Background An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to 95 333 confirmed cases as of March 5, 2020. Understanding the early transmission dynamics of the infection and evaluating the effectiveness of control measures is crucial for assessing the potential for sustained transmission to occur in new areas. Combining a mathematical model of severe SARS-CoV-2 transmission with four datasets from within and outside Wuhan, we estimated how transmission in Wuhan varied between December, 2019, and February, 2020. We used these estimates to assess the potential for sustained human-to-human transmission to occur in locations outside Wuhan if cases were introduced. Methods We combined a stochastic transmission model with data on cases of coronavirus disease 2019 (COVID-19) inWuhan and international cases that originated in Wuhan to estimate how transmission had varied over time during January, 2020, and February, 2020. Based on these estimates, we then calculated the probability that newly introduced cases might generate outbreaks in other areas. To estimate the early dynamics of transmission in Wuhan, we fitted a stochastic transmission dynamic model to multiple publicly available datasets on cases in Wuhan and internationally exported cases from Wuhan. The four datasets we fitted to were: daily number of new internationally exported cases (or lack thereof), by date of onset, as of Jan 26, 2020; daily number of new cases in Wuhan with no market exposure, by date of onset, between Dec 1, 2019, and Jan 1, 2020; daily number of new cases in China, by date of onset, between Dec 29, 2019, and Jan 23, 2020; and proportion of infected passengers on evacuation flights between Jan 29, 2020, and Feb 4, 2020. We used an additional two datasets for comparison with model outputs: daily number of new exported cases from Wuhan (or lack thereof) in countries with high connectivity to Wuhan (ie, top 20 most at-risk countries), by date of confirmation, as of Feb 10, 2020; and data on new confirmed cases reported in Wuhan between Jan 16, 2020, and Feb 11, 2020.Findings We estimated that the median daily reproduction number (R t ) in Wuhan declined from 2·35 (95% CI 1·15-4·77) 1 week before travel restrictions were introduced on Jan 23, 2020, to 1·05 (0·41-2·39) 1 week after. Based on our estimates of R t , assuming SARS-like variation, we calculated that in locations with similar transmission potential to Wuhan in early January, once there are at least four independently introduced cases, there is a more than 50% chance the infection will establish within that population.Interpretation Our results show that COVID-19 transmission probably declined in Wuhan during late January, 2020, coinciding with the introduction of travel control measures. As more cases arrive in international locations with similar transmission potential to Wuhan before these control measures, it is likely many chains of transmission will fail to establish initially, but might lead to new outbreaks eventually.

Understanding the function of histone modifications across inducible genes in mammalian cells requires quantitative, comparative analysis of their fate during gene activation and identification of enzymes responsible. We produced high-resolution comparative maps of the distribution and dynamics of H3K4me3, H3K36me3, H3K79me2 and H3K9ac across c-fos and c-jun upon gene induction in murine fibroblasts. In unstimulated cells, continuous turnover of H3K9 acetylation occurs on all K4-trimethylated histone H3 tails; distribution of both modifications coincides across promoter and 5′ part of the coding region. In contrast, K36- and K79-methylated H3 tails, which are not dynamically acetylated, are restricted to the coding regions of these genes. Upon stimulation, transcription-dependent increases in H3K4 and H3K36 trimethylation are seen across coding regions, peaking at 5′ and 3′ ends, respectively. Addressing molecular mechanisms involved, we find that Huntingtin-interacting protein HYPB/Setd2 is responsible for virtually all global and transcription-dependent H3K36 trimethylation, but not H3K36-mono- or dimethylation, in these cells. These studies reveal four distinct layers of histone modification across inducible mammalian genes and show that HYPB/Setd2 is responsible for H3K36 trimethylation throughout the mouse nucleus.

The transmissible nature of communicable diseases is what sets them apart from other diseases modeled by health economists. The probability of a susceptible individual becoming infected at any one point in time (the force of infection) is related to the number of infectious individuals in the population, will change over time, and will feed back into the future force of infection. These nonlinear interactions produce transmission dynamics that require specific consideration when modeling an intervention that has an impact on the transmission of a pathogen. Best practices for designing and building these models are set out in this article.

BackgroundMathematical modelling of infectious disease is increasingly used to help guide public health policy. As directly transmitted infections, such as influenza and tuberculosis, require contact between individuals, knowledge about contact patterns is a necessary pre-requisite of accurate model predictions. Of particular interest is the potential impact of school closure as a means of controlling pandemic influenza (and potentially other pathogens).MethodsThis paper uses a population-based prospective survey of mixing patterns in eight European countries to study the relative change in the basic reproduction number (R0 - the average number of secondary cases from a typical primary case in a fully susceptible population) on weekdays versus weekends and during regular versus holiday periods. The relative change in R0 during holiday periods and weekends gives an indication of the impact collective school closures (and prophylactic absenteeism) may have during a pandemic.ResultsSocial contact patterns differ substantially when comparing weekdays to the weekend and regular to holiday periods mainly due to the reduction in work and/or school contacts. For most countries the basic reproduction number decreases from the week to weekends and regular to holiday periods by about 21% and 17%, respectively. However for other countries no significant decrease was observed.ConclusionWe use a large-scale social contact survey in eight different European countries to gain insights in the relative change in the basic reproduction number on weekdays versus weekends and during regular versus holiday periods. The resulting estimates indicate that school closure can have a substantial impact on the spread of a newly emerging infectious disease that is transmitted via close (non sexual) contacts.

Phosphorylation of histone H3 is implicated in transcriptional activation and chromosome condensation, but its immediate molecular function has remained obscure. By affinity chromatography of nuclear extracts against modified H3 tail peptides, we identified 14-3-3 isoforms as proteins that bind these tails in a strictly phosphorylation-dependent manner. Acetylation of lysines 9 and 14 does not impede 14-3-3 binding to serine 10-phosphorylated H3 tails. In vivo, 14-3-3 is inducibly recruited to c-fos and c-jun nucleosomes upon gene activation, concomitant with H3 phosphoacetylation. We have determined the structures of 14-3-3zeta complexed with serine 10-phosphorylated or phosphoacetylated H3 peptides. These reveal a distinct mode of 14-3-3/phosphopeptide binding and provide a structural understanding for the lack of effect of acetylation at lysines 9 and 14 on this interaction. 14-3-3 isoforms thus represent a class of proteins that mediate the effect of histone phosphorylation at inducible genes.

Background: Isolation of symptomatic cases and tracing of contacts has been used as an early COVID-19 containment measure in many countries, with additional physical distancing measures also introduced as outbreaks have grown. To maintain control of infection while also reducing disruption to populations, there is a need to understand what combination of measures -including novel digital tracing approaches and less intensive physical distancing -may be required to reduce transmission.Methods: Using a model of individual-level transmission stratified by setting (household, work, school, other) based on BBC Pandemic data from 40,162 UK participants, we simulated the impact of a range of different testing, isolation, tracing and physical distancing scenarios. As well as estimating reduction in effective reproduction number, we estimated, for a given level of COVID-19 incidence, the number of contacts that would be newly quarantined each day under different strategies.Results: Under optimistic but plausible assumptions, we estimated that combined testing and tracing strategies would reduce transmission more than mass testing or self-isolation alone (50-65% compared to 2-30%). If limits are placed on gatherings outside of home/school/work (e.g. maximum of 4 daily contacts in other settings), then manual contact tracing of acquaintances only could have a similar effect on transmission reduction as detailed contact tracing. In a scenario where there were 10,000 new symptomatic cases per day, we estimated in most contact tracing strategies, 140,000 to 390,000 contacts would be newly quarantined each day. Conclusions:Consistent with previous modelling studies and country-specific COVID-19 responses to date, our analysis estimates that a high proportion of cases would need to self-isolate and a high proportion of their contacts to be successfully traced to ensure an effective reproduction number that is below one in the absence of other measures. If combined with moderate physical distancing measures, self-isolation and contact tracing would be more likely to achieve control.

Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.

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