bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in the trajectory of Long Covid symptoms following COVID-19 vaccination: community-based cohort study
Authors: Ayoubkhani Daniel , Bermingham Charlotte , Pouwels Koen B. , Glickman Myer , Nafilyan Vahé , Zaccardi Francesco , Khunti Kamlesh , Alwan Nisreen A. , Walker A. Sarah 
Published: December 2021

AbstractObjectiveTo estimate associations between COVID-19 vaccination and Long Covid symptoms in adults who were infected with SARS-CoV-2 prior to vaccination.DesignObservational cohort study using individual-level interrupted time series analysis.SettingRandom sample from the community population of the UK.Participants28,356 COVID-19 Infection Survey participants (mean age 46 years, 56% female, 89% white) aged 18 to 69 years who received at least their first vaccination after test-confirmed infection.Main outcome measuresPresence of long Covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021.ResultsMedian follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (84% of participants). First vaccination was associated with an initial 12.8% decrease (95% confidence interval: −18.6% to −6.6%) in the odds of Long Covid, but increasing by 0.3% (−0.6% to +1.2%) per week after the first dose. Second vaccination was associated with an 8.8% decrease (−14.1% to −3.1%) in the odds of Long Covid, with the odds subsequently decreasing by 0.8% (−1.2% to −0.4%) per week. There was no statistical evidence of heterogeneity in associations between vaccination and Long Covid by socio-demographic characteristics, health status, whether hospitalised with acute COVID-19, vaccine type (adenovirus vector or mRNA), or duration from infection to vaccination.ConclusionsThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose. Vaccination may contribute to a reduction in the population health burden of Long Covid, though longer follow-up time is needed.Summary boxWhat is already known on this topicCOVID-19 vaccines are effective at reducing rates of SARS-CoV-2 infection, transmission, hospitalisation, and deathThe incidence of Long Covid may be reduced if infected after vaccination, but the relationship between vaccination and pre-existing long COVID symptoms is unclear, as published studies are generally small and with self-selected participantsWhat this study addsThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second doseThere was no evidence of differences in this relationship by socio-demographic characteristics, health-related factors, vaccine type, or duration from infection to vaccinationAlthough causality cannot be inferred from this observational evidence, vaccination may contribute to a reduction in the population health burden of Long Covid; further research is needed to understand the biological mechanisms that may ultimately contribute to the development of therapeutics for Long Covid
Minor intron splicing efficiency increases with the development of lethal prostate cancer
Authors: Augspach Anke , Drake Kyle D. , Roma Luca , Qian Ellen , Lee Se Ri , Clarke Declan , Kumar Sushant , Jaquet Muriel , Gallon John , Bolis Marco , Triscott Joanna , Galván José A. , Chen Yu , Thalmann George , Julio Marianna Kruithof-de , Theurillat Jean-Philippe P. , Wuchty Stefan , Gerstein Mark , Piscuoglio Salvatore , Kanadia Rahul N. , Rubin Mark A. 
Published: December 2021

SummaryHere we explored the role of minor spliceosome (MiS) function and minor intron-containing gene (MIG) expression in prostate cancer (PCa). We show MIGs are enriched as direct interactors of cancer-causing genes and their expression discriminates PCa progression. Increased expression of MiS U6atac snRNA, including others, and 6x more efficient minor intron splicing was observed in castration-resistant PCa (CRPC) versus primary PCa. Notably, androgen receptor signalling influenced MiS activity. Inhibition of MiS through siU6atac in PCa caused minor intron mis-splicing and aberrant expression of MIG transcripts and encoded proteins, which enriched for MAPK activity, DNA repair and cell cycle. Single cell-RNAseq confirmed cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. siU6atac was ∼50% more efficient in lowering tumor burden of CRPC cells and organoids versus current state-of-the-art combination therapy. In all, MiS is a strong therapeutic target for lethal PCa and potentially other cancers.Graphical AbstractU6atac expression, MiS activity, and minor intron splicing correlate with PCa therapy resistance and PCa progression to CRPC-adeno and transdifferentiation to CRPC-NE. One major MiS regulator during that process is the AR-axis, which is re-activated during CRPC-adeno and blocked in CRPC-NE. Molecularly, an increase in MiS dependent splicing promotes changes of transcriptome and proteome. This results in cell cycle activation, increased MAPK signalling and increased DNA repair. U6atac mediated MiS inhibition renders MiS splicing error-prone through increased intron retention and alternative splicing events, which results in cell cycle block and decreased MAPK signalling and DNA repair. MiS inhibition blocks all stages of PCa. Figure created withBioRender.com.
Lessons on fruiting body morphogenesis from genomes and transcriptomes of Agaricomycetes
Authors: Nagy László G. , Vonk Peter Jan , Künzler Markus , Földi Csenge , Virágh Máté , Ohm Robin A. , Hennicke Florian , Bálint Balázs , Csernetics Árpád , Hegedüs Botond , Hou Zhihao , Liu Xiao-Bin , Nan Shen , Pareek Manish , Sahu Neha , Szathmári Benedek , Varga Torda , Wu Hongli , Yang Xiao , Merényi Zsolt 
Published: December 2021

AbstractFruiting bodies of mushroom-forming fungi (Agaricomycetes) are among the most complex structures produced by fungi. Unlike vegetative hyphae, fruiting bodies grow determinately and follow a genetically encoded developmental program that orchestrates tissue differentiation, growth and sexual sporulation. In spite of more than a century of research, our understanding of the molecular details of fruiting body morphogenesis is limited and a general synthesis on the genetics of this complex process is lacking. In this paper, we aim to comprehensively identify conserved genes related to fruiting body morphogenesis and distill novel functional hypotheses for functionally poorly characterized genes. As a result of this analysis, we report 921 conserved developmentally expressed gene families, only a few dozens of which have previously been reported in fruiting body development. Based on literature data, conserved expression patterns and functional annotations, we provide informed hypotheses on the potential role of these gene families in fruiting body development, yielding the most complete description of molecular processes in fruiting body morphogenesis to date. We discuss genes related to the initiation of fruiting, differentiation, growth, cell surface and cell wall, defense, transcriptional regulation as well as signal transduction. Based on these data we derive a general model of fruiting body development, which includes an early, proliferative phase that is mostly concerned with laying out the mushroom body plan (via cell division and differentiation), and a second phase of growth via cell expansion as well as meiotic events and sporulation. Altogether, our discussions cover 1480 genes ofCoprinopsis cinerea, and their orthologs inAgaricus bisporus, Cyclocybe aegerita, Armillaria ostoyae, Auriculariopsis ampla, Laccaria bicolor, Lentinula edodes, Lentinus tigrinus, Mycena kentingensis, Phanerochaete chrysosporium, Pleurotus ostreatus,andSchizophyllum commune, providing functional hypotheses for ∼10% of genes in the genomes of these species. Although experimental evidence for the role of these genes will need to be established in the future, our data provide a roadmap for guiding functional analyses of fruiting related genes in the Agaricomycetes. We anticipate that the gene compendium presented here, combined with developments in functional genomics approaches will contribute to uncovering the genetic bases of one of the most spectacular multicellular developmental processes in fungi.
eIF5B and eIF1A remodel human translation initiation complexes to mediate ribosomal subunit joining
Authors: Lapointe Christopher P. , Grosely Rosslyn , Sokabe Masaaki , Alvarado Carlos , Wang Jinfan , Montabana Elizabeth , Villa Nancy , Shin Byung-Sik , Dever Thomas E. , Fraser Christopher S. , Fernández Israel S. , Puglisi Joseph D. 
Published: December 2021

ABSTRACTJoining of the ribosomal subunits at a translation start site on a messenger RNA during initiation commits the ribosome to synthesize a protein. Here, we combined single-molecule spectroscopy and structural methods using anin vitroreconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when universally-conserved eukaryotic initiation factors (eIFs) eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we examined initiation complexes that contained both eIF1A and eIF5B using single-particle electron cryo-microscopy. The resulting structure illuminated how eukaryote-specific contacts between eIF1A and eIF5B remodel the initiation complex to orient initiator tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during human translation initiation.
Programmable in vivo CRISPR activation elucidates the oncogenic and immunosuppressive role of MYC in lung adenocarcinoma
Authors: Thege Fredrik I. , Rupani Dhwani N. , Barathi Bhargavi B. , Manning Sara L. , Maitra Anirban , Rhim Andrew D. , Wörmann Sonja M. 
Published: December 2021

AbstractConventional genetically engineered mouse models (GEMMs) are time consuming, laborious and offer limited spatio-temporal control. Here, we describe the development of a streamlined platform for in vivo gene activation using CRISPR activation (CRISPRa) technology. Unlike conventional GEMMs, our model system allows for flexible, sustained and timed activation of one or more target genes using single or pooled lentiviral guides. Using Myc and Yap1 as model oncogenes, we demonstrate gene activation in primary pancreatic organoid cultures in vitro and enhanced tumorigenic potential in Myc-activated organoids when transplanted orthotopically. By implementing our model as an autochthonous lung cancer model, we show that transduction-mediated Myc activation leads to accelerated tumor progression and significantly reduced overall survival relative to non-targeted tumor controls. Furthermore, we found that Myc-activation led to the acquisition of an immune suppressive “cold” tumor microenvironment. Through cross-species validation of our results using publicly available RNA/DNA-seq data sets, we were able to link MYC to a previously described, immunosuppressive transcriptomic subtype in patient tumors, thus identifying a patient cohort that may benefit from combined MYC/immune-targeted therapies. Overall, our work demonstrates how CRISPRa can be used for rapid functional validation of putative oncogenes and may allow for the identification and evaluation of potential metastatic and oncogenic drivers through competitive screening.
CD4+and CD8+regulatory T cells characterization in the rat using a unique transgenicFoxp3-EGFPmodel
Authors: Ménoret Séverine , Tesson Laurent , Remy Séverine , Gourain Victor , Sérazin Céline , Usal Claire , Guiffes Aude , Chenouard Vanessa , Ouisse Laure-Hélène , Gantier Malika , Heslan Jean-Marie , Fourgeux Cynthia , Poschmann Jeremie , Guillonneau Carole , Anegon Ignacio 
Published: December 2021

AbstractBackgroundCD4+and CD8+regulatory T cells (Treg) in diverse species include different subsets from different origins. In all species, CD8+Treg have been poorly characterized. CD4+and CD8+Treg in rats have only partially been characterized and there is no rat model in which FOXP3+Treg are genetically tagged.ResultsWe generated a rat transgenic line using the CRISPR/Cas9 system in which EGFP was inserted in frame on the 3’ end of theFoxp3gene using a 2A self-cleaving peptide. EGFP was exclusively expressed by CD4+and CD8+T cells in similar proportion as observed with anti-FOXP3 antibodies. CD4+EGFP+Treg were 5-10 times more frequent than CD8+EGFP+Treg. CD4+and CD8+EGFP+Treg expressed both the CD25highCD127lowCD45RClow/-markers. The suppressive activity of CD4+and CD8+Treg was largely confined to EGFP+cells. RNAseq analyses showed similarities but also differences among CD4+and CD8+EGFP+cells and provided the first description of the natural FOXP3+CD8+Treg transcriptome. In vitro culture of CD4+and CD8+EGFP-cells with TGFbeta and IL-2 resulted in the induction of EGFP+Treg. Preferential expansion of CD4+and CD8+EGFP+Treg could be detected upon in vivo administration of a low dose of IL-2.ConclusionsThis new and uniqueFoxp3-EGFPrat line constitutes a useful model to identify and isolate viable natural and induced CD4+and CD8+Treg. Additionally, it allows to identify new molecules expressed in CD8+Treg that may allow to better define their phenotype and function not only in rats but also in other species.
How growers make decisions impacts plant disease control
Authors: Murray-Watson Rachel E. , Hamelin Frédéric M. , Cunniffe Nik J. 
Published: December 2021

AbstractWhile the spread of plant disease depends strongly on biological factors driving transmission, it also has a human dimension. Disease control depends on decisions made by individual growers, who are in turn influenced by a broad range of factors. Despite this, human behaviour has rarely been included in plant epidemic models. Considering Cassava Brown Streak Disease, we model how the perceived increase in profit due to disease management influences participation in clean seed systems (CSS). Our models are rooted in game theory, with growers making strategic decisions based on the expected profitability of different control strategies. We find that both the information used by growers to assess profitability and the perception of economic and epidemiological parameters influence long-term participation in the CSS. Over-estimation of infection risk leads to lower participation in the CSS, as growers perceive that paying for the CSS will be futile. Additionally, even though good disease management can be achieved through the implementation of CSS, and a scenario where all controllers use the CSS is achievable when growers base their decision on the average of their entire strategy, CBSD is rarely eliminated from the system. These results are robust to stochastic and spatial effects. Our work highlights the importance of including human behaviour in plant disease models, but also the significance of how that behaviour is included.1Author SummaryModels of plant disease epidemics rarely account for the behaviour of growers undertaking management decisions. However, such behaviour is likely to have a large impact on disease spread. Growers may choose to participate in a control scheme based on the perceived economic advantages, acting to maximise their own profit. Yet if many growers participate in a control scheme, their participation will lower the probability of others becoming infected and consequently disincentivise them from participating themselves. How these dynamics play out will alter the course of the epidemic. We incorporate these economic considerations into an epidemic model of Cassava Brown Streak Disease using two broad approaches, which vary in the amount of information provided to growers. We also consider the effect of grower misperception of economic and epidemiological parameters. Our work shows that both the inclusion of grower behaviour, and its means of inclusion, affect disease dynamics, and highlights the importance of including grower decision-making in plant epidemic models.
Nuclear NAD+ homeostasis is essential for naive and chemoresistant BRCA1/2-deficient tumor survival
Authors: Musiani Daniele , Yücel Hatice , Sourd Laura , Marangoni Elisabetta , Ceccaldi Raphael 
Published: December 2021

AbstractResistance to PARP inhibitors (PARPi) is emerging as the major obstacle to their effectiveness for the treatment of BRCA1/2-mutated, also referred as homologous recombination (HR)-deficient, tumors (HRD). Over the years, mechanistic studies gained insights on effectors acting downstream of PARP1, lagging behind the understanding of earlier events upstream - and thus independent - of PARP1. Here, we investigated the role of nuclear NAD+, an essential cofactor for the activity of key DNA repair proteins, including PARP1 and sirtuins. We show that NMNAT1-the enzyme synthesizing nuclear NAD+ - is synthetically lethal with BRCA1/2 in a PARP1-independent but SIRT6-dependent manner. Consequently, inhibition of NMNAT1/SIRT6 axis not only kills naive but also PARPi-resistant HRD cancer cells. Our results unravel a unique vulnerability of HRD tumors, therapeutically exploitable even upon PARPi resistance development.One-Sentence SummaryTargeting NMNAT1 kills chemoresistant and naive BRCA1/2-deficient tumors by disrupting SIRT6-dependent base excision repair.
A striatal circuit balances learned fear in the presence and absence of sensory cues
Authors: Kintscher Michael , Kochubey Olexiy , Schneggenburger Ralf 
Published: December 2021

AbstractDuring fear learning, defensive behaviors like freezing need to be finely balanced in the presence or absence of threat-predicting cues (conditioned stimulus, CS). Nevertheless, the circuits underlying such balancing are largely unknown. Here, we investigate the role of the ventral tail striatum (vTS) in auditory-cued fear learning of male mice.In-vivoCa2+imaging showed that robust sub- populations of direct (D1R+) and indirect pathway neurons (Adora+) in the vTS responded to footshocks, and to the initiation of movements after freezing; moreover, a sub-population of D1R+ neurons increased its responsiveness to an auditory CS during fear learning.In-vivooptogenetic silencing shows that footshock-driven activity of D1R+ neurons contributes to fear memory formation, whereas Adora+ neurons modulate freezing in the absence of a learned CS. Circuit tracing identified the posterior insular cortex (pInsCx) as an important cortical input to the vTS, and recording of optogenetically-evoked EPSCs revealed long-term plasticity with opposite outcomes at the cortical synapses onto D1R+ - and Adora+ neurons. Thus, direct- and indirect pathways neurons of the vTS show differential signs of plasticity after fear learning, and balance defensive behaviors in the presence and absence of learned sensory cues.
Engineered biological neural networks on high density CMOS microelectrode arrays
Authors: Duru Jens , Küchler Joël , Ihle Stephan J. , Forró Csaba , Bernardi Aeneas , Girardin Sophie , Hengsteler Julian , Wheeler Stephen , Vörös János , Ruff Tobias 
Published: December 2021

ABSTRACTIn bottom-up neuroscience, questions on neural information processing are addressed by engineering small but reproducible biological neural networks of defined network topology in vitro. The network topology can be controlled by culturing neurons within polydimethylsiloxane (PDMS) microstructures that are combined with microelectrode arrays (MEAs) for electric access to the network. However, currently used glass MEAs are limited to 256 electrodes and pose a limitation to the spatial resolution as well as the design of more complex microstructures. The use of high density complementary metal-oxide-semiconductor (CMOS) MEAs greatly increases the spatiotemporal resolution, enabling sub-cellular readout and stimulation of neurons in defined neural networks. Unfortunately, the non-planar surface of CMOS MEAs complicates the attachment of PDMS microstructures. To overcome the problem of axons escaping the microstructures through the ridges of the CMOS MEA, we stamp-transferred a thin film of hexane-diluted PDMS onto the array such that the PDMS filled the ridges at the contact surface of the microstructures without clogging the axon guidance channels. Moreover, we provide an impedance-based method to visualize the exact location of the microstructures on the MEA and show that our method can confine axonal growth within the PDMS microstructures. Finally, the high spatiotemporal resolution of the CMOS MEA enabled us to show that we can guide action potentials using the unidirectional topology of our circular multi-node microstructure.
OSBP-mediated cholesterol transfer determines epithelial polarity and associated cargo secretion
Authors: Kovács Dávid , Gay Anne-Sophie , Fleuriot Lucile , Debayle Delphine , Dias Araújo Ana Rita , Patel Amanda , Mesmin Bruno , Luton Frédéric , Antonny Bruno 
Published: December 2021

AbstractGolgi lipid environment regulates sorting and cargo secretion. However, the mechanisms that spatiotemporally control the lipid composition of the secretory membranes to drive cargo trafficking are poorly understood. Lipid transfer proteins regulate the concentration of specific lipids at membrane contact sites. We hypothesised that by catalysing cholesterol/PI(4)P exchange at ER-trans-Golgi membrane contact sites the lipid transfer protein oxysterol binding protein (OSBP) affects the secretion of a subset of cargoes. Here, we report that OSBP is a major epithelial protein as its inhibition leads to complete loss of apico-basal polarity. By mapping the OSBP proximity proteome with the biotin ligase TurboID, we found that OSBP controls the secretion of multiple membrane associated proteins, including key polarity determinants such as E-cadherin. Mechanistically, we established that OSBP contributes to E-cadherin secretion by supplying cholesterol to post-Golgi membranes. Importantly, when cells downregulate cell-cell junctions upon epithelial-to-mesenchymal transition, they re-wire their lipid homeostasis and downregulate OSBP as well, thus altering the trafficking of the OSBP-dependent secretory cargoes.