bluuebunny/crossref_metadata_2025_split huggingface dataset:
The adverse impact of COVID-19 pandemic on cardiovascular disease prevention and management in England, Scotland and Wales: A population-scale analysis of trends in medication data
Authors: Dale Caroline E , Takhar Rohan , Carragher Ray , Torabi Fatemeh , Katsoulis Michalis , Duffield Stephen , Kent Seamus , Mueller Tanja , Kurdi Amanj , McTaggart Stuart , Abbasizanjani Hoda , Hollings Sam , Scourfield Andrew , Lyons Ronan , Griffiths Rowena , Lyons Jane , Davies Gareth , Harris Dan , Handy Alex , Mizani Mehrdad Alizadeh , Tomlinson Chris , Ashworth Mark , Denaxas Spiros , Banerjee Amitava , Sterne Jonathan , Lovibond Kate , Brown Paul , Bullard Ian , Priedon Rouven , Mamas Mamas A , Slee Ann , Lorgelly Paula , Pirmohamed Munir , Khunti Kamlesh , Sattar Naveed , Morris Andrew , Sudlow Cathie , Akbari Ashley , Bennie Marion , Sofat Reecha 
Published: January 2022

AbstractObjectivesTo estimate the impact of the COVID-19 pandemic on cardiovascular disease (CVD) and CVD management using routinely collected medication data as a proxy.DesignDescriptive and interrupted time series analysis using anonymised individual-level population-scale data for 1.32 billion records of dispensed CVD medications across 15.8 million individuals in England, Scotland and Wales.SettingCommunity dispensed CVD medications with 100% coverage from England, Scotland and Wales, plus primary care prescribed CVD medications from England (including 98% English general practices).Participants15.8 million individuals aged 18+ years alive on 1stApril 2018 dispensed at least one CVD medicine in a year from England, Scotland and Wales.Main outcome measuresMonthly counts, percent annual change (1stApril 2018 to 31stJuly 2021) and annual rates (1stMarch 2018 to 28thFebruary 2021) of medicines dispensed by CVD/ CVD risk factor; prevalent and incident use.ResultsYear-on-year change in dispensed CVD medicines by month were observed, with notable uplifts ahead of the first (11.8% higher in March 2020) but not subsequent national lockdowns. Using hypertension as one example of the indirect impact of the pandemic, we observed 491,203 fewer individuals initiated antihypertensive treatment across England, Scotland and Wales during the period March 2020 to end May 2021 than would have been expected compared to 2019. We estimated that this missed antihypertension treatment could result in 13,659 additional CVD events should individuals remain untreated, including 2,281 additional myocardial infarctions (MIs) and 3,474 additional strokes. Incident use of lipid-lowering medicines decreased by an average 14,793 per month in early 2021 compared with the equivalent months prior to the pandemic in 2019. In contrast, the use of incident medicines to treat type-2 diabetes (T2DM) increased by approximately 1,642 patients per month.ConclusionsManagement of key CVD risk factors as proxied by incident use of CVD medicines has not returned to pre-pandemic levels in the UK. Novel methods to identify and treat individuals who have missed treatment are urgently required to avoid large numbers of additional future CVD events, further adding indirect cost of the COVID-19 pandemic.
The hidden structural variability in avian genomes
Authors: Peona Valentina , Blom Mozes P. K. , Frankl-Vilches Carolina , Milá Borja , Ashari Hidayat , Thébaud Christophe , Benz Brett W. , Christidis Les , Gahr Manfred , Irestedt Martin , Suh Alexander 
Published: January 2022

AbstractStructural variants (SVs) are DNA mutations that can have relevant effects at micro- and macro-evolutionary scales. The detection of SVs is largely limited by the type and quality of sequencing technologies adopted, therefore genetic variability linked to SVs may remain undiscovered, especially in complex repetitive genomic regions. In this study, we used a combination of long-read and linked-read genome assemblies to investigate the occurrence of insertions and deletions across the chromosomes of 14 species of birds-of-paradise and two species of estrildid finches including highly repetitive W chromosomes. The species sampling encompasses most genera and representatives from all major clades of birds-of-paradise, allowing comparisons between individuals of the same species, genus, and family. We found the highest densities of SVs to be located on the microchromosomes and on the female-specific W chromosome. Genome assemblies of multiple individuals from the same species allowed us to compare the levels of genetic variability linked to SVs and single nucleotide polymorphisms (SNPs) on the W and other chromosomes. Our results demonstrate that the avian W chromosome harbours more genetic variability than previously thought and that its structure is shaped by the continuous accumulation and turnover of transposable element insertions, especially endogenous retroviruses.
Post-Translational Tubulin Modifications in Differentiated Human Neural Stem Cells
Authors: Knight V. Bleu , Jogalekar Manasi P. , Serrano Elba E. 
Published: January 2022

ABSTRACTThe tubulin protein fulfills a variety of cellular functions that range from chromosomal separation to locomotion. Functional diversity is achieved through the expression of specific tubulin isotypes in different cell types or developmental time periods. Post-translational modifications (PTMs) of tubulin also are vital for specific intracellular tasks, such as binding and recruiting motor proteins. In neurons, the isotypic expression profile for tubulin is well characterized, and the importance of PTMs for proper neuronal function has gained recent attention due to their implication in neurodegenerative disorders. In contrast, the role of tubulin specializations in the specification of neural cell fate has received minimal attention and studies of tubulin PTMs and isotypes in neuroglia such as astrocytes are relatively few. To bridge this knowledge gap, we undertook an analysis of PTMs in neurons and astrocytes derived from the federally approved H9 hESC-derived human neural stem cell (hNSC) line. In hNSCs, basal cells can be directed to assume neural fate as neurons or astrocytes by specifying different media growth conditions. Immunocytochemical methods, fluorescent antibody probes, and confocal microscopy facilitated image acquisition of fluorescent signals from class III β-tubulin (βIII-tubulin), acetylated tubulin, and polyglutamylated tubulin. Fluorescent probe intensities were assessed with the ‘EBImage’ package for the statistical programming language R, and compared using Student’s t-tests. Qualitative analysis indicated that βIII-tubulin, acetylated tubulin, and polyglutamylated tubulin were expressed to some degree in basal hNSCs and their media-differentiated hNSC neuronal and astroglial progeny. In media-differentiated hNSC astrocyte progeny, quantification and statistical analysis of fluorescence probe intensity showed that acetylated tubulin/ βIII-tubulin ratios were greater than the ratio for polyglutamylated tubulin/ βIII-tubulin. These findings represent a snapshot of the dynamic and varied changes in the tubulin expression profile during the specification of neural cell fate. Results imply that investigations of tubulin PTMs have the potential to advance our understanding of the generation and regeneration of nervous tissue.
Apoplastic CBM1-interacting proteins bind conserved carbohydrate binding module 1 motifs in fungal hydrolases to counter pathogen invasion
Authors: Takeda Takumi , Takahashi Machiko , Shimizu Motoki , Sugihara Yu , Saitoh Hiromasa , Fujisaki Koki , Ishikawa Kazuya , Utsushi Hiroe , Kanzaki Eiko , Sakamoto Yuichi , Abe Akira , Terauchi Ryohei 
Published: January 2022

AbstractWhen infecting plants, fungal pathogens secrete cell wall degrading enzymes (CWDEs) that break down cellulose and hemicellulose, the primary components of plant cell walls. Some fungal CWDEs contain a unique domain, named the carbohydrate binding module (CBM), that facilitates their access to polysaccharides. However, little is known about how plants counteract pathogen degradation of their cell walls. Here, we show that the rice cysteine-rich repeat secretion protein OsCBMIP binds to and inhibits xylanase MoCel10A of the blast fungus pathogen Magnaporthe oryzae, interfering with its access to the rice cell wall and degradation of rice xylan. We found binding of OsCBMIP to various CBM1-containing enzymes, suggesting it has a general role in inhibiting the catalytic activities of fungal enzymes. OsCBMIP is localized to the apoplast, and its expression is strongly induced in leaves infected with M. oryzae. Remarkably, knockdown of OsCBMIP reduced rice defense against M. oryzae, demonstrating that inhibition of CBM1-containing fungal enzymes by OsCBMIP is crucial for rice defense. We also identified additional CBMIP-related proteins from Arabidopsis thaliana and Setaria italica, indicating that a wide range of plants counteract pathogens through this mechanism.SummaryPlants have evolved various activity-inhibiting proteins as a defense against fungal cell wall degrading enzymes (CWDEs), but how plants counteract the function of fungal enzymes containing carbohydrate binding modules (CBMs) remains unknown. Here, we demonstrate that OsCBMIP, a member of the cysteine-rich repeat secretion protein family, interacts with fungal CBM1. OsCBMIP binding to CBM1 of a blast fungal xylanase blocks access to cellulose, resulting in the inhibition of xylanase enzymatic activity. Our study provides significant insights into plant countermeasure against CWDEs in the apoplastic space during plant–fungal pathogen interactions. It also reveals a molecular function of the DUF26 domain widely distributed in plant proteins.
Adjunctive inhibition of the integrated stress response pathway accelerates bacterial clearance in a mouse model of tuberculosis
Authors: Krug Stefanie , Prasad Pankaj , Xiao Shiqi , Lun Shichun , Ruiz-Bedoya Camilo A. , Klunk Mariah , Ordonez Alvaro A. , Jain Sanjay K. , Srikrishna Geetha , Kramnik Igor , Bishai William R. 
Published: January 2022

ABSTRACTTuberculosis (TB) is a devastating infectious disease that continues to cause millions of human deaths every year. Even though most cases of TB can be cured with a 6-month antibiotic combination therapy, these long treatment durations have led to the emergence of multi-drug resistance and pose a major hurdle to global TB control. Despite numerous advances in TB drug development, a substantially shortened treatment time has yet to be achieved. Given the rise in antibiotic resistance, an alternative strategy to the direct targeting of M. tuberculosis (M.tb) is the development of host-directed therapies (HDTs) that promote bacterial clearance and/or lung health when given adjunctive to standard TB antibiotics. We recently discovered that a small molecule inhibitor of the Integrated Stress Response (ISR), which is abnormally activated in TB and associated with the formation of necrotic granulomas, reduced M.tb numbers and lung inflammation in mice. Here, we evaluated the therapeutic potential of adjunctive ISR inhibition in the context of standard TB therapy. Throughout the course of treatment, ISR inhibition robustly lowered bacterial burdens compared to standard TB therapy alone and accelerated the time-to-sterility in mice, as demonstrated by significantly reduced relapse rates after 4 months of treatment. In addition, mice receiving adjunctive ISR inhibition tended to have reduced lung necrosis and inflammation. Together, our findings identify the ISR pathway as a promising therapeutic target with the potential of shortening TB treatment durations and improving lung health.
Liquid condensate is a common state of proteins and polypeptides at the regime of high intermolecular interactions
Authors: Poudyal Manisha , Patel Komal , Sawner Ajay Singh , Gadhe Laxmikant , Kadu Pradeep , Datta Debalina , Mukherjee Semanti , Ray Soumik , Navalkar Ambuja , Maiti Siddhartha , Chatterjee Debdeep , Bera Riya , Gahlot Nitisha , Padinhateeri Ranjith , Maji Samir K. 
Published: January 2022

AbstractLiquid-liquid phase separation (LLPS) has emerged as a crucial biological mechanism for sequestering macromolecules (such as proteins and nucleic acids) into membraneless organelles in cells. Unstructured and intrinsically disordered domains are known to facilitate multivalent interactions driving protein LLPS. We hypothesized that LLPS could be an intrinsic property of proteins/polypeptides at their high intermolecular interaction regime. To examine this, we studied many (a total of 23) proteins/polypeptides with different structures and sequences for LLPS study using molecular crowder polyethylene glycol (PEG-8000). We showed that all proteins and even highly charged polypeptides (under study) can undergo liquid condensate formation, however with different phase space and conditions. Using a single component and combinations of protein multicomponent (co-LLPS) systems, we establish that a variety of intermolecular interactions can drive proteins/polypeptides LLPS.
Region-specific alterations of perineuronal net expression in postmortem autism brain tissue
Authors: Brandenburg Cheryl , Blatt Gene J. 
Published: January 2022

AbstractGenetic variance in ASD is often associated with mechanisms that broadly fall into the category of neuroplasticity. Parvalbumin positive neurons and their surrounding perineuronal nets (PNNs) are important factors in critical period plasticity and have both been implicated in ASD. PNNs are found in high density within output structures of the cerebellum and basal ganglia, two regions that are densely connected to many other brain areas and have the potential to participate in the diverse array of symptoms present in an ASD diagnosis. The dentate nucleus and globus pallidus were therefore assessed for differences in PNN expression in human postmortem ASD brain tissue. While Purkinje cell loss is a consistent neuropathological finding in ASD, in this cohort, the Purkinje cell targets within the dentate nucleus did not show differences in number of cells with or without a PNN. However, the density of parvalbumin positive neurons with a PNN were significantly reduced in the globus pallidus internus and externus of ASD cases, which was not dependent on seizure status. It is unclear whether these alterations manifest during development or are a consequence of activity-dependent mechanisms that lead to altered network dynamics later in life.
Isoforms of the transcriptional cofactor SIN3 differentially regulate genes necessary for energy metabolism and cell survival
Authors: Mitra Anindita , Vo Linh , Soukar Imad , Chaubal Ashlesha , Greenberg Miriam L. , Pile Lori A. 
Published: January 2022

AbstractThe SIN3 scaffolding protein is a conserved transcriptional regulator known to fine-tune gene expression. In Drosophila, there are two major isoforms of SIN3, SIN3 220 and SIN3 187, which each assemble into multi-subunit histone modifying complexes. The isoforms have distinct developmental expression patterns and non-redundant functions. Gene regulatory network analyses indicate that both isoforms affect genes encoding proteins in pathways such as the cell cycle and cell morphogenesis. Interestingly, the SIN3 187 isoform uniquely regulates a subset of pathways including post-embryonic development, phosphate metabolism and apoptosis. Target genes in the phosphate metabolism pathway include nuclear-encoded mitochondrial genes coding for proteins responsible for oxidative phosphorylation. Here, we investigate the physiological effects of SIN3 isoforms on energy metabolism and cell survival. We find that ectopic expression of SIN3 187 represses expression of several nuclear-encoded mitochondrial genes affecting production of ATP and generation of reactive oxygen species (ROS). Forced expression of SIN3 187 also activates several pro-apoptotic and represses a few anti-apoptotic genes. In the SIN3 187 expressing cells, these gene expression patterns are accompanied with an increased sensitivity to paraquat-mediated oxidative stress. These findings indicate that SIN3 187 influences the regulation of mitochondrial function, apoptosis and oxidative stress response in ways that are dissimilar from SIN3 220. The data suggest that the distinct SIN3 histone modifying complexes are deployed in different cellular contexts to maintain homeostasis.
Interplay between LHCSR proteins and state transitions governs the NPQ response in intact cells of Chlamydomonas during light fluctuations
Authors: Steen Collin J. , Burlacot Adrien , Short Audrey H. , Niyogi Krishna K. , Fleming Graham R. 
Published: January 2022

AbstractPhotosynthetic organisms use sunlight as the primary energy source to fix CO2. However, in the environment, light energy fluctuates rapidly and often exceeds saturating levels for periods ranging from seconds to hours, which can lead to detrimental effects for cells. Safe dissipation of excess light energy occurs primarily by non-photochemical quenching (NPQ) processes. In the model green microalga Chlamydomonas reinhardtii, photoprotective NPQ is mostly mediated by pH-sensing light-harvesting complex stress-related (LHCSR) proteins and the redistribution of light-harvesting antenna proteins between the photosystems (state transition). Although each component underlying NPQ has been documented, their relative contributions to the dynamic functioning of NPQ under fluctuating light conditions remains unknown. Here, by monitoring NPQ throughout multiple high light-dark cycles with fluctuation periods ranging from 1 to 10 minutes, we show that the dynamics of NPQ depend on the frequency of light fluctuations. Mutants impaired in the accumulation of LHCSRs (npq4, lhcsr1, and npq4lhcsr1) showed significantly less quenching during illumination, demonstrating that LHCSR proteins are responsible for the majority of NPQ during repetitive exposure to high light fluctuations. Activation of NPQ was also observed during the dark phases of light fluctuations, and this was exacerbated in mutants lacking LHCSRs. By analyzing 77K chlorophyll fluorescence spectra and chlorophyll fluorescence lifetimes and yields in a mutant impaired in state transition, we show that this phenomenon arises from state transition. Finally, we quantified the contributions of LHCSRs and state transition to the overall NPQ amplitude and dynamics for all light periods tested and show that both processes interact to facilitate NPQ during light fluctuations. We further assess the role of LHCSRs in cell growth under various periods of fluctuating light. These results highlight the dynamic functioning of photoprotection under light fluctuations and open a new way to systematically characterize the photosynthetic response to an ever-changing light environment.One sentence summaryThe roles of LHCSR and STT7 in NPQ vary with the light fluctuation period and duration of light fluctuation.
High Speed Visual Insect Swarm Tracker (Hi-VISTA) used to identify the effects of confinement on individual insect flight
Authors: Ahmed Ishriak , Faruque Imraan A. 
Published: January 2022

AbstractIndividual insects flying in crowded assemblies perform complex aerial maneuvers by sensing and feeding back neighbor measurements to small changes in their wing motions. To understand the individual feedback rules that permit these fast, adaptive behaviors in group flight, a high-speed tracking system is needed capable of tracking both body motions and more subtle wing motion changes for multiple insects in simultaneous flight. This capability extends tracking beyond the previous focus on individual insects to multiple insects. This paper presents Hi-VISTA, which provides a capability to track wing and body motions of multiple insects using high speed cameras (9000 fps). Processing steps consist of automatic background identification, data association, hull reconstruction, segmentation, and feature measurement. To improve the biological relevance of laboratory experiments and develop a platform for interaction studies, this paper applies the Hi-VISTA measurement system toApis melliferaforagers habituated to transit flights through a transparent tunnel. Binary statistical analysis (Welch’s t-test, Cohen’s d effect size) of 95 flight trajectories is presented, quantifying the differences between flights in an unobstructed tunnel and in a confined tunnel volume. The results indicate that body pitch angle, heading rate, flapping frequency, and vertical speed (heave) are all affected by confinement, and other flight variables show minor or statistically insignificant changes. These results form a baseline as swarm tracking and analysis begins to isolate the effects of neighbors from environment.
Abnormal larval neuromuscular junction morphology and physiology in Drosophila Prickle isoform mutants with defective axonal transport and adult seizure behavior
Authors: O’Harrow Tristan , Ueda Atsushi , Xing Xiaomin , Ehaideb Salleh , Manak J. Robert , Wu Chun-Fang 
Published: January 2022

AbstractPrevious studies have demonstrated that mutations of the Drosophila planar cell polarity gene prickle (pk) result in altered microtubule-mediated vesicular transport in larval motor axons, as well as adult neuronal circuit hyperexcitability and epileptic behavior. It is also known that mutant alleles of the prickle-prickle (pkpk) and prickle-spiny-legs (pksple) isoforms differ in phenotype but display isoform counterbalancing effects in heteroallelic pkpk/pksple flies to ameliorate adult motor circuit and behavioral hyperexcitability. We have further investigated the larval neuromuscular junction (NMJ) and uncovered robust phenotypes in both pkpk and pksple alleles (heretofore referred to as pk and sple alleles, respectively), including synaptic terminal overgrowth, as well as irregular motor axon terminal excitability, poor vesicle release synchronicity, and altered efficacy of synaptic transmission. We observed significant increase in whole-cell excitatory junctional potential (EJP) in pk homozygotes, which was restored to near WT level in pk/sple heterozygotes. We further examined motor terminal excitability sustained by presynaptic Ca2+ channels, under the condition of pharmacological blockade of Na+ and K+ channel function. Such manipulation revealed extreme Ca2+ channel-dependent nerve terminal excitability in both pk and sple mutants. However, when combined in pk/sple heterozygotes, such terminal hyper-excitability was restored to nearly normal. Focal recording from individual synaptic boutons revealed asynchronous vesicle release in both pk and sple homozygotes, which nevertheless persisted in pk/sple heterozygotes without indications of isoform counter-balancing effects. Similarly, the overgrowth at NMJs was not compensated in pk/sple heterozygotes, exhibiting an extremity comparable to that in pk and sple homozygotes. Our observations uncovered differential roles of the pk and sple isoforms and their distinct interactions in the various structural and functional aspects of the larval NMJ and adult neural circuits.
Correlative cryogenic montage electron tomography for comprehensive in-situ whole-cell structural studies
Authors: Yang Jie E. , Larson Matthew R. , Sibert Bryan S. , Kim Joseph Y. , Parrell Daniel , Sanchez Juan C. , Pappas Victoria , Kumar Anil , Cai Kai , Thompson Keith , Wright Elizabeth R. 
Published: January 2022

AbstractImaging large fields of view while preserving high-resolution structural information remains a challenge in low-dose cryo-electron tomography. Here, we present robust tools for montage electron tomography tailored for vitrified specimens. The integration of correlative cryo-fluorescence microscopy, focused-ion beam milling, and micropatterning produces contextual three-dimensional architecture of cells. Montage tilt series may be processed in their entirety or as individual tiles suitable for sub-tomogram averaging, enabling efficient data processing and analysis.