bluuebunny/crossref_metadata_2025 huggingface dataset:
Pixel: a content management platform for quantitative omics data
Authors: Denecker Thomas , Durand William , Maupetit Julien , Hébert Charles , Camadro Jean-Michel , Poulain Pierre , Lelandais Gaëlle
Published: September 2018

Background

In biology, high-throughput experimental technologies, also referred as “omics” technologies, are increasingly used in research laboratories. Several thousands of gene expression measurements can be obtained in a single experiment. Researchers are routinely facing the challenge to annotate, store, explore and mine all the biological information they have at their disposal. We present here the Pixel web application (Pixel Web App), an original content management platform to help people involved in a multi-omics biological project.

Methods

The Pixel Web App is built with open source technologies and hosted on the collaborative development platform GitHub (https://github.com/Candihub/pixel). It is written in Python using the Django framework and stores all the data in a PostgreSQL database. It is developed in the open and licensed under the BSD 3-clause license. The Pixel Web App is also heavily tested with both unit and functional tests, a strong code coverage and continuous integration provided by CircleCI. To ease the development and the deployment of the Pixel Web App, Docker and Docker Compose are used to bundle the application as well as its dependencies.

Results

The Pixel Web App offers researchers an intuitive way to annotate, store, explore and mine their multi-omics results. It can be installed on a personal computer or on a server to fit the needs of many users. In addition, anyone can enhance the application to better suit their needs, either by contributing directly on GitHub (encouraged) or by extending Pixel on their own. The Pixel Web App does not provide any computational programs to analyze the data. Still, it helps to rapidly explore and mine existing results and holds a strategic position in the management of research data.
Isolation of cancer stem cells by selection for miR-302 expressing cells
Authors: Rahimi Karim , Füchtbauer Annette C. , Fathi Fardin , Mowla Seyed Javad , Füchtbauer Ernst-Martin
Published: September 2018

Cancer stem cells receive increasing interest because they are believed to be a major reason for long-term therapy failure. The reason for the therapy resistance of cancer stem cells lies partially in their multi-drug resistance and partially in the ability to rest mitotically inactive in the hypoxic center of tumors. Due to their variable number and their often low proliferation rate, cancer stem cells are difficult to purify in decent quantities and to grow in cell culture systems, where they are easily outcompeted by faster growing more ‘differentiated’, i.e. less stem cell-like tumor cells. Here we present a proof of principle study based on the idea to select cancer stem cells by means of the expression of a stem cell-specific gene. We inserted a selectableegfp-neocoding sequence in the last exon of the non-coding murinemiR-302host gene. As a stem cell specific regulatory element, we used 2.1 kb of the genomic region immediately upstream of themiR-302host gene transcription start. Stable transgenic CJ7 embryonic stem cells were used to induce teratomas. After three weeks, tumors were removed for analysis and primary cultures were established. Stem-like cells were selected from these culture based on G418 selection. When the selection was removed, stem cell morphology andmiR-302expression were rapidly lost, indicating that it were not the original ES cells that have been isolated. In conclusion, we show the possibility to use drug resistance expressed from a regulatory sequence of a stem cell-specific marker, to isolate and propagate cancer stem cells that otherwise might be hidden in the majority of tumor cells.
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

A 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.

Nephrotic 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

Background

Glomerular 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.

Methods

Renal 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.

Results

In 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).

Conclusion

AAV 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

Motivation

Computational 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.

Results

Here, 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 Implementation

rstoolbox 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

In 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

High 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

Amid 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

Leber 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

Imputation 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

As 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

Bacterial 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

Candida 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

Men 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

ST73 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.

Impact

ST73 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.
Lack of correlation between number of neurons and behavioral performance in Swiss mice
Authors: Kleber Neves , Duarte Guercio Gerson , Yuri Anjos-Travassos , Stella Costa , Ananda Perozzo , Karine Montezuma , Suzana Herculano-Houzel , Rogério Panizzutti
Published: September 2018

Neuronal number varies by several orders of magnitude across species, and has been proposed to predict cognitive capability across species. Remarkably, numbers of neurons vary across individual mice by a factor of 2 or more. We directly addressed the question of whether there is a relationship between performance in behavioral tests and the number of neurons in functionally relevant structures in the mouse brain. Naïve Swiss mice went through a battery of behavioral tasks designed to measure cognitive, motor and olfactory skills. We estimated the number of neurons in different brain regions (cerebral cortex, hippocampus, olfactory bulb, cerebellum and remaining areas) and crossed the two datasets to test the a priori hypothesis of correlation between cognitive abilities and numbers of neurons. As previous evidence indicates that environmental enrichment may increase neurogenesis and improve neuronal survival, we added a control group that did not undergo cognitive testing to rule out the possibility that our test battery could alter the neuronal number. We found that behavioral testing did not change numbers of neurons in the cerebral cortex and in the hippocampus. Surprisingly, performance in the behavioral tasks did not correlate strongly with number of neurons in any of the brain regions studied. Our results show that whereas neuronal number is a good predictor of cognitive skills across species, it is not a predictor of cognitive, sensory or motor ability across individuals within a species, which suggests that other factors are more relevant for explaining cognitive differences between individuals of the same species.
Geochemical and metagenomic characterization of Jinata Onsen, a Proterozoic-analog hot spring, reveals novel microbial diversity including iron-tolerant phototrophs and thermophilic lithotrophs
Authors: Ward Lewis M. , Idei Airi , Nakagawa Mayuko , Ueno Yuichiro , Fischer Woodward W. , McGlynn Shawn E.
Published: September 2018

Hydrothermal systems, including terrestrial hot springs, contain diverse geochemical conditions that vary over short spatial scales due to progressive interaction between the reducing hydrothermal fluids, the oxygenated atmosphere, and in some cases seawater. At Jinata Onsen, on Shikinejima Island, Japan, an intertidal, anoxic, iron-rich hot spring mixes with the oxygenated atmosphere and seawater over short spatial scales, creating a diversity of chemical potentials and redox pairs over a distance ~10 m. We characterized the geochemical conditions along the outflow of Jinata Onsen as well as the microbial communities present in biofilms, mats, and mineral crusts along its traverse via 16S rDNA amplicon and genome-resolved shotgun metagenomic sequencing. The microbial community changed significantly downstream as temperatures and dissolved iron concentrations decreased and dissolved oxygen increased. Near the spring source, biomass is limited relative to downstream, and primary productivity may be fueled by oxidation of ferrous iron and molecular hydrogen by members of the Zetaproteobacteria and Aquificae. Downstream, the microbial community is dominated by oxygenic Cyanobacteria. Cyanobacteria are abundant and active even at ferrous iron concentrations of ~150 μM, which challenges the idea that iron toxicity limited cyanobacterial expansion in Precambrian oceans. Several novel lineages of Bacteria are also present at Jinata Onsen, including previously uncharacterized members of the Chloroflexi and Caldithrichaeota phyla, positioning Jinata Onsen as a valuable site for future characterization of these clades.

Importance

High temperatures and reducing conditions allow hot springs to support microbial communities that are very different from those found elsewhere on the surface of the Earth today; in some ways, these environments and the communities they support can be similar to environments that existed on the early Earth and that may exist on other planets. Here, we describe a novel hot spring system where hot, iron-rich but oxygen-poor water flows into the ocean, supporting a range of unique microbial communities. Metagenomic sequencing recovered many novel microbial lineages, including deep-branching and uniquely thermotolerant members of known groups. Comparison of the biological communities in the upstream part of the hot spring, potentially supported by biological iron and hydrogen oxidizing metabolisms, to downstream microbial mats, supported by oxygenic photosynthesis, provides insight into the potential productivity of life during Proterozoic time and on other planets where oxygenic photosynthesis is not possible.
DNA co-methylation networks outline the structure and remodeling dynamics of colorectal cancer epigenome
Authors: Mallona Izaskun , Aussó Susanna , Díez-Villanueva Anna , Moreno Víctor , Peinado Miguel A.
Published: September 2018

Epigenomic plasticity is interconnected with chromatin structure and gene regulation. In tumor progression, orchestrated remodeling of genome organization accompanies the acquisition of malignant properties. DNA methylation, a key epigenetic mark extensively altered in cancer, is also linked to genome architecture and function. Based on this association, we postulate that the dissection of long-range co-methylation structure unveils cancer cell’s genome architecture remodeling.

We applied network-modeling of DNA methylation co-variation in two colon cancer cohorts and found abundant and consistent transchromosomal structures in both normal and tumor tissue. Normal-tumor comparison indicated substantial remodeling of the epigenome covariation and revealed novel genomic compartments with a unique signature of DNA methylation rank inversion.
Determination of sex of sacrum in adult Macaca mulatta1
Authors: Wang Yan-Mei , Han Xiao-Fan , Zhao Xiao-Jin
Published: September 2018

[Abstract]

Background

Sacrum being a part of pelvis is an important bone for identification of sex in both living primates and fossil ones.

Aim

Aim of this work was to examine the sex differences of sacral parameters in rhesus macaques and to compare with those of the other primates.

Materials and Methods

Fifty-six adult scara of macaques (17 males and 39 females) have been investigated. Measurement of various parameters was done using sliding vernier calliper; and statistical analysis was done using SPSS 23.0 package.

Results

The present study showed that the cranial breadth of the sacrum, the sacral length, transverse diameter and sagittal diameter of the cranial articular surface, and two indices of relative sacral breadth were highly significant for sex determination in Macaca mulatta. Comparison of the present data with other studies suggest that sex determination of sacrum can be very different in various types of primates.

Conclusion

The results suggest that these measures may be functionally integrated in response to locomotion, obstetric adequacy and cephalopelvic proportions in primates. Sacral index is more reliable and should be applied for sex determination of sacrum in various anatomical and anthropological investigations.
Enhancedin vivo-imaging in fish by optimized anaesthesia, fluorescent protein selection and removal of pigmentation
Authors: Lischik Colin Q. , Adelmann Leonie , Wittbrodt Joachim
Published: September 2018

Fish are ideally suited forin vivo-imaging due to their transparency at early stages combined with a large genetic toolbox. Key challenges to further advance imaging are fluorophore selection, immobilization of the specimen and approaches to eliminate pigmentation.

We addressed all three and identified the fluorophores and anaesthesia of choice by high throughput time-lapse imaging. Our results indicate that eGFP and mCherry are the best conservative choices forin vivo-fluorescence experiments, when availability of well-established antibodies and nanobodies matters. Still, mVenusNB and mGFPmut2 delivered highest absolute fluorescence intensitiesin vivo. Immobilization is of key importance during extendedin vivoimaging. Here, traditional approaches are outperformed by mRNA injection of α-Bungarotoxin which allows a complete and reversible, transient immobilization. In combination with fully transparent juvenile and adult fish established by the targeted inactivation of both,oca2andpnp4avia CRISPR/Cas9-mediated gene editing in medaka we could dramatically improve the state-of-the art imaging conditions in post-embryonic fish, now enabling light-sheet microscopy of the growing retina, brain, gills and inner organs in the absence of side effects caused by anaesthetic drugs or pigmentation.
On the optimal design of metabolic RNA labeling experiments
Authors: Uvarovskii Alexey , Naarmann-de Vries Isabel S. , Dieterich Christoph
Published: September 2018

Massively parallel RNA sequencing (RNA-seq) in combination with metabolic labeling has become thede factostandard approach to study alterations in RNA transcription, processing or decay. Regardless of advances in the experimental protocols and techniques, every experimentalist needs to specify the key aspects of experimental design: For example, which protocol should be used (biochemical separation vs. nucleotide conversion) and what is the optimal labeling time? In this work, we provide approximate answers to these questions using asymptotic theory of optimal design. Specifically, we derive the optimal labeling time for any given degradation rate and show that sub-optimal time points yield better rate estimates if they precede the optimal time point. Subsequently, we show that an increase in sample numbers should be preferred over an increase in sequencing depth. Lastly, we provide some guidance on use cases when laborious biochemical separation outcompetes recent nucleotide conversion based methods (such as SLAMseq).
Fast genetic mapping of complex traits in C. elegans using millions of individuals in bulk
Authors: Burga Alejandro , Ben-David Eyal , Vergara Tzitziki Lemus , Boocock James , Kruglyak Leonid
Published: September 2018

Genetic studies of complex traits in animals have been hindered by the need to generate, maintain, and phenotype large panels of recombinant lines. We developed a new method, C. elegans eXtreme Quantitative Trait Locus (ceX-QTL) mapping, that overcomes this obstacle via bulk selection on millions of unique recombinant individuals. We used ceX-QTL to map a drug resistance locus with high resolution. We also mapped differences in gene expression in live worms and discovered a regulatory feedback loop that responds to changes in HSP-90 chaperone activity. Lastly, we used ceX-QTL to map loci that influence fitness and discovered that one such locus is caused by a deletion in a highly conserved chromatin reader in the N2 reference strain. ceX-QTL is fast, powerful and cost-effective, and will accelerate the study of complex traits in animals.
Origin and evolution of papillomavirus (onco)genes and genomes
Authors: Willemsen Anouk , Bravo Ignacio G.
Published: September 2018

Papillomaviruses (PVs) are ancient viruses infecting vertebrates, from fish to mammals. Although the genomes of PVs are small and show conserved synteny, PVs display large genotypic diversity and ample variation in the phenotypic presentation of the infection. Most PVs genomes contain two small early genes E6 and E7. In a bunch of closely related human PVs, the E6 and E7 proteins provide the viruses with oncogenic potential.

The recent discoveries of PVs without E6 and E7 in different fish species place a new root on the PV tree, and suggest that the ancestral PV consisted of the minimal PV backbone E1-E2-L2-L1.

Bayesian phylogenetic analyses date the most recent common ancestor of the PV backbone to 424 million years ago (Ma). Common ancestry tests on extant E6 and E7 genes indicate that they share respectively a common ancestor dating back to at least 184 Ma. In AlphaPVs infecting primates, the appearance of the E5 oncogene 53-58 Ma concurred with i) a significant increase in substitution rate, ii) a basal radiation, and iii) key gain of functions in E6 and E7. This series of events was instrumental to build the extant phenotype of oncogenic human PVs.

Our results assemble the current knowledge on PV diversity and present an ancient evolutionary timeline punctuated by evolutionary innovations in the history of this successful viral family.
Social relationships, social isolation, and the human gut microbiota
Authors: Dill-McFarland Kimberly A. , Tang Zheng-Zheng , Kemis Julia H. , Kerby Robert L. , Chen Guanhua , Palloni Alberto , Sorenson Thomas , Rey Federico E. , Herd Pamela
Published: September 2018

Social relationships shape human health and mortality via behavioral, psychosocial, and physiological mechanisms, including inflammatory and immune responses. Though not tested in human studies, recent primate studies indicate that the gut microbiome may also be a biological mechanism linking relationships to health. Integrating microbiota data into the 60-year-old Wisconsin Longitudinal Study, we found that socialness with family and friends is associated with differences in the human fecal microbiota. Analysis of spouse (N = 94) and sibling pairs (N = 83) further revealed that spouses have more similar microbiota and more bacterial taxa in common than siblings, with no observed differences between sibling and unrelated pairs. These differences held even after accounting for dietary factors. The differences between unrelated individuals and married couples was driven entirely by couples who reported close relationships; there were no differences in similarity between couples reporting somewhat close relationships and unrelated individuals. Moreover, the microbiota of married individuals, compared to those living alone, has greater diversity and richness, with the greatest diversity among couples reporting close relationships, which is notable given decades of research documenting the health benefits of marriage. These results suggest that human interactions, especially sustained, close marital relationships, influence the gut microbiota.
WNT vampirization by glioblastoma leads to tumor growth and neurodegeneration
Authors: Portela Marta , Venkataramani Varun , Fahey-Lozano Natasha , Seco Esther , Losada-Perez Maria , Winkler Frank , Casas-Tintó Sergio
Published: September 2018

Glioblastoma (GB) is the most lethal brain tumor due to its high proliferation, aggressiveness, infiltration capacity and resilience to current treatments. Activation of the Wingless-related-integration-site (WNT) pathway is associated with a bad prognosis. UsingDrosophilaand primary xenograft models of human GB, we describe a mechanism that leads to the activation of WNT signaling [Wingless (Wg) inDrosophila] in tumor cells. GB cells display a network of tumor microtubes (TMs) which enwraps neurons, accumulates Wg receptor Frizzled1 (Fz1), and, thereby, actively depletes Wg from the neurons. Consequently, GB cells proliferate due to β-catenin activation, and neurons degenerate due to Wg signaling extinction. This novel view explains both neuron-dependent tumor progression, and also the neural decay associated with GB.
Relief from nitrogen starvation entails quick unexpected down-regulation of glycolytic/lipid metabolism genes in enologicalSaccharomyces cerevisiae
Authors: Catherine Tesnière , Chloé Bessière , Martine Pradal , Isabelle Sanchez , Bruno Blondin , Frédéric Bigey
Published: September 2018

Nitrogen composition of the grape must has an impact on yeast growth and fermentation kinetics as well as on the organoleptic properties of the final product. In some technological processes, such as white wine/rosé winemaking, the yeast-assimilable nitrogen content is sometimes insufficient to cover yeast requirements, which can lead to slow or sluggish fermentations. Growth is nevertheless quickly restored upon relief from nutrient starvation, e.g. through the addition of ammonium nitrogen, allowing fermentation completion. The aim of this study was to determine how nitrogen repletion affected the transcriptional response of aSaccharomyces cerevisiaewine yeast strain, in particular within the first hour after nitrogen addition. We found almost 4800 genes induced or repressed, sometimes within minutes after nutrient changes. Some of these responses to nitrogen depended on the TOR pathway, which controls positively ribosomal protein genes, amino acid and purine biosynthesis or amino acid permease genes and negatively stress-response genes, and genes related to the retrograde response (RTG) specific to the tricarboxylic acid (TCA) cycle and nitrogen catabolite repression (NCR). Some unexpected transcriptional responses concerned all the glycolytic genes, carbohydrate metabolism and TCA cycle-related genes that were down-regulated, as well as genes from the lipid metabolism.
Invasive aliens threatened with native extinction: examining best practice for species translocations under climate change
Authors: Egan Paul A. , Bourke David , Thuiller Wilfried , Baudraz Maude E.A. , Georges Damien , Renaud Julien , Stout Jane C.
Published: September 2018

Aim

Translocation remains a controversial strategy in species conservation. Here, we utilise the unusual scenario of invasive alien species (IAS) threatened with extinction in their native range to address key challenges in deciding ‘whether’, ‘where’, and ‘when’ to implement translocation, and how best to approach conservation under seemingly contradictory circumstances.

Location

Iberian Peninsula, NW Europe

Methods

Rhododendron ponticumssp.baeticumwas selected as a model IAS for case study analysis. We used species distribution models (SDMs) coupled with dynamic simulations of migration to assess: 1. the extinction risk posed to this species in its native Iberian range under climate change; 2. whether SDMs calibrated on the native range (replicating typical translocation planning) could predict invasive capacity in NW Europe; and 3. the extent to which recommended biogeographical constrains on translocations may limit available options. Insights gained on the above were used to build and test a generic decision framework for translocation, based on robust identification of microrefugia.

Results

Our findings suggest a high likelihood of climate-induced extinction forR.p. ssp.baeticumin its native range. Notably, SDMs completely failed to predict invasive capacity in NW Europe. However, application of our framework was successful in identifying sites more proximate to the native range – albeit outside this species’ current biogeographic region – potentially suited to translocation.

Main conclusions

The framework here developed can be used to guide translocation of climate-endangered species in a spatially and temporally precise manner. However, we caution that use of SDMs can possess short-comings in failing to capture a full picture of sites suited to translation, and in risk assessment of the capacity of translocated taxa to form invasive species. Strict biogeographic constraints to the selection of translocation sites can evidently help to safeguard against invasions, but may also severely hinder the options available to avert climate-induced extinctions.
Residual Structure of Unfolded Ubiquitin as Revealed by Hydrogen/Deuterium-Exchange 2D NMR
Authors: Chandak M. S. , Nakamura T. , Yagi-Utsumi M. , Yamaguchi T. , Kato K. , Kuwajima K.
Published: September 2018

The characterization of residual structures persistent in unfolded proteins in concentrated denaturant solution is currently an important issue in studies of protein folding, because the residual structure present, if any, in the unfolded state may form a folding initiation site and guide the subsequent folding reactions. Here, we thus studied the hydrogen/deuterium (H/D)-exchange behavior of unfolded ubiquitin in 6.0 M guanidinium chloride at pH 2.6 and 20°C. We employed a dimethylsulfoxide (DMSO)-quenched H/D-exchange NMR technique with the use of spin desalting columns, which allowed us to make a quick medium exchange from 6.0 M guanidinium chloride to a quenching DMSO solution. The technique is particularly effective for studies of the H/D-exchange kinetics of unfolded proteins in concentrated denaturant. By the backbone resonance assignment of the hetero-nuclear single quantum coherence spectrum of 15N-labeled ubiquitin in the DMSO solution, we successfully investigated the H/D-exchange kinetics of 27 identified peptide amide groups in the ubiquitin sequence. Although most of these amide groups were not protected, the four amide groups of Ile3, Val5, Ile13 and Leu73 were weakly but significantly protected with a protection factor of 2.5–3.0, indicating that there were residual structures in unfolded ubiquitin and that these amide groups were 60–67% hydrogen-bonded by the residual structures. We show that the first native β-hairpin, composed of residues 2–16 in the native ubiquitin structure, is partially structured even in 6.0 M guanidinium chloride and that the amide group of Leu73 is protected by a nonnative hydrogen-bonding interaction. From comparison with the previous folding studies of ubiquitin, it is concluded that the residual native β-hairpin in unfolded ubiquitin forms a folding initiation site and guides the subsequent folding reactions of the protein.