Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.

Mutations of the mitochondrial genome (mtDNA) underlie a substantial portion of mitochondrial disease burden. These disorders are currently incurable and effectively untreatable, with heterogeneous penetrance, presentation and prognosis. To address the lack of effective treatment for these disorders, we exploited a recently developed mouse model that recapitulates common molecular features of heteroplasmic mtDNA disease in cardiac tissue: the m.5024C>T tRNAAla mouse. Through application of a programmable nuclease therapy approach, using systemically administered, mitochondrially targeted zinc-finger nucleases (mtZFN) delivered by adeno-associated virus, we induced specific elimination of mutant mtDNA across the heart, coupled to a reversion of molecular and biochemical phenotypes. These findings constitute proof of principle that mtDNA heteroplasmy correction using programmable nucleases could provide a therapeutic route for heteroplasmic mitochondrial diseases of diverse genetic origin

Use of passive alpha detectors to screen for uranium contamination in a field at Fernald, Ohio

This paper reports the results from a field test of newly developed techniques for inexpensive, in situ screening of soil for alpha contamination. Passive alpha detectors that are commercially available for the detection indoor airborne alpha activity (i.e., {sup 222}Rn) have been modified so they can be applied to the detection of alpha contamination on surfaces or in soils. Results reported here are from an intercomparison involving several different techniques with all measurements being made at the same sites in a field near the formerly used uranium processing facility at Fernald, Ohio, during the summer of 1994. The results for two types of passive alpha detector show that the quality of calibration is improved if soils samples are milled to increase homogeneity within the soil matrices. The correlation between laboratory based radiochemical analyses and quick, field-based screening measurements is acceptable and can be improved if the passive devices are left for longer exposure times in the field. The total cost per measurement for either type of passive alpha detector is probably less than $25 and should provide a cost-effective means for site managers to develop the information needed to find areas with remaining alpha contamination so resources can be allocated efficiently

Linear mitochondrial DNA is rapidly degraded by components of the replication machinery.

Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5'-3'exonuclease MGME1, elimination of the 3'-5'exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1

Genetic and environmental influence on thyroid gland volume and thickness of thyroid isthmus: a twin study.

Objectives Decreased thyroid volume has been related to increased prevalence of thyroid cancer.Subjects and methods One hundred and fourteen Hungarian adult twin pairs (69 monozygotic, 45 dizygotic) with or without known thyroid disorders underwent thyroid ultrasound. Thickness of the thyroid isthmus was measured at the thickest portion of the gland in the midline using electronic calipers at the time of scanning. Volume of the thyroid lobe was computed according to the following formula: thyroid height*width*depth*correction factor (0.63).Results Age-, sex-, body mass index- and smoking-adjusted heritability of the thickness of thyroid isthmus was 50% (95% confidence interval [CI], 35 to 66%). Neither left nor right thyroid volume showed additive genetic effects, but shared environments were 68% (95% CI, 48 to 80%) and 79% (95% CI, 72 to 87%), respectively. Magnitudes of monozygotic and dizygotic co-twin correlations were not substantially impacted by the correction of covariates of body mass index and smoking. Unshared environmental effects showed a moderate influence on dependent parameters (24-50%).Conclusions Our analysis support that familial factors are important for thyroid measures in a general twin population. A larger sample size is needed to show whether this is because of common environmental (e.g. intrauterine effects, regional nutrition habits, iodine supply) or genetic effects

Impact of financial inclusion in low- and middle-income countries: a systematic review of reviews

Financial inclusion programmes seek to increase access to financial services such as credit, savings, insurance and money transfers and so allow poor and low-income households in low- and middle-income countries to enhance their welfare, grasp opportunities, mitigate shocks, and ultimately escape poverty. This systematic review of reviews assesses the evidence on economic, social, behavioural and gender-related outcomes from financial inclusion. It collects and appraises all of the existing meta-studies - that is systematic reviews and meta-analyses - of the impact of financial inclusion. The authors first analyse the strength of the methods used in those meta-studies, then synthesise the findings from those that are of a sufficient quality, and finally, report the implications for policy, programming, practice and further research arising from the evidence. Eleven studies are included in the analysis

Risk indicators for severe impaired oral health among indigenous Australian young adults

Background Oral health impairment comprises three conceptual domains; pain, appearance and function. This study sought to: (1) estimate the prevalence of severe oral health impairment as assessed by a summary oral health impairment measure, including aspects of dental pain, dissatisfaction with dental appearance and difficulty eating, among a birth cohort of Indigenous Australian young adults (n = 442, age range 16-20 years); (2) compare prevalence according to demographic, socio-economic, behavioural, dental service utilisation and oral health outcome risk indicators; and (3) ascertain the independent contribution of those risk indicators to severe oral health impairment in this population. Methods Data were from the Aboriginal Birth Cohort (ABC) study, a prospective longitudinal investigation of Aboriginal individuals born 1987-1990 at an Australian regional hospital. Data for this analysis pertained to Wave-3 of the study only. Severe oral health impairment was defined as reported experience of toothache, poor dental appearance and food avoidance in the last 12 months. Logistic regression models were used to evaluate effects of demographic, socio-economic, behavioural, dental service utilisation and clinical oral disease indicators on severe oral health impairment. Effects were quantified as odds ratios (OR). Results The percent of participants with severe oral health impairment was 16.3 (95% CI 12.9-19.7). In the multivariate model, severe oral health impairment was associated with untreated dental decay (OR 4.0, 95% CI 1.6-9.6). In addition to that clinical indicator, greater odds of severe oral health impairment were associated with being female (OR 2.0, 95% CI 1.2-3.6), being aged 19-20 years (OR 2.1, 95% CI 1.2-3.6), soft drink consumption every day or a few days a week (OR 2.6, 95% 1.2-5.6) and non-ownership of a toothbrush (OR 1.9, 95% CI 1.1-3.4). Conclusions Severe oral health impairment was prevalent among this population. The findings suggest that public health strategies that address prevention and treatment of dental disease, self-regulation of soft drink consumption and ownership of oral self-care devices are needed if severe oral health impairment among Indigenous Australian young adults is to be reduced.Lisa M Jamieson, Kaye F Roberts-Thomson and Susan M Sayer

An integrated framework for assessing coastal community vulnerability across cultures, oceans and scales.

Coastal communities are some of the most at-risk populations with respect to climate change impacts. It is therefore important to determine the vulnerability of such communities to co-develop viable adaptation options. Global efforts to address this issue include international scientific projects, such as Global Learning for Local Solutions (GULLS), which focuses on five fast warming regions of the southern hemisphere and aims to provide an understanding of the local scale processes influencing community vulnerability that can then be up-scaled to regional, country and global levels. This paper describes the development of a new social and ecological vulnerability framework which integrates exposure, sensitivity and adaptive capacity with the social livelihoods and food security approaches. It also measures community flexibility to understand better the adaptive capacity of different levels of community organization. The translation of the conceptual framework to an implementable method is described and its application in a number of “hotspot” countries, where ocean waters are warming faster than the rest of the world, is presented. Opportunities for cross-cultural comparisons to uncover similarities and differences in vulnerability and adaptation patterns among the study’s coastal communities, which can provide accelerated learning mechanisms to other coastal regions, are highlighted. The social and ecological framework and the associated survey approach allow for future integration of local-level vulnerability data with ecological and oceanographic models