bluuebunny/crossref_metadata_2025_split huggingface dataset:
REACT-1 round 15 interim report: High and rising prevalence of SARS-CoV-2 infection in England from end of September 2021 followed by a fall in late October 2021
Authors: Chadeau-Hyam Marc , Eales Oliver , Bodinier Barbara , Wang Haowei , Haw David , Whitaker Matthew , Walters Caroline E. , Atchison Christina , Diggle Peter J. , Page Andrew J. , Ashby Deborah , Barclay Wendy , Taylor Graham , Cooke Graham , Ward Helen , Darzi Ara , Donnelly Christl A. , Elliott Paul 
Published: November 2021

AbstractBackgroundThe third wave of COVID-19 in England coincided with the rapid spread of the Delta variant of SARS-CoV-2 from the end of May 2021. Case incidence data from the national testing programme (Pillar 2) in England may be affected by changes in testing behaviour and other biases. Community surveys may provide important contextual information to inform policy and the public health response.MethodsWe estimated patterns of community prevalence of SARS-CoV-2 infection in England using RT-PCR swab-positivity, demographic and other risk factor data from round 15 (interim) of the REal-time Assessment of Community Transmission-1 (REACT-1) study (round 15a, carried out from 19 to 29 October 2021). We compared these findings with those from round 14 (9 to 27 September 2021).ResultsDuring mid- to late-October 2021 (round 15a) weighted prevalence was 1.72% (1.61%, 1.84%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14). The overall reproduction number (R) from round 14 to round 15a was 1.12 (1.11, 1.14) with increases in prevalence over this period (September to October) across age groups and regions except Yorkshire and The Humber. However, within round 15a (mid- to late-October) there was evidence of a fall in prevalence with R of 0.76 (0.65, 0.88). The highest weighted prevalence was observed among children aged 5 to 12 years at 5.85% (5.10%, 6.70%) and 13 to 17 years at 5.75% (5.02%, 6.57%). At regional level, there was an almost four-fold increase in weighted prevalence in South West from round 14 at 0.59% (0.43%,0.80%) to round 15a at 2.18% (1.84%, 2.58%), with highest smoothed prevalence at subregional level also found in South West in round 15a. Age, sex, key worker status, and presence of children in the home jointly contributed to the risk of swab-positivity. Among the 126 sequenced positive swabs obtained up until 23 October, all were Delta variant; 13 (10.3%) were identified as the AY.4.2 sub-lineage.DiscussionWe observed the highest overall prevalence of swab-positivity seen in the REACT-1 study in England to date in round 15a (October 2021), with a two-fold rise in swab-positivity from round 14 (September 2021). Despite evidence of a fall in prevalence from mid- to late-October 2021, prevalence remains high, particularly in school-aged children, with evidence also of higher prevalence in households with one or more children. Thus, vaccination of children aged 12 and over remains a high priority (with possible extension to children aged 5-12) to help reduce within-household transmission and disruptions to education, as well as among adults, to lessen the risk of serious disease among those infected.
An intrinsic temporal order of c-Jun N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment
Authors: Waudby Christopher A. , Alvarez-Teijeiro Saul , Suppinger Simon , Brown Paul R. , Behrens Axel , Christodoulou John , Mylona Anastasia 
Published: November 2021

AbstractProtein phosphorylation is a major regulatory mechanism of cellular signalling. The c-Jun proto-oncoprotein is phosphorylated at four residues within its transactivation domain (TAD) by the JNK family kinases, but the functional significance of c-Jun multisite phosphorylation has remained elusive. Here we show that c-Jun phosphorylation by JNK exhibits a defined temporal kinetics, with serine63 and serine73 being phosphorylated more rapidly than threonine91 and threonine93. We identified the positioning of the phosphorylation sites relative to the kinase docking motif, and their primary sequence, as the main factors controlling phosphorylation kinetics. Functional analysis revealed three c-Jun phosphorylation states: unphosphorylated c-Jun recruits the Mbd3 repressor, serine63/73 doubly-phosphorylated c-Jun binds to the Tcf4 co-activator, whereas the fully phosphorylated form disfavours Tcf4 binding attenuating JNK signalling. Thus, c-Jun phosphorylation encodes multiple functional states that drive a complex signalling response from a single JNK input.
Asymmetry of cortical functional hierarchy in humans and macaques suggests phylogenetic conservation and adaptation
Authors: Wan Bin , Bayrak Şeyma , Xu Ting , Schaare H. Lina , Bethlehem Richard A.I. , Bernhardt Boris C. , Valk Sofie L. 
Published: November 2021

AbstractThe human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, i.e., asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a hierarchical functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization. These asymmetries were heritable and comparable between humans and macaques, suggesting (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques and variable heritability in humans. This may reflect an evolutionary adaptation allowing for experience-dependent specialization, linked to higher-order cognitive functions uniquely developed in humans.
PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness
Authors: Tung Wesley S. , Chembazhi Ullas Valiya , Yang Jing , Nguyen Ka Lam , Lalwani Aryan , Bangru Sushant , Yee Danielle , Chin Kristy , Kalsotra Auinash , Mei Wenyan 
Published: November 2021

AbstractProperly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuronal cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.
The plant-specific DDR factor SOG1 increases chromatin mobility in response to DNA damage
Authors: Meschichi Anis , Reeck Svenja , Sicard Adrien , Pontvianne Frédéric , Rosa Stefanie 
Published: November 2021

SUMMARYHomologous recombination (HR) is a conservative DNA repair pathway in which intact homologous sequences are used as a template for repair. How the homology search happens in the crowded space of the cell nucleus is, however, still poorly understood. Here, we measured global chromosome and double-strand break (DSB) site mobility in Arabidopsis thaliana, using lacO/LacI lines and two GFP-tagged HR reporters. We observed an increase in global chromatin mobility upon the induction of DNA damage, specifically at the S/G2 phases of the cell cycle. DSB sites showed remarkably high mobility levels at the early HR stage, with a subsequent drastic decrease in mobility associated with the relocation of DSBs to the nucleus periphery. Importantly, the increase in mobility was lost in sog1-1 mutant, a central transcription factor of the DNA damage response in plants. Our results indicate that repair mechanisms actively regulate chromatin mobility upon DNA damage, implying an important role for this process during the early steps of the DNA damage response.
Anatomically-based skeleton kinetics and pose estimation in freely-moving rodents
Authors: Monsees Arne , Voit Kay-Michael , Wallace Damian J. , Sawinski Juergen , Leks Edyta , Scheffler Klaus , Macke Jakob H. , Kerr Jason N. D. 
Published: November 2021

AbstractForming a complete picture of the relationship between neural activity and body kinetics requires quantification of skeletal joint biomechanics during behavior. However, without detailed knowledge of the underlying skeletal motion, inferring joint kinetics from surface tracking approaches is difficult, especially for animals where the relationship between surface anatomy and skeleton changes during motion. Here we developed a videography-based method enabling detailed three-dimensional kinetic quantification of an anatomically defined skeleton in untethered freely-behaving animals. This skeleton-based model has been constrained by anatomical principles and joint motion limits and provided skeletal pose estimates for a range of rodent sizes, even when limbs were occluded. Model-inferred joint kinetics for both gait and gap-crossing behaviors were verified by direct measurement of limb placement, showing that complex decision-making behaviors can be accurately reconstructed at the level of skeletal kinetics using our anatomically constrained model.
Organization and composition of apicomplexan kinetochores reveal plasticity in chromosome segregation across parasite modes of division
Authors: Brusini Lorenzo , Santos Pacheco Nicolas Dos , Soldati-Favre Dominique , Brochet Mathieu 
Published: November 2021

SummaryKinetochores are multiprotein assemblies directing mitotic spindle attachment and chromosome segregation. In apicomplexan parasites, most known kinetochore components and associated regulators are apparently missing, suggesting a minimal structure with limited control over chromosome segregation. In this study, we use interactomics combined with deep homology searches to identify six divergent eukaryotic components, in addition to a set of eight apicomplexan kinetochore proteins (AKiTs) that bear no detectable sequence similarity to known proteins. The nanoscale organization of the apicomplexan kinetochore includes four subdomains, each displaying different evolutionary rates across the phylum. Functional analyses confirm AKiTs are essential for mitosis and reveal architectures parallel to biorientation at metaphase. Furthermore, we identify a homolog of MAD1 at the apicomplexan kinetochore, suggesting conserved spindle assembly checkpoint signaling. Finally, we show unexpected plasticity in kinetochore composition and segregation throughout the parasite lifecycle, indicating diverse requirements to maintain fidelity of chromosome segregation across apicomplexan modes of division.
Challenging the notion of a task-negative network: default mode network involvement under varying levels of cognitive effort
Authors: Weber Sarah , Aleman André , Hugdahl Kenneth 
Published: November 2021

AbstractEveryday cognitive functioning is characterized by constant alternations between different modes of information processing, driven by fluctuations in environmental demands. At the neural level, this is realized through corresponding dynamic shifts in functional activation and network connectivity. A distinction is often made between the Default Mode Network (DMN) as a task-negative network that is upregulated in the absence of cognitive demands, and task-positive networks that are upregulated when cognitive demands such as attention and executive control are present. Such networks have been labelled the Extrinsic Mode Network (EMN). We investigated changes in brain activation and functional network connectivity during repeated alternations between levels of cognitive effort. Using fMRI and a block-design Stroop paradigm, participants switched back and forth between periods of no effort (resting), low effort (word reading, automatic processing) and high effort (color naming, cognitive control). Results showed expected EMN-activation for task versus rest, and likewise expected DMN-activation for rest versus task. The DMN was also more strongly activated during low effort contrasted with high effort, suggesting a gradual up- and down-regulation of the DMN, depending on the level of demand. The often reported “anti-correlation” between DMN and EMN was only present during periods of low effort, indicating intermittent contributions of both networks. These results challenge the traditional view of the DMN as solely a task-negative network. Instead, the present results suggest that both EMN and DMN may contribute to low-effort cognitive processing. In contrast, periods of resting and high effort are dominated by the DMN and EMN, respectively.
Significant Subgraph Mining for Neural Network Inference with Multiple Comparisons Correction
Authors: Gutknecht Aaron J. , Wibral Michael 
Published: November 2021

AbstractWe describe how the recently introduced method of significant subgraph mining can be employed as a useful tool in network comparison. It is applicable whenever the goal is to compare two sets of unweighted graphs and to determine differences in the processes that generate them. We provide an extension of the method to dependent graph generating processes as the occur for example in within-subject experimental designs. Furthermore, we present an extensive investigation of error-statistical properties of the method in simulation using Erdős-Rényi models and in empirical data. In particular, we perform an empirical power analysis for transfer entropy networks inferred from resting state MEG data comparing autism spectrum patients with neurotypical controls. From this analysis one may estimate that the appropriate sample size for similar studies should be chosen in the order of n=60 per group or larger.Author summaryA key objective of neuroscientifc research is to determine how different parts of the brain are connected. The end result of such investigations is always a graph consisting of nodes corresponding to brain regions or nerve cells and edges between the nodes indicating if they are connected or not. The connections may be structural (an actual anatomical connection) but can also be functional – meaning that there is a statistical dependency between the activity in one part of the brain and the activity in another. A prime example of the latter type of connection would be the information flow between brain areas. Differences in the patterns of connectivity are likely to be responsible for and indicative of various neurological disorders such as autism spectrum disorders. It is therefore important that efficient methods to detect such differences are available. The key problem in developing methods for comparing patterns of connectivity is that there is generally a vast number of different patterns (it can easily exceed the number of stars in the milky way). In this paper we describe how the recently developed method of significant subgraph mining accounts for this problem and how it can be usefully employed in neuroscientifc research.
Nicotinic modulation insecticides act on diverse receptor subtypes with distinct subunit compositions
Authors: Lu Wanjun , Liu Zhihan , Fan Xinyu , Zhang Xinzhong , Qiao Xiaomu , Huang Jia 
Published: November 2021

AbstractInsect nicotinic acetylcholine receptors (nAChRs) are ligand gated ion channels mainly expressed in the central nervous system of insects. They are the directed targets of nicotinic modulation insecticides including neonicotinoids, the most widely used insecticides in the world. However, the resistance development from pests and the negative impacts on the pollinators affect their applications and create demand for the alternatives. Thus, it is very important to understand the mode of action of these insecticides at the molecular level, which is actually unclear for more than 30 years. In this study, we systematically examined the susceptibility of ten Drosophila melanogaster nAChR subunits mutants against eleven nicotinic modulation insecticides. Our results showed that there are several subtypes of nAChRs with distinct subunits compositions that are responsible for the toxicity of different insecticides, respectively. At least three of them are the major molecular targets of seven structurally similar neonicotinoids in vivo. On the other hand, the spinosyns may exclusively act on the α6 homomeric nAChR but not any other heteromeric pentamers. Behavioral assays using thermogenetic tools further confirmed the bioassay results and support the idea that receptor activation rather than inhibition leads to the insecticidal effects of neonicotinoids. The present findings reveal native nAChR subunit interactions with various insecticides and have important implications for resistance management and the development of novel insecticides targeting this important ion channels.Author SummaryThe neonicotinoids and spinosyns make up about 27% of the insecticides by world market value. Novel insecticides like sulfoxaflor, flupyradifurone and triflumezopyrim are developed as alternatives due to the negative effects of neonicotinoids on pollinators. Although all act via insect nicotinic acetylcholine receptors, the mode of action is unclear. Our work shows that these insecticides act on diverse receptor subtypes with distinct subunit compositions. This finding could lead to the development of more selective insecticides to control pests with minimal effects on beneficial insects.
Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type specific manner
Authors: Raun Steffen H. , Knudsen Jonas Roland , Han Xiuqing , Jensen Thomas E. , Sylow Lykke 
Published: November 2021

AbstractMetabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation is not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389 and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent of muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, skeletal muscle could be a target for managing metabolism in cancer.HighlightsCancer abrogates insulin-stimulated glucose transport selectively in oxidative soleus muscleMultiple TBC1D4 phosphorylation sites are reduced in cancer-associated muscle insulin resistanceCancer leads to increased AMPK signaling in the glycolytic EDL muscleCancer alters anabolic insulin signaling in soleus and EDL muscle
A drug repurposing screen identifies altiratinib as a selective inhibitor of a key regulatory splicing kinase and a potential therapeutic for toxoplasmosis and malaria
Authors: Swale Christopher , Bellini Valeria , Bowler Matthew W. , Flore Nardella , Brenier-Pinchart Marie-Pierre , Cannella Dominique , Belmudes Lucid , Mas Caroline , Couté Yohann , Laurent Fabrice , Scherf Artur , Bougdour Alexandre , Hakimi Mohamed-Ali 
Published: November 2021

Introductory paragraphThe apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution, highlighting key residues within the kinase catalytic site that, when mutated, confer resistance to the drug. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for TgPRP4K as well as for its P. falciparum counterpart PfCLK3. Our data also point to structural features critical for binding of the other PfCLK3 inhibitor, TCMDC-135051. Consistent with the role of this kinase family in splicing in a broad spectrum of eukaryotes, we have shown that altiratinib causes global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum. Thus, our data establish parasitic PRP4K/CLK3 as a promising pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib.
Estimating the Designability of Protein Structures
Authors: Pan Feng , Zhang Yuan , Liu Xiuwen , Zhang Jinfeng 
Published: November 2021

AbstractThe total number of amino acid sequences that can fold to a target protein structure, known as “designability”, is a fundamental property of proteins that contributes to their structure and function robustness. The highly designable structures always have higher thermodynamic stability, mutational stability, fast folding, regular secondary structures, and tertiary symmetries. Although it has been studied on lattice models for very short chains by exhaustive enumeration, it remains a challenge to estimate the designable quantitatively for real proteins. In this study, we designed a new deep neural network model that samples protein sequences given a backbone structure using sequential Monte Carlo method. The sampled sequences with proper weights were used to estimate the designability of several real proteins. The designed sequences were also tested using the latest AlphaFold2 and RoseTTAFold to confirm their foldabilities. We report this as the first study to estimate the designability of real proteins.