bluuebunny/crossref_metadata_2025 huggingface dataset:
Recombinant chimpanzee adenovirus AdC7 expressing dimeric tandem-repeat RBD of SARS-CoV-2 spike protein protects mice against COVID-19
Authors: Xu Kun , An Yaling , Li Qunlong , Huang Weijin , Han Yuxuan , Zheng Tianyi , Fang Fang , Liu Hui , Liu Chuanyu , Gao Ping , Xu Senyu , Liu William J. , Bi Yuhai , Wang Youchun , Zhou Dongming , Wang Qinghan , Hou Wenli , Xia Qianfeng , Gao George F. , Dai Lianpan
Published: February 2021

A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus vectored vaccines expressing spike (S) protein have advanced into phase 3 trials, with three approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD) or dimeric tandem-repeat RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular (Th1-based) immune responses. AdC7-RBD-tr2 showed higher antibody responses compared with both AdC7-S and AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.
The human visual system preserves the hierarchy of 2-dimensional pattern regularity
Authors: Kohler Peter J. , Clarke Alasdair D. F.
Published: February 2021

Symmetries are present at many scales in images of natural scenes. A large body of literature has demonstrated contributions of symmetry to numerous domains of visual perception. The four fundamental symmetries, reflection, rotation, translation and glide reflection, can be combined in exactly 17 distinct ways. Thesewallpaper groupsrepresent the complete set of symmetries in 2D images and have recently found use in the vision science community as an ideal stimulus set for studying the perception of symmetries in textures. The goal of the current study is to provide a more comprehensive description of responses to symmetry in the human visual system, by collecting both brain imaging (Steady-State Visual Evoked Potentials measured using high-density EEG) and behavioral (symmetry detection thresholds) data using the entire set of wallpaper groups. This allows us to probe the hierarchy of complexity among wallpaper groups, in which simpler groups are subgroups of more complex ones. We find that this hierarchy is preserved almost perfectly in both behavior and brain activity: A multi-level Bayesian GLM indicates that for most of the 63 subgroup relationships, subgroups produce lower amplitude responses in visual cortex (posterior probability: > 0.95 for 56 of 63) and require longer presentation durations to be reliably detected (posterior probability: > 0.95 for 49 of 63). This systematic pattern is seen only in visual cortex and only in components of the brain response known to be symmetric-specific. Our results show that representations of symmetries in the human brain are precise and rich in detail, and that this precision is reflected in behavior. These findings expand our understanding of symmetry perception, and open up new avenues for research on how fine-grained representations of regular textures contribute to natural vision.
epitopepredict: A tool for integrated MHC binding prediction
Authors: Farrell Damien
Published: February 2021

A key step in the cellular adaptive immune response is the presentation of antigen to T cells. During this process short peptides processed from self or foreign proteins may be presented on the surface bound to MHC molecules for binding to T cell receptors. Those that bind and activate an immune response are called epitopes. Computational prediction of T cell epitopes has many applications in vaccine design and immuno-diagnostics. This is the basis of immunoinformatics which allows in silico screening of peptides before experiments are performed. The most effective approach is to estimate the binding affinity of a given peptide fragment to MHC class I or II molecules. With the availability of whole genomes for many microbial species it is now feasible to computationally screen whole proteomes for candidate peptides. epitopepredict is a programmatic framework and command line tool designed to aid this process. It provides access to multiple binding prediction algorithms under a single interface and scales for whole genomes using multiple target MHC alleles. A web interface is provided to assist visualization and filtering of the results. The software is freely available under an open source license fromhttps://github.com/dmnfarrell/epitopepredict
Exercise Attenuates Sickness Behavior And Protects Against Dopaminergic Impairment Induced By Neuroinflammation
Authors: de Bem Alves Ana Cristina , Pires Ananda Christina Staats , Speck Ana Elisa , Lopes Samantha Cristiane , Scheffer Débora da Luz , Melo Hiago Murilo , Prediger Rui Daniel , de Paula Martins Roberta , Latini Alexandra , Aguiar Aderbal S
Published: February 2021

Neuroinflammation affects dopamine metabolism and produces a set of symptoms known as sickness behavior, including fever, anhedonia, anorexia, weight loss, decreased sociability and mobility, and cognitive impairment. Motor and cognitive impairments related to sickness behavior are associated with dopamine (DA) metabolism imbalance in the prefrontal cortex. Lipopolysaccharide (LPS) administration induces neuroinflammation and causes sickness behavior in mice, while physical exercise has anti-inflammatory properties and may attenuate sickness behavior and DA impairment. We investigated the effect of exercise on DA levels and sickness behavior induced by LPS in mice. Adult Swiss male mice (8–10 weeks, 47.1 ± 0.7 g, n=495) performed six weeks of voluntary exercise in free-running wheels (RW group) or had the blocked wheel in their cages (sedentary, SED group). After six weeks of exercise, both groups received an intraperitoneal injection (i.p.) of either saline (SAL) or LPS (0.33 mg/kg, i.p.). All animals were submitted to behavioral tests for sickness behavior assessment (fatigue, locomotion, anhedonia, and social interaction). Neuroinflammation markers and DA metabolism were assessed in the prefrontal cortex. LPS administration provoked anorexia, body weight loss, impaired motor function, social withdrawal, and anhedonia. This sickness behavior was accompanied by reduced cortical DA metabolism and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC). Neuroinflammation was confirmed through increased levels of the proinflammatory cytokines IL-1β and IL-6. Inflammation was also confirmed in the blood by an increased content of IL-1β. Physical exercise intervention prevented animals from neurochemical, biochemical, and behavioral alterations. These findings provide new evidence of physical exercise’s potential as an environmental approach to treating neuroinflammatory conditions.
A Vascularized Tumoroid Model for Human Glioblastoma Angiogenesis
Authors: Tatla Agavi Stavropoulou , Justin Alexander W , Watts Colin , Markaki Athina E
Published: February 2021

Glioblastoma (GBM) angiogenesis is critical for tumor growth and recurrence, making it a compelling therapeutic target. Here, a disease-relevant, vascularized tumoroidin vitromodel with stem-like features and stromal surrounds is reported. The model is used to recapitulate how individual components of the GBM’s complex brain microenvironment such as hypoxia, vasculature-related stro-mal cells and growth factors support GBM angiogenesis. It is scalable, tractable, cost-effective and can be used with biologically-derived or biomimetic matrices. Patient-derived primary GBM cells are found to closely participate in blood vessel formation in contrast to a GBM cell line containing differentiated cells. Exogenous growth factors amplify this effect under normoxia but not at hypoxia suggesting that a significant amount of growth factors is already being produced under hypoxic conditions. Under hypoxia, primary GBM cells and umbilical vein endothelial cells are found to strongly co-localize in a mosaic pattern to form sprouting vascular networks, with GBM cells acquiring an endothelial-like behaviour, which has been reported to occurin vivo. These findings demonstrate that our 3D tumoroidin vitromodel exhibits biomimetic attributes that may permit its use as a preclinical model in studying microenvironment cues of tumor angiogenesis.
Differentiable molecular simulation can learn all the parameters in a coarse-grained force field for proteins
Authors: Greener Joe G , Jones David T
Published: February 2021

Finding optimal parameters for force fields used in molecular simulation is a challenging and time-consuming task, partly due to the difficulty of tuning multiple parameters at once. Automatic differentiation presents a general solution: run a simulation, obtain gradients of a loss function with respect to all the parameters, and use these to improve the force field. This approach takes advantage of the deep learning revolution whilst retaining the interpretability and efficiency of existing force fields. We demonstrate that this is possible by parameterising a simple coarse-grained force field for proteins, based on training simulations of up to 2,000 steps learning to keep the native structure stable. The learned potential matches chemical knowledge and PDB data, can fold and reproduce the dynamics of small proteins, and shows ability in protein design and model scoring applications. Problems in applying differentiable molecular simulation to all-atom models of proteins are discussed along with possible solutions. The learned potential, simulation scripts and training code are made available athttps://github.com/psipred/cgdms.
Cardiac and behavioural responses to hypoxia and warming in free-swimming gilthead seabreamSparus aurata
Authors: Mignucci Alexandre , Bourjea Jérôme , Forget Fabien , Allal Hossein , Dutto Gilbert , Gasset Eric , McKenzie David J.
Published: February 2021

Cardiac and behavioural responses to hypoxia and warming were investigated in free-swimming gilthead seabreamSparus aurataequipped with biologging tags in the peritoneal cavity. After suitable recovery in a holding tank, heart rate (fH) and the variance of tri-axial body acceleration (VARm) were logged during exposure to stepwise progressive hypoxia or warming, comparing when either swimming in a tank or confined to individual respirometer chambers. When undisturbed under control conditions (normoxia, 21 °C), meanfHwas significantly lower in tank than respirometers. In progressive hypoxia (100 - 15% oxygen saturation), meanfHin the tank was significantly lower than respirometers at oxygen levels until 40%, with significant bradycardia in both holding conditions below this. Mean VARmwas low and invariant in hypoxia. Warming (21 to 31 °C) caused progressive tachycardia with no differences infHbetween holding conditions. Mean VARmwas, however, significantly higher in the tank during warming, with a positive relationship between VARmandfHacross all temperatures. Therefore, spontaneous activity contributed to raisingfHof fish in the tank during warming. MeanfHin respirometers had a highly significant linear relationship with mean rates of oxygen uptake, considering data from hypoxia and warming together. The highfHof confinedS. aurataindicates that static respirometry techniques may bias estimates of metabolic traits in some fish species. Biologging on free-swimming fish revealed novel information about cardiac responses to environmental stressors, which may be closer to responses exhibited by fish in their natural environment.

SUMMARY STATEMENT

Implantable biologgers were used to provide the first measurements of cardiac responses to hypoxia and warming in a free-swimming fish, revealing that confinement in respirometer chambers raises heart rate, with consequences for estimates of metabolic rates.
Memory destabilization during reconsolidation – A consequence of homeostatic plasticity?
Authors: Amorim F.E. , Chapot R.L. , Moulin T.C. , Lee J.L.C. , Amaral O.B.
Published: February 2021

Remembering is not a static process: when retrieved, a memory can be destabilized and become prone to modifications. This phenomenon has been demonstrated in a number of brain regions, but the neuronal mechanisms that rule memory destabilization and its boundary conditions remain elusive. Using two distinct computational models that combine Hebbian plasticity and synaptic downscaling, we show that homeostatic plasticity can function as a destabilization mechanism, accounting for behavioral results of protein synthesis inhibition upon reactivation with different reexposure times. Furthermore, by performing systematic reviews, we identify a series of overlapping molecular mechanisms between memory destabilization and synaptic downscaling, although direct experimental links between both phenomena remain scarce. In light of these results, we propose a theoretical framework where memory destabilization can emerge as an epiphenomenon of homeostatic adaptations prompted by memory retrieval.
Differential optogenetic excitation of the auditory midbrain in freely moving behaving mice
Authors: Rogalla Meike M. , Seibert Adina , Hildebrandt K Jannis
Published: February 2021

In patients with severe sensory impairment due to compromised peripheral function, partial restoration can be achieved by implantation of sensory prostheses for the electrical stimulation of the central nervous system. However, these state of the art approaches suffer from the drawback of limited spectral resolution. Electrical field spread depends on the impedance of the surrounding medium, impeding spatially focused electrical stimulation in neural tissue. To overcome these technical limitations, optogenetic excitation could be applied in such prostheses to achieve enhanced resolution through precise and differential stimulation of nearby neuronal ensembles within the central sensory pathway. Previous experiments have provided a first proof for behavioral detectability of optogenetic excitation in the rodent auditory system. However, little is known about the generation of complex and behaviorally relevant sensory patterns involving differential excitation. In this study, we developed an optogenetic implant to excite two spatially separated points along the tonotopy of the murine central inferior colliculus (ICc). Using a newly-devised reward-based operant Go/No-Go paradigm for the evaluation of optogenetic excitation of the auditory midbrain in freely moving, behaving mice, we demonstrate that differential optogenetic excitation of a sub-cortical sensory pathway is possible and efficient. Here we demonstrate how animals which were previously trained in a frequency discrimination paradigm a) rapidly generalize between sound and optogenetic excitation, b) generally detect optogenetic excitation at two different neuronal ensembles, and c) discriminate between them. Our results demonstrate for the first time that optogenetic excitation at different points of the ICc tonotopy elicits a stable response behavior over time periods of several months. With this study, we provide the first proof of principle for sub-cortical differential stimulation of sensory systems using complex artificial cues in freely moving animals.
Modulating the left inferior frontal cortex by task domain, cognitive challenge and tDCS
Authors: Nardo Davide , Pappa Katerina , Duncan John , Zeidman Peter , Callaghan Martina F. , Leff Alexander , Crinion Jennifer
Published: February 2021

The left inferior frontal cortex (LIFC) is a key region for spoken language processing, but its neurocognitive architecture remains controversial. Here we assess the domain-generality vs. domain-specificity of the LIFC from behavioural, functional neuroimaging and neuromodulation data. Using concurrent fMRI and transcranial direct current stimulation (tDCS) delivered to the LIFC, we investigated how brain activity and behavioural performance are modulated by task domain (naming vs. non-naming), cognitive challenge (low vs. high), and tDCS (anodal vs. sham). The data revealed: (1) co-existence of neural signatures both common and distinct across tasks within the LIFC; (2) domain-preferential effects of task (naming); (3) significant tDCS modulations of activity in a LIFC sub-region selectively during high-challenge naming. The presence of both domain-specific and domain-general signals, and the existence of a gradient of activation where naming relied more on sub-regions within the LIFC, may help reconcile both perspectives on spoken language processing.
Neuronal modulation in the mouse superior colliculus during covert visual selective attention
Authors: Wang Lupeng , Herman James P. , Krauzlis Richard J.
Published: February 2021

Covert visual attention is accomplished by a cascade of mechanisms distributed across multiple brain regions. Recent studies in primates suggest a parcellation in which visual cortex is associated with enhanced representations of relevant stimuli, whereas subcortical circuits are associated with selection of visual targets and suppression of distractors. Here we identified how neuronal activity in the superior colliculus (SC) of head-fixed mice is modulated during covert visual attention. We found that spatial cues modulated both firing rate and spike-count correlations, and that the cue-related modulation in firing rate was due to enhancement of activity at the cued spatial location rather than suppression at the uncued location. This modulation improved the neuronal discriminability of visual-change-evoked activity between contralateral and ipsilateral SC neurons. Together, our findings indicate that neurons in the mouse SC contribute to covert visual selective attention by biasing processing in favor of locations expected to contain relevant information.
Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility
Authors: Zou Jennifer , Gopalakrishnan Shyam , Parker Clarissa C. , Nicod Jerome , Mott Richard , Cai Na , Lionikas Arimantas , Davies Robert W , Palmer Abraham A. , Flint Jonathan
Published: February 2021

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was surprisingly low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner’s Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Available methods to control Winner’s Curse were contingent on the power of the discovery sample, and depending on the method used, both overestimated and underestimated the true effect. Leveraging these observations we integrated information about replication rates, confounding, and Winner’s Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study.
Chronic COVID-19 Syndrome and Chronic Fatigue Syndrome (ME/CFS) following the first pandemic wave in Germany – a first analysis of a prospective observational study
Authors: Kedor C , Freitag H , Meyer-Arndt L , Wittke K , Zoller T , Steinbeis F , Haffke M , Rudolf G , Heidecker B , Volk HD , Skurk C , Paul F , Bellmann-Strobl J , Scheibenbogen C
Published: February 2021

Objective

Characterization of the clinical features of patients with persistent symptoms after mild to moderate COVID-19 infection and exploration of factors associated with the development of Chronic COVID-19 Syndrome (CCS).

Methods

Setting: Charité Fatigue Center with clinical immunologists and rheumatologist, neurologists and cardiologists at Charité University hospital.

Participants: 42 patients who presented with persistent moderate to severe fatigue six months following a mostly mild SARS-CoV-2 infection at the Charité Fatigue Center from July to November 2020.

Main outcome measures: The primary outcomes were clinical and paraclinical data and meeting diagnostic criteria for Chronic Fatigue Syndrome (ME/CFS). Relevant neurological and cardiopulmonary morbidity was excluded.

Results

The median age was 36.5, range 22–62, 29 patients were female and 13 male. At six months post acute COVID-19 all patients had fatigue (Chalder Fatigue Score median 25 of 33, range 14–32), the most frequent other symptoms were post exertional malaise (n=41), cognitive symptoms (n=40), headache (n=38), and muscle pain (n=35). Most patients were moderately to severely impaired in daily live with a median Bell disability score of 50 (range 15–90) of 100 (healthy) and Short Form 36 (SF-36) physical function score of 63 (range 15-80) of 100. 19 of 42 patients fulfilled the 2003 Canadian Consensus Criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). These patients reported more fatigue in the Chalder Fatigue Score (p=0.006), more stress intolerance (p=0.042) and more frequent and longer post exertional malaise (PEM) (p=0.003), and hypersensitivity to noise (p=0.029), light (p=0.0143) and temperature (p=0.024) compared to patients not meeting ME/CFS criteria. Handgrip force was diminished in most patients compared to healthy control values, and lower in CCS/CFS compared to non-CFS CCS (Fmax1 p=0.085, Fmax2, p=0.050, Fmean1 p=0.043, Fmean2 p=0.034, mean of 10 repeat handgrips, 29 female patients). Mannose-binding lectin (MBL) deficiency was observed frequently (22% of all patients) and elevated IL-8 levels were found in 43% of patients.

Conclusions

Chronic COVID-19 Syndrome at months 6 is a multisymptomatic frequently debilitating disease fulfilling diagnostic criteria of ME/CFS in about half of the patients in our study. Research in mechanisms and clinical trials are urgently needed.
Grey and white matter micro-structure is associated with polygenic risk for schizophrenia
Authors: Stauffer Eva-Maria , Bethlehem Richard A.I. , Warrier Varun , Murray Graham K. , Romero-Garcia Rafael , Seidlitz Jakob , Bullmore Edward T.
Published: February 2021

Background

Recent discovery of approximately 270 common genetic variants associated with schizophrenia has enabled polygenic risk scores (PRS) to be measured in the population. We hypothesized that normal variation in PRS would be associated with magnetic resonance imaging (MRI) phenotypes of brain morphometry and tissue composition.

Methods

We used the largest extant genome-wide association dataset (N = 69,369 cases and N = 236,642 healthy controls) to measure PRS for schizophrenia in a large sample of adults from the UK Biobank (Nmax = 29,878) who had multiple micro- and macro-structural MRI metrics measured at each of 180 cortical areas, seven subcortical structures, and 15 major white matter tracts. Linear mixed effect models were used to investigate associations between PRS and brain structure at global and regional scales, controlled for multiple comparisons.

Results

Polygenic risk was significantly associated with reduced neurite density index (NDI) at global brain scale, at 149 cortical regions, five subcortical structures and 14 white matter tracts. Other micro-structural parameters, e.g., fractional anisotropy, that were correlated with NDI were also significantly associated with PRS. Genetic effects on multiple MRI phenotypes were co-located in temporal, cingulate and prefrontal cortical areas, insula, and hippocampus. Post-hoc bidirectional Mendelian randomization analyses provided preliminary evidence in support of a causal relationship between (reduced) thalamic NDI and (increased) risk of schizophrenia.

Conclusions

Risk-related reduction in NDI is plausibly indicative of reduced density of myelinated axons and dendritic arborization in large-scale cortico-subcortical networks. Cortical, subcortical and white matter micro-structure may be linked to the genetic mechanisms of schizophrenia.
COVID-19 increases age- and sex-controlled 21-day fatality rates for patients with melanoma, hematologic malignancies, uterine cancer, or kidney cancer
Authors: Li Haiquan , Baldwin Edwin , Zhang Xiang , Kenost Colleen , Luo Wenting , Calhoun Elizabeth A. , An Lingling , Bennett Charles L. , Lussier Yves A.
Published: February 2021

Introduction

Prior research has reported an increased risk of fatality for cancer patients, but most studies investigated the risk by comparing cancer patients to non-cancer patients among COVID-19 infections. Only a few studies have compared the impact of a COVID-19 infection to non-infection with matched cancer patients and types.

Methods & Materials

We conducted survival analyses of 4,606 cancer patients with COVID-19 test results from March 16 to October 11, 2020 in UK Biobank and estimated the overall hazard ratio of fatality with and without COVID-19 infection. We also examined the hazard ratios of thirteen specific cancer types with at least 100 patients.

Results

COVID-19 resulted in an overall hazard ratio of 7.76 (95% CI: [5.78, 10.40], p<10−10) by studying the survival rate of 4,606 cancer patients for 21-days after the tests. The hazard ratio was shown to vary among cancer type, with over a 10-fold increase in fatality rate (false discovery rate≤0.02) for melanoma, hematologic malignancies, uterine cancer, and kidney cancer using a stratified analysis on each of the cancer types. Although COVID-19 imposed a higher risk for localized cancers compared to distant metastasis ones, those of distant metastasis yielded higher fatality rates due to their multiplicative effects.

Conclusion

The results highlight the importance of timely care for localized and hematological cancer patients and the necessity to vaccinate uninfected patients as soon as possible, particularly for the cancer types influenced most by COVID-19.
Social predictors of food insecurity during the stay-at-home order due to the COVID-19 pandemic in Peru. Results from a cross-sectional web-based survey
Authors: Cañari-Casaño Jorge L. , Cochachin-Henostroza Omaira , Elorreaga Oliver A. , Dolores-Maldonado Gandy , Aquino-Ramírez Anthony , Huaman-Gil Sindy , Giribaldi-Sierralta Juan P. , Aparco Juan Pablo , Antiporta Daniel A. , Penny Mary E.
Published: February 2021

Background

Stay-at-home orders and social distancing have been implemented as the primary tools to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, this approach has indirectly lead to the unemployment of 2·3 million Peruvians, in Lima, Perú alone. As a result, the risk of food insecurity may have increased, especially in low-income families who rely on a daily wage. This study estimates the prevalence of moderate or severe food insecurity (MSFI) and identifies the associated factors that explain this outcome during the stay-at-home order.

Methods

A cross-sectional web-based survey, with non-probabilistic sampling, was conducted between May 18 and June 30, 2020, during the stay-at-home order in Peru. We used social media advertisements on Facebook to reach 18-59-year-olds living in Peru. MSFI was assessed using the Food Insecurity Experience Scale (FIES). Rasch model methodology requirements were considered, and factors associated with MSFI were selected using stepwise forward selection. A Poisson generalized linear model (Poisson GLM), with log link function, was employed to estimate adjusted prevalence ratios (aPR).

Findings

This analysis is based on 1846 replies. The prevalence of MSFI was 23·2%, and FIES proved to be an acceptable instrument with reliability 0·72 and infit 0·8-1·3. People more likely to experience MSFI were those with low income (less than 255 US$/month) in the pre-pandemic period (aPR 3·77; 95%CI, 1·98-7·16), those whose income was significantly reduced during the pandemic period (aPR 2·27; 95%CI, 1·55-3·31), and those whose savings ran out in less than 21 days (aPR 1·86; 95%CI, 1·43-2·42). Likewise, heads of households (aPR 1·20; 95%CI, 1·00-1·44) and those with probable SARS-CoV2 cases as relatives (aPR 1·29; 95%CI, 1·05-1·58) were at an increased risk of MSFI. Additionally, those who perceived losing weight during the pandemic (aPR 1·21; 95%CI, 1·01-1·45), and increases in processed foods prices (aPR 1·31; 95%CI, 1·08-1·59), and eating less minimally processed food (aPR 1·82; 95%CI, 1·48-2·24) were more likely to experience MSFI.

Interpretation

People most at risk of MSFI were those in a critical economic situation before and during the pandemic. Social protection policies should be reinforced to prevent or mitigate these adverse effects.

Funding

None.
Dynamics of neutralizing antibody responses in acute-phase COVID-19: A potential relationship between disease progression and rapid neutralizing antibody response
Authors: Kawasuji Hitoshi , Morinaga Yoshitomo , Tani Hideki , Kimura Miyuki , Yamada Hiroshi , Yoshida Yoshihiro , Takegoshi Yusuke , Kaneda Makito , Murai Yushi , Kimoto Kou , Ueno Akitoshi , Miyajima Yuki , Kawago Koyomi , Fukui Yasutaka , Sakamaki Ippei , Yamamoto Yoshihiro
Published: February 2021

Introduction

Adaptive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dynamics remain largely unknown. The neutralizing antibody (NAb) levels in patients with coronavirus disease 2019 (COVID-19) are helpful for understanding the pathology.

Patients and Methods

Using SARS-CoV-2 pseudotyped virus, serum sample neutralization values in symptomatic COVID-19 patients were measured using the chemiluminescence reduction neutralization test (CRNT). At least two sequential serum samples collected during hospitalization were analyzed to assess NAbs neutralizing activity dynamics at different time points.

Results

Of the 11 patients, four (36.4%), six (54.5%), and one (9.1%) had moderate, severe, and critical disease, respectively. Fifty percent neutralization (N50%-CRNT) was observed upon admission in 90.9% (10/11); all patients acquired neutralizing activity 2–12 days after onset. In patients with moderate disease, neutralization was observed at earliest within two days after symptom onset. In patients with severe-to-critical disease, neutralization activity increased, plateauing 9–16 days after onset. Neutralization activity on admission was significantly higher in patients with moderate disease than in patients with severe-to-critical disease (relative % of infectivity, 6.4% vs. 41.1%; P=.0011).

Conclusions

Neutralization activity on admission inversely correlated with disease severity. The rapid NAb response may play a crucial role in preventing the progression of COVID-19.
Gastrointestinal carriage of Klebsiella pneumoniae in a general adult population in Norway: a cross-sectional study of risk factors and bacterial genomic diversity
Authors: Raffelsberger Niclas , Hetland Marit Andrea Klokkhammer , Svendsen Kristian , Småbrekke Lars , Löhr Iren H. , Andreassen Lotte Leonore Eivindsdatter , Brisse Sylvain , Holt Kathryn E. , Sundsfjord Arnfinn , Samuelsen Ørjan , Gravningen Kirsten
Published: February 2021

Background

Klebsiella pneumoniae is a leading public health threat due to its increasing prevalence of antibiotic resistance. Gastrointestinal carriage of K. pneumoniae is a risk factor for subsequent infections in hospitalised patients. We determined risk factors for gastrointestinal carriage and the genomic population structure of K. pneumoniae colonising humans in a representative sample of a general population.

Methods

2,975 individuals (54% women) ≥40y participating in the population-based Tromsø Study 7 (2015-2016) were included. Faecal samples were screened for K. pneumoniae which were characterised using whole-genome sequencing. Risk factors for carriage were analysed using data from the Norwegian Prescription Database and questionnaires, using multivariable logistic regression.

Findings

Prevalence of K. pneumoniae gastrointestinal carriage was 16·3% (95% CI 15·0-17·7%) with no gender difference. Risk factors associated with carriage included age ≥60y, travel to Greece or Asia past 12 months (adjusted odds ratio 1·49, 95% CI 1·11-2·00), Crohn’s disease/ulcerative colitis (2·26, 1·20-4·27), use of protein pump inhibitors (1·62, 1·18-2·22) and non-steroidal anti-inflammatory drugs past six months (1·38, 1·04-1·84), and antibiotic use last month (1·73, 1·05-2·86). Prevalence was higher among those having used combinations of drug classes and decreased over time with respect to preceding antibiotic use. The K. pneumoniae population was diverse with 300 sequence types among 484 isolates distributed across four phylogroups. Among the isolates, 5·2% and 11·6% harboured acquired resistance and virulence factors, respectively.

Interpretation

Identification of risk factors for gastrointestinal carriage in a representative sample of a general population allows for identification of individuals that may have a higher risk of extraintestinal infection during hospitalisation. The diverse population structure of K. pneumoniae carriage isolates reflects the ecologically adaptive capacity of the bacterium, and the low antibacterial consumption probably contributes to the low prevalence of resistance in clinical isolates in Norway.
Clinical and Economic Impact of Widespread Rapid Testing to Decrease SARS-CoV-2 Transmission
Authors: Paltiel A. David , Zheng Amy , Sax Paul E.
Published: February 2021

Background

The value of frequent, rapid testing to reduce community transmission of SARS-CoV-2 is poorly understood.

Objective

To define performance standards and predict the clinical, epidemiological, and economic outcomes of nationwide, home-based, antigen testing.

Design

A simple compartmental epidemic model estimated viral transmission, clinical history, and resource use, with and without testing.

Data Sources

Parameter values and ranges informed by Centers for Disease Control guidance and published literature.

Target Population

United States population.

Time Horizon

60 days.

Perspective

Societal.Costs include: testing, inpatient care, and lost workdays.

Intervention

Home-based SARS-CoV-2 antigen testing.

Outcome Measures

Cumulative infections and deaths, numbers isolated and/or hospitalized, and total costs.

Results of Base-Case Analysis

Without a testing intervention, the model anticipates 15 million infections, 125,000 deaths, and $10.4 billion in costs ($6.5 billion inpatient; $3.9 billion lost productivity) over a 60-day horizon. Weekly availability of testing may avert 4 million infections and 19,000 deaths, raising costs by $21.5 billion. Lower inpatient outlays ($5.9 billion) would partially offset additional testing expenditures ($12.0 billion) and workdays lost ($13.9 billion), yielding incremental costs per infection (death) averted of $5,400 ($1,100,000).

Results of Sensitivity Analysis

Outcome estimates vary widely under different behavioral assumptions and testing frequencies. However, key findings persist across all scenarios: large reductions in infections, mortality, and hospitalizations; and costs per death averted roughly an order of magnitude lower than commonly accepted willingness-to-pay values per statistical life saved ($5-17 million).

Limitations

Analysis restricted to at-home testing and limited by uncertainties about test performance.

Conclusion

High-frequency home testing for SARS-CoV-2 using an inexpensive, imperfect test could contribute to pandemic control at justifiable cost and warrants consideration as part of a national containment strategy.

Primary Funding Sources

Dr. Paltiel was supported by grant R37DA015612 from the National Institute on Drug Abuse of the National Institutes of Health.

Dr. Sax was supported by grant R01AI042006 from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health.
A Quantitative Evaluation of COVID-19 Epidemiological Models
Authors: Yogurtcu Osman N. , Messan Marisabel Rodriguez , Gerkin Richard C. , Belov Artur A. , Yang Hong , Forshee Richard A , Chow Carson C.
Published: February 2021

Quantifying how accurate epidemiological models of COVID-19 forecast the number of future cases and deaths can help frame how to incorporate mathematical models to inform public health decisions. Here we analyze and score the predictive ability of publicly available COVID-19 epidemiological models on the COVID-19 Forecast Hub. Our score uses the posted forecast cumulative distributions to compute the log-likelihood for held-out COVID-19 positive cases and deaths. Scores are updated continuously as new data become available, and model performance is tracked over time. We use model scores to construct ensemble models based on past performance. Our publicly available quantitative framework may aid in improving modeling frameworks, and assist policy makers in selecting modeling paradigms to balance the delicate trade-offs between the economy and public health.
Decreased SARS-CoV-2 viral load following vaccination
Authors: Levine-Tiefenbrun Matan , Yelin Idan , Katz Rachel , Herzel Esma , Golan Ziv , Schreiber Licita , Wolf Tamar , Nadler Varda , Ben-Tov Amir , Kuint Jacob , Gazit Sivan , Patalon Tal , Chodick Gabriel , Kishony Roy
Published: February 2021

Beyond their substantial protection of individual vaccinees, it is hoped that the COVID-19 vaccines would reduce viral load in breakthrough infections thereby further suppress onward transmission. Here, analyzing positive SARS-CoV-2 test results following inoculation with the BNT162b2 mRNA vaccine, we find that the viral load is reduced 4-fold for infections occurring 12-28 days after the first dose of vaccine. These reduced viral loads hint to lower infectiousness, further contributing to vaccine impact on virus spread.
Human spinal cord differentiation proceeds rapidly in vitro and only initially maintains differentiation pace in a heterologous environment
Authors: Dady Alwyn , Davidson Lindsay , Halley Pamela A. , Storey Kate G.
Published: February 2021

Species-specific differentiation pace in in vitro assays indicates that some aspects of neural differentiation are driven by cell-autonomous processes. Here we describe a novel in vitro human neural rosette assay that recapitulates the temporal sequence of dorsal spinal cord differentiation but proceeds more rapidly than in the human embryonic spinal cord, suggesting that in vitro conditions lack endogenous signalling dynamics. To test the extent to which this in vitro assay represents a cell intrinsic differentiation programme, human iPSC-derived neural rosettes were homo-chronically grafted into the faster differentiating chicken embryonic neural tube. Strikingly, in vitro human differentiation pace was not accelerated, even in single host-integrated cells. Moreover, rosette differentiation eventually stalled in a neural progenitor cell state. These findings demonstrate the requirement for timely extrinsic signalling to accurately recapitulate human neural differentiation tempo, and suggest that while intrinsic properties limit differentiation pace, such signals are also required to maintain differentiation progression.
Efficient gradient-based parameter estimation for dynamic models using qualitative data
Authors: Schmiester Leonard , Weindl Daniel , Hasenauer Jan
Published: February 2021

Motivation

Unknown parameters of dynamical models are commonly estimated from experimental data. However, while various efficient optimization and uncertainty analysis methods have been proposed for quantitative data, methods for qualitative data are rare and suffer from bad scaling and convergence.

Results

Here, we propose an efficient and reliable framework for estimating the parameters of ordinary differential equation models from qualitative data. In this framework, we derive a semi-analytical algorithm for gradient calculation of the optimal scaling method developed for qualitative data. This enables the use of efficient gradient-based optimization algorithms. We demonstrate that the use of gradient information improves performance of optimization and uncertainty quantification on several application examples. On average, we achieve a speedup of more than one order of magnitude compared to gradient-free optimization. Additionally, in some examples, the gradient-based approach yields substantially improved objective function values and quality of the fits. Accordingly, the proposed framework substantially improves the parameterization of models from qualitative data.

Availability

The proposed approach is implemented in the open-source Python Parameter EStimation TOolbox (pyPESTO). All application examples and code to reproduce this study are available athttps://doi.org/10.5281/zenodo.4507613.
The landscape of high-affinity human antibodies against intratumoral antigens
Authors: Rakocevic Goran , Glotova Irina , de Santiago Ines , Toptas Berke Cagkan , Popovic Milena , Popovic Milos , Leone Dario , Stachyra Andrew L. , Rozenfeld Raphael , Kural Deniz , Biasci Daniele
Published: February 2021

High expression of immunoglobulin transcripts is often detected in human tumours and correlates with favourable clinical outcomes across different cancer types. However, the antigens recognized by such immunoglobulins (Ig) and their biological significance remain largely unknown. We computationally inferred the paired sequence of thousands of clonally expanded Ig using bulk RNA sequencing data from solid tumors in The Cancer Genome Atlas (TCGA). After expressing 283 Ig as recombinant antibodies in mammalian cells, we individually tested them against a library of twenty thousands full-length human proteins and an additional library of six thousand structurally intact membrane proteins, thus identifying their candidate target antigens. Using surface plasmon resonance we then confirmed 16 high-affinity antibodies that bind to their targets withKDin the nanomolar range. Our work provides insights into the antigens that drive B cell responses in human cancers, while also obtaining fully human, high-affinity recombinant antibodies against them.
Spatial transcriptomics reveals unique molecular fingerprints of human nociceptors
Authors: Tavares-Ferreira Diana , Shiers Stephanie , Ray Pradipta R. , Wangzhou Andi , Jeevakumar Vivekanand , Sankaranarayanan Ishwarya , Cervantes Anna , Reese Jeffrey C , Chamessian Alexander , Copits Bryan A. , Dougherty Patrick M. , Gereau Robert W. , Burton Michael D. , Dussor Gregory , Price Theodore J.
Published: February 2021

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. These neurons are also primary targets for acute and chronic pain therapeutics. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and elucidating new drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single dorsal root ganglion (DRG) neurons from 8 organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors; as well as 1 Aβ nociceptor, 2 Aδ, 2 Aβ and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G-protein coupled receptors (GPCRs) and other pharmacological targets, we provide a rich map of drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compare human DRG neuronal subtypes to non-human primates showing conserved patterns of gene expression among many cell types, but divergence among specific nociceptor subsets. Finally, we identify sex differences in human DRG subpopulation transcriptomes, including a marked increase inCALCAexpression in female pruritogen receptor enriched nociceptors. Our data open the door to development of drug discovery programs for new pain targets and unparalleled molecular characterization of clinical sensory disorders.

One Sentence Summary

We used spatial transcriptomics to molecularly characterize human sensory neurons, comparing them to mouse and non-human primate finding similarities but also divergence, in particular among drug targets.
A data-driven method to learn a jump diffusion process from aggregate biological gene expression data
Authors: Gao Jia-Xing , Wang Zhen-Yi , Zhang Michael Q. , Qian Min-Ping , Jiang Da-Quan
Published: February 2021

Dynamic models of gene expression are urgently required. Different from trajectory inference and RNA velocity, our method reveals gene dynamics by learning a jump diffusion process for modeling the biological process directly. The algorithm needs aggregate gene expression data as input and outputs the parameters of the jump diffusion process. The learned jump diffusion process can predict population distributions of gene expression at any developmental stage, achieve long-time trajectories for individual cells, and offer a novel approach to computing RNA velocity. Moreover, it studies biological systems from a stochastic dynamics perspective. Gene expression data at a time point, which is a snapshot of a cellular process, is treated as an empirical marginal distribution of a stochastic process. The Wasserstein distance between the empirical distribution and predicted distribution by the jump diffusion process is minimized to learn the dynamics. For the learned jump diffusion equation, its trajectories correspond to the development process of cells and stochasticity determines the heterogeneity of cells. Its instantaneous rate of state change can be taken as “RNA velocity”, and the changes in scales and orientations of clusters can be noticed too. We demonstrate that our method can recover the underlying nonlinear dynamics better compared to parametric models and diffusion processes driven by Brownian motion for both synthetic and real world datasets. Our method is also robust to perturbations of data because it only involves population expectations.
Genomic analyses of 10,376 individuals provides comprehensive map of genetic variations, structure and reference haplotypes for Chinese population
Authors: Cong Peikuan , Bai Wei-Yang , Li Jinchen , Li Nan , Gai Sirui , Khederzadeh Saber , Liu Yuheng , Qiu Mochang , Zhu Xiaowei , Zhao Pianpian , Xia Jiangwei , Yu Shihui , Zhao Weiwei , Liu Junquan , Guan Penglin , Qian Yu , Tao Jianguo , Yang Mengyuan , Tian Geng , Xie Shuyang , Liu Keqi , Tang Beisha , Zheng Hou-Feng
Published: February 2021

Here, we initiated the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing individuals and 5,481 high-density genotyping individuals. We identified 80.99 million SNPs and INDELs, of which 38.6% are novel. The genetic evidence of Chinese population structure supported the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains. The genetic architecture within North Han was more homogeneous than South Han, and the history of effective population size of Lingnan began to deviate from the other three regions from 6 thousand years ago. In addition, we identified a novel locus (SNX29) under selection pressure and confirmed several loci associated with alcohol metabolism and histocompatibility systems. We observed significant selection of genes on epidermal cell differentiation and skin development only in southern Chinese. Finally, we provided an online imputation server (https://wbbc.westlake.edu.cn/) which could result in higher imputation accuracy compared to the existing panels, especially for lower frequency variants.