bluuebunny/crossref_metadata_2025_split huggingface dataset:
When 90% of the variance is not enough: residual EMG from muscle synergy extraction influences task performance
Authors: Barradas Victor R. , Kutch Jason J. , Kawase Toshihiro , Koike Yasuharu , Schweighofer Nicolas 
Published: May 2019

AbstractMuscle synergies are usually identified via dimensionality reduction techniques, such that the identified synergies reconstruct the muscle activity to a level of accuracy defined heuristically, such as 90% of the variance explained. Here, we question the assumption that the residual muscle activity not explained by the synergies is due to noise. We hypothesize instead that the residual activity is structured and can therefore influence the execution of a motor task. Young healthy subjects performed an isometric reaching task in which surface electromyography of 10 arm muscles was mapped onto estimated two-dimensional forces used to control a cursor. Three to five synergies were extracted to account for 90% of the variance explained. We then altered the muscle-force mapping via “hard” and “easy” virtual surgeries. Whereas in both surgeries the forces associated with synergies spanned the same single dimension of the virtual environment, the muscle-force mapping was as close as possible to the initial mapping in the easy surgery and as far as possible in the hard surgery. This design therefore maximized potential differences in reaching errors attributable to the residual muscle activity. Results show that the easy surgery produced much smaller directional errors than the hard task. In addition, systematic estimations of the errors for easy and hard surgeries constructed with 1 to 10 synergies show that the errors differ significantly for up to 8 synergies, which account for 98% of the variance on average. Our study therefore indicates the need for cautious interpretations of results derived from synergy extraction techniques based on heuristics with lenient levels of accuracy.Author summaryThe muscle synergy hypothesis states that the central nervous system simplifies motor control by grouping muscles that share common functions into modules called muscle synergies. Current techniques use unsupervised dimensionality reduction algorithms to identify these synergies. However, these techniques rely on arbitrary criteria to determine the number of synergies, which is actually unknown. An example of such criteria is that the identified synergies must be able to reconstruct the measured muscle activity to at least a 90% level of accuracy. Thus, the residual muscle activity, the remaining 10% of the muscle activity, is often disregarded as noise. We show that residual muscle activity following muscle synergy identification has a large systematic effect on movements even when the number of synergies approaches the number of muscles. This suggests that current synergy extraction techniques may discard a component of muscle activity that is important for motor control. Therefore, current synergy extraction techniques must be updated to identify true physiological synergies.
Fatty acid starvation activates RelA by depleting lysine precursor pyruvate
Authors: Sinha Anurag Kumar , Winther Kristoffer Skovbo , Roghanian Mohammad , Gerdes Kenn 
Published: May 2019

SummaryBacteria experiencing nutrient starvation induce the ubiquitous stringent response, a profound physiological change that reprograms cell physiology from fast to slow growth and stress survival. The stringent response is mediated by the secondary messengers pppGpp and ppGpp collectively referred to as (p)ppGpp or “alarmone”. InEscherichia coli, two paralogs, RelA and SpoT, synthesize (p)ppGpp. RelA is activated by amino acid starvation whereas SpoT, which can also degrade (p)ppGpp, responds to fatty acid (FA), carbon and phosphate starvation. Here, we discover that FA starvation leads to rapid activation of RelA and reveal the underlying mechanism. We show that fatty acid starvation leads to depletion of lysine that, in turn, leads to the accumulation of uncharged tRNAlysand activation of RelA. SpoT was also activated by fatty acid starvation but to a lower level and with a delayed kinetics. Next, we discovered that pyruvate, a precursor of lysine, is depleted by FA starvation. We also propose a mechanism that explains how FA starvation leads to pyruvate depletion. Together our results indicate that many responses to nutrient depletion may ultimately result indirectly from depletion of amino acids and thereby activating RelA. Interestingly, FA starvation provoked a ~100-fold increase inrelAdependent ampicillin tolerance.
Climate adaptation shaped by subtle to moderate allele frequency shifts in loblolly pine
Authors: De La Torre Amanda R. , Neale David B 
Published: May 2019

ABSTRACTUnderstanding the genomic basis of local adaptation is crucial to determine the potential of long-lived woody species to withstand changes in their natural environment. In the past, efforts to dissect the genomic architecture in gymnosperms species have been limited due to the absence of reference genomes. Recently, the genomes of some commercially important conifers, such as loblolly pine, have become available, allowing whole-genome studies of these species. In this study, we test for associations between 87k SNPs, obtained from whole-genome re-sequencing of loblolly pine individuals, and 270 environmental variables and combinations of them. We determine the geographic location of significant alleles and identify their genomic location using our newly constructed ultra-dense 26k SNP linkage map. We found that water availability is the main climatic variable shaping local adaptation of the species, and found 492 SNPs showing significant associations with climatic variables or combinations of them. Our results suggest that adaptation to climate in the species might have occurred by many changes in the allele frequency of alleles with moderate to small effect sizes, and by the smaller contribution of large effect alleles in genes related to moisture deficit, temperature and precipitation. Genomic regions of low recombination and high population differentiation harbored SNPs associated with principal components but not with individual climatic variables, suggesting climate adaptation might have evolved as a result of different selection pressures acting on groups of genes associated with an aspect of climate rather than on individual climatic variables.
Cell generation dynamics underlying naïve T cell homeostasis in adult humans
Authors: Mold Jeff E. , Réu Pedro , Olin Axel , Bernard Samuel , Michaëlsson Jakob , Rane Sanket , Yates Andrew , Khosravi Azadeh , Salehpour Mehran , Possnert Göran , Brodin Petter , Frisén Jonas 
Published: May 2019

ABSTRACTThymic involution and proliferation of naive T cells both contribute to shaping the naive T cell repertoire as humans age, but a clear understanding of the roles of each throughout a human lifespan has been difficult to determine. By measuring nuclear bomb test-derived14C in genomic DNA we determined the turnover rates of CD4+and CD8+naïve T cell populations and defined their dynamics in healthy individuals ranging from 20-65 years of age. We demonstrate that naïve T cell generation decreases with age, and that this could be explained by a combination of declining cell loss, peripheral division and thymic production during adulthood. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of naïve T cell turnover using mass cytometry to profile candidate signaling pathways involved in T cell activation and proliferation in CD4+naive T cells relative to CD31 expression, a marker of thymic proximity. We show that basal NF-κB phosphorylation inversely correlated with CD31 expression and thus is decreased in peripherally expanded naive T cell clones. Functionally we found that NF-κB signaling was essential for naive T cell proliferation to the homeostatic growth factor IL-7, and reduced NF-κB phosphorylation in CD4+CD31−naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naïve T cell turnover as a putative regulator of naïve T cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T cell clones that accumulate with age.
Drug-resistant epimutants exhibit organ-specific stability and induction during murine infections caused by the human fungal pathogenMucor circinelloides
Authors: Chang Zanetta , Heitman Joseph 
Published: May 2019

ABSTRACTThe environmentally ubiquitous fungusMucor circinelloidesis a primary cause of the emerging disease mucormycosis.Mucorinfection is notable for causing high morbidity and mortality, especially in immunosuppressed patients, while being inherently resistant to the majority of clinically available antifungal drugs. A new, RNAi-dependent, and reversible epigenetic mechanism of antifungal resistance – epimutation - was recently discovered inM. circinelloides. However, the effects of epimutation in a host-pathogen setting were unknown. We employed a systemic, intravenous murine model ofMucorinfection to elucidate the potential impact of epimutationin vivo. Infection with an epimutant strain resistant to the antifungal agents FK506 and rapamycin revealed that the epimutant-induced drug resistance was stablein vivoin a variety of different organs and tissues. Reversion of the epimutant-induced drug resistance was observed to be more rapid in isolates from the brain, as compared to those recovered from the liver, spleen, kidney, or lungs. Importantly, infection with a wild-type strain ofMucorled to increased rates of epimutation after strains were recovered from organs and exposed to FK506 stressin vitro.Once again, this effect was more pronounced in strains recovered from the brain than from other organs. In summary, we report the rapid induction and reversion of RNAi-dependent drug resistance afterin vivopassage through a murine model, with pronounced impact in strains recovered from brain. Defining the role played by epimutation in drug resistance and infection advances our understanding ofMucorand other fungal pathogens, and may have implications for antifungal therapy.IMPORTANCEThe emerging fungal pathogenMucor circinelloidescauses a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment ofMucorinfection is challenging becauseMucoris inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation, was recently described inMucor. Epimutation has not been studiedin vivoand it was unclear whether it would contribute to antifungal resistance observed clinically. We demonstrate that epimutation can be both induced and reverted afterin vivopassage through a mouse model; rates of both induction and reversion are higher after brain infection than after infection of other organs (liver, spleen, kidneys, or lungs). Elucidating the roles played by epimutation in drug resistance and infection will improve our understanding ofMucorand other fungal pathogens, and may have implications for antifungal treatment.
Dynamics of transcription-dependent H3K36me3 marking by the SETD2:IWS1:SPT6 ternary complex
Authors: Cermakova Katerina , Smith Eric A. , Veverka Vaclav , Hodges H. Courtney 
Published: May 2019

AbstractSETD2 contributes to gene expression by marking gene bodies with H3K36me3, which is thought to assist in the concentration of transcription machinery at the small portion of the coding genome. Despite extensive genome-wide data revealing the precise localization of H3K36me3 over gene bodies, the physical basis for the accumulation, maintenance, and sharp borders of H3K36me3 over these sites remains rudimentary. Here we propose a model of H3K36me3 marking based on stochastic transcription-dependent placement and transcription-independent spreading. Our analysis of the spatial distributions and dynamic features of these marks indicates that transcription-dependent placement dominates the establishment of H3K36me3 domains compared to transcription-independent spreading processes, and that turnover of H3K36me3 limits its capacity for epigenetic memory. By adding additional terms for asymmetric histone turnover occurring at transcription start sites, our model provides a remarkably accurate representation of H3K36me3 levels and dynamics over gene bodies. Furthermore, we validate our findings by revealing that loss of SPT6 impairs the transcription-coupled activity of the SETD2:IWS1:SPT6 ternary complex, thereby reducing the tight correlation between transcription and H3K36me3 levels at gene bodies.
Metastatic breast cancer cells induce altered microglial morphology and electrical excitabilityin vivo
Authors: Simon Anna , Yang Ming , Marrison Joanne L. , James Andrew D. , O’Toole Peter J. , Kaye Paul M. , Whittington Miles A. , Chawla Sangeeta , Brackenbury William J. 
Published: May 2019

AbstractBackgroundAn emerging problem in the treatment of breast cancer is the increasing incidence of metastases to the brain. Metastatic brain tumours are incurable and can cause epileptic seizures and cognitive impairment, so better understanding of this niche, and the cellular mechanisms, is urgently required. Microglia are the resident brain macrophage population, becoming “activated” by neuronal injury, eliciting an inflammatory response. Microglia promote proliferation, angiogenesis and invasion in brain tumours and metastases. However, the mechanisms underlying microglial involvement appear complex and better models are required to improve understanding of function.MethodsHere, we sought to address this need by developing a model to study metastatic breast cancer cell-microglial interactions using intravital imaging combined withex vivoelectrophysiology. We implanted an optical window on the parietal bone to facilitate observation of cellular behaviourin situin the outer cortex of heterozygousCx3cr1GFP/+mice. Results: We detected GFP-expressing microglia inCx3cr1GFP/+mice up to 350 µm below the window without significant loss of resolution. When DsRed-expressing metastatic MDA-MB-231 breast cancer cells were implanted in Matrigel under the optical window, significant accumulation of activated microglia around invading tumour cells could be observed. This inflammatory response resulted in significant cortical disorganisation and aberrant spontaneously-occurring local field potential spike events around the metastatic site.ConclusionsThese data suggest that peritumoral microglial activation and accumulation may play a critical role in local tissue changes underpinning aberrant cortical activity, which offers a possible mechanism for the disrupted cognitive performance and seizures seen in patients with metastatic breast cancer.
Electron cryomicroscopy observation of acyl carrier protein translocation in type I fungal fatty acid synthase
Authors: Lou Jennifer W. , Iyer Kali R. , Naimul Hasan S. M. , Cowen Leah E. , Mazhab-Jafari Mohammad T. 
Published: May 2019

ABSTRACTDuring fatty acid biosynthesis, acyl carrier proteins (ACPs) from type I fungal fatty acid synthase (FAS) shuttle substrates and intermediates within a reaction chamber that hosts multiple spatially-fixed catalytic centers. A major challenge in understanding the mechanism of ACP-mediated substrate shuttling is experimental observation of its transient interaction landscape within the reaction chamber. Here, we have shown that ACP spatial distribution is sensitive to the presence of substrates in a catalytically inhibited state, which enables high-resolution investigation of the ACP-dependent conformational transitions within the enoyl reductase (ER) reaction site. In two fungal FASs with distinct ACP localization, the shuttling domain is targeted to the ketoacyl-synthase (KS) domain and away from other catalytic centers, such as acetyl-transferase (AT) and ER domains by steric blockage of the KS active site followed by addition of substrates. These studies strongly suggest that acylation of phosphopantetheine arm of ACP may be an integral part of the substrate shuttling mechanism in type I fungal FAS.
Age and mortality associated DNA methylation patterns on the X-chromosome in male and female samples
Authors: Li Shuxia , Lund Jesper B. , Baumbach Jan , Christensen Kaare , Mengel-From Jonas , Li Weilong , Mohammadnejad Afsaneh , Pattie Alison , Marioni Riccardo E. , Deary Ian J. , Tan Qihua 
Published: May 2019

AbstractBackgroundMultiple epigenetic association studies on human aging have been performed reporting large numbers of sites differentially methylated across ages on the autosomal chromosomes. The X-chromosome has been studied little, due to analytical difficulties in dealing with sex differences in X-chromosome content and X-inactivation in females. Based on large collections of genome-wide DNA methylation data on two Danish cohorts of identical twins (mean ages, 66 and 79 years) and the Lothian Birth Cohort 1921 (mean age 79 years), we conducted a chromosome-wide association analysis on male and female samples separately with equal sample sizes to discover age-dependent X-linked DNA methylation patterns using chromosome 20 with about same number of CpGs analysed as an autosomal reference, and compare the age-related changes in DNA methylation between the two sexes. In addition, age-related methylation sites were assessed for their associations with mortality.ResultsWe identified more age-related DNA methylation sites (FDR<0.05) in females than in males. Among them, predominantly more sites were hypermethylated in the older as compared with the younger cohorts, a pattern similar to that observed on chromosome 20. Among the age-related sites, 13 CpGs in males and 24 CpGs in females were found significant (FDR<0.05) in all cohorts. Survival analysis showed that there are more age-methylated CpGs that contribute to reduce mortality than those that increase mortality in male but not in female samples.ConclusionThe X-chromosome displays significant age-and sex-dependent methylation patterns which might be differentially associated with mortality in the two sexes.
Detection and quantification of house mouse Eimeria at the species level – challenges and solutions for the assessment of Coccidia in wildlife
Authors: Jarquín-Díaz Víctor Hugo , Balard Alice , Jost Jenny , Kraft Julia , Dikmen Mert Naci , Kvičerová Jana , Heitlinger Emanuel 
Published: May 2019

AbstractDetection and quantification of coccidia in studies of wildlife can be challenging. Therefore, the prevalence of coccidia is often not assessed at the parasite species level in non-livestock animals. Parasite species-specific prevalences are especially important when studying evolutionary questions in wild populations. We tested whether increased host population density increases the prevalence of individual Eimeria species at the farm level, as predicted by epidemiological theory. We studied free-living commensal populations of the house mouse (Mus musculus) in Germany and established a strategy to detect and quantify Eimeria infections. We show that a novel diagnostic primer targeting the apicoplast genome (Ap5) and coprological assessment after flotation provide complementary detection results increasing sensitivity. Genotyping PCRs confirm detection in a subset of samples and cross-validation of different PCR markers does not indicate a bias towards a particular parasite species in genotyping. We were able to detect double infections and to determine the preferred niche of each parasite species along the distal-proximal axis of the intestine. Parasite genotyping from tissue samples provides an additional indication for the absence of species bias in genotyping amplifications. Three Eimeria species were found infecting house mice at different prevalences: Eimeria ferrisi (16.7%; 95% CI 13.2 – 20.7), E. falciformis (4.2%; 95% CI 2.6 – 6.8) and E. vermiformis (1.9%; 95% CI 0.9 – 3.8). We also find that mice in dense populations are more likely to be infected with E. falciformis and E. ferrisi.We provide methods for the assessment of prevalences of coccidia at the species level in rodent systems. We show and discuss how such data can help to test hypotheses in ecology, evolution and epidemiology on a species level.
LIR-dependent LMX1A/LMX1B autophagy crosstalk shapes human midbrain dopaminergic neuronal resilience
Authors: Jiménez-Moreno Natalia , Stathakos Petros , Antón Zuriñe , Shoemark Deborah K. , Sessions Richard B. , Witzgall Ralph , Caldwell Maeve , Lane Jon D. 
Published: May 2019

ABSTRACTThe LIM homeodomain transcription factors LMX1A and LMX1B are essential mediators of midbrain dopaminergic neuronal (mDAN) differentiation and survival. Here we show that LMX1A and LMX1B are autophagy transcription factors in iPSC-derived human mDANs, each contributing to the expression of important autophagy genes including ULK1, ATG7, ATG16L1 and TFEB. Suppression of LMX1A and LMX1B in mDANs reduces basal autophagy, lowers mitochondrial respiration, and elevates mitochondrial ROS levels; meanwhile overexpression protects against rotenone poisoning in mDANs in vitro. Significantly, we show that LMX1A and LMX1B bind to multiple ATG8 proteins via LIR-type interactions, in a manner dependent on subcellular localisation and nutrient status: LMX1B interacts with LC3B in the nucleus under basal conditions via a C-terminal LIR, but binds to cytosolic LC3B and is degraded by autophagy during nutrient starvation, and LIR mutant LMX1B is unable to protect mDANs against rotenone. This establishes an LMX1A/LMX1B-autophagy regulatory nexus that helps explain the protective roles of these transcription factors in the adult midbrain, thus having implications for our understanding of mDAN decline in PD.
A gene expression program activated by neuronal inactivity
Authors: Zhu Zhonghua , Lennon Jennifer , Barry Timothy M. , Ortiz Tamara Sanchez , Lymer Seana , Mezan Shaul , Kadener Sebastian , Blau Justin 
Published: May 2019

SummaryLong term synaptic plasticity requires transcriptional changes in response to neuronal activity. While neuronal activity rapidly increases transcription of activity-regulated genes, it is less clear how neurons respond to neuronal inactivity. The plasticity genePuraencodes a Rho1 GEF whose rhythmic expression drives 24 hour rhythms in the retraction of the projections ofDrosophilaLNvcircadian pacemaker neurons. We found thatPuratranscription in LNvs is repressed by neuronal activity and induced by neuronal inactivity – the opposite of canonical activity-regulated genes. We identified the Pax6 transcription factor Toy as the relevant activator ofPuratranscription, and found thattoytranscription itself is induced by neuronal inactivity and by reducing intracellular calcium. Thus we propose that neurons contain complementary gene expression programs that are activated by either increased or decreased neuronal activity.