Phenotypic Variation and Bistable Switching in Bacteria

Microbial research generally focuses on clonal populations. However, bacterial cells with identical genotypes frequently display different phenotypes under identical conditions. This microbial cell individuality is receiving increasing attention in the literature because of its impact on cellular differentiation, survival under selective conditions, and the interaction of pathogens with their hosts. It is becoming clear that stochasticity in gene expression in conjunction with the architecture of the gene network that underlies the cellular processes can generate phenotypic variation. An important regulatory mechanism is the so-called positive feedback, in which a system reinforces its own response, for instance by stimulating the production of an activator. Bistability is an interesting and relevant phenomenon, in which two distinct subpopulations of cells showing discrete levels of gene expression coexist in a single culture. In this chapter, we address techniques and approaches used to establish phenotypic variation, and relate three well-characterized examples of bistability to the molecular mechanisms that govern these processes, with a focus on positive feedback.

Existing and potential infection risk zones of yellow fever worldwide: a modelling analysis.

BACKGROUND: Yellow fever cases are under-reported and the exact distribution of the disease is unknown. An effective vaccine is available but more information is needed about which populations within risk zones should be targeted to implement interventions. Substantial outbreaks of yellow fever in Angola, Democratic Republic of the Congo, and Brazil, coupled with the global expansion of the range of its main urban vector, Aedes aegypti, suggest that yellow fever has the propensity to spread further internationally. The aim of this study was to estimate the disease's contemporary distribution and potential for spread into new areas to help inform optimal control and prevention strategies. METHODS: We assembled 1155 geographical records of yellow fever virus infection in people from 1970 to 2016. We used a Poisson point process boosted regression tree model that explicitly incorporated environmental and biological explanatory covariates, vaccination coverage, and spatial variability in disease reporting rates to predict the relative risk of apparent yellow fever virus infection at a 5 × 5 km resolution across all risk zones (47 countries across the Americas and Africa). We also used the fitted model to predict the receptivity of areas outside at-risk zones to the introduction or reintroduction of yellow fever transmission. By use of previously published estimates of annual national case numbers, we used the model to map subnational variation in incidence of yellow fever across at-risk countries and to estimate the number of cases averted by vaccination worldwide. FINDINGS: Substantial international and subnational spatial variation exists in relative risk and incidence of yellow fever as well as varied success of vaccination in reducing incidence in several high-risk regions, including Brazil, Cameroon, and Togo. Areas with the highest predicted average annual case numbers include large parts of Nigeria, the Democratic Republic of the Congo, and South Sudan, where vaccination coverage in 2016 was estimated to be substantially less than the recommended threshold to prevent outbreaks. Overall, we estimated that vaccination coverage levels achieved by 2016 avert between 94 336 and 118 500 cases of yellow fever annually within risk zones, on the basis of conservative and optimistic vaccination scenarios. The areas outside at-risk regions with predicted high receptivity to yellow fever transmission (eg, parts of Malaysia, Indonesia, and Thailand) were less extensive than the distribution of the main urban vector, A aegypti, with low receptivity to yellow fever transmission in southern China, where A aegypti is known to occur. INTERPRETATION: Our results provide the evidence base for targeting vaccination campaigns within risk zones, as well as emphasising their high effectiveness. Our study highlights areas where public health authorities should be most vigilant for potential spread or importation events. FUNDING: Bill & Melinda Gates Foundation

Global yellow fever vaccination coverage from 1970 to 2016: an adjusted retrospective analysis.

BACKGROUND: Substantial outbreaks of yellow fever in Angola and Brazil in the past 2 years, combined with global shortages in vaccine stockpiles, highlight a pressing need to assess present control strategies. The aims of this study were to estimate global yellow fever vaccination coverage from 1970 through to 2016 at high spatial resolution and to calculate the number of individuals still requiring vaccination to reach population coverage thresholds for outbreak prevention. METHODS: For this adjusted retrospective analysis, we compiled data from a range of sources (eg, WHO reports and health-service-provider registeries) reporting on yellow fever vaccination activities between May 1, 1939, and Oct 29, 2016. To account for uncertainty in how vaccine campaigns were targeted, we calculated three population coverage values to encompass alternative scenarios. We combined these data with demographic information and tracked vaccination coverage through time to estimate the proportion of the population who had ever received a yellow fever vaccine for each second level administrative division across countries at risk of yellow fever virus transmission from 1970 to 2016. FINDINGS: Overall, substantial increases in vaccine coverage have occurred since 1970, but notable gaps still exist in contemporary coverage within yellow fever risk zones. We estimate that between 393·7 million and 472·9 million people still require vaccination in areas at risk of yellow fever virus transmission to achieve the 80% population coverage threshold recommended by WHO; this represents between 43% and 52% of the population within yellow fever risk zones, compared with between 66% and 76% of the population who would have required vaccination in 1970. INTERPRETATION: Our results highlight important gaps in yellow fever vaccination coverage, can contribute to improved quantification of outbreak risk, and help to guide planning of future vaccination efforts and emergency stockpiling. FUNDING: The Rhodes Trust, Bill & Melinda Gates Foundation, the Wellcome Trust, the National Library of Medicine of the National Institutes of Health, the European Union's Horizon 2020 research and innovation programme

Concussion knowledge and experience among Welsh amateur rugby union coaches and referees

Background Rugby union is a collision sport where participants are at high risk of sustaining a concussion. In settings where there is little qualified medical supervision, certain stakeholders (eg, coaches and officials) should possess sufficient knowledge in regard to the recognition and management of concussion. Aim The aim of this study was to assess the knowledge and experience of various aspects of concussion among coaches and referees involved in Welsh amateur rugby union. Methods A questionnaire was distributed to 1843 coaches and 420 referees. Results A total of 333 coaches and 283 referees completed the questionnaire (18% and 68% response rates, respectively). Participants exhibited greater knowledge of concussion symptom recognition relative to knowledge of both the consequences of concussion and associated return-to-play protocols, both of which could be considered poor. There were no differences in knowledge levels between coaches and referees or between participants with or without a history of concussion. Two-thirds of participants incorrectly believed that headgear could prevent concussion, and nearly 30% of coaches reported having witnessed other coaches allowing a potentially concussed player to continue playing. Conclusions Identification of several misconceptions indicates that concussion management within Welsh amateur rugby union needs to be improved, warranting a multi-faceted educational intervention

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Socioeconomic position and overweight among adolescents: data from birth cohort studies in Brazil and the UK

<p>Abstract</p> <p>Background</p> <p>Developed and developing countries are facing rapid increases in overweight and obesity among children and adolescents. The patterns of overweight/obesity differ by age, sex, rural or urban residence and socioeconomic position (SEP) and vary between and within countries.</p> <p>Methods</p> <p>We investigated patterns of SEP – overweight status association among adolescents from the UK (ALSPAC) and Brazil (the 1982 and 1993 Pelotas birth cohort studies).</p> <p>All analyses were performed separately for males and females. Logistic regression analysis was used to examine the relationships between overweight status and two SEP indicators – family income and maternal education.</p> <p>Results</p> <p>A strong positive association was observed in 11-year-old boys from the 1993 Pelotas cohort, with higher prevalence of overweight among the least poor and among those whose mothers had more years of schooling (<it>x</it>²for linear trend p < 0.001). In ALSPAC study higher prevalence of overweight was seen among boys whose mothers had lower educational achievement (<it>x</it>²for linear trend p = 0.006). Among 11 year-old girls from 1993 Pelotas cohort study there was a positive association (higher prevalence of overweight in the higher socioeconomic and educational strata, <it>x</it>²for linear trend p < 0.001 and p = 0.01, respectively) while an inverse association was found in the ALSPAC study (<it>x</it>²for linear trend p < 0.001). Among males from the 1982 cohort study, overweight at 18 years of age showed a positive association with both SEP indicators while among females, the reverse association was found.</p> <p>Conclusion</p> <p>The results of this study demonstrate that the social patterning of overweight varies between and within populations over time. Specific approaches should be developed within populations in order to contain the obesity epidemic and reduce disparities.</p

The association between intimate partner violence, alcohol and depression in family practice

Background: Depressive symptoms, intimate partner violence and hazardous drinking are common among patients attending general practice. Despite the high prevalence of these three problems; the relationship between them remains relatively unexplored. Methods: This paper explores the association between depressive symptoms, ever being afraid of a partner and hazardous drinking using cross-sectional screening data from 7667 randomly selected patients from a large primary care cohort study of 30 metropolitan and rural general practices in Victoria, Australia. The screening postal survey included the Center for Epidemiological Studies Depression Scale, the Fast Alcohol Screening Test and a screening question from the Composite Abuse Scale on ever being afraid of any intimate partner. Results: 23.9% met criteria for depressive symptoms. A higher proportion of females than males (20.8% vs. 7.6%) reported ever being afraid of a partner during their lifetime (OR 3.2, 95%CI 2.5 to 4.0) and a lower proportion of females (12%) than males (25%) were hazardous drinkers (OR 0.4; 95%CI 0.4 to 0.5); and a higher proportion of females than males (20.8% vs. 7.6%) reported ever being afraid of a partner during their lifetime (OR 3.2, 95%CI 2.5 to 4.0). Men and women who had ever been afraid of a partner or who were hazardous drinkers had on average higher depressive symptom scores than those who had never been afraid or who were not hazardous drinkers. There was a stronger association between depressive symptoms and ever been afraid of a partner compared to hazardous drinking for both males (ever afraid of partner; Diff 6.87; 95% CI 5.42, 8.33; p < 0.001 vs. hazardous drinking in last year; Diff 1.07, 95% CI 0.21, 1.94; p = 0.015) and females (ever afraid of partner; Diff 5.26; 95% CI 4.55, 5.97; p < 0.001 vs. hazardous drinking in last year; Diff 2.23, 95% CI 1.35, 3.11; p < 0.001), even after adjusting for age group, income, employment status, marital status, living alone and education level. Conclusions: Strategies to assist primary care doctors to recognise and manage intimate partner violence and hazardous drinking in patients with depression may lead to better outcomes from management of depression in primary care