DNA methylation partially mediates antidiabetic effects of metformin on HbA1c levels in individuals with type 2 diabetes

Aims: Despite metformin being used as first-line pharmacological therapy for type 2 diabetes, its underlying mechanisms remain unclear. We aimed to determine whether metformin altered DNA methylation in newlydiagnosed individuals with type 2 diabetes. Methods and Results: We found that metformin therapy is associated with altered methylation of 26 sites in blood from Scandinavian discovery and replication cohorts (FDR < 0.05), using MethylationEPIC arrays. The majority (88%) of these 26 sites were hypermethylated in patients taking metformin for ~ 3 months compared to controls, who had diabetes but had not taken any diabetes medication. Two of these blood-based methylation markers mirrored the epigenetic pattern in muscle and adipose tissue (FDR < 0.05). Four type 2 diabetes-associated SNPs were annotated to genes with differential methylation between metformin cases and controls, e.g., GRB10, RPTOR, SLC22A18AS and TH2LCRR. Methylation correlated with expression in human islets for two of these genes. Three metformin-associated methylation sites (PKNOX2, WDTC1 and MICB) partially mediate effects of metformin on follow-up HbA1c levels. When combining methylation of these three sites into a score, which was used in a causal mediation analysis, methylation was suggested to mediate up to 32% of metformin’s effects on HbA1c. Conclusion: Metformin-associated alterations in DNA methylation partially mediates metformin’s antidiabetic effects on HbA1c in newly-diagnosed individuals with type 2 diabetes

Innovative Approaches to Development and Ground Testing of Advanced Bimodal Space Power and Propulsion Systems

The last major development effort for nuclear power and propulsion systems ended in 1993. Currently, there is not an initiative at either the National Aeronautical and Space Administration (NASA) or the U.S. Department of Energy (DOE) that requires the development of new nuclear power and propulsion systems. Studies continue to show nuclear technology as a strong technical candidate to lead the way toward human exploration of adjacent planets or provide power for deep space missions, particularly a 15,000 lbf bimodal nuclear system with 115 kW power capability. The development of nuclear technology for space applications would require technology development in some areas and a major flight qualification program. The last major ground test facility considered for nuclear propulsion qualification was the U.S. Air Force/DOE Space Nuclear Thermal Propulsion Project. Seven years have passed since that effort, and the questions remain the same, how to qualify nuclear power and propulsion systems for future space flight. It can be reasonable assumed that much of the nuclear testing required to qualify a nuclear system for space application will be performed at DOE facilities as demonstrated by the Nuclear Rocket Engine Reactor Experiment (NERVA) and Space Nuclear Thermal Propulsion (SNTP) programs. The nuclear infrastructure to support testing in this country is aging and getting smaller, though facilities still exist to support many of the technology development needs. By renewing efforts, an innovative approach to qualifying these systems through the use of existing facilities either in the U.S. (DOE's Advance Test Reactor, High Flux Irradiation Facility and the Contained Test Facility) or overseas should be possible

A Genetic Basis of Susceptibility to Acute Pyelonephritis

For unknown reasons, urinary tract infections (UTIs) are clustered in certain individuals. Here we propose a novel, genetically determined cause of susceptibility to acute pyelonephritis, which is the most severe form of UTI. The IL-8 receptor, CXCR1, was identified as a candidate gene when mIL-8Rh mutant mice developed acute pyelonephritis (APN) with severe tissue damage.We have obtained CXCR1 sequences from two, highly selected APN prone patient groups, and detected three unique mutations and two known polymorphisms with a genotype frequency of 23% and 25% compared to 7% in controls (p<0.001 and p<0.0001, respectively). When reflux was excluded, 54% of the patients had CXCR1 sequence variants. The UTI prone children expressed less CXCR1 protein than the pediatric controls (p<0.0001) and two sequence variants were shown to impair transcription.The results identify a genetic innate immune deficiency, with a strong link to APN and renal scarring

Drilling Predation on Serpulid Polychaetes (Ditrupa arietina) from the Pliocene of the Cope Basin, Murcia Region, Southeastern Spain

We report quantitative analyses of drilling predation on the free-living, tube-dwelling serpulid polychaete Ditrupa arietina from the Cope Cabo marine succession (Pliocene, Spain). Tubes of D. arietina are abundant in the sampled units: 9 bulk samples from 5 horizons yielded ∼5925 specimens of D. arietina. Except for fragmentation, tubes were well preserved. Complete specimens ranged from 3.1 to 13.4 mm in length and displayed allometric growth patterns, with larger specimens being relatively slimmer. Drilled Ditrupa tubes were observed in all samples. Drillholes, identified as Oichnus paraboloides, were characterized by circular to elliptical outline (drillhole eccentricity increased with its diameter), parabolic vertical profile, outer diameter larger than inner diameter, penetration of one tube wall only, narrow range of drill-hole sizes, and non-random (anterior) distribution of drillholes. A total of 233 drilled specimens were identified, with drilling frequencies varying across horizons from 2.7% to 21% (3.9% for pooled data). Many tube fragments were broken across a drillhole suggesting that the reported frequencies are conservative and that biologically-facilitated (drill-hole induced) fragmentation hampers fossil preservation of complete serpulid tubes. No failed or repaired holes were observed. Multiple complete drillholes were present (3.9%). Drilled specimens were significantly smaller than undrilled specimens and tube length and drill-hole diameter were weakly correlated. The results suggest that drillholes were produced by a size-selective, site-stereotypic predatory organism of unknown affinity. The qualitative and quantitative patterns reported here are mostly consistent with previous reports on recent and fossil Ditrupa and reveal parallels with drilling patterns documented for scaphopod mollusks, a group that is ecologically and morphologically similar to Ditrupa. Consistent with previous studies, the results suggest that free-dwelling serpulid polychaetes are preyed upon by drilling predators and may provide a viable source of data on biotic interactions in the fossil record

Plasma Dynamics

Contains reports on four research projects.National Science Foundation (Grant ECS82-13485)University of Maryland (Subcontract A200728)U.S. Air Force - Office of Scientific Research (Grant AFOSR-84-0026B)U.S. Department of Energy (Contract DE-ACO2-78-ET-51013)National Science Foundation (Grant ECS82-13430

Prevalence of lipid abnormalities before and after introduction of lipid modifying therapy among Swedish patients with dyslipidemia (PRIMULA)

<p>Abstract</p> <p>Background</p> <p>Data on the prevalence of dyslipidemia and attainment of goal/normal lipid levels in a Swedish population are scarce. The objective of this study is to estimate the prevalence of dyslipidemia and attainment of goal/normal lipid levels in patients treated with lipid modifying therapy (LMT).</p> <p>Methods</p> <p>This longitudinal retrospective observational study covers time periods before and after treatment. Data were collected from 1994-2007 electronic patient records in public primary healthcare centers in Uppsala County, Sweden. Patients were included if they had been treated with LMT and had at least one lipid abnormality indicating dyslipidemia and if complete lipid profile data were available. Thresholds levels for lipids were defined as per Swedish guidelines.</p> <p>Results</p> <p>Among 5,424 patients included, at baseline, the prevalence of dyslipidemia (≥1 lipid abnormality) was by definition 100%, while this figure was 82% at follow-up. At baseline, 60% had elevated low-density lipoprotein (LDL-C) combined with low high-density lipoprotein (HDL-C) and/or elevated triglycerides (TG s), corresponding figure at follow-up was 36%. Low HDL-C and/or elevated TGs at follow-up remained at 69% for patients with type 2 diabetes mellitus (T2DM), 50% among patients with coronary heart disease (CHD) and 66% among patients with 10 year CHD risk >20%. Of the total sample, 40% attained goal levels of LDL-C and 18% attained goal/normal levels on all three lipid parameters.</p> <p>Conclusions</p> <p>Focusing therapy on LDL-C reduction allows 40% of patients to achieve LDL-C goal and helps reducing triglyceride levels. Almost 60% of patients experience persistent HDL-C and/or triglyceride abnormality independently of LDL-C levels and could be candidates for additional treatments.</p

Specific Recognition of p53 Tetramers by Peptides Derived from p53 Interacting Proteins

Oligomerization plays a major role in regulating the activity of many proteins, and in modulating their interactions. p53 is a homotetrameric transcription factor that has a pivotal role in tumor suppression. Its tetramerization domain is contained within its C-terminal domain, which is a site for numerous protein-protein interactions. Those can either depend on or regulate p53 oligomerization. Here we screened an array of peptides derived from proteins known to bind the tetrameric p53 C-terminal domain (p53CTD) and identified ten binding peptides. We quantitatively characterized their binding to p53CTD using fluorescence anisotropy. The peptides bound tetrameric p53CTD with micromolar affinities. Despite the high charge of the binding peptides, electrostatics contributed only mildly to the interactions. NMR studies indicated that the peptides bound p53CTD at defined sites. The most significant chemical shift deviations were observed for the peptides WS100B(81–92), which bound directly to the p53 tetramerization domain, and PKCα(281–295), which stabilized p53CTD in circular dichroism thermal denaturation studies. Using analytical ultracentrifugation, we found that several of the peptides bound preferentially to p53 tetramers. Our results indicate that the protein-protein interactions of p53 are dependent on the oligomerization state of p53. We conclude that peptides may be used to regulate the oligomerization of p53

Pathogen Specific, IRF3-Dependent Signaling and Innate Resistance to Human Kidney Infection

The mucosal immune system identifies and fights invading pathogens, while allowing non-pathogenic organisms to persist. Mechanisms of pathogen/non-pathogen discrimination are poorly understood, as is the contribution of human genetic variation in disease susceptibility. We describe here a new, IRF3-dependent signaling pathway that is critical for distinguishing pathogens from normal flora at the mucosal barrier. Following uropathogenic E. coli infection, Irf3−/− mice showed a pathogen-specific increase in acute mortality, bacterial burden, abscess formation and renal damage compared to wild type mice. TLR4 signaling was initiated after ceramide release from glycosphingolipid receptors, through TRAM, CREB, Fos and Jun phosphorylation and p38 MAPK-dependent mechanisms, resulting in nuclear translocation of IRF3 and activation of IRF3/IFNβ-dependent antibacterial effector mechanisms. This TLR4/IRF3 pathway of pathogen discrimination was activated by ceramide and by P-fimbriated E. coli, which use ceramide-anchored glycosphingolipid receptors. Relevance of this pathway for human disease was supported by polymorphic IRF3 promoter sequences, differing between children with severe, symptomatic kidney infection and children who were asymptomatic bacterial carriers. IRF3 promoter activity was reduced by the disease-associated genotype, consistent with the pathology in Irf3−/− mice. Host susceptibility to common infections like UTI may thus be strongly influenced by single gene modifications affecting the innate immune response

Geographic genetic structure of Iberian columbines (gen. Aquilegia)

Southern European columbines (genus Aquilegia)are involved in active processes of diversification, and the Iberian Peninsula offers a privileged observatory to witness the process. Studies on Iberian columbines have provided significant advances on species diversification,but we still lack a complete perspective of the genetic diversification in the Iberian scenario. This work explores how genetic diversity of the genus Aquilegia is geographically structured across the Iberian Peninsula. We used Bayesian clustering methods, principal coordinates analyses, and NJ phenograms to assess the genetic relationships among 285 individuals from 62 locations and detect the main lineages. Genetic diversity of Iberian columbines consists of five geographically structured lineages, corresponding to different Iberian taxa. Differentiation among lineages shows particularly complex admixture patterns at Northeast and highly homogeneous toward Northwest and Southeast. This geographic genetic structure suggests the existence of incomplete lineage sorting and interspecific hybridization as could be expected in recent processes of diversification under the influence of quaternary postglacial migrations. This scenario is consistent with what is proposed by the most recent studies on European and Iberian columbines, which point to geographic isolation and divergent selection by habitat specialization as the main diversification drivers of the Iberian Aquilegia complex