Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.

Novel prognostic factors in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a malignant clonal blood disease that originates from a pluripotent hematopoietic stem cell. The cytogenetic hallmark of CML, the Philadelphia chromosome (Ph), is formed as a result of reciprocal translocation between chromosomes 9 and 22, which leads to a formation of a chimeric BCR-ABL fusion gene. The BCR-ABL protein is a constitutively active tyrosine kinase that changes the adhesion properties of cells, constitutively activates mitogenic signaling, enhances cell proliferation and reduces apoptosis. This results in leukemic growth and the clinical disease, CML. With the advent of targeted therapies against the BCR-ABL fusion protein, the treatment of CML has changed considerably during the recent decade. In this thesis, the clinical significance of different diagnostic methods and new prognostic factors in CML have been assessed. First, the association between two different methods for measuring CML disease burden (the RQ-PCR and the high mitotic index metaphase FISH) was assessed in bone marrow and peripheral blood samples. The correlation between positive RQ-PCR and metaphase FISH samples was high. However, RQ-PCR was more sensitive and yielded measurable transcripts in 40% of the samples that were negative by metaphase FISH. The study established a laboratory-specific conversion factor for setting up the International Scale when standardizing RQ-PCR measurements. Secondly, the amount of minimal residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (alloHSCT) was determined. For this, metaphase FISH was done for the bone marrow samples of 102 CML patients. Most (68%), had no residual cells during the entire follow-up time. Some (12 %) patients had minor (<1%) MRD which decreased even further with time, whereas 19% had a progressive rise in MRD that exceeded 1% or had more than 1% residual cells when first detected. Residual cells did not become eradicated spontaneously if the frequency of Ph+ cells exceeded 1% during follow-up. Next, the impact of deletions in the derivative chromosome 9, was examined. Deletions were observed in 15% of the CML patients who later received alloHSCT. After alloHSCT, there was no difference in the total relapse rate in patients with or without deletions. Nor did the estimates of overall survival, transplant-related mortality, leukemia-free survival and relapse-free time show any difference between these groups. When conventional treatment regimens are used, the der(9) status could be an important criterion, in conjunction with other prognostic factors, when allogeneic transplantation is considered. The significance of der(9) deletions for patients treated with tyrosine kinase inhibitors is not clear and requires further investigation. In addition to the der(9) status of the patient, the significance of bone marrow lymphocytosis as a prognostic factor in CML was assessed. Bone marrow lymphocytosis during imatinib therapy was a positive predictive factor and heralded optimal response. When combined with major cytogenetic response at three months of treatment, bone marrow lymphocytosis predicted a prognostically important major molecular response at 18 months of imatinib treatment. Although the validation of these findings is warranted, the determination of the bone marrow lymphocyte count could be included in the evaluation of early response to imatinib treatment already now. Finally, BCR-ABL kinase domain mutations were studied in CML patients resistant against imatinib treatment. Point mutations detected in the kinase domain were the same as previously reported, but other sequence variants, e.g. deletions or exon splicing, were also found. The clinical significance of the other variations remains to be determined.

Transport of sugars by the fat body of the silkworm, Bombyx mori

The transport of glucose and α-methyl glucoside into the fat body of the silkworm, Bombyx mori L., has been studied. Glucose is transported into the tissue by a mechanism similar to facilitated diffusion and α-methyl glucoside by a diffusion process. The uptake of these sugars is neither energy dependent nor coupled to a phosphotransferase system.

Correlación entre la personalidad y los factores de la Teoría del Comportamiento Planeado (TCP) en adolescentes escolarizados de 11-19 años del Caribe Colombiano

The increasing rate of pregnancies in teenagers and the high incident of the infections of sexual transmission (HIV/ AIDS, for example), these are health related issues (and especially the sexual and reproductive health), which have received great attention on the part of investigators and of the public opinion in general. Recently, there has been evidenced that teenagers carry out very easily risk sexual behaviors, and those who have not presented the above mentioned behaviors also show high levels of intention to carry out them. There is the hypothesis that besides cognitive variables such as attitudes, subjective norms, perceived behavioral control and intention, the personality of the young persons is an aspect that plays an important paper in their sexual and reproductive health. Significant correlations were found between the variales of the TPB and the personality traits; the results suggest that the direction of these correlations is associated with the specific type of behavior or situation that is assessed. Keywords: personality, theory of planned behavior, adolescents, reproductive sexuality.

Letter to K.K.S.I. from Moses and Simon Content, August 19, 1828

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Khersonskye fondy Uchastky N 1-9 i N 17-19

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Plan zemelʻnogo uchastka poselka Abramichevo N 19

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Kuka on potilas? : Suomalaisen sikiöseulontakäytännön sosiaalieettistä tarkastelua

Who is the patient? A social-ethical study of the Finnish practice of prenatal screening. The aim of this study is to examine the Finnish practice of prenatal screening from a social-ethical perspective. Analyzing ethical problems in medicine and medical practice only on a general scale may conceal relevant ethical dilemmas. Previous studies have suggested that many pregnant women view the prenatal screening practices customary in the Finnish maternal care system as intimidating and oppressive. This study analyzes the ethical questions of prenatal screening by focusing on the experiences and decision-making of a pregnant woman. Finnish women s experiences of and decision-making on the most common prenatal screening methods are reflected in the basic principles of biomedical ethics described by Tom L. Beauchamp and James F. Childress in Principles of Biomedical Ethics. To concretize women s experiences I refer to studies of Finnish women s experiences of prenatal screenings. This study shows that the principles of autonomy, non-maleficence and beneficence seem to materialize rather poorly in the Finnish practice of prenatal screening. The main ethical problem with prenatal screening is that the likelihood of a foetal cure is very limited and, upon detection of an affected foetus, the choice is usually whether to continue with the pregnancy or to undergo an abortion. Although informed consent should be required, women s participation in prenatal testing is, in many cases at least, not based on their active decision. Many women experience severe anxiety when they receive a positive screening result and must wait for the final results. Medical studies indicate that long- term anxiety may negatively influence the foetus and the mother-child relationship. This study shows that the practice of prenatal screening as such may cause more harm than benefit to many pregnant women and their foetuses. This study examines the decision-making process of a pregnant woman by using the theory of medical casuistry described in Jonsen, Siegler and Winslade s Clinical Ethics. This study focuses on each of the four points of view recommended by the theory. The main problem seems to be the question of whom the patient of prenatal screening is and whom the practice is intended to benefit: the mother, the foetus, the family or society? This study shows that the concepts of health in Finnish maternal care in general, and of the prenatal screening system in particular, differ considerably. It also demonstrates that the purpose and the aims of prenatal screening, aside from the woman s right to choose, has been expressed neither in Finnish public health programmes nor in the public recommendations of prenatal screening. This study suggests that the practice of prenatal screening is a statement, though unexpressed, of public health policy and as such comprises part of the policy of disability. This study further demonstrates that through a single explicit aim (the woman s right to choose) society actually evades its obligation to women by saddling pregnant women with the entire moral responsibility as well as the possible negative consequences of her choice, such as sorrow, regrets and moral balancing. The study reveals several ethical problems in the Finnish practice of prenatal screening. Such problems should be dealt with as the Finnish practice of prenatal screening advances.

Oxidation of thiones by singlet and triplet oxygen

Molecular oxygen (012) i8 eatabliehed to be a good electrophile' and haabean Pound to yield many interesting moleculae upon reaction with olefinic, aromatic and other mu1 tipla bonded compounda. Although, oxidation of carbon ulphur double bond (thiones) by air her bean know for a longtime, nai the r the aechaniam nor the reactive species involved in theae oxidationa have bean etabliahodo Although there is no clear experimental verification, involvement of malecular oxygen in such types of oxidationa oP activated thiocarbonyl coc pounds has been recently auggeetad.4.

Regulation of arginine decarboxylase and putrescine levels in Cucumis sativus cotyledons

Arginine decarboxylase (arginine carboxy-lyase EC 4.1.1.19) of Cucumis sativus cotyledons, has a pH optimum of 8.3 and a temperature optimum of 40°. Among the various plant hormones administered to excised cotyledons in culture, benzyladenine and its riboside were most effective in increasing the arginine decarboxylase activity and putrescine content. The enzyme activity and putrescine content were significantly increased on acid feeding of the cotyledons and decreased by KCl treatment. The KCl effect could be only partially reversed by benzyladenine. Abscisic acid inhibited cotyledon growth and also reduced arginine decarboxylase and putrescine levels. This effect was overcome by cytokinins. The half life of the enzyme using cycloheximide was 3.7 hr. Dibutyryl cyclic AMP and 5′-AMP also marginally stimulated the enzyme and putrescine levels. Mixing experiments indicate that there is neither a non-dialysable activator nor inhibitor of the enzyme.

Folding and Selective Exit of Reporter Proteins from the Yeast Endoplasmic Reticulum

The present study analyses the traffic of Hsp150 fusion proteins through the endoplasmic reticulum (ER) of yeast cells, from their post-translational translocation and folding to their exit from the ER via a selective COPI-independent pathway. The reporter proteins used in the present work are: Hsp150p, an O-glycosylated natural secretory protein of Saccharomyces cerevisiae, as well as fusion proteins consisting of a fragment of Hsp150 that facilitates in the yeast ER proper folding of heterologous proteins fused to it. It is thought that newly synthesized polypeptides are kept in an unfolded form by cytosolic chaperones to facilitate the post-translational translocation across the ER membrane. However, beta-lactamase, fused to the Hsp150 fragment, folds in the cytosol into bioactive conformation. Irreversible binding of benzylpenicillin locked beta-lactamase into a globular conformation, and prevented the translocation of the fusion protein. This indicates that under normal conditions the beta-lactamase portion unfolds for translocation. Cytosolic machinery must be responsible for the unfolding. The unfolding is a prerequisite for translocation through the Sec61 channel into the lumen of the ER, where the polypeptide is again folded into a bioactive and secretion-competent conformation. Lhs1p is a member of the Hsp70 family, which functions in the conformational repair of misfolded proteins in the yeast ER. It contains Hsp70 motifs, thus it has been thought to be an ATPase, like other Hsp70 members. In order to understand its activity, authentic Lhs1p and its recombinant forms expressed in E. coli, were purified. However, no ATPase activity of Lhs1p could be detected. Nor could physical interaction between Lhs1p and activators of the ER Hsp70 chaperone Kar2p, such as the J-domain proteins Sec63p, Scj1p, and Jem1p and the nucleotide exchange factor Sil1p, be demonstrated. The domain structure of Lhs1p was modelled, and found to consist of an ATPase-like domain, a domain resembling the peptide-binding domain (PBD) of Hsp70 proteins, and a C-terminal extension. Crosslinking experiments showed that Lhs1p and Kar2p interact. The interacting domains were the C-terminal extension of Lhs1p and the ATPase domain of Kar2p, and this interaction was independent of ATPase activity of Kar2p. A model is presented where the C-terminal part of Lhs1p forms a Bag-like 3 helices bundle that might serve in the nucleotide exchange function for Kar2p in translocation and folding of secretory proteins in the ER. Exit of secretory proteins in COPII-coated vesicles is believed to be dependent of retrograde transport from the Golgi to the ER in COPI-coated vesicles. It is thought that receptors escaping to the Golgi must be recycled back to the ER exit sites to recruit cargo proteins. We found that Hsp150 leaves the ER even in the absence of functional COPI-traffic from the Golgi to the ER. Thus, an alternative, COPI-independent ER exit pathway must exists, and Hsp150 is recruited to this route. The region containing the signature guiding Hsp150 to this alternative pathway was mapped.

Nitrification (DMPP) and urease (NBPT) inhibitors had no effect on pasture yield, nitrous oxide emissions nor nitrate leaching under irrigation in a hot-dry climate

Modern dairy farming in Australia relies on substantial inputs of fertiliser nitrogen (N) to underpin economic production. However, N lost from dairy systems represents an opportunity cost and can pose a number of environmental risks. Nitrogen cycle inhibitors can be co-applied with N fertilisers to slow the conversion of urea to NH4+ to reduce losses via volatilisation, and slow the conversion of NH4+ to NO3- to minimize leaching of NO3- and gaseous losses via nitrification and denitrification. In a field campaign in a high input ryegrass-kikuyu pasture system we compared the soil N pools, losses and pasture production between a) urea coated with the nitrification inhibitor (3,4-dimethyl pyrazole phosphate - DMPP) b) urea coated with the urease inhibitor (N-(n-butyl) thiophosphoric triamide - NBPT) and c) standard urea. There was no treatment effect (P>0.05) on soil mineral N, pasture yield, N2O flux nor leaching of NO3- cf. standard urea. We hypothesise that at our site, because gaseous losses were highly episodic (rainfall was erratic and displayed no seasonal rainfall nor soil wetting pattern) that there was a lack of coincidence of N application and conditions conducive to gaseous losses, thus the effectiveness of the inhibitor products was minimal and did not result in an increase in pasture yield. There remains a paucity of knowledge on N cycle inhibitors in relation to their effective use in field system to increase N use efficiency. Further research is required to define under what field conditions inhibitor products are effective in order to be able to provide accurate advice to managers of nitrogen in production systems.

Characterization of genomic diversity in extraintestinal pathogenic Escherichia coli (ExPEC) and development of a diagnostic DNA microarray for the differentiation of ExPEC isolates causing urinary tract infections

Extraintestinal pathogenic Escherichia coli (ExPEC) represent a diverse group of strains of E. coli, which infect extraintestinal sites, such as the urinary tract, the bloodstream, the meninges, the peritoneal cavity, and the lungs. Urinary tract infections (UTIs) caused by uropathogenic E. coli (UPEC), the major subgroup of ExPEC, are among the most prevalent microbial diseases world wide and a substantial burden for public health care systems. UTIs are responsible for serious morbidity and mortality in the elderly, in young children, and in immune-compromised and hospitalized patients. ExPEC strains are different, both from genetic and clinical perspectives, from commensal E. coli strains belonging to the normal intestinal flora and from intestinal pathogenic E. coli strains causing diarrhea. ExPEC strains are characterized by a broad range of alternate virulence factors, such as adhesins, toxins, and iron accumulation systems. Unlike diarrheagenic E. coli, whose distinctive virulence determinants evoke characteristic diarrheagenic symptoms and signs, ExPEC strains are exceedingly heterogeneous and are known to possess no specific virulence factors or a set of factors, which are obligatory for the infection of a certain extraintestinal site (e. g. the urinary tract). The ExPEC genomes are highly diverse mosaic structures in permanent flux. These strains have obtained a significant amount of DNA (predictably up to 25% of the genomes) through acquisition of foreign DNA from diverse related or non-related donor species by lateral transfer of mobile genetic elements, including pathogenicity islands (PAIs), plasmids, phages, transposons, and insertion elements. The ability of ExPEC strains to cause disease is mainly derived from this horizontally acquired gene pool; the extragenous DNA facilitates rapid adaptation of the pathogen to changing conditions and hence the extent of the spectrum of sites that can be infected. However, neither the amount of unique DNA in different ExPEC strains (or UPEC strains) nor the mechanisms lying behind the observed genomic mobility are known. Due to this extreme heterogeneity of the UPEC and ExPEC populations in general, the routine surveillance of ExPEC is exceedingly difficult. In this project, we presented a novel virulence gene algorithm (VGA) for the estimation of the extraintestinal virulence potential (VP, pathogenicity risk) of clinically relevant ExPECs and fecal E. coli isolates. The VGA was based on a DNA microarray specific for the ExPEC phenotype (ExPEC pathoarray). This array contained 77 DNA probes homologous with known (e.g. adhesion factors, iron accumulation systems, and toxins) and putative (e.g. genes predictably involved in adhesion, iron uptake, or in metabolic functions) ExPEC virulence determinants. In total, 25 of DNA probes homologous with known virulence factors and 36 of DNA probes representing putative extraintestinal virulence determinants were found at significantly higher frequency in virulent ExPEC isolates than in commensal E. coli strains. We showed that the ExPEC pathoarray and the VGA could be readily used for the differentiation of highly virulent ExPECs both from less virulent ExPEC clones and from commensal E. coli strains as well. Implementing the VGA in a group of unknown ExPECs (n=53) and fecal E. coli isolates (n=37), 83% of strains were correctly identified as extraintestinal virulent or commensal E. coli. Conversely, 15% of clinical ExPECs and 19% of fecal E. coli strains failed to raster into their respective pathogenic and non-pathogenic groups. Clinical data and virulence gene profiles of these strains warranted the estimated VPs; UPEC strains with atypically low risk-ratios were largely isolated from patients with certain medical history, including diabetes mellitus or catheterization, or from elderly patients. In addition, fecal E. coli strains with VPs characteristic for ExPEC were shown to represent the diagnostically important fraction of resident strains of the gut flora with a high potential of causing extraintestinal infections. Interestingly, a large fraction of DNA probes associated with the ExPEC phenotype corresponded to novel DNA sequences without any known function in UTIs and thus represented new genetic markers for the extraintestinal virulence. These DNA probes included unknown DNA sequences originating from the genomic subtractions of four clinical ExPEC isolates as well as from five novel cosmid sequences identified in the UPEC strains HE300 and JS299. The characterized cosmid sequences (pJS332, pJS448, pJS666, pJS700, and pJS706) revealed complex modular DNA structures with known and unknown DNA fragments arranged in a puzzle-like manner and integrated into the common E. coli genomic backbone. Furthermore, cosmid pJS332 of the UPEC strain HE300, which carried a chromosomal virulence gene cluster (iroBCDEN) encoding the salmochelin siderophore system, was shown to be part of a transmissible plasmid of Salmonella enterica. Taken together, the results of this project pointed towards the assumptions that first, (i) homologous recombination, even within coding genes, contributes to the observed mosaicism of ExPEC genomes and secondly, (ii) besides en block transfer of large DNA regions (e.g. chromosomal PAIs) also rearrangements of small DNA modules provide a means of genomic plasticity. The data presented in this project supplemented previous whole genome sequencing projects of E. coli and indicated that each E. coli genome displays a unique assemblage of individual mosaic structures, which enable these strains to successfully colonize and infect different anatomical sites.