Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.     

Do grandparents favor granddaughters? Biased grandparental investment in UK

Differential grandparental investment in grandchildren is often explained with paternity uncertainty. The asymmetric inheritance of the sex chromosomes, especially of the X chromosomes, may also bias grandparental investment. Recent studies show that ignoring the sex of the grandchild can mask important differences in the investment patterns of the same grandparent category, but this has not been tested in contemporary societies with nationally representative data. With 17 variables from the Involved Grandparenting and Child Well-Being 2007 survey, we tested differential grandparental investment as reported by British and Welsh adolescents and compared predictions based on X-chromosomal relatedness with predictions based on paternity uncertainty. The theories are expected to differ with regard to grandmaternal investment in grandsons and granddaughters. We test whether paternal grandmothers invest (H1) more in granddaughters than in grandsons, (H2) more in granddaughters than maternal grandmothers do and (H3) less in grandsons than maternal grandmothers do. In addition, following the suggestion that paternal grandmothers may reduce sibling competition between girls and boys by harming grandsons, we study whether (H4) paternal grandmothers channel more noninvestment into grandsons than into granddaughters. The results show no convincing support for the type of sex discrimination of grandchildren that is predicted by X-chromosomal relatedness theories, but do provide support for the paternity uncertainty theory. X-chromosomal relatedness does not appear to shape grandparental behavior in developed societies.     

Dimerization of human lysyl hydroxylase 3 (LH3) is mediated by the amino acids 541-547

Lysyl hydroxylases (LH), which catalyze the post-translational modifications of lysines in collagen and collagen-like proteins, function as dimers. However, the amino acids responsible for dimerization and the role of dimer formation in the enzymatic activities of LH have not yet been identified. We have localized the region responsible for the dimerization of lysyl hydroxylase 3 (LH3), a multifunctional enzyme of collagen biosynthesis, to a sequence of amino acids between the glycosyltransferase activity and the lysyl hydroxylase activity domains. This area is covered by amino acids 541-547 in human LH3, but contains no cysteine residues. The region is highly conserved among LH isoforms, and is also involved in the dimerization of LH1 subunits. Dimerization is required for the LH activity of LH3, whereas it is not obligatory for the glycosyltransferase activities. In order to determine whether complex formation can occur between LH molecules originating from different species, and between different LH isoforms, double expressions were generated in a baculovirus system. Heterocomplex formation between mouse and human LH3, between human LH1 and LH3 and between human LH2 and LH3 was detected by western blot analyses. However, due to the low amount of complexes formed, the in vivo function of heterocomplexes remains unclear.     

Voltage noise influences action potential duration in cardiac myocytes

Stochastic gating of ion channels introduces noise to membrane currents in cardiac muscle cells (myocytes). Since membrane currents drive membrane potential, noise thereby influences action potential duration (APD) in myocytes. To assess the influence of noise on APD, membrane potential is in this study formulated as a stochastic process known as a diffusion process, which describes both the current-voltage relationship and voltage noise. In this framework, the response of APD voltage noise and the dependence of response on the shape of the current-voltage relationship can be characterized analytically. We find that in response to an increase in noise level, action potential in a canine ventricular myocytes is typically prolonged and that distribution of APDs becomes more skewed towards long APDs, which may lead to an increased frequency of early after-depolarization formation. This is a novel mechanism by which voltage noise may influence APD. The results are in good agreement with those obtained from more biophysically-detailed mathematical models, and increased voltage noise (due to gating noise) may partially underlie an increased incidence of early after-depolarizations in heart failure.     

Life without GAG: the BARE-2 retrotransposon as a parasite's parasite

A large proportion of the plant LTR (Long Terminal Repeat) retrotransposons are partly or completely unable to synthesize their own machinery for transposition. However, most of these inactive or non-autonomous elements are likely able to retrotranspose, based on their insertional polymorphism. Therefore, they must be parasitic on one or more active partners. Here, we describe the parasitism of the chimeric BARE-2 element on the active BARE-1 (Barley RetroElement-2 and -1 respectively). These two elements are present in the Triticeae and related species, and are together polymorphic among closely related accessions. BARE-2 elements are unable to synthesize their own GAG protein, and harbor a specific ATG deletion in the gag ORF. However, BARE-2 sequences are conserved with BARE-1 in the PBS (Primer Binding Site), PSI (Packaging SIgnal) and DIS (DImerization Signal) domains. As these motifs have been shown to allow parasitism among the lentiviruses, we conclude that BARE-2 is probably a partial parasite of the BARE-1 element because the machinery of the latter can complement the defective GAG of the former. This example emphasizes that we must characterize the parasitic network of LTR retrotransposons and its implication for integration of autonomous, inactive, and non-autonomous elements in order to understand current and past host genome evolution.     

Étude de la cohorte nord-finlandaise de 1966: facteurs prédictifs et conséquences de la schizophrénie

Subtle motor, emotional, cognitive and behavioural abnormalities are often present in apparently healthy children and adolescents who later develop schizophrenia. This suggests that some aspects of causation are established long before psychosis becomes manifest. We aim to assess the factors contributing to the development of schizophrenia focusing mainly on genetic factors, pregnancy and delivery complications, early development and scholastic performance, as well as later educational, social and health consequences. This is done by reviewing the Northern Finland 1966 Birth Cohort, its scientific activities, publications and work in progress.     

CENL1 expression in the rib meristem affects stem elongation and the transition to dormancy in Populus

We investigated the short day (SD)-induced transition to dormancy in wild-type hybrid poplar (Populus tremula x P. tremuloides) and its absence in transgenic poplar overexpressing heterologous PHYTOCHROME A (PHYA). CENTRORADIALIS-LIKE1 (CENL1), a poplar ortholog of Arabidopsis thaliana TERMINAL FLOWER1 (TFL1), was markedly downregulated in the wild-type apex coincident with SD-induced growth cessation. By contrast, poplar overexpressing a heterologous Avena sativa PHYA construct (P35S:AsPHYA), with PHYA accumulating in the rib meristem (RM) and adjacent tissues but not in the shoot apical meristem (SAM), upregulated CENL1 in the RM area coincident with an acceleration of stem elongation. In SD-exposed heterografts, both P35S:AsPHYA and wild-type scions ceased growth and formed buds, whereas only the wild type assumed dormancy and P35S:AsPHYA showed repetitive flushing. This shows that the transition is not dictated by leaf-produced signals but dependent on RM and SAM properties. In view of this, callose-enforced cell isolation in the SAM, associated with suspension of indeterminate growth during dormancy, may require downregulation of CENL1 in the RM. Accordingly, upregulation of CENL1/TFL1 might promote stem elongation in poplar as well as in Arabidopsis during bolting. Together, the results suggest that the RM is particularly sensitive to photoperiodic signals and that CENL1 in the RM influences transition to dormancy in hybrid poplar.     

Effects of temperature and oxygenavailability on greenhouse gas and nutrient dynamics in sediment of a eutrophic mid-boreal lake

The effects of oxygen conditions and temperature on dynamics of greenhousegases (CH₄, CO₂, N₂O) and nutrients(NH₄ ⁺, NO₂ ^–+NO₃ ^–, tot-P) were studied in sediment of hyper-eutrophic LakeKevätön, Finland. Undisturbed sediment cores were incubated at 6, 11,16, and 23 °C in a laboratory microcosm using a continuouswater flowtechnique with an oxic or anoxic water flow. The production of CO₂increased with increasing temperature in both oxic (Q₁₀ 3.2 ±0.6) and anoxic (Q₁₀ 2.3 ± 0.4) flows. The release ofCH₄ increased with temperature in anoxic conditions (Q₁₀2.3 ± 0.2), but was negligible with the oxic flow at all temperatures.The release of NH₄ ⁺ increased with temperature with the oxic and anoxic flows(Q₁₀ 2.4 ± 0.1). There was a net production of NO₂ ^–, NO₃ ^– and N₂O with the oxic flow at temperatures below16 °C. The release of phosphorus was greater from the anoxicsediments and increased with temperature with both the anoxic (Q₁₀2.9 ± 0.5) and oxic (Q₁₀ 1.9 ± 0.1) flows. It isprobable that the temperature of boreal lakes and the associated oxygendeficiency will increase as the climate becomes warmer. Our experiments showedthat this change would increase the global warming potential of greenhousegasesreleased from sediments of eutrophic lakes predominately attributable to theincrease in the CH₄ production. Furthermore, warming would alsoaccelerate the eutrophication of lakes by increasing release of phosphorus andmineral nitrogen from sediments, which further enhance CH₄productionin sediments.     

Cell surface proteins of encapsulated Streptococcus cremoris: identification and immunochemical characterization

Cell surface proteins of two slime-forming, encapsulated Streptococcus cremoris strains, MLS96 and T₅ from the fermented milk product viili, were extracted with the non-ionic detergent Triton X-100. The isolated protein antigens were characterized by sodium dodecyl sulphate polyacrylamide gel electrophoresis and immuno-blotting with antisera produced against whole Strep. cremoris cells. When protein profiles of these strains were compared, seven prominent polypeptides were found common to both and were recognized by both antisera. Five of these polypeptides with molecular weights of 70000, 54000, 50000, 47000 and 40000 were identified as cell wall components. The remaining two polypeptides with molecular weights of 42000 and 26000 are being studied further in connection with slime formation for which modified Triton X-100 extraction provides a suitable method for isolation of the surface-associated antigens of lactic streptococci.     

Involvement of superoxide in the prolyl and lysyl hydroxylase reactions

Four superoxide dismutase active copper chelates, Cu(acetylsalicylate)₂, Cu(salicylate)₂, Cu(lysine)₂ and Cu(tyrosine)₂, proved to be inhibitors of prolyl and lysyl hydroxylase. The kinetics of the inhibition are consistent with the proposal that these compounds dismutated ${}^{\mathrm{?}}\text{O}{}_2{}^{\mathrm{staggered?}}$ at the active site of the enzymes. The data strongly suggest that ${}^{\mathrm{?}}\text{O}{}_2{}^{\mathrm{staggered?}}$ is the active form of O₂ in the prolyl and lysyl hydroxylase reactions.