Rates for repair of pBR 322 DNA radicals by thiols as measured by the gas explosion technique: evidence that counter-ion condensation and co-ion depletion are significant at physiological ionic strength.

Rates of rapair of pBR 322 plasmid DNA radicals by thiols of varying net charge (Z) at pH 7 and physiological ionic strength were measured using the oxygen explosion technique. The extent of conversion of supercoiled to relaxed circular plasmid was measured by HPLC as a function of the time of oxygen exposure before or after irradiation, the time-courses being fitted by a pseudo-first-order kinetic expression with k1 = k2[RSH]. Values of k2 (M-1 S-1) were: 2.1 x 10(5) (GSH, Z = -1), 1.4 x 10(6) (2-mercaptoethanol, Z = 0), 1.2 x 10(7) (cysteamine, Z = +1), 6.6 x 10(7) (WR-1065 or N-(2-mercaptoethyl)-1,3-diamino?? propane, Z = +2). The approximately 6-fold increase in rate with each unit increase in Z is attributed to concentration of cationic thiols near DNA as a consequence of counter-ion condensation and reduced levels of anionic thiols near DNA owing to co-ion depletion. The results are quantitatively consistent with chemical repair as a significant mechanism for radioprotection of cells by neutral and cationic thiols under aerobic conditions, but indicate that repair by GSH will compete effectively with oxygen only at low oxygen tension.

A study of endonuclease III-sensitive sites in irradiated DNA: detection of alpha-particle-induced oxidative damage

An important difference between chemical agents that induce oxidative damage in DNA and ionizing radiation is that radiation-induced damage is clustered locally on the DNA, Both modelling and experimental studies have predicted the importance of clustering of lesions induced by ionizing radiation and its dependence on radiation quality. With increasing linear energy transfer, it is predicted that complex lesions will be formed within 1-20 bp regions of the DNA, As well as strand breaks, these sites may contain multiple damaged bases, We have compared the yields of single strand breaks (ssb) and double strand breaks (dsb) along with those produced by treatment of irradiated DNA with the enzyme endonuclease III, which recognizes a number of oxidized pyrimidines in DNA and converts them to strand breaks. Plasmid DNA was irradiated under two different scavenging conditions to test the involvement of OH radicals with either Co-60 gamma-rays or alpha-particles from a Pu-238 source. Under low scavenging conditions (10 mM Tris) gamma-irradiation induced 7.1x10(-7) ssb Gy/bp, which increased 3.7-fold to 2.6 x 10(-6) ssb Gy/bp with endo III treatment. In contrast the yields of dsb increased by 4.2-fold from 1.5 x 10(-8) to 6.3 x 10(-8) dsb Gy/bp, This equates to an additional 2.5% of the endo III-sensitive sites being converted to dsb on enzyme treatment. For alpha-particles this increased to 9%. Given that endo III sensitive sites may only constitute similar to 40% of the base lesions induced in DNA, this suggests that up to 6% of the ssb measured in X- and 22% in alpha-particle-irradiated DNA could have damaged bases associated with them contributing to lesion complexity.

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (P(combined) = 4.09 × 10(-9); odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (P(combined) = 2.74 × 10(-10); OR = 1.14, 95% CI = 1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

RADIATIVE SIGNATURES OF RELATIVISTIC SHOCKS

Particle-in-cell simulations of relativistic, weakly magnetized collisionless shocks show that particles can gain energy by repeatedly crossing the shock front. This requires scattering off self-generated small length-scale magnetic fluctuations. The radiative signature of this first-order Fermi acceleration mechanism is important for models of both the prompt and afterglow emission in gamma-ray bursts and depends on the strength parameter a = lambda e/delta B/mc(2) of the fluctuations (lambda is the length scale and vertical bar delta B vertical bar is the magnitude of the fluctuations). For electrons (and positrons), acceleration saturates when the radiative losses produced by the scattering cannot be compensated by the energy gained on crossing the shock. We show that this sets an upper limit on both the electron Lorentz factor gamma <10(6) (n/1 cm(-3))(-1/6)(-1/6) and on the energy of the photons radiated during the scattering process h omega(max) <40Max(a, 1)(n/1 cm(-3))(1/6)(-1/6) eV, where n is the number density of the plasma and (gamma) over bar is the thermal Lorentz factor of the downstream plasma, provided a <a(crit) similar to 10(6). This rules out "jitter" radiation on self-excited fluctuations with a <I as a source of gamma rays, although high-energy photons might still be produced when the jitter photons are upscattered in an analog of the synchrotron self-Compton process. In fluctuations with a > 1, radiation is generated by the standard synchrotron mechanism, and the maximum photon energy rises linearly with a, until saturating at 70 MeV, when a = a(crit).

Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus

Glycation, oxidation, and nonenzymatic browning of protein have all been implicated in the development of diabetic complications. The initial product of glycation of protein, fructoselysine (FL), undergoes further reactions, yielding a complex mixture of browning products, including the fluorescent lysine-arginine cross-link, pentosidine. Alternatively, FL may be cleaved oxidatively to form N(epsilon)-(carboxymethyl)lysine (CML), while glycated hydroxylysine, an amino-acid unique to collagen, may yield N(epsilon)-(carboxymethyl)hydroxylysine (CMhL). We have measured FL, pentosidine, fluorescence (excitation = 328 nm, emission = 378 nm), CML, and CMhL in insoluble skin collagen from 14 insulin-dependent diabetic patients before and after a 4-mo period of intensive therapy to improve glycemic control. Mean home blood glucose fell from 8.7 +/- 2.5 (mean +/- 1 SD) to 6.8 +/- 1.4 mM (P less than 0.005), and mean glycated hemoglobin (HbA1) from 11.6 +/- 2.3% to 8.3 +/- 1.1% (P less than 0.001). These changes were accompanied by a significant decrease in glycation of skin collagen, from 13.2 +/- 4.3 to 10.6 +/- 2.3 mmol FL/mol lysine (P less than 0.002). However, levels of browning and oxidation products (pentosidine, CML, and CMhL) and fluorescence were unchanged. These results show that the glycation of long-lived proteins can be decreased by improved glycemic control, but suggest that once cumulative damage to collagen by browning and oxidation reactions has occurred, it may not be readily reversed. Thus, in diabetic patients, institution and maintenance of good glycemic control at any time could potentially limit the extent of subsequent long-term damage to proteins by glycation and oxidation reactions.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 1: Development of a potent and CNS penetrant [3.1.0]-based lead

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach that provided a robust intellectual property position, in lieu of a traditional, expensive HTS campaign. Members within this new [3.1.0]​-​based series displayed excellent GlyT1 potency, selectivity, free fraction, CNS penetration and efficacy in a preclin. model of schizophrenia (prepulse inhibition)​.

The Map of Connections 3.1: Unofficial and previously unmapped Irish border crossings

I charted unofficial border-crossings along Ireland's border, those not found on any other map.

During many surveys of Ireland's border I discovered that it is often perforated. Gates are set in hedgerows for the convenience of farmers, stepping stones and community-built bridges span rivers, walkers’ routes and muddy by-ways go wherever they please. These kinds of connections have always been there, although I think it is fair to say that their numbers have increased during the Peace Process. Roads blocked or cratered during the Troubles are being re-connected at a rate too fast for the Ordnance Survey to keep up with. On the local level cross-border movement is quietly happening, unchecked and often unmapped, until now.

This map attempts to throw the borderline in perpendicular, showing it as a place of connection rather than division.

Convergent genetic and expression data implicate immunity in Alzheimer's disease

Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.

Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.

Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05).

Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.

On the solubility of three disperse anthraquinone dyes in supercritical carbon dioxide: new experimental data and correlation

Solubility measurements of quinizarin. (1,4-dihydroxyanthraquinone), disperse red 9 (1-(methylamino) anthraquinone), and disperse blue 14 (1,4-bis(methylamino)anthraquinone) in supercritical carbon dioxide (SC CO2) were carried out in a flow type apparatus, at a temperature range from (333.2 to 393.2) K and at pressures from (12.0 to 40.0) MPa. Mole fraction solubility of the three dyes decreases in the order quinizarin (2.9 x 10(-6) to 2.9.10(-4)), red 9 (1.4 x 10(-6) to 3.2 x 10(-4)), and blue 14 (7.8 x 10(-8) to 2.2 x 10(-5)). Four semiempirical density based models were used to correlatethe solubility of the dyes in the SC CO2. From the correlation results, the total heat of reaction, heat of vaporization plus the heat of solvation of the solute, were calculated and compared with the results presented in the literature. The solubilities of the three dyes were correlated also applying the Soave-Redlich-Kwong cubic equation of state (SRK CEoS) with classical mixing rules, and the physical properties required for the modeling were estimated and reported.

Is thinness more prevalent than obesity in Portuguese adolescents?

There is little information regarding the prevalence of thinness in European adolescents. This was assessed in a convenience sample of children and adolescents from the Lisbon area (Portugal). Cross-sectional study including 2494 boys and 2519 girls aged 10-18 years. Body mass index (BMI), waist and hip were measured using standardized methods; thinness was defined using international criteria. Body fat was assessed by bioelectrical impedance. In girls, prevalence of thinness, overweight and obesity were 5.6%, 19.7% and 4.7%, respectively, whereas the corresponding numbers in boys were 3.9%, 17.4% and 5.3%. Prevalence of thinness increased whereas obesity decreased with age: from 1.5% to 7.6% for thinness and from 9.2% to 3.8% for obesity in girls aged 10 and 18, respectively. In boys, the corresponding trends were from 0% to 7.3% for thinness and from 10.6% to 3% for obesity. After adjusting for age, differences were found between BMI groups for weight, body fat percentage, fat mass, lean mass, waist and hip, while no differences regarding height were found between thin and normal weight participants. The prevalence of thinness is more frequent than obesity after age 14 in girls and 16 years in boys. Thinness is associated with a decreased body weight and body fat, whereas no consistent effect on height was noted.

Prospective comparison of clinical prognostic scores in elderly patients with pulmonary embolism.

Background: The Geneva Prognostic Score (GPS), the Pulmonary Embolism Severity Index (PESI), and its simplified version (sPESI) are well known clinical prognostic scores for pulmonary embolism (PE).Objectives: To compare the prognostic performance of these scores in elderly patients with PE. Patients/Methods: In a multicenter Swiss cohort of elderly patients with venous thromboembolism, we prospectively studied 449 patients aged ≥65 years with symptomatic PE. The outcome was 30-day overall mortality. We dichotomized patients as low- vs. higher-risk in all three scores using the following thresholds: GPS scores ≤2 vs. >2, PESI risk classes I-II vs. III-V, and sPESI scores 0 vs. ≥1. We compared 30-day mortality in low- vs. higher-risk patients and the areas under the receiver operating characteristic curve (ROC). Results: Overall, 3.8% of patients (17/449) died within 30 days. The GPS classified a greater proportion of patients as low risk (92% [413/449]) than the PESI (36.3% [163/449]) and the sPESI (39.6% [178/449]) (P<0.001 for each comparison). Low-risk patients based on the sPESI had a mortality of 0% (95% confidence interval [CI] 0-2.1%) compared to 0.6% (95% CI 0-3.4%) for low-risk patients based on the PESI and 3.4% (95% CI 1.9-5.6%) for low-risk patients based on the GPS. The areas under the ROC curves were 0.77 (95%CI 0.72-0.81), 0.76 (95% CI 0.72-0.80), and 0.71 (95% CI 0.66-0.75), respectively (P=0.47). Conclusions: In this cohort of elderly patients with PE, the GPS identified a higher proportion of patients as low-risk but the PESI and sPESI were more accurate in predicting mortality.

10-6-20, championnats de France [de] tennis, Miss Lenglen [associée en double à Mlle d'Ayen, courts de la Croix-Catelan] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59628

10-6-20, championnats de France [de] tennis, Miss Lenglen [associée en double à Mlle d'Ayen, courts de la Croix-Catelan] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59629

10-6-20, championnats de France [de] tennis, Miss Lenglen [associée en double à Mlle d'Ayen, courts de la Croix-Catelan] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 59630