bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inequalities in the decline and recovery of pathological cancer diagnoses during the first six months of the COVID-19 pandemic: a population-based study
Authors: Hamilton Ashleigh C. , Donnelly David W. , Loughrey Maurice B. , Turkington Richard C. , Fox Colin , Fitzpatrick Deirdre , O’Neill Ciaran E. , Gavin Anna T. , Coleman Helen G. 
Published: February 2021

AbstractBackgroundThe restructuring of healthcare systems to cope with the demands of the COVID-19 pandemic has led to a reduction in clinical services such as cancer screening and diagnostics.MethodsData from the four Northern Ireland pathology labs was used to assess trends in pathological cancer diagnoses from 1st March to 12th September 2020 overall and by cancer site, gender and age. These trends were compared to the same timeframe from 2017-2019.ResultsBetween 1st March and 12th September 2020 there was a 23% reduction in cancer diagnoses compared to the same time period in the preceding three years. Although some recovery occurred in August and September 2020, this revealed inequalities across certain patient groups. Pathological diagnoses of lung, prostate and gynaecological malignancies remained well below pre-pandemic levels. Males and younger/middle-aged adults, particularly the 50-59 year old patient group, also lagged behind other population demographic groups in terms of returning to expected numbers of pathological cancer diagnoses.ConclusionsThere is a critical need to protect cancer diagnostic services in the ongoing pandemic to facilitate timely investigation of potential cancer cases. Targeted public health campaigns may be needed to reduce emerging inequalities in cancer diagnoses as the COVID-19 pandemic continues.
Consequences of the constitutive NOX2 activity in living cells: cytosol acidification, apoptosis, and localized lipid peroxidation
Authors: Valenta Hana , Dupré-Crochet Sophie , Bizouarn Tania , Baciou Laura , Nüsse Oliver , Deniset-Besseau Ariane , Erard Marie 
Published: February 2021

ABSTRACTThe phagocyte NADPH oxidase (NOX2) is a key enzyme of the innate immune system generating superoxide anions (O2•−), precursors of reactive oxygen species. The NOX2 protein complex is composed of six subunits: two membrane proteins (gp91phoxand p22phox) forming the catalytic core, three cytosolic proteins (p67phox, p47phoxand p40phox) and a small GTPase Rac. The sophisticated activation mechanism of the NADPH oxidase relies on the assembly of cytosolic subunits with the membrane-bound components. A chimeric protein, called ‘Trimera’, composed of the essential domains of the cytosolic proteins p47phox(aa 1-286), p67phox(aa 1-212) and full-length Rac1Q61L, enables a constitutive and robust NOX2 activity in cells without the need of any stimulus. We employed Trimera as a single activating protein of the phagocyte NADPH oxidase in living cells and examined the consequences on the cell physiology of this continuous and long-term NOX activity. We showed that the sustained high level of NOX activity causes acidification of the intracellular pH, triggers apoptosis and leads to local peroxidation of lipids in the membrane. These local damages to the membrane correlate with the strong tendency of the Trimera to clusterize in the plasma membrane observed by FRET-FLIM microscopy.HighlightsTrimera is a tool to trigger a continuous ROS production in living cellsContinuous NOX2 activity causes cytosol acidification and apoptosisROS overproduction leads to localized oxidation of the membrane lipidsTrimera tends to clusterize in the plasma membrane of COSNOX and COS-7 cells
Developmental depression-facilitation shift controls excitation-inhibition balance
Authors: Jia David W. , Costa Rui Ponte , Vogels Tim P. 
Published: February 2021

AbstractChanges in the short-term dynamics of excitatory synapses over development have been observed throughout cortex, but their purpose and consequences remain unclear. Here, we propose that developmental changes in synaptic dynamics buffer the effect of slow inhibitory long-term plasticity, allowing for continuously stable neural activity. Using computational modelling we demonstrate that early in development excitatory short-term depression quickly stabilises neural activity, even in the face of strong, unbalanced excitation. We introduce a model of the commonly observed developmental shift from depression to facilitation and show that neural activity remains stable throughout development, while inhibitory synaptic plasticity slowly balances excitation, consistent with experimental observations. Our model predicts changes in the input responses from phasic to phasic-and-tonic and more precise spike timings. We also observe a gradual emergence of synaptic working memory mediated by short-term facilitation. We conclude that the developmental depression-to-facilitation shift may control excitation-inhibition balance throughout development with important functional consequences.
Dense Functional and Molecular Readout of a Circuit Hub in Sensory Cortex
Authors: Condylis Cameron , Ghanbari Abed , Manjrekar Nikita , Bistrong Karina , Yao Shenqin , Yao Zizhen , Nguyen Thuc Nghi , Zeng Hongkui , Tasic Bosiljka , Chen Jerry L. 
Published: February 2021

ABSTRACTInformation processing in the neocortex is carried out by neuronal circuits composed of different cell types. Recent census of the neocortex using single cell transcriptomic profiling has uncovered more than 100 putative cell types which subdivide major classes of excitatory and inhibitory neurons into distinct subclasses. The extent to which this molecular classification predicts distinct functional roles during behavior is unclear. Here, we combined population recordings using two-photon calcium imaging with spatial transcriptomics using multiplexed fluorescentin situhybridization to achieve dense functional and molecular readout of cortical circuits during behavior. We characterized task-related responses across major transcriptomic neuronal subclasses and types in layer 2/3 of primary somatosensory cortex as mice performed a tactile working memory task. We find that as neurons are segregated into increasingly discrete molecular types, their task-related properties continue to differentiate. We identify an excitatory cell type, Baz1a, that is highly driven by tactile stimuli. Baz1a neurons homeostatically maintain stimulus responsiveness during altered sensory experience and show persistent enrichment of subsets of immediately early genes includingFos. Measurements of functional and anatomical connectivity reveal that upper layer 2/3 Baz1a neurons preferentially innervate somatostatin-expressing inhibitory neurons. We propose that this connection motif reflects a sensory-driven circuit hub that orchestrates local sensory processing in superficial layers of the neocortex.
A mitochondrial genome phylogeny of voles and lemmings (Rodentia: Arvicolinae): evolutionary and taxonomic implications
Authors: Abramson Natalia I. , Bodrov Semyon Yu. , Bondareva Olga V. , Genelt-Yanovskiy Evgeny A. , Petrova Tatyana V. 
Published: February 2021

AbstractArvicolinae is one of the most impressive placental radiations with over 150 extant and numerous extinct species that emerged since the Miocene in the Northern Hemisphere. The phylogeny of Arvicolinae has been studied intensively for several decades using morphological and genetic methods. Here, we sequenced 30 new mitochondrial genomes to better understand the evolutionary relationships among the major tribes and genera within the subfamily. The phylogenetic and molecular dating analyses based on 11,391 bp concatenated alignment of protein-coding mitochondrial genes confirmed the monophyly of the subfamily. While Bayesian analysis provided a high resolution across the entire tree, Maximum Likelihood tree reconstruction showed weak support for the ordering of divergence and interrelationships of tribal level taxa within the most ancient radiation. Both the interrelationships among tribes Lagurini, Ellobiusini and Arvicolini, comprising the largest radiation and the position of the genusDinaromyswithin it also remained unresolved. For the first time complex relationships between genus level taxa within the species-rich tribe Arvicolini received full resolution. ParticularlyLemmiscuswas robustly placed as sister to the snow volesChionomysin the tribe Arvicolini in contrast with a long-held belief of its affinity with Lagurini. Molecular dating of the origin of Arvicolinae and early divergences obtained from the mitogenome data were consistent with fossil records. The mtDNA estimates for putative ancestors of the most genera within Arvicolini appeared to be much older than it was previously proposed in paleontological studies.
Validation of the Early Warning and Response System (EWARS) for dengue outbreaks: Evidence from the national vector control program in Mexico
Authors: Benitez-Valladares David , Kroeger Axel , Sánchez Tejeda Gustavo , Hussain-Alkhateeb Laith 
Published: February 2021

AbstractBackgroundDuring 2017, twenty health districts (locations) in Mexico implemented a dengue outbreak early warning and response system (EWARS) that uses epidemiological, meteorological and entomological variables (alarm indicators) to predict dengue outbreaks and triggers early response activities.Eleven of these districts were analyzed as they presented reliable information. Nine districts presented outbreak alarms but without subsequent outbreaks (“non-outbreak districts”) and two presented after the alarms dengue outbreaks (“outbreak districts”). This study is concerned with i) if the alarms without outbreaks were false alarms or if the control services had established effective response activities averting an outbreak and ii) if vector control activities can mitigate or even avert dengue outbreaks.MethodsFive components of dengue outbreak response (larval control, entomological studies with water container interventions, focal spraying, indoor residual spraying, space spraying) were quantitatively analyzed across two groups (”outbreak districts” and “non-outbreak districts”).ResultsThe average coverage of vector control and responses were higher in non-outbreak districts and across all five components. In the “outbreak districts” the response activities started late and were of much lower intensity compared to “non-outbreak districts”. District vector control teams demonstrated diverse compliance with local guidlines for ‘initial’, ‘early’ and ‘late’ responses to outbreak alarms which could explain the different outcomes observed following the outbreak alarms.Conclusionfindings from this study plausibly demonstrates important operational scenarios when succeeding or failing alarms signals generated by EWARS at national level. This study presents evidence warranting for further investigation into the effectiveness and cost-effectiveness of EWARS using gold-standard designs.
CD4 T cell help prevents CD8 T cell exhaustion and promotes control ofMycobacterium tuberculosisinfection
Authors: Lu Yu-Jung , Barreira-Silva Palmira , Boyce Shayla , Powers Jennifer , Cavallo Kelly , Behar Samuel M. 
Published: February 2021

SummaryCD4 T cells are essential for immunity to tuberculosis because they produce cytokines including interferon-γ. Whether CD4 T cells act as “helper” cells to promote optimal CD8 T cell responses duringMycobacterium tuberculosisis unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growthin vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 T cell responses againstM. tuberculosisinfectionin vitroandin vivo. We infer vaccines that elicit both CD4 and CD8 T cells are more likely to be successful than vaccines that elicit only CD4 or CD8 T cells.
Oral Hsp90 inhibitor, SNX-5422, attenuates SARS-CoV-2 replication and dampens inflammation in airway cells
Authors: Goswami Ria , Russell Veronica S. , Tu Joshua J. , Hughes Philip , Kelly Francine , Langel Stephanie N. , Steppe Justin , Palmer Scott M. , Haystead Timothy , Blasi Maria , Permar Sallie R. 
Published: February 2021

SUMMARYCurrently available SARS-CoV-2 therapeutics are targeted towards moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. While vaccines have demonstrated protective efficacy, vaccine hesitancy and logistical distribution challenges will delay their ability to end the pandemic. Hence, there is a need for rapidly translatable, easy-to-administer-therapeutics, that can prevent SARS-CoV-2 disease progression, when administered in the early stages of infection. We demonstrate that an orally bioavailable Hsp90 inhibitor, SNX-5422, currently in clinical trials as an anti-cancer therapeutic, inhibits SARS-CoV-2 replicationin vitroat a high selectivity index. SNX-5422 treatment of human primary airway epithelial cells dampened expression of inflammatory pathways associated with poor SARS-CoV-2 disease outcomes. Additionally, SNX-5422 interrupted expression of host factors that are crucial for SARS-CoV-2 replication machinery. Development of SNX-5422 as SARS-CoV-2-early-therapy will dampen disease severity, resulting in better clinical outcomes and reduced hospitalizations.
The Mesodiencephalic Junction as a Central Hub for Cerebro-Cerebellar Communication
Authors: Wang Xiaolu , Novello Manuele , Gao Zhenyu , Ruigrok Tom J.H. , De Zeeuw Chris I. 
Published: February 2021

AbstractMost studies investigating the impact of cerebral cortex (CC) onto the cerebellum highlight the role of the pontine mossy fibre system. However, cerebro-cerebellar communication may also be mediated by the olivary climbing fibres via a hub in the mesodiencephalic junction (MDJ). Here, we show that rostromedial and caudal parts of mouse CC predominantly project to the principal olive via the rostroventral MDJ and that more rostrolateral CC regions prominently project to the rostral medial accessory olive via the caudodorsal MDJ. Moreover, transneuronal tracing results show that the cerebellar nuclei innervate the olivary-projecting neurons in the MDJ that receive input from CC, and that they adhere to the same topographical relations. By unravelling these topographic and dense, mono- and disynaptic projections from the CC through the MDJ and inferior olive to the cerebellum, this work establishes that cerebro-cerebellar communication can be mediated by both the mossy fibre and climbing fibre system.
Deep Brain Stimulation for Parkinson’s Disease Induces Spontaneous Cortical Hypersynchrony In Extended Motor and Cognitive Networks
Authors: Wang Maxwell B , Boring Matthew J , Ward Michael J , Richardson R Mark , Ghuman Avniel Singh 
Published: February 2021

AbstractThe mechanism of action of deep brain stimulation (DBS) for Parkinson’s disease remains unclear. Studies have shown that DBS decreases pathological beta hypersynchrony between the basal ganglia and motor cortex. However, little is known about DBS’s effects on long range corticocortical synchronization. Here, we use machine learning combined with spectral graph theory to compare resting-state cortical connectivity between the off and on-stimulation states and compare these differences to healthy controls. We found that turning DBS on increased high beta and gamma band coherence in a cortical circuit spanning the motor, occipitoparietal, middle temporal, and prefrontal cortices. We found no significant difference between DBS-off and controls in this network with multivariate pattern classification showing that the brain connectivity pattern in control subjects is more like those during DBS-off than DBS-on. These results show that therapeutic DBS increases spontaneous high beta-gamma synchrony in a network that couples motor areas to broader cognitive systems.
Blood progenitor redox homeostasis through GABA control of TCA cycle inDrosophilahematopoiesis
Authors: Goyal Manisha , Tomar Ajay , Madhwal Sukanya , Mukherjee Tina 
Published: February 2021

AbstractThe importance of reactive oxygen species (ROS) in myeloid cell development and function is well-established. However, a comprehensive understanding of metabolic states controlling ROS levels during hematopoiesis remains elusive. Myeloid-like blood progenitor cells of theDrosophilalarvae reside in a specialized hematopoietic organ called the lymph gland. We find that these progenitors in homeostasis, utilize TCA to generate ROS. Excessive activation of TCA however raises ROS levels causing them to precociously differentiate and leads to retardation of lymph gland size. Thus, to maintain ROS homeostasis, progenitor cells utilize systemically derived GABA. GABA internalization and catabolism via inhibiting hydroxy prolyl hydroxylase (Hph) activity, promotes pyruvate dehydrogenase kinase enzyme activity (PDK). PDK controls inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme, connecting pyruvate to TCA cycle and OXPHOS. Thus, by regulating PDK, GABA regulates progenitor TCA activity and ROS levels. In addition to this, GABA-catabolism/Hph axis via Hifα/Sima drives a glycolytic state in progenitor cells. The dual control established by GABA on PDK and Sima maintains progenitor cell metabolism and sustains ROS homeostasis necessary for their development. Taken together, our study demonstrates the metabolic underpinnings of GABA in myeloid ROS regulation and their development, the relevance of which may be broadly conserved.
Marine heatwaves depress metabolic activity and impair cellular acid-base homeostasis in reef-building corals regardless of bleaching susceptibility
Authors: Innis Teegan , Allen-Waller Luella , Brown Kristen Taylor , Sparagon Wesley , Carlson Christopher , Kruse Elisa , Huffmyer Ariana S. , Nelson Craig E. , Putnam Hollie M. , Barott Katie L. 
Published: February 2021

AbstractOcean warming is causing global coral bleaching events to increase in frequency, resulting in widespread coral mortality and disrupting the function of coral reef ecosystems. However, even during mass bleaching events, many corals resist bleaching despite exposure to abnormally high temperatures. While the physiological effects of bleaching have been well documented, the consequences of heat stress for bleaching resistant individuals are not well understood. In addition, much remains to be learned about how heat stress affects cellular level processes that may be overlooked at the organismal level, yet are crucial for coral performance in the short term and ecological success over the long term. Here we compared the physiological and cellular responses of bleaching resistant and bleaching susceptible corals throughout the 2019 marine heatwave in Hawai‘i, a repeat bleaching event that occurred four years after the previous regional event. Relative bleaching susceptibility within species was consistent between the two bleaching events, yet corals of both resistant and susceptible phenotypes exhibited pronounced metabolic depression during the heatwave. At the cellular level, bleaching susceptible corals had lower intracellular pH than bleaching resistant corals at the peak of bleaching for both symbiont-hosting and symbiont-free cells, indicating greater disruption of acid-base homeostasis in bleaching susceptible individuals. Notably, cells from both phenotypes were unable to compensate for experimentally induced cellular acidosis, indicating that acid-base regulation was significantly impaired at the cellular level even in bleaching resistant corals and in cells containing symbionts. Thermal disturbances may thus have substantial ecological consequences, as even small reallocations in energy budgets to maintain homeostasis during stress can negatively affect fitness. These results suggest concern is warranted for corals coping with ocean acidification alongside ocean warming, as the feedback between temperature stress and acid-base regulation may further exacerbate the physiological effects of climate change.
Cell Communication Network factor 4 promotes tumor-induced immunosuppression in melanoma
Authors: Fernandez Audry , Deng Wentao , McLaughlin Sarah L. , Pirkey Anika C. , Rellick Stephanie L. , Klinke David J. 
Published: February 2021

ABSTRACTImmune cell composition within the tumor microenvironment is regulated by tumor-derived factors. Cell Communication Network factor 4 (CCN4/WISP1) is a matricellular protein secreted by cancer cells that promotes metastasis by inducing the epithelial-mesenchymal transition. While metastatic dissemination limits patient survival, the absence of anti-tumor immunity also associates with poor patient out-comes with recent work suggesting these two clinical correlates are linked. Motivated by finding that CCN4 was associated with a dampened anti-tumor immune contexture in patients diagnosed with primary melanoma, we tested for a direct causal link by knocking out CCN4 (CCN4-KO) in the B16F0 and YUMM1.7 mouse models for melanoma. Tumor growth was significantly reduced when CCN4-KO melanoma cells were implanted subcutaneously in immunocompetent C57BL/6 mice but not in immunodeficient NSG mice. Correspondingly, the frequency of total CD45+tumor-infiltrating leukocytes was significantly increased in CCN4-KO tumors, with increased natural killer (NK) and effector CD8+T cells and reduced myeloid-derived suppressor cells (MDSC). Additionally, the absence of tumor-derived CCN4 was associated with an impaired splenic generation of suppressive granulocytic MDSC. Among mechanisms linked to local immunosuppression, we found CCN4 directly suppressed antigen-induced IFNγrelease by CD8+T cells, promoted glycolysis and consequent lactate release by melanoma cells, and enhanced tumor secretion of MDSC-attracting chemokines like CCL2 and CXCL1. Finally, CCN4-KO in B16F0 and YUMM1.7 melanoma cells complemented the anti-tumor effect of immune checkpoint blockade (ICB) therapy. Overall, our results suggest that CCN4 promotes tumor-induced immunosuppression and is a potential target for therapeutic combinations with ICB.Statement of SignificanceGiven emerging interest in understanding the interplay between functional plasticity and anti-tumor immunity, Cell Communication Network factor 4, a secreted matricellular protein linked to promoting metastasis in melanoma, also suppresses anti-tumor immunity.
CellWalkR: An R Package for integrating single-cell and bulk data to resolve regulatory elements
Authors: Przytycki Pawel F. , Pollard Katherine S. 
Published: February 2021

AbstractWhile single-cell open chromatin (scATAC-seq) data allows for the identification of cell type-specific regulatory regions, it is much sparser than bulk data. CellWalkR is an R package that performs an integration of external labeling and bulk epigenetic data with scATAC-seq using a network-based random walk model to help overcome this sparsity. Outputs include cell type labels for individual cells and regulatory regions.Availability and implementationCellWalkR is freely available as an R package under a GNU GPL-2.0 License, and can be accessed fromhttps://github.com/PFPrzytycki/CellWalkRwith an accompanying vignette for analyzing example data.