bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-Stratified Genome-Wide Association Study of Multisite Chronic Pain in UK Biobank
Authors: Johnston Keira JA , Ward Joey , Ray Pradipta R , Adams Mark J , McIntosh Andrew M , Smith Blair H , Strawbridge Rona J , Price Theodore J , Smith Daniel J , Nicholl Barbara I , Bailey Mark E.S 
Published: June 2020

AbstractChronic pain is highly prevalent worldwide and imparts significant socioeconomic and public health burden and is more prevalent in women than in men. Factors that influence susceptibility and mechanisms of chronic pain development, are not fully understood.To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype in UK Biobank. Genetic correlations between MCP in each sex and a range of psychiatric, autoimmune, and anthropometric phenotypes were examined. The relationship between female and male MCP, and chronic widespread pain was investigated using polygenic risk scoring. Expression of sex-specific MCP-associated loci in a range of tissues was examined using GTEx, and separately in neural and non-neural human tissues with assessment for dorsal-root ganglion (DRG) enrichment. For genes enriched for neural-tissue expression the full GTEx database was queried for sex-differential gene expression in CNS regions, and for high expression in sex-specific tissues. Expression in neural mouse tissue was also examined for orthologs of these genes.A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS output found 87 independent SNPs to be significantly associated with MCP. We found sex-specific MCP-associated genes, with 31 genes and 37 genes associated with female and male MCP respectively and one gene associated with MCP in both sexes (DCC).We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at rgsignificantly less than 1. All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the DRG, and many showed elevated expression in sex-specific tissues.Overall, findings indicate sex differences in chronic pain at the SNP, gene and transcriptomic level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong nervous-system component to chronic pain in both sexes, emphasise the importance of the DRG, and indicate specific loci which may play a specialised role in nociception.
Peptide ligands of the cardiac ryanodine receptor as super-resolution imaging probes
Authors: Sheard Thomas M. D. , Howlett Luke , Kirton Hannah , Yang Zhaokang , Gurrola Georgina , Steele Derek , Jayasinghe Izzy , Valdivia Hector H. , Colyer John 
Published: June 2020

AbstractTo study the structural basis of pathological remodelling and altered calcium channel functional states in the heart, we sought to re-purpose high-affinity ligands of the cardiac calcium channel, the ryanodine receptor (RyR2), into super-resolution imaging probes. Imperacalcin (IpCa), a scorpion toxin peptide which induces channel sub-conduction states, and DPc10, a synthetic peptide corresponding to a sequence of the RyR2, which replicates arrhythmogenic CPVT functional changes, were used in fluorescent imaging experiments.Isolated adult rat ventricular cardiomyocytes were saponin-permeabilised and incubated with each peptide. IpCa-A546 became sequestered into the mitochondria. This was prevented by treatment of the permeabilised cells with the ionophore FCCP, revealing a striated staining pattern in confocal imaging which had weak colocalisation with RyR2 clusters. Poor specificity (as an RyR2 imaging probe) was confirmed at higher resolution with expansion microscopy (proExM) (~70 nm).DPc10-FITC labelled a striated pattern, which had moderate colocalisation with RyR2 cluster labelling in confocal and proExM. There was also widespread non-target labelling of the Z-discs, intercalated discs, and nuclei, which was unaffected by incubation times or 10 mM caffeine. The inactive peptide mut-DPc10-FITC (which causes no functional effects) displayed a similar labelling pattern.Significant labelling of structures unrelated to RyR2 by both peptide conjugates makes their use as highly specific imaging probes of RyR2 in living isolated cardiomyocytes highly challenging.We investigated the native DPc10 sequence within the RyR2 structure to understand the domain interactions and proposed mechanism of peptide binding. The native DPc10 sequence does not directly interact with another domain, and but is downstream of one such domain interface. The rabbit Arg2475 (equivalent to human Arg2474, mutated in CPVT) in the native sequence is the most accessible portion and most likely location for peptide disturbance, suggesting FITC placement does not impact peptide binding.
Ag nanoparticles-based antimicrobial polycotton fabrics to prevent the transmission and spread of SARS-CoV-2
Authors: Tremiliosi Guilherme C. , Simoes Luiz Gustavo P. , Minozzi Daniel T. , Santos Renato I. , Vilela Daiane C. B. , Durigon Edison Luiz , Machado Rafael Rahal Guaragna , Medina Douglas Sales , Ribeiro Lara Kelly , Rosa Ieda Lucia Viana , Assis Marcelo , Andrés Juan , Longo Elson , Freitas-Junior Lucio H. 
Published: June 2020

ABSTRACTPathogens (bacteria, fungus and virus) are becoming a potential threat to the health of human beings and environment worldwide. They widely exist in the environment, with characteristics of variety, spreading quickly and easily causing adverse reactions. In this work, an Ag-based material is used to be incorporated and functionalized in polycotton fabrics using pad-dry-cure method. This composite proved to be effective for inhibiting the SARS-CoV-2 virus, decreasing the number of replicates in 99.99% after an incubation period of 2 minutes. In addition, it caused 99.99% inhibition of the pathogensS. aureus,E. coliandC. albicans, preventing cross-infections and does not cause allergies or photoirritation processes, demonstrating the safety of its use.
p53 drives premature neuronal differentiation in response to radiation-induced DNA damage during early neurogenesis
Authors: Mfossa André-Claude Mbouombouo , Verslegers Mieke , Verreet Tine , Fida Haris bin , Mysara Mohamed , Van IJcken Wilfred F.J. , De Vos Winnok H. , Moons Lieve , Baatout Sarah , Benotmane Mohammed A. , Huylebroeck Danny , Quintens Roel 
Published: June 2020

Abstractp53 regulates the cellular DNA damage response (DDR). Hyperactivation of p53 during embryonic development, however, can lead to a range of developmental defects including microcephaly. Here, we induce microcephaly by acute irradiation of mouse fetuses at the onset of neurogenesis. Besides a classical DDR culminating in massive apoptosis, we observe ectopic neurons in the subventricular zone in the brains of irradiated mice, indicative of premature neuronal differentiation. A transcriptomic study indicates that p53 activates both DDR genes and differentiation-associated genes. In line with this, mice with a targeted inactivation ofTrp53in the dorsal forebrain, do not show this ectopic phenotype and partially restore brain size after irradiation. Irradiation furthermore induces an epithelial-to-mesenchymal transition-like process resembling the radiation-induced proneural-mesenchymal transition in glioma and glioma stem-like cells. Our results demonstrate a critical role for p53 beyond the DDR as a regulator of neural progenitor cell fate in response to DNA damage.
Aberrant perceptual judgements on speech-relevant acoustic features in hallucination-prone individuals
Authors: Erb Julia , Kreitewolf Jens , Pinheiro Ana P. , Obleser Jonas 
Published: June 2020

AbstractHallucinations constitute an intriguing model of how percepts are generated and how perception can fail. Here, we investigate the hypothesis that an altered perceptual weighting of the spectro-temporal modulations that characterize speech contributes to the emergence of auditory verbal hallucinations. Healthy adults (N=168) varying in their predisposition for hallucinations had to choose the ‘more speech-like’ of two presented ambiguous sound textures and give a confidence judgement. Using psychophysical reverse correlation, we quantified the contribution of different acoustic features to a listener’s perceptual decisions. Higher hallucination proneness covaried with perceptual down-weighting of speech-typical, low-frequency acoustic energy while prioritising high frequencies. Remarkably, higher confidence judgements in single trials depended not only on acoustic evidence but also on an individual’s hallucination proneness and schizotypy score. In line with an account of altered perceptual priors and differential weighting of sensory evidence, these results show that hallucination-prone individuals exhibit qualitative and quantitative changes in their perception of the modulations typical for speech.Author summaryHallucinations -- that is, percepts in the absence of an external stimulus -- are prevalent in psychotic disorders such as schizophrenia, but also occur in the general population. To date it is unknown whether the emergence of hallucinations is rooted in an altered perception of sounds. Fusing the psychophysical technique of reverse correlation with concepts from computational psychiatry, this research reveals alterations of sensory processing in hallucination-prone adults. We show that the higher nonclinical adults’ predisposition to hallucinations, the more they prioritise the sound features atypical for speech such as higher frequencies. At the same time, they express higher confidence in their perceptual judgements. The present approach may contribute to improving early diagnosis and prevention strategies in individuals at risk for psychosis.
Gray matter covariations and core symptoms of autism. The EU-AIMS Longitudinal European Autism Project
Authors: Mei Ting , Llera Alberto , Floris Dorothea L. , Forde Natalie J. , Tillmann Julian , Durston Sarah , Moessnang Carolin , Banaschewski Tobias , Holt Rosemary J. , Baron-Cohen Simon , Rausch Annika , Loth Eva , Dell’Acqua Flavio , Charman Tony , Murphy Declan G. M. , Ecker Christine , Beckmann Christian F. , Buitelaar Jan K. ,   the EU-AIMS LEAP group
Published: June 2020

AbstractBackgroundVoxel-based Morphometry (VBM) studies in Autism Spectrum Disorder (autism) have yielded diverging results. This might partly be attributed to structural alterations being associating with the combined influence of several regions rather than with a single region. Further, these structural covariation differences may relate to continuous measures of autism rather than with categorical case-control contrasts. The current study aimed to identify structural covariation alterations in autism, and assessed canonical correlations between brain covariation patterns and core autism symptoms.MethodsWe studied 347 individuals with autism and 252 typically developing individuals, aged between 6 and 30 years, who have been deeply phenotyped in the Longitudinal European Autism Project (LEAP). All participants’ VBM maps were decomposed into spatially independent components using Independent Component Analysis. A Generalized Linear Model (GLM) was used to examine case-control differences. Next, Canonical Correlation Analysis (CCA) was performed to separately explore the integrated effects between all the brain sources of gray matter variation and two sets of core autism symptoms.ResultsGLM analyses showed significant case-control differences for two independent components. The first component was primarily associated with decreased density of bilateral insula, inferior frontal gyrus, orbitofrontal cortex, and increased density of caudate nucleus in the autism group relative to typically developing individuals. The second component was related to decreased densities of the bilateral amygdala, hippocampus, and parahippocampal gyrus in the autism group relative to typically developing individuals. The CCA results showed significant correlations between components that involved variation of thalamus, putamen, precentral gyrus, frontal, parietal, and occipital lobes, and the cerebellum, and repetitive, rigid and stereotyped behaviors and abnormal sensory behaviors in autism individuals.LimitationsOnly 55.9% of the participants with autism had complete questionnaire data on continuous parent-reported symptom measures.ConclusionsCovaried areas associated with autism diagnosis and/or symptoms are scattered across the whole brain and include the limbic system, basal ganglia, thalamus, cerebellum, precentral gyrus, and parts of the frontal, parietal, and occipital lobes. Some of these areas potentially subserve social-communicative behavior whereas others may underpin sensory processing and integration, and motor behavior.
A scalable device-less biomaterial approach for subcutaneous islet transplantation
Authors: Vlahos Alexander E. , Talior-Volodarsky Ilana , Kinney Sean M. , Sefton Michael V. 
Published: June 2020

AbstractThe subcutaneous space has been shown to be a suitable site for islet transplantation, however an abundance of islets is required to achieve normoglycemia, often requiring multiple donors. The loss of islets is due to the hypoxic conditions islets experience during revascularization, resulting in apoptosis. Therefore, to reduce the therapeutic dosage required to achieve normoglycemia, pre-vascularization of the subcutaneous space has been pursued. In this study, we highlight a biomaterial-based approach using a methacrylic acid copolymer coating to generate a robust pre-vascularized subcutaneous cavity for islet transplantation. We also devised a simple, but not-trivial, procedure for filling the cavity with an islet suspension in collagen. We show that the pre-vascularized site can support a marginal mass of islets to rapidly return streptozotocin-induced diabetic SCID/bg mice to normoglycemia. Furthermore, immunocompetent Sprague Daley rats remained normoglycemia for up to 70 days until they experienced graft destabilization as they outgrew their implants. This work highlights methacrylic acid-based biomaterials as a suitable pre-vascularization strategy for the subcutaneous space that is scalable and doesn’t require exogenous cells or growth factors.SummaryIn this study methacrylic acid copolymer coated tubes generated a robust vascular response in the subcutaneous space, which was critical to support islet transplantation in a streptozotocin-induced diabetic mouse model. More importantly, the subcutaneous pre-vascularization approach using this copolymer coating was scalable into a larger allogeneic rat model and returned animals to normoglycemia for up to 70 days. This platform highlights the potential of a scalable biomaterial approach for pre-vascularization of the subcutaneous space in larger animal models.
Age and genetic background modify hybrid male sterility in house mice
Authors: Widmayer Samuel J. , Handel Mary Ann , Aylor David L. 
Published: June 2020

AbstractHybrid male sterility (HMS) contributes to reproductive isolation commonly observed among house mouse(Mus musculus)subspecies, both in the wild and in laboratory crosses. Incompatibilities involving specificPrdm9alleles and certain Chromosome (Chr) X genotypes are known determinants of fertility and HMS, and previous work in the field has demonstrated that genetic background modifies these two major loci. We constructed hybrids that have identical genotypes atPrdm9and identical X chromosomes, but differ widely across the rest of the genome. In each case, we crossed female PWK/PhJ mice representative of theM. m. musculussubspecies to males from a classical inbred strain representative ofM. m. domesticus:129S1/SvImJ, A/J, C57BL/6J, or DBA/2J. We detected three distinct trajectories of fertility among the hybrids using breeding experiments. The PWK129S1 males were always infertile. PWKDBA2 males were fertile, despite their genotypes at the major HMS loci. We also observed age-dependent changes in fertility parameters across multiple genetic backgrounds. The PWKB6 and PWKAJ males were always infertile before 15 weeks and after 35 weeks, yet some PWKB6 and PWKAJ males were fertile between fifteen and 35 weeks. This observation could resolve previous contradictory reports about the fertility of PWKB6. Taken together, these results point to multiple segregating HMS modifier alleles, some of which have age-related modes of action. The ultimate identification of these alleles and their age-related mechanisms will advance understanding both of the genetic architecture of HMS and of how reproductive barriers are maintained between house mouse subspecies.
Dynamics of a neuronal pacemaker in the weakly electric fish Apteronotus
Authors: Shifman Aaron R. , Sun Yiren , Benoit Chloé M. , Lewis John E. 
Published: June 2020

AbstractThe precise timing of neuronal activity is critical for normal brain function. In weakly electric fish, the medullary pacemaker network (PN) sets the timing for an oscillating electric organ discharge (EOD) used for electric sensing. This network is the most precise biological oscillator known, with sub-microsecond variation in oscillator period. The PN consists of two principle sets of neurons, pacemaker and relay cells, that are connected by gap junctions and normally fire in synchrony, one-to-one with each EOD cycle. However, the degree of gap junctional connectivity between these cells appears insufficient to provide the population averaging required for the observed temporal precision of the EOD. This has led to the hypothesis that individual cells themselves fire with high precision, but little is known about the oscillatory dynamics of these pacemaker cells. To this end, we have developed a biophysical model of a pacemaker neuron action potential based on experimental recordings. We validated the model by comparing the changes in oscillatory dynamics produced by different experimental manipulations. Our results suggest that a relatively simple model captures the complex dynamics exhibited by pacemaker cells, and that these dynamics may enhance network synchrony and precision.Author summaryMany neural networks in the brain exhibit activity patterns which oscillate regularly in time. These oscillations, like a clock, can provide a precise sense of time, enabling drummers to maintain complex beat patterns and pets to anticipate “feeding time”. The exact mechanisms by which brain networks give rise to these biological clocks are not clear. The pacemaker network of weakly electric fish has the highest precision of all known biological clocks. In this study, we develop a detailed biophysical model of neurons in the pacemaker network. We then validate the model against experiments using a nonlinear dynamics approach. Our results show that pacemaker precision is due, at least in part, to how individual pacemaker cells generate their activity. This supports the idea that temporal precision in this network is not solely an emergent property of the network but also relies on the dynamics of individual neurons.
Capturing heterogeneous infectiousness in transmission dynamic models of tuberculosis: a compartmental modelling approach
Authors: Melsew Yayehirad A , Ragonnet Romain , Cheng Allen C , McBryde Emma S , Trauer James M 
Published: June 2020

AbstractInfectiousness heterogeneity among individuals with tuberculosis (TB) is substantial and is likely to have a significant impact on the long-term dynamics of TB and the effectiveness of interventions. However, there is a gap in capturing heterogeneous infectiousness and evaluating its impact on the effectiveness of interventions.Informed by observed distribution of secondary infections, we constructed a deterministic model of TB transmission using ordinary differential equations. The model incorporated assumption of heterogeneous infectiousness with three levels of infectivity, namely non-spreaders, low-spreaders and super-spreaders. We evaluated the effectiveness of dynamic transmission untargeted and targeted implementation of an intervention intended to represent active case finding with a point-of-care diagnostic tool. The simulated intervention detected 20% of all TB patients who would otherwise have been missed by the health system during their disease episode and was compared across four epidemiological scenarios.Our model suggested that targeting the active case finding intervention towards super-spreaders was more effective than untargeted intervention in all setting scenarios, with more effectiveness in settings with low case detection and high transmission intensity. For instance, a targeted intervention achieved a 42.2% reduction in TB incidence, while the untargeted intervention achieved only a 20.7% reduction over 20 years, given the same number of people treated. Although the most marked impact on equilibrium TB incidence came from the rate of late reactivation, the proportion of super-spreaders and their relative infectiousness had shown substantial impact.Targeting active case-finding interventions to highly infectious cases likely to be particularly beneficial in settings where case detection is poor. Heterogeneity-related parameters had an equivalent effect to several other parameters that have been established as being very important to TB transmission dynamics.
CRISPR-induced indels and base editing using theStaphylococcus aureusCas9 in potato
Authors: Veillet Florian , Kermarrec Marie-Paule , Chauvin Laura , Chauvin Jean-Eric , Nogué Fabien 
Published: June 2020

AbstractGenome editing is now widely used in plant science for both fundamental research and molecular crop breeding. The clustered regularly interspaced short palindromic repeats (CRISPR) technology, through its precision, high efficiency and versatility, allows to edit many sites in plant genomes. This system has been highly successful to produce of knock-out mutants through the introduction of frameshift mutations due to error-prone repair pathways. Nevertheless, recent new CRISPR-based technologies such as base editing and prime editing can generate precise and on request nucleotide conversion, allowing to fine-tune protein function and generate gain-of-function mutants. However, genome editing through CRISPR systems still have some drawbacks and limitations, such as the PAM restriction and the need for more diversity in CRISPR tools to simultaneously mediate different catalytic activities. In this study, we successfully used the CRISPR-Cas9 system fromStaphylococcus aureus(SaCas9) for the introduction of frameshift mutations in the tetraploid genome of the cultivated potato (Solanum tuberosum). We also developed aS. aureus-cytosine base editor that mediate nucleotide conversions, allowing to precisely modify specific residues or regulatory elements in potato. Our proof-of-concept results in potato expand the plant dicot CRISPR toolbox for biotechnology and precision breeding applications.