bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age-Related Differences in Alpha Power for Distractor Inhibition During Visual Working Memory
Authors: Sghirripa Sabrina , Graetz Lynton , Semmler John G. , Sutton Rebecca , Williams Ellen E.R. , Goldsworthy Mitchell R. 
Published: July 2023

AbstractAs visual working memory (WM) is limited in capacity, it is important to direct neural resources towards task-relevant information and away from task-irrelevant information. Neural oscillations in the alpha frequency band (8-12 Hz) have been suggested to play a role in the inhibition of distracting information during WM retention in younger adults, but it is unclear if alpha power modulation also supports distractor inhibition in older adults. Here, we recorded electroencephalography (EEG) while 24 younger (aged 18-35) and 24 older (aged 60-86) adults completed a modified delay match-to-sample task in which distractors of varying strength appeared during the retention period. We found: (1) strong distractors impaired WM performance compared with weak and no distractors in both age groups, but there were no age-differences in WM performance; (2) while younger adults demonstrated significant increases in alpha power prior to the onset of the distractor in all conditions, decreases in alpha power were seen in all distractor conditions in older adults; (3) there was no difference in alpha power between the strong and no distractor conditions; and (4) alpha power in anticipation of the distractor was only associated with task performance in younger adults. Our results suggest that younger adults, but not older adults, modulate alpha power in anticipation of distractors during the visual WM retention period.
Machine learning forecasts for seasonal epidemic peaks: lessons learnt from an atypical respiratory syncytial virus season
Authors: Morbey Roger A. , Todkill Dan , Watson Conall , Elliot Alex J. 
Published: July 2023

ABSTRACTSeasonal peaks in infectious disease incidence put pressures on health services. Therefore, early warning of the timing and magnitude of peak activity during seasonal epidemics can provide information for public health practitioners to take appropriate action. Whilst many infectious diseases have predictable seasonality, newly emerging diseases and the impact of public health interventions can result in unprecedented seasonal activity. We propose a machine learning process for generating short-term forecasts, where models are selected based on their ability to correctly forecast peaks in activity and can be useful during the aforementioned atypical seasonal activity, in contrast to traditional modelling. We have validated our forecasts using typical and atypical seasonal activity, using respiratory syncytial virus (RSV) activity during 2019-2021 as an example. During the winter of 2020/21 the usual winter peak in RSV activity in England did not occur but was ‘deferred’ until the Spring of 2021.We compare a range of machine learning regression models, with alternate models including different independent variables, e.g. with or without seasonality or trend variables. We show that the best-fitting model which minimises daily forecast errors is not the best model for forecasting peaks when the selection criterion is based on peak timing and magnitude. Furthermore, we show that best-fitting models for typical seasons contain different variables to those for atypical black swan seasons. Specifically, including seasonality in models improves performance during typical seasons but worsens it for the atypical seasons. In conclusion, we have found that including seasonality in forecast models can result in overfitting, where the models are required to be used out-of-season or during atypical seasons.
Genome-wide Association Study of Long COVID
Authors: Lammi Vilma , Nakanishi Tomoko , Jones Samuel E. , Andrews Shea J. , Karjalainen Juha , Cortés Beatriz , O’Brien Heath E. , Fulton-Howard Brian E. , Haapaniemi Hele H. , Schmidt Axel , Mitchell Ruth E. , Mousas Abdou , Mangino Massimo , Huerta-Chagoya Alicia , Sinnott-Armstrong Nasa , Cirulli Elizabeth T. , Vaudel Marc , Kwong Alex S.F. , Maiti Amit K. , Marttila Minttu , Batini Chiara , Minnai Francesca , Dearman Anna R. , Warmerdam C.A. Robert , Sequeros Celia B. , Winkler Thomas W. , Jordan Daniel M. , Guare Lindsay , Vergasova Ekaterina , Marouli Eirini , Striano Pasquale , Zainulabid Ummu Afeera , Kumar Ashutosh , Ahmad Hajar Fauzan , Edahiro Ryuya , Azekawa Shuhei ,   Long COVID Host Genetics Initiative,   FinnGen,   DBDS Genomic Consortium,   GEN-COVID Multicenter Study, Grzymski Joseph J. , Ishii Makoto , Okada Yukinori , Beckmann Noam D. , Kumari Meena , Wagner Ralf , Heid Iris M. , John Catherine , Short Patrick J. , Magnus Per , Banasik Karina , Geller Frank , Franke Lude H. , Rakitko Alexander , Duncan Emma L. , Renieri Alessandra , Tsilidis Konstantinos K. , de Cid Rafael , Niavarani Ahmadreza , Tusié-Luna Teresa , Verma Shefali S. , Smith George Davey , Timpson Nicholas J. , Daly Mark J. , Ganna Andrea , Schulte Eva C. , Richards J. Brent , Ludwig Kerstin U. , Hultström Michael , Zeberg Hugo , Ollila Hanna M. 
Published: July 2023

SummaryInfections can lead to persistent or long-term symptoms and diseases such as shingles after varicella zoster, cancers after human papillomavirus, or rheumatic fever after streptococcal infections1, 2. Similarly, infection by SARS-CoV-2 can result in Long COVID, a condition characterized by symptoms of fatigue and pulmonary and cognitive dysfunction3–5. The biological mechanisms that contribute to the development of Long COVID remain to be clarified. We leveraged the COVID-19 Host Genetics Initiative6, 7to perform a genome-wide association study for Long COVID including up to 6,450 Long COVID cases and 1,093,995 population controls from 24 studies across 16 countries. We identified the first genome-wide significant association for Long COVID at theFOXP4locus.FOXP4has been previously associated with COVID-19 severity6, lung function8, and cancers9, suggesting a broader role for lung function in the pathophysiology of Long COVID. While we identify COVID-19 severity as a causal risk factor for Long COVID, the impact of the genetic risk factor located in theFOXP4locus could not be solely explained by its association to severe COVID-19. Our findings further support the role of pulmonary dysfunction and COVID-19 severity in the development of Long COVID.
Regulation of bacterial stringent response by an evolutionary conserved ribosomal protein L11 methylation
Authors: Walukiewicz Hanna E. , Farris Yuliya , Burnet Meagan C. , Feid Sarah C. , You Youngki , Christensen David , Payne Samuel H. , Wolfe Alan J. , Rao Christopher V. , Nakayasu Ernesto S. 
Published: July 2023

AbstractLysine and arginine methylation is an important regulator of enzyme activity and transcription in eukaryotes. However, little is known about this covalent modification in bacteria. In this work, we investigated the role of methylation in bacteria. By reanalyzing a large phyloproteomics dataset from 48 bacterial strains representing 6 phyla, we found that almost a quarter of the bacterial proteome is methylated. Many of these methylated proteins are conserved across diverse bacterial lineages, including those involved in central carbon metabolism and translation. Among the proteins with the most conserved methylation sites is ribosomal protein L11 (bL11). bL11 methylation has been a mystery for five decades, as the deletion of its methyltransferase PrmA causes no cell growth defects. A comparative proteomics analysis combined with a guanosine polyphosphate assay of the ΔprmAmutant inEscherichia colirevealed that bL11 methylation is important for stringent response signaling. Moreover, we show that the ΔprmAmutant has an abnormal polysome profile, suggesting a role in ribosomal homeostasis during stationary growth phase. Overall, our investigation demonstrates that the evolutionary conserved bL11 methylation is important for stringent response signaling and ribosomal homeostasis.ImportanceProtein methylation in bacteria was first identified over sixty years ago. Since then, its functional role has been identified for only a few proteins. To better understand the functional role of methylation in bacteria, we analyzed a large phyloproteomics dataset encompassing 48 diverse bacteria. Our analysis revealed that ribosomal proteins are often methylated at conserved residues, suggesting that methylation of these sites may have a functional role in translation. Further analysis revealed that methylation of ribosomal protein L11 is important for stringent response signaling and ribosomal homeostasis.
Human Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiont
Authors: Gronke Konrad , Nguyen Mytien , Santamaria Noemi , Schumacher Julia , Yang Yi , Sonnert Nicole , Leopold Shana , Martin Anjelica L. , Hallet Remy , Richter Kirsten , Schubert David A. , Daniel Guillaume M. , Dylus David , Forkel Marianne , Vieira Silvio Manfredo , Schwinge Dorothee , Schramm Christoph , Lassen Kara G. , Piali Luca , Palm Noah W. , Bieniossek Christoph , Kriegel Martin A. 
Published: July 2023

AbstractExtraintestinal autoimmune diseases are multifactorial with translocating gut pathobionts implicated as instigators and perpetuators in mice. However, the microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. We show here that the translocating pathobiontEnterococcus gallinaruminduces human IFNγ+Th17 differentiation and IgG3 subclass switch of anti-E. gallinarumRNA and correlating anti-human RNA autoantibody responses in patients with systemic lupus erythematosus and autoimmune hepatitis. Human Th17 induction byE. gallinarumis cell-contact dependent and involves TLR8-mediated human monocyte activation. In murine gnotobiotic lupus models,E. gallinarumtranslocation triggers IgG3 anti-RNA autoantibody titers that correlate with renal autoimmune pathophysiology and with disease activity in patients. Overall, we define cellular mechanisms of how a translocating pathobiont induces human T- and B-cell-dependent autoimmune responses, providing a framework for developing host- and microbiota-derived biomarkers and targeted therapies in extraintestinal autoimmune diseases.One Sentence SummaryTranslocating pathobiontEnterococcus gallinarumpromotes human Th17 and IgG3 autoantibody responses linked to disease activity in autoimmune patients.
Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication
Authors: Yang Zemin , Johnson Bryan A. , Meliopoulos Victoria A. , Ju Xiaohui , Zhang Peipei , Hughes Michael P. , Wu Jinjun , Koreski Kaitlin P. , Chang Ti-Cheng , Wu Gang , Hixon Jeff , Duffner Jay , Wong Kathy , Lemieux Rene , Lokugamage Kumari G. , Alvardo Rojelio E. , Crocquet-Valdes Patricia A. , Walker David H. , Plante Kenneth S. , Plante Jessica A. , Weaver Scott C. , Kim Hong Joo , Meyers Rachel , Schultz-Cherry Stacey , Ding Qiang , Menachery Vineet D. , Taylor J. Paul 
Published: July 2023

AbstractG3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules.
MKT1alleles regulate stress responses through post-transcriptional modulation of Puf3 targets in budding yeast
Authors: Chaithanya Koppisetty Viswa , Sinha Himanshu 
Published: July 2023

ABSTRACTMKT1is a pleiotropic stress response gene identified by several quantitative trait studies withMKT189Gas a causal variant, contributing to growth advantage in multiple stress environments.MKT1has been shown to regulateHOendonuclease post-transcriptionally via the Pbp1-Pab1 complex. RNA-binding protein Puf3 modulates a set of nuclear-encoded mitochondrial transcripts whose expression was found to be affected byMKT1alleles. This study attempts to relate theMKT1allele-derived growth advantage with the stability of Puf3 targets during stress and elucidate the roles of Pbp1 and Puf3 in this mechanism. Our results showed that the growth advantage of theMKT189Gallele in cycloheximide and H O wasPBP1-dependent, whereas in 4NQO, the growth advantage was dependent on bothPUF3andPBP1. We compared the mRNA decay kinetics of a set of Puf3 targets in multiple stress environments to understand the allele-specific regulation byMKT1. In oxidative stress, theMKT189Gallele modulated the differential expression of nuclear-encoded mitochondrial genes in aPBP1andPUF3-dependent manner. Additionally,MKT189Gstabilised Puf3 targets, namely,COX17,MRS1, andRDL2,in an allele and stress-specific manner. Our results showed that COX17, MRS1, and RDL2 had a stress-specific response in stress environments, with theMKT189Gallele contributing to better growth; this response was bothPBP1andPUF3-dependent. Our results indicate that the common allele,MKT189G, regulates stress responses by differentially stabilising Puf3-target mitochondrial genes, which allows for the strain’s better growth in stress environments.TAKE AWAYMKT1alleles vary stress responses by post-transcriptional modulation of Puf3 targets.PBP1andPUF3influence the regulation of Puf3 target stability under stress.Nuclear-encoded mitochondrial Puf3 targetsCOX17, MRS1andRDL2,contribute to the growth advantage ofMKT189Gallele in oxidative stress.
An ex vivo human model for safety assessment of immunotoxicity of engineered nanomaterials
Authors: Blersch Josephine , Kurkowsky Birgit , Meyer-Berhorn Anja , Grabowska Agnieszka K. , Feidt Eva , Junglas Ellen , Roth Wera , Stappert Dominik , Kübelbeck Armin , Denner Philip , Fava Eugenio 
Published: July 2023

AbstractThe unique physicochemical properties of nanomaterials (NM) and engineered nanomaterials (ENM) have pushed their use in many applications ranging from medicine to the food industry, textiles, and many more fields. Thus, human exposure to NM and ENM is growing by the day. However, the current toxicity tests do not reflect the special characteristics of ENM and are not developed for ENM risk assessment. Here we propose a high-throughput cell-based assay using human peripheral blood mononuclear cells (PBMCs) that can monitor the effects of NM and ENM on cytotoxicity and innate immunity. The proposed assay is fully automated and miniaturized, with excellent assay performance parameters (Z’-score >0.5), amenable for large screening campaigns in industrial setting. Immunotoxicity data for ENM safety assessment are collected in dose-response format. At different states, multiparametric readouts for cytotoxicity, and innate immunity are conducted in a combinatorial method, avoiding ENM-induced bias by endotoxin contamination. Integrating this high-dimensional data, allows (i) holistic safety assessment of immunotoxicity effects caused by ENM, classifying safe and toxic ENM phenotypes, and (ii) to deconvolve mode of action of the ENM effect on the PBMCs. As added value the data obtained can be used to troubleshoot ENM or for a safe-by-design approach in product development.
Mesenchyme governs hair follicle induction
Authors: Mäkelä Otto J.M. , Mikkola Marja L. 
Published: July 2023

AbstractTissue interactions are essential to guide organogenesis. The development of hair follicles is regulated by inductive signalling between the embryonic surface epithelium and the adjacent mesenchyme. Previous studies have established that the mesenchymal component of the hair follicle, the dermal papilla and its precursor dermal condensate, has the capacity for de novo hair follicle induction. However, studies prior to dermal condensate formation have been inconclusive, and therefore the source and the identity of the primary inductive signal have remained unknown. Here, we performed epithelial-mesenchymal tissue recombination experiments using hair-forming back skin and glabrous plantar skin from mouse embryos to unveil that the back skin mesenchyme is inductive even prior to dermal condensate formation. Moreover, the naïve, unpatterned mesenchyme was sufficient to trigger hair follicle formation even in the oral epithelium. Considering the recognized role of Wnt signalling and Bmp activity inhibition in initiation of hair follicle development, we explored the hair-inductive ability of the Wnt agonist R-spondin-1 and a Bmp receptor inhibitor in embryonic skin explants. Although R-spondin-1 instigated precocious placode-specific transcriptional responses, it alone or in combination with the Bmp receptor inhibitor was insufficient for hair follicle induction. Our findings pave the way for identifying the hair follicle-inducing cue.
Electrophysiology of human iPSC-derived vascular smooth muscle cells and cell autonomous consequences of Cantu Syndrome mutations
Authors: Hanson Alex , McClenaghan Conor , Weng Kuo-Chan , Colijn Sarah , Stratman Amber N. , Halabi Carmen M. , Grange Dorothy K. , Silva Jonathan R. , Nichols Colin G. 
Published: July 2023

AbstractObjectiveCantu Syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by GoF variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels, and is characterized by low systemic vascular resistance, as well as tortuous, dilated vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with distinct hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell-autonomously within vascular smooth muscle cells (VSMCs), or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs.Approach and ResultsWhole-cell voltage-clamp of isolated aortic and mesenteric VSMCs isolated from wild type (WT) and Kir6.1[V65M] (CS) mice revealed no difference in voltage-gated K+(Kv) or Ca2+currents. Kvand Ca2+currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. Pinacidil-sensitive KATPcurrents in control hiPSC-VSMCs were consistent with those in WT mouse VSMCs, and were considerably larger in CS hiPSC-VSMCs. Consistent with lack of any compensatory modulation of other currents, this resulted in membrane hyperpolarization, explaining the hypomyotonic basis of CS vasculopathy. Increased compliance and dilation in isolated CS mouse aortae, was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs, suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATPGoF.ConclusionsThe results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. The results further indicate that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATPoveractivity within VSMCs.
Identification of side effects of COVID-19 drug candidates on embryogenesis using an integrated zebrafish screening platform
Authors: Ernst Alexander , Piragyte Indre , Ayisha Marwa MP , Dung Le Ngoc , Grandgirard Denis , Leib Stephen L. , Oates Andrew , Mercader Nadia 
Published: July 2023

AbstractDrug repurposing is an important strategy in COVID-19 treatment, but many clinically approved compounds have not been extensively studied in the context of embryogenesis, thus limiting their administration during pregnancy. Here we used the zebrafish embryo model organism to test the effects of 162 marketed drugs on cardiovascular development. Among the compounds used in the clinic for COVD-19 treatment, we found that Remdesivir led to reduced body size and heart functionality at clinically relevant doses. Ritonavir and Baricitinib showed reduced heart functionality and Molnupiravir and Baricitinib showed effects on embryo activity. Sabizabulin was highly toxic at concentrations only 5 times higher than Cmax and led to a mean mortality of 20% at Cmax. Furthermore, we tested if zebrafish could be used as a model to study inflammatory response in response to spike protein treatment and found that Remdesivir, Ritonavir, Molnupiravir, Baricitinib as well as Sabizabulin counteracted the inflammatory response related gene expression upon SARS-CoV-2 spike protein treatment. Our results show that the zebrafish allows to study immune-modulating properties of COVID-19 compounds and highlights the need to rule out secondary defects of compound treatment on embryogenesis. All results are available on a user friendly web-interfacehttps://share.streamlit.io/alernst/covasc_dataapp/main/CoVasc_DataApp.pythat provides a comprehensive overview of all observed phenotypic effects and allows personalized search on specific compounds or group of compounds. Furthermore, the presented platform can be expanded for rapid detection of developmental side effects of new compounds for treatment of COVID-19 and further viral infectious diseases.Summary statementA zebrafish screening platform assesses side effects on cardiovascular development and behavior of FDA approved drugs used in clinical practice to treat COVID-19 and their immune modulatory effect upon spike protein treatment.
Cellular Substrate of Eligibility Traces
Authors: Caya-Bissonnette Léa , Naud Richard , Béïque Jean-Claude 
Published: July 2023

ABSTRACTThe ability of synapses to undergo associative, activity-dependent weight changes constitutes a linchpin of current cellular models of learning and memory. It is, however, unclear whether canonical forms of Hebbian plasticity, which inherently detect correlations of cellular events occurring over short time scales, can solve the temporal credit assignment problem proper to learning driven by delayed behavioral outcomes. Recent evidence supports the existence of synaptic eligibility traces, a time decaying process that renders synapses momentarily eligible for a weight update by a delayed instructive signal. While eligibility traces offer a means of retrospective credit assignment, their material nature is unknown. Here, we combined whole-cell recordings with two-photon uncaging, calcium imaging and biophysical modeling to address this question. We observed and parameterized a form of behavioral timescale synaptic plasticity (BTSP) in layer 5 pyramidal neurons of mice prefrontal areas wherein the pairing of temporally separated pre- and postsynaptic events (0.5 s – 1 s), irrespective of order, induced synaptic potentiation. By imaging calcium in apical oblique dendrites, we reveal a short-term and associative plasticity of calcium dynamics (STAPCD) whose time-dependence mirrored the induction rules of BTSP. We identified a core set of molecular players that were essential for both STAPCD and BTSP and that, together with computational simulations, support a model wherein the dynamics of intracellular handling of calcium by the endoplasmic reticulum (ER) provides a latent memory trace of neural activity that instantiates synaptic weight updates upon a delayed instructive signal. By satisfying the requirements expected of eligibility traces, this mechanism accounts for how individual neurons can conjunctively bind cellular events that are separated by behaviorally relevant temporal delays, and thus offers a cellular model of reinforced learning.