfr2. In conclusion, differentiation genes were governed by DNA methylation, resulting in repressed expression in hair follicle induction stage and high expression in hair follicle differentiation stage. Furtherly, potential lncRNAs associated with DNA methylation on target genes were delineated. This study would enrich the regulatory network and molecular mechanisms on hair morphogenesis.
Evolution and variation of 2019-novel coronavirus
Authors: Xiong Chenglong , Jiang Lufang , Chen Yue , Jiang Qingwu 
Published: January 2020

AbstractBackgroundThe current outbreak caused by novel coronavirus (2019-nCoV) in China has become a worldwide concern. As of 28 January 2020, there were 4631 confirmed cases and 106 deaths, and 11 countries or regions were affected.MethodsWe downloaded the genomes of 2019-nCoVs and similar isolates from the Global Initiative on Sharing Avian Influenza Database (GISAID and nucleotide database of the National Center for Biotechnology Information (NCBI). Lasergene 7.0 and MEGA 6.0 softwares were used to calculate genetic distances of the sequences, to construct phylogenetic trees, and to align amino acid sequences. Bayesian coalescent phylogenetic analysis, implemented in the BEAST software package, was used to calculate the molecular clock related characteristics such as the nucleotide substitution rate and the most recent common ancestor (tMRCA) of 2019-nCoVs.ResultsAn isolate numbered EPI_ISL_403928 showed different phylogenetic trees and genetic distances of the whole length genome, the coding sequences (CDS) of ployprotein (P), spike protein (S), and nucleoprotein (N) from other 2019-nCoVs. There are 22, 4, 2 variations in P, S, and N at the level of amino acid residues. The nucleotide substitution rates from high to low are 1·05 × 10−2(nucleotide substitutions/site/year, with 95% HPD interval being 6.27 × 10−4to 2.72 × 10−2) for N, 5.34 × 10−3(5.10 × 10−4, 1.28 × 10−2) for S, 1.69 × 10−3(3.94 × 10−4, 3.60 × 10−3) for P, 1.65 × 10−3(4.47 × 10−4, 3.24 × 10−3) for the whole genome, respectively. At this nucleotide substitution rate, the most recent common ancestor (tMRCA) of 2019-nCoVs appeared about 0.253-0.594 year before the epidemic.ConclusionOur analysis suggests that at least two different viral strains of 2019-nCoV are involved in this outbreak that might occur a few months earlier before it was officially reported.
Conventional dose rate spatially-fractionated radiation therapy (SFRT) treatment response and its association with dosimetric parameters – A preclinical study in a Fisher 344 rat model
Authors: Rivera Judith N. , Kierski Thomas M. , Kasoji Sandeep K. , Abrantes Anthony S. , Dayton Paul A. , Chang Sha X. 
Published: January 2020

AbstractPurposeTo identify key dosimetric parameters that have close associations with tumor treatment response and body weight change in SFRT treatments with a large range of spatial-fractionation scale at dose rates of several Gy/min.MethodsSix study arms using uniform tumor radiation, half-tumor radiation, 2mm beam array radiation, 0.3mm minibeam radiation, and an untreated arm were used. All treatments were delivered on a 320kV x-ray irradiator. Forty-two female Fischer 344 rats with fibrosarcoma tumor allografts were used. Dosimetric parameters studied are peak dose and width, valley dose and width, peak-to-valley-dose-ratio, volumetric average dose, percentage volume directly irradiated, and tumor- and normal-tissue EUD. Animal survival, tumor volume change, and body weight change (indicative of treatment toxicity) are tested for association with the dosimetric parameters using linear regression and Cox Proportional Hazards models.ResultsThe dosimetric parameters most closely associated with tumor response are tumor EUD (R2=0.7923, F-stat=15.26*; z-test=−4.07***), valley/minimum dose (R2=0.7636, F-stat=12.92*; z-test=−4.338***), and percentage tumor directly irradiated (R2=0.7153, F-stat=10.05*; z-test=−3.837***) per the linear regression and Cox Proportional Hazards models, respectively. Tumor response is linearly proportional to valley/minimum doses and tumor EUD. Average dose (R2=0.2745, F-stat=1.514 (no sig.); z-test=−2.811**) and peak dose (R2=0.04472, F-stat=0.6874 (not sig.); z-test=−0.786 (not sig.)) show the weakest associations to tumor response. Only the uniform radiation arm did not gain body weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetric parameters except for valley/min dose (R2=0.3814, F-stat=13.56**), valley width (R2=0.2853, F-stat=8.783**), and peak width (R2=0.2759, F-stat=8.382**).ConclusionsFor a single-fraction SFRT at conventional dose rates, valley, not peak, dose is closely associated with tumor treatment response and thus should be used for treatment prescription. Tumor EUD, valley/min dose, and percentage tumor directly irradiated are the top three dosimetric parameters that exhibited close associations with tumor response.
Niche preference ofEscherichia coliin a peri-urban pond ecosystem
Authors: NandaKafle Gitanjali , Huegen Taylor , Potgieter Sarah C. , Steenkamp Emma , Venter Stephanus N. , Brözel Volker S. 
Published: January 2020

AbstractEscherichia colicomprises of diverse strains with a large accessory genome, indicating functional diversity and the ability to adapt to a range of niches. Specific strains would display greatest fitness in niches matching their combination of phenotypic traits. Given this hypothesis, we sought to determine whetherE. coliin a peri-urban pond and associated cattle pasture display niche preference. Samples were collected from water, sediment, aquatic plants, water snails associated with the pond as well as bovine feces from cattle in an adjacent pasture. Isolates (120) were obtained after plating on Membrane Lactose Glucuronide Agar (MLGA). We used theuidAandmutSsequences for all isolates to determine phylogeny by maximum likelihood, and population structure through gene flow analysis. PCR was used to allocate isolates to phylogroups and to determine the presence of pathogenicity / virulence genes (stxI, stxII, eaeA, hlyA, ST and LT). Antimicrobial resistance was determined using a disk diffusion assay for Tetracycline, Gentamicin, Ciprofloxacin, Meropenem, Ceftriaxone, and Azitrhomycin. Our results showed that isolates from water, sediment and water plants were similar by phylogroup distribution, virulence gene distribution and antibiotic resistance while both snail and feces populations were significantly different. Few of the feces isolates were significantly similar to aquatic ones, and most of the snail isolates were also different. Population structure analysis indicated three genetic backgrounds associated with bovine, snail and aquatic environments. Collectively these data support niche preference ofE. coliisolates occurring in this ecosystem.
Differential virulence ofTrypanosoma brucei rhodesienseisolates does not influence the outcome of treatment with anti-trypanosomal drugs in the mouse model
Authors: Ndung’u Kariuki , Murilla Grace Adira , Thuita John Kibuthu , Ngae Geoffrey Njuguna , Auma Joanna Eseri , Gitonga Purity Kaari , Thungu Daniel Kahiga , Kurgat Richard Kiptum , Chemuliti Judith Kusimba , Mdachi Raymond Ellie 
Published: January 2020

AbstractWe assessed the virulence and anti-trypanosomal drug sensitivity patterns ofTrypanosoma brucei rhodesiense(Tbr) isolates in the Kenya Agricultural and Livestock Research Organization-Biotechnology Research Institute (KALRO-BioRI) cryobank. Specifically, the study focused onTbrclones originally isolated from the western Kenya/eastern Uganda focus of human African Trypanosomiasis (HAT). Twelve (12)Tbrclones were assessed for virulence using groups(n=10) of Swiss White Mice monitored for 60 days post infection (dpi). Based on survival time, four classes of virulence were identified: (a) very-acute: 0-15, (b) acute: 16-30, (c) sub-acute: 31-45 and (d) chronic: 46-60 dpi. Other virulence biomarkers identified included: prepatent period (pp), parasitaemia progression, packed cell volume (PCV) and body weight changes. The testTbrclones together with KALRO-BioRi reference drug-resistant and drug sensitive isolates were then tested for sensitivity to melarsoprol (mel B) pentamidine, diminazene aceturate and suramin, using mice groups (n= 5) treated with single doses of each drug at 24 hours post infection. Our results showed that the clones were distributed among four classes of virulence as follows: 3/12 (very-acute), 3/12 (acute), 2/12 (sub-acute) and 4/12 (chronic) isolates. Differences in survivorship, parasitaemia progression and PCV were significant (P<0.001) and correlated. The isolate considered to be drug resistant at KALRO-BioRI, KETRI 2538, was confirmed to be resistant to melarsoprol, pentamidine and diminazene aceturate but it was not resistant to suramin. At least 80% cure rates of all the test isolates was achieved with melarsoprol (1mg/Kg and 20 mg/kg), pentamidine (5 and 20 mg/kg), diminazene aceturate (5 mg/kg) and suramin (5 mg/kg) indicating that the isolates were not resistant to any of the drugs despite the differences in virulence. This study provides evidence of variations in virulence ofTbrisolates from a single HAT focus and confirms that these variations are not a significant determinant of isolate sensitivity to anti-trypanosomal drugs.
Robust design capture-recapture analysis of abundance and demographic parameters of Indian River Lagoon common bottlenose dolphins (Tursiops truncatus truncatus)
Authors: Durden Wendy Noke , Stolen Eric D. , Moreland Lydia , Howells Elisabeth , Jablonski Teresa , Sleeman Anne , Denny Matthew , Biedenbach George , Mazzoil Marilyn 
Published: January 2020

AbstractAccurate estimates of abundance are critical to species management and conservation. Common bottlenose dolphins (Tursiops truncatus truncatus) inhabiting the Indian River Lagoon (IRL) estuarine system along the east coast of Florida are impacted by anthropogenic activities and have had multiple unexplained mortality events, necessitating precise estimates of demographic and abundance parameters to implement management strategies. Mark-recapture methodology following a Robust Design survey was used to estimate abundance, adult survival, and temporary emigration for the IRL estuarine system stock of bottlenose dolphins. Models included a parameter (time since first capture) to assess evidence for transient individuals. Boat-based photo-identification surveys (n= 135) were conducted along predetermined contour and transect lines throughout the entire IRL (2016-2017). The best fitting model included the “transient” parameter to survival, allowed survival to vary by primary period, detection to vary by secondary session, and did not allow temporary emigration. Dolphin abundance ranged from 981 (95% CI: 882-1,090) in winter to 1,078 (95% CI: 968-1,201) in summer with a mean of 1,032 (95% CI: 969 -1,098). Model averaged seasonal survival rate for marked residents ranged from 0.85-1.00. Capture probability ranged from 0.20 to 0.42 during secondary sessions and transient rate from 0.06 to 0.07. This study represents the first Robust design mark-recapture survey effort to estimate abundance for IRL dolphins and provides parameter estimates to optimize sampling design of future studies. Transients included individuals with home ranges extending north of the IRL requiring further assessment of stock delineation. Results were remarkably similar to prior abundance estimates resulting from line-transect aerial surveys and were consistent with a stable population. Data will enable managers to evaluate the impact of fisheries-related takes as well as enable future comparisons of demographic parameters for a dolphin population that continues to sustain large scale mortality events and anthropogenic impacts.
The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome
Authors: Brueffer Christian , Gladchuk Sergii , Winter Christof , Vallon-Christersson Johan , Hegardt Cecilia , Häkkinen Jari , George Anthony M. , Chen Yilun , Ehinger Anna , Larsson Christer , Loman Niklas , Malmberg Martin , Rydén Lisa , Borg Åke , Saal Lao H. 
Published: January 2020

AbstractBreast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network–Breast project (SCAN-B; ClinicalTrials.govNCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such asPIK3CA,TP53, andERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible athttp://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
Aluinsertion-mediated dsRNA structure formation with pre-existingAluelements as a novel disease-causing mechanism
Authors: Masson Emmanuelle , Maestri Sandrine , Bordeau Valérie , Cooper David N. , Férec Claude , Chen Jian-Min 
Published: January 2020

AbstractWe previously identified a homozygousAluinsertion variant (Alu_Ins) in the 3’-UTR of theSPINK1gene as the cause of a novel pediatric disease. Although we established thatAlu_Ins leads to the complete loss ofSPINK1mRNA expression, the precise mechanisms remained elusive. Here we aimed to elucidate these mechanisms through a hypothesis-driven approach. Initially, we speculated thatAlu_Ins could independently disrupt mRNA 3’ end formation and/or affect other post-transcriptional processes such as nuclear export and translation, due to its particular location. However, the presence ofAlu_Ins in the 3’-UTR resulted in only an ~50% reduction in luciferase reporter activity compared to the wild-type, suggesting the involvement of additional mechanisms. Using RepeatMasker, we identified twoAluelements withinSPINK1’s third intron, both of which resided in an orientation opposite to that ofAlu_Ins. Through RNAfold predictions and full-length gene expression assays designed to examine orientation-dependent interactions betweenAlurepeats, we present evidence linking the detrimental effect ofAlu_Ins to extensive double-stranded RNA structures formed betweenAlu_Ins and pre-existing intronicAlusequences. Our results reveal a novel pathogenetic mechanism involving anAluinsertion, highlighting the importance of considering interactions between new and pre-existingAluelements in inverted orientations within disease-associated genes.