“We are not stray leaves blowing about in the wind”: exploring the impact of Family Wellbeing empowerment research, 1998–2021

Background: An Aboriginal-developed empowerment and social and emotional wellbeing program, known as Family Wellbeing (FWB), has been found to strengthen the protective factors that help Indigenous Australians to deal with the legacy of colonisation and intergenerational trauma. This article reviews the research that has accompanied the implementation of the program, over a 23 year period. The aim is to assess the long-term impact of FWB research and identify the key enablers of research impact and the limitations of the impact assessment exercise. This will inform more comprehensive monitoring of research impact into the future. Methods: To assess impact, the study took an implementation science approach, incorporating theory of change and service utilisation frameworks, to create a logic model underpinned by Indigenous research principles. A research impact narrative was developed based on mixed methods analysis of publicly available data on: 1) FWB program participation; 2) research program funding; 3) program outcome evaluation (nine studies); and 4) accounts of research utilisation (seven studies). Results: Starting from a need for research on empowerment identified by research users, an investment of $2.3 million in research activities over 23 years produced a range of research outputs that evidenced social and emotional wellbeing benefits arising from participation in the FWB program. Accounts of research utilisation confirmed the role of research outputs in educating participants about the program, and thus, facilitating more demand (and funding acquisition) for FWB. Overall research contributed to 5,405 recorded participants accessing the intervention. The key enablers of research impact were; 1) the research was user- and community-driven; 2) a long-term mutually beneficial partnership between research users and researchers; 3) the creation of a body of knowledge that demonstrated the impact of the FWB intervention via different research methods; 4) the universality of the FWB approach which led to widespread application. Conclusions: The FWB research impact exercise reinforced the view that assessing research impact is best approached as a “wicked problem” for which there are no easy fixes. It requires flexible, open-ended, collaborative learning-by-doing approaches to build the evidence base over time. Steps and approaches that research groups might take to build the research impact knowledge base within their disciplines are discussed

Epigenetics and Oxidative Stress in Aging

Aging is a multifactorial process characterized by the progressive loss of physiological functions, leading to an increased vulnerability to age-associated diseases and finally to death. Several theories have been proposed to explain the nature of aging. One of the most known identifies the free radicals produced by the mitochondrial metabolism as the cause of cellular and DNA damage. However, there are also several evidences supporting that epigenetic modifications, such as DNA methylation, noncoding RNAs, and histone modifications, play a critical role in the molecular mechanism of aging. In this review, we explore the significance of these findings and argue how the interlinked effects of oxidative stress and epigenetics can explain the cause of age-related declines

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

Forouzanfar MH, Afshin A, Alexander LT, et al. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. LANCET. 2016;388(10053):1659-1724.Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Copyright (C) The Author(s). Published by Elsevier Ltd

Cdc14 activation requires coordinated Cdk1-dependent phosphorylation of Net1 and PP2A-Cdc55 at anaphase onset

59 páginas 5 figuras, 1 tablaExit from mitosis and completion of cytokinesis require the inactivation of mitotic cyclin-dependent kinase (Cdk) activity. In budding yeast, Cdc14 phosphatase is a key mitotic regulator that is activated in anaphase to counteract Cdk activity. In metaphase, Cdc14 is kept inactive in the nucleolus, where it is sequestered by its inhibitor, Net1. At anaphase onset, downregulation of PP2ACdc55 phosphatase by separase and Zds1 protein promotes Net1 phosphorylation and, consequently, Cdc14 release from the nucleolus. The mechanism by which PP2ACdc55 activity is downregulated during anaphase remains to be elucidated. Here, we demonstrate that Cdc55 regulatory subunit is phosphorylated in anaphase in a Cdk1-Clb2-dependent manner. Interestingly, cdc55-ED phosphomimetic mutant inactivates PP2ACdc55 phosphatase activity towards Net1 and promotes Cdc14 activation. Separase and Zds1 facilitate Cdk-dependent Net1 phosphorylation and Cdc14 release from the nucleolus by modulating PP2ACdc55 activity via Cdc55 phosphorylation. In addition, human Cdk1-CyclinB1 phosphorylates human B55, indicating that the mechanism is conserved in higher eukaryotes.We thank CERCA Program/Generalitat de Catalunya for institutional support. Our laboratory is funded by the Spanish Ministry of Economy, Industry and Competitiveness (MINECO), which is part of the State Agency, through the projects BFU2013-43132-P and BFU2016-77975-R, (co-funded by the European Regional Development Fund, ERDF, a way to build Europe). The proteomics analyses were performed in the IDIBELL Clinical Proteomics Unit which is part of Proteored, PRB3 and is supported by Grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDFPeer reviewe

Dual Regulation of the Mitotic Exit Network (MEN) by PP2A-Cdc55 Phosphatase

Exit from mitosis in budding yeast is triggered by activation of the key mitotic phosphatase Cdc14. At anaphase onset, the protease separase and Zds1 promote the downregulation of PP2A(Cdc55) phosphatase, which facilitates Cdk1-dependent phosphorylation of Net1 and provides the first wave of Cdc14 activity. Once Cdk1 activity starts to decline, the mitotic exit network (MEN) is activated to achieve full Cdc14 activation. Here we describe how the PP2A(Cdc55) phosphatase could act as a functional link between FEAR and MEN due to its action on Bfa1 and Mob1. We demonstrate that PP2A(Cdc55) regulates MEN activation by facilitating Cdc5- and Cdk1-dependent phosphorylation of Bfa1 and Mob1, respectively. Downregulation of PP2A(Cdc55) initiates MEN activity up to Cdc15 by Bfa1 inactivation. Surprisingly, the premature Bfa1 inactivation observed does not entail premature MEN activation, since an additional Cdk1-Clb2 inhibitory signal acting towards Dbf2-Mob1 activity restrains MEN activity until anaphase. In conclusion, we propose a clear picture of how PP2A(Cdc55) functions affect the regulation of various MEN components, contributing to mitotic exit

Percepción de privacidad en servicios basados en localización para dispositivos móviles en la comunidad universitaria de la costa norte de Colombia

Introduction: The use of mobile applications has increased in the last years. Most of them require the knowledge of the user location, either for their core service or for marketing purposes. Location-based services (LBS) offer context-based assistance to users based on their location. Although these applications ask the user for permission to use their location and even explain in detail how this information will be used in its terms and conditions, most users are not aware or even interested in the fact that their location information is stored in databases and monetized by selling it to third-party companies. Regarding this situation, we developed a study with the aim to assess perception, concerns and awareness from users about their location information. Methods: This work is based on an exploratory survey applied to the university community, mainly from the North Coast of Colombia, to measure the perception of location privacy of users with mobile devices. The questionnaire was applied using Google Forms. The survey has nineteen questions organized in three sections: personal information, identification of privacy and privacy management. These questions were designed to know the users’ perceptions of privacy concerns in LBS and any actions they take to preserve it. Results: The results show that, in general, the respondents do not have a real concern regarding the privacy of their geolocation data, and the majority is not willing to pay to protect their privacy. Conclusions: This type of surveys can generate awareness among participants about the use of their private information. The results expose in this paper can be used to create government policies and regulations by technology companies about the privacy management.Introducción: El uso de aplicaciones móviles se ha incrementado en los últimos años. La mayoría de ellas requiere conocer la ubicación del usuario, ya sea para su servicio principal o para fines de marketing. Los servicios basados en localización (SBL) ofrecen asistencia contextual para los usuarios según su ubicación. Aunque estas aplicaciones le piden permiso al usuario para usar su ubicación e incluso explican en detalle cómo se usará esta información en sus términos y condiciones, la mayoría de los usuarios no están conscientes ni incluso interesados en el hecho de que la información de su ubicación se almacene en bases de datos y se monetice, vendiéndolo a terceros. Con respecto a esta situación, desarrollamos un estudio con el objetivo de evaluar la percepción, las preocupaciones y el conocimiento de los usuarios sobre la información de su ubicación. Métodos: este trabajo se basa en una encuesta exploratoria aplicada a la comunidad universitaria, principalmente de la costa norte de Colombia, para medir la percepción de la privacidad de ubicación de los usuarios con dispositivos móviles. El cuestionario se aplicó utilizando los formularios de Google. La encuesta tiene diecinueve preguntas organizadas en tres secciones: información personal, identificación de privacidad y gestión de la privacidad. Estas preguntas fueron diseñadas para conocer las percepciones de los usuarios sobre las preocupaciones de privacidad en SBL y cualquier acción que tomen para preservarla. Resultados: los resultados muestran que, en general, los encuestados no tienen una preocupación real con respecto a la privacidad de sus datos de geolocalización, y la mayoría no está dispuesta a pagar para proteger su privacidad. Conclusiones: este tipo de encuestas puede generar conciencia entre los participantes sobre el uso de su información privada. Los resultados expuestos en este documento se pueden utilizar para crear políticas y regulaciones gubernamentales por parte de las compañías de tecnología sobre la administración de la privacidad

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy

Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15-25% of cases). In this report all known NM related genes were screened by Next Generation Sequencing in five Spanish patients in order to genetically confirm the clinical and histological diagnosis of NM. Four mutations in NEB (c.17779_17780delTA, c.11086A>C, c.21076C>T and c.2310+5G>A) and one mutation in ACTA1 (c.871A>T) were found in four patients. Three of the four mutations in NEB were novel. A cDNA sequencing assay of the nove/variants c.17779_17780delTA, c.11086A>C and c.2310+5G>A revealed that the intronic variant c.2310+5G>A affected the splicing process. Mutations reported here could help clinicians and geneticists in NM diagnosis.Peer reviewe

PP2A^Cdc55 counteracts Bfa1 phosphorylation.

<p>(A) Premature Bfa1 phosphorylation in metaphase in the absence of PP2A^Cdc55. Strains Y513 (<i>MATa MET-CDC20 CDC14-Pk₉ BFA1-HA₆</i>) and Y514 (as Y513, but <i>cdc55</i>Δ) were arrested in metaphase by Cdc20 depletion and released into synchronous anaphase by Cdc20 reintroduction. Bfa1 phosphorylation was analyzed by western blot. Pgk1 served as loading control. FACS profiles were used as a control of anaphase progression. At least 100 cells were scored at each time. Tubulin served as a loading control. (B) PP2A^Cdc55 catalytic activity is required to keep Bfa1 under-phosphorylated in metaphase. Strains Y1021 (<i>MATa Pk₃-CDC55 BFA1-HA₆</i>) and Y1020 (<i>MATa pph3</i>Δ <i>pph21</i>Δ <i>pph22-172 BFA1-HA₆</i>) were arrested in metaphase by nocodazole treatment and shifted to 37°C. (C) Zds1-dependent inactivation of PP2A^Cdc55 promotes Bfa1 phosphorylation. Strain Y597 (<i>MATa MET-CDC20 GAL1-Flag₃-ZDS1 CDC14-Pk₉ BFA1-HA₆</i>) was arrested in metaphase by Cdc20 depletion and Zds1 ectopic expression was induced by addition of galactose. Bfa1 phosphorylation and Zds1 expression levels were analyzed by western blot. (D) Overexpression of Cdc55 restrains Bfa1 phosphorylation. Strain Y1190 (<i>MATa</i> 4×<i>GAL1-CDC55 CDC14-Pk₉ BFA1-HA₆</i>) was arrested at G1 with α-factor and released into a synchronous cell cycle. Half of the culture was released into medium containing galactose to induce Cdc55 overexpression and the other half was released without galactose as a control. Bfa1 phosphorylation was analyzed by western blot and Pgk1 served as a loading control. FACS profiles were used as a control of cell cycle progression. (E) Cdc55 and Bfa1 interact. Co-immunoprecipitation of Cdc55 and Bfa1 was analyzed in protein extracts from strains Y1021 (<i>MATa Pk₃-CDC55 BFA1-HA₆</i>), Y1146 (<i>MATa pph3</i>Δ <i>pph21</i>Δ <i>pph22-172 Pk₃-CDC55 BFA1-HA₆</i>) and Y1145 (<i>MATa MET-CDC20 GAL1-Flag₃-ESP1 Pk₃-CDC55 BFA1-HA₆</i>). Strains Y1146 and Y1021 were treated at 37°C for 120 min. Strain Y1145 was arrested in metaphase by Cdc20 depletion, and separase ectopic expression was induced for 120 min. Protein extracts from strain Y1063 (<i>MATα BFA1-HA₆</i>) lacking a Pk epitope on Cdc55 served as a control.</p