bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-terminal mutant Huntingtin deposition correlates with CAG repeat length and disease onset, but not neuronal loss in Huntington’s disease
Authors: Layburn Florence E. , Tan Adelie Y. S. , Mehrabi Nasim F. , Curtis Maurice A. , Tippett Lynette J. , Riguet Nathan , Aeschbach Lorène , Lashuel Hilal A. , Dragunow Mike , Faull Richard L. M. , Singh-Bains Malvindar K. 
Published: May 2022

AbstractHuntington’s disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strategies for HD, however, the lack of translation from preclinical research to disease-modifying treatments highlights the need to improve our understanding of the role of Htt protein in the human brain. This study aims to undertake a high-throughput screen of 12 candidate antibodies against various sequences along the Htt protein to characterize Htt distribution and expression in post-mortem human brain tissue microarrays (TMAs).Immunohistochemistry was performed on middle temporal gyrus TMAs comprising of up to 28 HD and 27 age-matched control cases, using 12 antibodies specific to various sequences along the Htt protein. From this study, six antibodies directed to the Htt N-terminus successfully immunolabelled human brain tissue. The Htt aggregates and Htt protein expression levels for the six successful antibodies were subsequently quantified with high-throughput analysis. Htt aggregates were detected in HD cases using antibodies MAB5374, MW1, and EPR5526, despite no change in overall Htt protein expression compared to control cases, suggesting a redistribution of Htt into aggregates in HD. Significant associations were found between the number of Htt aggregates and both age of disease onset, and CAG repeat length in HD. However, the number of Htt aggregates did not correlate with the degree of striatal degeneration or the degree of cortical neuron loss. Together, these results suggest that longer CAG repeat lengths correlate with Htt aggregation in the HD human brain, and Htt cortical aggregate deposition is associated with the onset of clinical symptoms. This study also reinforces that antibodies MAB5492, MW8, and 2B7 which have been utilized to characterize Htt in animal models of HD are not specific for Htt in human brain tissue, thereby highlighting the need for validated means of Htt detection to support drug development for HD.
Genomic patterns of malignant peripheral nerve sheath tumour (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA
Authors: Cortes-Ciriano I , Steele CD , Piculell K , Al-Ibraheemi A , Eulo V , Bui MM , Chatzipli A , Dickson BC , Borcherding DC , Feber A , Galor A , Hart J , Jones KB , Jordan JT , Kim RH , Lindsay D , Miller C , Nishida Y , Proszek P , Serrano J , Sundby RT , Szymanski JJ , Ullrich NJ , Viskochil D , Wang X ,   Genomics of MPNST (GeM) Consortium, Snuderl M , Park PJ , Flanagan AM , Hirbe AC , Pillay N , Miller DT 
Published: May 2022

AbstractMalignant peripheral nerve sheath tumour (MPNST) is an aggressive soft-tissue sarcoma that arises in peripheral nerves. MPNST occurs either sporadically or in people with neurofibromatosis type 1 (NF1), a common cancer predisposition syndrome caused by germline pathogenic variants in NF1. Although MPNST is the most common cause of death and morbidity for individuals with NF1, the molecular underpinnings of MPNST pathogenesis remain unclear. Here, we report the analysis of whole-genome sequencing, multi-regional exome sequencing, transcriptomic and methylation profiling data for 95 MPNSTs and precursor lesions (64 NF1-related; 31 sporadic) from 77 individuals. Early events in tumour evolution include biallelic inactivation of NF1 followed by inactivation of CDKN2A and in some cases also TP53 and polycomb repressive complex 2 (PRC2) genes. Subsequently, both sporadic and NF1-related MPNSTs acquire a high burden of somatic copy number alterations (SCNAs). Our analysis revealed distinct pathways of tumour evolution and immune infiltration associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumours with loss of H3K27me3 evolve through extensive chromosomal losses with retention of chromosome 8 heterozygosity followed by whole genome doubling and chromosome 8 amplification. These tumours show lower levels of immune cell infiltration with low cytotoxic activity and low expression of immune checkpoints. In contrast, tumours with retention of H3K27me3 evolve through extensive genomic instability in the absence of recurrent alterations and exhibit an immune cell-rich phenotype. Specific SCNAs detected in both tumour samples and cell-free DNA (cfDNA) act as a surrogate for loss of H3K27me3 and immune infiltration, and predict prognosis. Our results suggest that SCNA profiling of tumour or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups.
HIV integration in the human brain is linked to microglial activation and 3D genome remodeling
Authors: Plaza-Jennings Amara L. , Valada Aditi , O’Shea Callan , Iskhakova Marina , Hu Benxia , Javidfar Behnam , Hutta Gabriella Ben , Lambert Tova , Murray Jacinta , Kassim Bibi , Chandrasekaran Sandhya , Chen Benjamin K. , Morgello Susan , Won Hyejung , Akbarian Schahram 
Published: May 2022

AbstractExploration of genome organization and function in the HIV infected brain is critical to aid in the development of treatments for HIV-associated neurocognitive disorder (HAND) and HIV cure strategies. Here, we generated a resource comprised of single nuclei transcriptomics, complemented by cell-type-specific Hi-C chromosomal conformation (‘3D genome’) and viral integration site sequencing (IS-seq) in frontal brain tissues from individuals with HIV encephalitis (HIVE), HIV-infected people without encephalitis (HIV+), and HIV uninfected (HIV-) controls. We observed profound 3D genomic reorganization of open/repressive (A/B) compartment structures encompassing 6.4% of the HIVE microglial genome that was associated with transcriptomic reprogramming, including down-regulation of homeostasis and synapse-related functions and robust activation of interferon signaling and cell migratory pathways. HIV RNA was detected in 0.003% of all nuclei in HIVE brain, predominantly in the most activated microglia where it ranked as the second most highly expressed transcript. Microglia from HIV+ brains showed, to a lesser extent, similar transcriptional alterations. IS-seq recovered 1,221 insertion events in glial nuclei that were enriched for chromosomal domains newly mobilized into a permissive chromatin environment in HIVE microglia. Brain and peripheral myeloid cell integration revealed a preference overall for transcription-permissive chromatin, but robust differences in the frequency of recurrent insertions, intergenic integration, and enrichment for pre-integration complex-associated factors at integration sites. Our resource highlights critical differences in the genomic patterns of HIV infection in brain versus blood and points to a dynamic interrelationship between inflammation-associated 3D genome remodeling and successful integration in brain.
Enhanced cognitive interference during visuomotor tasks may cause eye-hand dyscoordination
Authors: Singh Tarkeshwar , Rizzo John R , Bonnet Cédrick , Semrau Jennifer , Herter Troy M 
Published: May 2022

AbstractIn complex visuomotor tasks, such as cooking, people make many saccades to continuously search for items before and during reaching movements. These tasks require use of short-term memory and task-switching (e.g., switching search between vegetables and spices). Cognitive load may affect visuomotor performance by increasing the demands on mental processes mediated by the prefrontal cortex, but mechanisms remain unclear. It is also unclear how patients with neurological injuries, e.g., stroke survivors, manage greater cognitive loads during visuomotor tasks. Using the Trail-Making Test, we have previously shown that stroke survivors make many more saccades, which are associated limb movements that are less smooth and slower. In this test, participants search for and make reaching movements towards twenty-five numbers and letters. It has a simple variant (Trails-A), and a cognitively challenging variant (Trails-B) that requires alphanumeric switching. The switching makes the task gradually harder as the Trails-B trial progresses (greater cognitive load). Here, we show that stroke survivors and healthy controls made many more saccades and had longer fixations as the Trails-B trial progressed. In addition, reaching speed slowed down for controls in Trails-B. We propose a mechanism where enhanced cognitive load may reduce inhibition from the prefrontal cortex and disinhibit the ocular motor system into making more saccades. These additional saccades may subsequently slow down motor function by disrupting the visual feedback loops used to control limb movements. These findings augment our understanding of the mechanisms that underpin cognitive interference dynamics when visual, ocular, and limb motor systems interact in visuocognitive motor tasks.NEW & NoteworthyoWe used a neuropsychological test called the Trails-Making-test and analyze patterns of eye and reaching movements in controls and stroke survivors. We characterized how gaze and reaching movements change within a trial in the easier Trails-A and the more cognitively challenging Trails-B variant that requires alphanumeric switching. We found that as the Trails-B trial progressed participants made more saccadic eye movements and longer fixations, likely because of greater cognitive load.
Large-Scale, Multi-Year Microbial Community Survey of a Freshwater Trout Aquaculture Facility
Authors: Testerman Todd , Beka Lidia , Reichley Stephen R. , King Stacy , Welch Timothy J. , Wiens Gregory D. , Graf Joerg 
Published: May 2022

AbstractAquaculture is an important tool for solving growing worldwide food demand, but infectious diseases of the farmed animals represent a serious roadblock to continued industry growth. Therefore, it is essential to understand the microbial communities that reside within the built environments of aquaculture facilities to identify reservoirs of bacterial pathogens and potential correlations between commensal species and specific disease agents. Here, we present the results from three years of sampling a commercial rainbow trout aquaculture facility. The sampling was focused on the early-life stage hatchery building and included sampling of the facility source water and outdoor production raceways. We observed that the microbial communities residing on the abiotic surfaces within the hatchery were distinct from those residing on the surfaces of the facility water source as well as the production raceways, despite similar communities in the water column at each location. Within the hatchery building, most of the microbial classes and families within surface biofilms were also present within the water column, suggesting that these biofilms are seeded by a unique subgroup of microbial taxa from the water. Lastly, we detected a common fish pathogen,Flavobacterium columnare, within the hatchery, including at the source water inlet. Importantly, the relative abundance of this pathogen was correlated with clinical disease. Our results characterized the microbial communities in an aquaculture facility, established that the hatchery environment contains a unique community composition, and demonstrated that a specific fish pathogen resides within abiotic surface biofilms and is seeded from the natural source water.ImportanceThe complex microbial consortium residing in the built environment of aquaculture facilities is poorly understood. In this study, we provide a multi-year profile of the surface- and water-associated microbial communities of this biome. The results demonstrated that distinct community structures exist in the water and on surfaces. Furthermore, it was shown that a common and economically impactful bacterial pathogen,F. columnare, is continually introduced via the source water, is widespread within surface biofilms in the hatchery environment, and is likely amplified within these raceways but does not always cause disease despite being present. These results advance our understanding of pathogen localization at fish farms, show the interplay between host and environmental microbiomes, and reveal the importance of microbial community sequencing in aquaculture for identifying potential beneficial and harmful microbes. This study adds to the aquaculture microecology dataset and enhances our ability to understand this environment from a “One Health” perspective.
Subtyping evaluation of Salmonella Enteritidis using SNP and core genome MLST with nanopore reads
Authors: Xian Zhihan , Li Shaoting , Mann David Ames , Huang Yixiao , Xu Feng , Wu Xingwen , Tang Silin , Zhang Guangtao , Stevenson Abigail , Ge Chongtao , Deng Xiangyu 
Published: May 2022

ABSTRACTWhole genome sequencing (WGS) for public health surveillance and epidemiological investigation of foodborne pathogens predominantly relies on sequencing platforms that generate short reads. Continuous improvement of long-read nanopore sequencing such as Oxford Nanopore Technologies (ONT) presents a potential for leveraging multiple advantages of the technology in public health and food industry settings, including rapid turnaround and onsite applicability in addition to superior read length. However, evaluation, standardization and implementation of the ONT approach to WGS-based, strain-level subtyping is challenging, in part due to its relatively high base-calling error rates and frequent iterations of sequencing chemistry and bioinformatic analytics. Using an established cohort of Salmonella Enteritidis isolates for subtyping evaluation, we assessed the technical readiness of ONT for single nucleotide polymorphism (SNP) analysis and core-genome multilocus sequence typing (cgMLST) of a major foodborne pathogen. By multiplexing three isolates per flow cell, we generated sufficient sequencing depths under seven hours of sequencing for robust subtyping. SNP calls by ONT and Illumina reads were highly concordant despite homopolymer errors in ONT reads (R9.4.1 chemistry). In silico correction of such errors allowed accurate allelic calling for cgMLST and allelic difference measurements to facilitate heuristic detection of outbreak isolates. Our study established a baseline for the continuously evolving nanopore technology as a viable solution to high quality subtyping of Salmonella, delivering comparable subtyping performance when used standalone or together with short-read platforms.
Antimicrobial susceptibility testing using MYCO test-system and MIC distribution of 8 drugs against clinical isolates from Shanghai of Nontuberculous Mycobacteria
Authors: Ying Ruoyan , Yang Jinghui , Sha Wei 
Published: May 2022

AbstractGiven the increased incidence and prevalence of nontuberculous mycobacteria (NTM) diseases and the natural resistance of NTM to multiple antibiotics, in vitro susceptibility testing of different NTM species against drugs from the MYCO test system and new applied drugs are required. 241 NTM clinically isolates were under analyzed, including 181 slowly growing mycobacterium (SGM) and 60 rapidly growing mycobacterium (RGM). The Sensititre SLOMYCO and RAPMYCO panels were used for the drug susceptibility testing to commonly used anti-NTM antibiotics. Furthermore, Minimum inhibitory concentration (MIC) distributions were determined against 8 potential anti-NTM drugs, including vancomycin (VA), bedaquiline (BDQ), delamanid (DLM), faropenem (FAR), meropenem (MPM), clofazimine (CFZ), avibactam (CAZ), and Cefoxitin (FOX) and epidemiological cut-off values (ECOFFs) were analyzed using ECOFFinder. The results showed that most of the SGM strains were susceptible to clarithromycin (CLA), rifampicin (RFB) from the SLOMYCO panels and BDQ, CFZ from the 8 applied drugs, while, RGM strains were susceptible to tigecycline (TGC) from the RAPMYCO panels and also BDQ, CFZ. The ECOFF values of CFZ were 0.25μg/ml, 0.25μg/ml, 0.5μg/ml, and 1μg/ml for M. kansasii, M. avium, M. intracellulare, and M. abscessus, respectively, and BDQ was 0.5μg/ml for the same four prevalent NTM species. Due to the weak activity of the other 6 drugs, no ECOFF was determined. This study on the susceptibility of NTM includes 8 potential anti-NTM drugs and a large sample size of Shanghai clinical isolates. and demonstrated that BDQ and CFZ had efficient activities against different NTM species in vitro, which can be applied for the treatment of NTM diseases.
Thermal acclimation to warmer temperatures can protect host populations from both further heat stress and the potential invasion of pathogens
Authors: Hector Tobias E. , Shocket Marta S. , Sgrò Carla M. , Hall Matthew D. 
Published: May 2022

AbstractPhenotypic plasticity in response to shifts in temperature, known as thermal acclimation, is an essential component of the ability of a species to cope with environmental change. Not only does this process potentially improve an individual’s thermal tolerance, it will also act simultaneously on various fitness related traits that determine whether a population increases or decreases in size. In light of global change, thermal acclimation therefore has consequences for population persistence that extend beyond simply coping with heat stress. This particularly important when we consider the additional threat of parasitism associated with global change, as the ability of a pathogen to invade a host population depends on both its capacity to proliferate within a host and spread between hosts, and thus the supply of new susceptible hosts in a population. Here, we use the hostDaphnia magnaand its bacterial pathogenPasteuria ramosato investigate how thermal acclimation may impact various aspects of host and pathogen performance at the scale of both an individual and the population. We independently test the effect of maternal thermal acclimation and direct thermal acclimation on host thermal tolerance, measured as knockdown times, as well as host fecundity and lifespan, and pathogen infection success and spore production. We find that direct thermal acclimation enhances host thermal tolerance and intrinsic rates of population growth, despite a decline observed for host fecundity and lifespan. Pathogens, on the other hand, faired consistently worse at warmer temperatures at the within-host scale, and also in their potential to invade a host population. Our results suggest that hosts could benefit more from warming than their pathogens, but highlight that considering both within- and between-host thermal performance, including thermal tolerance and fitness traits, is needed to fully appreciate how increasing thermal variability will impact host and pathogen populations.
Different combinations of laccase paralogs non-redundantly control the lignin amount and composition of specific cell types and cell wall layers in Arabidopsis
Authors: Blaschek Leonard , Murozuka Emiko , Ménard Delphine , Pesquet Edouard 
Published: May 2022

AbstractVascular plants reinforce the cell walls of the different xylem cell types with lignin, a phenolic polymer. Specific lignin chemistries are conserved between the cell wall layers of each cell type to support their functions. Yet the mechanisms controlling the tight spatial localisation of specific lignin chemistries remain unclear. Current hypotheses focus on a control by monomer biosynthesis and/or export, while their cell wall polymerisation is viewed as random and non-limiting. Here we show that cell wall polymerisation using combinations of multiple different laccases (LACs) non-redundantly and specifically control the lignin chemistry in different cell types and their distinct cell wall layers. We dissected the roles of Arabidopsis thaliana LAC4, 5, 10, 12 and 17 by generating quadruple and quintuple loss-of-function mutants. Different combinatory loss of these LACs lead to specific changes in lignin chemistry affecting both residue ring structures and/or aliphatic tails in specific cell types and cell wall layers. We moreover showed that the LAC-mediated lignification had distinct functions in specific cell types. Altogether, we propose that the spatial control of lignin chemistry depends on different combinations of LACs with non-redundant activities immobilised in specific cell types and cell wall layers.
Perceptual cycles travel across retinotopic space
Authors: Fakche Camille , Dugué Laura 
Published: May 2022

AbstractVisual perception waxes and wanes periodically over time at low frequencies (theta, 4-7Hz; alpha, 8-13Hz) creatingperceptual cycles. These perceptual cycles can be induced when stimulating the brain with a flickering visual stimulus at the theta or alpha frequency. Here, we took advantage of the well-known organization of the visual system into retinotopic maps (topographic correspondence between visual and cortical spaces) to assess the spatial organization of induced perceptual cycles. Specifically, we tested the hypothesis that they can propagate across the retinotopic space. A disk oscillating in luminance (inducer) at 4, 6, 8 or 10 Hz was presented in the periphery of the visual field to induce perceptual cycles at specific frequencies. Electroencephalographic (EEG) recordings verified that the brain responded at the corresponding inducer frequencies and their first harmonics. Perceptual cycles were assessed with a concurrent detection task –target stimuli were displayed at threshold contrast (50% detection) at random times during the inducer. Behavioral results confirmed that perceptual performance was modulated periodically by the inducer at each frequency. We additionally manipulated the distance between the target and the inducer (3 possible positions) and showed that the optimal phase, i.e., moment of highest target detection, shifted across target distance to the inducer, specifically when its flicker frequency was in the alpha range (8 and 10 Hz). These results demonstrate that induced alpha perceptual cycles travel across the retinotopic space in human at a propagation speed of 0.3-0.5 m/s, consistent with the speed of unmyelinated horizontal connections in the visual cortex.