A Network of Multi-Tasking Proteins at the DNA Replication Fork Preserves Genome Stability

To elucidate the network that maintains high fidelity genome replication, we have introduced two conditional mutant alleles of DNA2, an essential DNA replication gene, into each of the approximately 4,700 viable yeast deletion mutants and determined the fitness of the double mutants. Fifty-six DNA2-interacting genes were identified. Clustering analysis of genomic synthetic lethality profiles of each of 43 of the DNA2-interacting genes defines a network (consisting of 322 genes and 876 interactions) whose topology provides clues as to how replication proteins coordinate regulation and repair to protect genome integrity. The results also shed new light on the functions of the query gene DNA2, which, despite many years of study, remain controversial, especially its proposed role in Okazaki fragment processing and the nature of its in vivo substrates. Because of the multifunctional nature of virtually all proteins at the replication fork, the meaning of any single genetic interaction is inherently ambiguous. The multiplexing nature of the current studies, however, combined with follow-up supporting experiments, reveals most if not all of the unique pathways requiring Dna2p. These include not only Okazaki fragment processing and DNA repair but also chromatin dynamics

An innovative method in creating healthier environment in rural areas

Rural areas in the northern parts of the Netherlands have lots of potentials to provide a healthy environment for their residents. However, population changes (ageing, outmigration) have a negative impact on the quality of life of residents. The GO!-Method that has been developed by the National Institute of Public Health and Environment (RIVM) in The Netherlands is used in this study. It allows us to identify the opportunities and needs in a systematic way and combine local knowledge by involving residents and local authorities with results of research for a sustainable move towards a healthier environment. Our presentation will focus on the GO!-Method as a bottom up method and its use in identifying threats and changes in realising a healthy living environment

Identifying the Effects of the Rural Demographic Changes in the Northern Netherlands: A Holistic Approach to Create Healthier Environment

The Northern region of the Netherlands has beautiful landscapes, a nice diversity of green and blue areas, and dispersed settlements. However, some recent population changes can become threats to health and wellbeing in these areas. The rural areas in the three northern provinces - Groningen, Friesland and Drenthe, see youngsters leave the region for which reason they are aging faster than other regions in the Netherlands. As a result, some villages have faced major population decline that is leading to lose of facilities/amenities and decrease in accessibility and social cohesion. Those who still live in these villages; are relatively old, low educated and have low-income. To develop a deeper understanding of the health status of the people living in these areas, and help them to improve their living environment, the GO!-Method is being applied in this study. This method has been developed by the National Institute for Public Health and the Environment (RIVM) of the Netherlands and is inspired by the broad definition of health by Machteld Huber: the ability to adapt and direct control, in terms of the physical, emotional and social challenges of life, while paying extra attention to vulnerable groups. A healthy living environment is defined as an environment that residents find it pleasant, and encourages and supports healthy behavior. The GO!-method integrates six domains that constitutes a healthy living environment: Health and lifestyle, facilities and development, Safety and hygiene, Social cohesion and active citizens, Green areas, and Air and noise pollution. First of all this method will identify opportunities for a healthier living environment using existing information and perceptions of residents and other local stakeholders in order to strengthen social participation and quality of life in these rural areas. Second this approach will connect identified opportunities with available and effective evidence based interventions in order to develop an action plan from the residents and local authorities perspective which will help them to design their municipalities healthier and more resilient. This method is being used for the first time in rural areas to our best knowledge, in close collaboration with the residents and local authorities of the three provinces to create a sustainable process and stimulate social participation. Our paper will present the outcomes of the first phase of this project in collaboration with the municipality of Westerkwartier, located in the northwest of the province of Groningen. And will describe the current situation, and identify local assets, opportunities, and policies relating to healthier environment; as well as needs and challenges to achieve goals. The preliminary results show that rural demographic changes in the northern Netherlands have negative impacts on service provisions and social cohesion, and there is a need to understand this complicated situation and improve the quality of life in those areas

Governance conditions to overcome the challenges of realizing safe urban bathing water sites

This study aims to identify governance conditions to realize urban bathing water sites using case study material from two cities in the Netherlands. Urban waters in Europe are increasingly considered an attractive feature for bathing, but research on the realization of urban bathing water sites has been limited. We find that it is important to account for the connectivity between water systems characteristics and governance conditions to increase effectiveness in the realization of urban bathing water sites. Ambitions regarding urban bathing water sites should be addressed in a wider policy context to create co-benefits, like other ambitions related to water quality, resilience and health. An analytical framework has been developed that could be used to support development and evaluation of future urban bathing water initiatives

The health potential of urban water: Future scenarios on local risks and opportunities

Although cities can be characterised as sources of economic, environmental and social challenges, they can also be part of the solution for healthy and sustainable societies. While most cities are situated close to water, whether inland waterways, lakes, or the sea, these blue spaces are not integrated into urban planning to their full potential and their public health impacts are not always recognised by planning authorities. Furthermore, cities face future challenges regarding climate change, socio-economic developments like tourism, urbanization, and rising social inequalities. The development of healthy blue spaces can support cities in their pursuit of ways to confront these challenges. Interdisciplinary and transdisciplinary analyses of the local impacts of these trends and promising interventions have been scarce to date. This study explores the use of such methodology by presenting experiences related to five European cities: Amsterdam, Barcelona, Plymouth, Tallinn and Thessaloniki, using an interactive and participative approach with local experts and stakeholders. Future scenarios have been developed based on the question: How can blue spaces contribute to a healthier city population, given the long term trends? The results highlight the importance of addressing the local context when seeking sustainable solutions for cities. The future scenarios deliver information that could serve as useful input for local planning processes

The health potential of urban water: Future scenarios on local risks and opportunities

This is the final version. Available on open access from Elsevier via the DOI in this recordAlthough cities can be characterised as sources of economic, environmental and social challenges, they can also be part of the solution for healthy and sustainable societies. While most cities are situated close to water, whether inland waterways, lakes, or the sea, these blue spaces are not integrated into urban planning to their full potential and their public health impacts are not always recognised by planning authorities. Furthermore, cities face future challenges regarding climate change, socio-economic developments like tourism, urbanization, and rising social inequalities. The development of healthy blue spaces can support cities in their pursuit of ways to confront these challenges. Interdisciplinary and transdisciplinary analyses of the local impacts of these trends and promising interventions have been scarce to date. This study explores the use of such methodology by presenting experiences related to five European cities: Amsterdam, Barcelona, Plymouth, Tallinn and Thessaloniki, using an interactive and participative approach with local experts and stakeholders. Future scenarios have been developed based on the question: How can blue spaces contribute to a healthier city population, given the long term trends? The results highlight the importance of addressing the local context when seeking sustainable solutions for cities. The future scenarios deliver information that could serve as useful input for local planning processes.European Union Horizon 202

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods - recursive partitioning and regression - to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; Pcombined = 2.01 × 10-19 and 2.35 × 10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. ©2007 Nature Publishing Group

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570