bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Metabolic Network Disruption in Engineered Microbial Hosts due to Enzyme Promiscuity
Authors: Porokhin Vladimir , Amin Sara A. , Nicks Trevor B. , Gopinarayanan Venkatesh Endalur , Nair Nikhil U. , Hassoun Soha 
Published: September 2020

AbstractBackgroundIncreasing understanding of metabolic and regulatory networks underlying microbial physiology has enabled creation of progressively more complex synthetic biological systems for biochemical, biomedical, agricultural, and environmental applications. However, despite best efforts, confounding phenotypes still emerge from unforeseen interplay between biological parts, and the design of robust and modular biological systems remains elusive. Such interactions are difficult to predict when designing synthetic systems and may manifest during experimental testing as inefficiencies that need to be overcome. Despite advances in tools and methodologies for strain engineering, there remains a lack of tools that can systematically identify incompatibilities between the native metabolism of the host and its engineered modifications.ResultsTransforming organisms such asEscherichia coliinto microbial factories is achieved via a number of engineering strategies, used individually or in combination, with the goal of maximizing the production of chosen target compounds. One technique relies on suppressing or overexpressing selected genes; another involves on introducing heterologous enzymes into a microbial host. These modifications steer mass flux towards the set of desired metabolites but may create unexpected interactions. In this work, we develop a computational method, termedMetabolicDisruption Workflow(MDFlow), for discovering interactions and network disruption arising from enzyme promiscuity – the ability of enzymes to act on a wide range of molecules that are structurally similar to their native substrates. We applyMDFlowto two experimentally verified cases where strains with essential genes knocked out are rescued by interactions resulting from overexpression of one or more other genes. We then applyMDFlowto predict and evaluate a number of putative promiscuous reactions that can interfere with two heterologous pathways designed for 3-hydroxypropic acid (3-HP) production.ConclusionsUsingMDFlow, we can identify putative enzyme promiscuity and the subsequent formation of unintended and undesirable byproducts that are not only disruptive to the host metabolism but also to the intended end-objective of high biosynthetic productivity and yield. In addition, we show how enzyme promiscuity can potentially be responsible for the adaptability of cells to the disruption of essential pathways in terms of biomass growth.
Myosin-gelsolin cooperativity in actin filament severing and actomyosin motor activity
Authors: Vemula Venukumar , Huber Tamas , Usaj Marko , Bugyi Beáta , Mansson Alf 
Published: September 2020

AbstractActin is a major intracellular protein with key functions in cellular motility, signalling and structural rearrangements. Its dynamic behavior with actin filaments (F-actin) polymerising and depolymerising in response to intracellular changes, is controlled by actin-binding proteins (ABPs). Gelsolin is one of the most potent filament severing ABPs. However, myosin motors that interact with actin in the presence of ATP also produce actin filament fragmentation through motor induced shearing forces. To test the idea that gelsolin and myosin cooperate in these processes we used the in vitro motility assay, where actin filaments are propelled by surface-adsorbed heavy meromyosin (HMM) motor fragments. This allows studies of both motility and filament dynamics using isolated proteins. Gelsolin (5 nM) at very low [Ca2+] (free [Ca2+] ∼6.8 nM) appreciably enhanced actin filament severing caused by HMM-induced forces at 1 mM [MgATP], an effect that was increased at increased HMM motor density. This finding is consistent with cooperativity between actin filament severing by myosin-induced forces and by gelsolin. As further support of myosin-gelsolin cooperativity we observed reduced sliding velocity of the HMM propelled filaments in the presence of gelsolin. Overall, the results corroborate ideas for cooperative effects between gelsolin-induced alterations in the actin filaments and changes due to myosin motor activity, leading among other effects to enhanced F-actin severing of possible physiological relevance.
Calorie Restriction Prevents Age-Related Changes in the Intestinal Microbiota
Authors: Kurup Kavitha , Matyi Stephanie , Giles Cory B. , Wren Jonathan D. , Jones Kenneth , Ericsson Aaron , Raftery Daniel , Wang Lu , Promislow Daniel , Richardson Arlan , Unnikrishnan Archana 
Published: September 2020

AbstractThe effect of calorie restriction (CR) on the microbiome, fecal metabolome, and colon transcriptome of adult and old male mice was compared. Life-long CR increased microbial diversity and theBacteriodetes/Fermicutesratio and prevented the age-related changes in the microbiota, shifting it to a younger microbial and fecal metabolite profile in both C57BL/6JN and B6D2F1 mice. Old mice fed CR were enriched in theRikenellaceae, S24-7andBacteroidesfamilies. The changes in the microbiome that occur with age and CR were initiated in the cecum and further modified in the colon. Short-term CR in adult mice had a minor effect on the microbiome but a major effect on the transcriptome of the colon mucosa. These data suggest that the primary impact of CR is on the physiological status of the gastrointestinal system, maintaining it in a more youthful state, which in turn results in a more diverse and youthful microbiome.
Kcns3Deficiency Disrupts Parvalbumin Neuron Physiology in Mouse Prefrontal Cortex: Implications for the pathophysiology of schizophrenia
Authors: Miyamae Takeaki , Hashimoto Takanori , Abraham Monica , Kawabata Rika , Koshikizawa Sho , Bian Yufan , Kikuchi Mitsuru , Ermentrout G Bard , Lewis David A , Gonzalez-Burgos Guillermo 
Published: September 2020

AbstractThe unique fast spiking (FS) phenotype of cortical parvalbumin-positive (PV) neurons depends on multiple subtypes of voltage-gated potassium channels (Kv). PV neurons selectively expressKcns3, the gene encoding Kv9.3 subunits, suggesting thatKcns3expression is critical for the FS phenotype.KCNS3expression is lower in PV neurons in schizophrenia, but the effects of this alteration are unclear, because Kv9.3 subunit function is poorly understood. We therefore assessed the role of Kv9.3 subunits in PV neuron function by combining gene expression analyses, computational modeling, and electrophysiology in acute slices from the cortex ofKcns3-deficient miceKcns3mRNA levels were ~50% lower in cortical PV neurons fromKcns3-deficient relative to wildtype mice. While silentper se, Kv9.3 subunits are believed to amplify the Kv2.1 current in Kv2.1-Kv9.3 channel complexes. Hence, to assess the consequences of reducing Kv9.3 levels, we simulated the effects of decreasing the Kv2.1-mediated current in a computational model. The FS cell model with reduced Kv2.1 produced spike trains with irregular inter-spike intervals, or stuttering, and greater Na+channel inactivation, possibly due to a smaller afterhyperpolarization. As in the computational model, PV basket cells (PVBCs) fromKcns3-deficient mice displayed spike trains with strong stuttering, which depressed PVBC firing, and smaller afterhyperpolarization. Moreover,Kcns3deficiency impaired the recruitment of PVBCs by stimuli mimicking synaptic input during cortical UP states, which elicited bursts of spikes at gamma frequency. Our data suggest that Kv9.3 subunits are critical for PVBC physiology, and thatKCNS3deficiency in schizophrenia may impair the substrate of gamma oscillations.Significance statementIn the neocortex,Kcns3, the gene encoding voltage-dependent potassium (Kv) channel subunits Kv9.3, is selectively expressed by parvalbumin-positive (PV) neurons. Moreover,KCNS3expression is decreased in PV neurons in schizophrenia. Kv 9.3 subunits are believed to amplify the current mediated by Kv2.1 subunits, however Kv9.3 function has not been investigated in PV cells.Here, simulations in a computational model and electrophysiological experiments withKcns3-deficient mice revealed thatKcns3deficiency disrupts repetitive firing in cortical PV neurons, possibly enhancing Na+channel inactivation, and particularly with stimuli eliciting firing at gamma frequency band (30-80Hz). Our results suggest that Kv9.3 subunits are essential for PV neuron electrophysiology and that KCNS3 deficiency likely contributes to PV neuron dysfunction and gamma oscillation impairments in schizophrenia.
Impaired labyrinth formation prevents the establishment of the maternal-fetal interface in conditional Hand1-deficient mice
Authors: Courtney Jennifer A. , Cnota James , Jones Helen 
Published: September 2020

AbstractIntroductionCongenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. Placental development and function is vital to ensure normal fetal development. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas, and placental expression changes in genes important for heart development. Hand1 has roles in both heart and placental development and is implicated in CHDs including double right outlet, hypoplastic left heart syndrome, and septal defects; however, Hand1 involvement in placental vascularization and development is under-investigated. We utilized the Hand1A126fs/+murine model to investigate Hand1 in placentation and vascularization.MethodsHand1A126fs/+female mice were time-mated with Nkx2.5cre(placenta- and heart-specific) males to produce either Nkx2.5cre;Hand1+/+or Nkx2.5cre;Hand1A126fs/+fetuses. Feto-placental units were harvested at timepoints from E8.5 to E14.5 for histological analysis; vascular assessment by immunohistochemistry for Hand1, CD-31, and CK-7; and angiogenesis by qPCR.ResultsEmbryonic lethality occurs in Nkx2.5cre/Hand1A126fs/+by E14.5 due to a failure of placental labyrinth formation and vascularization. Chorionic trophoblasts did not form, although trophoblast giant cell subtypes were present. Fetal vessels failed to develop properly and were significantly lower in the labyrinth by day E12.5. Placental growth factor levels were significantly increased, and Angiopoietin2 expression trended higher in Nkx2.5cre/Hand1A126fs/+placental labyrinths compared to control littermates.ConclusionWe demonstrate that Hand1 expression in placental chorion and trophoblast is necessary for proper patterning of the labyrinth and vascularization within the labyrinth. Multiple angiogenic factors known to be expressed in trophoblast were disrupted in Nkx2.5cre/Hand1A126fs/+placental labyrinths compared to control littermates. Alterations in Hand1 expression represent a potential mechanism for abnormal placentation and early miscarriage in cases of CHD.
Machine learning enables new insights into clinical significance of and genetic contributions to liver fat accumulation
Authors: Haas Mary E. , Pirruccello James P. , Friedman Samuel N. , Emdin Connor A. , Ajmera Veeral H. , Simon Tracey G. , Homburger Julian R. , Guo Xiuqing , Budoff Matthew , Corey Kathleen E. , Zhou Alicia Y. , Philippakis Anthony , Ellinor Patrick T. , Loomba Rohit , Batra Puneet , Khera Amit V. 
Published: September 2020

AbstractExcess accumulation of liver fat – termed hepatic steatosis when fat accounts for > 5.5% of liver content – is a leading risk factor for end-stage liver disease and is strongly associated with important cardiometabolic disorders. Using a truth dataset of 4,511 UK Biobank participants with liver fat previously quantified via abdominal MRI imaging, we developed a machine learning algorithm to quantify liver fat with correlation coefficients of 0.97 and 0.99 in hold-out testing datasets and applied this algorithm to raw imaging data from an additional 32,192 participants. Among all 36,703 individuals with abdominal MRI imaging, median liver fat was 2.2%, with 6,250 (17%) meeting criteria for hepatic steatosis. Although individuals afflicted with hepatic steatosis were more likely to have been diagnosed with conditions such as obesity or diabetes, a prediction model based on clinical data alone without imaging could not reliably estimate liver fat content. To identify genetic drivers of variation in liver fat, we first conducted a common variant association study of 9.8 million variants, confirming three known associations for variants in theTM6SF2, APOE, andPNPLA3genes and identifying five new variants associated with increased hepatic fat in or near theMARC1, ADH1B, TRIB1, GPAMandMAST3genes. A polygenic score that integrated information from each of these eight variants was strongly associated with future clinical diagnosis of liver diseases. Next, we performed a rare variant association study in a subset of 11,021 participants with gene sequencing data available, identifying an association between inactivating variants in theAPOBgene and substantially lower LDL cholesterol, but more than 10-fold increased risk of steatosis. Taken together, these results provide proof of principle for the use of machine learning algorithms on raw imaging data to enable epidemiologic studies and genetic discovery.
Common abnormality of gray matter integrity in substance use disorder and obsessive-compulsive disorder: A comparative voxel-based meta-analysis
Authors: Klugah-Brown Benjamin , Jiang Chenyang , Agoalikum Elijah , Zhou Xinqi , Zou Liye , Yu Qian , Becker Benjamin , Biswal Bharat 
Published: September 2020

AbstractAimTo determine robust transdiagnostic brain structural markers for compulsivity by capitalizing on the increasing number of case-control studies examining gray matter alterations in substance use disorders (SUD) and obsessive-compulsive disorder (OCD).DesignPre-registered voxel-based meta-analysis of grey matter volume (GMV) changes through seed-based d Mapping (SDM), follow-up functional, and network-level characterization of the identified transdiagnostic regions by means of co-activation and Granger Causality (GCA) analysis.ParticipantsLiterature search resulted in 31 original VBM studies comparing SUD (n = 1191, mean-age = 40.03, SD = 10.87) and 30 original studies comparing OCD (n = 1293, mean-age = 29.18, SD = 10.34) patients with healthy controls (SUD: n = 1585, mean-age = 42.63, SD = 14.27, OCD: n = 1374, mean-age = 28.97, SD = 9.96).MeasurementsVoxel-based meta-analysis within the individual disorders as well as conjunction analysis were employed to reveal common GMV alterations between SUDs and OCD. Meta-analytic coordinates and signed brain volumetric maps determining directed (reduced or increased) brain volumetric alterations between the disorder groups and controls served as the primary outcome. Meta-analytic results employed statistical significance thresholding (FWE< 0.05).FindingsSeparate meta-analysis demonstrated that SUD (cocaine, alcohol, and nicotine) as well as OCD patients exhibited widespread GMV reductions in frontocortical regions including prefrontal, cingulate, and insular regions. Conjunction analysis revealed that the left inferior frontal gyrus (IFG) consistently exhibited decreased GMV across all disorders. Functional characterization suggests that the IFG represents a core hub in the cognitive control network and exhibits bidirectional (Granger) causal interactions with the striatum. Only OCD showed increased GMV in the dorsal striatum with higher changes being associated with more severe OCD symptomatology.ConclusionsFindings demonstrate robustly decreased GMV across the disorders in the left IFG, suggesting a transdiagnostic brain structural marker. The functional characterization as a key hub in the cognitive control network and casual interactions with the striatum suggest that deficits in inhibitory control mechanisms may promote compulsivity and loss of control that characterize both disorders.
A novel microcosm for recruiting inherently competitive biofertilizer-candidate microorganisms from soil environments
Authors: Pittroff S , Olsson S , Doolette Ashlea , Greiner R. , Richardson A.E. , Nicolaisen M 
Published: September 2020

AbstractFertilizer phosphorus (P) is both a necessary crop nutrient and finite resource, necessitating the development of innovative solutions for P fertilizer efficiency and recycling in agricultural systems.Myo-inositol hexakisphosphate (phytate) and its lower order derivatives constitute the majority of identified organic P in many soil types and has been shown to accumulate with increasing application of P fertilizer. Phytate is only poorly available to plants, and in alkaline soils it often precipitated as even more unavailable calcium (Ca)-phytate. Incorporating phytase-producing biofertilizers (i.e., microbial-based products with capacity to mineralize phytate) into soil presents a viable and environmentally acceptable way of utilizing P from phytate, whilst reducing the need for mineral P application. Here we present an in-soil microcosm that utilizes precipitated Ca-phytate to recruit microorganisms with degradation activity towards phytatein solum. Our results show both direct and indirect evidence for Ca-phytate mineralizationin vitroandin solum. Furthermore, the abundance of bacteria recruited was measured via 16S rRNA gene copy number, as was three genes relating to organic P degradation;phoXandphoDphosphatases and the BPP (β-propeller phytase) gene. Amplicon sequencing as well as BioLog catabolism studies show that microcosm treatments containing the ‘bait’ Ca-phytate, recruited a different set of microorganisms when compared to controls. These Ca-phytate microcosms recruited mainly Actinobacteria, Firmicutes, and Proteobacteria, and the genusStreptomyceswas specifically enriched. We conclude that our microcosm presents an innovative approach for isolating soil microorganisms with the potential to degrade precipitated phytatein solumand represents a new isolation method with the potential to isolate inherently robust biofertilizer candidates directly from target soils.
Environment and sex control lifespan and telomere length in wild-derived African killifish
Authors: Reichard Martin , Giannetti Kety , Ferreira Tania , Vrtílek Milan , Polačik Matej , Blažek Radim , Ferreira Miguel Godinho 
Published: September 2020

ABSTRACTTelomere length is correlated positively with longevity at the individual level, but negatively when compared across species. Here, we tested the association between lifespan and telomere length in African annual killifish. We analyzed telomere length in 18Nothobranchiusstrains derived from diverse habitats and measured the laboratory lifespan of 14 strains ofN. furzeriandN. kadleci. We found that males had shorter telomeres than females. The longest telomeres were recorded in strains derived from dry region where male lifespans were shortest. At the individual level, we detected a weak negative association between rapid juvenile growth and shorter telomeres in early adulthood. Overall, average telomere length was a good descriptor of telomere length distribution. However, within-individual telomere length spread was not related to any pattern. This substantial variation in telomere length between strains from different environments provides killifish as powerful tool to understand the evolutionarily adaptive value of telomere length.
Genomic insight into the biogeographic history, divergence, and adaptive potential ofG. purpurascens, a forgotten landrace ofG. hirsutum
Authors: Nazir Mian Faisal , He Shoupu , Ahmed Haris , Sarfraz Zareen , Jia Yinhua , Li Hongge , Sun Gaofei , Iqbal Muhammad Shahid , Pan Zhaoe , Du Xiongming 
Published: September 2020

AbstractContinuous selection and adaptation to the local environment resulted in the loss of genetic variation inGossypium hirsutum, which is the most important source of natural fiber. Wild progenitors are an excellent source for strengthening the genetic base and accumulation of desirable traits in modern cultivars. Here we reevaluate a landrace ofGossypium hirsutum, formerly known asGossypium purpurascens. We seek to understand the genomic structure, variation, and the adaptive/breeding potential among largely neglected landraces ofGossypium hirsutum purpurascens, providing insights into the biogeographic history and genomic changes likely associated with domestication. Population fixation statistics suggested marked differentiation betweenG. purpurascensand current varieties, obsolete accessions, and geographical landraces of upland cotton, emphasizing the divergent behavior ofG. purpurascens. Phylogeny established the primitive nature ofG. purpurascens, the inclusion of which in upland cotton gene-pool can enhance the narrowed genetic base of upland cultivars. Genome-wide associations comprehend multiple loci associated with domestication regions corresponding to flowering and fiber quality. Moreover, the conserved nature ofG. purpurascenscan provide insight into understanding the evolutionary process ofG. hirsutum.
Rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK) targets glucocorticoid receptor signaling: a longitudinal cerebrospinal fluid proteome study
Authors: Herzog David P. , Perumal Natarajan , Manicam Caroline , Treccani Giulia , Nadig Jens , Rossmanith Milena , Engelmann Jan , Jene Tanja , Hasch Annika , van der Kooij Michael A. , Lieb Klaus , Gassen Nils C. , Grus Franz H. , Müller Marianne B. 
Published: September 2020

AbstractDelayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapidacting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as a animal model to assess the antidepressant-like effects of ketamine and HNKin vivo.To decode the molecular mechanisms mediating HNK’s rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GRin vitro.In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK’s rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future.