bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple optimal phenotypes overcome redox and glycolytic intermediate metabolite imbalances inEscherichia coli pgiknockout evolutions
Authors: McCloskey Douglas , Xu Sibei , Sandberg Troy E. , Brunk Elizabeth , Hefner Ying , Szubin Richard , Feist Adam M. , Palsson Bernhard O. 
Published: June 2018

AbstractA mechanistic understanding of how new phenotypes develop to overcome the loss of a gene product provides valuable insight on both the metabolic and regulatory function of the lost gene. Thepgigene, whose product catalyzes the second step in glycolysis, was deleted in a growth optimizedEscherichia coliK-12 MG1655 strain. The knock-out (KO) strain exhibited an 80% drop in growth rate, that was largely recovered in eight replicate, but phenotypically distinct, cultures after undergoing adaptive laboratory evolution (ALE). Multi omic data sets showed that the loss ofpgisubstantially shifted pathway usage leading to a redox and sugar phosphate stress response. These stress responses were overcome by unique combinations of innovative mutations selected for by ALE. Thus, we show the coordinated mechanisms from genome to metabolome that lead to multiple optimal phenotypes after loss of a major gene product.ImportanceA mechanistic understanding of how new phenotypes develop to overcome the loss of a gene product provides valuable insight on both the metabolic and regulatory function of the lost gene. Thepgigene, whose product catalyzes the second step in glycolysis, was deleted in a growth optimizedEscherichia coliK-12 MG1655 strain. Eight replicate adaptive laboratory evolution (ALE) resulted in eight phenotypically distinct endpoints that were able to overcome the gene loss. Utilizing multi-omics analysis, we show the coordinated mechanisms from genome to metabolome that lead to multiple optimal phenotypes after loss of a major gene product.
Th17/regulatory T cells balance is predictive ofCoccidioidesinfection outcome in pediatric patients
Authors: Davini Dan , Naeem Fouzia , Phong Aron , Al-Kuhlani Mufadhal , Valentine Kristen M. , McCarty James , Ojcius David M. , Gravano David M. , Hoyer Katrina K. 
Published: June 2018

ABSTRACTBackgroundProtective immunity against the fungal pathogen Coccidioides requires specific T helper responses. Mouse vaccine and infection studies have defined CD4+T helper (Th)1 and Th17 cells in the resolution of infection and in effective protection. Patients with persistentCoccidioidesinfection demonstrate reduced cellular responses.MethodsPeripheral blood and serum were collected from 30 pediatricCoccidioides-infected patients and 20 healthy controls in the California San Joaquin Valley. Samples were evaluated by flow cytometry for innate and adaptive immune populations and cytokines to define the early immune response and identify clinically useful biomarkers for predicting disease outcome. Clinical and flow data were evaluated according to disease outcome (resolved or persistent) using principal component analysis, high-dimensional flow cytometry analysis tools, chi-square automatic interaction detection, and individual cell population comparisons.ResultsPatients with persistent infection had lower Th17 and higher Treg frequencies, but similar Th1 responses, relative to patients that resolved disease. Treg frequency, eosinophil numbers and neutrophil numbers together distinguish patients that resolve infection from those that develop persistent infection.ConclusionsThe inability to resolveCoccidioidesinfection may be a result of elevated Treg frequency and functional capacity, and Treg frequency may predict patient disease outcome at diagnosis. In our study, Th1 responses were similar in persistent and resolved infection, in contrast to prior human studies. Instead, our data suggest that Th17 cells provide an effective protection duringCoccidioidesinfection, and that elevated Treg frequency inhibits protective immunity.
Linear stability analysis of morphodynamics during tissue regeneration in plants
Authors: Reijne Anne-Mieke , Pruessner Gunnar , Sena Giovanni 
Published: June 2018

AbstractOne of the key characteristics of multicellular organisms is the ability to establish and maintain shapes, or morphologies, under a variety of physical and chemical perturbations. A quantitative description of the underlying morphological dynamics is a critical step to fully understand the self-organising properties of multicellular systems. Although many powerful mathematical tools have been developed to analyse stochastic dynamics, rarely these are applied to experimental developmental biology.Here, we take root tip regeneration in the plant model system Arabidopsis thaliana as an example of robust morphogenesis in living tissue, and present a novel approach to quantify and model the relaxation of the system to its unperturbed morphology. By generating and analysing time-lapse series of regenerating root tips captured with confocal microscopy, we are able to extract and model the dynamics of key morphological traits at cellular resolution. We present a linear stability analysis of its Markovian dynamics, with the stationary state representing the intact root in the space of morphological traits. We find that the resulting eigenvalues can be classified into two groups, suggesting the co-existence of two distinct temporal scales during the process of regeneration.We discuss the possible biological implications of our specific results, and suggest future experiments to further probe the self-organising properties of living tissue.
Statistical loadings and latent significance simplify and improve interpretation of multivariate projection models
Authors: Jonsson Pär , Björkblom Benny , Chorell Elin , Olsson Tommy , Antti Henrik 
Published: June 2018

AbstractMultivariate projection methods are unique in being both multivariable by combining many variables into stronger predictive features (latent variables), and multivariate for being able to model systematic variation both related and orthogonal to an observed response. Orthogonal partial least squares (OPLS) is a versatile multivariate projection method for analysis of correlation, discrimination and effect changes. However, currently OPLS is not fully using its multivariate potential since orthogonal systematic variation is not considered in model interpretation, resulting in univariate interpretation of variable significance. We present a strategy for improved interpretation of OPLS models based upon a post-hoc linear regression analysis that can be used with or without the orthogonal OPLS score(s) as a covariate to make the interpretation multivariate or univariate respectively. By selecting the observed response y or estimated response yhat as a one of the factors in the linear regression the results are related to either of the OPLS loadings w or p. Furthermore, converting the OPLS loading values to statistical t-values creates a direct link to statistical significance. Finally, by applying three different Boolean loadings W, P and W∧P variable significance can be summarized based on three criteria. W and P reveal if the values in w or p respectively are outside the statistical limits with W∧P being the logical conjunction of W and P (significant if outside limits in both W and P). Two examples are used to verify the proposed strategy. First, a synthetic example, simulating a mix of mass spectra, and second a clinical metabolomics study of a dietary intervention. In the simulated example we show that multivariate interpretation gives higher accuracy for estimation of true differences, mainly due to higher true positive rate. Furthermore, we highlight how application of W∧P for summarizing variable significance leads to higher accuracy. For the metabolomics example, we show that a more detailed interpretation, i.e. larger number of significant metabolites of relevance, is obtained using the multivariate interpretation. In summary, the suggested strategy provides means for facilitated interpretation of OPLS models, beyond univariate statistics, and offers a multivariate tool for discovery of biomarker patterns, i.e. latent biomarkers.
Genome-wide association study of circadian rhythmicity in 71 500 UK Biobank participants and polygenic association with mood instability
Authors: Ferguson Amy , Lyall Laura M. , Ward Joey , Strawbridge Rona J. , Cullen Breda , Graham Nicholas , Niedzwiedz Claire L. , Johnston Keira J.A. , MacKay Daniel , Biello Stephany M. , Pell Jill P. , Cavanagh Jonathan , McIntosh Andrew M. , Doherty Aiden , Bailey Mark E.S. , Lyall Donald M. , Wyse Cathy A. , Smith Daniel J. 
Published: June 2018

AbstractBackgroundCircadian rhythms are fundamental to health and are particularly important for mental wellbeing. Disrupted rhythms of rest and activity are recognised as risk factors for major depressive disorder and bipolar disorder.MethodsWe conducted a genome-wide association study (GWAS) of low relative amplitude (RA), an objective measure of circadian rhythmicity derived from the accelerometer data of 71 500 UK Biobank participants. Polygenic risk scores (PRS) for low RA were used to investigate potential associations with psychiatric phenotypes.OutcomesTwo independent genetic loci were associated with low RA, within genomic regions for Neurofascin (NFASC) and Solute Carrier Family 25 Member 17 (SLC25A17). A secondary GWAS of RA as a continuous measure identified a locus within Meis Homeobox 1 (MEIS1). There were no significant genetic correlations between low RA and any of the psychiatric phenotypes assessed. However, PRS for low RA was significantly associated with mood instability across multiple PRS thresholds (at PRS threshold 0·05: OR=1·02, 95% CI=1·01-1·02, p=9·6×10−5), and with major depressive disorder (at PRS threshold 0·1: OR=1·03, 95% CI=1·01-1·05, p=0·025) and neuroticism (at PRS threshold 0·5: Beta=0·02, 95% CI=0·007-0·04, p=0·021).InterpretationOverall, our findings contribute new knowledge on the complex genetic architecture of circadian rhythmicity and suggest a putative biological link between disrupted circadian function and mood disorder phenotypes, particularly mood instability, but also major depressive disorder and neuroticism.
Parasitoid wasp venom elevates sorbitol and alters expression of metabolic genes in human kidney cells
Authors: Siebert Aisha L. , Doucette Luticha A. , Simpson-Haidaris PJ , Werren John H. 
Published: June 2018

AbstractVenom from the parasitoid waspNasonia vitripennisdramatically elevates sorbitol levels in its natural fly hosts. In humans, sorbitol elevation is associated with complications of diabetes. Here we demonstrate that venom also induces this disease-relevant phenotype in human cells, and investigate possible pathways involved. Key findings are that (a) low doses ofNasoniavenom elevate sorbitol levels in human renal mesangial cells (HRMCs) without changing glucose or fructose levels; (b) venom is a much more potent inducer of sorbitol elevation than glucose; (c) low venom doses significantly alter expression of genes involved in sterol and alcohol metabolism, transcriptional regulation, and chemical/stimulus response; (d) although venom treatment does not alter expression of the key sorbitol pathway gene aldose reductase (AR); (e) venom elevates expression of a related gene implicated in diabetes complications (AKR1C3) as well as the fructose metabolic gene (GFPT2). Although elevated sorbitol is accepted as a major contributor to secondary complications of diabetes, the molecular mechanism of sorbitol regulation and its contribution to diabetes complications are not fully understood. Our findings suggest that genes other than AR could contribute to sorbitol regulation, and more broadly illustrate the potential of parasitoid venoms for medical application.
TTL proteins scaffold brassinosteroid signaling components at the plasma membrane to optimize signal transduction in plant cells
Authors: Amorim-Silva Vítor , García-Moreno Álvaro , Castillo Araceli G. , Lakhssassi Naoufal , Pérez-Sancho Jessica , Li Yansha , del Valle Alicia Esteban , Posé David , Pérez-Rodriguez Josefa , Lin Jinxing , Valpuesta Victoriano , Borsani Omar , Zipfel Cyril , Macho Alberto P. , Botella Miguel A. 
Published: June 2018

AbstractBrassinosteroids (BRs) form a group of steroidal hormones essential for plant growth, development and stress responses. Here, we report that plant-specific TETRATRICOPEPTIDE THIOREDOXIN-LIKE (TTL) proteins are positive regulators of BR signaling functioning as scaffold for BR signaling components in Arabidopsis. TTL3 forms a complex with all core components involved in BR signaling, including the receptor kinase BRASSINOSTEROID INSENSITIVE1 (BRI1), the transcription factor BRASSINAZOLE RESISTANT1 (BZR1) and the phosphatase BRI1-SUPPRESSOR1 (BSU1), but excluding the co-receptor BAK1. TTL3 is mainly localized in the cytoplasm, but BR treatment increases its localization at the plasma membrane, where it strengthens the association with BR signaling components. Consistent with a role in BR signaling, mutations inTTL3and relatedTTL1andTTL4genes cause reduced BR responsiveness. We propose a mechanistic model for BR signaling, in which cytoplasmic/nuclear BR components bound to TTL proteins are recruited to the plasma membrane upon BR perception, which in turn allows the assembly of a BR signaling complex, leading to the de-phosphorylation and nuclear accumulation of the transcription factors BZR1 and BES1.
An atlas of protein-protein interactions across mammalian tissues
Authors: Skinnider Michael A. , Scott Nichollas E. , Prudova Anna , Stoynov Nikolay , Stacey R. Greg , Gsponer Joerg , Foster Leonard J. 
Published: June 2018

SummaryCellular processes arise from the dynamic organization of proteins in networks of physical interactions. Mapping the complete network of biologically relevant protein-protein interactions, the interactome, has therefore been a central objective of high-throughput biology. Yet, because widely used methods for high-throughput interaction discovery rely on heterologous expression or genetically manipulated cell lines, the dynamics of protein interactions across physiological contexts are poorly understood. Here, we use a quantitative proteomic approach combining protein correlation profiling with stable isotope labelling of mammals (PCP SILAM) to map the interactomes of seven mouse tissues. The resulting maps provide the first proteome-scale survey of interactome dynamics across mammalian tissues, revealing over 27,000 unique interactions with an accuracy comparable to the highest-quality human screens. We identify systematic suppression of cross-talk between the evolutionarily ancient housekeeping interactome and younger, tissue-specific modules. Rewiring of protein interactions across tissues is widespread, and is poorly predicted by gene expression or coexpression. Rewired proteins are tightly regulated by multiple cellular mechanisms and implicated in disease. Our study opens up new avenues to uncover regulatory mechanisms that shape in vivo interactome responses to physiological and pathophysiological stimuli in mammalian systems.
The quiescent X, the replicative Y and the Autosomes
Authors: Achaz Guillaume , Gangloff Serge , Arcangioli Benoit 
Published: June 2018

AbstractFrom the analysis of the mutation spectrum in the 2,504 sequenced human genomes from the 1000 genomes project (phase 3), we show that sexual chromosomes (X and Y) exhibit a different proportion of indel mutations than autosomes (A), ranking them X>A>Y. We further show that X chromosomes exhibit a higher ratio of deletion/insertion when compared to autosomes. This simple pattern shows that the recent report that non-dividing quiescent yeast cells accumulate relatively more indels (and particularly deletions) than replicating ones also applies to metazoan cells, including humans. Indeed, the X chromosomes display more indels than the autosomes, having spent more time in quiescent oocytes, whereas the Y chromosomes are solely present in the replicating spermatocytes. From the proportion of indels, we have inferred that de novo mutations arising in the maternal lineage are twice more likely to be indels than mutations from the paternal lineage. Our observation, consistent with a recent trio analysis of the spectrum of mutations inherited from the maternal lineage, is likely a major component in our understanding of the origin of anisogamy.
Bilateral asymmetry favours the left hemimandibular side in companion rabbits
Authors: Parés-Casanova Pere M. , Cabello Maria , Gambo Baba Gana , Samuel Michael Oluwale , Olopade James Olukayode 
Published: June 2018

AbstractDirectional asymmetry (DA) appears when the left and right body sides differ consistently from each other. This asymmetry is characterized as a type of natural asymmetry typical of the population’s biology, which can be derived both from genetic inheritance, as of the functional importance acquired by certain features with respect to the environment in which they develop. We report here preliminary findings that for the first time to quantify size asymmetry mandibles of companion rabbits. A total sample of 64 companion rabbits from the same farm were studied by means of geometric morphometric techniques. The mandible morphology was described by a set of 18 landmarks and semilandmarks on the lateral aspect. Tests showed paired differences with variations in distributions, demonstrating a DA in favour of left mandibular side. The detected unilaterality could be interpreted as a manifestation of lateralized masticatory activity. This is a first time report to quantify size asymmetry in this species.
Haplotypes spanning centromeric regions reveal persistence of large blocks of archaic DNA
Authors: Langley Sasha A. , Miga Karen , Karpen Gary , Langley Charles H. 
Published: June 2018

AbstractDespite critical roles in chromosome segregation and disease, the repetitive structure and vast size of centromeres and their surrounding heterochromatic regions impede studies of genomic variation. We report here large-scale haplotypes (cenhaps) in humans that span the centromere-proximal regions of all metacentric chromosomes, including the arrays of highly repeated α-satellites on which centromeres form.Cenhapsreveal surprisingly deep diversity, including entire introgressed Neanderthal centromeres and equally ancient lineages among Africans. These centromere-spanning haplotypes contain variants, including large differences in α-satellite DNA content, which may influence the fidelity and bias of chromosome transmission. The discovery ofcenhapscreates new opportunities to investigate their contribution to phenotypic variation, especially in meiosis and mitosis, as well as to more incisively model the unexpectedly rich evolution of these challenging genomic regions.One Sentence SummaryGenomic polymorphism across centromeric regions of humans is organized into large-scale haplotypes with great diversity, including entire Neanderthal centromeres.
Endoplasmic reticulum stress may activate NLRP3 inflammasomes via TXNIP in preeclampsia
Authors: Yang Yong , Li Jianxin , Han Ting-Li , Zhou Xiaobo , Qi Hongbo , Baker Philip N. , Zhou Wei , Zhang Hua 
Published: June 2018

AbstractPreeclampsia (PE) development is often associated with placental immune and inflammatory dysregulation, as well as endoplasmic reticulum (ER) stress. However, the mechanisms linking ER stress and inflammatory dysregulation to PE have not been clarified. It has been reported that thioredoxin-interacting protein (TXNIP), which can bind with and activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome, plays a critical role in immune regulation. Recent experimental evidence suggests that activated NLRP3 inflammasomes can activate interleukin-1β (IL-1β) production in the placenta of patients with PE. The objective of the current study was to explore if TXNIP plays a critical signaling role linking ER stress with NLRP3 inflammasome activation in PE. We hypothesised that ER stress would induce TXNIP production, which would bind with NLRP3 inflammasomes to activate IL-1β production. HTR8/SVneo cells were subjected to six hours hypoxia followed by six hours reoxygenation (H/R). These cells showed a higher protein level of NLRP3 and IL-1β, as well as a higher enzymatic activity of caspase-1, indicating enhanced inflammatory dysregulation and ER stress. Cells transfected with TXNIP siRNA showed reduced NLRP3 inflammasome activation. Cells treated with 4-phenylbutyric acid, an inhibitor of ER stress, showed a similar result. In addition, the outgrowth of explant with TXNIP lentivirus in H/R or Tunicamycin (inducers of ER stress) was also measured to verify our hypothesis. These findings demonstrated that TXNIP could influence inflammatory dysregulation by mediating ER stress and NLRP3 inflammasome activation in PE. This novel mechanism may further explain the inflammation observed at the maternal-fetal interface, which leads to placental dysfunction in a patient with PE.
Population dynamics and transcriptomic responses ofPseudomonas aeruginosain a complex laboratory microbial community
Authors: Cheng Yingying , Yam Joey Kuok Hoong , Cai Zhao , Ding Yichen , Zhang Lian-Hui , Deng Yinyue , Yang Liang 
Published: June 2018

AbstractPseudomonas aeruginosais one of the dominant species when it co-exists with many other bacterial species in diverse environments. To understand its physiology and interactions with co-existing bacterial species in different conditions, we established physiologically reproducible eighteen-species communities, and found thatP. aeruginosabecame the dominant species in mixed-species biofilm community but not in the planktonic community.P. aeruginosaH1 type VI secretion system was highly induced in the mixed-species biofilm community compare to its mono-species biofilm, which was further demonstrated to play a key role forP. aeruginosato gain fitness over other bacterial species. In addition, the type IV pili and Psl exopolysaccharide were shown to be required forP. aeruginosato compete with other bacterial species in the biofilm community. Our study showed that the physiology ofP. aeruginosais strongly affected by interspecies interactions, and both biofilm determinants and H1 type VI secretion system contribute toP. aeruginosafitness over other species in complex biofilm communities.ImportancePseudomonas aeruginosausually coexists with different bacterial species in natural environment. However, systematic comparative characterization ofP. aeruginosain complex microbial communities with its mono-species communities is lacking. We constructed mixed-species planktonic and biofilm communities consistingP. aeruginosaand seventeen other bacterial species to study the physiology and interaction ofP. aeruginosain complex multiple-species community. A single molecule detection platform, NanoString nCounter®16S rRNA array, was used to shown thatP. aeruginosacan become the dominant species in the biofilm communities while not in the planktonic communities. Comparative transcriptomic analysis and fluorescence-based quantification further revealed thatP. aeruginosaH1 type VI secretion system and biofilm determinants are both required for its fitness in mixed-species biofilm communities.