Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription.

Deregulated expression of MYC induces a dependence on the NUAK1 kinase, but the molecular mechanisms underlying this dependence have not been fully clarified. Here, we show that NUAK1 is a predominantly nuclear protein that associates with a network of nuclear protein phosphatase 1 (PP1) interactors and that PNUTS, a nuclear regulatory subunit of PP1, is phosphorylated by NUAK1. Both NUAK1 and PNUTS associate with the splicing machinery. Inhibition of NUAK1 abolishes chromatin association of PNUTS, reduces spliceosome activity, and suppresses nascent RNA synthesis. Activation of MYC does not bypass the requirement for NUAK1 for spliceosome activity but significantly attenuates transcription inhibition. Consequently, NUAK1 inhibition in MYC-transformed cells induces global accumulation of RNAPII both at the pause site and at the first exon-intron boundary but does not increase mRNA synthesis. We suggest that NUAK1 inhibition in the presence of deregulated MYC traps non-productive RNAPII because of the absence of correctly assembled spliceosomes

Health impacts of industrial mining on surrounding communities: local perspectives from three sub-Saharan African countries

Industrial mining projects can play an important role in global sustainable development if associated health risks are minimised and opportunities maximised. While a broad body of evidence from quantitative studies exists that establishes the interlinkages between mining operations and effects on public health, little research has been conducted investigating health impacts from the perspective of affected communities. This is particularly true in sub-Saharan Africa, where about a third of the remaining global mineral resources are endowed and health-related indicators for sustainable development are lagging behind. In this multi-country qualitative study, we explore community perceptions regarding impacts of industrial mining on their health and well-being. In nine study sites in Burkina Faso, Mozambique and Tanzania, we conducted 83 participatory focus group discussions with a total of 791 participants (385 men, 406 women). Our findings reveal a broad range of perceived impacts on environmental, economic and social determinants of health, with secondary health implications related to morbidity, mortality and well-being. Overall, perceived negative impacts prevailed, mainly related to environmental pollution, change in livelihoods or social disruption. Perceived positive impacts on health and well-being were related to interventions implemented by the mines such as new or improved water sources, health care facilities, roads and schools. The consistency of these findings across countries and study sites suggests a structural problem and indicates a pressing need to address health by acting on the wider determinants of health in mining regions. Participatory health impact assessment should be strengthened in host countries to foster strategic interventions, include marginalised population groups, and protect and promote the health of local communities. By including community perspectives on health before and during project implementation, policymakers can take advantage of economic opportunities while avoiding the pitfalls, bringing their communities closer to achieving good health and well-being goals by 2030 and beyond

Investigating health impacts of natural resource extraction projects in Burkina Faso, Ghana, Mozambique, and Tanzania: protocol for a mixed methods study

Natural resource extraction projects offer both opportunities and risks for sustainable development and health in host communities. Often, however, the health of the community suffers. Health impact assessment (HIA) can mitigate the risks and promote the benefits of development but is not routinely done in the developing regions that could benefit the most.; Our study aims to investigate health and health determinants in regions affected by extractive industries in Burkina Faso, Ghana, Mozambique, and Tanzania. The evidence generated in our study will inform a policy dialogue on how HIA can be promoted as a regulatory approach as part of the larger research initiative called the HIA4SD (Health impact assessment for sustainable development) project.; The study is a concurrent triangulation, mixed methods, multi-stage, multi-focus project that specifically addresses the topics of governance and policy, social determinants of health, health economics, health systems, maternal and child health, morbidity and mortality, and environmental determinants, as well as the associated health outcomes in natural resource extraction project settings across four countries. To investigate each of these health topics, the project will (1) use existing population-level databases to quantify incidence of disease and other health outcomes and determinants over time using time series analysis; (2) conduct two quantitative surveys on mortality and cost of disease in producer regions; and (3) collect primary qualitative data using focus groups and key informant interviews describing community perceptions of the impacts of extraction projects on health and partnership arrangements between the projects and local and national governance. Differences in health outcomes and health determinants between districts with and without an extraction project will be analyzed using matched geographical analyses in quasi-Poisson regression models and binomial regression models. Costs to the health system and to the households from diseases found to be associated with projects in each country will be estimated retrospectively.; Fieldwork for the study began in February 2019 and concluded in February 2020. At the time of submission, qualitative data collection had been completed in all four study countries. In Burkina Faso, 36 focus group discussions and 74 key informant interviews were conducted in three sites. In Ghana, 34 focus group discussions and 64 key informant interviews were conducted in three sites. In Mozambique, 75 focus group discussions and 103 key informant interviews were conducted in four sites. In Tanzania, 36 focus group discussions and 84 key informant interviews were conducted in three sites. Quantitative data extraction and collection is ongoing in all four study countries. Ethical approval for the study was received in all four study countries prior to beginning the fieldwork. Data analyses are underway and results are expected to be published in 2020 and 2021.; Disentangling the complex interactions of resource extraction projects with their host communities requires an integrative approach drawing on many methodologies under the HIA umbrella. By using complementary data sources to address the question of population health in project areas from several angles, bias and missing data will be reduced, generating high-quality evidence to aid countries in moving toward sustainable development.; DERR1-10.2196/17138

Interfacing Sca-1pos Mesenchymal Stem Cells with Biocompatible Scaffolds with Different Chemical Composition and Geometry

An immortalized murine mesenchymal stem cell line (mTERT-MSC) enriched for Linneg/Sca-1pos fraction has been obtained through the transfection of MSC with murine TERT and single-cell isolation. Such cell line maintained the typical MSC self-renewal capacity and continuously expressed MSC phenotype. Moreover, mTERT-MSC retained the functional features of freshly isolated MSC in culture without evidence of senescence or spontaneous differentiation events. Thus, mTERT-MSC have been cultured onto PLA films, 30 and 100 μm PLA microbeads, and onto unpressed and pressed HYAFF-11 scaffolds. While the cells adhered preserving their morphology on PLA films, clusters of mTERT-MSC were detected on PLA beads and unpressed fibrous scaffolds. Finally, mTERT-MSC were not able to colonize the inner layers of pressed HYAFF-11. Nevertheless, such cell line displayed the ability to preserve Sca-1 expression and to retain multilineage potential when appropriately stimulated on all the scaffolds tested

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

BACKGROUND: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. PATIENTS AND METHODS: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. RESULTS: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. CONCLUSIONS: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor

Meeting Report: Methylmercury in Marine Ecosystems—From Sources to Seafood Consumers

Mercury and other contaminants in coastal and open-ocean ecosystems are an issue of great concern globally and in the United States, where consumption of marine fish and shellfish is a major route of human exposure to methylmercury (MeHg). A recent National Institute of Environmental Health Sciences–Superfund Basic Research Program workshop titled “Fate and Bioavailability of Mercury in Aquatic Ecosystems and Effects on Human Exposure,” convened by the Dartmouth Toxic Metals Research Program on 15–16 November 2006 in Durham, New Hampshire, brought together human health experts, marine scientists, and ecotoxicologists to encourage cross-disciplinary discussion between ecosystem and human health scientists and to articulate research and monitoring priorities to better understand how marine food webs have become contaminated with MeHg. Although human health effects of Hg contamination were a major theme, the workshop also explored effects on marine biota. The workgroup focused on three major topics: a) the biogeochemical cycling of Hg in marine ecosystems, b) the trophic transfer and bioaccumulation of MeHg in marine food webs, and c) human exposure to Hg from marine fish and shellfish consumption. The group concluded that current understanding of Hg in marine ecosystems across a range of habitats, chemical conditions, and ocean basins is severely data limited. An integrated research and monitoring program is needed to link the processes and mechanisms of MeHg production, bioaccumulation, and transfer with MeHg exposure in humans

Age-specific mortality patterns in Central Mozambique during and after the end of the Civil War

<p>Abstract</p> <p>Background</p> <p>In recent years, vigorous debate has developed concerning how conflicts contribute to the spread of infectious diseases, and in particular, the role of post-conflict situations in the epidemiology of HIV/AIDS. This study details the age-specific mortality patterns among the population in the central provincial capital of Beira, Mozambique, during and after the Mozambican civil war which ended in 1992.</p> <p>Methods</p> <p>Data was collected from the death register at Beira's Central Hospital between 1985 and 2003 and descriptively analyzed.</p> <p>Results</p> <p>The data show two distinct periods: before and after the peace agreements in 1992. Before 1992 (during the civil war), the main impact of mortality was on children below 5 years of age, including still births, accounting for 58% of all deaths. After the war ended in 1992, the pattern shifted dramatically and rapidly to the 15-49 year old age group which accounted for 49% of all deaths by 2003.</p> <p>Conclusions</p> <p>As under-5 mortality rates were decreasing at the end of the conflict, rates for 24-49 year old adults began to dramatically increase due to AIDS. This study demonstrates that strategies can be implemented during conflicts to decrease mortality rates in one vulnerable population but post-conflict dynamics can bring together other factors which contribute to the rapid spread of other infectious diseases in other vulnerable populations.</p