Identifying key controls on storm formation over the Lake Victoria Basin

The Lake Victoria region in East Africa is a hotspot for intense convective storms that are responsible for the deaths of thousands of fisherman each year. The processes responsible for the initiation, development and propagation of the storms are poorly understood and forecast skill is limited. Key processes for the lifecycle of two storms are investigated using Met Office Unified Model convection-permitting simulations with 1.5 km horizontal gridspacing. The two cases are analysed alongside a simulation of a period with no storms to assess the roles of the lake–land breeze, downslope mountain winds, prevailing large-scale winds and moisture availability. Whilst seasonal changes in large-scale moisture availability play a key role in storm development, the lake–land breeze circulation is a major control on the initiation location, timing and propagation of convection. In the dry season, opposing offshore winds form a bulge of moist air above the lake surface overnight that extends from the surface to ~1.5 km and may trigger storms in high CAPE/low CIN environments. Such a feature has not been explicitly observed or modelled in previous literature. Storms over land on the preceding day are shown to alter the local atmospheric moisture and circulation to promote storm formation over the lake. The variety of initiation processes and differing characteristics of just two storms analysed here show that the mean diurnal cycle over Lake Victoria alone is inadequate to fully understand storm formation. Knowledge of daily changes in local-scale moisture variability and circulations are key for skilful forecasts over the lake

Analysis of the transcriptional activity of endogenous NFAT5 in primary cells using transgenic NFAT-luciferase reporter mice

<p>Abstract</p> <p>Background</p> <p>The transcription factor NFAT5/TonEBP regulates the response of mammalian cells to hypertonicity. However, little is known about the physiopathologic tonicity thresholds that trigger its transcriptional activity in primary cells. Wilkins et al. recently developed a transgenic mouse carrying a luciferase reporter (9xNFAT-Luc) driven by a cluster of NFAT sites, that was activated by calcineurin-dependent NFATc proteins. Since the NFAT site of this reporter was very similar to an optimal NFAT5 site, we tested whether this reporter could detect the activation of NFAT5 in transgenic cells.</p> <p>Results</p> <p>The 9xNFAT-Luc reporter was activated by hypertonicity in an NFAT5-dependent manner in different types of non-transformed transgenic cells: lymphocytes, macrophages and fibroblasts. Activation of this reporter by the phorbol ester PMA plus ionomycin was independent of NFAT5 and mediated by NFATc proteins. Transcriptional activation of NFAT5 in T lymphocytes was detected at hypertonic conditions of 360–380 mOsm/kg (isotonic conditions being 300 mOsm/kg) and strongly induced at 400 mOsm/kg. Such levels have been recorded in plasma in patients with osmoregulatory disorders and in mice deficient in aquaporins and vasopressin receptor. The hypertonicity threshold required to activate NFAT5 was higher in bone marrow-derived macrophages (430 mOsm/kg) and embryonic fibroblasts (480 mOsm/kg). Activation of the 9xNFAT-Luc reporter by hypertonicity in lymphocytes was insensitive to the ERK inhibitor PD98059, partially inhibited by the PI3-kinase inhibitor wortmannin (0.5 μM) and the PKA inhibitor H89, and substantially downregulated by p38 inhibitors (SB203580 and SB202190) and by inhibition of PI3-kinase-related kinases with 25 μM LY294002. Sensitivity of the reporter to FK506 varied among cell types and was greater in primary T cells than in fibroblasts and macrophages.</p> <p>Conclusion</p> <p>Our results indicate that NFAT5 is a sensitive responder to pathologic increases in extracellular tonicity in T lymphocytes. Activation of NFAT5 by hypertonicity in lymphocytes was mediated by a combination of signaling pathways that differed from those required in other cell types. We propose that the 9xNFAT-Luc transgenic mouse model might be useful to study the physiopathological regulation of both NFAT5 and NFATc factors in primary cells.</p

Diet-related selectivity of macroplastic ingestion in green turtles (Chelonia mydas) in the eastern Mediterranean

Understanding the drivers of key interactions between marine vertebrates and plastic pollution is now considered a research priority. Sea turtles are primarily visual predators, with the ability to discriminate according to colour and shape; therefore these factors play a role in feeding choices. Classifcation methodologies of ingested plastic currently do not record these variables, however here, refned protocols allow us to test the hypothesis that plastic is selectively ingested when it resembles the food items of green turtles (Chelonia mydas). Turtles in the eastern Mediterranean displayed strong diet-related selectivity towards certain types (sheet and threadlike), colours (black, clear and green) and shapes (linear items strongly preferred) of plastic when compared to the environmental baseline of plastic beach debris. There was a signifcant negative relationship between size of turtle (curved carapace length) and number/mass of plastic pieces ingested, which may be explained through naivety and/or ontogenetic shifts in diet. Further investigation in other species and sites are needed to more fully ascertain the role of selectivity in plastic ingestion in this marine vertebrate group

A theoretical entropy score as a single value to express inhibitor selectivity

<p>Abstract</p> <p>Background</p> <p>Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity.</p> <p>Results</p> <p>Here we propose a new theoretical entropy score that can be calculated from a set of IC₅₀data. In contrast to previous measures such as the 'selectivity score', Gini score, or partition index, the entropy score is non-arbitary, fully exploits IC₅₀data, and is not dependent on a reference enzyme. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clinical compounds, we show quantitatively that a more selective kinase inhibitor is not necessarily more drug-like.</p> <p>Conclusions</p> <p>For quantifying selectivity from panel profiling, a theoretical entropy score is the best method. It is valuable for studying the molecular mechanisms of selectivity, and to steer compound progression in drug discovery programs.</p

Resequencing of genes for transforming growth factor β1 (TGFB1) type 1 and 2 receptors (TGFBR1, TGFBR2), and association analysis of variants with diabetic nephropathy

BACKGROUND: Diabetic nephropathy is the leading cause of end stage renal failure in the western world. There is substantial epidemiological evidence supporting a genetic predisposition to diabetic nephropathy, however the exact molecular mechanisms remain unknown. Transforming growth factor (TGFβ1) is a crucial mediator in the pathogenesis of diabetic nephropathy. METHODS: We investigated the role of five known single nucleotide polymorphisms (SNPs) in the TGFB1 gene for their association with diabetic nephropathy in an Irish, type 1 diabetic case (n = 272) control (n = 367) collection. The activity of TGFβ1 is facilitated by the action of type 1 and type 2 receptors, with both receptor genes (TGFBR1 and TGFBR2) shown to be upregulated in diabetic kidney disease. We therefore screened TGFBR1 and TGFBR2 genes for genomic variants using WAVE™ (dHPLC) technology and confirmed variants by direct capillary sequencing. Allele frequencies were determined in forty-eight healthy individuals. Data for all SNPs was assessed for Hardy Weinberg equilibrium, with genotypes and allele frequencies compared using the χ(2 )test for contingency tables. Patterns of linkage disequilibrium were established and common haplotypes estimated. RESULTS: Fifteen variants were identified in these genes, seven of which are novel, and putatively functional SNPs were subsequently genotyped using TaqMan™, Invader™ or Pyrosequencing(® )technology. No significant differences (p > 0.1) were found in genotype or allele distributions between cases and controls for any of the SNPs assessed. CONCLUSION: Our results suggest common variants in TGFB1, TGFBR1 and TGFBR2 genes do not strongly influence genetic susceptibility to diabetic nephropathy in an Irish Caucasian population

Molecular Characterisation of Small Molecule Agonists Effect on the Human Glucagon Like Peptide-1 Receptor Internalisation

The glucagon-like peptide receptor (GLP-1R), which is a G-protein coupled receptor (GPCR), signals through both Gαs and Gαq coupled pathways and ERK phosphorylation to stimulate insulin secretion. The aim of this study was to determine molecular details of the effect of small molecule agonists, compounds 2 and B, on GLP-1R mediated cAMP production, intracellular Ca2+ accumulation, ERK phosphorylation and its internalisation. In human GLP-1R (hGLP-1R) expressing cells, compounds 2 and B induced cAMP production but caused no intracellular Ca2+ accumulation, ERK phosphorylation or hGLP-1R internalisation. GLP-1 antagonists Ex(9-39) and JANT-4 and the orthosteric binding site mutation (V36A) in hGLP-1R failed to inhibit compounds 2 and B induced cAMP production, confirming that their binding site distinct from the GLP-1 binding site on GLP-1R. However, K334A mutation of hGLP-1R, which affects Gαs coupling, inhibited GLP-1 as well as compounds 2 and B induced cAMP production, indicating that GLP-1, compounds 2 and B binding induce similar conformational changes in the GLP-1R for Gαs coupling. Additionally, compound 2 or B binding to the hGLP-1R had significantly reduced GLP-1 induced intracellular Ca2+ accumulation, ERK phosphorylation and hGLP-1R internalisation. This study illustrates pharmacology of differential activation of GLP-1R by GLP-1 and compounds 2 and B

To what extent does IQ 'explain' socio-economic variations in function?

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to examine the extent to which higher intellectual abilities protect higher socio-economic groups from functional decline and to examine whether the contribution of intellectual abilities is independent of childhood deprivation and low birth weight and other socio-economic and developmental factors in early life.</p> <p>Methods</p> <p>The Maastricht Aging Study (MAAS) is a prospective cohort study based upon participants in a registration network of general practices in The Netherlands. Information was available on 1211 men and women, 24 – 81 years old, who were without cognitive impairment at baseline (1993 – 1995), who ever had a paid job, and who participated in the six-year follow-up. Main outcomes were longitudinal decline in important components of quality of life and successful aging, i.e., self-reported physical, affective, and cognitive functioning.</p> <p>Results</p> <p>Persons with a low occupational level at baseline showed more functional decline than persons with a high occupational level. Socio-economic and developmental factors from early life hardly contributed to the adult socio-economic differences in functional decline. Intellectual abilities, however, took into account more than one third of the association between adult socio-economic status and functional decline. The contribution of the intellectual abilities was independent of the early life factors.</p> <p>Conclusion</p> <p>Rather than developmental and socio-economic characteristics of early life, the findings substantiate the importance of intellectual abilities for functional decline and their contribution – as potential, but neglected confounders – to socio-economic differences in functioning, successful aging, and quality of life. The higher intellectual abilities in the higher socio-economic status groups may also underlie the higher prevalences of mastery, self-efficacy and efficient coping styles in these groups.</p

Total blood lymphocyte counts in hemochromatosis probands with HFE C282Y homozygosity: relationship to severity of iron overload and HLA-A and -B alleles and haplotypes

BACKGROUND: It has been reported that some persons with hemochromatosis have low total blood lymphocyte counts, but the reason for this is unknown. METHODS: We measured total blood lymphocyte counts using an automated blood cell counter in 146 hemochromatosis probands (88 men, 58 women) with HFE C282Y homozygosity who were diagnosed in medical care. Univariate and multivariate analyses of total blood lymphocyte counts were evaluated using these variables: sex; age, transferrin saturation, and serum ferritin concentration at diagnosis; units of blood removed by phlebotomy to achieve iron depletion; and human leukocyte antigen (HLA)-A and -B alleles and haplotypes. RESULTS: The mean age at diagnosis was 49 ± 14 years (range 18 – 80 years) in men and 50 ± 13 years (range 22 – 88 years) in women. The correlations of total blood lymphocyte counts with sex, age, transferrin saturation, and serum ferritin concentration at diagnosis, and units of blood removed by phlebotomy to achieve iron depletion were not significant at the 0.05 level. Univariate analyses revealed significant associations between total blood lymphocyte counts and presence of the HLA-A*01, -B*08, and -B*14 alleles, and the A*01-B*08 haplotype. Presence of the A*01 allele, B*08 allele, or A*01-B*08 haplotype were associated with a lower total blood lymphocyte count, whereas presence of the B*14 allele was associated with a greater total blood lymphocyte count. There was an inverse association of total blood lymphocyte count with units of phlebotomy to achieve iron depletion, serum ferritin concentration, and with presence of the A*01-B*08 haplotype. CONCLUSION: We conclude that there is a significant inverse relationship of total blood lymphocyte counts and severity of iron overload in hemochromatosis probands with HFE C282Y homozygosity. The presence of the HLA-A*01 allele or the -B*08 allele was also associated with significantly lower total blood lymphocyte counts, whereas presence of the -B*14 allele was associated with significantly higher total blood lymphocyte counts. In univariate and multivariate analyses, total blood lymphocyte counts were significantly lower in probands with the HLA-A*01-B*08 haplotype than in probands without this haplotype

Integrated Ecosystem Assessment: Lake Ontario Water Management

BACKGROUND: Ecosystem management requires organizing, synthesizing, and projecting information at a large scale while simultaneously addressing public interests, dynamic ecological properties, and a continuum of physicochemical conditions. We compared the impacts of seven water level management plans for Lake Ontario on a set of environmental attributes of public relevance. METHODOLOGY AND FINDINGS: Our assessment method was developed with a set of established impact assessment tools (checklists, classifications, matrices, simulations, representative taxa, and performance relations) and the concept of archetypal geomorphic shoreline classes. We considered each environmental attribute and shoreline class in its typical and essential form and predicted how water level change would interact with defining properties. The analysis indicated that about half the shoreline of Lake Ontario is potentially sensitive to water level change with a small portion being highly sensitive. The current water management plan may be best for maintaining the environmental resources. In contrast, a natural water regime plan designed for greatest environmental benefits most often had adverse impacts, impacted most shoreline classes, and the largest portion of the lake coast. Plans that balanced multiple objectives and avoided hydrologic extremes were found to be similar relative to the environment, low on adverse impacts, and had many minor impacts across many shoreline classes. SIGNIFICANCE: The Lake Ontario ecosystem assessment provided information that can inform decisions about water management and the environment. No approach and set of methods will perfectly and unarguably accomplish integrated ecosystem assessment. For managing water levels in Lake Ontario, we found that there are no uniformly good and bad options for environmental conservation. The scientific challenge was selecting a set of tools and practices to present broad, relevant, unbiased, and accessible information to guide decision-making on a set of management options

Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.</p> <p>We have therefore set out to conduct a prospective study testing the diagnostic accuracy of TCD in patients with a parkinsonism of unclear origin.</p> <p>Methods/Design</p> <p>We will enrol 250 consecutive patients, who are referred to neurology outpatient clinics of two teaching hospitals, for analysis of clinically unclear parkinsonism. Patients, whose parkinsonism is clearly diagnosable at the first visit, will be excluded from the study. All patients will undergo a TCD of the substantia nigra. As a surrogate gold standard we will use the consensus clinical diagnosis reached by two independent, blinded, movement disorder specialist neurologists after 2 years follow-up. At the time of TCD, patients will also undergo a SPECT scan of the brain.</p> <p>Discussion</p> <p>As this prospective trial enrols only patients with an early-stage parkinsonism, it will yield data on the diagnostic accuracy of TCD that is relevant to daily clinical practice: The neurologist needs a diagnostic tool that provides additional information in patients with a clinically indefinable parkinsonian syndrome. The above described observational longitudinal study was designed to explicitly study this aspect in the diagnostic process.</p> <p>Trial registration</p> <p><b>(ITRSCC) NCT00368199</b></p