bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optical microscopy reveals the dynamic nature ofB. pseudomalleimorphology during β-lactam antimicrobial susceptibility testing
Authors: McLaughlin Heather P. , Bugrysheva Julia , Sue David 
Published: January 2020

AbstractBackgroundIn Gram-negative species, β-lactam antibiotics target penicillin binding proteins (PBPs) resulting in morphological alterations of bacterial cells. Observations of antibiotic-induced cell morphology changes can rapidly and accurately differentiate drug susceptible from resistant bacterial strains; however, resistant cells do not always remain unchanged.Burkholderia pseudomalleiis a Gram-negative, biothreat pathogen and the causative agent of melioidosis, an often fatal infectious disease for humans.ResultsHere, we identified β-lactam targets inB. pseudomalleibyin silicoanalysis. Ten genes encoding putative PBPs, including PBP-1, PBP-2, PBP-3 and PBP-6, were detected in the genomes of susceptible and resistant strains. Real-time, live-cell imaging ofB. pseudomalleistrains demonstrated dynamic morphological changes in broth containing clinically relevant β-lactam antibiotics. At sub-inhibitory concentrations of ceftazidime (CAZ), amoxicillin-clavulanic acid (AMC), and imipenem (IPM), filamentation, varying in length and proportion, was an initial response of the multidrug-resistant strain Bp1651 in exponential phase. However, a dominant morphotype reemerged during stationary phase that resembled cells unexposed to antibiotics. Similar morphology dynamics were observed for AMC-resistant strains, MSHR1655 and 724644, when exposed to sub-inhibitory concentrations of AMC. For allB. pseudomalleistrains evaluated, increased exposure time and exposure to increased concentrations of AMC at and above minimal inhibitory concentrations (MICs) in broth resulted in cell morphology shifts from filaments to spheroplasts and/or cell lysis.B. pseudomalleimorphology changes were more consistent in IPM. Spheroplast formation followed by cell lysis was observed for all strains in broth containing IPM at concentrations greater than or equal to MICs, however, the time to cell lysis was variable. Length ofB. pseudomalleicells was strain-, drug- and drug concentration-dependent.ConclusionsBoth resistant and susceptibleB. pseudomalleistrains exhibited filamentation during early exposure to AMC and CAZ at concentrations used to interpret susceptibility (based on CLSI guidelines). While developing a rapid β-lactam antimicrobial susceptibility test based on cell-shape alone requires more extensive analyses, optical microscopy detectedB. pseudomalleigrowth attributes that lend insight into antibiotic response and antibacterial mechanisms of action.
Recent fluctuations in Mexican American genomes have altered the genetic architecture of biomedical traits
Authors: Spear Melissa L. , Diaz-Papkovich Alex , Ziv Elad , Yracheta Joseph M. , Gravel Simon , Torgerson Dara G. , Hernandez Ryan D. 
Published: January 2020

AbstractPeople in the Americas represent a diverse group of populations with varying degrees of admixture among African, European, and Amerindigenous ancestries. In the United States, many populations with non-European ancestry remain understudied, and thus little is known about the genetic architecture of phenotypic variation in these populations. Using genome-wide genotype data from the Hispanic Community Health Study/Study of Latinos, we find that Amerindigenous ancestry has increased over time across Hispanic/Latino populations, particularly in Mexican Americans where Amerindigenous ancestry increased by an average of ∼20% over the 50-year period spanning 1940s-1990s. We find similar patterns across American cities, and replicate our observations in an independent sample of Mexican Americans. These dynamic ancestry patterns are a result of a complex interaction of several population and cultural factors, including strong ancestry-related assortative mating and subtle shifts in migration with differences in subcontinental Amerindigenous ancestry over time. These factors have shaped patterns of genetic variation, including an increase in runs of homozygosity in Amerindigenous ancestral tracts, and also influenced the genetic architecture of complex traits within the Mexican American population. We show for height, a trait correlated with ancestry, polygenic risk scores based on summary statistics from a European-based genome-wide association study perform poorly in Mexican Americans. Our findings reveal temporal changes in population structure within Hispanics/Latinos that may influence biomedical traits, demonstrating a crucial need to improve our understanding of the genetic diversity of admixed populations.
Factor VIII exhibits chaperone-dependent and glucose-regulated reversible amyloid formation in the endoplasmic reticulum
Authors: Poothong Juthakorn , Pottekat Anita , Siirin Marina , Campos Alexandre Rosa , Paton Adrienne W. , Paton James C. , Lagunas-Acosta Jacqueline , Chen Zhouji , Swift Mark , Volkmann Niels , Hanein Dorit , Yong Jing , Kaufman Randal J. 
Published: January 2020

AbstractFactor VIII (FVIII) is the coagulation factor deficient in hemophilia A, which is treated by protein replacement. Unfortunately, this regimen is costly due to the expense of producing recombinant FVIII as a consequence of its low level secretion. FVIII expression activates the endoplasmic reticulum (ER) stress response, causes oxidative stress and induces apoptosis. Importantly, little is known about the factors that cause protein misfolding and aggregation in metazoans. Here we identified intrinsic and extrinsic factors that cause FVIII to form aggregates in the ER. We show that FVIII forms amyloid-like fibrils within the ER upon increased FVIII synthesis or inhibition of glucose metabolism. Significantly, FVIII amyloids can be dissolved upon restoration of glucose metabolism to produce functional secreted FVIII. Two ER chaperones and their co-chaperones, BiP and CANX/CRT, promote FVIII solubility in the ER, where the former is also required for disaggregation. A short aggregation motif in the FVIII A1 domain (termed Aggron) is necessary and sufficient to seed β-sheet polymerization and BiP binding to this Aggron prevents amyloidogenesis. Our findings provide novel insight into mechanisms that limit FVIII secretion and ER protein folding in general and have implication for ongoing hemophilia A gene therapy clinical trials.Key Points-FVIII forms amyloid aggregates in the ER that are dissolved in a chaperone- and glucose-dependent manner to produce secreted active FVIII.-A short amino acid sequence in the A1 domain causes β sheet polymerization and ER chaperone BiP binding to this site prevents aggregation.
Fluidity of gender identity induced by illusory body-sex change
Authors: Tacikowski P. , Fust J. , Ehrsson H. H. 
Published: January 2020

AbstractGender identity is the inner sense of being male, female, both, or neither. How this sense is linked to the perception of one’s own masculine or feminine body remains unclear. Here, in a series of three behavioral experiments conducted on a large group of healthy volunteers (N=140), we show that a perceptual illusion of having the opposite-sex body was associated with a shift toward more balanced identification with both genders and less gender-stereotypical beliefs about one’s own personality characteristics, as indicated by subjective reports and implicit behavioral measures. These findings demonstrate that the ongoing perception of one’s own body affects the sense of one’s own gender in a dynamic, robust, and automatic manner.
Dietary Amino Acids Impact LRRK2-induced Neurodegeneration in Parkinson’s Disease Models
Authors: Chittoor-Vinod Vinita G. , Villalobos-Cantor Steffany , Roshak Hanna , Shea Kelsey , Martin Ian 
Published: January 2020

ABSTRACTThe G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson’s disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under non-pathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5’-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.
SalmonellaEnteritidis Effector AvrA suppresses autophagy by reducing Beclin-1 protein
Authors: Jiao Yang , Zhang Yong-guo , Lin Zhijie , Lu Rong , Xia Yinglin , Meng Chuang , Pan Zhimin , Xu Xiulong , Jiao Xinan , Sun Jun 
Published: January 2020

AbstractAutophagy is a cellular process to clear pathogens.Salmonella entericaserovar Enteritidis (S.E) has emerged as one of the most important food-borne pathogens. However, major studies still focus onSalmonella entericaserovar Typhimurium. Here, we reported that AvrA, aS. Enteritidis effector, inhibited autophagy to promote bacterial survival in the host. We found that AvrA regulates the conversion of LC3 I into LC3 II and the enrichment of lysosomes. Beclin-1, a key molecular regulator of autophagy, was decreased after AvrA expressed strain colonization. InS.E-AvrA--infected cells, we found the increases of protein levels of p-JNK and p-c-Jun and the transcription level of AP-1. AvrA-reduction of Beclin-1 protein expression is through the JNK pathway. The JNK inhibitor abolished the AvrA-reduced Beclin-1 protein expression. Moreover, we identified that the AvrA mutation C186A abolished its regulation of Beclin-1 expression. In addition, AvrA protein interacted with Beclin-1. In organoids and infected mice, we explored the physiologically related effects and mechanism of AvrA in reducing Beclin-1 through the JNK pathway, thus attenuating autophagic responses.ImportanceSalmonellaEnteritidis is an important pathogen with a public health concern and farm production risk, yet the host-pathogen interactions that govern the survival ofS. Enteritidis infections are incompletely understood. Anti-bacterial autophagy provides potent cell-autonomous immunity against bacterial colonization. Here, we report that a new role for effector AvrA ofS. Enteritidis in the reduction of Beclin-1 protein expression through the JNK pathway and the attenuation of the autophagic response in intestinal epithelial cells. This finding not only indicates an important role ofS. Enteritidis effector in reducing host protein as a strategy to suppress autophagy, but also suggests manipulating autophagy as a new strategy to treat infectious diseases.
Natural infection withGiardiais associated with altered community structure of the human and canine gut microbiome
Authors: Berry Alexander S.F. , Johnson Kaylynn , Martins Rene , Sullivan Megan , Amorim Camila Farias , Putre Alexandra , Scott Aiysha , Wang Shuai , Lindsay Brianna , Baldassano Robert , Nolan Thomas J. , Beiting Daniel P. 
Published: January 2020

AbstractEnteric parasitic infections are among the most prevalent infections in lower- and middle-income countries (LMICs), and have a profound impact on global public health. While the microbiome is increasingly recognized as a key determinant of gut health and human development, the impact of naturally-acquired parasite infections on microbial community structure in the gut, and the extent to which parasite-induced changes in the microbiome may contribute to gastrointestinal symptoms, is poorly understood. Enteric parasites are routinely identified in companion animals in the United States, presenting a unique opportunity to leverage this animal model to investigate the impact of naturally-acquired parasite infections on the microbiome. Clinical, parasitological, and microbiome profiling of a cohort of 258 dogs revealed a significant correlation between parasite infection and composition of the bacterial community in the gut. Relative to other enteric pathogens,Giardiawas associated with a more pronounced perturbation of the microbiome. Using a database mining approach that allowed us to compare our findings to a large-scale epidemiological study of enteric diseases in humans, we also observed a substantial alteration to microbiome structure inGiardia-infected children. Importantly, infection was associated with a reduction in the relative abundance of potential pathobionts, includingGammaproteobacteria, and an increase inPrevotella- a profile often associated with gut health. Taken together, our data show that widespreadGiardiainfection in young animals and humans is associated with significant remodeling of the gut microbiome, and provide a possible explanation for the high prevalence of asymptomaticGiardiainfections observed across host species.ImportanceWhile enteric parasitic infections are among the most important infections in lower- and middle-income countries, their impact on gut microbiota is poorly understood. We reasoned that clinical symptoms associated with these infections may be influenced by alterations of the microbiome that occur during infection. To explore this notion, we took a two-pronged approach. First, we studied a cohort of dogs naturally infected with various enteric parasites and found a strong association between parasite infection and altered gut microbiota composition.Giardia, one of the most prevalent parasite infections globally, had a particularly large impact on the microbiome. Second, we took a database-driven strategy to integrate microbiome data with clinical data from large human field studies and found thatGiardiainfection is also associated with marked alteration of the gut microbiome of children, suggesting a possible explanation for whyGiardiahas been reported to be associated with protection from moderate-to-severe diarrhea.
A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants
Authors: Chawner Samuel J.R.A. , Doherty Joanne L. , Anney Richard , Antshel Kevin M. , Bearden Carrie E. , Bernier Raphael , Chung Wendy K. , Clements Caitlin C. , Curran Sarah R. , Cuturilo Goran , Fiksinski Ania M. , Gallagher Louise , Goin-Kochel Robin P. , Kushan Leila , Gur Raquel E. , Hanson Ellen , Jacquemont Sebastien , Kates Wendy R. , Maillard Anne M. , McDonald-McGinn Donna M. , Mihaljevic Marina , Miller Judith S , Moss Hayley , Pejovic-Milovancevic Milica , Schultz Robert T. , Green-Snyder LeeAnne , Vorstman Jacob A. , Wenger Tara L. ,   IMAGINE-ID Consortium, Hall Jeremy , Owen Michael J. , van den Bree Marianne 
Published: January 2020

AbstractObjectiveCertain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships.MethodsThis international study included 547 individuals (12.3 years (SD=4.2), 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers and 45 22q11.2 duplication carriers), as well as 2027 individuals (9.1 years (SD=4.9), 86% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted.ResultsThe four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within individual genetic variant groups (74% to 97% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to individuals with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of individuals with one of the 4 CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits.ConclusionMany CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.
The interdomain helix between the kinase and RNase domains of IRE1α transmits the conformational change that underlies ER stress-induced activation
Authors: Ricci Daniela , Tutton Stephen , Marrocco Ilaria , Ying Mingjie , Blumenthal Daniel , Eletto Daniela , Vargas Jade , Boyle Sarah , Fazelinia Hossein , Paton James C. , Paton Adrienne W. , Anthony Tang Chih-Hang , Andrew Hu Chih-Chi , Gidalevitz Tali , Argon Yair 
Published: January 2020

AbstractThe unfolded protein response (UPR) plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum (ER) stress to biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that upon sensing unfolded proteins via its ER luminal domain, IRE1α dimerizes and oligomerizes (often visualized as clustering), and then trans-autophosphorylates. The IRE1α kinase activity is required for activation of its RNase effector domain and for clustering of IRE1α. It is not yet clear if IRE1α clustering is a platform for the RNase activity, or if the two represent distinct biological functions. Here, we uncover a previously unrecognized role for helix αK between IRE1α kinase and RNase domains in conveying critical conformational changes. Using mutants within this inter-domain helix, we show for the first time that: 1) distinct substitutions (specifically, of Leu827) selectively affect oligomerization, RNase activity, and, unexpectedly, the kinase activity of IRE1α; 2) RNase activation can be uncoupled from IRE1α oligomerization, and phosphorylation of S729 marks the former but not the latter; 3) The nature of residue 827 determines the conformation that the IRE1α protein adopts, leading to different patterns of biochemical activities. In summary, this work reveals a previously unappreciated role for the inter-domain helix as a pivotal conduit for attaining the stress-responsive conformation of IRE1α.
Modulation of white matter bundle connectivity in the presence of axonal truncation pathologies
Authors: Smith Robert E. , Calamante Fernando , Gajamange Sanuji , Kolbe Scott , Connelly Alan 
Published: January 2020

AbstractEndpoint-to-endpoint fibre bundle connectivity estimated using spherical deconvolution & streamlines tractography in diffusion MRI may be excessive in the presence of pathologies that involve truncation of axons within the white matter. Here we propose a simple modification to an existing method that directly quantifies and corrects for this over-estimation.
Conceptual knowledge affects early stages of visual mental imagery and object perception
Authors: Maier Martin , Frömer Romy , Rost Johannes , Sommer Werner , Rahman Rasha Abdel 
Published: January 2020

AbstractWhen we imagine an object and when we actually see that object, similar brain regions become active. Yet, the time course and mechanisms with which imagery engages perceptual networks remain to be better understood. An emerging view holds that imagery and perception follow distinct dynamics during early visual processing with similarities arising only during later, high-level visual processing. However, confounds of visual stimulation and paradigms favoring observation of high-level processes associated with subjective imagery strength may have precluded evidence of earlier shared mechanisms. We therefore manipulated prior knowledge that informs early-stage top-down predictions and tracked electrophysiological brain responses while fully controlling visual stimulation. Participants saw and imagined objects associated with varying amounts of semantic knowledge. Imagery and perception were equally influenced by knowledge at an early stage (P1 component), revealing shared mechanisms that support low-level visual processing. This finding complements previous research by showing that imagery is not merely perception in reverse. Instead, in line with the predictive processing framework, both, perception and imagery are active and constructive processes that share top-down mechanisms already in early phases of processing.
Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations
Authors: Wang Ying , Guo Jing , Ni Guiyan , Yang Jian , Visscher Peter M. , Yengo Loic 
Published: January 2020

AbstractPolygenic scores (PGS) have been widely used to predict complex traits and risk of diseases using variants identified from genome-wide association studies (GWASs). To date, most GWASs have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European populations. Here, we develop a new theory to predict the relative accuracy (RA, relative to the accuracy in populations of the same ancestry as the discovery population) of PGS across ancestries. We used simulations and real data from the UK Biobank to evaluate our results. We found across various simulation scenarios that the RA of PGS based on trait-associated SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of SNP effect sizes and heritability. Altogether, we find that LD and MAF differences between ancestries explain alone up to ~70% of the loss of RA using European-based PGS in African ancestry for traits like body mass index and height. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWASs are mostly shared across continents.