Asymptomatic or subclinical SARS-CoV-2 infections are often unreported, which means that confirmed case counts may not accurately reflect underlying epidemic dynamics. Understanding the level of ...ascertainment (the ratio of confirmed symptomatic cases to the true number of symptomatic individuals) and undetected epidemic progression is crucial to informing COVID-19 response planning, including the introduction and relaxation of control measures. Estimating case ascertainment over time allows for accurate estimates of specific outcomes such as seroprevalence, which is essential for planning control measures.
Using reported data on COVID-19 cases and fatalities globally, we estimated the proportion of symptomatic cases (i.e. any person with any of fever ≥ 37.5 °C, cough, shortness of breath, sudden onset of anosmia, ageusia or dysgeusia illness) that were reported in 210 countries and territories, given those countries had experienced more than ten deaths. We used published estimates of the baseline case fatality ratio (CFR), which was adjusted for delays and under-ascertainment, then calculated the ratio of this baseline CFR to an estimated local delay-adjusted CFR to estimate the level of under-ascertainment in a particular location. We then fit a Bayesian Gaussian process model to estimate the temporal pattern of under-ascertainment.
Based on reported cases and deaths, we estimated that, during March 2020, the median percentage of symptomatic cases detected across the 84 countries which experienced more than ten deaths ranged from 2.4% (Bangladesh) to 100% (Chile). Across the ten countries with the highest number of total confirmed cases as of 6 July 2020, we estimated that the peak number of symptomatic cases ranged from 1.4 times (Chile) to 18 times (France) larger than reported. Comparing our model with national and regional seroprevalence data where available, we find that our estimates are consistent with observed values. Finally, we estimated seroprevalence for each country. As of 7 June, our seroprevalence estimates range from 0% (many countries) to 13% (95% CrI 5.6-24%) (Belgium).
We found substantial under-ascertainment of symptomatic cases, particularly at the peak of the first wave of the SARS-CoV-2 pandemic, in many countries. Reported case counts will therefore likely underestimate the rate of outbreak growth initially and underestimate the decline in the later stages of an epidemic. Although there was considerable under-reporting in many locations, our estimates were consistent with emerging serological data, suggesting that the proportion of each country's population infected with SARS-CoV-2 worldwide is generally low.
MS has been used to investigate the composition of fibrillin‐rich microfibrils from non‐elastic and elastic tissues, and to compare fibrillin‐1 tryptic fingerprints derived from whole zonules, ...microfibrils and recombinant fibrillin‐1. In all microfibril preparations, fibrillin‐1 was abundant and the only fibrillin isoform. MAGP‐1 was the only other microfibril‐associated molecule. γ‐Crystallin co‐purified with zonular microfibrils, so this association may contribute to ciliary zonule anchorage to lens. Recombinant fibrillin‐1 tryptic peptides mapped throughout the molecule and included virtually all predicted peptides except for those larger than 4.5 kDa, smaller than 600 Da or post‐translationally modified. In contrast, fewer microfibril tryptic fibrillin‐1 peptides were detected, although they were derived from domains throughout the molecule and included two peptides after the C‐terminal furin processing site. Several microfibril‐derived N‐ and C‐terminal domains never yielded any peptides, while tryptic peptides from other domains yielded numerous peptides, suggesting that some tissue microfibril features are retained after trypsinisation. This first MS analysis of a purified extracellular matrix assembly has provided new insights into microfibril composition and fibrillin‐1 organisation within them.
Mosaic tissues are composed of two or more genetically distinct cell types. They occur naturally, and are also a useful experimental method for exploring tissue growth and maintenance. By marking the ...different cell types, one can study the patterns formed by proliferation, renewal and migration. Here, we present mathematical modelling suggesting that small changes in the type of interaction that cells have with their local cellular environment can lead to very different outcomes for the composition of mosaics. In cell renewal, proliferation of each cell type may depend linearly or nonlinearly on the local proportion of cells of that type, and these two possibilities produce very different patterns. We study two variations of a cellular automaton model based on simple rules for renewal. We then propose an integrodifferential equation model, and again consider two different forms of cellular interaction. The results of the continuous and cellular automata models are qualitatively the same, and we observe that changes in local environment interaction affect the dynamics for both. Furthermore, we demonstrate that the models reproduce some of the patterns seen in actual mosaic tissues. In particular, our results suggest that the differing patterns seen in organ parenchymas may be driven purely by the process of cell replacement under different interaction scenarios.
In this paper, we present a two-population continuous integro-differential model of cell differentiation, using a non-local term to describe the influence of the local environment on differentiation. ...We investigate three different versions of the model, with differentiation being cell autonomous, regulated via a community effect, or weakly dependent on the local cellular environment. We consider the spatial patterns that such different modes of differentiation produce, and investigate the formation of both stripes and spots by the model. We show that pattern formation only occurs when differentiation is regulated by a strong community effect. In this case, permanent spatial patterns only occur under a precise relationship between the parameters characterising cell dynamics, although transient patterns can persist for biologically relevant timescales when this condition is relaxed. In all cases, the long-lived patterns consist only of stripes, not spots.
Studies of cyclic microtine populations (voles and lemmings) have suggested a relationship between the previous year's population density and the subsequent timing of the onset of reproduction by ...overwintered breeding females. No studies have explored the importance of this relationship in the generation of population cycles. Here we mathematically examine the implications of variation in reproductive season length caused by delayed density‐dependent changes in its start date. We demonstrate that when reproductive season length is a function of past population densities, it is possible to get realistic population cycles without invoking any changes in birth rates or survival. When parameterized for field voles (Microtus agrestis) in Kielder Forest (northern England), our most realistic model predicts population cycles of similar periodicity to the Kielder populations. Our study highlights the potential importance of density‐dependent reproductive timing in microtine population cycles and calls for investigations into the mechanism(s) underlying this phenomenon.
Fibrillin-rich microfibrils have endowed tissues with elasticity throughout multicellular evolution. We have used molecular combing techniques to determine Young's modulus for individual microfibrils ...and X-ray diffraction of zonular filaments of the eye to establish the linearity of microfibril periodic extension. Microfibril periodicity is not altered at physiological zonular tissue extensions and Young's modulus is between 78 MPa and 96 MPa, which is two orders of magnitude stiffer than elastin. We conclude that elasticity in microfibril-containing tissues arises primarily from reversible alterations in supra-microfibrillar arrangements rather than from intrinsic elastic properties of individual microfibrils which, instead, act as reinforcing fibres in fibrous composite tissues.
Mice carrying the Tight skin (Tsk) mutation harbor a genomic duplication within the fibrillin-1 (Fbn 1) gene that results in a larger than normal in-frame Fbn 1 transcript. In this study, the ...consequences of the Tsk mutation for fibrillin-containing microfibrils have been examined. Dermal fibroblasts from Tsk/+ mice synthesized and secreted both normal fibrillin (∼330 kD) and the mutant oversized Tsk fibrillin-1 (∼450 kD) in comparable amounts, and Tsk fibrillin-1 was stably incorporated into cell layers. Immunohistochemical and ultrastructural analyses of normal and Tsk/+ mouse skin highlighted differences in the gross organization and distribution of microfibrillar arrays. Rotary shadowing of high Mrpreparations from Tsk/+ skin demonstrated the presence of abundant beaded microfibrils. Some of these had normal morphology and periodicity, but others were distinguished by diffuse interbeads, longer periodicity, and tendency to aggregate. The presence of a structurally abnormal population of microfibrils in Tsk/+ skin was unequivocally demonstrated after calcium chelation and in denaturating conditions. Scanning transmission electron microscopy highlighted the presence of more mass in Tsk/+ skin microfibrils than in normal mice skin microfibrils. These data indicate that Tsk fibrillin-1 polymerizes and becomes incorporated into a discrete population of beaded microfibrils with altered molecular organization.
Collagen VI has a ubiquitous distribution throughout connective tissues, and has key roles in linking cells and matrix macromolecules. We have generated three-dimensional reconstructions of collagen ...VI microfibrils using automated electron tomography (AET) in order to obtain new insights into the organisation of collagen VI in assembled microfibrils. Analysis of the reconstruction data has allowed the resolution of the double-beaded structure into smaller subunits. Volume calculations from the tomography data indicate that ten and six A-domains could be packed into the N and C-terminal regions from each monomer, respectively. A putative location for the globular N-terminal regions of the α3 chain, important for microfibril assembly and function, has been identified. Some surfaces of the α3 chain N-terminal domains appear to be exposed on the surface of a microfibril, where they may provide an interactive surface for molecules. Analysis of the interbead region provides evidence for complex triple helical supercoiling in microfibrils. Frequently, two strands were visualised emerging from the beaded region and merging into a single interbead region. Measurements taken from the AET data show that there is a decrease in periodicity from dimer/tetramer to microfibrils. Molecular combing reverses this effect by mechanically increasing periodicity to give measurements similar to the component dimers/tetramers. Together, these data have provided important new insights into the organisation and function of these large macromolecular assemblies.
Fibrillin-rich microfibrils are a unique class of extensible connective tissue macromolecules. Their critical contribution to the establishment and maintenance of diverse extracellular matrices was ...underlined by the linkage of their principal structural component fibrillin to Marfan syndrome, a heritable connective tissue disorder with pleiotropic manifestations. Microscopy and preparative techniques have contributed substantially to the understanding of microfibril structure and function. The supramolecular organisation of microfibrillar assemblies in tissues has been examined by tissue sectioning and X-ray diffraction methods. Published findings are discussed and new information reported on the organisation of microfibrils in the ciliary zonular fibrils by environmental scanning electron microscopy. This review summarises microscopy and X-ray diffraction studies that are informing current understanding of the ultrastructure of fibrillin-rich microfibrils.
Chromosome dimers form in bacteria by recombination between circular chromosomes. Resolution of dimers is a highly integrated process involving recombination between dif sites catalysed by the XerCD ...recombinase, cell division and the integrity of the division septum‐associated FtsK protein and the presence of dif inside a restricted region of the chromosome terminus, the dif activity zone (DAZ). We analyse here how these phenomena collaborate. We show that (i) both inter‐ and intrachromosomal recombination between dif sites are activated by their presence inside the DAZ; (ii) the DAZ‐specific activation only occurs in conditions supporting the formation of chromosome dimers; (iii) overexpression of FtsK leads to a general increase in dif recombination irrespective of dif location; (iv) overexpression of FtsK does not improve the ability of dif sites inserted outside the DAZ to resolve chromosome dimers. Our results suggest that the formation of an active XerCD‐FtsK–dif complex is restricted to when a dimer is present, the features of chromosome organization that determine the DAZ playing a central role in this control.
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