bluuebunny/crossref_metadata_2025_split huggingface dataset:
Test-retest reliability and concurrent validity of the Adapted Short QUestionnaire to ASsess Health-enhancing physical activity (Adapted-SQUASH) in adults with disabilities
Authors: Seves Bregje L. , Hoekstra Femke , Schoenmakers Jorrit W.A. , Brandenbarg Pim , Hoekstra Trynke , Hettinga Florentina J. , Dekker Rienk , van der Woude Lucas H.V. , van der Schans Cees P. 
Published: September 2020

AbstractThe current study determined the test-retest reliability and concurrent validity of the Adapted Short QUestionnaire to ASsess Health-enhancing physical activity (Adapted-SQUASH) in adults with disabilities. Before filling in the Adapted-SQUASH twice with a recall period of two weeks, participants wore the Actiheart activity monitor up to one week. For the test-retest reliability (N = 68), Intraclass correlation coefficients (ICCs) were 0.67 (p < 0.001) for the total activity score (min x intensity/week) and 0.76 (p< 0.001) for the total minutes of activity (min/week). For the concurrent validity (N = 58), the Spearman correlation coefficient was 0.40 (p = 0.002) between the total activity score of the first administration of the Adapted-SQUASH and activity energy expenditure from the Actiheart (kcals kg−1 min−1). The ICC was 0.22 (p = 0.027) between the total minutes of activity assessed with the first administration of the Adapted-SQUASH and Actiheart. The Adapted-SQUASH is an acceptable measure to assess self-reported physical activity in large populations of adults with disabilities, but is not applicable at the individual level due to wide limits of agreement. Self-reported physical activity assessed with the Adapted-SQUASH does not accurately represent physical activity assessed with the Actiheart in adults with disabilities, as indicated with a systematic bias between both instruments in the Bland-Altman analysis.
Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma
Authors: Chiaro Jacopo , Kasanen Henna H. E. , Whalley Thomas , Capasso Cristian , Grönholm Mikaela , Feola Sara , Peltonen Karita D. , Hamdan Firas S. , Hernberg Micaela M. , Mäkelä Siru , Karhapää Hanna , Brown Paul E. , Martins Beatriz , Fusciello Manlio , Ylösmäki Erkko , Kreutzman Anna S. , Mustjoki Satu M. , Szomolay Barbara , Cerullo Vincenzo 
Published: September 2020

AbstractMolecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response.To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides.In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.One Sentence SummaryMolecular mimicry can play a role in anti-tumor immune responses and should thus be further exploited in the development of novel cancer treatments.
Peripheral inflammation is associated with micro-structural and functional connectivity changes in depression-related brain networks
Authors: Kitzbichler Manfred G , Aruldass Athina R , Barker Gareth J , Wood Tobias C , Dowell Nicholas G , Hurley Samuel A , McLean John , Correia Marta , Clarke Charlotte , Pointon Linda , Cavanagh Jonathan , Cowen Phil , Pariante Carmine , consortium NIMA , Cercignani Mara , Bullmore Edward T , Harrison Neil A 
Published: September 2020

AbstractPeripheral inflammation can cause depressive symptoms – but how? Here, we measured brain MRI functional connectivity and micro-structural parameters, including proton density (PD, a measure of tissue water), at 360 cortical and 16 subcortical brain regions in 46 healthy controls and 83 depressed cases. Blood C-reactive protein (CRP) was positively correlated with PD in key precuneus/posterior cingulate cortex (pC/pCC) and medial prefrontal cortex (mPFC) components of the default mode network (DMN). CRP concentration was associated with increased connectivity within the DMN (nodes pC/pCC, mPFC and hippocampus), but decreased connectivity between DMN and non-DMN nodes. Depressed cases had reduced weighted degree, a metric of hubness, in anatomically co-located DMN regions. Our interpretation is that low-grade peripheral inflammation is associated with increased water (oedema) within a few highly connected but metabolically vulnerable medial cortical nodes, and this “rock in the pond” serves to perturb the functional connectivity of large-scale cortico-subcortical systems associated with depression.
Exhaled CO2 as COVID-19 infection risk proxy for different indoor environments and activities
Authors: Peng Zhe , Jimenez Jose L. 
Published: September 2020

AbstractCO2 is co-exhaled with aerosols containing SARS-CoV-2 by COVID-19 infected people and can be used as a proxy of SARS-CoV-2 concentrations indoors. Indoor CO2 measurements by low-cost sensors hold promise for mass monitoring of indoor aerosol transmission risk for COVID-19 and other respiratory diseases. We derive analytical expressions of CO2-based risk proxies and apply them to various typical indoor environments. The relative infection risk in a given environment scales with excess CO2 level, and thus keeping CO2 as low as feasible in a space allows optimizing the protection provided by ventilation. We show that the CO2 level corresponding to a given absolute infection risk varies by over 2 orders of magnitude for different environments and activities. Although large uncertainties, mainly from virus exhalation rates, are still associated with infection risk estimates, our study provides more specific and practical recommendations for low-cost CO2-based indoor infection risk monitoring.Table of Contents Graphic
Altered blood cell traits underlie a major genetic locus of severe COVID-19
Authors: Zhou Jingqi , Sun Yitang , Huang Weishan , Ye Kaixiong 
Published: September 2020

AbstractPurposeThe genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown.MethodsTo identify intermediate traits of the COVID-19 risk variant, we performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310,999 European individuals from UK Biobank. For candidate target genes, we examined associations between their expression and the polygenic score (PGS) of 1,263 complex traits in a meta-analysis of 31,684 blood samples.ResultsOur PheWAS identified and replicated multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07×10−8, 4.09×10−13), eosinophil count and percentage (p = 5.73×10−3, 2.20×10−3), and neutrophil percentage (p = 3.23×10−3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73×10−21, 5.08×10−19); CCR2 with monocytes (p = 2.40×10−10); and CCRl with monocytes and neutrophil (p = 1.78×10−6, 7.17×10−5).ConclusionsMultiple blood cell traits, especially monocyte, eosinophil, and neutrophil numbers, are associated with the COVID-19 risk variant and the expression of its candidate target genes, representing probable mechanistic links between the genetic locus 3p21.31 and severe COVID-19.
The Lonidamine Derivative H2-Gamendazole Reduces Cyst Formation in Polycystic Kidney Disease
Authors: Sundar Shirin V. , Zhou Xia , Magenheimer Brenda S. , Reif Gail A. , Wallace Darren P. , Georg Gunda I. , Jakkaraj Sudhakar R. , Tash Joseph S. , Yu Alan S.L. , Li Xiaogang , Calvet James P. 
Published: September 2020

ABSTRACTAutosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl−secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation usingin vitroandin vivomodels of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl−channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement.In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in thePkd1flox/flox:Pkhd1-Cremouse model. Thus, H2-GMZ treatment decreases Cl−secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.
Age-related differences in the role of the prefrontal cortex in sensory-motor training gains: A tDCS study
Authors: Tan Si Jing , Filmer Hannah L. , Dux Paul E. 
Published: September 2020

AbstractThe ability to process multiple sources of information concurrently is particularly impaired as individuals age and such age-related increases in multitasking costs have been linked to impairments in response selection. Previous neuroimaging studies with young adults have implicated the left hemisphere prefrontal cortex (PFC) as a key neural substrate of response selection. In addition, several transcranial direct current stimulation studies (tDCS) have provided causal evidence implicating this region in response selection and multitasking operations. For example, Filmer at al. (2013b) demonstrated that typically observed response selection learning/training gains in young adults were disrupted via offline transcranial direct current stimulation (tDCS) of left, but not right, PFC. Here, considering evidence of functional dedifferentiation in the brains of older adults, we assessed if this pattern of response selection learning disruption via tDCS to the left PFC is observed in older adults, testing if this region remains a key response selection node as individuals age. In a pre-registered study with 58 older adults, we applied anodal, cathodal, and sham stimulation to left and right PFC, and measured performance as participants trained on low- and high-response selection load tasks. Active stimulation did not disrupt training in older adults as compared to younger adults. However, there was evidence of enhanced training gains via tDCS, which scaled with response selection task difficulty. The results highlight age-related differences in the casual neural substrates that subserve response selection and learning.
Transcriptome Alterations in Myotonic Dystrophy Frontal Cortex
Authors: Otero Brittney A. , Poukalov Kiril , Hildebrandt Ryan P. , Thornton Charles A. , Jinnai Kenji , Fujimura Harutoshi , Kimura Takashi , Hagerman Katharine A. , Sampson Jacinda B. , Day John W. , Wang Eric T. 
Published: September 2020

AbstractMyotonic dystrophy (dystrophia myotonica, DM) is caused by expanded CTG/CCTG microsatellite repeats, leading to multi-systemic symptoms in skeletal muscle, heart, gastrointestinal, endocrine, and central nervous systems (CNS), among others. For some patients, CNS issues can be as debilitating or more so than muscle symptoms; they include hypersomnolence, executive dysfunction, white matter atrophy, and neurofibrillary tangles. Although transcriptomes from DM type 1 (DM1) skeletal muscle have provided useful insights into pathomechanisms and biomarkers, limited studies of transcriptomes have been performed in the CNS. To elucidate underlying causes of CNS dysfunction in patients, we have generated and analyzed RNA-seq transcriptomes from the frontal cortex of 21 DM1 patients, 4 DM type 2 (DM2) patients, and 8 unaffected controls. One hundred and thirty high confidence splicing changes were identified, most occurring exclusively in the CNS and not in skeletal muscle or heart. Mis-spliced exons were found in neurotransmitter receptors, ion channels, and synaptic scaffolds, and we identified an alternative exon in GRIP1 that modulates association with kinesins. Splicing changes exhibited a gradient of severity correlating with CTG repeat length, as measured by optical mapping of individual DNA molecules. All individuals studied, including those with modest splicing defects, showed extreme somatic mosaicism, with a subset of alleles having >1000 CTGs. Analyses of gene expression changes showed up-regulation of genes transcribed in microglia and endothelial cells, suggesting neuroinflammation, and downregulation of genes transcribed in neurons. Gene expression of RNAs encoding proteins detectable in cerebrospinal fluid were also found to correlate with mis-splicing, with implications for CNS biomarkers of disease severity. These findings provide a framework for future mechanistic and therapeutic studies of CNS issues in DM.
De Novo Design of Allosteric Control into Rotary Motor V1-ATPase by Restoring Lost Function
Authors: Kosugi Takahiro , Iida Tatsuya , Tanabe Mikio , Iino Ryota , Koga Nobuyasu 
Published: September 2020

AbstractProtein complexes exert various functions through allosterically controlled cooperative work. De novo design of allosteric control into protein complexes provides understanding of their working principles and potential tools for synthetic biology. Here, we hypothesized that an allosteric control can be created by restoring lost functions of pseudo-enzymes contained as subunits in protein complexes. This was demonstrated by computationally de novo designing ATP binding ability of the pseudo-enzyme subunits in a rotary molecular motor, V1-ATPase. Single molecule experiments with solved crystal structures revealed that the designed V1is allosterically accelerated than the wild-type by the ATP binding to the created allosteric site and the rate is tunable by modulating the binding affinity. This work opened up an avenue for programming allosteric control into proteins exhibiting concerted functions.
Metazoan-like kinetochore arrangement masked by the interphase RabI configuration
Authors: Jiménez-Martín Alberto , Pineda-Santaella Alberto , León-Periñán Daniel , Delgado-Gestoso David , Marín-Toral Laura , Fernández-Álvarez Alfonso 
Published: September 2020

AbstractDuring cell cycle progression in metazoan, the kinetochore, the protein complex attached to centromeres which directly interacts with the spindle microtubules, the vehicle of chromosome segregation, is assembled at mitotic onset and disassembled during mitotic exit. This program is assumed to be absent in budding and fission yeast because kinetochore proteins are stably maintained at the centromeres throughout the entire cell cycle. In this work, we show that the assembly program at the mitotic onset of the Ndc80 complex, a crucial part of the outer kinetochore, is unexpectedly conserved inSchizosaccharomyces pombe. We have identified this behavior by removing the Rabl chromosome configuration during interphase, in which centromeres are permanently associated with the nuclear envelope beneath the spindle pole body. Hence, the Rabl configuration masks the presence of a program to recruit Ndc80 at mitotic onset in fission yeast, similar to that taking place in metazoan. Besides the evolutionary implications of our observations, we think that our work will help understand the molecular processes behind the kinetochore assembly program during mitotic entry using fission yeast as the model organism.
Mfge8 attenuates human gastric antrum smooth muscle contractions
Authors: Li Wen , Olseen Ashley , Xie Yeming , Alexandru Cristina , Perrino Brian A. 
Published: September 2020

AbstractCoordinated gastric smooth muscle contraction is critical for proper digestion and is adversely affected by a number of gastric motility disorders. In this study we report that the secreted protein Mfge8 (milk fat globule-EGF factor 8) inhibits the contractile responses of human gastric antrum muscles to cholinergic stimuli by reducing the inhibitory phosphorylation of the MYPT1 (myosin phosphatase-targeting subunit 1) subunit of MLCP (myosin light chain phosphatase), resulting in reduced LC20 (smooth muscle myosin regulatory light chain 2) phosphorylation. We show that endogenous Mfge8 is bound to its receptor, α8β1 integrin, in human gastric antrum muscles, suggesting that human gastric antrum muscle mechanical responses are regulated by Mfge8. The regulation of gastric antrum smooth muscles by Mfge8 and α8 integrin functions as a brake on gastric antrum mechanical activities. Further studies of the role of Mfge8 and α8 integrin in regulating gastric antrum function will likely reveal additional novel aspects of gastric smooth muscle motility mechanisms.
Pervasive selection pressure in wild and domestic pigs
Authors: Leno-Colorado J. , Guirao-Rico S. , Pérez-Enciso M. , Ramos-Onsins S. E. 
Published: September 2020

ABSTRACTAnimal domestication typically affected numerous polygenic quantitative traits, such as behaviour, development and reproduction. However, uncovering the genetic basis of quantitative trait variation is challenging, since it is probably caused by small allele-frequency changes. To date, only a few causative mutations related to domestication processes have been reported, strengthening the hypothesis that small effect variants have a prominent role. So far, the studies on domestication have been limited to the detection of the global effect of domestication on deleterious mutations and on strong beneficial variants, ignoring the importance of variants with small selective effects. In addition, very often, the study of the effects of selection are conducted on genome sequences that contain a non-negligible fraction of missing data, especially in non-model organisms. Hence, appropriate methods to account for these positions are needed. To overcome these difficulties, here we propose to estimate the proportion of beneficial variants using the asymptotic MacDonald-Kreitman (MK) method based on estimates of variability that summarizes the site frequency spectrum (SFS) while accounting for missing data and use them to perform an Approximate Bayesian Computation (ABC) analysis to infer the Distribution of Fitness Effects (DFE) of each population. We applied this approach to 46 genome sequences of pigs from three different populations, one wild and two domestics, with very different demographic histories and selective pressures. The obtained results showed that domestic and wild pig populations do not differ in nonsynonymous fixed mutations. Therefore, differences inαestimation among breeds are determined by their polymorphisms. The comparison ofαfor total and exclusive mutations suggests that the different domestic populations have suffered recent divergent changes in their functional versus neutral polymorphisms ratio, while the wild population is compatible withα=0. Besides, the DFE inferred with ABC indicates that both wild and domestic pigs display a large number of deleterious mutations at low frequency and a high number of neutral and/or nearly-neutral mutations that may have a significant effect on the evolution of domestic and wild populations. In addition, models not considering beneficial mutations have higher posterior probabilities, suggesting that beneficial mutations are difficult to detect or are scarce. Indeed, for all three populations, the median proportion of the strong favourable mutations are very low (≤ 0.1%) in those models that includes positive selection, with the average values of weak beneficial mutations around 0.6% for wild boar and 0.8-1.0% for the domestic pigs. Lastly, the analysis based on exclusive mutations showed that recent demographic changes may have severely affected the fitness of populations, especially that of the local Iberian breed.
Host adaptation in gut Firmicutes is associated with sporulation loss and altered colonisation patterns
Authors: Browne Hilary P. , Almeida Alexandre , Kumar Nitin , Vervier Kevin , Adoum Anne T. , Viciani Elisa , Dawson Nicholas JR , Forster Samuel C. , Cormie Claire , Goulding David , Lawley Trevor D. 
Published: September 2020

AbstractHuman-to-human transmission of symbiotic, anaerobic bacteria is a fundamental evolutionary adaptation essential for membership of the human gut microbiota. However, despite its importance, the genomic and biological adaptations underpinning symbiont transmission remain poorly understood. Here, we show that sporulation ability, which promotes transmission of anaerobic bacteria, has been independently lost in many distinct evolutionary lineages of gut bacteria belonging to the Firmicutes phyla. Analysis of 1358 genome-sequenced Firmicutes reveals loss of sporulation is associated with features of host-adaptation such as genome reduction and specialized metabolic capabilities. Consistent with these data, analysis of 28,000 gut metagenomes from people around the world demonstrates that bacteria now incapable of sporulation are more abundant but less prevalent in the human population compared to spore-forming bacteria. Our results suggest host adaptation in gut Firmicutes is an evolutionary trade-off between transmission range and colonisation abundance, leading to distinct transmission cycles. We reveal host transmission as an underappreciated process that shapes the evolution, assembly and functions of gut Firmicutes.