Calculation of antihydrogen formation via antiproton scattering with excited positronium

Detailed presentation of results shown in the ealrier Phys. Rev. Lett. (114, 183201, (2015)).Shows all partial cross sections for antihydrogen formation in collisions of antiprotons with positronium in quantum states n = 1-3

The C-Terminal Domain of the MutL Homolog from Neisseria gonorrhoeae Forms an Inverted Homodimer

The mismatch repair (MMR) pathway serves to maintain the integrity of the genome by removing mispaired bases from the newly synthesized strand. In E. coli, MutS, MutL and MutH coordinate to discriminate the daughter strand through a mechanism involving lack of methylation on the new strand. This facilitates the creation of a nick by MutH in the daughter strand to initiate mismatch repair. Many bacteria and eukaryotes, including humans, do not possess a homolog of MutH. Although the exact strategy for strand discrimination in these organisms is yet to be ascertained, the required nicking endonuclease activity is resident in the C-terminal domain of MutL. This activity is dependent on the integrity of a conserved metal binding motif. Unlike their eukaryotic counterparts, MutL in bacteria like Neisseria exist in the form of a homodimer. Even though this homodimer would possess two active sites, it still acts a nicking endonuclease. Here, we present the crystal structure of the C-terminal domain (CTD) of the MutL homolog of Neisseria gonorrhoeae (NgoL) determined to a resolution of 2.4 Å. The structure shows that the metal binding motif exists in a helical configuration and that four of the six conserved motifs in the MutL family, including the metal binding site, localize together to form a composite active site. NgoL-CTD exists in the form of an elongated inverted homodimer stabilized by a hydrophobic interface rich in leucines. The inverted arrangement places the two composite active sites in each subunit on opposite lateral sides of the homodimer. Such an arrangement raises the possibility that one of the active sites is occluded due to interaction of NgoL with other protein factors involved in MMR. The presentation of only one active site to substrate DNA will ensure that nicking of only one strand occurs to prevent inadvertent and deleterious double stranded cleavage

КЛИНИКО-ЭПИДЕМИОЛОГИЧЕСКАЯ ХАРАКТЕРИСТИКА ПНЕВМОКОККОВЫХ МЕНИНГИТОВ У ДЕТЕЙ

Authors present clinical and epidemiological characterization of the 108 patients with pneumococcal meningitis of the age from 6 months to 14 years old. The data analysis showed that pneumococcal meningitis is characterized with severity and complications. It was also observed that the role of S. pneumoniae in etiology of the acute bacterial meningitis has increased for the children in the last years. The use of rapid immunochromatographic test along with cultural methods increases the detection of the etiology of bacterial meningitis in children.Дана клинико-эпидемиологическая характеристика 108 больным с пневмококковым гнойным менингитом в возрасте от 6 месяцев до 14 лет. Анализ данных показал, что пневмококковый менингит характеризуется крайне тяжелым течением с отягощающими последствиями и исходами. В последние годы отмечается повышение роли S. pneumoniae в этиологической структуре острых гнойных менингитов у детей. Использование современных тест-систем (иммунохроматографический тест BinaxNOWS pneumoniae тест), наряду с бактериологическим методом, существенно улучшает этиологическую расшифровку гнойных менингитов у детей

Epistasis between COMT and MTHFR in Maternal-Fetal Dyads Increases Risk for Preeclampsia

Preeclampsia is a leading cause of perinatal morbidity and mortality. This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease. One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction. Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses. COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor. Variations in MTHFR have been associated with preeclampsia. By accounting for allelic variation in both genes, the role of COMT has been clarified. COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity. We tested for association between COMT haplotypes and the MTHFR 677 C→T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads. The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0.004), and that risk increased linearly from low to high activity haplotypes (P = 0.003). In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p = 0.022). We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0.052) and the fetal risk alleles in combination with a maternal balancing allele (P<0.001). This non-random distribution was not observed in controls (P = 0.341 and P = 0.219, respectively). Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR

A free weekly iron-folic acid supplementation and regular deworming program is associated with improved hemoglobin and iron status indicators in Vietnamese women

Background Anemia due to iron deficiency is recognized as one of the major nutritional deficiencies in women and children in developing countries. Daily iron supplementation for pregnant women is recommended in many countries although there are few reports of these programs working efficiently or effectively. Weekly iron-folic acid supplementation (WIFS) and regular deworming treatment is recommended for non-pregnant women living in areas with high rates of anemia. Following a baseline survey to assess the prevalence of anemia, iron deficiency and soil transmitted helminth infections, we implemented a program to make WIFS and regular deworming treatment freely and universally available for all women of reproductive age in two districts of a province in northern Vietnam over a 12 month period. The impact of the program at the population level was assessed in terms of: i) change in mean hemoglobin and iron status indicators, and ii) change in the prevalence of anemia, iron deficiency and hookworm infections. Method Distribution of WIFS and deworming were integrated with routine health services and made available to 52,000 women. Demographic data and blood and stool samples were collected in baseline, and three and 12-month post-implementation surveys using a population-based, stratified multi-stage cluster sampling design. Results The mean Hb increased by 9.6 g/L (95% CI, 5.7, 13.5, p < 0.001) during the study period. Anemia (Hb<120 g/L) was present in 131/349 (37.5%, 95% CI 31.3, 44.8) subjects at baseline, and in 70/363 (19.3%, 95% CI 14.0, 24.6) after twelve months. Iron deficiency reduced from 75/329 (22.8%, 95% CI 16.9, 28.6) to 33/353 (9.3%, 95% CI 5.7, 13.0) by the 12-mnth survey, and hookworm infection from 279/366 (76.2%,, 95% CI 68.6, 83.8) to 66/287 (23.0%, 95% CI 17.5, 28.5) over the same period. Conclusion A free, universal WIFS program with regular deworming was associated with reduced prevalence and severity of anemia, iron deficiency and h

Validation of pharmacodynamic assays to evaluate the clinical efficacy of an antisense compound (AEG 35156) targeted to the X-linked inhibitor of apoptosis protein XIAP

The inhibitor of apoptosis protein, XIAP, is frequently overexpressed in chemoresistant human tumours. An antisense oligonucleotide (AEG 35156/GEM 640) that targets XIAP has recently entered phase I trials in the UK. Method validation data are presented on three pharmacodynamic assays that will be utilised during this trial. Quantitative RT-PCR was based on a Taqman assay and was confirmed to be specific for XIAP. Assay linearity extended over four orders of magnitude. MDA-MB-231/U6-E1 cells and clone X-G4 stably expressing an RNAi vector against XIAP were chosen as high and low XIAP expression quality controls (QCs). Within-day and between-day coefficients of variation (CVs) in precision for cycle threshold (CT) and delta CT values (employing GAPDH and beta 2 microglobulin as housekeepers) were always less than 10%. A Western blotting technique was validated using a GST–XIAP fusion protein as a standard and HeLa cells and SF268 (human glioblastoma) cells as high and low XIAP expression QCs. Specificity of the final choice of antibody for XIAP was evaluated by analysing a panel of cell lines including clone X-G4. The assay was linear over a 29-fold range of protein concentration and between-day precision was 29% for the low QC and 23% for the high QC when normalised to GAPDH. XIAP protein was also shown to be stable at −80°C for at least 60 days. M30-Apoptosense™ plasma Elisa detects a caspase-cleaved fragment of cytokeratin 18 (CK18), believed to be a surrogate marker for tumour cell apoptosis. Generation of an independent QC was achieved through the treatment of X-G4 cells with staurosporine and collection of media. Measurements on assay precision and kit-to-kit QC were always less than 10%. The M30 antigen (CK18-Asp396) was stable for 3 months at −80°C, while at 37°C it had a half-life of 80–100 h in healthy volunteer plasma. Results from the phase I trial are eagerly awaited

HFE Gene Variants Modify the Association between Maternal Lead Burden and Infant Birthweight: A Prospective Birth Cohort Study in Mexico City, Mexico

<p>Abstract</p> <p>Background</p> <p>Neonatal growth is a complex process involving genetic and environmental factors. Polymorphisms in the hemochromatosis (<it>HFE</it>) iron regulatory genes have been shown to modify transport and toxicity of lead which is known to affect birth weight.</p> <p>Methods</p> <p>We investigated the role of <it>HFE C282Y</it>, <it>HFE H63 D</it>, and transferrin <it>(TF) P570 S </it>gene variants in modifying the association of lead and infant birthweight in a cohort of Mexican mother-infant pairs. Subjects were initially recruited between 1994-1995 from three maternity hospitals in Mexico City and 411 infants/565 mothers had archived blood available for genotyping. Multiple linear regression models, stratified by either maternal/infant <it>HFE </it>or <it>TF </it>genotype and then combined with interaction terms, were constructed examining the association of lead and birthweight after controlling for covariates.</p> <p>Results</p> <p>3.1%, 16.8% and 17.5% of infants (N = 390) and 1.9%, 14.5% and 18.9% of mothers (N = 533) carried the <it>HFE C282Y</it>, <it>HFE H63D</it>, and <it>TF P570 S </it>variants, respectively. The presence of infant <it>HFE H63 D </it>variants predicted 110.3 g (95% CI -216.1, -4.6) decreases in birthweight while maternal <it>HFE H63 D </it>variants predicted reductions of 52.0 g (95% CI -147.3 to 43.2). Interaction models suggest that both maternal and infant <it>HFE H63 D </it>genotype may modify tibia lead's effect on infant birthweight in opposing ways. In our interaction models, maternal <it>HFE H63 D </it>variant carriers had a negative association between tibia lead and birthweight.</p> <p>Conclusions</p> <p>These results suggest that the <it>HFE H63 D </it>genotype modifies lead's effects on infant birthweight in a complex fashion that may reflect maternal-fetal interactions with respect to the metabolism and transport of metals.</p

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers

Atomic collisional data for neutral beam modeling in fusion plasmas

The injection of energetic neutral particles into the plasma of magnetic confinement fusion reactors is a widely-accepted method for heating such plasmas; various types of neutral beam are also used for diagnostic purposes. Accurate atomic data are required to properly model beam penetration into the plasma and to interpret photoemission spectra from both the beam particles themselves (e.g. beam emission spectroscopy) and from plasma impurities with which they interact (e.g. charge exchange recombination spectroscopy). This paper reviews and compares theoretical methods for calculating ionization, excitation and charge exchange cross sections applied to several important processes relevant to neutral hydrogen beams, including H + Be4+ and H + H+. In particular, a new cross section for the proton-impact ionization of H (1s) is recommended which is significantly larger than that previously accepted at fusion-relevant energies. Coefficients for an empirical fit function to this cross section and to that of the first excited states of H are provided and uncertainties estimated. The propagation of uncertainties in this cross section in modeling codes under JET-like conditions has been studied and the newly-recommended values determined to have a significant effect on the predicted beam attenuation. In addition to accurate calculations of collisional atomic data, the use of these data in codes modeling beam penetration and photoemission for fusion-relevant plasma density and temperature profiles is discussed. In particular, the discrepancies in the modeling of impurities are reported. The present paper originates from a Coordinated Research Project (CRP) on the topic of fundamental atomic data for neutral beam modeling that the International Atomic Energy Agency (IAEA) ran from 2017 to 2022; this project brought together ten research groups in the fields of fusion plasma modeling and collisional cross section calculations. Data calculated during the CRP is summarized in an appendix and is available online in the IAEA’s atomic database, CollisionDB