bluuebunny/crossref_metadata_2025 huggingface dataset:
Noise source importance in linear stochastic models of biological systems that grow, shrink, wander, or persist
Authors: Strang Alexander , Huffmyer William , Rollins Hilary , Abbott Karen C. , Thomas Peter J.
Published: January 2022

While noise is an important factor in biology, biological processes often involve multiple noise sources, whose relative importance can be unclear. Here we develop tools that quantify the importance of noise sources in a network based on their contributions to variability in a quantity of interest. We generalize the edge importance measures proposed by Schmidt and Thomas [1] for first-order reaction networks whose steady-state variance is a linear combination of variance produced by each directed edge. We show that the same additive property extends to a general family of stochastic processes subject to a set of linearity assumptions, whether in discrete or continuous state or time. Our analysis applies to both expanding and contracting populations, as well as populations obeying a martingale (“wandering”) at long times. We show that the original Schmidt-Thomas edge importance measure is a special case of our more general measure, and is recovered when the model satisfies a conservation constraint (“persists”). In the growing and wandering cases we show that the choice of observables (measurements) used to monitor the process does not influence which noise sources are important at long times. In contrast, in the shrinking or persisting case, which noise sources are important depends on what is measured. We also generalize our measures to admit models with affine moment update equations, which admit additional limiting scenarios, and arise naturally after linearization. We illustrate our results using examples from cell biology and ecology: (i) a model for the dynamics of the inositol trisphospate receptor, (ii) a model for an endangered population of white-tailed eagles, and (iii) a model for wood frog dispersal.

Author summary

Biological processes are frequently subject to an ensemble of independent noise sources. Noise sources produce fluctuations that propagate through the system, driving fluctuations in quantities of interest such as population size or ion channel configuration. We introduce a measure that quantifies how much variability each noise source contributes to any given quantity of interest. Using these methods, we identify which binding events contribute significantly to fluctuations in the state of a molecular signalling channel, which life history events contribute the most variability to an eagle population before and after a successful conservation effort rescued the population from the brink of extinction, and which dispersal events, at what times, matter most to variability in the recolonization of a series of ponds by wood frogs after a drought.
Short periods of bipolar anodal TDCS induce no instantaneous dose-dependent increase in cerebral blood flow in the targeted human motor cortex
Authors: Liu Marie Louise , Karabanov Anke Ninija , Piek Marjolein , Petersen Esben Thade , Thielscher Axel , Siebner Hartwig Roman
Published: January 2022

Background

Anodal transcranial direct current stimulation (aTDCS) of primary motor hand area (M1-HAND) can enhance corticomotor excitability. Yet, it is still unknown which current intensity produces the strongest effect on regional neural activity. Magnetic resonance imaging (MRI) combined with pseudo-continuous Arterial Spin Labeling (pc-ASL MRI) can map regional cortical blood flow (rCBF) and may thus be useful to probe the relationship between current intensity and neural response at the individual level.

Objective

Here we employed pc-ASL MRI to map acute rCBF changes during short-duration aTDCS of left M1-HAND. Using the rCBF response as a proxy for regional neuronal activity, we investigated if short-duration aTDCS produces an instantaneous dose-dependent rCBF increase in the targeted M1-HAND that may be useful for individual dosing.

Methods

Nine healthy right-handed participants received 30 seconds of aTDCS at 0.5, 1.0, 1.5, and 2.0 mA with the anode placed over left M1-HAND and cathode over the right supraorbital region. Concurrent pc-ASL MRI at 3 T probed TDCS-related rCBF changes in the targeted M1-HAND. Movement-induced rCBF changes were also assessed.

Results

Apart from a subtle increase in rCBF at 0.5 mA, short-duration aTDCS did not modulate rCBF in the M1-HAND relative to no-stimulation periods. None of the participants showed a dose-dependent increase in rCBF during aTDCS, even after accounting for individual differences in TDCS-induced electrical field strength. In contrast, finger movements led to robust activation of left M1-HAND before and after aTDCS.

Conclusion

Short-duration bipolar aTDCS does not produce instantaneous dose-dependent rCBF increases in the targeted M1-HAND at conventional intensity ranges.

Therefore, the regional hemodynamic response profile to short-duration aTDCS may not be suited to inform individual dosing of TDCS intensity.

Highlights

Arterial spin labeling (ASL) MRI probed regional cerebral blood flow (rCBF) during anodal TDCS.

Short-duration anodal TDCS was applied to left motor hand area (M1-HAND) at 0.5, 1.0, 1.5 and 2.0 mA.

Anodal TDCS produced no instantaneous dose-dependent rCBF increase in left M1-HAND.

Apart from a subtle increase at 0.5 mA, rCBF was not modified in M1-HAND during anodal TDCS.
Ecosystem size-induced environmental fluctuations affect the temporal dynamics of community assembly mechanisms
Authors: Bier Raven L. , Vass Máté , Székely Anna J. , Langenheder Silke
Published: January 2022

Understanding processes that determine community membership and abundance is important for many fields from theoretical community ecology to conservation. However, spatial community studies are often conducted only at a single timepoint despite the known influence of temporal variability on community assembly processes. Here we used a spatiotemporal study to determine how environmental fluctuation differences induced by mesocosm volumes (larger volumes were more stable) influence assembly processes of aquatic bacterial metacommunities along a press disturbance gradient. By combining path analysis and network approaches, we found mesocosm size categories had distinct relative influences of assembly process and environmental factors that determined spatiotemporal bacterial community composition, including dispersal and species sorting by conductivity. These processes depended on, but were not affected proportionately by, mesocosm size. Low fluctuation, large mesocosms primarily developed through the interplay of species sorting that became more important over time and transient priority effects as evidenced by more time-delayed associations. High fluctuation, small mesocosms had regular disruptions to species sorting and greater importance of ecological drift and dispersal limitation indicated by lower richness and higher taxa replacement. Together, these results emphasize that environmental fluctuations influence ecosystems over time and its impacts are modified by biotic properties intrinsic to ecosystem size.
Optimal experimental designs for estimating genetic and non-genetic effects underlying infectious disease transmission
Authors: Pooley Christopher , Marion Glenn , Bishop Stephen , Doeschl-Wilson Andrea
Published: January 2022

Background

Infectious disease spread in populations is controlled by individuals’ susceptibility (propensity to acquire infection), infectivity (propensity to pass on infection to others) and recoverability (propensity to recover/die). Estimating the effects of genetic risk factors on these host epidemiological traits can help reduce disease spread through genetic control strategies. However, the effects of previously identified ‘disease resistance SNPs’ on these epidemiological traits are usually unknown. Recent advances in computational statistics make it now possible to estimate the effects of single nucleotide polymorphisms (SNPs) on these traits from longitudinal epidemic data (e.g. infection and/or recovery times of individuals or diagnostic test results). However, little is known how to optimally design disease transmission experiments or field studies to maximise the precision at which pleiotropic SNP effects estimates for susceptibility, infectivity and recoverability can be estimated.

Results

We develop and validate analytical expressions for the precision of SNP effects estimates on the three host traits assuming a disease transmission experiment with one or more non-interacting contact groups. Maximising these leads to three distinct ‘experimental’ designs, each specifying a different set of ideal SNP genotype compositions across groups: a) appropriate for a single contact-group, b) a multi-group design termed “pure”, and c) a multi-group design termed “mixed”, where ‘pure’ and ‘mixed’ refer to contact groups consisting of individuals with the same or different SNP genotypes, respectively. Precision estimates for susceptibility and recoverability were found to be less sensitive to the experimental design than infectivity. Data from multiple groups were found more informative about infectivity effects than from a single group containing the same number of individuals. Whilst the analytical expressions suggest that the multi-group pure and mixed designs estimate SNP effects with similar precision, the mixed design is preferable because it uses information from naturally occurring infections rather than those artificially induced. The same optimal design principles apply to estimating other categorical fixed effects, such as vaccinations status, helping to more effectively quantify their epidemiological impact.

An onlinesoftware toolSIRE-PChas been developed which calculates the precision of estimated substitution and dominance effects of a single SNP (or vaccine status) associated with all three traits depending on experimental design parameters.

Conclusions

The developed methodology and software tool can be used to aid the design of disease transmission experiments for estimating the effect of individual SNPs and other categorical variables underlying host susceptibility, infectivity and recoverability.
Maternal transmission as a microbial symbiont sieve, and the absence of lactation in male mammals
Authors: Fagan Brennen T. , Constable George W. A. , Law Richard
Published: January 2022

Gut microbiomes of humans carry a complex symbiotic assemblage of microorganisms. As in all mammals, the special mode of feeding newborn infants through milk from the mammary gland enhances the opportunity for vertical transmission of the milk microbiome from parents to the gut microbiome of offspring. This has potential benefits, but it also brings with it some hazards for the host. Here we use mathematical and numerical models to demonstrate that vertical transmission from both parents would allow host populations to be invaded by microbiome elements that are deleterious. In contrast, vertical transmission, when restricted to one parent, acts as a sieve preventing the spread of such elements. We show that deleterious symbionts generate selection for uniparental transmission in host populations, and that this selective advantage is maintained in the presence of moderate horizontal transmission. Some vertical transmission from mother to infant is bound to happen in placental mammals. This paper therefore puts forward the hypothesis that the asymmetry between females and males, together with the hazards that come with biparental transmission of the milk microbiome, generate selection against male lactation in humans, and in mammals in general.
Model-based hearing-enhancement strategies for cochlear synaptopathy pathologies
Authors: Drakopoulos Fotios , Vasilkov Viacheslav , Osses Vecchi Alejandro , Wartenberg Tijmen , Verhulst Sarah
Published: January 2022

It is well known that ageing and noise exposure are important causes of sensorineural hearing loss, and can result in damage of the outer hair cells or other structures of the inner ear, including synaptic damage to the auditory nerve (AN), i.e., cochlear synaptopathy (CS). Despite the suspected high prevalence of CS among people with self-reported hearing difficulties but seemingly normal hearing, conventional hearing-aid algorithms do not compensate for the functional deficits associated with CS. Here, we present and evaluate a number of auditory signal-processing strategies designed to maximally restore AN coding for listeners with CS pathologies. We evaluated our algorithms in subjects with and without suspected age-related CS to assess whether physiological and behavioural markers associated with CS can be improved. Our data show that after applying our algorithms, envelope-following responses and perceptual amplitude-modulation sensitivity were consistently enhanced in both young and older listeners. Speech-in-noise intelligibility showed small improvements after processing but mostly for young normal-hearing participants, with median improvements of up to 8.3%. Since our hearing-enhancement strategies were designed to optimally drive the AN fibres, they were able to improve temporal-envelope processing for listeners both with and without suspected CS. Our proposed algorithms can be rapidly executed and can thus extend the application range of current hearing aids and hearables, while leaving sound amplification unaffected.
Microstructural Impairments in a Topologically Distinct Prefrontal-Habenular Connection in Cocaine Addiction
Authors: King Sarah G. , Gaudreault Pierre-Olivier , Malaker Pias , Kim Joo-won , Alia-Klein Nelly , Xu Junqian , Goldstein Rita Z.
Published: January 2022

Drug addiction is characterized by neuroadaptations in mesocorticolimbic networks regulating reward and inhibitory control. The habenula (Hb) is central to adaptive reward and aversion-driven behaviors, serving as a hub connecting emotion/cognitive processing regions including the prefrontal cortex (PFC). However, its role in human drug addiction has not been fully explored. Using diffusion tractography, we detailed PFC structural connectivity with three regions, namely the Hb, ventral tegmental area (VTA), and anterior thalamus (AT), and quantified the tract-specific microstructural integrity using diffusion tensor imaging within the anterior limb of the internal capsule (ALIC) in healthy and cocaine-addicted individuals. White matter microstructure in cocaine-addicted individuals was uniquely impaired in PFC-Hb projections in the ALIC, distinguishable from adjacent PFC-VTA and PFC-AT projections, with more pronounced abnormalities in short-term abstinence. These findings extend preclinical evidence of PFC-Hb circuit impairments in addiction and contextualize the plausible existence of a similar PFC-Hb connection in the human brain.
Differential Requirement of DICER1 Activity during Development of Mitral and Tricuspid Valves
Authors: Yan Shun , Peng Yin , Lu Jin , Shakil Saima , Shi Yang , Crossman David K. , Johnson Walter H , Liu Shanrun , Lincoln Joy , Wang Qin , Jiao Kai
Published: January 2022

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivatedDicer1in the endocardium during cardiogenesis, and unexpectedly found thatDicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

Summary statement

Although mitral and tricuspid heart valves are both derived from same cell sources in the atrioventricular region through similar initiation and remodeling processes, congenital dysplasia simultaneously affecting both valves is clinically uncommon. We show that DICER1 activity is only essential for mitral valve development whereas it is dispensable for other valves. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that is differentially required to regulate mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.
Parameterized syncmer schemes improve long-read mapping
Authors: Dutta Abhinav , Pellow David , Shamir Ron
Published: January 2022

Motivation

Sequencing long reads presents novel challenges to mapping. One such challenge is low sequence similarity between the reads and the reference, due to high sequencing error and mutation rates. This occurs, e.g., in a cancer tumor, or due to differences between strains of viruses or bacteria. A key idea in mapping algorithms is to sketch sequences with their minimizers. Recently, syncmers were introduced as an alternative sketching method that is more robust to mutations and sequencing errors.

Results

We introduce parameterized syncmer schemes, a generalization of syncmers, and provide a theoretical analysis for multi-parameter schemes. By combining these schemes with downsampling or minimizers we can achieve any desired compression and window guarantee. We implemented the use of parameterized syncmer schemes in the popular minimap2 and Winnowmap2 mappers. In tests on simulated and real long read data from a variety of genomes, the syncmer-based algorithms, with scheme parameters selected on the basis of the theoretical analysis, reduced unmapped reads by 20-60% at high compression while usually using less memory. The advantage was more pronounced at low sequence identity. At sequence identity of 75% and medium compression, syncmer-minimap had only 37% as many unmapped reads, and 8% fewer of the reads that did map were incorrectly mapped. Even at lower compression and error rates, parameterized syncmer based mapping mapped more reads than the original minimizer-based mappers as well as mappers using the original syncmer schemes. We conclude that using parameterized syncmer schemes can improve mapping of long reads in a wide range of settings.

Availability

https://github.com/Shamir-Lab/syncmer_mapping

Supplementary information

Supplementary data are available at https://github.com/Shamir-Lab/syncmer_mapping.

Author summary

Popular long read mappers use minimizers, the minimal hashed k-mers from overlapping windows, as alignment seeds. Recent work showed that syncmers, which select a fixed set of k-mers as seeds, are more likely to be conserved under errors or mutations than minimizers, making them potentially useful for mapping error-prone long reads. We introduce a framework for creating syncmers, that we call parameterized syncmer schemes, which generalize those introduced so far, and provide a theoretical analysis of their properties. We implemented parameterized syncmer schemes in the minimap2 and Winnowmap2 long read mappers. Using parameters selected on the basis of our theoretical analysis we demonstrate improved mapping performance, with fewer unmapped and incorrectly mapped reads on a variety of simulated and real datasets. The improvements are consistent across a broad range of compression rates and sequence identities, with the most significant improvements for lower sequence identity (high error or mutation rates) and high compression.
Single-molecule mapping of replisome progression
Authors: Claussin Clémence , Vazquez Jacob , Whitehouse Iestyn
Published: January 2022

Fundamental aspects of DNA replication, such as the anatomy of replication stall sites, how replisomes are influenced by gene transcription and whether the progression of sister replisomes is coordinated are poorly understood. Available techniques do not allow the precise mapping of the positions of individual replisomes on chromatin. We have developed a new method called Replicon-seq that entails the excision of full-length replicons by controlled nuclease cleavage at replication forks. Replicons are sequenced using Nanopore, which provides a single molecule readout of long DNA molecules. Using Replicon-seq, we have investigated replisome movement along chromatin. We found that sister replisomes progress with remarkable consistency from the origin of replication but function autonomously. Replication forks that encounter obstacles pause for a short duration but rapidly resume synthesis. The helicase Rrm3 plays a critical role both in mitigating the effect of protein barriers and facilitating efficient termination. Replicon-seq provides an unprecedented means of defining replisome movement across the genome.
UV-C light completely blocks highly contagious Delta SARS-CoV-2 aerosol transmission in hamsters
Authors: Fischer Robert J. , Port Julia R. , Holbrook Myndi G. , Yinda Kwe Claude , Creusen Martin , ter Stege Jeroen , de Samber Marc , Munster Vincent J.
Published: January 2022

Behavioral and medical control measures are not effective in containing the spread of SARS-CoV-2. Here we report on the effectiveness of a preemptive environmental strategy using UV-C light to prevent airborne transmission of the virus in a hamster model and show that UV-C exposure completely prevents airborne transmission between individuals
Adeno-associated Virus Receptor-binding: Flexible Domains and Alternative Conformations through cryo-Electron Tomography of AAV2 and AAV5 complexes
Authors: Hu Guiqing , Silveria Mark A. , Chapman Michael S. , Stagg Scott M.
Published: January 2022

Recombinant forms of adeno-associated virus (rAAV) are vectors of choice in the development of treatments for a number of genetic dispositions. Greater understanding of AAV’s molecular virology is needed to underpin needed improvements in efficiency and specificity. Recent advances have included identification of a near universal entry receptor, AAVR, and structures by cryo-electron microscopy (EM) single particle analysis (SPA) that revealed, at high resolution, only the domains of AAVR most tightly bound to AAV. Here, cryogenic electron tomography (cryo-ET) is applied to reveal the neighboring domains of the flexible receptor. For AAV5, where the PKD1 domain is bound strongly, PKD2 is seen in three configurations extending away from the virus. AAV2 binds tightly to the PKD2 domain at a distinct site, and cryo-ET now reveals four configurations of PKD1, all different from that seen in AAV5. The AAV2 receptor complex also shows unmodeled features on the inner surface that appear to be an equilibrium alternate configuration. Other AAV structures start near the 5-fold axis, but now β-strand A is the minor conformer and, for the major conformer, partially ordered N-termini near the 2-fold axis join the canonical capsid jellyroll fold at the βA-βB turn. The addition of cryo-ET is revealing unappreciated complexity that is likely relevant to viral entry and to the development of improved gene therapy vectors.

IMPORTANCE

With 150 clinical trials for 30 diseases underway, AAV is a leading gene therapy vector. Immunotoxicity at high doses used to overcome inefficient transduction, has occasionally proven fatal and highlighted gaps in fundamental virology. AAV enters cells, interacting through distinct sites with different domains of the AAVR receptor, according to AAV clade. Single domains are resolved in structures by cryogenic electron microscopy. Here, the adjoining domains are revealed by cryo-electron tomography of AAV2 and AAV5 complexes. They are in flexible configurations interacting minimally with AAV, despite measurable dependence of AAV2 transduction on both domains.
Type I IFN promotes pathogenic inflammatory monocyte maturation during H5N1 infection
Authors: Fourati Slim , Jimenez-Morales David , Hultquist Judd , Chang Max W. , Benner Christopher , Krogan Nevan , Pache Lars , Chanda Sumit , Sekaly Rafick-Pierre , García-Sastre Adolfo , Uccellini Melissa B.
Published: January 2022

Ly6Chi inflammatory monocytes show high IFN responses, and contribute to both protective and pathogenic functions following influenza virus infection. In order to understand the significance of IFN responses in this subset, we examined monocytes during infection with a lethal H5N1 virus that induces high levels of IFN and a low-pathogenicity H1N1 virus that induces low levels of IFN. We show that H5N1 infection results in early recruitment of high numbers of Ly6Chi monocytes and induction of chemokines and Ifnb1. Using unbiased transcriptomic and proteomic approaches, we also find that monocytes are significantly enriched during H5N1 infection and are associated with chemokine and IFN signatures in mice, and with severity of symptoms after influenza virus infection in humans. Recruited Ly6Chi monocytes subsequently become infected in the lung, produce IFN-β, and mature into FasL+ monocyte-derived cells (FasL+MCs) expressing dendritic cell markers. Both Ccr2-/- and Faslgld mice are protected from lethal infection, indicating that monocytes contribute to pathogenesis. Global loss of type I and type III IFN signaling in Stat2-/- mice results in loss of monocyte recruitment, likely reflecting a requirement for IFN-dependent chemokine induction. Here we show that IFN is not directly required for monocyte recruitment on an IFN-sufficient background, but is required for maturation to FasL+MCs. Loss of IFN signaling skews to a Ly6Clo phenotype associated with tissue repair, suggesting that IFN signaling in monocytes is a critical determinant of influenza virus pathogenesis.
Screening for SARS-CoV-2 persistence in Long COVID patients using sniffer dogs and scents from axillary sweats samples
Authors: GRANDJEAN Dominique , SLAMA Dorsaf , GALLET Capucine , JULIEN Clothilde , SEYRAT Emilie , BLONDOT Marc , BENAZAZIEZ Maissa , ELBAZ Judith , SALMON Dominique
Published: January 2022

Objectives: Dogs can be trained to identify several substances not detected by humans, corresponding to specific volatile organic compounds (VOCs). The presence of VOCs, triggered by SARS-CoV-2 infection, was tested in sweat from Long COVID patients.
Patients and methods: An axillary sweat sample of Long COVID patients and of COVID-19 negative, asymptomatic individuals was taken at home to avoid any hospital contact. Swabs were randomly placed in olfaction detection cones, and the material sniffed by at least 2 trained dogs.
Results: Forty-five Long COVID patients, mean age 45 (6-71), 73.3% female, with prolonged symptoms evolving for a mean of 15.2 months (5-22) were tested. Dogs discriminated in a positive way 23/45 (51.1%) Long COVID patients versus 0/188 (0%) control individuals (p<.0001).
Conclusion:This study suggests the persistence of a viral infection in some Long COVID patients and the possibility of providing a simple, highly sensitive, non-invasive test to detect viral presence, during acute and extended phases of COVID-19.
Improving Machine Learning Prediction of ADHD Using Gene Set Polygenic Risk Scores and Risk Scores from Genetically Correlated Phenotypes
Authors: Barnett Eric J , Zhang-James Yanli , Faraone Stephen V
Published: January 2022

Background: Polygenic risk scores (PRSs), which sum the effects of SNPs throughout the genome to measure risk afforded by common genetic variants, have improved our ability to estimate disorder risk for Attention-Deficit/Hyperactivity Disorder (ADHD) but the accuracy of risk prediction is rarely investigated.
Methods: With the goal of improving risk prediction, we performed gene set analysis of GWAS data to select gene sets associated with ADHD within a training subset. For each selected gene set, we generated gene set polygenic risk scores (gsPRSs), which sum the effects of SNPs for each selected gene set. We created gsPRS for ADHD and for phenotypes having a high genetic correlation with ADHD. These gsPRS were added to the standard PRS as input to machine learning models predicting ADHD. We used feature importance scores to select gsPRS for a final model and to generate a ranking of the most consistently predictive gsPRS.
Results: For a test subset that had not been used for training or validation, a random forest (RF) model using PRSs from ADHD and genetically correlated phenotypes and an optimized group of 20 gsPRS had an area under the receiving operating characteristic curve (AUC) of 0.72 (95% CI: 0.70 to 0.74). This AUC was a statistically significant improvement over logistic regression models and RF models using only PRS from ADHD and genetically correlated phenotypes.
Conclusions: Summing risk at the gene set level and incorporating genetic risk from disorders with high genetic correlations with ADHD improved the accuracy of predicting ADHD. Learning curves suggest that additional improvements would be expected with larger study sizes. Our study suggests that better accounting of genetic risk and the genetic context of allelic differences results in more predictive models.
Summaries, Analysis and Simulations of COVID-19 Epidemics in Shanghai
Authors: Min Lequan
Published: January 2022

Shanghai is the best city to prevent the spread of COVID-19 infection in China. Since February 20, 2020, Shanghai has experienced five waves of COVID-19. Out of a total of 388 patients with COVID-19 symptoms, 381 were cured and seven died. Medical staff achieved zero infection. This paper summarizes, analyzes and simulates COVID-19 epidemics in Shanghai.
The simulation results show that for five waves of epidemics, after reaching the infection turning point, the blocking rate of symptomatic infection is over 99%.
The administration needs to maintain the prevention and control implemented 7 days after reaching the infection turning point until the new infection goes away.
Intermittent calorie restriction alters T cell subsets and metabolic markers in people with multiple sclerosis
Authors: Fitzgerald Kathryn C. , Bhargava Pavan , Smith Matthew D. , Vizthum Diane , Henry-Barron Bobbie , Kornberg Michael D. , Cassard Sandra D. , Kapogiannis Dimitrios , Sullivan Patrick , Baer David J. , Calabresi Peter A. , Mowry Ellen M.
Published: January 2022

Abstract

Background: Intermittent fasting or calorie restriction (CR) diets provide anti-inflammatory and neuroprotective advantages in models of multiple sclerosis (MS); data in humans are sparse.

Methods: We conducted a randomized-controlled feeding study of different CR diets in 36 people with MS over 8 weeks. Patients were randomized to receive either: a daily CR diet (22% reduction in calories, 7 days/week), an intermittent CR diet (75% reduction, 2 days/week; 100%, 5 days/week), or a weight-stable diet (100%, 7 days/week). Untargeted metabolomics was performed on plasma samples at weeks 0, 4 and 8 at Metabolon Inc (Durham, NC). Flow cytometry of cryopreserved peripheral blood mononuclear cells at weeks 0 and 8 were used to identify CD4+ and CD8+ T cell subsets including effector memory, central memory, and naïve cells.

Results: 31 (86%) completed the trial. Over time, individuals randomized to intermittent CR had significant reductions in CD4+CM -4.87%; 95%CI: -8.59%, -1.15%; p=0.01), CD4+EM (-3.82%; 95%CI: -7.44, -0.21; p=0.04), and CD8+EM (-6.96%; 95%CI: -11.96, -1.97; p=0.006) with proportional increases in naïve subsets (CD4+Naïve: 5.81%; 95%CI: -0.01, 11.63%; p=0.05; CD8+Naïve: 10.11%; 95%CI: 3.30, 16.92%; p=0.006). No changes were observed for daily CR or weight-stable diets. Larger within-person changes in lysophospholipid and lysoplasmalogen metabolites in intermittent CR were associated with larger reductions in memory T cell subsets and larger increases in naïve T cell subsets.

Conclusions: In people with MS, an intermittent CR diet was associated with reduction in memory T cell subsets. The observed changes may be mediated by changes in specific classes of lipid metabolites.

Trial Registration: This study is registered on Clinicaltrials.gov with identifier NCT02647502.

Funding: National MS Society, NIH, Johns Hopkins Catalyst Award
COVID-19 policies in practice and their direct and indirect impacts in Northern California jails
Authors: Liu Yiran E. , LeBoa Christopher , Rodriguez Marcela , Sherif Beruk , Trinidad Chrisele , Rosario Michael del , Allen Sophie , Clifford Christine , Redding Jennifer , Chen Wei-ting , Rosas Lisa G. , Morales Carlos , Chyorny Alexander , Andrews Jason R.
Published: January 2022

Background

Although the increased risk of COVID-19 in carceral facilities is well documented, little is known about the practical barriers to infection control and indirect impacts of pandemic policies in these settings. Evidence in jails is especially scarce.

Methods

Between July 8, 2020 and April 30, 2021 we performed SARS-CoV-2 serology testing and administered a questionnaire among residents and staff in four Northern California jails. We analyzed seroprevalence in conjunction with demographic factors and survey responses of self-perceived COVID-19 risk, recent illness, COVID-19 test results, and symptom reporting behaviors. We additionally assessed COVID-19 policies in practice and evaluated their impacts on court dates, mental health, and routine health care. We engaged stakeholder representatives, including incarcerated individuals and their advocates, to guide study design, conduct, and interpretation.

Results

We enrolled 788 incarcerated individuals and 380 staff across four county jails. Most seropositive individuals had not previously tested positive for COVID-19, despite many suspecting prior infection. Among incarcerated participants, we identified deficient access to face masks and prevalent symptom underreporting associated with fears of isolation and perceptions of medical neglect in jail. Incarcerated participants also reported substantial hindrances to court cases and reductions in routine health care due to COVID-19. Incarcerated individuals and staff both cited worsened mental health due to COVID-19, which for incarcerated individuals was largely attributable to further isolation from loved ones and other pandemic restrictions on recreation and programming.

Conclusion

Perceptions of inadequate protection from COVID-19 were pervasive among incarcerated individuals. Simultaneously, restrictive measures compounded poor mental health and fostered fears of isolation that undermined effective infection control. Custody officials should work to systematically improve provision of masks, understand and mitigate fears and mistrust, and take proactive steps to minimize the detrimental impacts of restrictive policies on residents’ mental health and well-being.
Immunologic response, Efficacy, and Safety of Vaccines Against COVID-19 Infection in Children and Adolescents Aged 2 – 21 years old: A Systematic Review
Authors: Sadeghi Sara , Kalantari Yasamin , Shokri Sima , Fallahpour Morteza , Nafisi Nahid , Goodarzi Azadeh
Published: January 2022

Backgrounds

Children and adolescents form a large proportion of societies and play an important role in the transmission of COVID-19. On the other hand, their education, mental and physical wellness, and safety are compromised which makes vaccination a crucial step to return to normal life.

Aims and objectives

To collect and summarize all data about the immune response, effectiveness, and safety of available COVID-19 vaccines for people aged 2 – 21 years old.

Methods

A thorough systematic review was performed on available publications in English language regarding immunogenicity, efficacy, and safety of COVID-19 vaccines in individuals aged 2 – 21 years old. Types of selected studies were clinical trials, observational studies, and cohort. Searched databases comprised Ovid Medline, Cochrane Library, Embase, Scopus, Web of Sciences, Google Scholar, andClinicalTrials.govwebsite. Data extraction and analysis were performed in Microsoft Word software, version 16.56.

Results

The COVID-19 vaccination was evaluated in a total of 50,148 children and adolescents in 22 published studies and 5,279 participants in two ongoing clinical trials. Data were collected about multiple vaccines including BNT162b2 (Pfizer), mRNA-1273 (Moderna), JNJ-78436735 (Johnson and Johnson), CoronaVac (Sinovac), BBIBP-CorV (Sinopharm), adenovirus type-5-vectored vaccine, ZyCov-D, and BBV152 (COVAXIN). The immune response and efficacy of such vaccines were 96% – 100% in healthy children and adolescents and were also acceptable in those with underlying diseases and suppressed immune systems. The current systematic review revealed favorable safety profiles of employed vaccines in children and adolescents; however, adverse reactions such as myocarditis and myopericarditis were reported which were transient and resolved entirely.

Conclusion

Vaccinating children and adolescents aged 2 – 21 years old is beneficial to abort the COVID-19 pandemic. Moreover, the risk-benefit assessments revealed favorable results for vaccinating children and adolescents, especially those with underlying disease, alongside adults to prevent transmission, severe infection, negative outcomes, and new variants formation.
Precise DNA Cloning via PAMless CRISPR-SpRYgests
Authors: Christie Kathleen A. , Guo Jimmy A. , Silverstein Rachel A. , Doll Roman M. , Mabuchi Megumu , Stutzman Hannah E. , Ma Linyuan , Robb G. Brett , Kleinstiver Benjamin P.
Published: January 2022

While restriction enzymes (REs) remain the gold-standard for manipulating DNA in vitro, they have notable drawbacks including a dependence on short binding motifs that constrain their ability to cleave DNA substrates. Here we overcome limitations of REs by developing an optimized molecular workflow that leverages the PAMless nature of a CRISPR-Cas enzyme named SpRY to cleave DNA at practically any sequence. Using SpRY for DNA digests (SpRYgests), we establish a method that permits the efficient cleavage of DNA substrates at any base pair. We demonstrate the effectiveness of SpRYgests using more than 130 gRNAs, illustrating the versatility of this approach to improve the precision of and simplify several cloning workflows, including those not possible with REs. We also optimize a rapid and simple one-pot gRNA synthesis protocol, which reduces cost and makes the overall SpRYgest workflow comparable to that of RE digests. Together, SpRYgests are straightforward to implement and can be utilized to improve a variety of DNA engineering applications.
Optimized cell culture conditions promote ex-vivo manipulation and expansion of primitive hematopoietic stem cells for therapeutic gene editing
Authors: Rai Rajeev , Vetharoy Winston , Naseem Asma , Steinberg Zohar , Thrasher Adrian J , Santilli Giorgia , Cavazza Alessia
Published: January 2022

During the last few years, gene editing has emerged as a powerful tool for the therapeutic correction of monogenic diseases. CRISPR/Cas9 applied to hematopoietic stem and progenitor cells (HSPCs) has shown great promise in proof-of-principle preclinical studies to treat haematological disorders, and clinical trials using these tools are now underway. Nonetheless, there remain important challenges that need to be addressed, such as the efficiency of targeting primitive, long-term repopulating HSPCs and expand them in vitro for clinical purposes. Here we have tested the effect exerted by different culture media compositions on the ability of HSPCs to proliferate and undergo homology directed repair-mediated knock-in of a reporter gene, while preserving their stemness features during ex-vivo culture. We tested different combinations of compounds and demonstrated that by supplementing the culture media with inhibitors of histone deacetylases, and/or by fine-tuning its cytokine composition it is possible to achieve high levels of gene targeting in long-term repopulating HSPCs both in vitro and in vivo, with a beneficial balance between preservation of stemness and cell expansion, thus allowing to obtain a significant amount of edited, primitive HSPCs compared to established, state-of-the-art culture conditions. Overall, the implantation of this optimized ex vivo HSPC culture protocol will improve the efficacy, feasibility and applicability of gene editing and will likely provide one step further to unlock the full therapeutic potential of such powerful technology.
Identification of Salivary Gland Escape Barriers to Western Equine Encephalitis Virus in the Natural Vector, Culex tarsalis
Authors: Stauft Charles B. , Phillips Aaron T. , Wang Tony T. , Olson Kenneth E.
Published: January 2022

Herein we describe a previously uninvestigated salivary gland escape barrier (SEB) in Culex tarsalis mosquitoes infected with two different strains of Western equine encephalitis virus (WEEV). The WEEV strains were originally isolated either from mosquitoes (IMP181) or a human patient (McMillan). Both IMP181 and McMillan viruses were fully able to infect the salivary glands of Culex tarsalis after intrathoracic injection as determined by expression of mCherry fluorescent protein. IMP181, however, was better adapted to transmission as measured by virus titer in saliva as well as transmission rates in infected mosquitoes. We used chimeric recombinant WEEV strains to show that inclusion of IMP181-derived structural genes partially circumvents the SEB.

Author Statement

During the first half of the previous century, WEEV was responsible for large outbreaks throughout the northern United States and Canada that caused severe disease in horses and people. Over the past 60 years, cases of WEEV have mysteriously faded and the pathogen is rarely encountered in the clinic today. Salivary gland escape barriers (SEB) are a relatively neglected field of study in arbovirology, and this study provides a valuable contribution to the field by describing a SEB found in otherwise vector competent Culex tarsalis mosquitoes. Although midgut barriers are well studied, less is known about barriers to transmission in the salivary glands. Although salivary gland infection occurs at a high rate following direct injection of virus into the hemocoel, we noticed that only ∼20-30% of infected mosquitoes transmit detectable infectious virus in their saliva. Additionally, although the more pathogenic patient-derived McMillan strain of WEEV infected salivary glands at a similar rate, its transmission was more severely restricted than the mosquito-derived but less pathogenic Imperial 181 strain. We were able to trace determinants of viral transmission to the 6K/E1 region of the gene encoding the viral structural polyprotein. WEEV is a valuable research model for the closely related Eastern equine encephalitis virus and Venezuelan equine encephalitis virus we believe that our findings are applicable to other members of Togaviridae.
Forward masking in a bottlenose dolphin Tursiops truncatus: Dependence on azimuthal positions of the masker and test sources
Authors: Popov Vladimir V. , Nechaev Dmitry I. , Supin Alexander Ya. , Sysueva Evgeniya V.
Published: January 2022

Forward masking was investigated by the auditory evoked potentials (AEP) method in a bottlenose dolphin Tursiops truncatus using stimulation by two successive acoustic pulses (the masker and test) projected from spatially separated sources. The positions of the two sound sources either coincided with or were symmetrical relative to the head axis at azimuths from 0 to ±90°. AEPs were recorded either from the vertex or from the lateral head surface next to the auditory meatus. In the last case, the test source was ipsilateral to the recording side, whereas the masker source was either ipsi- or contralateral. For lateral recording, AEP release from masking (recovery) was slower for the ipsi-than for the contralateral masker source position. For vertex recording, AEP recovery was equal both for the coinciding positions of the masker and test sources and for their symmetrical positions relative to the head axis. The data indicate that at higher levels of the auditory system of the-dolphin, binaural convergence makes the forward masking nearly equal for ipsi- and contralateral positions of the masker and test.
Structural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY
Authors: Sauer David B. , Marden Jennifer J. , Sudar Joseph C. , Song Jinmei , Mulligan Christopher , Wang Da-Neng
Published: January 2022

The Na+-dependent dicarboxylate transporter from Vibrio cholerae (VcINDY) is a prototype for the divalent anion sodium symporter (DASS) family. While the utilization of an electrochemical Na+ gradient to power substrate transport is well established for VcINDY, the structural basis of this coupling between sodium and substrate binding is not currently understood. Here, using a combination of cryo-EM structure determination, succinate binding and site-directed cysteine alkylation assays, we demonstrate that the VcINDY protein couples sodium- and substrate-binding via a previously unseen induced-fit mechanism. In the absence of sodium, substrate binding is abolished, with the succinate binding regions exhibiting increased flexibility, including HPinb, TM10b and the substrate clamshell motifs. Upon sodium binding, these regions become structurally ordered and create a proper binding site for the substrate. Taken together, these results provide strong evidence that VcINDY’s induced-fit mechanism is a result of the sodium-dependent formation of the substrate binding site.
EnteroBase: Hierarchical clustering of 100,000s of bacterial genomes into species/sub-species and populations
Authors: Achtman Mark , Zhou Zhemin , Charlesworth Jane , Baxter Laura
Published: January 2022

The definition of bacterial species is traditionally a taxonomic issue while bacterial populations are identified by population genetics. These assignments are species specific, and depend on the practitioner. Legacy multilocus sequence typing is commonly used to identify sequence types (STs) and clusters (ST Complexes). However, these approaches are not adequate for the millions of genomic sequences from bacterial pathogens that have been generated since 2012. EnteroBase (http://enterobase.warwick.ac.uk) automatically clusters core genome MLST allelic profiles into hierarchical clusters (HierCC) after assembling annotated draft genomes from short read sequences. HierCC clusters span core sequence diversity from the species level down to individual transmission chains. Here we evaluate HierCC’s ability to correctly assign 100,000s of genomes to the species/subspecies and population levels for Salmonella, Escherichia, Clostridoides, Yersinia, Vibrio and Streptococcus. HierCC assignments were more consistent with maximum-likelihood super-trees of core SNPs or presence/absence of accessory genes than classical taxonomic assignments or 95% ANI. However, neither HierCC nor ANI were uniformly consistent with classical taxonomy of Streptococcus. HierCC was also consistent with legacy eBGs/ST Complexes in Salmonella or Escherichia and with O serogroups in Salmonella. Thus, EnteroBase HierCC supports the automated identification of and assignment to species/subspecies and populations for multiple genera.