bluuebunny/crossref_metadata_2025_split huggingface dataset:
Host genetic and environmental factors shape the human gut resistome
Authors: Le Roy C.I. , Bowyer R.C. E. , Carr V.R. , Costeira R. , Castillo-Fernandez J.E. , Martin T.C. , Spector T.D. , Steves C.J. , Moyes D. , Forslund S.K. , Bell J.T. 
Published: May 2020

AbstractBackgroundUnderstanding and controlling the spread of antimicrobial resistance is one of the greatest challenges of modern medicine. To this end many efforts focus on characterising the human resistome or the set of antibiotic resistance determinants within the microbiome of an individual. Aside from antibiotic use, other host environmental and genetic factors that may shape the resistome remain relatively underexplored.MethodsUsing gut metagenome data from 250 TwinsUK female twins, we quantified known antibiotic resistance genes to estimate gut microbiome antibiotic resistance potential for 41 types of antibiotics and resistance mechanisms. Using heritability modelling, we assessed the influence of host genetic and environmental factors on the gut resistome. We then explored links between gut resistome, host health and specific environmental exposures using linear mixed effect models adjusted for age, BMI, alpha diversity and family structure.ResultsWe considered gut microbiome antibiotic resistance to 21 classes of antibiotics, for which resistance genes were detected in over 90% of our population sample. Using twin modelling, we estimated that on average about 25% of resistome variability could be attributed to host genetic influences. Greatest heritability estimates were observed for resistance potential to acriflavine (70%), dalfopristin (51%), clindamycin (48%), aminocoumarin (48%) and the total score summing across all antibiotic resistance genes (38%). As expected, the majority of resistome variability was attributed to host environmental factors specific to an individual. We compared antibiotic resistance profiles to multiple environmental exposures, lifestyle and health factors. The strongest associations were observed with alcohol and vegetable consumption, followed by high cholesterol medication and antibiotic usage. Overall, inter-individual variation in host environment showed modest associations with antibiotic resistance profiles, and host health status had relatively minor signals.ConclusionOur results identify host genetic and environmental influences on the human gut resistome. The findings improve our knowledge of human factors that influence the spread of antibiotic resistance genes and may contribute towards helping to attenuate it.
Non-linear randomized Haseman-Elston regression for estimation of gene-environment heritability
Authors: Kerin Matthew , Marchini Jonathan 
Published: May 2020

AbstractGene-environment (GxE) interactions are one of the least studied aspects of the genetic architecture of human traits and diseases. The environment of an individual is inherently high dimensional, evolves through time and can be expensive and time consuming to measure. The UK Biobank study, with all 500,000 participants having undergone an extensive baseline questionnaire, represents a unique opportunity to assess GxE heritability for many traits and diseases in a well powered setting. We have developed a non-linear randomized Haseman-Elston (RHE) regression method applicable when many environmental variables have been measured on each individual. The method (GPLEMMA) simultaneously estimates a linear environmental score (ES) and its GxE heritability. We compare the method via simulation to a whole-genome regression approach (LEMMA) for estimating GxE heritability. We show that GPLEMMA is computationally efficient and produces results highly correlated with those from LEMMA when applied to simulated data and real data from the UK Biobank.
Short- and long-read metagenomics of urban and rural South African gut microbiomes reveal a transitional composition and novel taxa
Authors: Tamburini Fiona B. , Maghini Dylan , Oduaran Ovokeraye H. , Brewster Ryan , Hulley Michaella R. , Sahibdeen Venesa , Norris Shane A. , Tollman Stephen , Kahn Kathleen , Wagner Ryan G. , Wade Alisha N. , Wafawanaka Floidy , Xavier Gómez-Olivé F. , Twine Rhian , Lombard Zané , Hazelhurst Scott , Bhatt Ami S. 
Published: May 2020

AbstractHuman gut microbiome research focuses on populations living in high-income countries or on the other end of the spectrum, namely non-urban agriculturalist and hunter-gatherer societies. The scarcity of research between these extremes limits our understanding of how the gut microbiota relates to health and disease in the majority of the world’s population. We present the first study evaluating gut microbiome composition in transitioning South African populations using short- and long-read sequencing. We analyzed stool samples from adult females (age 40 - 72) living in rural Bushbuckridge municipality (n=118) or urban Soweto (n=51) and find that these microbiomes are taxonomically intermediate between those of individuals living in high-income countries and traditional communities. We demonstrate that reference collections are incomplete for characterization of microbiomes of individuals living outside high-income countries, resulting in artificially low species-level beta diversity measurements. To improve reference databases, we generated complete genomes of undescribed taxa, includingTreponema, Lentisphaerae, andSuccinatimonasspecies. Our results suggest that the gut microbiome in South African populations do not exist along a simple “western-nonwestern” axis and that these populations contain microbial diversity that remains to be described.
ITPK1 is an InsP6/ADP phosphotransferase that controls systemic phosphate homeostasis in Arabidopsis
Authors: Riemer Esther , Laha Debabrata , Harmel Robert K. , Gaugler Philipp , Pries Verena , Frei Michael , Hajirezaei Mohammad-Reza , Laha Nargis P. , Krusenbaum Lukas , Schneider Robin , Jessen Henning J. , Saiardi Adolfo , Fiedler Dorothea , Schaaf Gabriel , Giehl Ricardo F.H. 
Published: May 2020

ABSTRACTIn plants, phosphate (Pi) homeostasis is regulated by the interaction of Pistarvation response transcription factors (PHRs) with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates (PP-InsPs). Recently, ITPK1 was shown to generate the PP-InsP InsP7from InsP6in vitro, but the importance of this activity in Pisignaling remained unknown. Here, we show that uncontrolled Piaccumulation in ITPK1-deficient plants is accompanied by impaired Pi-dependent InsP7and InsP8synthesis. Reciprocal grafting demonstrates that Pistarvation responses are mainly controlled by ITPK1 activity in shoots. Nuclear magnetic resonance assays and PAGE analyses with recombinant protein reveal that besides InsP6phosphorylation, ITPK1 is also able to catalyze ATP synthesis using 5-InsP7but not any other InsP7isomer as a P-donor when ATP is low. Additionally, we show that the dynamic changes in InsP7and InsP8to cellular Piare conserved from land plant species to human cells, suggesting that Pi-dependent PP-InsP synthesis is a common component of Pisignaling across kingdoms. Together, our study demonstrates how Pi-dependent changes in nutritional and energetic states modulate ITPK1 activities to fine-tune the synthesis of PP-InsPs.
Spontaneous eye-movements during eyes-open rest reduce resting-state-network modularity by increasing visual-sensorimotor connectivity
Authors: Koba Cemal , Notaro Giuseppe , Tamm Sandra , Nilsonne Gustav , Hasson Uri 
Published: May 2020

ABSTRACTDuring wakeful rest, individuals make small eye movements when asked to fixate. We examined how these endogenously-driven oculomotor patterns impact topography and topology of functional brain networks. We used a dataset consisting of eyes-open resting-state (RS) fMRI data with simultaneous eye-tracking (Nilsonne et al., 2016). The eye-tracking data indicated minor movements during rest, on the order of 1.0 degree on average when analyzed over 2sec epochs, which correlated modestly with RS BOLD data. However, the eye-tracking data correlated well with echo-planar imaging (EPI) time series sampled from the area of the Eye-Orbit (EO-EPI), which is a signal previously used to identify eye movements during exogenous saccades and movie viewing. We found that EO-EPI data correlated with activity in an extensive motor and sensory-motor network, but also some components of the dorsal attention network including the frontal and supplementary eye fields. Partialling out variance related to EO-EPI from RS data reduced connectivity, primarily between sensory-motor and visual areas. For three different network sparsity levels, the resulting RS connectivity networks showed higher modularity, lower mean connectivity strength, and lower mean clustering coefficient. Our results highlight new aspects of endogenous eye movement control during wakeful rest. They show that oculomotor-related contributions form an important component of RS network topology, and that those should be considered in interpreting differences in network structure between populations, or as a function of different experimental conditions.
Mud, microbes, and macrofauna: seasonal dynamics of the iron biogeochemical cycle in an intertidal mudflat
Authors: Beam Jacob P. , George Sarabeth , Record Nicholas R. , Countway Peter D. , Johnston David T. , Girguis Peter R. , Emerson David 
Published: May 2020

AbstractMicroorganisms and burrowing animals exert a pronounced impact on the cycling of redox sensitive metals in coastal sediments. Sedimentary metal cycling is likely controlled by seasonal processes including changes in temperature, animal feeding behavior due to food availability, and availability of organic matter in sediments. We hypothesized that the iron biogeochemical cycle and associated sedimentary microbial community will respond to seasonal changes in a bioturbated intertidal mudflat. In this study, we monitored the spatiotemporal dynamics of porewater and highly reactive solid phase iron with the corresponding prokaryotic and eukaryotic sedimentary microbial communities over one annual cycle from November 2015 to November 2016. Continuous and seasonally variable pools of both porewater Fe(II) and highly reactive iron (FeHR) were observed throughout the season with significant increases of Fe(II) and FeHRin response to increased sediment temperature in summer months. Maximum concentrations of Fe(II) and FeHRwere predominantly confined to the upper 5 cm of sediment throughout the season. Iron-oxidizing and -reducing microorganisms were present and stable throughout the season, and exhibited strong depth-dependent stratification likely due to availability of Fe(II) and FeHRpools, respectively. Otherwise, the community was dominated by Deltaproteobacteria, which are involved in sulfur and potentially iron cycling, as well as Gammaproteobacteria and Bacteroidetes. The microbial community was relatively stable throughout the seasonal cycle, but showed strong separation with depth, probably driven by changes in oxygen availability and organic matter. The relative abundance of diatoms revealed a noticeable seasonal signature, which we attribute to spring and fall blooms recorded in the sediments. Macro-, meio, and microfauna were detected throughout the season with some seasonal variations that may influence sedimentary iron transformations by active microbial grazing. The seasonal dynamics of the sedimentary iron cycle are controlled by numerous, interdependent processes, with macrobiota-microbiota relationships and depth stratification comprising primary components. Deciphering these processes in natural ecosystems is essential to understand how they might respond to future environmental perturbations, such as anthropogenic nutrient release to coastal systems.
The minor and major spliceosome interact to regulate alternative splicing around minor introns
Authors: Olthof Anouk M. , White Alisa K. , Lee Madisen F. , Chakroun Almahdi , Abdel Aleem Alice K. , Rousseau Justine , Magnani Cinzia , Campeau Philippe M. , Kanadia Rahul N. 
Published: May 2020

AbstractMutations in minor spliceosome components are linked to diseases such as Roifman syndrome, Lowry-Wood syndrome, and early-onset cerebellar ataxia (EOCA). Here we report that besides increased minor intron retention, Roifman syndrome and EOCA can also be characterized by elevated alternative splicing (AS) around minor introns. Consistent with the idea that the assembly/activity of the minor spliceosome informs AS in minor intron-containing genes (MIGs), inhibition of all minor spliceosome snRNAs led to upregulated AS. Notably, alternatively spliced MIG isoforms were bound to polysomes in the U11-null dorsal telencephalon, which suggested that aberrant MIG protein expression could contribute to disease pathogenesis. In agreement, expression of an aberrant isoform of the MIGDctn3byin uteroelectroporation, affected radial glial cell divisions. Finally, we show that AS around minor introns is executed by the major spliceosome and is regulated by U11-59K of the minor spliceosome, which forms exon-bridging interactions with proteins of the major spliceosome. Overall, we extend the exon-definition model to MIGs and postulate that disruptions of exon-bridging interactions might contribute to disease severity and pathogenesis.
Role of Inflammasome-independent Activation of IL-1β by thePseudomonas aeruginosaProtease LasB
Authors: Sun Josh , LaRock Doris L. , Skowronski Elaine A. , Kimmey Jacqueline M. , Olson Joshua , Jiang Zhenze , O’Donoghue Anthony J. , Nizet Victor , LaRock Christopher N. 
Published: May 2020

AbstractPulmonary damage byPseudomonas aeruginosaduring cystic fibrosis lung infection and ventilator-associated pneumonia is mediated both by pathogen virulence factors and host inflammation. Impaired immune function due to tissue damage and inflammation, coupled with pathogen multidrug resistance, complicates management of these deep-seated infections. Therefore, preservation of lung function and effective immune clearance may be enhanced by selectively controlling inflammation. Pathological inflammation duringP. aeruginosapneumonia is driven by interleukin-1β (IL-1β). This proinflammatory cytokine is canonically regulated by caspase-family inflammasome proteases, but we report that plasticity in IL-1β proteolytic activation allows for its direct maturation by the pseudomonal protease LasB. LasB promotes IL-1β activation, neutrophilic inflammation, and destruction of lung architecture characteristic of severeP. aeruginosapulmonary infection. Discovery of this IL-1β regulatory mechanism provides a distinct target for anti-inflammatory therapeutics, such that matrix metalloprotease inhibitors blocking LasB limit inflammation and pathology duringP. aeruginosapulmonary infections.HighlightsIL-1β drives pathology during pulmonary infection byPseudomonas aeruginosa.ThePseudomonasprotease LasB cleaves and activates IL-1β independent of canonical and noncanonical inflammasomesMetalloprotease inhibitors active against LasB limit inflammation and bacterial growthResearch in ContextInflammation is highly damaging during lung infections by the opportunistic pathogenPseudomonas aeruginosa. Sun et al. demonstrate that thePseudomonasLasB protease directly activates IL-1β in an inflammasome-independent manner. Inhibition of IL-1β conversion by LasB protects against neutrophilic inflammation and destruction of the lung. Adjunctive therapeutics that limit pathological inflammation induced by infection would be beneficial for the treatment of pulmonary infections when used with conventional antibiotics.
Adenine Nucleotide Translocase regulates the airway epithelium, mitochondrial metabolism and ciliary function
Authors: Kliment Corrine R. , Nguyen Jennifer M. K. , Kaltreider Mary Jane , Lu YaWen , Claypool Steven M. , Radder Josiah E. , Sciurba Frank C. , Zhang Yingze , Gregory Alyssa D. , Iglesias Pablo A. , Sidhaye Venkataramana K. , Robinson Douglas N. 
Published: May 2020

AbstractAirway hydration and ciliary function are critical to airway homeostasis and dysregulated in chronic obstructive lung disease (COPD). COPD is the 4thleading cause of death in the US and is impacted by cigarette smoking with no therapeutic options. We utilized a genetic selection approach in the amoebaDictyostelium discoideumas a comparative discovery tool in lung biology to identify genetic protectors from cigarette smoke (CS). Adenine nucleotide translocase (ANT), a mitochondrial ADP/ATP transporter, was protective against CS inDictyosteliumand human bronchial epithelial cells. ANT2 gene expression is reduced in lung tissue from COPD patients and in a mouse smoking model. ANT1 and ANT2 overexpression resulted in enhanced oxidative respiration and ATP flux. In addition to ANT’s presence in the mitochondria, ANT1 and ANT2 reside at the plasma membrane in airway epithelial cells and this localization plays a role in how ANTs regulate airway homeostasis. ANT2 overexpression stimulates airway surface liquid hydration by ATP and maintains ciliary beating after CS exposure, which are key functions of the airway. Our study highlights the potential of ANT modulation in protecting from dysfunctional mitochondrial metabolism, airway hydration, and ciliary motility in COPD.
Alterations in resting-state network dynamics along the Alzheimer’s disease continuum: a combined MEG-PET/MR approach
Authors: Puttaert D. , Coquelet N. , Wens V. , Peigneux P. , Fery P. , Rovai A. , Trotta N. , Bier J-C. , Goldman S. , De Tiège X. 
Published: May 2020

AbstractHuman brain activity is intrinsically organized into resting-state networks (RSNs) that transiently activate or deactivate at the sub-second timescale. Few neuroimaging studies have addressed how Alzheimer’s disease (AD) affects these fast temporal brain dynamics, and how they relate to the cognitive, structural and metabolic abnormalities characterizing AD.We aimed at closing this gap by investigating both brain structure and function using magnetoencephalography (MEG) and hybrid positron emission tomography-magnetic resonance (PET/MR) in 10 healthy elders, 10 patients with Subjective Cognitive Decline (SCD), 10 patients with amnestic Mild Cognitive Impairment (aMCI) and 10 patients with typical Alzheimer’s disease with dementia (AD). The fast activation/deactivation state dynamics of RSNs were assessed using hidden Markov modeling (HMM) of power envelope fluctuations at rest measured with MEG. HMM patterns were related to participants’ cognitive test scores, whole hippocampal grey matter volume and regional brain glucose metabolism.The posterior default-mode network (DMN) was less often activated and for shorter durations in AD patients than matched healthy elders. No significant difference was found in patients with SCD or aMCI. The time spent by participants in the activated posterior DMN state did not correlate significantly with cognitive scores. However, it correlated positively with the whole hippocampal volume and regional glucose consumption in the right temporo-parietal junctions and dorsolateral prefrontal cortex, and negatively with glucose consumption in the cerebellum.In AD patients, alterations of posterior DMN power activation dynamics at rest correlate with structural and neurometabolic abnormalities. These findings represent an additional electrophysiological correlate of AD-related synaptic and neural dysfunction.
Quantitative Mapping of Human Hair Graying and Reversal in Relation to Life Stress
Authors: Rosenberg Ayelet , Rausser Shannon , Ren Junting , Mosharov Eugene , Sturm Gabriel , Todd Ogden R , Patel Purvi , Soni Rajesh Kumar , Lacefield Clay , Tobin Desmond J , Paus Ralf , Picard Martin 
Published: May 2020

AbstractHair graying is a universal hallmark of aging believed to be linked to psychological stress. Here we develop a novel approach to quantitatively profile natural graying events along individual human hair shafts, resulting in a quantifiable physical timescale of hair pigmentation patterns (HPPs). Using this approach, we quantify rare events of white/gray hairs that naturally regain pigmentation within days to weeks, thereby quantitatively defining the reversibility of graying in healthy, unmedicated individuals. Proteomic analysis shows that graying is marked by the upregulation of proteins related to energy metabolism, mitochondria, and antioxidant defenses. Combining hair pigmentation profiling and proteomics at the single hair level, we also report hair graying and its reversal occurring in parallel with behavioral and psychological stressors. A computational simulation suggests a threshold-based mechanism for the temporary reversibility of graying. Quantitatively mapping HPPs in humans provides an opportunity to longitudinally examine the influence of life exposures on biological aging.
A rapid, sensitive, scalable method for Precision Run-On sequencing (PRO-seq)
Authors: Judd Julius , Wojenski Luke A. , Wainman Lauren M. , Tippens Nathaniel D. , Rice Edward J. , Dziubek Alexis , Villafano Geno J. , Wissink Erin M. , Versluis Philip , Bagepalli Lina , Shah Sagar R. , Mahat Dig B. , Tome Jacob M. , Danko Charles G. , Lis John T. , Core Leighton J. 
Published: May 2020

AbstractTracking active transcription with the nuclear run-on (NRO) assays has been instrumental in uncovering mechanisms of gene regulation. The coupling of NROs with high-throughput sequencing has facilitated the discovery of previously unannotated or undetectable RNA classes genome-wide. Precision run-on sequencing (PRO-seq) is a run-on variant that maps polymerase active sites with nucleotide or near-nucleotide resolution. One main drawback to this and many other nascent RNA detection methods is the somewhat intimidating multi-day workflow associated with creating the libraries suitable for high-throughput sequencing. Here, we present an improved PRO-seq protocol where many of the enzymatic steps are carried out while the biotinylated NRO RNA remains bound to streptavidin-coated magnetic beads. These adaptations reduce time, sample loss and RNA degradation, and we demonstrate that the resulting libraries are of the same quality as libraries generated using the original published protocol. The assay is also more sensitive which permits reproducible, high-quality libraries from 104–105cells instead of 106–107. Altogether, the improved protocol is more tractable allows for nascent RNA profiling from small samples, such as rare samples or FACS sorted cell populations.
Apico-basal cell compression regulates Lamin A/C levels in Epithelial tissues
Authors: Iyer K Venkatesan , Dye Natalie A. , Eaton Suzanne , Jülicher Frank 
Published: May 2020

ABSTRACTNuclear lamina bridges mechanical forces from the cytoskeleton to the nucleus, to initiate nuclear mechanotransduction. The concentration of nuclear Lamin proteins, particularly Lamin A/C is crucial for the mechanical properties of the nucleus and nuclear mechanotransduction. Recent studies in mesenchymal tissues show that the concentration of Lamin A/C scales with stiffness and concentration of the underlying extracellular matrix (ECM). But in epithelial tissues, that lack a strong cell-ECM interaction, it is still unclear how Lamin A/C is regulated. Here, we show that concentration of Lamin A/C in epithelial tissues scales with apico-basal compression of cells and is independent of ECM concentration. But, ectopically altering the concentration of Lamin A/C does not influence cell shapes in epithelial tissues. Using genetic perturbations inDrosophilaepithelial tissues, we reveal that apico-basal cell compression regulates the concentration of Lamin A/C by deforming the nucleus. We observe a similar mechanism of Lamin A/C regulation in mammalian Madin Darby Canine Kidney (MDCK) cells suggesting that this mechanism is evolutionarily conserved. Taken together, our results reveal a unidirectional mechanical coupling between cell mechanics and nuclear mechanics via the regulation of Lamin A/C. We anticipate that mechanism of Lamin A/C regulation that we revealed, could form the basis for understanding nuclear mechanotransduction in epithelial tissues.