Effect of posttranslational modification on the Na+, K+ ATPase kinetics

The Na+, K+ ATPase is an essential membrane protein in eukaryotic cells, which transports Na+ out of the cell in exchange for K+ into the cell. For this transport it hydrolyses one molecule of ATP for each cycle. The partial reactions of the ATPase cycle and the effects of posttranslational modifications on ATPase activity have been studied extensively. However, amalgamation of the reported rate constants for the partial reactions along with the effect of posttranslational modifications have never been attempted. We have designed a simplified four-state mathematical model of the Na+, K+ ATPase using published results for the partial reactions. We have incorporated the effect of the Na+ allosteric site and poise dependent glutathionylation and attempted to replicate K+ activated transient currents reported in voltage clamped cardiomyocytes. Our voltage clamped cardiomyocyte results indicate the K+ activated transient is an effect of poise dependent glutathionylation rather than the Na+ subsarcolemmal space. These results can be replicated to some extent by the proposed kinetic model. This is the first kinetic model of the Na+, K+ ATPase that incorporates both partial rate constants and a reported posttranslational modification which is able to reproduce voltage clamped cardiomyocyte data

Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial

Background: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI.Objective: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients.Methods: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis.Discussion: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients.Development and application of statistical models for medical scientific researc

The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

Observed climate-induced changes in plant phenology in the Netherlands

We determined whether climate change in the Netherlands has caused phenological changes since 1868. We analysed over 150,000 plant phenological observations of 320 plant species, obtained by four volunteer networks and one series collected by Mr. Braaksma. With the network data, we compared the timing of life cycle events in three different periods: 1894–1932 (Period 1), 1940–1968 (Period 2) and 2001–2010 (Period 3). For the Braaksma series, we compared the periods 1953–1968 (Period A) with 1969–1992 (Period B). We conclude that until the beginning of the 1990s, there have been no significant changes in the timing of life cycle events. The timing of life cycle events in Period 3 showed an average advance of flowering, leaf unfolding and fruit ripening of 14 days compared with Period 1 and 13 days compared with Period 2. Some species have advanced up to over 35 days. Autumn events occurred up to an average of 7 days later in Period 3 compared to earlier periods. This study shows that, based on network data, changes in climate explain on average 66 % of the variation in timing of phenological events from year to year. For the Braaksma data, this is 38 %. The expected future changes in climate will undoubtedly result in a further lengthening of the growing season. We believe that phenological networks, supported by thousands of volunteers, are needed to quantify, analyse, predict and communicate these phenological changes so various sectors in society can adapt to these changes and prevent significant socio-economic impacts

Observed climate-induced changes in plant phenology in the Netherlands

We determined whether climate change in the Netherlands has caused phenological changes since 1868. We analysed over 150,000 plant phenological observations of 320 plant species, obtained by four volunteer networks and one series collected by Mr. Braaksma. With the network data, we compared the timing of life cycle events in three different periods: 1894–1932 (Period 1), 1940–1968 (Period 2) and 2001–2010 (Period 3). For the Braaksma series, we compared the periods 1953–1968 (Period A) with 1969–1992 (Period B). We conclude that until the beginning of the 1990s, there have been no significant changes in the timing of life cycle events. The timing of life cycle events in Period 3 showed an average advance of flowering, leaf unfolding and fruit ripening of 14 days compared with Period 1 and 13 days compared with Period 2. Some species have advanced up to over 35 days. Autumn events occurred up to an average of 7 days later in Period 3 compared to earlier periods. This study shows that, based on network data, changes in climate explain on average 66 % of the variation in timing of phenological events from year to year. For the Braaksma data, this is 38 %. The expected future changes in climate will undoubtedly result in a further lengthening of the growing season. We believe that phenological networks, supported by thousands of volunteers, are needed to quantify, analyse, predict and communicate these phenological changes so various sectors in society can adapt to these changes and prevent significant socio-economic impacts

Urbanization and water management

On May 4th 1977, a symposium was held at Lunteren, Netherlands, that had been jointly organized by TNO's Committee for Hydrological Research, the Netherlands Association of Water Boards and the Netherlands Institute for Directors and Engineers of Municipal Public Works Departments. The symposium's central topic was: Relationships between urbanization and water management

Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridisation.

Contains fulltext : 69885.pdf (publisher's version ) (Closed access)AIM AND METHOD: We analysed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridisation (array-CGH). RESULTS: Of 83 syndromic cases analysed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in five of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 non-syndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1-25.2 and another with a 2.2 Mb deletion at 10q26.11-26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1-25.2 were de novo, while the deletion of 10q26.11-26.13 was inherited from the mother, who also has a cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1-25.2 and 10q26.11-26.13, respectively, were identified as likely causative genes using a gene prioritization software. CONCLUSION: We have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies

A pro-inflammatory genotype predisposes to Barrett's esophagus

INTRODUCTION: Severity of mucosal inflammation is shown to be associated with Barrett's esophagus (BE) development in animals. It has therefore been postulated that a strong pro-inflammatory host response predisposes to BE. AIM: To determine the impact of cytokine gene polymorphisms on the development of BE. METHODS: The multiplex SNaPshot method was used to determine interleukin (IL)-12B (A+1188C), IL-10 (C-592A, C-819T, A-1082G), IL-8 (A-251T), IL-6 (G-174C) and IL-2 (G-330T) gene polymorphisms in 255 patients with BE and 247 patients with reflux esophagitis (RE). RESULTS: The presence of the IL-12B C-allele, which is associated with increased IL-12p70 expression, was more frequently observed in BE than in RE patients [odds ratio (OR) 1.8; 95% confidence interval (CI) 1.2-2.7; P = 0.007). The risk of BE was increased in patients in whom the IL-12B C-allele coincided with a hiatal hernia (OR 2.9; 95% CI 1.32-6.58; P = 0.008). The IL-10(-1082) GG genotype, which is associated with higher IL-10 levels, was also associated with a decreased risk of BE when it was associated with the IL-12B C-allele, indicating IL-10-dependent down-regulation of IL-12p70 expression. A combination of the IL-12B AA genotype and the IL-10 AA or AG genotypes was associated with RE (OR 1.4; 95% CI 1.05-1.85; P = 0.011). CONCLUSION: A genetic profile predisposing to a strong pro-inflammatory host response, mediated by IL-12p70 and partially dependent on IL-10, is associated with BE. This risk further increases when this genotype coincides with a hiatal hernia, suggesting that exposure to gastroesophageal reflux in the presence of a pro-inflammatory genetic background is a driving force in the development of BE