The Ankyrin Repeats and DHHC S-acyl Transferase Domain of AKR1 Act Independently to Regulate Switching from Vegetative to Mating States in Yeast

Signal transduction from G-protein coupled receptors to MAPK cascades through heterotrimeric G-proteins has been described for many eukaryotic systems. One of the best-characterised examples is the yeast pheromone response pathway, which is negatively regulated by AKR1. AKR1-like proteins are present in all eukaryotes and contain a DHHC domain and six ankyrin repeats. Whilst the DHHC domain dependant S-acyl transferase (palmitoyl transferase) function of AKR1 is well documented it is not known whether the ankyrin repeats are also required for this activity. Here we show that the ankyrin repeats of AKR1 are required for full suppression of the yeast pheromone response pathway, by sequestration of the Gβγ dimer, and act independently of AKR1 S-acylation function. Importantly, the functions provided by the AKR1 ankyrin repeats and DHHC domain are not required on the same molecule to fully restore WT phenotypes and function. We also show that AKR1 molecules are S-acylated at locations other than the DHHC cysteine, increasing the abundance of AKR1 in the cell. Our results have important consequences for studies of AKR1 function, including recent attempts to characterise S-acylation enzymology and kinetics. Proteins similar to AKR1 are found in all eukaryotes and our results have broad implications for future work on these proteins and the control of switching between Gβγ regulated pathways

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m2 intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m2/day to 2750 mg/m2/day as a continuous infusion from day 1–3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m2 on day 1 and ifosfamide 2750 mg/m2/day on days 1–3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m2 on day 1 and ifosfamide 2500 mg/m2/day continuous infusion on days 1–3

A change in the optical polarization associated with a gamma-ray flare in the blazar 3C 279

It is widely accepted that strong and variable radiation detected over all accessible energy bands in a number of active galaxies arises from a relativistic, Doppler-boosted jet pointing close to our line of sight. The size of the emitting zone and the location of this region relative to the central supermassive black hole are, however, poorly known, with estimates ranging from light-hours to a light-year or more. Here we report the coincidence of a gamma-ray flare with a dramatic change of optical polarization angle. This provides evidence for co-spatiality of optical and gamma-ray emission regions and indicates a highly ordered jet magnetic field. The results also require a non-axisymmetric structure of the emission zone, implying a curved trajectory for the emitting material within the jet, with the dissipation region located at a considerable distance from the black hole, at about 10^5 gravitational radii.Comment: Published in Nature issued on 18 February 2010. Corresponding authors: Masaaki Hayashida and Greg Madejsk

Secondary school students’ epistemic insight into the relationships between science and religion – a preliminary enquiry

A number of previous studies have shown that there is a widespread view among young people that science and religion are opposed. In this paper, we suggest that it requires a significant level of what can be termed ‘epistemic insight’ to access the idea that some people see science and religion as compatible while others do not. To explore this further, we draw on previous work to devise a methodology to discover students’ thinking about apparent contradictions between scientific and religious explanations of the origins of the universe. In our discussion of the findings, we highlight that students’ epistemic insight in this context does seem in many cases to be limited and we outline some of the issues emerging from the study that seem to boost or limit students’ progress in this area

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

SummaryBackground 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. Funding Bill & Melinda Gates Foundation

Docetaxel plus cisplatin is effective for patients with metastatic breast cancer resistant to previous anthracycline treatment: a phase II clinical trial

BACKGROUND: Patients with metastatic breast cancer (MBC) are frequently exposed to high cumulative doses of anthracyclines and are at risk of resistance and cardiotoxicity. This phase II trial evaluated the efficacy and toxicity of docetaxel plus cisplatin, as salvage chemotherapy in patients with MBC resistant to prior anthracyclines. METHODS: Patients with MBC that had progressed after at least one prior chemotherapy regimen containing anthracyclines received docetaxel 75 mg/m(2 )followed by cisplatin 60 mg/m(2 )every 3 weeks for a maximum of 6 cycles or until disease progression. RESULTS: Between Jan 2000 and May 2002, 24 patients with tumors primary resistant and 15 with secondary resistant disease were accrued. All 39 patients were evaluable for safety and 36 for efficacy. The objective response rate was 31% (95% CI, 16–45%) with 3 complete responses. The median time to disease progression was 7 months, and the median overall survival was 23 months (median follow-up of 41 months). Neutropenia was the most frequently observed severe hematologic toxicity (39% of patients), whereas asthenia and nausea were the most common non-hematologic toxicities. No treatment-related death was observed. CONCLUSION: In conclusion, we found docetaxel plus cisplatin to be an active and safe chemotherapy regimen for patients with MBC resistant to anthracyclines

The insulin polymorphism -23Hph increases the risk for type 1 diabetes mellitus in the Romanian population

The insulin -23Hph and IGF2 Apa polymorphisms were genotyped in Romanian patients with T1DM (n = 204), T2DM (n = 215) or obesity (n = 200) and normoponderal healthy subjects (n = 750). The genotypes of both polymorphisms were distributed in concordance with Hardy-Weinberg equilibrium in all groups. The -23Hph AA genotype increased the risk for T1DM (OR: 3.22, 95%CI: 2.09-4.98, p < 0,0001), especially in patients without macroalbuminuria (OR: 4.32, 95%CI: 2.54-7.45, p < 0,0001). No other significant association between the alleles or genotypes of insulin -23Hph and IGF2 Apa and diabetes or obesity was identified

Striving to promote male involvement in maternal health care in rural and urban settings in Malawi - a qualitative study

<p>Abstract</p> <p>Background</p> <p>Understanding the strategies that health care providers employ in order to invite men to participate in maternal health care is very vital especially in today's dynamic cultural environment. Effective utilization of such strategies is dependent on uncovering the salient issues that facilitate male participation in maternal health care. This paper examines and describes the strategies that were used by different health care facilities to invite husbands to participate in maternal health care in rural and urban settings of southern Malawi.</p> <p>Methods</p> <p>The data was collected through in-depth interviews from sixteen of the twenty health care providers from five different health facilities in rural and urban settings of Malawi. The health facilities comprised two health centres, one district hospital, one mission hospital, one private hospital and one central hospital. A semi-structured interview guide was used to collect data from health care providers with the aim of understanding strategies they used to invite men to participate in maternal health care.</p> <p>Results</p> <p>Four main strategies were used to invite men to participate in maternal health care. The strategies were; health care provider initiative, partner notification, couple initiative and community mobilization. The health care provider initiative and partner notification were at health facility level, while the couple initiative was at family level and community mobilization was at village (community) level. The community mobilization had three sub-themes namely; male peer initiative, use of incentives and community sensitization. The sustainability of each strategy to significantly influence behaviour change for male participation in maternal health care is discussed.</p> <p>Conclusion</p> <p>Strategies to invite men to participate in maternal health care were at health facility, family and community levels. The couple strategy was most appropriate but was mostly used by educated and city residents. The male peer strategy was effective and sustainable at community level. There is need for creation of awareness in men so that they sustain their participation in maternal health care activities of their female partners even in the absence of incentives, coercion or invitation.</p