bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kevlar: a mapping-free framework for accurate discovery ofde novovariants
Authors: Standage Daniel S. , Brown C. Titus , Hormozdiari Fereydoun 
Published: February 2019

AbstractMotivationDiscovery of genetic variants by whole genome sequencing has proven a powerful approach to study the etiology of complex genetic disorders. Elucidation of all variants is a necessary step in identifying causative variants and disease genes. In particular, there is an increased interest in detection ofde novovariation and investigation of its role in various disorders. State-of-the-art methods for variant discovery rely on mapping reads from each individual to a reference genome and predicting variants from difference observed between the mapped reads and the reference genome. This process typically results in millions of variant predictions, most of which are inherited and irrelevant to the phenotype of interest. To distinguish between inherited variation and novel variation resulting fromde novogermline mutation, whole-genome sequencing of close relatives (especially parents and siblings) is commonly used. However, standard mapping-based approaches tend to have a high false-discovery rate forde novovariant prediction, which in many cases arises from problems with read mapping. This is a particular challenge in predictingde novoindels and structural variants.ResultsWe have developed a mapping-free method, Kevlar, forde novovariant discovery based on direct comparison of sequence content between related individuals. Kevlar identifies high-abundancek-mers unique to the individual of interest and retrieves the reads containing thesek-mers. These reads are easily partitioned into disjoint sets by sharedk-mer content for subsequent locus-by-locus processing and variant calling. Kevlar also utilizes a novel probabilistic approach to score and rank the variant predictions to identify the most likelyde novovariants. We evaluated Kevlar on simulated and real pedigrees, and demonstrate its ability to detect bothde novoSNVs and indels with high sensitivity and specificity.Availabilityhttps://github.com/kevlar-dev/kevlar
SpectralTAD: an R package for defining a hierarchy of Topologically Associated Domains using spectral clustering
Authors: Cresswell Kellen G. , Stansfield John C. , Dozmorov Mikhail G. 
Published: February 2019

AbstractThe three-dimensional (3D) structure of the genome plays a crucial role in regulating gene expression. Chromatin conformation capture technologies (Hi-C) have revealed that the genome is organized in a hierarchy of topologically associated domains (TADs), the fundamental building blocks of the genome. Identifying such hierarchical structures is a critical step in understanding regulatory interactions within the genome. Existing tools for TAD calling frequently require tunable parameters, are sensitive to biases such as sequencing depth, resolution, and sparsity of Hi-C data, and are computationally inefficient. Furthermore, the choice of TAD callers within the R/Bioconductor ecosystem is limited. To address these challenges, we frame the problem of TAD detection in a spectral clustering framework. Our SpectralTAD R package has automatic parameter selection, robust to sequencing depth, resolution and sparsity of Hi-C data, and detects hierarchical, biologically relevant TAD structure. Using simulated and real-life Hi-C data, we show that SpectralTAD outperforms rGMAP and TopDom, two state-of-the-art R-based TAD callers. TAD boundaries that are shared among multiple levels of the hierarchy were more enriched in relevant genomic annotations, e.g., CTCF binding sites, suggesting their higher biological importance. In contrast, boundaries of primary TADs, defined as TADs which cannot be split into sub-TADs, were found to be less enriched in genomic annotations, suggesting their more dynamic role in genome regulation. In summary, we present a simple, fast, and user-friendly R package for robust detection of TAD hierarchies supported by biological evidence. SpectralTAD is available on https://github.com/dozmorovlab/SpectralTAD and Bioconductor (submitted).
Emergence of multidrug-resistantMycobacterium simiae: An in vitro study from a regional tuberculosis reference laboratory in Iran
Authors: Nasiri Mohammad Javad , Amini Sirus , Nikpor Zahra , Arefzadeh Samaneh , Mosavi Mohammad , Dabiri Hossein , Goudarzi Mehdi , Goudarzi Hossein , Tabarsi Payam , Sarokhalil Davood Darban , Fooladi Abbas Ali Imani , Feizabadi Mohammad Mehdi 
Published: February 2019

AbstractIntroductionMycobacterium simiaeis an emerging pathogen in Iran and little is known about drug susceptibility patterns of this pathogen.Materials and methodsTwenty five clinical isolates ofM. simiaefrom 80 patients with confirmed NTM pulmonary disease were included in this study. For drug susceptibility testing (DST), proportional and broth microdilution methods were used according to the clinical and laboratory standards institute (CLSI) guideline.ResultsAll clinical isolates ofM. simiaewere resistant to isoniazid, rifampicin, ethambutol, streptomycin, amikacin, kanamycin, ciprofloxacin and clarithromycin. They also were highly resistant to ofloxacin (80%). Susceptibility to ofloxacin was only noted in the 5 isolates.ConclusionsClinical isolates ofM.simiaewere multidrug resistant, and had different drug susceptibility patterns than previously published studies. DST results can assist in selecting more appropriate treatment regimens. Newer drugs with proven clinical efficacy correlating with in vitro susceptibility should be substituted with first- and second line anti-TB drug testing.
Comparative genome analysis ofLactobacillus mudanjiangensis, an understudied member of theLactobacillus plantarumgroup
Authors: Wuyts Sander , Allonsius Camille Nina , Wittouck Stijn , Thys Sofie , Lievens Bart , Weckx Stefan , Vuyst Luc De , Sarah Lebeer 
Published: February 2019

AbstractThe genusLactobacillusis known to be extremely diverse and consists of different phylogenetic groups that show a diversity roughly equal to the expected diversity of a typical bacterial genus. One of the most prominent phylogenetic groups within this genus is theLactobacillus plantarumgroup which contains the understudiedLactobacillus mudanjiangensisspecies. Before this study, only oneL. mudanjiangensisstrain, DSM 28402T, was described but without whole-genome analysis. In this study, three strains classified asL. mudanjiangensis, were isolated from three different carrot juice fermentations and their whole-genome sequence was determined, together with the genome sequence of the type strain. The genomes of all four strains were compared with publicly availableL. plantarumgroup genome sequences. This analysis showed thatL. mudanjiangensisharbored the second largest genome size and gene count of the wholeL. plantarumgroup. In addition, all members of this species showed the presence of a gene coding for a putative cellulose-degrading enzyme. Finally, three of the fourL. mudanjiangensisstrains studied showed the presence of pili on scanning electron microscopy (SEM) images, which were linked to conjugative gene regions, coded on plasmids in at least two of the strains studied.Author summaryLactobacillus mudanjiangensisis an understudied species within theLactobacillus plantarumgroup. Since its first description, no other studies have reported its isolation. Here, we present the first four genome sequences of this species, which include the genome sequence of the type strain and three newL. mudanjiangensisstrains isolated from fermented carrot juice. The genomes of all four strains were compared with publicly availableL. plantarumgroup genome sequences. We found that this species harbored the second largest genome size and gene count of the wholeL. plantarumgroup. Furthermore, we present the first scanning electron microscopy (SEM) images ofL. mudanjiangensis, which showed the formation of pili in three strains that we linked to genes related to conjugation. Finally, we found the presence of a unique putative cellulose-degrading enzyme, opening the door for different industrial applications of theseLactobacillusstrains.
Dynamics of visual contextual interactions is altered in Parkinson’s disease
Authors: Vanegas M. Isabel , Blangero Annabelle , Galvin James E , Rocco Alessandro Di , Quartarone Angelo , Ghilardi M. Felice , Kelly Simon P. 
Published: February 2019

AbstractOver the last decades, psychophysical and electrophysiological studies in patients and animal models of Parkinson’s disease (PD), have consistently revealed a number of visual abnormalities. In particular, specific alterations of contrast sensitivity curves, electroretinogram (ERG), and visual evoked potentials (VEP), have been attributed to dopaminergic retinal depletion. However, fundamental mechanisms of cortical visual processing, such as normalization or “gain-control” computations, have not yet been examined in PD patients. Here we measured electrophysiological indices of gain control in both space (surround suppression) and time (sensory adaptation) in PD patients based on steady-state VEP (ssVEP). Compared to controls, patients exhibited a significantly higher initial ssVEP amplitude that quickly decayed over time, and greater relative suppression of ssVEP amplitude as a function of surrounding stimulus contrast. Meanwhile, EEG frequency spectra were broadly elevated in patients relative to controls. Thus, contrary to what might be expected given the reduced contrast sensitivity often reported in PD, visual neural responses are not weaker; rather, they are initially larger but undergo an exaggerated degree of spatial and temporal gain control and are embedded within a greater background noise level. We conclude that compensatory cortical mechanisms may play a role in determining dysfunctional center-surround interactions at the retinal level.
Cannabis use, depression and self-harm: phenotypic and genetic relationships
Authors: Hodgson K , Coleman JRI , Hagenaars SP , Purves KL , Glanville K , Choi SW , O’Reilly P , Breen G ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Lewis CM 
Published: February 2019

AbstractBackground and AimsThe use of cannabis has previously been linked to both depression and self-harm, however the role of genetics in this relationship are unclear. We aimed to examine the phenotypic and genetic relationships between these traits.DesignGenetic and cross-sectional phenotypic data collected through UK Biobank, together with consortia genome-wide association study summary statistics. These data were used to assess the phenotypic and genetic relationship between cannabis use, depression and self harm.SettingUK, with additional international consortia dataParticipantsN=126,291 British adults aged between 40 and 70 years, recruited into UK BiobankMeasurementsGenome-wide genetic data, phenotypic data on lifetime history of cannabis use, depression and self-harm.FindingsIn UK Biobank, cannabis use is associated with increased likelihood of depression (OR=1.64, 95% CI=1.59-1.70, p=1.19×10−213) and self-harm (OR=2.85, 95% CI=2.69-3.01, p=3.46×10−304). The strength of this phenotypic association is stronger when more severe trait definitions of cannabis use and depression are considered. Additionally, significant genetic correlations are seen between cannabis use and depression using consortia summary statistics (rg=0.289, SE=0.036, p=1.45×10−15). Polygenic risk scores for cannabis use and depression both explain a small but significant proportion of variance in cannabis use, depression and self harm within a UK Biobank target sample. However, two-sample Mendelian randomisation analyses were not significant.ConclusionsCannabis use is both phenotypically and genetically associated with depression and self harm. Future work dissecting the causal mechanism linking these traits may have implications for cannabis users.
Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2)
Authors: Chaikuad Apirat , Koschade Sebastian E. , Stolz Alexandra , Zivkovic Katarina , Pohl Christian , Shaid Shabnam , Ren Huiyu , Lambert Lester J. , Cosford Nicholas D.P. , Brandts Christian H. , Knapp Stefan 
Published: February 2019

ABSTRACTAutophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2. Here we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provides structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition.
Survey of severe fever with thrombocytopenia syndrome virus covert infection for healthy people in Henan Province, China
Authors: Du Yanhua , Cheng Ningning , Li Yi , Wang Haifeng , You Aiguo , Su Jia , Nie Yifei , Ma Hongxia , Xu Bianli , Huang Xueyong 
Published: February 2019

AbstractBackground:Severe fever with thrombocytopenia syndrome (SFTS) is a severe emerging disease, and its incidence has been increasing in recent years. A cross-sectional study was conducted for healthy people in high SFTS endemic areas of Henan province in 2016.Methods:This study used stratified random sampling method and finally 14 natural villages were selected as the investigation site. The questionnaire survey and serum collection were carried out from April to May in 2016. All the serum samples were detected by SFTSV IgM and IgG antibodies by ELISA. Only positive samples of SFTSV IgM antibody need be tested SFTSV RNA and virus cultured. A month after the specimen collection, all persons positive for IgM antibody were followed up one by one to confirm whether he or she was recessive infection.Results:1463 healthy persons were investigated in total. The average seropositive rates of SFTS virus specific IgG and IgM antibodies were 10.46% (153/1463) and 0.82% (12/1463), respectively. IgM antibody was positive in 12 individuals, and 6 of them SFTS virus RNA were also detected. In addition, 5 SFTS virus were isolated from the 6 SFTS virus RNA (+) individuals. By genomic sequencing and phylogenetic analysis, 5 new isolates from healthy crowd all belonged to groups A, which were similar to other isolates from SFTS patients. After one month, all people with SFTS virus IgM antibody had no illness or symptoms.Conclusions:This study confirmed there is SFTS recessive infection in human, and it is the first report about SFTS virus isolation in healthy people.Author Summary:Severe fever with thrombocytopenia syndrome (SFTS), a severe emerging infectious disease, was discovered in rural areas of China. The first SFTS case was found in Henan province, which has had the largest number of SFTS cases in China every year since the disease was discovered. However, as a high incidence area of SFTS in Henan province, the serum prevalence rate of the virus in healthy people is still not clear. Therefore, a cross-sectional survey was performed in high endemic areas and epidemic seasons in 2016. The results showed that the level of specific SFTS seroprevlence was relatively higher and possibility increasing. SFTS RNA were positive and SFTS virus was isolated from the specimens of healthy people. This study confirmed there is SFTS recessive infection in human, and it is the first report about SFTS virus isolation in healthy people.
The essential role played by B cells in supporting protective immunity againstTrichuris murisinfection is dependent on host genetic background and is independent of antibody
Authors: Sahputra Rinal , Ruckerl Dominik , Couper Kevin , Muller Werner , Else Kathryn J 
Published: February 2019

AbstractThis study investigates the role of B cells in immunity toTrichuris muris(T. muris) infection in two genetically distinct strains of mouse, using anti-CD20 monoclonal antibody (mAb) (Genentech-clone 5D2) to deplete B cells. Data is presented for the mouse strains: C57BL/6 and BALB/c, which mount mixed Th1/Th2, and highly polarised Th2 immune responses toT. muris, respectively. C57BL/6 mice receiving anti-CD20 treatment prior to and during, or anti-CD20 treatment that commenced two weeks post infection (p.i.), were susceptible toT. muris. Parasite-specific IgG1 antibodies were absent and Th2 type cytokines produced by mesenteric lymph nodes cells from mice receiving α-CD20 mAb treatment were significantly lower than produced by cells from isotype control treated mice. T follicular helper cells were also significantly reduced. Importantly, and in complete contrast, BALB/c mice were still able to expelT.murisin the absence of B cells, revealing that the essential role played by B cells in protective immunity was dependent on genetic background. To explore whether the important role played by the B cell in the protective immune response of C57BL/6 mice was in enabling strong Th2 responses in the presence of IFN-γ, IFN-γ was blocked using anti-IFN-γ mAb post B cell depletion. Depleting IFN-γ, in the absence of B cells restored worm expulsion in the absence of parasite-specific IgG1/IgG2c and partially rescued theT. murisspecific IL-13 response. Thus, our data suggest an important, antibody independent role for B cells in supporting Th2 type immune responses in mixed IFN-γ-rich Th1/Th2 immune response settings.Author summaryHow B cells contribute to protective immunity against parasitic nematodes remains unclear, with their importance as accessory cells under-explored. This study reveals that, on some genetic backgrounds, B cells are important for the expulsion ofT. murisby acting as accessory cells, supporting Th2 immune responses.
Anopheles gambiae TEP1 forms a complex with the coiled-coil domain of LRIM1/APL1C following a conformational change in the thioester domain
Authors: Williams Marni , Contet Alicia , Levashina Elena A. , Baxter Richard H. G. 
Published: February 2019

AbstractThe complement-like protein thioester-containing protein 1 (TEP1) is a key factor in the immune response of the malaria vector Anopheles gambiae to pathogens. Multiple allelic variants of TEP1 have been identified in laboratory strains and in the field, and are correlated with distinct immunophenotypes. TEP1 is tightly regulated by conformational changes induced by cleavage in a protease-sensitive region. Cleaved TEP1 forms a soluble complex with a heterodimer of two leucine-rich repeat proteins, LRIM1 and APL1C, and precipitates in the absence of this complex. The molecular structure and oligomeric state of the TEP1/LRIM1/APL1C complex is unclear. We have analyzed the stability of the cleaved form of four TEP1 alleles. Soluble TEP1 forms exhibit significant variation in stability from hours to days at room temperature. Stability is correlated with allelic variation within two specific loops in direct proximity to the thioester bond. The variable loops are part of an interface between the TED and MG8 domains TEP1 that protect the thioester from hydrolysis. Engineering specific disulfide bonds to prevent separation of the TED-MG8 interface stabilizes the cleaved form of TEP1 for months at room temperature. The C-terminal coiled-coil domain of the LRIM1/APL1C complex is sufficient to stabilize the cleaved form of TEP1 in solution but cleaved forms of disulfide-stabilized TEP1 do not interact with LRIM1/APL1C. This implies that formation of the TEP1cut/LRIM1/APL1C complex is dependent on the same conformational change that induces the precipitation of cleaved TEP1.Author SummaryThe mosquito Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. A mosquito’s own immune system affects how readily it transmits disease. A protein in A. gambiae called TEP1 is responsible for targeting malaria parasites that traverse the mosquito’s midgut. TEP1 has multiple alleles and some are associated with a stronger immune response to malaria than others. How genetic variability in TEP1 is linked to phenotypic diversity is not understood. We show that the variation between TEP1 alleles affects the stability of the protein in solution. We also show that the different TEP1 alleles have a wide range in stability of the protein, from hours to days. Engineering disulfide bonds into TEP1 can increase this stability to months. TEP1 activity in vivo is maintained by a complex of two leucine-rich proteins called LRIM1 and APL1C, which binds TEP1 through its C-terminal coiled-coil domain. We found that LRIM1/APL1C does not bind disulfide-stabilized TEP1, suggesting that LRIM1/APL1C binds to activated TEP1. This research advances our molecular understanding of a key immune response that affects the capacity of A. gambiae mosquitoes to transmit malaria.
Dilated Saliency U-Net for White Matter Hyperintensities Segmentation using Irregularity Age Map
Authors: Jeong Yunhee , Rachmadi Muhammad Febrian , Valdés-Hernández Maria del C. , Komura Taku 
Published: February 2019

ABSTRACTWhite matter hyperintensities(WMH) appear as regions of abnormally high signal intensity on T2-weighted magnetic resonance image(MRI) sequences. In particular, WMH have been noteworthy in age-related neuroscience for being a crucial biomarker for Alzheimer’ s disease and brain aging processes. However, the automatic WMH segmentation is challenging because of the variable intensity range, size and shape. U-Net tackled this problem through the dense prediction and showed competitive performances on not only WMH segmentation/detection but also on varied image segmentation tasks, but it still accompanies a high complexity of the network architecture. In this study, we propose to use Saliency U-Net architecture and irregularity age map(IAM) to decrease the U-Net complexity without a performance loss. We trained Saliency U-Net using both T2-FLAIR MRI sequence and IAM. Since IAM guides where irregularities, in which WMH is possibly included, exist on the MRI slice, Saliency U-Net performs better than the original U-Net trained only using T2-FLAIR. The better performance was achieved with fewer parameters and shorter training time. Moreover, the application of dilated convolution enhanced Saliency U-Net to recognise the shape of large WMH more accurately by learning multi-context on MRI slices. This network named Dilated Saliency U-Net improved Dice coefficient score to 0.5588 which is the best score among our experimental models, and recorded a relatively good sensitivity of 0.4747 with the shortest train time and the least number of parameters. In conclusion, based on the experimental results, incorporating IAM through Dilated Saliency U-Net resulted an appropriate approach for WMH segmentation.