bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applicability of subcortical EEG metrics of synaptopathy to older listeners with impaired audiograms
Authors: Garrett Markus , Verhulst Sarah 
Published: November 2018

AbstractEmerging evidence suggests that cochlear synaptopathy is a common feature of sensorineural hearing loss, but it is not known whether electrophysiological metrics targeting synaptopathy in animals can be applied to a broad range of people, such as those with impaired audiograms. This study investigates the applicability of subcortical electrophysiological measures associated with synaptopathy such as auditory brainstem responses (ABRs) and envelope following responses (EFRs) in older participants with high-frequency sloping audiograms. This is important for the development of reliable and sensitive synaptopathy diagnostics in people with normal or impaired outer-hair-cell function. Broadband click-ABRs at different sound pressure levels and EFRs to amplitude-modulated stimuli were recorded, as well as relative EFR and ABR metrics which reduce individual factors such as head size and noise floor level. Most tested metrics showed significant differences between the groups and did not always follow the trends expected from synaptopathy. Audiometric hearing loss and age-related hearing related deficits interacted to affect the electrophysiological metrics and complicated their interpretation in terms of synaptopathy. This study contributes to a better understanding of how electrophysiological synaptopathy metrics differ in ears with healthy and impaired audiograms, which is an important first step towards unravelling the perceptual consequences of synaptopathy.
Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver
Authors: Fokkelman Michiel , Koedoot Esmee , Rogkoti Vasiliki-Maria , Le Dévédec Sylvia E. , de Sandt Iris van , de Bont Hans , Pont Chantal , Klip Janna E. , Wiemer Erik A.C. , Smid Marcel , Stoilov Peter , Foekens John A. , Martens John W.M. , de Water Bob van 
Published: November 2018

AbstractMetastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen using two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231) to provide a repository for signaling determinants that functionally drive cancer cell migration. We screened ~4,200 individual target genes covering most cell signaling components and discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 43 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily down-regulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for triple negative breast cancer cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository of candidate metastasis drug targets.
Facial Emotions Perceptions in Young Female Students with High- Level Anxity and Subclinical Panic Disorder. ERP and BEhavioral Study
Authors: Karpova V.Yu. , Mikhailova E.S. , Gerasimenko N.Yu. , Kushnir A.B. , Gordeev S.A. , Alipov N.N. 
Published: November 2018

ABSRACTThis study investigated facial emotion processing in non-medicated young students (girls) with panic disorder. 13 young girls with panic disorder and 14 matched healthy controls were recruited. Evoked potential (EP) components P100, N150, and P300 in the posterior areas, and N200, P300, and late negativity were evaluated while the participants recognize angry, fearful, happy, and neutral facial stimuli. The girls with panic disorder showed increased levels of situational anxiety compared to healthy controls. EP demonstrated an increased reactivity to facial expression at sensory stage (P100 component), in particular, on angry faces, that indicates a shift automated attention on threat facial stimuli. The increased reactivity was also found in later processing, corresponding to the P300 component, reflecting an enhanced selective attention to socially important events. In subjects with panic disorder, we also found signs of increased activation in the right temporal area in the P300 time window, and the increased late frontal negativity in 350-450 ms time window. It can be assumed, that altered functional state of the prefrontal regions results in reduced top-down modulating effects on the lower limbic and sensory cortex levels.
Impact of deleterious mutations, sexually antagonistic selection and mode of recombination suppression on transitions between male and female heterogamety
Authors: Saunders Paul A. , Neuenschwander Samuel , Perrin Nicolas 
Published: November 2018

AbstractDeleterious mutations accumulating on non-recombining Y chromosomes can drive XY to XY turnovers, but are thought to prevent XY to ZW turnovers, because the latter require fixation of the ancestral Y. Using individual-based simulations, we explored whether and how a dominant W allele can spread in a young XY system that gradually accumulates deleterious mutations. We also investigated how sexually antagonistic (SA) polymorphism on the ancestral sex chromosomes, and the mechanism controlling X-Y recombination suppression affect these transitions. In contrast with XY to XY turnovers, XY to ZW turnovers cannot be favored by Y chromosome mutation load. If the arrest of X-Y recombination depends on genotypic sex, transitions are strongly hindered by deleterious mutations, and totally suppressed by very small SA cost, because deleterious mutations and female-detrimental SA alleles would have to fix with the Y. If, however, the arrest of X-Y recombination depends on phenotypic sex, X and Y recombine in XY ZW females, allowing for the purge of Y-linked deleterious mutations and loss of the SA polymorphism, causing XY to ZW turnovers to occur at a neutral rate. We generalize our results to other types of turnovers (e.g., triggered by non-dominant sex-determining mutations) and discuss their empirical relevance.
Neurocognitive and psychiatric markers for addiction: Common vs. specific (endo)phenotypes for opiate and stimulant dependence
Authors: Long Elizabeth C. , Kaneva Radka , Vasilev Georgi , Moeller F. Gerard , Vassileva Jasmin 
Published: November 2018

AbstractBACKGROUNDThe differential utility of neurocognitive impulsivity and externalizing/internalizing traits as putative addiction endophenotypes among individuals dependent on opiates vs. stimulants is unclear. The present study aims to determine: (1) whether neurocognitive impulsivity dimensions and externalizing/internalizing traits are correlated between siblings discordant for opiate and stimulant dependence; and (2) which of these associations are common across substances and which are substance-specific.METHODPearson correlations between individuals with ‘pure’ heroin and ‘pure’ amphetamine dependence and their unaffected biological siblings (n = 37 heroin sibling pairs; n = 30 amphetamine sibling pairs) were run on 10 neurocognitive measures, 6 externalizing measures, and 5 internalizing measures. Sibling pair effects were further examined using regression.RESULTSSiblings discordant for heroin dependence were significantly correlated on delay aversion on the Cambridge Gambling Task, risk-taking on the Balloon Analogue Risk Task, sensation seeking, and hopelessness. Siblings discordant for amphetamine dependence were significantly correlated on quality of decision-making on the Cambridge Gambling Task, discriminability on the Immediate Memory Task, commission errors on the Go/No-Go Task, trait impulsivity, ADHD, and anxiety sensitivity.CONCLUSIONSDimensions of impulsivity and externalizing/internalizing traits appear to aggregate among siblings discordant for substance dependence. Risk-taking propensity, sensation seeking, and hopelessness were specific for heroin sibling pairs. Motor/action impulsivity and trait impulsivity were specific to amphetamine sibling pairs. Decisional/choice impulsivity was common across both heroin and amphetamine sibling pairs. These findings provide preliminary evidence for the utility of neurocognitive impulsivity and externalizing/internalizing traits as candidate endophenotypes for substance dependence in general and for substance-specific dependencies.
The transcriptional landscape of cortical interneurons underlies in-vivo brain function and schizophrenia risk
Authors: Anderson Kevin M , Collins Meghan A , Chin Rowena , Ge Tian , Rosenberg Monica D , Holmes Avram J 
Published: November 2018

AbstractInhibitory interneurons orchestrate information flow across cortex and are implicated in psychiatric illness. Although classes of interneurons have unique functional properties and spatial distributions throughout the brain, the relative influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped organizational properties of somatostatin and parvalbumin related transcripts within human and non-human primates. Interneuron spatial distributions recapitulate cortico-striato-thalamic functional networks and track regional differences in functional MRI signal amplitude. In the general population (n=9,627), parvalbumin-linked genes account for an enriched proportion of genome-wide heritable variance in in-vivo functional MRI signal amplitude. This relationship is spatially dependent, following the topographic organization of parvalbumin expression in independent post-mortem brain tissue. Finally, genetic risk for schizophrenia is enriched among interneuron-linked genes and predictive of cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular genetic basis of resting-state brain function across cortex is shaped by the spatial distribution of interneuron-related transcripts and underlies individual differences in risk for schizophrenia.Key FindingsSpatial distributions of somatostatin (SST) and parvalbumin (PVALB) are negatively correlated in mature human and non-human primate cortex, paralleling patterns observed in utero.SST and PVALB are differentially expressed within distinct limbic and somato/motor cortico-striato-thalamic networks, respectively.In-vivo resting-state signal amplitude is heritable in the general population and tracks relative SST/PVALB expression across cortex.Single-nucleotide polymorphisms tied to PVALB-related genes account for an enriched proportion of the heritable variance in resting-state signal amplitude.PVALB-mediated heritability of resting-state signal amplitude in the general population is spatially heterogeneous, mirroring the cortical expression of PVALB in independent post-mortem brain tissue.Polygenic risk for schizophrenia is enriched among interneuron-linked genes and predicts resting-state signal amplitude in a manner that also follows the cortical expression of PVALB.
Both Fallopian Tube and Ovarian Surface Epithelium Can Act as Cell-of-Origin for High Grade Serous Ovarian Carcinoma
Authors: Zhang Shuang , Zhang Tao , Dolgalev Igor , Ran Hao , Levine Douglas A. , Neel Benjamin G. 
Published: November 2018

ABSTRACTThe cell-of-origin of high grade serous ovarian carcinoma (HGSOC) remains controversial, with fallopian tube epithelium (FTE) and ovarian surface epithelium (OSE) each suggested as candidates. Here, by using genetically engineered mouse models and novel organoid systems, we assessed the tumor-forming capacity and properties of FTE and OSE harboring the same oncogenic abnormalities. Combined RB family inactivation (via T121 expression) and Tp53 mutation in Pax8+ FTE caused transformation to Serous Tubal Intraepithelial Carcinoma (STIC), which rapidly metastasized to the ovarian surface. This mouse model was recapitulated by FTE organoids, which, upon orthotopic injection, generated widely metastatic HGSOC. The same genetic lesions in Lgr5+ OSE cells or organoids also caused metastatic HGSOC, although with longer latency and lower penetrance. Comparative transcriptome analysis was consistent with different human HGSOCs arising from FTE and OSE. Furthermore, FTE- and OSE-derived organoids showed differential sensitivity to HGSOC chemotherapeutics. Our results comport with a dualistic origin for HGSOC and suggest the cell-of-origin could influence therapeutic response.SIGNIFICANCEThe cell-of-origin for high grade serous ovarian carcinoma (HGSOC) has been controversial. By generating novel GEMMs and organoid models with the same oncogenic defects, we demonstrate that HGSOC can originate from either fallopian tube epithelium (FTE) or ovarian surface epithelium (OSE). Importantly, FTE- and OSE-derived tumors differ significantly in biologic properties.
The Hi-Culfite assay reveals relationships between chromatin contacts and DNA methylation state
Authors: Stamenova Elena K. , Durand Neva C. , Dudchenko Olga , Shamim Muhammad S. , Huang Su-Chen , Jiang Yiqun , Bochkov Ivan D. , Rao Suhas S. P. , Lander Eric S. , Gnirke Andreas , Aiden Erez Lieberman 
Published: November 2018

AbstractHi-Culfite, a protocol combining Hi-C and whole-genome bisulfite sequencing (WGBS), determines chromatin contacts and DNA methylation simultaneously. Hi-Culfite also reveals relationships that cannot be seen when the two assays are performed separately. For instance, we show that loci associated with open chromatin exhibit context-sensitive methylation: when their spatial neighbors lie in closed chromatin, they are much more likely to be methylated.
A schizophrenia risk gene, NRGN, bidirectionally modulates synaptic plasticity via regulating the neuronal phosphoproteome
Authors: Hwang Hongik , Szucs Matthew J. , Ding Lei J. , Allen Andrew , Haensgen Henny , Gao Fan , Andrade Arturo , Pan Jennifer Q. , Carr Steven A. , Ahmad Rushdy , Xu Weifeng 
Published: November 2018

AbstractNRGN is a schizophrenia risk gene identified in recent genetic studies, encoding a small neuronal protein, neurogranin (Ng). Individuals carrying a risk variant of NRGN showed decreased hippocampal activation during contextual fear conditioning. Furthermore, the expression of Ng was reduced in the post-mortem brains of schizophrenic patients. Using the mouse model, we found that the translation of Ng in hippocampus is rapidly increased in response to novel context exposure, and this up-regulation is required for encoding contextual memory. The extent and degree of the effect that altered Ng expression has on neuronal cellular functions are largely unknown. Here, we found that Ng bidirectionally regulates synaptic plasticity in the hippocampus. Elevated Ng levels facilitated long-term potentiation (LTP), whereas decreased Ng levels impaired LTP. Quantitative phosphoproteomic analysis revealed that decreasing Ng caused a significant shift in the phosphorylation status of postsynaptic density proteins, highlighting clusters of schizophrenia- and autism-related genes. In particular, decreasing Ng led to the hypo-phosphorylation of NMDAR subunit Grin2A at newly identified sites, resulting in accelerated decay of NMDAR-mediated channel currents. blocking protein phosphatase PP2B activity rescued the accelerated synaptic NMDAR current decay and the impairment of LTP caused by decreased Ng levels, suggesting that enhanced synaptic PP2B activity led to the deficits. Taken together, our work suggests that altered Ng levels under pathological conditions affect the phosphorylation status of neuronal proteins by tuning PP2B activity and thus the induction of synaptic plasticity, revealing a novel mechanistic link of a schizophrenia risk gene to cognitive deficits.
Bedsect: An integrated web server application to perform intersection, visualization and functional annotation of genomic regions from multiple datasets
Authors: Mishra Gyan Prakash , Ghosh Arup , Jha Atimukta , Raghav Sunil Kumar 
Published: November 2018

AbstractA large number of genomic regions captured during next generation sequencing (NGS) data analyses are generally overlapped to answer a variety of biological questions. Though several command-line tools are available to perform such analysis, there is lack of a comprehensive web server application to perform the genomic region intersections from multiple datasets, to generate a plot for the subsets of the overlapped regions and to perform integrated functional annotation. To address this gap, we have developed a user-friendly integrated web server application i.e. Bedsect, where users can upload genomic regions from multiple datasets without any file number limitation and perform intersection analysis along with visualization of the intersection regions as UpSet and Correlation plot using integrated Shiny application. Bedsect also integrates GREAT for functional annotation, gene ontology, and biological pathways enrichment analysis from identified unique as well as intersected genomic regions. These genomic regions can be further uploaded in the UCSC genome browser for visualization of the results as custom tracks directly from the tool. Bedsect is available at http://imgsb.org/bedsect/.
Proof of concept: Malaria rapid diagnostic tests and massively parallel sequencing for surveillance of molecular markers of antimalarial resistance in Bissau, Guinea-Bissau during 2014-2017
Authors: Nag Sidsel , Ursing Johan , Rodrigues Amabelia , Crespo Marina , Krogsgaard Camilla , Lund Ole , Aarestrup Frank M. , Alifrangis Michael , Kofoed PouL-Erik 
Published: November 2018

AbstractReal-time and large-scale surveillance of molecular markers of antimalarial drug resistance is a potential method of resistance monitoring, to complement therapeutic efficacy studies in settings where the latter are logistically challenging. This study investigates whether routinely used malaria rapid diagnostic tests (RDTs) can be used for massive parallel amplicon sequencing. RDTs used for malaria diagnosis were routinely collected together with patient age and sex between 2014 and 2017, from two health centres in Bissau, Guinea-Bissau. A subset of positive RDTs (n=2,184) were tested for Plasmodium DNA content. Those containing sufficient Plasmodium DNA (n=1,390) were used for library preparation, consisting of amplification of gene fragments from pfcrt, pfmdr1, pfdhfr, pfdhps and pfK13. A total of 5532 gene fragments were successfully analysed on a single Illumina Miseq flow cell. Pre-screening of samples for Plasmodium DNA content proved necessary and the nested PCR protocol applied for library preparation varied notably in PCR-positivity from 13-87%. We found a high frequency of the pfmdr1 codon 86N at 88%-97%, a significant decrease of the pfcrt wildtype CVMNK haplotype and elevated levels of the pfdhfr/pfdhps quadruple mutant ranging from 33%-51% between 2014-2017. No polymorphisms indicating artemisinin tolerance were discovered. Lastly, the demographic data indicate a large proportion of young adults (66%, interquartile range 11-28 years) presenting with P. falciparum infections. With some caution, our findings suggest that routine collection of RDTs could facilitate large-scale molecular surveillance of antimalarial resistance.Importance (word count: 147)Continuous spread and repeated emergence of Plasmodium falciparum parasites resistant towards one or more antimalarials represents an enormous threat to current treatment efficacy levels, especially in sub-Saharan Africa, where 90% of malaria infections occur. In order to prevent substantial treatment failure, it is therefore recommended to monitor treatment efficacy every 2-3 years. Therapeutic efficacy studies, however, can present insurmountable logistical and financial challenges in some settings in sub-Saharan Africa. Molecular surveillance of antimalarial resistance is therefore an important proxy for treatment efficacy. However, the scale by which such studies can be performed depends on the development of high-throughput protocols and the accessibility of samples. If RDTs can be used in the high-throughput protocols available with Next Generation Sequencing (NGS)-technology, surveillance can be performed efficiently for any setting in which RDTs are already used for malaria diagnosis. The majority of settings in sub-Saharan Africa have access to RDTs.
The novelDblhomology/BAR domain protein, MsgA, ofTalaromyces marneffeiregulates yeast morphogenesis during growth inside host cells
Authors: Weerasinghe Harshini , Bugeja Hayley E. , Andrianopoulos Alex 
Published: November 2018

AbstractMicrobial pathogens have evolved many strategies to evade recognition by the host immune system, including the use of phagocytic cells as a niche within which to proliferate. Dimorphic pathogenic fungi employ an induced morphogenetic transition, switching from multicellular hyphae to unicellular yeast that are more compatible with intracellular growth. A switch to mammalian host body temperature (37°C) is a key trigger for the dimorphic switch. This study describes a novel gene,msgA, from the dimorphic fungal pathogenTalaromyces marneffeithat controls cell morphology in response to host cues rather than temperature. ThemsgAgene is upregulated during murine macrophage infection, and deletion results in aberrant yeast morphology solely during growth inside macrophages. MsgA contains a Dbl homology domain, and aBin,Amphiphysin,Rvs (BAR) domain instead of a Plekstrin homology domain typically associated with guanine nucleotide exchange factors (GEFs). The BAR domain is crucial in maintaining yeast morphology and cellular localisation during infection. The data suggests that MsgA does not act as a canonical GEF during macrophage infection and identifies a temperature independent pathway inT.marneffeithat controls intracellular yeast morphogenesis.
Mechanism of action of methotrexate against Zika virus
Authors: Beck Sungjun , Bernatchez Jean A. , Zhu Zhe , Oliveira Michelli F. , Smith Davey M. , Siqueira-Neto Jair L. 
Published: November 2018

AbstractZika virus (ZIKV), which is associated with microcephaly in infants and Guillain-Barré syndrome, reemerged as a serious public health threat in Latin America in recent years. Previous high-throughput screening (HTS) campaigns have revealed several potential hit molecules against ZIKV, including methotrexate (MTX), which is clinically used as an anti-cancer chemotherapy and anti-rheumatoid agent. We studied the mechanism of action of MTX against ZIKV in relation to its inhibition of dihydrofolate reductase (DHFR)in vitrousing Vero and human neural stem cells (hNSCs). As expected, an antiviral effect for MTX against ZIKV was observed, showing up to ten-fold decrease in virus titer during MTX treatment. We also observed that addition of leucovorin (a downstream metabolite of DHFR pathway) rescued the ZIKV replication impaired by MTX treatment in ZIKV-infected cells, explaining the antiviral effect of MTX through inhibition of DHFR. We also found that addition of adenosine to ZIKV-infected cells was able to rescue ZIKV replication inhibited by MTX, suggesting that restriction ofde novosynthesis adenosine triphosphate (ATP) pools suppresses viral replication. These results confirm that the DFHR pathway can be targeted to inhibit replication of ZIKV, similar to other published results showing this effect in related flaviviruses.