bluuebunny/crossref_metadata_2025_split huggingface dataset:
Zika virus seroprevalence declines and neutralization antibodies wane in adults following outbreaks in French Polynesia and Fiji
Authors: Henderson Alasdair D , Aubry Maite , Kama Mike , Vanhomwegen Jessica , Teissier Anita , Mariteragi-Helle Teheipuaura , Paoaafaite Tuterarii , Manuguerra Jean-Claude , Edmunds W John , Whitworth Jimmy , Watson Conall H , Lau Colleen L , Cao-Lormeau Van-Mai , Kucharski Adam J 
Published: March 2019

SUMMARYBackgroundSerosurveys published following major outbreaks of Zika virus (ZIKV) have so far shown a high level of seroprevalence from samples collected within 12 months of the first confirmed case. A common assumption is that ZIKV infection confers long-term protection against reinfection, preventing ZIKV from re-emerging in previously affected areas for many years. However, the long-term immune response to ZIKV following an outbreak remains poorly documented.MethodsWe compared results from eight serological surveys, with sample sizes ranging from 49 to 700, before and after known ZIKV outbreaks in the Pacific region: five from cross-sectional studies of schoolchildren and the general population in French Polynesia over a seven-year period; and three from a longitudinal cohort in Fiji over a four-year period.FindingsWe found strong evidence of a decline in seroprevalence in both countries over a two-year period following first reported ZIKV transmission. In the cohort in Fiji, there was also a significant decline in antibody titres against ZIKV. However, the decline in seroprevalence was concentrated in adults, while high seroprevalence persisted in children.InterpretationThe observed patterns of long-term anti-ZIKV antibody levels following outbreaks in the Pacific could be an early indication of the dynamics of population immunity in Latin America. Given that ZIKV antibody levels can wane substantially over time, follow-up seroprevalence studies and prospective clinical trial designs in Latin America may need to be revised, and assumptions about the potential for ZIKV to re-emerge may need to be revisited.FundingPacific Funds, ANR, MRC, Wellcome, Royal Society.
Effect of Antimicrobial Peptides HNP-1 and hBD-1 on Staphylococcus aureus Clinical Strains in vitro and in vivo
Authors: Bolatchiev Albert , Baturin Vladimir , Bazikov Igor , Maltsev Alexander , Kunitsina Elena 
Published: March 2019

ABSTRACTThe aims of this study were: (1) To investigate the activity of recombinant AMPs HNP-1 and hBD-1 in combination with cefotaxime against Staphylococcus aureus clinical strains (MSSA and MRSA) in vitro using checkerboard method; (2) To investigate the activity of HNP-1 and hBD-1 encapsulated in silicon nanoparticles (niosomes) in the treatment of MRSA-infected wound in rats. For this S. aureus clinical strains (MSSA and MRSA) were isolated from patients with diabetic foot infection. Cefotaxime, recombinant HNP-1 and hBD-1 (in all possible combinations with each other) were used for testing by the checkerboard method. Two niosomal topical gels with HNP-1/hBD-1 were prepared to treat MRSA-infected wounds in rats. Gels were administered once a day, the control group – without treatment. Wound healing rate was calculated on the 4th, 9th and 16th days of the experiment and compared using one-way ANOVA with Bonferroni correction. MIC of HNP-1 for MSSA and MRSA was the same – 1 mg/L. MIC of hBD-1 for MSSA and MRSA was also the same – 0.5 mg/L. Topical gels with niosomal HNP-1 (or hBD-1) showed a significantly faster wound healing in comparison with the control. The data obtained open up prospects for use of AMPs encapsulated in silica nanoparticles for the development of new antibiotics.
Tricalbin-mediated contact sites control ER curvature to maintain plasma membrane integrity
Authors: Collado Javier , Kalemanov Maria , Martínez-Sánchez Antonio , Campelo Felix , Baumeister Wolfgang , Stefan Christopher J. , Fernández-Busnadiego Ruben 
Published: March 2019

SummaryMembrane contact sites (MCS) between the endoplasmic reticulum (ER) and the plasma membrane (PM) play fundamental roles in all eukaryotic cells. ER-PM MCS are particularly abundant in S. cerevisiae, where approximately half of the PM surface is covered by cortical ER (cER). Several proteins, including Ist2, Scs2/22 and Tcb1/2/3 are implicated in cER formation, but the specific roles of these molecules are poorly understood. Here we use cryo-electron tomography to show that ER-PM tethers are key determinants of cER morphology. In particular, Tcb proteins form peaks of extreme curvature on the cER membrane facing the PM. Semi-quantitative modeling and functional assays suggest that Tcb-mediated cER peaks facilitate the transport of lipids from the cER to the PM, necessary to maintain PM integrity under stress conditions. ER peaks were also present at other MCS, implying that membrane curvature enforcement may be a widespread mechanism to expedite lipid transport at MCS.
The Hidden Repertoire of Brain Dynamics and Dysfunction
Authors: McIntosh Anthony R. , Jirsa Viktor K. 
Published: March 2019

SummaryThe purpose of this paper is to describe a framework for the understanding of rules that govern how neural system dynamics are coordinated to produce behavior. The framework, structured flows on manifolds (SFM), posits that neural processes are flows depicting system interactions that occur on relatively low-dimension manifolds, which constrain possible functional configurations. Although this is a general framework, we focus on the application to brain disorders. We first explain the Epileptor, a phenomenological computational model showing fast and slow dynamics, but also a hidden repertoire whose expression is similar to refractory status epilepticus. We suggest that epilepsy represents an innate brain state whose potential may be realized only under certain circumstances. Conversely, deficits from damage or disease processes, such as stroke or dementia, may reflect both the disease process per se and the adaptation of the brain. SFM uniquely captures both scenarios.The Hidden Repertoire of Brain Dynamics and Dysfunction
Proteome-wide signatures of function in highly diverged intrinsically disordered regions
Authors: Zarin Taraneh , Strome Bob , Nguyen Ba Alex N , Alberti Simon , Forman-Kay Julie D , Moses Alan M 
Published: March 2019

AbstractIntrinsically disordered regions make up a large part of the proteome, but the sequence-to-function relationship in these regions is poorly understood, in part because the primary amino acid sequences of these regions are poorly conserved in alignments. Here we use an evolutionary approach to detect molecular features that are preserved in the amino acid sequences of orthologous intrinsically disordered regions. We find that most disordered regions contain multiple molecular features that are preserved, and we define these as “evolutionary signatures” of disordered regions. We demonstrate that intrinsically disordered regions with similar evolutionary signatures can rescue functionin vivo,and that groups of intrinsically disordered regions with similar evolutionary signatures are strongly enriched for functional annotations and phenotypes. We propose that evolutionary signatures can be used to predict function for many disordered regions from their amino acid sequences.
Inferring biophysical models of evolution from genome-wide patterns of codon usage
Authors: Kion-Crosby Willow B. , Manhart Michael , Morozov Alexandre V. 
Published: March 2019

AbstractFrequencies of synonymous codons are typically non-uniform, despite the fact that such codons correspond to the same amino acid in the genetic code. This phenomenon, known as codon bias, is broadly believed to be due to a combination of factors including genetic drift, mutational biases, and selection for speed and accuracy of codon translation; however, quantitative modeling of codon bias has been elusive. We have developed a biophysical population genetics model which explains genome-wide codon frequencies observed across 20 organisms. We assume that codons evolve independently of each other under the influence of mutation and selection forces, and that the codon population has reached evolutionary steady state. Our model implements codon-level treatment of mutations with transition/transversion biases, and includes two contributions to codon fitness which describe codon translation speed and accuracy. Furthermore, our model includes wobble pairing – the possibility of codon-anticodon base pairing mismatches at the 3’ nucleotide position of the codon. We find that the observed patterns of genome-wide codon usage are consistent with a strong selective penalty for mistranslated amino acids. Thus codons undergo purifying selection and their relative frequencies are affected in part by mutational robustness. We find that the dependence of codon fitness on translation speed is weaker on average compared to the strength of selection against mistranslation. Although no constraints on codon-anticodon pairing are imposeda priori, a reasonable hierarchy of pairing rates, which conforms to the wobble hypothesis and is consistent with available structural evidence, emerges spontaneously as a model prediction. Finally, treating the translation process explicitly in the context of a finite ribosomal pool has allowed us to estimate mutation rates per nucleotide directly from the coding sequences. Reminiscent of Drake’s observation that mutation rates are inversely correlated with the genome size, we predict that mutation rates are inversely proportional to the number of genes. Overall, our approach offers a unified biophysical and population genetics framework for studying codon bias across all domains of life.
Myosin II isoforms play distinct roles in adherens junction biogenesis
Authors: Heuzé Mélina L. , Sankara Gautham , Dang Tien , d’Alessandro Joseph , Cellerin Victor , Williams David S. , van Hest Jan C. M. , Marcq Philippe , Mège René-Marc , Ladoux Benoît 
Published: March 2019

AbstractAdherens junction (AJ) assembly under force is essential for many biological processes like epithelial monolayer bending, collective cell migration, cell extrusion and wound healing. The acto-myosin cytoskeleton acts as a major force-generator during the de novo formation and remodelling of AJ. Here, we investigated the role of myosinII isoforms in epithelial junction assembly. Myosin IIA (NMIIA) and Myosin IIB (NMIIB) differentially regulate biogenesis of adherens junction through association with distinct actin networks. Analysis of junction dynamics, actin organization, and mechanical forces of control and knockdown cells for myosins revealed that NMIIA provides the mechanical tugging force necessary for cell-cell junction reinforcement and maintenance. NMIIB is involved in E-cadherin clustering, maintenance of a branched actin layer connecting E-cadherin complexes and perijunctional actin fibres leading to the building-up of anisotropic stress. These data reveal unanticipated complementary functions of NMIIA and NMIIB in the biogenesis and integrity of AJ.
Somatic mutations in miRNA genes in lung cancer – potential functional consequences of non-coding sequence variants
Authors: Galka-Marciniak Paulina , Urbanek-Trzeciak Martyna Olga , Nawrocka Paulina Maria , Dutkiewicz Agata , Giefing Maciej , Lewandowska Marzena Anna , Kozlowski Piotr 
Published: March 2019

AbstractA growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis. However, little is known about somatic mutations in miRNA genes. To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of ∼500 lung adenocarcinoma (LUAD) and ∼500 lung squamous cell carcinoma (LUSC) samples generated in the TCGA. Altogether, we identified >1000 mutations affecting ∼500 different miRNA genes and showed that half of all cancers had at least one such mutation. Mutations occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences. We showed that seed mutations strongly affected miRNA:target interactions, drastically changing the pool of predicted targets. Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs. We identified 10 significantly overmutated hotspot miRNA genes, including themiR-379gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences. The occurrence of mutations in the hotspot miRNA genes was also shown experimentally. We present a comprehensive analysis of somatic mutations in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.
Reduced insulin and IGF-1 signalling synergistically extend healthspan in male mice
Authors: Walker Andrew MN , Watt Nicole T , Warmke Nele , Yuldasheva Nadira Y , Drozd Michael , Haywood Natalie J , Skromna Anna , Makava Natasha , Wheatcroft Stephen B , Kearney Mark T , Cubbon Richard M 
Published: March 2019

AbstractReduced IGF-1 signalling is an evolutionarily conserved mediator of longevity, yet the magnitude of this effect is substantially larger in organisms retaining a common insulin and IGF-1 receptor. Whether this discrepancy reflects the failure to simultaneously reduce IGF-1 and insulin signalling in mammalian model systems remains unexplored. Moreover, studies of invertebrates cannot ascertain whether substantial effects upon lifespan are associated with preserved cognitive performance, a crucial component of healthspan. We compared the healthspan of male mice with haploinsufficiency of the insulin receptor (IRKO), IGF-1 receptor (IGF-1RKO), or both (DKO), with wildtype (WT) littermates. DKO mice survived longer than WT, with IRKO and IGF-1RKO being intermediate. At 2 years of age, DKO also exhibited preserved nesting behaviour in contrast with all other genotypes. Differential insulin sensitivity or weight gain during ageing did not explain the preserved healthspan of DKO, since these were comparable to IRKO littermates. These data provide the first demonstration that reduced insulin and IGF-1 signalling have synergistic effects upon healthspan in a mammalian model system, suggesting future mechanistic and translational studies should target insulin and IGF-1 signalling.
Rod-shaped tricalbins contribute to PM asymmetry at curved ER-PM contact sites
Authors: Hoffmann Patrick C. , Bharat Tanmay A. M. , Wozny Michael R. , Miller Elizabeth A. , Kukulski Wanda 
Published: March 2019

AbstractLipid flow between cellular organelles occurs via membrane contact sites that form dynamic conduits. Extended-synaptotagmins, known as tricalbins in yeast, mediate lipid transfer between the endoplasmic reticulum (ER) and plasma membrane (PM). How these proteins regulate the membrane architecture to transport lipids across the aqueous space between bilayers remains unknown. Using correlative microscopy, electron cryo-tomography and high-throughput genetics we address this interplay of architecture and function in budding yeast. We find that ER-PM contacts are diverse in protein composition and membrane morphology, not in intermembrane distance. In situ cryo-EM of tricalbins reveals their molecular organisation that suggests an unexpected structural framework for lipid transfer. Genetic analysis identifies functional redundancies, both for tricalbin domains and cellular lipid routes, and points to tricalbin function in maintenance of PM asymmetry. These results uncover a modularity of molecular and structural functions of tricalbins, and of their roles within the network of cellular lipid fluxes.
Balancing selection of the Intracellular Pathogen Response in natural Caenorhabditis elegans populations
Authors: van Sluijs Lisa , Bosman Kobus J. , Pankok Frederik , Blokhina Tatiana , Wilten Jop I. H. A. , Riksen Joost A. G. , Snoek Basten L. , Pijlman Gorben P. , Kammenga Jan E. , Sterken Mark G. 
Published: March 2019

AbstractGenetic variation in host populations may lead to differential viral susceptibilities. Here, we investigate the role of natural genetic variation in the Intracellular Pathogen Response (IPR), an important antiviral pathway in the model organism Caenorhabditis elegans against Orsay virus (OrV). The IPR involves transcriptional activity of 80 genes including the pals-genes. We examine the genetic variation in the pals-family for traces of selection and explore the molecular and phenotypic effects of having distinct pals-gene alleles. Genetic analysis of 330 global C. elegans strains reveals that genetic diversity within the IPR-related pals-genes can be categorized in a few haplotypes worldwide. Importantly, two key IPR regulators, pals-22 and pals-25, are in a genomic region carrying signatures of balancing selection, suggesting that different evolutionary strategies exist in IPR regulation. We infected eleven C. elegans strains that represent three distinct pals-22 pals-25 haplotypes with Orsay virus to determine their susceptibility. For two of these strains, N2 and CB4856, the transcriptional response to infection was also measured. The results indicate that pals-22 pals-25 haplotype shapes the defense against OrV and host genetic variation can result in constitutive activation of IPR genes. Our work presents evidence for balancing genetic selection of immunity genes in C. elegans and provides a novel perspective on the functional diversity that can develop within a main antiviral response in natural host populations.
Jomon genome sheds light on East Asian population history
Authors: Gakuhari Takashi , Nakagome Shigeki , Rasmussen Simon , Allentoft Morten , Sato Takehiro , Korneliussen Thorfinn , Chuinneagáin Blánaid Ní , Matsumae Hiromi , Koganebuchi Kae , Schmidt Ryan , Mizushima Souichiro , Kondo Osamu , Shigehara Nobuo , Yoneda Minoru , Kimura Ryosuke , Ishida Hajime , Masuyama Yoshiyuki , Yamada Yasuhiro , Tajima Atsushi , Shibata Hiroki , Toyoda Atsushi , Tsurumoto Toshiyuki , Wakebe Tetsuaki , Shitara Hiromi , Hanihara Tsunehiko , Willerslev Eske , Sikora Martin , Oota Hiroki 
Published: March 2019

AbstractAnatomical modern humans reached East Asia by >40,000 years ago (kya). However, key questions still remain elusive with regard to the route(s) and the number of wave(s) in the dispersal into East Eurasia. Ancient genomes at the edge of East Eurasia may shed light on the detail picture of peopling to East Eurasia. Here, we analyze the whole-genome sequence of a 2.5 kya individual (IK002) characterized with a typical Jomon culture that started in the Japanese archipelago >16 kya. The phylogenetic analyses support multiple waves of migration, with IK002 forming a lineage basal to the rest of the ancient/present-day East Eurasians examined, likely to represent some of the earliest-wave migrants who went north toward East Asia from Southeast Asia. Furthermore, IK002 has the extra genetic affinity with the indigenous Taiwan aborigines, which may support a coastal route of the Jomon-ancestry migration from Southeast Asia to the Japanese archipelago. This study highlight the power of ancient genomics with the isolated population to provide new insights into complex history in East Eurasia.
Live detection of neural stem and glioblastoma cells by an oligothiophene derivative
Authors: Ilkhanizadeh Shirin , Gracias Aileen , Åslund Andreas K.O. , Bäck Marcus , Simon Rozalyn , Rraklli Vilma , Migliori Bianca , Kavanagh Edel , Nelander Sven , Westermark Bengt , Uhrbom Lene , Forsberg-Nilsson Karin , Teixeira Ana I. , Konradsson Peter , Uhlén Per , Joseph Bertrand , Hermanson Ola , Nilsson K. Peter R. 
Published: March 2019

AbstractHere we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) cells and embryonic neural stem cells (NSCs). While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. p-HTMI were readily able to detect a subpopulation of human cells in vivo in mouse brain sections with tumors developed from orthotopically transplanted patient-derived GBM cells. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of subpopulations of neural stem and glioma cells.
Neuronal programming by microbiota enables environmental regulation of intestinal motility
Authors: Obata Yuuki , Boeing Stefan , Castaño Álvaro , Bon-Frauches Ana Carina , Gomez de Agüero Mercedes , Boesmans Werend , Yilmaz Bahtiyar , Lopes Rita , Huseynova Almaz , Maradana Muralidhara Rao , Vanden Berghe Pieter , Murray Andrew J. , Stockinger Brigitta , Macpherson Andrew J. , Pachnis Vassilis 
Published: March 2019

AbstractEnvironmental signals modulate the activity of the nervous system and harmonize its output with the outside world. Synaptic activity is crucial for integrating sensory and effector neural pathways but the role of transcriptional mechanisms as environmental sensors in the nervous system remains unclear. By combining a novel strategy for transcriptomic profiling of enteric neurons with microbiota manipulation, we demonstrate that the transcriptional programs of intestinal neural circuits depend on their anatomical and physiological context. We also identify the ligand-dependent transcription factor Aryl hydrocarbon Receptor (AhR) is an intrinsic regulator of enteric nervous system output. AhR is instated as a neuronal biosensor in response to microbiota colonization allowing resident enteric neurons to directly monitor and respond to the intestinal microenvironment. We suggest that AhR signaling integrates neuronal activity with host defence mechanisms towards gut homeostasis and health.One Sentence SummaryMicrobiota induce expression of AhR in enteric neurons of the distal intestine enabling them to respond to environmental signals.
Multi-grip classification-based prosthesis control with two EMG-IMU sensors
Authors: Krasoulis Agamemnon , Vijayakumar Sethu , Nazarpour Kianoush 
Published: March 2019

AbstractIn the field of upper-limb myoelectric prosthesis control, the use of statistical and machine learning methods has been long proposed as a means of enabling intuitive grip selection and actuation. Recently, this paradigm has found its way toward commercial adoption. Machine learning-based prosthesis control typically relies on the use of a large number of electrodes. Here, we propose an end-to-end strategy for multi-grip, classification-based prosthesis control using only two sensors, comprising electromyography (EMG) electrodes and inertial measurement units (IMUs). We emphasize the importance of accurately estimating posterior class probabilities and rejecting predictions made with low confidence, so as to minimize the rate of unintended prosthesis activations. To that end, we propose a confidence-based error rejection strategy using grip-specific thresholds. We evaluate the efficacy of the proposed system with real-time pick and place experiments using a commercial multi-articulated prosthetic hand and involving 12 able-bodied and two transradial (i.e., below-elbow) amputee participants. Results promise the potential for deploying intuitive, classification-based multi-grip control in existing upper-limb prosthetic systems subject to small modifications.