bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors for long COVID: analyses of 10 longitudinal studies and electronic health records in the UK
Authors: Thompson Ellen J. , Williams Dylan M. , Walker Alex J. , Mitchell Ruth E. , Niedzwiedz Claire L. , Yang Tiffany C. , Huggins Charlotte F. , Kwong Alex S. F. , Silverwood Richard J. , Gessa Giorgio Di , Bowyer Ruth C.E. , Northstone Kate , Hou Bo , Green Michael J. , Dodgeon Brian , Doores Katie J. , Duncan Emma L. , Williams Frances M. K. ,   OpenSAFELY Collaborative, Steptoe Andrew , Porteous David J. , McEachan Rosemary R. C. , Tomlinson Laurie , Goldacre Ben , Patalay Praveetha , Ploubidis George B. , Katikireddi Srinivasa Vittal , Tilling Kate , Rentsch Christopher T. , Timpson Nicholas J , Chaturvedi Nishi , Steves Claire J. 
Published: June 2021

AbstractBackgroundThe impact of long COVID is considerable, but risk factors are poorly characterised. We analysed symptom duration and risk factor from 10 longitudinal study (LS) samples and electronic healthcare records (EHR).MethodsSamples: 6907 adults self-reporting COVID-19 infection from 48,901 participants in the UK LS, and 3,327 adults with COVID-19, were assigned a long COVID code from 1,199,812 individuals in primary care EHR. Outcomes for LS included symptom duration lasting 4+ weeks (long COVID) and 12+ weeks. Association with of age, sex, ethnicity, socioeconomic factors, smoking, general and mental health, overweight/obesity, diabetes, hypertension, hypercholesterolaemia, and asthma was assessed.ResultsIn LS, symptoms impacted normal functioning for 12+ weeks in 1.2% (mean age 20 years) to 4.8% (mean age 63 y) of COVID-19 cases. Between 7.8% (mean age 28 y) and 17% (mean age 58 y) reported any symptoms for 12+ weeks, and greater proportions for 4+ weeks. Age was associated with a linear increased risk in long COVID between 20 and 70 years. Being female (LS: OR=1.49; 95%CI:1.24-1.79; EHR: OR=1.51 [1.41-1.61]), having poor pre-pandemic mental health (LS: OR=1.46 [1.17-1.83]; EHR: OR=1.57 [1.47-1.68]) and poor general health (LS: OR=1.62 [1.25-2.09]; EHR: OR=1.26; [1.18-1.35]) were associated with higher risk of long COVID. Individuals with asthma (LS: OR=1.32 [1.07-1.62]; EHR: OR=1.56 [1.46-1.67]), and overweight or obesity (LS: OR=1.25 [1.01-1.55]; EHR: OR=1.31 [1.21-1.42]) also had higher risk. Non-white ethnic minority groups had lower risk (LS: OR=0.32 [0.22-0.47]), a finding consistent in EHR. . Few participants had been hospitalised (0.8-5.2%).ConclusionLong COVID is associated with sociodemographic and pre-existing health factors. Further investigations into causality should inform strategies to address long COVID in the population.
Analysis of host immunological response of adenovirus-based COVID-19 vaccines
Authors: Farhang-Sardroodi Suzan , Korosec Chapin , Gholami Samaneh , Craig Morgan , Moyles Iain R , Ghaemi Mohammad Sajjad , Ooi Hsu Kiang , Heffernan Jane M 
Published: June 2021

AbstractDuring the SARS-CoV-2 global pandemic, several vaccines, including mRNA and ade-novirus vector approaches, have received emergency or full approval. However, supply chain logistics have hampered global vaccine delivery, which is impacting mass vaccination strategies. Recent studies have identified different strategies for vaccine dose administration so that supply constraints issues are diminished. These include increasing the time between consecutive doses in a two-dose vaccine regimen and reducing the dosage of the second dose. We consider both of these strategies in a mathematical modeling study of a non-replicating viral vector adenovirus vaccine in this work. We investigate the impact of different prime-boost strategies by quantifying their effects on immunological outcomes based on simple ordinary differential equations. The boost dose is administered either at a standard dose (SD) of 1000 or at a low dose (LD) of 500 or 250 vaccine particles. Simulated Second dose fractionation highlights previously shown dose-dependent features of the immune mechanism. In agreement with clinical characteristics of 175 COVID-19 recovered patients, the model predictions for either SD/SD or SD/LD regimens mainly show that by stretching the prime-boost interval until 18 or 20 weeks, the minimum promoted antibody (Nab) response is comparable with the neutralizing antibody level of COVID-19 recovered patients. The minimum stimulated antibody in SD/SD regimen is identical with the high level of clinical trial data. It is at the same range of the medium-high level of Nab in SD/LD, where the second dose is half or quarter of the standard dose.
Predicting elimination of evolving virus variants
Authors: Hughes Elliott , Binny Rachelle , Hendy Shaun , James Alex 
Published: June 2021

AbstractAs the SARS-CoV-2 virus spreads around the world new variants are appearing regularly. Although some countries have achieved very swift and successful vaccination campaigns, on a global scale the vast majority of the population is unvaccinated and new variants are proving more resistant to the current set of vaccines. We present a simple model of disease spread which includes the evolution of new variants and varying vaccine effectiveness to these new strains. We show that rapid vaccine updates to target new strains are more effective than slow updates and containing spread through non-pharmaceutical interventions is vital whilst these vaccines are delivered. Finally when measuring the key model inputs, e.g. the rate at which new mutations and variants of concern emerge, is difficult we show how an observable model output, the number of new variants which have been seen, is strongly correlated with the probability the virus is eliminated.
Probing Neuro-Endocrine Interactions Through Wireless Magnetothermal Stimulation of Peripheral Organs
Authors: Maeng Lisa Y. , Rosenfeld Dekel , Simandl Gregory J. , Koehler Florian , Senko Alexander W. , Moon Junsang , Varnavides Georgios , Murillo Maria F. , Reimer Adriano E. , Wald Aaron , Anikeeva Polina , Widge Alik S. 
Published: June 2021

AbstractExposure to stress alters hypothalamic-pituitary-adrenal (HPA) axis reactivity; however, it is unclear exactly how or where within the HPA pathway these changes occur. Dissecting these mechanisms requires tools to reliably probe HPA function, particularly the adrenal component, with temporal precision. We previously demonstrated magnetic nanoparticle (MNP) technology to remotely trigger adrenal hormone release by activating thermally sensitive ion channels. Here, we applied adrenal magnetothermal stimulation to probe stress-induced HPA axis changes. MNP and control nanoparticles were injected into the adrenal glands of outbred rats subjected to a tone-shock conditioning/extinction/recall paradigm. We measured MNP-triggered adrenal release before and after conditioning through physiologic (heart rate) and serum (epinephrine, corticosterone) markers. Aversive conditioning altered adrenal function, reducing corticosterone and blunting heart rate increases post-conditioning. MNP-based organ stimulation provides a novel approach to probing the function of HPA and other neuro-endocrine axes and could help elucidate changes across stress and disease models.
PpRPK2 modulates auxin homeostasis and transport to specify stem cell identity and plant shape in the moss Physcomitrella
Authors: Venza Zoe Nemec , Madden Connor , Stewart Amy , Liu Wei , Novák Ondřej , Pěnčík Aleš , Cuming Andrew C. , Kamisugi Yasuko , Harrison C. Jill 
Published: June 2021

AbstractPlant shape is determined by the activity of stem cells in the growing tips, and evolutionary changes in shape are linked to changes in stem cell function. The CLAVATA pathway is a key regulator of stem cell function in the multicellular shoot tips of Arabidopsis, acting via the WUSCHEL transcription factor to modulate hormone homeostasis. Broad scale evolutionary comparisons have shown that CLAVATA is a conserved regulator of land plant stem cell function, but CLAVATA acts independently of WUSCHEL-like (WOX) proteins in bryophytes, raising questions about the evolution of stem cell function and the role of the CLAVATA pathway.Here we show that the moss (Physcomitrella) CLAVATA pathway affects stem cell activity and overall plant shape by modulating hormone homeostasis. CLAVATA pathway components are expressed in the tip cells of filamentous tissues, regulating cell identity, filament branching patterns and plant spread. The PpRPK2 receptor-like kinase plays the major role and is expressed more strongly than other receptor-encoding genes. Pprpk2 mutants have abnormal responses to cytokinin, and auxin transport inhibition and show reduced PIN auxin transporter expression.We propose a model whereby PpRPK2 modulates PIN activity to determine stem cell identity and overall plant form in Physcomitrella. Our data indicate that CLAVATA-mediated auxin homeostasis is a fundamental property of plant stem cell function likely exhibited by the last shared common ancestor of land plants.
Synthesis and Structure Elucidation of the Human tRNA Nucleoside Mannosyl-Queuosine
Authors: Hillmeier Markus , Wagner Mirko , Ensfelder Timm , Korytiakova Eva , Thumbs Peter , Müller Markus , Carell Thomas 
Published: June 2021

AbstractQueuosine (Q) is a structurally complex, non-canonical RNA nucleoside. It is present in many eukaryotic and bacterial species, where it is part of the anticodon loop of certain tRNAs. In higher vertebrates, including humans, two further modified queuosine-derivatives exist - galactosyl-(galQ) and mannosyl-queuosine (manQ). The function of these low abundant hypermodified RNA nucleosides remains unknown. While the structure of galQ was elucidated and confirmed by total synthesis, the reported structure of manQ still awaits confirmation. By combining total synthesis and LC-MS-co-injection, together with a metabolic feeding study of labelled hexoses, we show here that the natural compound manQ isolated from mouse liver deviates from the literature-reported structure. The chemical structure of the natural product manQ features a novel α-allyl connectivity. The data reported here shows that the yet unidentified glycosylases that attach galactose and mannose to the Q-base have different constitutional connectivity preferences. Knowing the correct structure of manQ will now pave the way towards further elucidation of its biological function.
Unidirectional migration of populations with Allee effect
Authors: Röst Gergely , Sadeghimanesh AmirHosein 
Published: June 2021

AbstractIn this note we consider two populations living on identical patches, connected by unidirectional migration, and subject to strong Allee effect. We show that by increasing the migration rate, there are more bifurcation sequences than previous works showed. In particular, the number of steady states can change from 9 (small migration) to 3 (large migration) at a single bifurcation point, or via a sequences of bifurcations with the system having 9,7,5,3 or 9,7,9,3 steady states, depending on the Allee threshold. This is in contrast with the case of bidirectional migration, where the number of steady states always goes through the same bifurcation sequence of 9,5,3 steady states as we increase the migration rate, regardless of the value of the Allee threshold.
Superior colliculus saccade motor bursts do not dictate movement kinematics
Authors: Zhang Tong , Malevich Tatiana , Baumann Matthias , Hafed Ziad M. 
Published: June 2021

AbstractThe primate superior colliculus (SC) contains a topographic map of space, such that the anatomical location of active neurons defines a desired eye movement vector. Complementing such a spatial code, SC neurons also exhibit saccade-related bursts that are tightly synchronized with movement onset. Current models suggest that such bursts constitute a rate code dictating movement kinematics. Here, using two complementary approaches, we demonstrate a dissociation between the SC rate code and saccade kinematics. First, we show that SC burst strength systematically varies depending on whether saccades of the same amplitude are directed towards the upper or lower visual fields, but the movements themselves have similar kinematics. Second, we show that for the same saccade vector, when saccades are significantly slowed down by the absence of a visible saccade target, SC saccade-related burst strengths can be elevated rather than diminished. Thus, SC saccade-related motor bursts do not necessarily dictate movement kinematics.
Structural basis of ALC1/CHD1L autoinhibition and the mechanism of activation by the nucleosome
Authors: Wang Li , Chen Kangjing , Chen Zhucheng 
Published: June 2021

AbstractChromatin remodeler ALC1 (amplification in liver cancer 1) is crucial for repairing damaged DNA. It is autoinhibited and activated by nucleosomal epitopes. However, the mechanisms by which ALC1 is regulated remain unclear. Here we report the crystal structure of human ALC1 and the cryoEM structure bound to the nucleosome. The structure shows the macro domain of ALC1 binds to lobe 2 of the ATPase motor, sequestering two elements for nucleosome recognition, explaining the autoinhibition mechanism of the enzyme. The H4 tail competes with the macro domain for lobe 2-binding, explaining the requirement for this nucleosomal epitope for ALC1 activation. A dual-arginine-anchor motif of ALC1 recognizes the acidic pocket of the nucleosome, which is critical for chromatin remodeling in vitro. Together, our findings illustrate the structures of ALC1 and shed light on its regulation mechanisms, paving the way for the discovery of drugs targeting ALC1 for the treatment of cancer.
Inequalities in the Distribution of National Institutes of Health Research Project Grant Funding
Authors: Lauer Michael , Roychowdhury Deepshikha 
Published: June 2021

AbstractPrevious reports have described worsening inequalities of National Institutes of Health (NIH) funding of principal investigators. We analyzed data through the end of Fiscal Year 2020, confirming worsening inequalities beginning at the time of the NIH budget doubling (1998-2003), but finding that trends have reversed over the past 3 years. We also find that career-stage trends have stabilized, with equivalent proportions of early-, mid-, and late-career investigators funded from 2017 to 2020. Women continue to constitute a greater proportion of funded principal investigators, though not at parity. Analyses of funding inequalities over time show that inequalities have consistently been greater within groups (i.e., within groups by career stage, gender, race, and degree) than between groups.
Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates
Authors: Toth Andrea , Steinmeyer Shelby , Kannan Paranthaman , Gray Jerilyn , Jackson Courtney M. , Mukherjee Shibabrata , Demmert Martin , Sheak Joshua R. , Benson Daniel , Kitzmiller Joe , Wayman Joseph A. , Presicce Pietro , Cates Christopher , Rubin Rhea , Chetal Kashish , Du Yina , Miao Yifei , Gu Mingxia , Guo Minzhe , Kalinichenko Vladimir V. , Kallapur Suhas G. , Miraldi Emily R. , Xu Yan , Swarr Daniel , Lewkowich Ian , Salomonis Nathan , Miller Lisa , Sucre Jennifer S. , Whitsett Jeffrey A. , Chougnet Claire A. , Jobe Alan H. , Deshmukh Hitesh , Zacharias William J. 
Published: June 2021

AbstractMalformations of or injuries to the developing lung are associated with perinatal morbidity and mortality with lifelong consequences for subsequent pulmonary health. One fetal exposure linked with poor health outcomes is chorioamnionitis, which impacts up to 25-40% of preterm births. Severe chorioamnionitis with prematurity is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may significantly alter developmental ontogeny of the lung. To test this hypothesis, we used intra-amniotic lipopolysaccharide (LPS, endotoxin) to generate experimental chorioamnionitis in prenatal Rhesus macaque (Macaca mulatta), a model which shares critical structural and temporal aspects of human lung development. Inflammatory injury directly disrupts the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis which was extensively disrupted by perinatal inflammation, leading to loss of gas exchange surface and alveolar simplification similar to that found in chronic lung disease of newborns. Blockade of IL1β and TNFα ameliorated endotoxin-induced inflammatory lung injury by blunting stromal response to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.
Evidence of multiple origins of glyphosate resistance evolution in Lolium multiflorum
Authors: Brunharo Caio A. C. G. , Streisfeld Matthew A. 
Published: June 2021

SUMMARYThe multitude of herbicide resistance patterns in the weed Lolium multiflorum L. is a remarkable example of the rapid adaptation to anthropogenic-driven disturbance. Recently, resistance to glyphosate was identified in multiple populations of L. multiflorum in Oregon.We used phenotypic approaches, as well as population genomic and gene expression analyses, to determine if known mechanisms were responsible for glyphosate resistance, if resistance phenotypes evolved independently in different populations, and to identify potential loci contributing to resistance.We found no evidence of genetic alterations or expression changes at known target and non-target sites of glyphosate resistance. Population genomic analyses indicated that resistant populations tended to have largely distinct ancestry from one another, with little evidence of admixture, suggesting that glyphosate resistance did not spread among populations via gene flow. Rather, resistance appears to have evolved independently on different genetic backgrounds. We also detected potential loci associated with the resistance phenotype, some of which encode proteins with potential effects on herbicide metabolism.Our results suggest that Oregon populations of L. multiflorum evolved resistance to glyphosate due to a novel mechanism. Future studies that characterize the gene or genes involved in resistance will be necessary to confirm this conclusion.
Cohesin is required for long-range enhancer action
Authors: Kane Lauren , Williamson Iain , Flyamer Ilya M. , Kumar Yatendra , Hill Robert E. , Lettice Laura A. , Bickmore Wendy A. 
Published: June 2021

SummaryThe mammalian genome is organised into topologically associating domains (TADs) that are formed through the process of cohesin-driven loop extrusion1–3 and whose extent is constrained at TAD boundaries by orientation-dependent CTCF binding4–7. The large regulatory landscapes of developmental genes frequently correspond to TADs, leading to the hypothesis that TADs and/or loop extrusion are important for enhancers to act on their cognate gene8,9. However, it has proven hard to interpret the consequences of experimental disruption of TADs or loop-extrusion on gene regulation3,6,10, in part because of the difficulty in distinguishing direct from indirect effects on enhancer-driven gene expression. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment in mouse embryonic stem cells, here we show that cohesin, but not CTCF, is required for activation of a target gene by distant distal regulatory elements. Cohesin is not required for activation directly at the promoter or activation from an enhancer located closer to the gene. Our findings support the hypothesis that chromatin compaction mediated by cohesin-mediated loop extrusion allows for genes to be activated by regulatory elements that are located many hundreds of kilobases away in the linear genome but suggests that cohesin is dispensable for more genomically close enhancers.
Sensory and choice responses in MT distinct from motion encoding
Authors: Levi Aaron J , Zhao Yuan , Park Il Memming , Huk Alexander C 
Published: June 2021

AbstractMacaque area MT is well known for its visual motion selectivity and relevance to motion perception, but the possibility of it also reflecting non-sensory functions has largely been ignored. Manipulating subjects’ temporal evidence weighting revealed multiple components of MT responses that were, surprisingly, not interpretable as behaviorally-relevant modulations of motion encoding, nor as consequences of readout of motion direction. MT’s time-varying motion-driven responses were starkly changed by our strategic manipulation, but with timecourses opposite the subjects’ temporal weighting strategies. Furthermore, large choice-correlated signals were represented in population activity distinctly from motion responses (even after the stimulus) with multiple phases that both lagged psychophysical readout and preceded motor responses. These results reveal multiple cognitive contributions to MT responses that are task-related but not functionally relevant to encoding or decoding of motion for psychophysical direction discrimination, calling into question its nature as a simple sensory area.
SynapseJ: an automated, synapse identification macro for ImageJ
Authors: Moreno Manrique Juan Felipe , Voit Parker R. , Windsor Kathryn E. , Karla Aamuktha R. , Rodriguez Sierra R. , Beaudoin Gerard M. J. 
Published: June 2021

AbstractWhile electron microscopy represents the gold standard for detection of synapses, a number of limitations prevent its broad applicability. A key method for detecting synapses is immunostaining for markers of pre- and post-synaptic proteins, which can infer a synapse based upon the apposition of the two markers. While immunostaining and imaging techniques have improved to allow for identification of synapses in tissue, analysis and identification of these appositions are not facile, and there has been a lack of tools to accurately identify these appositions. Here, we delineate a macro that uses open-source and freely available ImageJ or FIJI for analysis of multichannel, z-stack confocal images. With use of a high magnification with a high NA objective, we outline two methods to identify puncta in either sparsely or densely labeled images. Puncta from each channel are used to eliminate non-apposed puncta and are subsequently linked with their cognate from the other channel. These methods are applied to analysis of a presynaptic marker, bassoon, with two different postsynaptic markers, gephyrin and N-methyl-d-aspartate (NMDA) receptor subunit 1 (NR1). Using gephyrin as an inhibitory, postsynaptic scaffolding protein, we identify inhibitory synapses in basolateral amygdala, central amygdala, arcuate and the ventromedial hypothalamus. Systematic variation of the settings identify the parameters most critical for this analysis. Identification of specifically overlapping puncta allows for correlation of morphometry data between each channel. Finally, we extend the analysis to only examine puncta overlapping with a cytoplasmic marker of specific cell types, a distinct advantage beyond electron microscopy. Bassoon puncta are restricted to virally transduced, pedunculopontine tegmental neuron (PPN) axons expressing yellow fluorescent protein. NR1 puncta are restricted to tyrosine hydroxylase labeled dopaminergic neurons of the substantia nigra pars compacta (SNc). The macro identifies bassoon-NR1 overlap throughout the image, or those only restricted to the PPN-SNc connections. Thus, we have extended the available analysis tools that can be used to study synapses in situ. Our analysis code is freely available and open-source allowing for further innovation.