bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redefining Nephrotic Syndrome in Molecular Terms: Outcome-associated molecular clusters and patient stratification with noninvasive surrogate biomarkers
Authors: Mariani Laura H. , Eddy Sean , Martini Sebastian , Eichinger Felix , Godfrey Brad , Nair Viji , Adler Sharon G. , Appel Gerry B. , Athavale Ambarish , Barisoni Laura , Brown Elizabeth , Cattran Dan C. , Dell Katherine M. , Derebail Vimal , Fervenza Fernando C. , Fornoni Alessia , Gadegbeku Crystal A. , Gibson Keisha L. , Gipson Deb , Greenbaum Lawrence A. , Hingorani Sangeeta R. , Hlandunewich Michelle A. , Hogan John , Holzman Larry B. , Jefferson J. Ashley , Kaskel Frederick J. , Kopp Jeffrey B. , Lafayette Richard A. , Lemley Kevin V. , Lieske John C. , Lin Jen-Jar , Myers Kevin E. , Nachman Patrick H. , Nast Cindy C. , Neu Alicia M. , Reich Heather N. , Sambandam Kamal , Sedor John R. , Sethna Christine B. , Srivastava Tarak , Trachtman Howard , Tran Cheryl , Wang Chia-shi , Kretzler Matthias 
Published: September 2018

SummaryA tissue transcriptome driven classification of nephrotic syndrome patients identified a high risk group of patients with TNF activation and established a non-invasive marker panel for pathway activity assessment paving the way towards precision medicine trials in NS.AbstractNephrotic syndrome from primary glomerular diseases can lead to chronic kidney disease (CKD) and/or end-stage renal disease (ESRD). Conventional diagnoses using a combination of clinical presentation and descriptive biopsy information do not accurately predict risk for progression in patients with nephrotic syndrome, which complicates disease management. To address this challenge, a transcriptome-driven approach was used to classify patients with minimal change disease and focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network (NEPTUNE). Transcriptome-based classification revealed a group of patients at risk for disease progression. High risk patients had a transcriptome profile consistent with TNF activation. Non-invasive urine biomarkers TIMP1 and CCL2 (MCP1), which are causally downstream of TNF, accurately predicted TNF activation in the NEPTUNE cohort setting the stage for patient stratification approaches and precision medicine in kidney disease.
Inflammatory and JAK-STAT Pathways as Shared Molecular Targets for ANCA-Associated Vasculitis and Nephrotic Syndrome
Authors: Eddy Sean , Nair Viji , Mariani Laura H. , Eichinger Felix H. , Hartman John , Huang Huateng , Parikh Hemang , Taroni Jaclyn N. , Lindenmeyer Maja T. , Ju Wenjun , Greene Casey S. , Grayson Peter C. , Godfrey Brad , Cohen Clemens D. , Sampson Matt G. , Lafayette Richard A. ,   Nephrotic Syndrome Study Network (NEPTUNE),   European Renal cDNA Bank – Else Kröner-Fresenius Biopsy Bank (ERCB),   Vasculitis Clinical Research Consortium (VCRC), Krischer Jeffrey , Merkel Peter A. , Kretzler Matthias 
Published: September 2018

ABSTRACTBackgroundGlomerular diseases of the kidney are presently differentiated, diagnosed and treated according to conventional clinical or structural features. While etiologically diverse, these diseases share common clinical features including but not limited to reduced glomerular filtration rate, increased serum creatinine and proteinuria suggesting shared pathogenic mechanisms across diseases. Renal biopsies from patients with nephrotic syndrome (NS) or ANCA-associated vasculitis (AAV) were evaluated for molecular signals cutting across conventional disease categories as candidates for therapeutic targets.MethodsRenal biopsies were obtained from patients with NS (minimal change disease, focal segmental glomerulosclerosis, or membranous nephropathy) (n=187) or AAV (granulomatosis with polyangiitis or microscopic polyangiitis) (n=80) from the Nephrotic Syndrome Study Network (NEPTUNE) and the European Renal cDNA Bank. Transcriptional profiles were assessed for shared disease mechanisms.ResultsIn the discovery cohort, 10–25% transcripts were differentially regulated versus healthy controls in both NS and AAV, >500 transcripts were shared across diseases. The majority of shared transcripts (60–77%) were validated in independent samples. Therapeutically targetable networks were identified, including inflammatory JAK-STAT signaling. STAT1 eQTLs were identified and STAT1 expression associated with GFR-based outcome. A transcriptional STAT1 activity score was generated from STAT1-regulated target genes which correlated with CXCL10 (p<0.001), a JAK-STAT biomarker, predictors of CKD progression, interstitial fibrosis (r=0.41, p<0.001), and urinary EGF (r=-0.51, p<0.001).ConclusionAAV and NS caused from histopathologically distinct disease categories share common intra-renal molecular pathways cutting across conventional disease classifications. This approach provides a starting point for de novo drug development, and repurposing efforts in rare kidney diseases.
rstoolbox: management and analysis of computationally designed structural ensembles
Authors: Bonet Jaume , Harteveld Zander , Sesterhenn Fabian , Scheck Andreas , Correia Bruno E. 
Published: September 2018

AbstractMotivationComputational protein design (CPD) calculations rely on the generation of large amounts of data on the search for the best sequences. As such, CPD workflows generally include the batch generation of designed decoys (sampling) followed by ranking and filtering stages to select those with optimal metrics (scoring). Due to these factors, the proper analysis of the decoy population is a key element for the effective selection of designs for experimental validation.ResultsHere, we present a set of tools for the analysis of protein design ensembles. The tool is oriented towards protein designers with basic coding training aiming to process efficiently their decoy sets as well as for protocol developers interested in benchmarking their new approaches. Although initially devised to process Rosetta design outputs, the library is extendable to other design tools.Availability and Implementationrstoolbox is implemented for python2.7 and 3.5+. Code is freely available athttps://github.com/lpdi-epfl/rstoolboxunder the MIT license. Full documentation and examples can be found athttps://lpdi-epfl.github.io/rstoolbox.
Resumption of spermatogenesis in senescent goldfish Carassius auratus (Linnaeus, 1758) through spermatogonial cell therapy
Authors: Majhi Sullip Kumar , Chowdhury Labrechai Mog , Kumar Santosh , Singh Rajeev Kumar , Mohindra Vindhya , Lal Kuldeep Kumar 
Published: September 2018

AbstractIn recent times, stem cell research has gained considerable prominence because of its applications in assisted reproductive technology and the treatment of deadly diseases. In teleost fishes, spermatogonial stem cells have been effectively used to produce progeny of difficult-to-breed fish species and/or commercially valuable species through the surrogacy technique. The present study is the first report of an innovative application of stem cell therapy in teleostean fish species for revitalising the reproductive competence of senescent individuals. Senescent male goldfish, Carassius auratus aged approximately 10 years were procured from an ornamental fish-breeding farm and were reared locally for an additional 2 years. The senescence of the fish was evaluated and confirmed using histological analysis, gonadal index assessment, and germ-cell specific vasa gene expression. Analyses revealed the absence of spermatogonial cells and other germ cells in the testes of the senescent fish (n = 5). Spermatogonial cells from a prepubertal C. auratus male donor were isolated using discontinuous percoll gradients, labelled with the fluorescent dye PKH-26, and transplanted into the gonads of senescent C. auratus males through the urogenital papilla. Six months after the therapy, spermatozoa from males were collected through applying gentle manual pressure on the abdomen and were observed under the microscope. All the senescent therapy-treated C. auratus males produced spermatozoa from the transplanted cells; this was confirmed by retention of PKH-26 in the spermatozoa and diagnostic SSR locus. The senescent males were crossed with gravid C. auratus females through artificial insemination and natural spawning, and viable progeny was produced. These observations suggest that the reproductive competence of senescent individuals of commercially valuable and/or endangered fish species can be revitalised and extended through spermatogonia stem cell therapy to produce functional gametes.
Molecular Classification and Comparative Taxonomics of Foveal and Peripheral Cells in Primate Retina
Authors: Peng Yi-Rong , Shekhar Karthik , Yan Wenjun , Herrmann Dustin , Sappington Anna , Bryman Greg S. , van Zyl Tavé , Do Michael Tri. H. , Regev Aviv , Sanes Joshua R. 
Published: September 2018

ABSTRACTHigh acuity vision in primates, including humans, is mediated by a small central retinal region called the fovea. As more accessible model organisms lack a fovea, its specialized function and dysfunction in ocular diseases remain poorly understood. We used 165,000 single-cell RNA-seq profiles to generate and validate comprehensive cellular taxonomies of macaque fovea and peripheral retina. More than 80% of >65 cell types match between the two regions, but exhibit substantial differences in proportions and gene expression, some of which we relate to functional differences. Comparison of macaque retinal types with those of mice reveals that interneuron types are tightly conserved, but that projection neuron types and programs diverge, despite conserved transcription factor codes. Key macaque types are conserved in humans, allowing mapping of cell-type and region-specific expression of >190 genes associated with 6 human retinal diseases. Our work provides a framework for comparative single-cell analysis across tissue regions and species.
Characterizing Inpatient Medicine Resident Electronic Health Record Usage Patterns Using Event Log Data
Authors: Chen Jonathan H. , Wang Jason K. , Ouyang David , Hom Jason , Chi Jeffrey 
Published: September 2018

ABSTRACTAmid growing rates of burnout, physicians report increasing electronic health record (EHR) usage alongside decreasing clinical facetime with patients. There exists a pressing need to improve physician-computer-patient interactions by streamlining EHR workflow.To identify interventions to improve EHR design and usage, we systematically characterize EHR activity among internal medicine residents at a tertiary academic hospital across various inpatient rotations and roles from June 2013 to November 2016.Logged EHR timestamps were extracted from Stanford Hospital’s EHR system (Epic) and cross-referenced against resident rotation schedules. We tracked the quantity of EHR logs across 24-hour cycles to reveal daily usage patterns. In addition, we decomposed daily EHR time into time spent on specific EHR actions (e.g. chart review, note entry and review, results review).In examining 24-hour usage cycles from general medicine day and night team rotations, we identified a prominent trend in which night team activity promptly ceased at the shift’s end, while day team activity tended to linger post-shift. Across all rotations and roles, residents spent on average 5.38 hours (standard deviation=2.07) using the EHR. PGY1 (post-graduate year one) interns and PGY2+ residents spent on average 2.4 and 4.1 times the number of EHR hours on information review (chart, note, and results review) as information entry (note and order entry).Analysis of EHR event log data can enable medical educators and programs to develop more targeted interventions to improve physician-computer-patient interactions, centered on specific EHR actions.
Molecular and clinical analysis of 27 German patients with Leber congenital amaurosis
Authors: Weisschuh Nicole , Feldhaus Britta , Khan Muhammad Imran , Cremers Frans P. M. , Kohl Susanne , Wissinger Bernd , Zobor Ditta 
Published: September 2018

AbstractLeber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies (IRD) and the most frequent cause of inherited blindness in children. The phenotypic overlap with other early-onset and severe IRDs as well as difficulties associated with the ophthalmic examination of infants can complicate the clinical diagnosis. To date, 25 genes have been implicated in the pathogenesis of LCA. The disorder is usually inherited in an autosomal recessive fashion, although rare dominant cases have been reported. We report the mutation spectra and frequency of genes in 27 German index patients initially diagnosed with LCA. A total of 108 LCA- and other genes implicated in IRD were analysed using a cost-effective targeted next-generation sequencing procedure based on molecular inversion probes (MIPs). Sequencing and variant filtering led to the identification of putative pathogenic variants in 25 cases, thereby leading to a detection rate of 93%. The mutation spectrum comprises 34 different alleles, 17 of which are novel. In line with previous studies, the genetic results led to a revision of the initial clinical diagnosis in a substantial proportion of cases, demonstrating the importance of genetic testing in IRD. In addition, our detection rate of 93% shows that MIPs are a cost-efficient and sensitive tool for targeted next-generation sequencing in IRD.
Fast Bayesian fine-mapping of 35 production, reproduction and body conformation traits in dairy cattle
Authors: Jiang Jicai , Cole John B. , Da Yang , VanRaden Paul M. , Ma Li 
Published: September 2018

AbstractImputation has been routinely used to infer sequence variants in large genotyped populations based on reference populations of sequenced individuals. With increasing numbers of animals sequenced and the implementation of the 1000 Bull Genomes Project, fine-mapping of causal variants for complex traits is becoming possible in cattle. Using 404 ancestor bull sequences as reference, we imputed over 3 million selected sequence variants to 27,214 Holstein bulls with highly reliable phenotypes (breeding values) for 35 production, reproduction, and body conformation traits. We first performed whole-genome single-marker scans for each of the 35 traits using a mixed-model association test. The single-trait association statistics were then merged into multi-trait tests of 3 trait groups: production, reproduction, and body conformation. Both single- and multi-trait GWAS results were used to identify 282 candidate QTL regions for fine-mapping in the cattle genome. To facilitate fast and powerful fine-mapping analyses, we developed a Bayesian Fine-MAPping approach (BFMAP) to integrate fine-mapping with functional enrichment analysis. Our fine-mapping results identified 69 promising candidate genes for dairy traits, including ABCC9, VPS13B, MGST1, SCD, MKL1, and CSN1S1 for production traits; CHEK2, GC, and KALRN for reproduction traits; and TMTC2, ARRDC3, ZNF613, CCND2, and FGF6 for body conformation traits. Based on existing functional annotation data for cattle, we revealed biologically meaningful enrichment in our fine-mapped variants that can be readily tested in functional validation studies. In summary, these results demonstrated the utility of a fast Bayesian approach for fine-mapping and functional enrichment analysis, identified candidate causative genes and variants, and enhanced our understanding of the genetic basis of complex traits in dairy cattle.
Architectural Principles for Characterizing the Performance of Sequestration Feedback Networks
Authors: Olsman Noah , Xiao Fangzhou , Doyle John C. 
Published: September 2018

SummaryAs we begin to design increasingly complex synthetic biomolecular systems, it is essential to develop rational design methodologies that yield predictable circuit performance. Here we apply theoretical tools from the theory of control and dynamical systems to yield practical insights into the architecture and function of a particular class of biological feedback circuit. Specifically, we show that it is possible to analytically characterize both the operating regime and performance tradeoffs of a sequestration feedback circuit architecture. Further, we demonstrate how these principles can be applied to inform the design process of a particular synthetic feedback circuit.
Structural basis for substrate gripping and translocation by the ClpB AAA+ disaggregase
Authors: Rizo Alexandrea N. , Lin JiaBei , Gates Stephanie N. , Tse Eric , Bart Stephen M. , Castellano Laura M. , DiMaio Frank , Shorter James , Southworth Daniel R. 
Published: September 2018

ABSTRACTBacterial ClpB and yeast Hsp104 are homologous Hsp100 protein disaggregases that serve critical functions in proteostasis by solubilizing protein aggregates. Two AAA+ nucleotide binding domains (NBDs) power polypeptide translocation through a central channel comprised of a hexameric spiral of protomers that contact substrate via conserved pore-loop interactions. To elucidate the translocation mechanism, we determined the cryo-EM structure of a hyperactive ClpB variant to 2.9 Å resolution bound to the model substrate, casein in the presence of slowly hydrolysable ATPγS. Distinct substrate-gripping mechanisms are identified for NBD1 and NBD2 pore loops. A trimer of N-terminal domains define a channel entrance that binds the polypeptide substrate adjacent the topmost NBD1 contact. NBD conformations at the spiral seam reveal how ATP hydrolysis and substrate engagement or disengagement are precisely tuned to drive a stepwise translocation cycle.
Antibiotic-induced decreases in the levels of microbial-derived short-chain fatty acids promote gastrointestinal colonization ofCandida albicans
Authors: Guinan Jack , Wang Shaohua , Yadav Hariom , Thangamani Shankar 
Published: September 2018

ABSTRACTCandida albicansis the fourth most common cause of systemic nosocomial infections, posing a significant risk in immunocompromised individuals. As the majority of systemicC. albicansinfections stem from endogenous gastrointestinal (GI) colonization, understanding the mechanisms associated with GI colonization is essential in the development of novel methods to preventC. albicans-related mortality. In this study, we investigated the role of microbial-derived short-chain fatty acids (SCFAs) including acetate, butyrate, and propionate on growth, morphogenesis, and GI colonization ofC. albicans. Our results indicate that cefoperazone-treated mice susceptible toC. albicansinfection had significantly decreased levels of SCFAs in the cecal contents that correlate with a higher fungal load in the feces. Further, usingin vivoconcentration of SCFAs, we demonstrated that SCFAs inhibit the growth, germ tube, hyphae and biofilm development ofC. albicans in vitro. Collectively, results from this study demonstrate that antibiotic-induced decreases in the levels of SCFAs in the cecum enhances the growth and GI colonization ofC. albicans.
Alcoholism Gender Differences in Brain Responsivity to Emotional Stimuli
Authors: Sawyer Kayle S. , Maleki Nasim , Urban Trinity , Marinkovic Ksenija , Karson Steven A. , Ruiz Susan M. , Harris Gordon J. , Oscar-Berman Marlene 
Published: September 2018

AbstractMen and women may use alcohol to regulate their emotions differently, with corresponding differences in neural responses. We examined how photographs of emotional stimuli impacted brain activity obtained through functional magnetic resonance imaging (fMRI) from 42 alcoholic (25 women) and 46 nonalcoholic (24 women) participants. Brain responsivity was blunted in alcoholic compared to nonalcoholic groups. Further analyses indicated significant gender differences in the impact of alcoholism. Brain activation of the alcoholic men (ALCM) was significantly lower than that of the alcoholic women (ALCW) and nonalcoholic men (NCM) in regions including the inferior parietal gyrus, anterior cingulate gyrus, and postcentral gyrus, whereas activation was higher in the ALCWthan in the nonalcoholic women (NCW) in superior frontal and supramarginal cortical regions. The reduced brain reactivity of ALCMand increases for ALCWhighlighted divergent brain regions and gender effects, suggesting possible differences in the underlying basis for development of alcohol use disorders.
Whole genome analysis of ExPEC ST73 from a single hospital over a 2-year period identified different circulating clonal groups
Authors: Bogema DR , McKinnon J , Liu M , Hitchick N , Miller N , Venturini C , Iredell J , Darling AE , Roy Chowdury P , Djordjevic SP 
Published: September 2018

AbstractST73 has emerged as one of the most frequently isolated extraintestinal pathogenic E. coli (ExPEC). To examine the localised diversity of ST73 clonal groups including their mobile genetic elements profile, we sequenced the genomes of 16 multiple drug-resistant ST73 isolates from patients with urinary tract infection from a single hospital in Sydney, Australia between 2009 and 2011. Genome sequences were used to generate a SNP-based phylogenetic tree to determine the relationship of these isolates in a global context with ST73 sequences (n=210) from public databases. There was no evidence of a dominant outbreak strain of ST73 in patients from this hospital, rather we identified at least eight separate groups, several of which reoccur, over a two-year period. The inferred phylogeny of all ST73 strains (n=226) including the ST73 Clone D i2 reference genome shows high bootstrap support and clusters into four major groups which correlate with serotype. The Sydney ST73 strains carry a wide variety of virulence-associated genes but the presence of iss, pic and several iron acquisition operons was notable.ImpactST73 is a major clonal lineage of ExPEC that causes urinary tract infections often with uroseptic sequelae but has not garnered substantial scientific interest as the globally disseminated ST131. Isolation of multiple antimicrobial resistant variants of ExPEC ST73 have increased in frequency, but little is known about the carriage of class 1 integrons in this sequence type and the plasmids that are likely to mobilise them. This pilot study examines the ST73 isolates within a single hospital in Sydney Australia and provides the first large-scale core-genome phylogenetic analysis of ST73 utilizing public sequence read datasets. We used this analysis to identify at least 8 sub-groups of ST73 within this single hospital. Mobile genetic elements associated with antibiotic resistance were less diverse and only three class 1 integron structures were identified, all sharing the same basic structure suggesting that the acquisition of drug resistance is a recent event. Genomic epidemiological studies are needed to further characterise established and emerging clonal populations of multiple drug resistant ExPEC to identify sources and aid outbreak investigations.