bluuebunny/crossref_metadata_2025_split huggingface dataset:
A temporal map of gene expression pattern during zebrafish liver regeneration
Authors: Jagtap Urmila , Sivadas Ambily , Basu Sandeep , Verma Ankit , Sivasubbu Sridhar , Scaria Vinod , Sachidanandan Chetana 
Published: June 2019

AbstractBackground & AimsZebrafish is increasingly being used to study liver injury and regeneration. However, very little is known about molecular players that respond to injury and participate in liver regeneration. Here we aim to generate a temporal map of gene expression changes at injury and during regeneration of the adult zebrafish liver.MethodsWe use a metronidazole-nitroreductase (MTZ-nfsb) based system to selectively ablate hepatocytes in adult zebrafish to create a model for liver injury and regeneration. Through RNA sequencing of liver samples at multiple time points we generate a comprehensive temporal map of gene expression changes during injury and regeneration.ResultsGene expression reveals that soon after injury the immediate early transcription factor MYC induces a battery of genes that respond to the metronidazole-induced ROS by activating oxido-reductase pathways and apoptosis machinery. Upon injury, liver cells down regulate genes encoding complement proteins, bile acid and lipid biosynthesis pathway in a concerted manner. Midway through regeneration, we discover a spike of cholesterol biosynthesis and protein folding machinery genes suggesting an important role for these pathways in liver regeneration.ConclusionsThe temporal transcriptomic map of liver regeneration would serve as a framework for further studies in understanding, and for screening for compounds that augment liver regeneration.General significanceUsing a hepatocyte specific ablation of zebrafish liver, we create a model of adult liver regeneration. This model was used to generate a comprehensive transcriptomic map of gene expression trends during liver regeneration. This temporal map lays the groundwork to study important events in liver regeneration.HighlightsZebrafish is a valuable model for developing therapeutic strategies to augment liver regenerationLiver regeneration in zebrafish is not well studied and pathways poorly understoodWe develop a hepatocyte ablation model of liver injury and regeneration in adult zebrafishWe generate a comprehensive transcriptomic map of various stages of liver injury and regenerationWe discover a novel regulation of cholesterol biosynthesis pathways during liver regenerationGraphical abstract
Biomechanical Analysis of Angular Motion in Association with Bilateral Semicircular Canal Function
Authors: Shen Shuang , Zhao Fei , Chen Zhaoyue , Zheng Qingyin , Yu Shen , Cao Tongtao , Ma Peng 
Published: June 2019

AbstractThe aim of this study was to develop a finite element (FE) model of bilateral human semicircular canals (SCCs) in order to simulate and analyze the complex fluid-structural interaction between the endolymph and cupulae by calculating the degree of cupular expansion and the cupular deflection. The results showed that cupular deflection responses were consistent with Ewald’s II law, whereas each pair of bilateral cupulae simultaneously expanded or compressed to the same degree. In addition, both the degree of cupular expansion and cupular deflection can be expressed as the solution of forced oscillation during head sinusoidal rotation, and the amplitude of cupular expansion was approximately two times greater than that of cupular deflection. Regarding the amplitude-frequency and phase-frequency characteristics, the amplitude ratios among the horizontal semicircular canal (HC) cupular expansion, the anterior semicircular canal (AC) cupular expansion, and the posterior semicircular canal (PC) cupular expansion was constant at 1:0.82:1.62, and the phase differences among them were constant at 0 or 180 degrees at the frequencies of 0.5 to 6 Hz. However, both the amplitude ratio and the phase differencies of the cupular deflection incresed nonlinearly with the increase of frequency and tended to be constant at the frequency band between 2 and 6 Hz. The results indicate that the responses of cupular expansion might only be related to the mass and rigidity of three cupulae and the endolymph, but the responses of cupular deflection are related to the mass, rigidity, or damping of them, and these physical properties would be affected by vestibular dysfunction. Therefore, both the degree of cupular expansion and cupular deflection should be considered important mechanical variables for induced neural signals. Such a numerical model can be further built to provide a useful theoretical approach for exploring the biomechanical nature underlying vestibular dysfunction.Statement of significanceBy taking the advantage of the torsional pendulum model and the FE model, a healthy human vestibular SCCs was developed to investigate the angular motion in association with SCC function. As a result, the responses of cupular expansion and deflection during head horizontal sinusoidal rotation were analyzed for the first time, showing quantitative correlation to the eye movement due to the vestibular ocular reflex (VOR) pathway. These responses play important roles in the cupular mechano-electrical transduction process. The significant outcome derived from this study provides a useful theoretical approach for further exploring the biomechanical nature underlying vestibular dysfunction.
Rho-kinase mediates the anorexigenic action of melanocortin by suppressing AMPK
Authors: Kim Sang Soo , Hwang Won Min , Yang Won-Mo , Lee Hyon , Park Kyong Soo , Dagon Yossi , Kim Young-Bum 
Published: June 2019

ABSTRACTObjectiveMelanocortin action is essential for the maintenance of energy homeostasis. However, knowledge of the signaling mechanism(s) that mediates the effect of melanocortin remains incomplete.MethodsROCK1 is a key regulator of energy balance in the hypothalamus. To explore the role of ROCK1 in the anorexigenic action of melanocortin, we deleted ROCK1 in MC4R neurons in mice. Next, we studied the metabolic effects of MC4R neuron-specific ROCK1-deficiency and following treatment with α-melanocyte-stimulating hormone (MSH).ResultsHere we show that α-MSH increases Rho-kinase 1 (ROCK1) activity in the hypothalamus. Deficiency of ROCK1 in MC4R-expressing neurons results in increased body weight in mice fed normal chow diet. This is likely due to increased food intake and decreased energy expenditure. Importantly, we find that ROCK1 activation in MC4R expressing neurons is required for melanocortin action, as evidenced by the fact that α– MSH’s ability to suppress food intake is impaired in MC4R neuron-specific ROCK1-deficient mice. To elucidate the mechanism by which ROCK1 mediates melanocortin action, we performedin vitrostudies in hypothalamic cells expressing MC4R. We demonstrate that α–MSH promotes the physical interaction of ROCK1 and Gα12, and this results in suppression of AMPK activity.ConclusionsOur study identifies ROCK1 as a novel mediator of melanocortin’s anorexigenic action and uncover a new MC4R→Gα12→ROCK1→AMPK signaling pathway. Targeting Rho-kinase in MC4R-expressing neurons could provide a new strategy to combat obesity and its related complications.
Temporal distribution of deleterious variations influences the estimation of FST
Authors: Subramanian Sankar 
Published: June 2019

AbstractEstimating the extent of genetic differentiation between populations is an important measure in population genetics, ecology and evolutionary biology. Fixation index or FST is an important measure, which is routinely used to quantify this. Previous studies have shown that FST estimated for selectively constrained regions was significantly lower than that estimated for neutral regions. By deriving the theoretical relationship between FST at neutral and constrained sites we show that an excess in the fraction of deleterious variations segregating within populations compared to that segregates between populations is the cause for the reduction in FST estimated at constrained sites. Using whole genome data, our results revealed that the magnitude of reduction in FST estimates obtained for selectively constrained regions was much higher for distantly related populations compared to those estimated for closely related pairs. For example, the reduction was 49% for comparison between European-African populations, 31% for European-Asian comparison, 16% for the Northern-Southern European pair and only 4% for the comparison involving two Southern European (Italian and Spanish) populations. Since deleterious variants are purged over time due to purifying selection, their contribution to the among population diversity at constrained sites decreases with the increase in the divergence between populations. However, within population diversity remain the same for all pairs compared above and therefore FST estimated at constrained sites for distantly related populations are much smaller than those estimated for closely related populations. Our results suggest that the level of population divergence should be considered when comparing constrained site FST estimates obtained for different pairs of populations.
Genome-wide sequence information reveals recurrent hybridization among diploid wheat wild relatives
Authors: Bernhardt Nadine , Brassac Jonathan , Dong Xue , Willing Eva-Maria , Poskar C. Hart , Kilian Benjamin , Blattner Frank R. 
Published: June 2019

AbstractMany conflicting hypotheses regarding the relationships among crops and wild species closely related to wheat (the generaAegilops,Amblyopyrum, andTriticum) have been postulated. The contribution of hybridization to the evolution of these taxa is intensely discussed. To determine possible causes for this, and provide a phylogeny of the diploid taxa based on genome-wide sequence information, independent data was obtained from genotyping-by-sequencing and a target-enrichment experiment that returned 244 low-copy nuclear loci. The data were analyzed with Bayesian, likelihood and coalescent-based methods.Dstatistics were used to test if incomplete lineage sorting alone or together with hybridization is the source for incongruent gene trees. Here we present the phylogeny of all diploid species of the wheat wild relatives. We hypothesize that most of the wheat-group species were shaped by a primordial homoploid hybrid speciation event involving the ancestralTriticumandAm. muticumlineages to form all other species butAe. speltoides. This hybridization event was followed by multiple introgressions affecting all taxa butTriticum. Mostly progenitors of the extant species were involved in these processes, while recent interspecific gene flow seems insignificant. The composite nature of many genomes of wheat group taxa results in complicated patterns of diploid contributions when these lineages are involved in polyploid formation, which is, for example, the case in the tetra-and hexaploid wheats. Our analysis provides phylogenetic relationships and a testable hypothesis for the genome compositions in the basic evolutionary units within the wheat group of Triticeae.
Predicting dysfunctional age-related task activations from resting-state network alterations
Authors: Mill Ravi D. , Gordon Brian A. , Balota David A. , Zacks Jeffrey M. , Cole Michael W. 
Published: June 2019

AbstractAlzheimer’s disease (AD) is linked to changes in fMRI task activations and fMRI resting-state functional connectivity (restFC), which can emerge early in the timecourse of illness. Study of these fMRI correlates of unhealthy aging has been conducted in largely separate subfields. Taking inspiration from neural network simulations, we propose a unifying mechanism wherein restFC network alterations associated with Alzheimer’s disease disrupt the ability for activations to flow between brain regions, leading to aberrant task activations. We apply this activity flow modeling framework in a large sample of clinically unimpaired older adults, which was segregated into healthy (low-risk) and at-risk subgroups based on established imaging (positron emission tomography amyloid) and genetic (apolipoprotein) risk factors for AD. We identified healthy task activations in individuals at low risk for AD, and then by estimating activity flow using at-risk AD restFC data we were able to predict the altered at-risk AD task activations. Thus, modeling the flow of healthy activations over at-risk AD connectivity effectively transformed the healthy aged activations into unhealthy aged activations. These results provide evidence that activity flow over altered intrinsic functional connections may act as a mechanism underlying Alzheimer’s-related dysfunction, even in very early stages of the illness. Beyond these mechanistic insights linking restFC with cognitive task activations, this approach has potential clinical utility as it enables prediction of task activations and associated cognitive dysfunction in individuals without requiring them to perform in-scanner cognitive tasks.Significance StatementDeveloping analytic approaches that can reliably predict features of Alzheimer’s disease is a major goal for cognitive and clinical neuroscience, with particular emphasis on identifying such diagnostic features early in the timeline of disease. We demonstrate the utility of an activity flow modeling approach, which predicts fMRI cognitive task activations in subjects identified as at-risk for Alzheimer’s disease. The approach makes activation predictions by transforming a healthy aged activation template via the at-risk subjects’ individual pattern of fMRI resting-state functional connectivity (restFC). The observed prediction accuracy supports activity flow as a mechanism linking age-related alterations in restFC and task activations, thereby providing a theoretical basis for incorporating restFC into imaging biomarker and personalized medicine interventions.
Emergence of alternative stable states in microbial communities in a fluctuating environment
Authors: Andersen Woltz Vilhelm L. , Abreu Clare I. , Friedman Jonathan , Gore Jeff 
Published: June 2019

AbstractThe effect of environmental fluctuations is a major question in ecology. While it is widely accepted that fluctuations and other types of disturbances can increase biodiversity, we have only a limited understanding of the circumstances in which other types of outcomes can occur in a fluctuating environment. Here we explore this question with laboratory microcosms, using cocultures of two bacterial species, P. putida and P. veronii. At low dilution rates we observe competitive exclusion of P. veronii, whereas at high dilution rates we observe competitive exclusion of P. putida. When the dilution rate alternates between high and low, we do not observe coexistence between the species, but rather alternative stable states, in which only one species survives and initial species’ fractions determine the identity of the surviving species. The Lotka-Volterra model with a fluctuating mortality rate predicts that this outcome is independent of the timing of the fluctuations, and that the time-averaged mortality would also lead to alternative stable states, a prediction that we confirm experimentally. Other pairs of species can coexist in a fluctuating environment, and again consistent with the model we observe coexistence in the time-averaged dilution rate. We find a similar time-averaging result holds in a three-species community, highlighting that simple linear models can in some cases provide powerful insight into how communities will respond to environmental fluctuations.
Precise Coordination of 3-dimensional Rotational Kinematics by Ventral Tegmental Area GABAergic Neurons
Authors: Hughes Ryan N. , Watson Glenn D.R. , Petter Elijah , Kim Namsoo , Bakhurin Konstantin I. , Yin Henry H. 
Published: June 2019

SummaryThe Ventral Tegmental Area (VTA) is a midbrain region implicated in a variety of motivated behaviors. However, the function of VTA GABAergic (Vgat+) neurons remains poorly understood. Here, using 3D motion capture, in vivo electrophysiology and calcium imaging, and optogenetics, we demonstrate a novel function of VTAVgat+ neurons. We found three distinct populations of neurons, each representing head angle about a principal axis of rotation: pitch, roll, and yaw. For each axis, opponent cell groups were found that increase firing when the head moves in one direction, and decrease firing in the opposite direction. Selective excitation and inhibition of VTAVgat+ neurons generate opposite rotational movements. The relationship between these neurons and head angle is degraded only at the time of reward consumption, at which point all head-angle related neuronal subpopulations show indistinguishable reward-related responses. Thus, VTAVgat+ neurons serve a critical role in the control of rotational kinematics while pursuing a moving target. This general-purpose steering function can guide animals toward desired spatial targets in any motivated behavior.
Persister Cells Resuscitate via Ribosome Modification by 23S rRNA Pseudouridine Synthase RluD
Authors: Song Sooyeon , Wood Thomas K. 
Published: June 2019

ABSTRACTUpon a wide range of stress conditions (e.g., nutrient, antibiotic, oxidative), a subpopulation of bacterial cells known as persisters survive by halting metabolism. These cells resuscitate rapidly to reconstitute infections once the stress is removed and nutrients are provided. However, how these dormant cells resuscitate is not understood well but involves reactivating ribosomes. By screening 10,000 compounds directly for stimulatingEscherichia colipersister cell resuscitation, we identified that 2-{[2-(4-bromophenyl)-2-oxoethyl]thio}-3-ethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (BPOET) stimulates resuscitation. Critically, by screening 4,267E. coliproteins, we determined that BPOET activates hibernating ribosomes via 23S rRNA pseudouridine synthase RluD, which increases ribosome activity. Corroborating the increased waking with RluD, production of RluD increased the number of active ribosomes in persister cells. Also, inactivating the small RNA RybB which repressesrluDled to faster persister resuscitation. Hence, persister cells resuscitate via activation of RluD.
Conjugative delivery of CRISPR-Cas9 for the selective depletion of antibiotic-resistant enterococci
Authors: Rodrigues Marinelle , McBride Sara W. , Hullahalli Karthik , Palmer Kelli L. , Duerkop Breck A. 
Published: June 2019

AbstractThe innovation of new therapies to combat multidrug-resistant (MDR) bacteria is being outpaced by the continued rise of MDR bacterial infections. Of particular concern are hospital-acquired infections (HAIs) recalcitrant to antibiotic therapies. The Gram-positive intestinal pathobiontEnterococcus faecalisis associated with HAIs and some strains are MDR. Therefore, novel strategies to controlE. faecalispopulations are needed. We previously characterized anE. faecalisType II CRISPR-Cas system and demonstrated its utility in the sequence-specific removal of antibiotic resistance determinants. Here we present work describing the adaption of this CRISPR-Cas system into a constitutively expressed module encoded on a pheromone-responsive conjugative plasmid that efficiently transfers toE. faecalisfor the selective removal of antibiotic resistance genes. Usingin vitrocompetition assays, we show that these CRISPR-Cas-encoding delivery plasmids, or CRISPR-Cas antimicrobials, can reduce the occurrence of antibiotic resistance in enterococcal populations in a sequence-specific manner. Furthermore, we demonstrate that deployment of CRISPR-Cas antimicrobials in the murine intestine reduces the occurrence of antibiotic-resistantE. faecalisby several orders of magnitude. Finally, we show thatE. faecalisdonor strains harboring CRISPR-Cas antimicrobials are immune to uptake of antibiotic resistance determinantsin vivo. Our results demonstrate that conjugative delivery of CRISPR-Cas antimicrobials may be adaptable for future deployment from probiotic bacteria for exact targeting of defined MDR bacteria or for precision engineering of polymicrobial communities in the mammalian intestine.ImportanceCRISPR-Cas nucleic acid targeting systems hold promise for the amelioration of multidrug-resistant enterococci, yet the utility of such tools in the context of the intestinal environment where enterococci reside is understudied. We describe the development of a CRISPR-Cas antimicrobial, deployed on a conjugative plasmid, for the targeted removal of antibiotic resistance genes from intestinalEnterococcus faecalis. We demonstrate that CRISPR-Cas targeting reduces antibiotic resistance ofE. faecalisby several orders of magnitude in the intestine. Although barriers exist that influence the penetrance of the conjugative CRISPR-Cas antimicrobial among target recipientE. faecaliscells, the removal of antibiotic resistance genes inE. faecalisupon uptake of the CRISPR-Cas antimicrobial is absolute. In addition, cells that obtain the CRISPR-Cas antimicrobial are immunized against the acquisition of new antibiotic resistance genes. This study suggests a potential path toward plasmid based CRISPR-Cas therapies in the intestine.
Highly Multiplexed Spatial Mapping of Microbial Communities
Authors: Shi Hao , Zipfel Warren , Brito Ilana , De Vlaminck Iwijn 
Published: June 2019

ABSTRACTMapping the complex biogeography of microbial communities in situ with high taxonomic and spatial resolution poses a major challenge because of the high density and rich diversity of species in environmental microbiomes and the limitations of optical imaging technology. Here, we introduce High Phylogenetic Resolution microbiome mapping by Fluorescence In-Situ Hybridization (HiPR-FISH), a versatile and cost-effective technology that uses binary encoding and spectral imaging and machine learning based decoding to create micron-scale maps of the locations and identities of hundreds of microbial species in complex communities. We demonstrate the ability of 10-bit HiPR-FISH to distinguish 1023 E. coli strains, each fluorescently labeled with a unique binary barcode. HiPR-FISH, in conjunction with custom algorithms for automated probe design and segmentation of single-cells in the native context of tissues, reveals the intricate spatial architectures formed by bacteria in the human oral plaque microbiome and disruption of spatial networks in the mouse gut microbiome in response to antibiotic treatment. HiPR-FISH provides a framework for analyzing the spatial organization of microbial communities in tissues and the environment at single cell resolution.