Heterogeneity in transmissibility and shedding SARS-CoV-2 via droplets and aerosols

Background: Which virological factors mediate overdispersion in the transmissibility of emerging viruses remains a longstanding question in infectious disease epidemiology. Methods: Here, we use systematic review to develop a comprehensive dataset of respiratory viral loads (rVLs) of SARS-CoV-2, SARS-CoV-1 and influenza A(H1N1)pdm09. We then comparatively meta-analyze the data and model individual infectiousness by shedding viable virus via respiratory droplets and aerosols. Results: The analyses indicate heterogeneity in rVL as an intrinsic virological factor facilitating greater overdispersion for SARS-CoV-2 in the COVID-19 pandemic than A(H1N1)pdm09 in the 2009 influenza pandemic. For COVID-19, case heterogeneity remains broad throughout the infectious period, including for pediatric and asymptomatic infections. Hence, many COVID-19 cases inherently present minimal transmission risk, whereas highly infectious individuals shed tens to thousands of SARS-CoV-2 virions/min via droplets and aerosols while breathing, talking and singing. Coughing increases the contagiousness, especially in close contact, of symptomatic cases relative to asymptomatic ones. Infectiousness tends to be elevated between 1-5 days post-symptom onset. Conclusions: Intrinsic case variation in rVL facilitates overdispersion in the transmissibility of emerging respiratory viruses. Our findings present considerations for disease control in the COVID-19 pandemic as well as future outbreaks of novel viruses.</p

PP-235 Analysis of clinical features of 70 adult patients with varicella

Analysing the genomic data of pathogens with the help of next-generation sequencing (NGS) is an increasingly important part of disease outbreak investigations and helps guide responses. While this technology has already been successfully employed to elucidate and control disease outbreaks, wider implementation of NGS also depends on its cost-effectiveness. COMPARE - short for 'Collaborative Management Platform for detection and Analyses of (Re-) emerging and foodborne outbreaks' - is a major project, funded by the European Union, to develop a global platform for sharing and analysing NGS data and thereby improve the rapid identification, containment and mitigation of emerging infectious diseases and foodborne outbreaks. This article introduces the project and presents the results of a review of the literature, composed of previous relevant cost-benefit and cost-effectiveness analyses. The authors also outline the implications for a methodological framework to assess the cost- effectiveness of COMPARE and similar systems

Substrate Flexibility of a Mutated Acyltransferase Domain and Implications for Polyketide Biosynthesis

SummaryPolyketides are natural products frequently used for the treatment of various diseases, but their structural complexity hinders efficient derivatization. In this context, we recently introduced enzyme-directed mutasynthesis to incorporate non-native extender units into the biosynthesis of erythromycin. Modeling and mutagenesis studies led to the discovery of a variant of an acyltransferase domain in the erythromycin polyketide synthase capable of accepting a propargylated substrate. Here, we extend molecular rationalization of enzyme-substrate interactions through modeling, to investigate the incorporation of substrates with different degrees of saturation of the malonic acid side chain. This allowed the engineered biosynthesis of new erythromycin derivatives and the introduction of additional mutations into the AT domain for a further shift of the enzyme's substrate scope. Our approach yields non-native polyketide structures with functional groups that will simplify future derivatization approaches, and provides a blueprint for the engineering of AT domains to achieve efficient polyketide synthase diversification

The Stellar Kinematic Signature of Massive Black Hole Binaries

The stalling radius of a merging massive binary black hole (BBH) is expected to be below 0".1 even in nearby galaxies (Yu 2002), and thus BBHs are not expected to be spatially resolved in the near future. However, as we show below, a BBH may be detectable through the significantly anisotropic stellar velocity distribution it produces on scales 5-10 times larger than the binary separation. We calculate the velocity distribution of stable orbits near a BBH by solving the restricted three body problem for a BBH embedded in a bulge potential. We present high resolution maps of the projected velocity distribution moments, based on snapshots of ~ 10^8 stable orbits. The kinematic signature of a BBH in the average velocity maps is a counter rotating torus of stars outside the BBH Hill spheres. The velocity dispersion maps reveal a dip in the inner region, and an excess of 20-40% further out, compared to a single BH of the same total mass. More pronounced signatures are seen in the third and fourth Gauss-Hermite velocity moments maps. The detection of these signatures may indicate the presence of a BBH currently, or at some earlier time, which depends on the rate of velocity phase space mixing following the BBH merger.Comment: Accepted to MNRA

The Kinematic Connection Between Galaxies and Dark Matter Haloes

Using estimates of dark halo masses from satellite kinematics, weak gravitational lensing, and halo abundance matching, combined with the Tully-Fisher and Faber-Jackson relations, we derive the mean relation between the optical, V_opt, and virial, V_200, circular velocities of early- and late-type galaxies at redshift z~0. For late-type galaxies V_opt ~ V_200 over the velocity range V_opt=90-260 km/s, and is consistent with V_opt = V_maxh (the maximum circular velocity of NFW dark matter haloes in the concordance LCDM cosmology). However, for early-type galaxies V_opt \ne V_200, with the exception of early-type galaxies with V_opt simeq 350 km/s. This is inconsistent with early-type galaxies being, in general, globally isothermal. For low mass (V_opt V_maxh, indicating that baryons have modified the potential well, while high mass (V_opt > 400 km/s) early-types have V_opt < V_maxh. Folding in measurements of the black hole mass - velocity dispersion relation, our results imply that the supermassive black hole - halo mass relation has a logarithmic slope which varies from ~1.4 at halo masses of ~10^{12} Msun/h to ~0.65 at halo masses of 10^{13.5} Msun/h. The values of V_opt/V_200 we infer for the Milky Way and M31 are lower than the values currently favored by direct observations and dynamical models. This offset is due to the fact that the Milky Way and M31 have higher V_opt and lower V_200 compared to typical late-type galaxies of the same stellar masses. We show that current high resolution cosmological hydrodynamical simulations are unable to form galaxies which simultaneously reproduce both the V_opt/V_200 ratio and the V_opt-M_star (Tully-Fisher/Faber-Jackson) relation.Comment: 17 pages, 7 figures, accepted to MNRA

The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Background: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Methods: Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. Results: SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Conclusion: Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression

Single-cell isoform RNA sequencing characterizes isoforms in thousands of cerebellar cells

Full-length RNA sequencing (RNA-Seq) has been applied to bulk tissue, cell lines and sorted cells to characterize transcriptomes1–11, but applying this technology to single cells has proven to be difficult, with less than ten single-cell transcriptomes having been analyzed thus far12,13. Although single splicing events have been described for ≤200 single cells with statistical confidence14,15, full-length mRNA analyses for hundreds of cells have not been reported. Single-cell short-read 3′ sequencing enables the identification of cellular subtypes16–21, but full-length mRNA isoforms for these cell types cannot be profiled. We developed a method that starts with bulk tissue and identifies single-cell types and their full-length RNA isoforms without fluorescence-activated cell sorting. Using single-cell isoform RNA-Seq (ScISOr-Seq), we identified RNA isoforms in neurons, astrocytes, microglia, and cell subtypes such as Purkinje and Granule cells, and cell-type-specific combination patterns of distant splice sites6–9,22,23. We used ScISOr-Seq to improve genome annotation in mouse Gencode version 10 by determining the cell-type-specific expression of 18,173 known and 16,872 novel isoforms

Internal kinematics of groups of galaxies in the Sloan Digital Sky Survey data release 7

We present measurements of the velocity dispersion profile (VDP) for galaxy groups in the final data release of the Sloan Digital Sky Survey (SDSS). For groups of given mass we estimate the redshift-space cross-correlation function (CCF) with respect to a reference galaxy sample, xi(r_p, pi), the projected CCF, w_p(r_p), and the real-space CCF, xi(r). The VDP is then extracted from the redshift distortion in xi(r_p, pi), by comparing xi(r_p, pi) with xi(r). We find that the velocity dispersion (VD) within virial radius (R_200) shows a roughly flat profile, with a slight increase at radii below ~0.3 R_200 for high mass systems. The average VD within the virial radius, sigma_v, is a strongly increasing function of central galaxy mass. We apply the same methodology to N-body simulations with the concordance Lambda cold dark matter cosmology but different values of the density fluctuation parameter sigma_8, and we compare the results to the SDSS results. We show that the sigma_v-M_* relation from the data provides stringent constraints on both sigma_8 and sigma_ms, the dispersion in log M_* of central galaxies at fixed halo mass. Our best-fitting model suggests sigma_8 = 0.86 +/- 0.03 and sigma_ms = 0.16 +/- 0.03. The slightly higher value of sigma_8 compared to the WMAP7 result might be due to a smaller matter density parameter assumed in our simulations. Our VD measurements also provide a direct measure of the dark matter halo mass for central galaxies of different luminosities and masses, in good agreement with the results obtained by Mandelbaum et al. (2006) from stacking the gravitational lensing signals of the SDSS galaxies.Comment: 17 pages, 10 figures, 1 table, accepted for publication in ApJ, text slightly changed, abstract substantially shortened, two new panels added to Figs. 2 and 3 showing w_p and VDP as functions of r_p/R_200 instead of r_

Case study on the efficacy of a lanthanum-enriched clay (Phoslock®) in controlling eutrophication in Lake Het Groene Eiland (The Netherlands)

Lake Het Groene Eiland was created in the beginning of 2008 by construction of dikes for isolating it from the surrounding 220-ha water body. This so-called claustrum of 5 ha was treated using lanthanum-modified clay (Phoslock®) to control eutrophication and mitigate cyanobacterial nuisance. Cyanobacteria chlorophyll-a were significantly lower in the claustrum than those in the reference water body, where a massive bloom developed in summer, 2008. However, PO4-P and TP did not statistically differ in these two waters. TN and NO3-N were significantly lower in the claustrum, where dense submerged macrophytes beds developed. Lanthanum concentrations were elevated after the applications of the modified clay in the claustrum, but filterable lanthanum dropped rapidly below the Dutch standard of 10.1 μg l−1. During winter, dozens of Canada geese resided at the claustrum. Geese droppings contained an average of 2 mg PO4-P g−1 dry weight and 12 mg NH3-N g−1 dry weight and might present a growing source of nutrients to the water. Constructing the claustrum enabled unrestricted bathing in subsequent three summers, as no swimming bans had to be issued due to cyanobacteria blooms. However, the role of the modified clay in this positive outcome remains unclear, and longevity of the measures questionable.

Monitoring SARS-CoV-2 Circulation and Diversity through Community Wastewater Sequencing, the Netherlands and Belgium

Severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) has rapidly become a major global health problem, and public health surveillance is crucial to monitor and prevent virus spread. Wastewater-based epidemiology has been proposed as an addition to disease-based surveillance because virus is shed in the feces of ≈40% of infected persons. We used next-generation sequencing of sewage samples to evaluate the diversity of SARS-CoV-2 at the community level in the Netherlands and Belgium. Phylogenetic analysis revealed the presence of the most prevalent clades (19A, 20A, and 20B) and clustering of sewage samples with clinical samples from the same region. We distinguished multiple clades within a single sewage sample by using low-frequency variant analysis. In addition, several novel mutations in the SARS-CoV-2 genome were detected. Our results illustrate how wastewater can be used to investigate the diversity of SARS-CoV-2 viruses circulating in a community and identify new outbreaks