Length heterogeneity at conserved sequence block 2 in human mitochondrial DNA acts as a rheostat for RNA polymerase POLRMT activity

The guanine (G)-tract of conserved sequence block 2 (CSB 2) in human mitochondrial DNA can result in transcription termination due to formation of a hybrid G-quadruplex between the nascent RNA and the nontemplate DNA strand. This structure can then influence genome replication, stability and localization. Here we surveyed the frequency of variation in sequence identity and length at CSB 2 amongst human mitochondrial genomes and used in vitro transcription to assess the effects of this length heterogeneity on the activity of the mitochondrial RNA polymerase, POLRMT. In general, increased G-tract length correlated with increased termination levels. However, variation in the population favoured CSB 2 sequences which produced efficient termination while particularly weak or strong signals were avoided. For all variants examined, the 3′ end of the transcripts mapped to the same downstream sequences and were prevented from terminating by addition of the transcription factor TEFM. We propose that CSB 2 length heterogeneity allows variation in the efficiency of transcription termination without affecting the position of the products or the capacity for regulation by TEFM

Towards environmentally sustainable human behaviour: targeting non-conscious and conscious processes for effective and acceptable policies.

Meeting climate change targets to limit global warming to 2°C requires rapid and large reductions in demand for products that most contribute to greenhouse gas (GHG) emissions. These include production of bulk materials (e.g. steel and cement), energy supply (e.g. fossil fuels) and animal source foods (particularly ruminants and their products). Effective strategies to meet these targets require transformative changes in supply as well as demand, involving changes in economic, political and legal systems at local, national and international levels, building on evidence from many disciplines. This paper outlines contributions from behavioural science in reducing demand. Grounded in dual-process models of human behaviour (involving non-conscious and conscious processes) this paper considers first why interventions aimed at changing population values towards the environment are usually insufficient or unnecessary for reducing demand although they may be important in increasing public acceptability of policies that could reduce demand. It then outlines two sets of evidence from behavioural science towards effective systems-based strategies, to identify interventions likely to be effective at: (i) reducing demand for products that contribute most to GHG emissions, mainly targeting non-conscious processes and (ii) increasing public acceptability for policy changes to enable these interventions, targeting conscious processes.This article is part of the themed issue 'Material demand reduction'

The Way Forward

As understanding of the interdependence between a healthy planet and healthy people becomes more developed, complex issues that thread through systems and societies gain new importance. Beyond the traditional Global Environment Outlook (GEO) themes addressing air, biodiversity, oceans, land and fresh water, this GEO-6 assessment addresses cross-cutting issues worthy of further examination. Using a systems approach, these cross-cutting issues offer entry points allowing another dimension for analysing GEO-6 themes as well as understanding the network of interconnections throughout earth and human systems. These cross-cutting issues are grouped according to shared characteristics: health, environmental disasters, gender, education and urbanization are grouped as ‘people and livelihoods’; climate change, polar and mountain regions, chemicals and waste and wastewater are grouped as ‘changing environments’; and resource use, energy and food systems are considered as ‘resources and materials’. While each issue provides useful entry points into GEO-6 themes, it is important to discuss the state of the environment and policy context for each one

Clinical, biochemical and genetic spectrum of 70 patients with ACAD9 deficiency: Is riboflavin supplementation effective?

Background: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. Results: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and

Chromosomal disorders:estimating baseline birth prevalence and pregnancy outcomes worldwide

Chromosomal disorders, of which Down syndrome is the most common, can cause multi-domain disability. In addition, compared to the general population, there is a higher frequency of death before the age of five. In many settings, large gaps in data availability have hampered policy-making, programme priorities and resource allocation for these important conditions. We have developed methods, which overcome this lack of data and allow estimation of the burden of affected pregnancies and their outcomes in different settings worldwide. For example, the methods include a simple equation relating the percentage of mothers 35 and over to Down syndrome birth prevalence. The results obtained provide a starting point for consideration of services that can be implemented for the care and prevention of these disorders

Geographic variation and localised clustering of congenital anomalies in Great Britain

Background: Environmental pollution as a cause of congenital anomalies is sometimes suspected because of clustering of anomalies in areas of higher exposure. This highlights questions around spatial heterogeneity (clustering) in congenital anomaly rates. If spatial variation is endemic, then any one specific cluster is less remarkable, though the presence of uncontrolled geographically clustered risk factors is suggested. If rates are relatively homogeneous across space other than around specific hazards, then evidence for these hazards causing the clusters is strengthened. We sought to estimate the extent of spatial heterogeneity in congenital anomaly rates in the United Kingdom. Methods: The study population covered about one million births from five registers in Britain from 1991–1999. We estimated heterogeneity across four geographical levels: register area, hospital catchment, electoral ward, and enumeration district, using a negative binomial regression model. We also sought clusters using a circular scan statistic. Results: Congenital anomaly rates clearly varied across register areas and hospital catchments (p 0.2). Adjusting for socioeconomic deprivation and maternal age made little difference to the extent of geographical variation for most congenital anomaly subtypes. The two most significant circular clusters (of four ano-rectal atresias and six congenital heart diseases) contained two or more siblings. Conclusion: The variation in rates between registers and hospital catchment area may have resulted in part from differences in case ascertainment, and this should be taken into account in geographical epidemiological studies of environmental exposures. The absence of evidence for variation below this level should be interpreted cautiously in view of the low power of general heterogeneity tests. Nevertheless, the data suggest that strong localised clusters in congenital anomalies are uncommon, so clusters around specific putative environmental hazards are remarkable when observed. Negative binomial models applied at successive hierarchical levels provide an approach of intermediate complexity to characterising geographical heterogeneity

Living bioethics, clinical ethics committees and children's consent to heart surgery

This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theory–practice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee members’ reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and children’s interests and rights. Different approaches to framing ethical questions are also considered. Being aware of the four theories’ influence can help when seeking to understand and possibly change clinical ethics committee routines. The paper is not a research report but is informed by a recent study in two London paediatric cardiac units. Forty-five practitioners and related experts were interviewed, including eight members of ethics committees, about the work of informing, preparing and supporting families during the extended process of consent to children’s elective heart surgery. The mosaic of multidisciplinary teamwork is reported in a series of papers about each profession, including this one on bioethics and law and clinical ethics committees’ influence on clinical practice. The qualitative social research was funded by the British Heart Foundation, in order that more may be known about the perioperative views and needs of all concerned. Questions included how disputes can be avoided, how high ethical standards and respectful cooperation between staff and families can be encouraged, and how minors’ consent or refusal may be respected, with the support of clinical ethics committees

Letter from R.D. Blackmore, Teddington, England : autograph manuscript signed, 1888 February 21

Note in pencil on the top of the letter regarding the location of R. D. Blackmore\u27s gravehttps://repository.wellesley.edu/autographletters/1298/thumbnail.jp

Letter from R.D. Blackmore, Teddington, London, England, to Edmund Gosse : autograph manuscript signed, 1896 June 17

Regarding reproduction of Blackmore\u27s portrait in America contrary to copyright. Written on the back of a typed manuscript letter, signed, from G.P. Putnam\u27s Sons, London, to R.D. Blackmore, June 16, 1896. Written above this typed letter is an autograph manuscript copy, signed, of a letter to from R.D. Blackman, Teddington, to G.P. Putnam\u27s Sons, June 15, 1896https://repository.wellesley.edu/autographletters/1299/thumbnail.jp