bluuebunny/crossref_metadata_2025_split huggingface dataset:
Self-powered piezo-bioelectronic device mediates tendon repair through modulation of mechanosensitive ion channels
Authors: Fernandez-Yague Marc A. , Trotier Alex , Abbah Sunny Akogwu , Larrañaga Aitor , Thirumaran Arun , Stapleton Aimee , Tofail Syed A. M. , Palma Matteo , Pandit Abhay , Biggs Manus J 
Published: August 2020

AbstractTendon disease constitutes an unmet clinical need and remains a critical challenge in the field of orthopaedic surgery. Innovative solutions are required to overcome the limitations of current tendon grafting approaches, and bioelectronic therapies are showing promise in the treatment of musculoskeletal disease, accelerating functional recovery through the activation of tissue regeneration signalling pathways (guided regeneration). Self-powered bioelectronic devices, and in particular piezoelectric materials represent a paradigm shift in biomedicine, negating the need for battery or external powering and complementing existing mechanotherapy to accelerate the repair processes. Here, we show the dynamic response of tendon cells to a piezoelectric collagen-analogue scaffold comprised of aligned nanoscale fibres made of the ferroelectric material poly(vinylidenefluoride-co-trifluoroethylene), (PVDF-TrFE). We demonstrate that electromechanical stimulation of tendon tissue results in guided regeneration by ion channel modulation. Finally, we show the potential of the bioelectronic device in regulating the progression of tendinopathy associated processes using a rat Achilles tendinopathy model. This study indicates that body motion-powered electromechanical stimulation can control the expression of TRPA1 and PIEZO2 receptors and stimulate tendon-specific tissue repair processes.
Distracting stimuli evoke ventral tegmental area responses in rats during ongoing saccharin consumption
Authors: Peters Kate Z , Young Andrew M J , McCutcheon James E 
Published: August 2020

AbstractDisruptions in attention, salience and increased distractibility are implicated in multiple psychiatric conditions. The ventral tegmental area (VTA) is a potential site for converging information about external stimuli and internal states to be integrated and guide adaptive behaviours. Given the dual role of dopamine signals in both driving ongoing behaviours (e.g. feeding) and monitoring salient environmental stimuli, understanding the interaction between these functions is crucial. Here we investigate VTA neuronal activity during distraction from ongoing feeding. We developed a task to assess distraction exploiting self-paced licking in rats. Rats trained to lick for saccharin were given a distraction test, in which three consecutive licks within 1 second triggered a random distractor (e.g. light and tone stimulus). On each trial they were quantified as distracted or not based on the length of their pauses in licking behaviour. We expressed GCaMP6s in VTA neurons and used fibre photometry to record calcium fluctuations during this task as a proxy for neuronal activity. Distractor stimuli caused rats to interrupt their consumption of saccharin, a behavioural effect which quickly habituated with repeat testing. VTA neural activity showed consistent increases to distractor presentations and, furthermore, these responses were greater on distracted trials compared to non-distracted trials. Interestingly, neural responses show a slower habituation than behaviour with consistent VTA responses seen to distractors even after they are no longer distracting. These data highlight the complex role of the VTA in maintaining ongoing appetitive and consummatory behaviours while also monitoring the environment for salient stimuli.
A miR-137-related biological pathway of risk for Schizophrenia is associated with human brain emotion processing
Authors: Pergola G. , Rampino A. , Di Carlo P. , Marakhovskaia A. , Quarto T. , Fazio L. , Papalino M. , Torretta S. , Amoroso N. , Castro M. N. , Domenici E. , Dukart J. , Khlghatyan J. , Monaco A. , Popolizio T. , Romano R. , Sportelli L. , Zunuer H. , Blasi G. , Beaulieu J.M. , Bertolino A. 
Published: August 2020

AbstractGenome-Wide-Association studies have involved miR-137 in schizophrenia. However, the biology underlying this statistical evidence is unclear. Statistical polygenic risk for schizophrenia is associated with working memory, while other biological evidence involves miR-137 in emotion processing. We investigated the function of miR-137 target schizophrenia risk genes in humans.We identified a prefrontal co-expression pathway of schizophrenia-associated miR-137 targets and validated the association with miR-137 expression in neuroblastoma cells. Alleles predicting greater co-expression of this pathway were associated with greater prefrontal activation during emotion processing in two independent cohorts of healthy volunteers (N1=222; N2=136). Statistical polygenic risk for schizophrenia was instead associated with prefrontal activation during working memory.A co-expression pathway links miR-137 and its target genes to emotion processing and risk for schizophrenia. Low prefrontal miR-137 expression may be related with SCZ risk via increased expression of target risk genes, itself associated with increased prefrontal activation during emotion processing.
Theta-burst TMS of lateral occipital cortex reduces BOLD responses across category-selective areas in ventral temporal cortex
Authors: Groen Iris I A , Silson Edward H , Pitcher David , Baker Chris I 
Published: August 2020

AbstractHuman visual cortex contains three scene-selective regions in the lateral, medial and ventral cortex, termed the occipital place area (OPA), medial place area (MPA) and parahippocampal place area (PPA). Using functional magnetic resonance imaging (fMRI), all three regions respond more strongly when viewing visual scenes compared with isolated objects or faces. To determine how these regions are functionally and causally connected, we applied transcranial magnetic stimulation to OPA and measured fMRI responses before and after stimulation, using a theta-burst paradigm (TBS). To test for stimulus category-selectivity, we presented a range of visual categories (scenes, buildings, objects, faces). To test for specificity of any effects to TBS of OPA we employed two control conditions: Sham, with no TBS stimulation, and an active TBS-control with TBS to a proximal face-selective cortical region (occipital face area, or OFA). We predicted that TBS to OPA (but not OFA) would lead to decreased responses to scenes and buildings (but not other categories) in other scene-selective cortical regions. Across both ROI and whole-volume analyses, we observed decreased responses to scenes in PPA as a result of TBS. However, these effects were neither category specific, with decreased responses to all stimulus categories, nor limited to scene-selective regions, with decreases also observed in face-selective fusiform face area (FFA). Furthermore, similar effects were observed with TBS to OFA, thus effects were not specific to the stimulation site in the lateral occipital cortex. Whilst these data are suggestive of a causal, but non-specific relationship between lateral occipital and ventral temporal cortex, we discuss several factors that could have underpinned this result, such as the differences between TBS and online TMS, the role of anatomical distance between stimulated regions and how TMS effects are operationalised. Furthermore, our findings highlight the importance of active control conditions in brain stimulation experiments to accurately assess functional and causal connectivity between specific brain regions.
Maternal iron deficiency perturbs embryonic cardiovascular development
Authors: Kalisch-Smith Jacinta I. , Ved Nikita , Szumska Dorota , Munro Jacob , Troup Michael , Harris Shelley E. , Jacquemot Aimée , Miller Jack J. , Stuart Eleanor M. , Wolna Magda , Hardman Emily , Prin Fabrice , Lana-Elola Eva , Aoidi Rifdat , Fisher Elizabeth M. C. , Tybulewicz Victor L. J. , Mohun Timothy J. , Lakhal-Littleton Samira , Giannoulatou Eleni , Sparrow Duncan B. 
Published: August 2020

AbstractCongenital heart disease (CHD) is the most common type of birth defect, with a global prevalence of 0.9% of live births1. Most research in the last 30 years has focused on finding genetic causes of CHD. However, despite the association of over 100 genes with CHD, mutations in these genes only explain ~30% of cases2. Many of the remaining cases of CHD are caused by in utero exposure to environmental factors3. Here we have identified a completely new environmental teratogen causing CHD: maternal iron deficiency. In humans, iron deficiency anaemia is a major global health problem. 38% of pregnant women worldwide are anaemic4, and at least half of these are due to iron deficiency, the most prevalent micronutrient deficiency. We describe a mouse model of maternal iron deficiency anaemia that causes severe cardiovascular defects in her offspring. We show that these defects likely arise from increased retinoic acid signalling in iron deficient embryos, probably due to reduced activity of the iron-dependent retinoic acid catabolic CYP26 enzymes. The defects can be prevented by maternal iron administration early in pregnancy, and are also greatly reduced in offspring of mothers deficient in both iron and the retinoic acid precursor vitamin A. Finally, one puzzling feature of many genetic forms of CHD in humans is the considerable variation in penetrance and severity of defects. We show that maternal iron deficiency acts as a significant modifier of heart and craniofacial phenotype in a mouse model of Down syndrome. Given the high incidence of maternal iron deficiency, peri-conceptional iron monitoring and supplementation could be a viable strategy to reduce the prevalence and severity of CHD in human populations worldwide.
Phylogenomic Insights into the Origin of Primary Plastids
Authors: Irisarri Iker , Strassert Jürgen F. H. , Burki Fabien 
Published: August 2020

AbstractThe origin of plastids was a major evolutionary event that paved the way for an astonishing diversification of photosynthetic eukaryotes. Plastids originated by endosymbiosis between a heterotrophic eukaryotic host and a cyanobacterium, presumably in a common ancestor of all primary photosynthetic eukaryotes (Archaeplastida). A single origin of primary plastids is well supported by plastid evidence but not by nuclear phylogenomic analyses, which have consistently failed to recover the monophyly of Archaeplastida hosts. Importantly, the monophyly of both plastid and host (nuclear) genomes is required to support a single ancestral endosymbiosis, whereas non-monophyletic hosts could be explained under scenarios of independent or serial eukaryote-to-eukaryote endosymbioses. Here, we assessed the strength of the signal for the Archaeplastida host monophyly in four available phylogenomic datasets. The effect of phylogenetic methodology, data quality, alignment trimming strategy, gene and taxon sampling, and the presence of outlier genes loci were investigated. Our analyses revealed a general lack of support for host monophyly in the shorter individual datasets. However, when analyzed together under rigorous data curation and complex mixture evolutionary models, the combined dataset consistently recovered the monophyly of Archaeplastida hosts. This study represents an important step towards better understanding the eukaryotic evolution and the origin of plastids.
De novodesign of ACE2 protein decoys to neutralize SARS-CoV-2
Authors: Linsky Thomas W. , Vergara Renan , Codina Nuria , Nelson Jorgen W. , Walker Matthew J. , Su Wen , Hsiang Tien-Ying , Esser-Nobis Katharina , Yu Kevin , Hou Yixuan J. , Priya Tanu , Mitsumoto Masaya , Pong Avery , Lau Uland Y. , Mason Marsha L. , Chen Jerry , Chen Alex , Berrocal Tania , Peng Hong , Clairmont Nicole S. , Castellanos Javier , Lin Yu-Ru , Josephson-Day Anna , Baric Ralph , Walkey Carl D. , Swanson Ryan , Gale Michael , Blancas-Mejia Luis M. , Yen Hui-Ling , Silva Daniel-Adriano 
Published: August 2020

AbstractThere is an urgent need for the ability to rapidly develop effective countermeasures for emerging biological threats, such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes the ongoing coronavirus disease 2019 (COVID-19) pandemic. We have developed a generalized computational design strategy to rapidly engineerde novoproteins that precisely recapitulate the protein surface targeted by biological agents, like viruses, to gain entry into cells. The designed proteins act as decoys that block cellular entry and aim to be resilient to viral mutational escape. Using our novel platform, in less than ten weeks, we engineered, validated, and optimizedde novoprotein decoys of human angiotensin-converting enzyme 2 (hACE2), the membrane-associated protein that SARS-CoV-2 exploits to infect cells. Our optimized designs are hyperstable de novo proteins (∼18-37 kDa), have high affinity for the SARS-CoV-2 receptor binding domain (RBD) and can potently inhibit the virus infection and replication in vitro. Future refinements to our strategy can enable the rapid development of other therapeuticde novoprotein decoys, not limited to neutralizing viruses, but to combat any agent that explicitly interacts with cell surface proteins to cause disease.
Functional Predictors of CausativeCis-Regulatory Mutations in Mendelian Disease
Authors: Bengani Hemant , Grozeva Detelina , Moyon Lambert , Bhatia Shipra , Louros Susana R , Hope Jilly , Jackson Adam , Prendergast James G , Owen Liusaidh J. , Naville Magali , Rainger Jacqueline , Grimes Graeme , Halachev Mihail , Murphy Laura C , Spasic-Boskovic Olivera , van Heyningen Veronica , Kind Peter , Abbott Catherine M , Osterweil Emily , Raymond F Lucy , Crollius Hugues Roest , FitzPatrick David R 
Published: August 2020

AbstractUndiagnosed neurodevelopmental disease is significantly associated with rare variants incis-regulatory elements (CRE) but demonstrating causality is challenging as target gene consequences may differ from a causative variant affecting the coding region. Here, we address this challenge by applying a procedure to discriminate likely diagnostic regulatory variants from those of neutral/low-penetrant effect. We identified six rare CRE variants using targeted and whole genome sequencing in 48 unrelated males with apparent X-linked intellectual disability (XLID) but without detectable coding region variants. These variants segregated appropriately in families and altered conserved bases in predicted CRE targeting known XLID genes. Three were unique and three were rare but too common to be plausibly causative for XLID. We compared thecis-regulatory activity of wild-type and mutant alleles in zebrafish embryos using dual-color fluorescent reporters. Two variants showed striking changes: one plausibly causative (FMR1CRE) and the other likely neutral/low-penetrant (TENM1CRE). These variants were “knocked-in” to mice and both altered embryonic neural expression of their target gene. OnlyFmr1CREmice showed disease-relevant behavioral defects.FMR1CREis plausibly disease-associated resulting in complex misregulation ofFmr1/FMRP rather than loss-of-function. This is consistent both with absence of Fragile X syndrome in the probands and the observed electrophysiological anomalies in theFMR1CREmouse brain. Although disruption ofin vivopatterns of endogenous gene expression in disease-relevant tissues by CRE variants cannot be used as strong evidence for Mendelian disease association, in conjunction with extreme rarity in human populations and with relevant knock-in mouse phenotypes, such variants can become likely pathogenic.
Internetwork connectivity of molecular networks across species of life
Authors: Mahajan Tarun , Dar Roy D 
Published: August 2020

AbstractBackgroundMolecular interactions have been studied as independent complex networks in systems biology. However, molecular networks dont exist independently of each other. In a network of networks approach (called multiplex), we uncover the design principles for the joint organization of transcriptional regulatory network (TRN) and protein-protein interaction (PPI) network.ResultsWe find that TRN and PPI networks are non-randomly coupled in the TRN-PPI multiplex across five different eukaryotic species. Gene degrees in TRN (number of downstream genes) are positively correlated with protein degrees in PPI (number of interacting protein partners). Gene-gene interactions in TRN and protein-protein interactions in PPI also non-randomly overlap in the multiplex. These design principles are conserved across the five eukaryotic species. We show that the robustness of the TRN-PPI multiplex is dependent on these design principles. Further, functionally important genes and proteins, such as essential, disease-related and those involved in host-pathogen PPI networks, are preferentially situated in essential parts of the human multiplex with highly overlapping interactions.ConclusionWe unveil the multiplex architecture of TRN and PPI networks across different species. Multiplex architecture may thus define a general framework for studying molecular networks across the different species of life. This approach may uncover the building blocks of the hierarchical organization of molecular interactions.
PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Reveals Important Insights into the Outbreak
Authors: Maitra Arindam , Raghav Sunil , Dalal Ashwin , Ali Farhan , Paynter Vanessa Molin , Paul Dhiraj , Biswas Nidhan K , Ghosh Arup , Jani Kunal , Chinnaswamy Sreedhar , Pati Sanghamitra , Sahu Arvind , Mitra Debashis , Bhat Manoj Kumar , Mayor Satyajit , Sarin Apurva ,   The PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium, Sauche Yogesh S. , Seshasayee Aswin Sai Narain , Palakodeti Dasaradhi , Bashyam Murali D. , Parida Ajay , Das Saumitra 
Published: August 2020

AbstractThe PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium has achieved its initial goal of completing the sequencing of 1000 SARS-CoV-2 genomes from nasopharyngeal and oropharyngeal swabs collected from individuals testing positive for COVID-19 by Real Time PCR. The samples were collected across 10 states covering different zones within India. Given the importance of this information for public health response initiatives investigating transmission of COVID-19, the sequence data is being released in GISAID database. This information will improve our understanding on how the virus is spreading, ultimately helping to interrupt the transmission chains, prevent new cases of infection, and provide impetus to research on intervention measures. This will also provide us with information on evolution of the virus, genetic predisposition (if any) and adaptation to human hosts.One thousand and fifty two sequences were used for phylodynamic, temporal and geographic mutation patterns and haplotype network analyses. Initial results indicate that multiple lineages of SARS-CoV-2 are circulating in India, probably introduced by travel from Europe, USA and East Asia. A2a (20A/B/C) was found to be predominant, along with few parental haplotypes 19A/B. In particular, there is a predominance of the D614G mutation, which is found to be emerging in almost all regions of the country. Additionally, mutations in important regions of the viral genome with significant geographical clustering have also been observed. The temporal haplotype diversities landscape in each region appears to be similar pan India, with haplotype diversities peaking between March-May, while by June A2a (20A/B/C) emerged as the predominant one. Within haplotypes, different states appear to have different proportions. Temporal and geographic patterns in the sequences obtained reveal interesting clustering of mutations. Some mutations are present at particularly high frequencies in one state as compared to others. The negative estimate Tajimas D (D = −2.26817) is consistent with the rapid expansion of SARS-CoV-2 population in India. Detailed mutational analysis across India to understand the gradual emergence of mutants at different regions of the country and its possible implication will help in better disease management.
Comparative genomics and community curation further improve gene annotations in the nematodePristionchus pacificus
Authors: Athanasouli Marina , Witte Hanh , Weiler Christian , Loschko Tobias , Eberhardt Gabi , Sommer Ralf J. , Rödelsperger Christian 
Published: August 2020

AbstractBackgroundNematode model organisms such asCaenorhabditis elegansandPristionchus pacificusare powerful systems for studying the evolution of gene function at a mechanistic level. However, the identification ofP. pacificusorthologs of candidate genes known fromC. elegansis complicated by the discrepancy in the quality of gene annotations, a common problem in nematode and invertebrate genomics.ResultsHere, we combine comparative genomic screens for suspicious gene models with community-based curation to further improve the quality of gene annotations inP. pacificus. We extend previous curations of one-to-one orthologs to larger gene families and also orphan genes. Cross-species comparisons of protein lengths and screens for atypical domain combinations and species-specific orphan genes resulted in 4,221 candidate genes that were subject to community-based curation. Corrections for 2,851 gene models were implemented in a new version of theP. pacificusgene annotations. The new set of gene annotations contains 28,896 genes and has a single copy ortholog completeness level of 97.6%.ConclusionsOur work demonstrates the effectiveness of comparative genomic screens to identify suspicious gene models and the scalability of community-based approaches to improve the quality of thousands of gene models. Similar community-based approaches can help to improve the quality of gene annotations in other invertebrate species, including parasitic nematodes.
Interannual variability of net ecosystem carbon production and its climatic and biotic mechanism during 2005-2018 in a rain-fed maize ecosystem
Authors: Zhang Hui , Zhao Tianhong , Lyu Sidan , Wu Hang , Yang Yang , Wen Xuefa 
Published: August 2020

AbstractThe interannual variation (IAV) of net ecosystem carbon production (NEP) plays an important role in understanding the mechanisms of the carbon cycle in the agriculture ecosystem. In this study, the IAV of NEP, which were expressed as annual values and anomalies, and its climatic and biotic controls mechanism, were investigated based on an eddy covariance dataset of rain-fed spring maize during 2005–2018 in the northeast of China. The annual NEP was 270±115 g C m−2yr−1. Annual values and anomalies of NEP were positively correlated with that of precipitation (PPT), gross ecosystem production (GEP) and daily maximum NEP (NEPmax). Annual anomalies of NEP were dominantly and positively controlled by the soil water content (SWC) through GEP and the soil temperature (Ts) through RE. In comparison, annual anomalies of NEP were dominantly and negatively controlled by summer VPD through the NEPmax, positively adjusted by spring precipitation and the effective accumulative temperature through the beginning date (BDOY) of the affecting carbon uptake period (CUP), and by autumn precipitation and leaf area index through the end date (EDOY) of the affecting CUP. Residues restrained the carbon release at the beginning of the year, and accelerated the carbon release at the end of the year. Our results hightlight that NEP might be more sensitive to the change of water condition (such as PPT, SWC and VPD) induced by the climate changes.