Hazardous alcohol consumption is a major factor in male premature mortality in a typical Russian city: prospective cohort study 2003-2009

Introduction

Russia has experienced massive fluctuations in mortality at working ages over the past three decades. Routine data analyses suggest that these are largely driven by fluctuations in heavy alcohol drinking. However, individual-level evidence supporting alcohol having a major role in Russian mortality comes from only two case-control studies, which could be subject to serious biases due to their design.

Methods and Findings

A prospective study of mortality (2003–9) of 2000 men aged 25–54 years at recruitment was conducted in the city of Izhevsk, Russia. This cohort was free from key limitations inherent in the design of the two earlier case-control studies. Cox proportional hazards regression was used to estimate hazard ratios of all-cause mortality by alcohol drinking type as reported by a proxy informant. Hazardous drinkers were defined as those who either drank non-beverage alcohols or were reported to regularly have hangovers or other behaviours related to heavy drinking episodes.Over the follow-up period 113 men died. Compared to non-hazardous drinkers and abstainers, men who drank hazardously had appreciably higher mortality (HR = 3.4, 95% CI 2.2, 5.1) adjusted for age, smoking and education. The population attributable risk percent (PAR%) for hazardous drinking was 26% (95% CI 14,37). However, larger effects were seen in the first two years of follow-up, with a HR of 4.6 (2.5, 8.2) and a corresponding PAR% of 37% (17, 51).

Interpretation

This prospective cohort study strengthens the evidence that hazardous alcohol consumption has been a major determinant of mortality among working age men in a typical Russian city. As such the similar findings of the previous case-control studies cannot be explained as artefacts of limitations of their design. As Russia struggles to raise life expectancy, which even in 2009 was only 62 years among men, control of hazardous drinking must remain a top public health priority.     

A new species of Peucoglyphus Bernhauer from New Guinea (Coleoptera, Staphylinidae, Staphylininae)

Peucoglyphus kensp. n., a new species from New Guinea is described. Adding the new species, this rare Wallacean genus from the tribe Staphylinini (subtribe Philonthina) currently includes five species. An updated identification key for the genus is provided.     

Centrosome amplification can initiate tumorigenesis in flies

Centrosome amplification is a common feature of many cancer cells, and it has been previously proposed that centrosome amplification can drive genetic instability and so tumorigenesis. To test this hypothesis, we generated Drosophila lines that have extra centrosomes in approximately 60% of their somatic cells. Many cells with extra centrosomes initially form multipolar spindles, but these spindles ultimately become bipolar. This requires a delay in mitosis that is mediated by the spindle assembly checkpoint (SAC). As a result of this delay, there is no dramatic increase in genetic instability in flies with extra centrosomes, and these flies maintain a stable diploid genome over many generations. The asymmetric division of the larval neural stem cells, however, is compromised in the presence of extra centrosomes, and larval brain cells with extra centrosomes can generate metastatic tumors when transplanted into the abdomens of wild-type hosts. Thus, centrosome amplification can initiate tumorigenesis in flies.     

Stimuli-dependent cleavage of Dicer during apoptosis

The 'stalk' is a large ribosomal subunit domain that regulates translation. In the present study the role of the ribosomal stalk P proteins in modulating ribosomal activity has been investigated in human cells using RNA interference. A strong down-regulation of P2 mRNA and a drastic decrease in P2 protein in a stable human cell line was achieved using a doxycycline-inducible system. Interestingly, the amount of P1 protein was similarly decreased in these cells, in contrast with the expression of P1 mRNA. The loss of P1/P2 proteins produced a decrease in the growth rate of these cells, as well as an altered polysome pattern with reduced translation efficiency, but without affecting the free 40 S/60 S subunit ratio. A decrease in the ribosomal-subunit joining capacity was also observed. These data indicate that P1/P2 proteins modulate cytoplasmic translation by influencing the interaction between subunits, thereby regulating the rate of cell proliferation.     

A structural model of the GDP dissociation inhibitor rab membrane extraction mechanism

Rab GDP dissociation inhibitors (GDI)-facilitated extraction of prenylated Rab proteins from membranes plays an important role in vesicular membrane trafficking. The investigated thermodynamic properties of yeast Rab.GDI and Rab.MRS6 complexes demonstrated differences in the Rab binding properties of the closely related Rab GDI and MRS6 proteins, consistent with their functional diversity. The importance of the Rab C terminus and its prenylation for GDI/MRS6 binding was demonstrated using both biochemical and structural data. The presented structures of the apo-form yeast Rab GDI and its two complexes with unprenylated Rab proteins, together with the earlier published structures of the prenylated Ypt1.GDI, provide evidence of allosteric regulation of the GDI lipid binding site opening, which plays a key role in the proposed mechanism of GDI-mediated Rab extraction. We suggest a model for the interaction of GDI with prenylated Rab proteins that incorporates a stepwise increase in affinity as the three different partial interactions are successively formed.     

Can diffuse extrasynaptic signaling form a guiding template?

Brain functions such as information processing, learning and memory are commonly associated with changes in synaptic strength, the synaptic plasticity. Extrasynaptic diffusion of transmitters thought to mediate only a modulatory effect. Here I suggest a hypothesis that concentration profile of signaling molecules in the extracellular space can form a "diffuse guiding template" for signal propagation through neuronal network. Such template can be potentially involved in information processing and storage. This hypothesis requires further experimental investigation and, thus, provides a framework for future studies in the field of non-synaptic transmission in the brain.     

Semi-continuum electrostatic calculations of redox potentials in photosystem I

The midpoint redox potentials (E(m)) of all cofactors in photosystem I from Synechococcus elongatus as well as of the iron-sulfur (Fe(4)S(4)) clusters in two soluble ferredoxins from Azotobacter vinelandii and Clostridium acidiurici were calculated within the framework of a semi-continuum dielectric approach. The widely used treatment of proteins as uniform media with single dielectric permittivity is oversimplified, particularly, because permanent charges are considered both as a source for intraprotein electric field and as a part of dielectric polarizability. Our approach overcomes this inconsistency by using two dielectric constants: optical epsilon(o)=2.5 for permanent charges pre-existing in crystal structure, and static epsilon(s) for newly formed charges. We also take into account a substantial dielectric heterogeneity of photosystem I revealed by photoelectric measurements and a liquid junction potential correction for E(m) values of relevant redox cofactors measured in aprotic solvents. We show that calculations based on a single permittivity have the discrepancy with experimental data larger than 0.7 V, whereas E(m) values calculated within our approach fall in the range of experimental estimates. The electrostatic analysis combined with quantum chemistry calculations shows that (i) the energy decrease upon chlorophyll dimerization is essential for the downhill mode of primary charge separation between the special pair P(700) and the primary acceptor A(0); (ii) the primary donor is apparently P(700) but not a pair of accessory chlorophylls; (iii) the electron transfer from the A branch quinone Q(A) to the iron-sulfur cluster F(X) is most probably downhill, whereas that from the B branch quinone Q(B) to F(X) is essentially downhill.     

Analysis of DsRed Mutants. Space around the fluorophore accelerates fluorescence development.

Earlier mutagenesis of the red fluorescent protein drFP583, also called DsRed, resulted in a mutant named Fluorescent Timer (Terskikh, A., Fradkov, A., Ermakova, G., Zaraisky, A., Tan, P., Kajava, A. V., Zhao, X., Lukyanov, S., Matz, M., Kim, S., Weissman, I., and Siebert, P. (2000) Science 290, 1585--1588). Further mutagenesis generated variants with novel and improved fluorescent properties. The mutant called AG4 exhibits only green fluorescence. The mutant, called E5up (V105A), shows complete fluorophore maturation, eventually eliminating residual green fluorescence present in DsRed. Finally, the mutant, called E57 (V105A, I161T, S197A), matures faster than DsRed as demonstrated in vitro with purified protein and in vivo with recombinant protein expressed in Escherichia coli and Xenopus leavis. Comparative analysis of the mutants in the context of the crystal structure of DsRed suggests that mutants with free space around the fluorophore mature faster and more completely.     

Study of the late embryogenesis of Daphnia (Anomopoda, ‘Cladocera’, Branchiopoda) and a comparison of development in Anomopoda and Ctenopoda

The embryonic development of Daphnia galeata and D. hyalina (`Cladocera', Anomopoda, Daphniidae) has been investigated by observing living embryos removed from female brood pouches. The sequence of morphological changes was analysed, as was the time at which the activity of certain organs began. The timing of these events at 22 °C is documented for both species.These data were compared with similar information, previously obtained for two representatives of the Ctenopoda (Kotov & Boikova, 1998). The sequence of events is basically similar in the two groups during early and late phases of their development, but the time of shedding of the embryonic membranes is different in the Anomopoda and Ctenopoda. The ctenopod embryo hatching from the second egg membrane is covered by the third membrane, which will be cast some hours later. The anomopod embryo hatches from the second egg membrane approximately simultaneously with the shedding of the third membrane, and it is covered already by the fourth membrane after the shedding of the second egg membrane.Earlier (Kotov & Boikova, 1998), we determined four embryonic instars in the course of the development of the Ctenopoda. Two of them are passed within the egg membranes, the next two instars occur after the shedding the egg membranes within the mother's brood pouch. However, in anomopods, one of the latter (the third) occurs within the second egg membrane, one is incorporated into the egg. Thus, the development of the Anomopoda is more embryonized in comparison with that of the Ctenopoda.