bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative genomics reveals different population structures associated with host and geographic origin in antimicrobial-resistantSalmonella enterica
Authors: Liao Jingqiu , Orsi Renato Hohl , Carroll Laura , Wiedmann Martin 
Published: January 2020

SummaryGenetic variation in a pathogen, including the causative agent of salmonellosis,Salmonella enterica, can occur as a result of eco-evolutionary forces triggered by dissimilarities of ecological niches. Here, we applied comparative genomics to study 90 antimicrobial resistant (AMR)S. entericaisolates from bovine and human hosts in New York state and Washington state to understand host- and geographic-associated population structure. Results revealed distinct presence/absence profiles of functional genes and pseudogenes (e.g., virulence genes) associated with bovine and human isolates. Notably, bovine isolates contained significantly more transposase genes but fewer transposase pseudogenes than human isolates, suggesting the occurrence of large-scale transposition in genomes of bovine and human isolates at different times. The high correlation between transposase genes and AMR genes, as well as plasmid replicons, highlights the potential role of horizontally transferred transposons in promoting adaptation to antibiotics. By contrast, a number of potentially geographic-associated single-nucleotide polymorphisms (SNPs), rather than geographic-associated genes, were identified. Interestingly, 38% of these SNPs were in genes annotated as cell surface protein-encoding genes, including some essential for antibiotic resistance and host colonization. Overall, different evolutionary forces and limited recent inter-population transmission appear to shape AMRS. entericapopulation structure in different hosts and geographic origins.Originality/Significance StatementSalmonella enterica, which is the causative agent of salmonellosis, poses a growing public health concern due to the emergence and spread of antimicrobial resistant (AMR) strains. The mechanisms underlying the population structure associated with different hosts and geographic origins of AMRS. entericaare underexplored due to limited genome-wide studies assessing the impact of ecological niches on genetic variations. By employing comparative genomics, our study provided insights into the genomic profiles of AMRS. entericaassociated with two distinct hosts and two distant geographic locations, improving the mechanistic understanding of how bacterial population structure is shaped by different ecological niches. Our findings have broad implications for elucidating the impact of ecological and evolutionary forces on the adaptation, antimicrobial resistance, and pathogenicity of bacteria. Also, specific genetic markers we identified may help predict host or geographic origin of AMRSalmonellaisolates, which could benefit the source tracking (e.g., host and geographic origins) of human disease cases and contamination events caused by AMRS. enterica.
Responsive fluorophore aggregation provides spectral contrast for fluorescence lifetime imaging
Authors: Schleyer Kelton A. , Datko Benjamin D. , Burnside Brandon , Cui Chao , Ma Xiaowei , Grey John K. , Cui Lina 
Published: January 2020

AbstractFluorophores experience altered emission lifetimes when incorporated into and liberated from macromolecules or molecular aggregates; this trend suggests the potential for a fluorescent, responsive probe capable of undergoing self-assembly and aggregation and consequently altering the lifetime of its fluorescent moiety to provide contrast between the active and inactive probes. We developed a cyanobenzothioazole-fluorescein conjugate (1), and spectroscopically examined the lifetime changes caused by its reduction-induced aggregationin vitro. A decrease in lifetime was observed for compound1in a buffered system activated using the biological reducing agent glutathione, suggesting a possible approach for designing responsive self-aggregating lifetime imaging probes.
Acquisition of Innate Odor Preference Depends on Spontaneous and Experiential Activities During Critical Period
Authors: Qiu Qiang , Wu Yunming , Ma Limei , Ramalingam Vivekanandan , Yu C. Ron 
Published: January 2020

AbstractAnimals possess inborn ability to recognize certain odors, which enables them to seek food, avoid predators and find mates even in the absence of prior experiences. The establishment of innate odor preference has been thought to be genetically hardwired. Here we report that the acquisition of innate odor recognition requires spontaneous neural activity and is influenced by sensory experience during early postnatal development. Genetic silencing of mouse olfactory sensory neurons during the developmental critical period has little impact on odor sensitivity, odor discrimination and recognition later in life. However, it abolishes innate odor preference and alters the patterns of activation in brain centers. Moreover, exposure to an innately aversive odor during the critical period abolishes aversion in adulthood in an odor specific manner. The loss of innate aversion is associated with broadened projection of OSNs expressing the cognate receptor such that they innervate ectopic glomeruli in the olfactory bulb. These results indicate that a delicate balance of neural activity is required during critical period in establishing innate odor preference and that ectopic projection is a convergent mechanism to alter innate odor valence.
Synchronized genetic activities in Alzheimer’s brains revealed by heterogeneity-capturing network analysis
Authors: Climer Sharlee , Templeton Alan R. , Garvin Michael , Jacobson Daniel , Lane Matthew , Hulver Scott , Scheid Brittany , Chen Zheng , Cruchaga Carlos , Zhang Weixiong 
Published: January 2020

AbstractIt is becoming increasingly evident that the efficacy of single-gene computational analyses for complex traits is nearly exhausted and future advances hinge on unraveling the intricate combinatorial interactions among multiple genes. However, the discovery of modules of genes working in concert to manifest a complex trait has been crippled by combinatorial complexity, genetic heterogeneity, and validation biases. We introduce Maestro, a novel network approach that employs a multifaceted correlation measure, which captures heterogeneity, and a rigorous validation method. Maestro’s utilization for Alzheimer’s disease (AD) reveals an expression pattern that has virtually zero probability of simultaneous expression by an individual, assuming independence. Yet this pattern is exhibited by 19.0% of AD cases and 7.3% of controls, establishing an unprecedented pattern of synchronized genetic activities in the human brain. This pattern is significantly associated with AD, with an odds ratio of 3.0. This study substantiates Maestro’s power for discovery of orchestrated genetic activities underlying complex traits. More generally, Maestro can be applied in diverse domains in which heterogeneity exists.HighlightsSynchronized genetic activities associated with Alzheimer’s diseaseNovel vector-based correlation measure that captures genetic heterogeneityEnhanced network model for revealing combinatorial genetic interactionsPro-survival genetic activities associated with Alzheimer’s diseaseGeneral approach for revealing patterns in data subject to heterogeneity
Exome-wide age-of-onset analysis reveals exonic variants inERN1, TACR3andSPPL2Cassociated with Alzheimer’s disease
Authors: He Liang , Loika Yury , Park Yongjin ,   Genotype Tissue Expression (GTEx) consortium, Bennett David A. , Kellis Manolis , Kulminski Alexander M. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2020

AbstractDespite recent discovery in GWAS of genomic variants associated with Alzheimer’s disease (AD), its underlying biological mechanisms are still elusive. Discovery of novel AD-associated genetic variants, particularly in coding regions and from APOE ε4 non-carriers, is critical for understanding the pathology of AD. In this study, we carried out an exome-wide association analysis of age-of-onset of AD with ~20,000 subjects and placed more emphasis on APOE ε4 non-carriers. Using Cox mixed-effects models, we find that age-of-onset shows a stronger genetic signal than AD case-control status, capturing many known variants with stronger significance, and also revealing new variants. We identified two novel rare variants, rs56201815, a synonymous variant in ERN1, from the analysis of APOE ε4 non-carriers, and a missense variant rs144292455 in TACR3. In addition, we detected rs12373123, a common missense variant in SPPL2C in the MAPT region in APOE ε4 non-carriers. In an attempt to unravel their regulatory and biological functions, we found that the minor allele of rs56201815 was associated with lower average FDG uptake across five brain regions in ADNI. Our eQTL analyses based on 6198 gene expression samples from ROSMAP and GTEx revealed that the minor allele of rs56201815 was associated with elevated expression of ERN1, a key gene triggering unfolded protein response (UPR), in multiple brain regions, including posterior cingulate cortex and nucleus accumbens. Our cell-type-specific eQTL analysis of based on ~80,000 single nuclei in the prefrontal cortex revealed that the protective minor allele of rs12373123 significantly increased expression of GRN in microglia, and was associated with MAPT expression in astrocytes. These findings provide novel evidence supporting the hypothesis of the potential involvement of the UPR to ER stress in the pathological pathway of AD, and also give more insights into underlying regulatory mechanisms behind the pleiotropic effects of rs12373123 in multiple degenerative diseases including AD and Parkinson’s disease.
Expert programmers have fine-tuned cortical representations of source code
Authors: Ikutani Yoshiharu , Kubo Takatomi , Nishida Satoshi , Hata Hideaki , Matsumoto Kenichi , Ikeda Kazushi , Nishimoto Shinji 
Published: January 2020

ABSTRACTExpertise enables humans to achieve outstanding performance on domain-specific tasks, and programming is no exception. Many have shown that expert programmers exhibit remarkable differences from novices in behavioral performance, knowledge structure, and selective attention. However, the underlying differences in the brain are still unclear. We here address this issue by associating the cortical representation of source code with individual programming expertise using a data-driven decoding approach. This approach enabled us to identify seven brain regions, widely distributed in the frontal, parietal, and temporal cortices, that have a tight relationship with programming expertise. In these brain regions, functional categories of source code could be decoded from brain activity and the decoding accuracies were significantly correlated with individual behavioral performances on source-code categorization. Our results suggest that programming expertise is built up on fine-tuned cortical representations specialized for the domain of programming.
Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II and Pol III
Authors: Jiang Yongpeng , Huang Jie , Lun Kehuan , Li Boyuan , Zheng Haonan , Li Yuanjun , Zhou Rong , Duan Wenjia , Feng Yuanqing , Yao Hong , Li Cheng , Ji Xiong 
Published: January 2020

AbstractBackgroundThe relationship between transcription and the 3D genome organization is one of the most important questions in molecular biology, but the roles of transcription in 3D chromatin remain controversial. Multiple groups showed that transcription affects global Cohesin binding and genome 3D structures. At the same time, several studies have indicated that transcription inhibition does not affect global chromatin interactions.ResultsHere, we provide the most comprehensive evidence to date to demonstrate that transcription plays a marginal role in organizing the 3D genome in mammalian cells: 1) degraded Pol I, Pol II and Pol III proteins in mESCs, and showed their loss results in little or no changes of global 3D chromatin structures for the first time; 2) selected RNA polymerases high abundance binding sites-associated interactions and found they still persist after the degradation; 3) generated higher resolution chromatin interaction maps and revealed that transcription inhibition mildly alters small loop domains; 4) identified Pol II bound but CTCF and Cohesin unbound loops and disclosed that they are largely resistant to transcription inhibition. Interestingly, Pol II depletion for a longer time significantly affects the chromatin accessibility and Cohesin occupancy, suggesting RNA polymerases are capable of affecting the 3D genome indirectly. So, the direct and indirect effects of transcription inhibition explain the previous confusing effects on the 3D genome.ConclusionsWe conclude that Pol I, Pol II, and Pol III loss only mildly alter chromatin interactions in mammalian cells, suggesting the 3D chromatin structures are pre-established and relatively stable.
DASC, a sensitive classifier for measuring discrete early stages in clathrin-mediated endocytosis
Authors: Wang Xinxin , Chen Zhiming , Mettlen Marcel , Noh Jungsik , Schmid Sandra L. , Danuser Gaudenz 
Published: January 2020

AbstractClathrin-mediated endocytosis (CME) in mammalian cells is driven by resilient machinery that includes >70 endocytic accessory proteins (EAP). Accordingly, perturbation of individual EAPs often results in minor effects on biochemical measurements of CME, thus providing inconclusive/misleading information regarding EAP function. Live-cell imaging can detect earlier roles of EAPs preceding cargo internalization; however, this approach has been limited because unambiguously distinguishing abortive-clathrin coats (ACs) frombona fideclathrin-coated pits (CCPs) is required but unaccomplished. Here, we develop a thermodynamics-inspired method, “disassembly asymmetry score classification (DASC)”, that unambiguously separates ACs from CCPs without an additional marker. After extensive verification, we use DASC-resolved ACs and CCPs to quantify CME progression in 11 EAP knockdown conditions. We show that DASC is a sensitive detector of phenotypic variation in CCP dynamics that is orthogonal to the variation in biochemical measurements of CME. Thus, DASC is an essential tool for uncovering the function of individual EAPs.
Testing a convolutional neural network-based hippocampal segmentation method in a stroke population
Authors: Zavaliangos-Petropulu Artemis , Tubi Meral A. , Haddad Elizabeth , Zhu Alyssa , Braskie Meredith N. , Jahanshad Neda , Thompson Paul M. , Liew Sook-Lei 
Published: January 2020

AbstractAs stroke mortality rates decrease, there has been a surge of effort to study post-stroke dementia (PSD) to improve long-term quality of life for stroke survivors. Hippocampal volume may be an important neuroimaging biomarker in post-stroke dementia, as it has been associated with many other forms of dementia. However, studying hippocampal volume using MRI requires hippocampal segmentation. Advances in automated segmentation methods have allowed for studying the hippocampus on a large scale, which is important for robust results in the heterogeneous stroke population. However, most of these automated methods use a single atlas-based approach and may fail in the presence of severe structural abnormalities common in stroke. Hippodeep, a new convolutional neural network-based hippocampal segmentation method, does not rely solely on a single atlas-based approach and thus may be better suited for stroke populations. Here, we compared quality control and the accuracy of segmentations generated by Hippodeep and two well-accepted hippocampal segmentation methods on stroke MRIs (FreeSurfer 6.0 whole hippocampus and FreeSurfer 6.0 sum of hippocampal subfields). Quality control was performed using a stringent protocol for visual inspection of the segmentations, and accuracy was measured as volumetric and spatial comparisons to the manual segmentations. Hippodeep performed significantly better than both FreeSurfer methods in terms of quality control and spatial accuracy. Overall, this study suggests that both Hippodeep and FreeSurfer may be useful for hippocampal segmentation in stroke rehabilitation research, but Hippodeep may be more robust to stroke lesion anatomy.
Phytophthora infestansAgo1-bound miRNA promotes potato late blight disease
Authors: Hu Xinyi , Persson Hodén Kristian , Liao Zhen , Dölfors Fredrik , Åsman Anna , Dixelius Christina 
Published: January 2020

SummaryPhytophthoraspp. incite serious plant damages by exploiting a large number of effector proteins and small RNAs (sRNAs). Several reports are describing modulation of host RNA biogenesis and defence gene expression. Here, we analysedP. infestansArgonaute (Ago) 1 associated small RNAs during potato leaf infection.sRNAs were co-immunoprecipitated, deep sequenced and analysed against theP. infestansand potato genomes, followed by transgenic and biochemical analyses on a predicted host target.Extensive targeting of potato and pathogen-derived sRNAs to a large number of mRNAs was observed, including 206 sequences coding for resistance (R) proteins in the host genome. The single miRNA encoded byP. infestans(miR8788) was found to target a potato lipase-like membrane protein-encoding gene (StLL1) localized to the tonoplast. Analyses of stable transgenic potato lines harbouring overexpressedStLL1or artificial miRNA gene constructs demonstrated the importance of StLL1 during infection byP. infestans. Similarly, a miR8788 knock-down strain showed reduced growth on potato compared to the wild-type strain 88069.The data suggest that sRNA encoded byP. infestanscan affect potato mRNA and thereby promote disease. Knowledge of the impact of pathogen small RNAs in plant defence mechanisms is of major significance to succeed in improved disease control management.
Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells
Authors: Peruzzotti-Jametti Luca , Bernstock Joshua D. , Manferrari Giulia , Rogall Rebecca , Fernandez-Vizarra Erika , Williamson James C , Braga Alice , van den Bosch Aletta , Leonardi Tommaso , Kittel Ágnes , Benincá Cristiane , Vicario Nunzio , Tan Sisareuth , Bastos Carlos , Bicci Iacopo , Iraci Nunzio , Smith Jayden A. , Lehner Paul J , Buzas Edit Iren , Faria Nuno , Zeviani Massimo , Frezza Christian , Brisson Alain , Matheson Nicholas J , Viscomi Carlo , Pluchino Stefano 
Published: January 2020

AbstractNeural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs).EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics.Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells.Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs (Mito-EVs) with conserved membrane potential and respiration. We found that the transfer of Mito-EVs to mtDNA-deficient L929 Rho0cells rescued mitochondrial function and increased Rho0cell survival. Furthermore, the incorporation of Mito-EVs into inflammatory professional phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits.Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via Mito-EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
FCHSD2 Controls Oncogenic ERK1/2 Signaling Outcome by Regulating Endocytic Trafficking
Authors: Xiao Guan-Yu , Schmid Sandra L. 
Published: January 2020

AbstractCancer progression is driven, in part, by altered signaling downstream of receptor tyrosine kinases (RTKs). Surface expression and RTK activity are regulated by clathrin-mediated endocytosis (CME), endosomal recycling or degradation. In turn, oncogenic signaling downstream of RTKs can reciprocally regulate endocytic trafficking, creating feedback loops that enhance tumor progression. We previously reported a cancer-cell specific function of FCHSD2 (FCH/F-BAR and double SH3 domain-containing protein) in regulating CME in non-small-cell lung cancer (NSCLC) cells. Here, we report that FCHSD2 loss impacts recycling of EGFR and MET, diverting their trafficking toward late endosomes and lysosomes. FCHSD2 depletion results in the nuclear translocation of active ERK1/2, leading to enhanced transcription and upregulation of EGFR and MET. The small GTPase, Rab7, is essential for the FCHSD2 depletion-induced effects. Correspondingly, FCHSD2 loss correlates with higher tumor grades of NSCLC. Clinically, NSCLC patients expressing high FCHSD2 exhibit elevated survival, whereas patients with high Rab7 expression display decreased survival rates. Our study provides new insight into the molecular nexus for crosstalk between oncogenic signaling and RTK trafficking that controls cancer progression.