One of the characteristic features of cells from patients with ataxia telangiectasia (A-T) is that they are in a state of continuous oxidative stress and exhibit constitutive activation of pathways that normally respond to oxidative damage. In this report, we investigated whether the oxidative stress phenotype of A-T cells might be a reflection of an intrinsic mitochondrial dysfunction. Mitotracker Red staining showed that the structural organization of mitochondria in A-T cells was abnormal compared to wild-type. Moreover, A-T cells harbored a much larger population of mitochondria with decreased membrane potential (DeltaPsi) than control cells. In addition, the basal expression levels of several nuclear DNA-encoded oxidative damage responsive genes whose proteins are targeted to the mitochondria--polymerase gamma, mitochondrial topoisomerase I, peroxiredoxin 3 and manganese superoxide dismutase--are elevated in A-T cells. Consistent with these results, we found that overall mitochondrial respiratory activity was diminished in A-T compared to wild-type cells. Treating A-T cells with the antioxidant, alpha lipoic acid (ALA), restored mitochondrial respiration rates to levels approaching those of wild-type. When wild-type cells were transfected with ATM-targeted siRNA, we observed a small but significant reduction in the respiration rates of mitochondria. Moreover, mitochondria in A-T cells induced to stably express full-length ATM, exhibited respiration rates approaching those of wild-type cells. Taken together, our results provide evidence for an intrinsic mitochondrial dysfunction in A-T cells, and implicate a requirement for ATM in the regulation of mitochondrial function.

Chronic infection and associated inflammation are key contributors to human carcinogenesis. Ulcerative colitis (UC) is an oxyradical overload disease and is characterized by free radical stress and colon cancer proneness. Here we examined tissues from noncancerous colons of ulcerative colitis patients to determine (a) the activity of two base excision-repair enzymes, AAG, the major 3-methyladenine DNA glycosylase, and APE1, the major apurinic site endonuclease; and (b) the prevalence of microsatellite instability (MSI). AAG and APE1 were significantly increased in UC colon epithelium undergoing elevated inflammation and MSI was positively correlated with their imbalanced enzymatic activities. These latter results were supported by mechanistic studies using yeast and human cell models in which overexpression of AAG and/or APE1 was associated with frameshift mutations and MSI. Our results are consistent with the hypothesis that the adaptive and imbalanced increase in AAG and APE1 is a novel mechanism contributing to MSI in patients with UC and may extend to chronic inflammatory or other diseases with MSI of unknown etiology.

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In 1988, the gene responsible for the autosomal recessive disease ataxia- telangiectasia (A-T) was localized to 11q22.3-23.1. It was eventually cloned in 1995. Many independent laboratories have since demonstrated that in replicating cells, ataxia telangiectasia mutated (ATM) is predominantly a nuclear protein that is involved in the early recognition and response to double-stranded DNA breaks. ATM is a high-molecular-weight PI3K-family kinase. ATM also plays many important cytoplasmic roles where it phosphorylates hundreds of protein substrates that activate and coordinate cell-signaling pathways involved in cell-cycle checkpoints, nuclear localization, gene transcription and expression, the response to oxidative stress, apoptosis, nonsense-mediated decay, and others. Appreciating these roles helps to provide new insights into the diverse clinical phenotypes exhibited by A-T patients—children and adults alike—which include neurodegeneration, high cancer risk, adverse reactions to radiation and chemotherapy, pulmonary failure, immunodeficiency, glucose transporter aberrations, insulin-resistant diabetogenic responses, and distinct chromosomal and chromatin changes. An exciting recent development is the ATM-dependent pathology encountered in mitochondria, leading to inefficient respiration and energy metabolism and the excessive generation of free radicals that themselves create life-threatening DNA lesions that must be repaired within minutes to minimize individual cell losses.

BackgroundThere is limited research to inform effective pedagogies for teaching global health to undergraduate medical students. Theoretically, using a combination of teaching pedagogies typically used in ‘international classrooms’ may prove to be an effective way of learning global health. This pilot study aimed to explore the experiences of medical students in Australia and Indonesia who participated in a reciprocal intercultural participatory peer e-learning activity (RIPPLE) in global health.MethodsSeventy-one third year medical students (49 from Australia and 22 from Indonesia) from the University of Tasmania (Australia) and the University of Nusa Cendana (Indonesia) participated in the RIPPLE activity. Participants were randomly distributed into 11 intercultural ‘virtual’ groups. The groups collaborated online over two weeks to study a global health topic of their choice, and each group produced a structured research abstract. Pre— and post-RIPPLE questionnaires were used to capture students’ experiences of the activity. Descriptive quantitative data were analysed with Microsoft Excel and qualitative data were thematically analysed.ResultsStudents’ motivation to volunteer for this activity included: curiosity about the innovative approach to learning; wanting to expand knowledge of global health; hoping to build personal and professional relationships; and a desire to be part of an intercultural experience. Afer completing the RIPPLE program, participants reported on global health knowledge acquisition, the development of peer relationships, and insight into another culture. Barriers to achieving the learning outcomes associated with RIPPLE included problems with establishing consistent online communication, and effectively managing time to simultaneously complete RIPPLE and other curricula activities.ConclusionsMedical students from both countries found benefits in working together in small virtual groups to complement existing teaching in global health. However, our pilot study demonstrated that while intercultural collaborative peer learning activities like RIPPLE are feasible, they require robust logistical support and an awareness of the need to manage curriculum alignment in ways that facilitate more effective student engagement.Electronic supplementary materialThe online version of this article (doi:10.1186/s12909-016-0851-6) contains supplementary material, which is available to authorized users.