bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell tumor phylogeny inference with copy-number constrained mutation losses
Authors: Satas Gryte , Zaccaria Simone , Mon Geoffrey , Raphael Benjamin J. 
Published: November 2019

AbstractMotivationSingle-cell DNA sequencing enables the measurement of somatic mutations in individual tumor cells, and provides data to reconstruct the evolutionary history of the tumor. Nearly all existing methods to construct phylogenetic trees from single-cell sequencing data use single-nucleotide variants (SNVs) as markers. However, most solid tumors contain copy-number aberrations (CNAs) which can overlap loci containing SNVs. Particularly problematic are CNAs that delete an SNV, thus returning the SNV locus to the unmutated state. Such mutation losses are allowed in some models of SNV evolution, but these models are generally too permissive, allowing mutation losses without evidence of a CNA overlapping the locus.ResultsWe introduce a novel loss-supported evolutionary model, a generalization of the infinite sites and Dollo models, that constrains mutation losses to loci with evidence of a decrease in copy number. We design a new algorithm, Single-Cell Algorithm for Reconstructing the Loss-supported Evolution of Tumors (Scarlet), that infers phylogenies from single-cell tumor sequencing data using the loss-supported model and a probabilistic model of sequencing errors and allele dropout. On simulated data, we show that Scarlet outperforms current single-cell phylogeny methods, recovering more accurate trees and correcting errors in SNV data. On single-cell sequencing data from a metastatic colorectal cancer patient, Scarlet constructs a phylogeny that is both more consistent with the observed copy-number data and also reveals a simpler monooclonal seeding of the metastasis, contrasting with published reports of polyclonal seeding in this patient. Scarlet substantially improves single-cell phylogeny inference in tumors with CNAs, yielding new insights into the analysis of tumor evolution.AvailabilitySoftware is available at github.com/raphael-group/scarletContactbraphael@princeton.edu
Independence of HIF1a and androgen signaling pathways in prostate cancer
Authors: Tran Maxine GB , Bibby Becky AS , Yang Lingjian , Lo Franklin , Warren Anne , Shukla Deepa , Osborne Michelle , Hadfield James , Carroll Thomas , Stark Rory , Scott Helen , Ramos-Montoya Antonio , Massie Charlie , Maxwell Patrick , West Catharine ML , Mills Ian G. , Neal David E. 
Published: November 2019

AbstractAndrogen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.
Tensor Image Registration Library: Automated Non-Linear Registration of Sparsely Sampled Histological Specimens to Post-Mortem MRI of the Whole Human Brain
Authors: Huszar Istvan N. , Pallebage-Gamarallage Menuka , Foxley Sean , Tendler Benjamin C. , Leonte Anna , Hiemstra Marlies , Mollink Jeroen , Smart Adele , Bangerter-Christensen Sarah , Brooks Hannah , Turner Martin R. , Ansorge Olaf , Miller Karla L. , Jenkinson Mark 
Published: November 2019

AbstractThere is a need to understand the histopathological basis of MRI signal characteristics in complex biological matter. Microstructural imaging holds promise for sensitive and specific indicators of the early stages of human neurodegeneration but requires validation against traditional histological markers before it can be reliably applied in the clinical setting. Validation relies on a precise and preferably automatic method to align MRI and histological images of the same tissue, which poses unique challenges compared to more conventional MRI-to-MRI registration.A customisable open-source platform, Tensor Image Registration Library (TIRL) is presented. Based on TIRL, a fully automated pipeline was implemented to align small stained histological images with dissection photographs of corresponding tissue blocks and coronal brain slices, and further with high-resolution (0.5 mm) whole-brain post-mortem MRI data. The pipeline performed three separate deformable registrations to achieve accurate mapping between whole-brain MRI and small-slide histology coordinates. The robustness and accuracy of the individual registration steps were evaluated using both simulated data and real-life images from 6 different anatomical locations of one post-mortem human brain.The automated registration method demonstrated sub-millimetre accuracy in all steps, robustness against tissue damage, and good reproducibility between experiments. The method also outperformed manual landmark-based slice-to-volume registration, also correcting for curvatures in the slicing plane. Due to the customisability of TIRL, the pipeline can be conveniently adapted for other research needs and is therefore suitable for the large-scale comparison of routinely collected histology and MRI data.HighlightsTIRL: new framework for prototyping bespoke image registration pipelinesPipeline for automated registration of small-slide histology to whole-brain MRISlice-to-volume registration accounting for through-plane deformationsNo need for serial histological sampling
Functional channels in matureE. colicolonies
Authors: Rooney Liam M. , Amos William B. , Hoskisson Paul A. , McConnell Gail 
Published: November 2019

AbstractBiofilms are important in medicine, industry and the natural environment, however their structure is largely unexplored across multiple spatial scales. We have studied the architecture of matureEscherichia colimacro-colony biofilms by means of the Mesolens, an optical system which uniquely allows simultaneous imaging of individual bacteria and over one hundred cubic millimetres of its biofilm milieu. Our chief finding is the presence of intra-colony channels on the order of 10 μm in diameter inE. colibiofilms. These channels have a characteristic structure and reform after total mechanical disaggregation of the colony. We present evidence that the channels transport particles and function to assist the absorption of nutrients. These channels potentially offer a new route for the delivery of dispersal agents or antimicrobial drugs to biofilms, ultimately lowering their impact on public health and industry.
Refining the transcriptome of the human malaria parasite Plasmodium falciparum using amplification-free RNA-seq
Authors: Chappell Lia , Ross Philipp , Orchard Lindsey , Otto Thomas D. , Berriman Matthew , Rayner Julian C. , Llinás Manuel 
Published: November 2019

AbstractPlasmodium parasites undergo several major developmental transitions during their complex lifecycle, which are enabled by precisely ordered gene expression programs. Transcriptomes from the 48-hour blood stages of the major human malaria parasite Plasmodium falciparum have been described using cDNA microarrays and RNA-seq, but these assays have not always performed well within non-coding regions, where the AT-content is often 90-95%. We developed a directional, amplification-free RNA-seq protocol (DAFT-seq) to reduce bias against AT-rich cDNA, which we have applied to three strains of P. falciparum (3D7, HB3 and IT). While strain-specific differences were detected, overall there is strong conservation between the transcriptional profiles. For the 3D7 reference strain, transcription was detected from 89% of the genome, with over 75% of the genome transcribed into mRNAs. These datasets allowed us to refine the 5’ and 3’ untranslated regions (UTRs), which can be variable, long (>1,000 nt), and often overlap those of adjacent transcripts. We also find that transcription from bidirectional promoters frequently results in non-coding, antisense transcripts. By capturing the 5’ ends of mRNAs, we reveal both constant and dynamic use of transcriptional start sites across the intraerythrocytic developmental cycle resulting in an updated view of the P. falciparum transcriptome.
Neutrophil swarming in damaged tissue is orchestrated by connexin-dependent calcium signals
Authors: Poplimont Hugo , Georgantzoglou Antonios , Boulch Morgane , Coombs Caroline , Papaleonidopoulou Foteini , Sarris Milka 
Published: November 2019

AbstractNeutrophils are major inflammatory cells that rapidly infiltrate injured tissues to provide antimicrobial functions. A key step in their response is the paracrine release of the attractant LTB4, which switches the migration mode from exploratory patrolling to coordinated swarming. This leads to dense clusters that may further disrupt tissue architecture. The coordination mechanism underpinning neutrophil swarms is elusive. Here we show that neutrophils swarms require mutual reinforcement of damage signalling at the wound core. New biosensors and live imaging in zebrafish revealed that neutrophil chemoattractant synthesis is triggered by a sustained calcium flux upon contact with necrotic tissue and sensing of the damage signal ATP. This ‘calcium alarm’ signal propagates in the nascent neutrophil cluster through connexin-43 hemichannels, which allow release of intracellular ATP. This enables rapid assembly of a centralised, supracellular chemoattractant source, which is instrumental for coordinated recruitment and maximal cell gathering.
Raw milk for human consumption may carry antimicrobial resistance genes
Authors: Gréta Tóth Adrienn , Csabai István , Krikó Eszter , Tőzsér Dóra , Maróti Gergely , Patai Árpád V. , Makrai László , Szita Géza , Solymosi Norbert 
Published: November 2019

AbstractBackgroundThe increasing prevalence of antimicrobial resistance (AMR) is a significant threat to global health. The widespread use of antibiotics is increasingly shortening the time it takes for resistant strains to develop. More and more multi-drug-resistant bacterial strains cause life-threatening infections and the death of tens of thousands of people each year. Beyond disease control animals are often given antibiotics for growth promotion or increased feed efficiency, which further increase the chance of the development of multi-resistant strains. After the consumption of unprocessed animal products, these strains may meet the human bacteriota. Among the foodborne and the human populations, antimicrobial resistance genes (ARGs) may be shared by horizontal gene transfer. This study aims to test the presence of antimicrobial resistance genes in milk metagenome, investigate their genetic position and their linkage to mobile genetic elements.ResultsWe have analyzed raw milk samples from public markets sold for human consumption. The milk samples contained genetic material from various bacterial species and the detailed analysis uncovered the presence of several antimicrobial resistance genes. The samples contained complete ARGs influencing the effectiveness of acridine dye, cephalosporin, cephamycin, fluoroquinolone, penam, peptide antibiotics and tetracycline. One of the ARGs, PC1 beta-lactamase may also be a mobile element that facilitates the transfer of resistance genes to other bacteria, e.g. to the ones living in the human gut.ConclusionBesides the animal products’ antibiotic residuals, their potentially transmissible antimicrobial resistance gene content may also contribute to the development of human pathogenic bacteria’s antimicrobial resistance.
Heat production in a feeding matrix formed on carrion by communally breeding beetles
Authors: Matuszewski Szymon , Mądra-Bielewicz Anna 
Published: November 2019

AbstractInsects regulate their body temperature mostly behaviourally, by changing posture or microhabitat. These strategies may be ineffective in some habitats, for example on carrion. Carrion beetles create a feeding matrix by applying to cadaver surface anal or oral exudates. We tested the hypothesis that the matrix, which is formed on carrion by communally breeding beetleNecrodes littoralisL. (Silphidae), produces heat that enhances insect fitness. Using thermal imaging we demonstrate that heat produced in the matrix formed on meat by adult or larval beetles is larger than in meat decomposing without insects. Larval beetles regularly warmed up in the matrix. Moreover, by comparing matrix temperature and larval fitness in colonies with and without preparation of meat by adult beetles, we provide evidence that formation of a matrix by adult beetles has deferred thermal effects for larval microhabitat. We found an increase in heat production of the matrix and a decrease in development time and mortality of larvae after adult beetles applied their exudates on meat in the pre-larval phase. Our findings indicate that spreading of exudates over carrion byNecrodeslarvae, apart from other likely functions (e.g. digesting carrion or promoting growth of beneficial microbes), facilitates thermoregulation. In case of adult beetles, this behaviour brings distinct thermal benefits for their offspring and therefore may be viewed as a new form of indirect parental care with an important thermal component.
Wounding and insect feeding trigger two independent MAPK pathways with distinct regulation and kinetics
Authors: Sözen Cécile , Schenk Sebastian T. , Boudsocq Marie , Chardin Camille , Almeida-Trapp Marilia , Krapp Anne , Hirt Heribert , Mithöfer Axel , Colcombet Jean 
Published: November 2019

AbstractWounding is caused by abiotic and biotic factors and triggers complex short- and long-term responses at the local and systemic level. These responses are under the control of complex signaling pathways, which are still poorly understood. Here, we show that the rapid activation of MKK4/5-MPK3/6 by wounding is independent of jasmonic acid (JA) signaling and that, contrary to what happens in tobacco, this fast module does not control wound-triggered JA accumulation in Arabidopsis. We also demonstrate that a second MAPK module, constituted by MKK3 and the clade-C MAPKs MPK1/2/7, is activated by wounding in an independent manner. We provide evidence that the activation of this MKK3-MPK1/2/7 module occurs mainly through wound-induced JA production via the transcriptional regulation of upstream clade-III MAP3Ks and particularly MAP3K14. We show that mkk3 mutant plants are more susceptible to the larvae of the generalist lepidopteran herbivore Spodoptera littoralis, indicating that the MKK3-MPK1/2/7 module is involved in counteracting insect feeding.One sentence summaryWounding induces the parallel activation of a rapid signaling module (MKK4/5-MPK3/6) and a JA-dependent slow one (MAP3K14-MKK3-MPK1/2/7/14) to restrict insect feeding.
STing: accurate and ultrafast genomic profiling with exact sequence matches
Authors: Espitia-Navarro Hector F. , Chande Aroon T. , Nagar Shashwat D. , Smith Heather , Jordan I. King , Rishishwar Lavanya 
Published: November 2019

AbstractGenome-enabled approaches to molecular epidemiology have become essential to public health agencies and the microbial research community. We developed the algorithm STing to provide turn-key solutions for molecular typing and gene detection directly from next-generation sequence data of microbial pathogens. Our implementation of STing uses an innovative k-mer search strategy that eliminates the computational overhead associated with the time consuming steps of quality control, assembly, and alignment required by more traditional methods. We compared STing to six of the most widely used programs for genome-based molecular typing and demonstrate its ease of use, accuracy, speed, and efficiency. STing shows superior accuracy and performance for standard multilocus sequence typing schemes, along with larger genome-scale typing schemes, and it enables rapid automated detection of antimicrobial resistance and virulence factor genes. We hope that the adoption of STing will help to democratize microbial genomics and thereby maximize its benefit for public health.
Systematic analyses of factors required for adhesion ofSalmonella entericaserovar Typhimurium to corn salad (Valerianella locusta)
Authors: Elpers Laura , Kretzschmar Juliane , Nuccio Sean-Paul , Bäumler Andreas J. , Hensel Michael 
Published: November 2019

AbstractSalmonella entericais a foodborne pathogen leading to gastroenteritis and is commonly acquired by consumption of contaminated food of animal origin. However, numbers of outbreaks linked to the consumption of fresh or minimally processed food of non-animal origin are increasing. New infection routes ofS. entericaby vegetables, fruits, nuts and herbs have to be considered. This leads to special interest inS. entericainteractions with leafy products, e.g. salads, that are consumed unprocessed. The attachment ofS. entericato salad is a crucial step in contamination, but little is known about the bacterial factors required and mechanisms of adhesion.S. entericapossesses a complex set of adhesive structures whose functions are only partly understood. Potentially,S. entericamay deploy multiple adhesive strategies for adhering to various salad species, and other vegetables. Here, we systematically analyzed the contribution of the complete adhesiome, of LPS, and of flagella-mediated motility ofS. entericaserovar Typhimurium (STM) in adhesion to corn salad. We deployed a reductionist, synthetic approach to identify factors involved in the surface binding of STM to leaves of corn salad with particular regard to the expression of all known adhesive structures using the Tet-on system. This work reveals the contribution of Saf fimbriae, type 1 secretion system-secreted BapA, an intact LPS, and flagella-mediated motility of STM in adhesion to corn salad leaves.ImportanceHuman gastrointestinal pathogens are often transmitted by animal products, but recent outbreaks show increasing importance of vegetables as source of infection by pathogenicE. coliorSalmonella enterica.The mechanisms of binding ofS. entericato vegetables such as salad are only poorly understood. We established an experimental model system to systematically investigate the role of adhesive structures ofS. entericaserovar Typhimurium in binding to corn salad leaves. The contributions of all members of the complex adhesiome, flagella, and O-antigen were evaluated. We identified that Saf fimbriae, type 1 secretion system-secreted BapA, an intact LPS, and flagella-mediated motility contribute to adhesion ofSalmonellato corn salad leaves. These results will enable future investigations on factors contributing to contamination of vegetables under agricultural conditions.
Can we use it? On the utility ofde novoand reference-based assembly of Nanopore data for plant plastome sequencing
Authors: Scheunert Agnes , Dorfner Marco , Lingl Thomas , Oberprieler Christoph 
Published: November 2019

AbstractThe chloroplast genome harbors plenty of valuable information for phylogenetic research. Illumina short-read data is generally used forde novoassembly of whole plastomes. PacBio or Oxford Nanopore long reads are additionally employed in hybrid approaches to enable assembly across the highly similar inverted repeats of a chloroplast genome. Unlike for PacBio, plastome assemblies based solely on Nanopore reads are rarely found, due to their high error rate and non-random error profile. However, the actual quality decline connected to their use has never been quantified. Furthermore, no study has employed reference-based assembly using Nanopore reads, which is common with Illumina data. UsingLeucanthemumMill. as an example, we compared the sequence quality of seven plastome assemblies of the same species, using combinations of two sequencing platforms and three analysis pipelines. In addition, we assessed the factors which might influence Nanopore assembly quality during sequence generation and bioinformatic processing.The consensus sequence derived fromde novoassembly of Nanopore data had a sequence identity of 99.59% compared to Illumina short-readde novoassembly. Most of the found errors comprise indels (81.5%), and a large majority of them is part of homopolymer regions. The quality of reference-based assembly is heavily dependent upon the choice of a close-enough reference. Using a reference with 0.83% sequence divergence from the studied species, mapping of Nanopore reads results in a consensus comparable to that from Nanoporede novoassembly, and of only slightly inferior quality compared to a reference-based assembly with Illumina data (0.49% and 0.26% divergence from Illuminade novo). For optimal assembly of Nanopore data, appropriate filtering of contaminants and chimeric sequences, as well as employing moderate read coverage, is essential.Based on these results, we conclude that Nanopore long reads are a suitable alternative to Illumina short reads in plastome phylogenomics. Only few errors remain in the finalized assembly, which can be easily masked in phylogenetic analyses without loss in analytical accuracy. The easily applicable and cost-effective technology might warrant more attention by researchers dealing with plant chloroplast genomes.
α-Synuclein-induced Kv4 channelopathy in mouse vagal motoneurons causes non-motor parkinsonian symptoms
Authors: Chiu Wei-Hua , Kovacheva Lora , Musgrove Ruth E. , Arien-Zakay Hadar , Koprich James B. , Brotchie Jonathan M. , Yaka Rami , Ben-Zvi Danny , Hanani Menachem , Roeper Jochen , Goldberg Joshua A. 
Published: November 2019

AbstractNo disease modifying therapy is currently available for Parkinson’s disease (PD), the second most common neurodegenerative disease. The long non-motor prodromal phase of PD is a window of opportunity for early detection and intervention. However, we lack the pathophysiological understanding to develop selective biomarkers and interventions. By developing a mutant α-synuclein selective-overexpression mouse model of prodromal PD, we identified a cell-autonomous selective Kv4 channelopathy in dorsal motor nucleus of the vagus (DMV) neurons. This functional remodeling of intact DMV neurons leads to impaired pacemaker function in vitro and in vivo, which in turn reduces gastrointestinal motility which is a common, very early symptom of prodromal PD. We show for the first time a causal chain of events from α-synuclein via a biophysical dysfunction of specific neuronal populations to a clinically relevant prodromal symptom. These findings can facilitate the rational design of clinical biomarkers to identify people at risk for PD.