PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, beta-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.     

Mitochondrial differentiation and biogeography of Hyla meridionalis (Anura: Hylidae): an unusual phylogeographical pattern

Aim To study the patterns of genetic variation and the historical events and processes that influenced the distribution and intraspecific diversity in Hyla meridionalis Boettger, 1874. Location Hyla meridionalis is restricted to the western part of the Mediterranean region. In northern Africa it is present in Tunisia, Algeria and Morocco. In south‐western Europe it is found in the south of France, north‐western Italy and north‐eastern and south‐western Iberian Peninsula. There are also insular populations, as in the Canaries and Menorca. Methods Sampling included 112 individuals from 36 populations covering the range of the species. We used sequences of mitochondrial DNA Cytochrome Oxidase I (COI) for the phylogeographical analysis (841 bp) and COI plus a fragment including part of tRNA lysine, ATP synthase subunits 6 and 8 and part of Cytochrome Oxidase III for phylogenetic analyses (2441 bp). Phylogenetic analyses were performed with paup *4.0b10 (maximum likelihood, maximum parsimony) and Mr Bayes 3.0 (Bayesian analysis). Nested clade analysis was performed using tcs 1.18 and Geo Dis 2.2. A dispersal‐vicariant analysis was performed with diva 1.0 to generate hypotheses about the geographical distribution of ancestors. Results We found little genetic diversity within samples from Morocco, south‐western Europe and the Canary Islands, with three well‐differentiated clades. One is distributed in south‐western Iberia and the High Atlas, Anti‐Atlas and Massa River in Morocco. The second is restricted to the Medium Atlas Mountains. The third one is present in northern Morocco, north‐eastern Iberia, southern France and the Canaries. These three groups are also represented in the nested clade analysis. Sequences from Tunisian specimens are highly divergent from sequences of all other populations, suggesting that the split between the two lineages is ancient. diva analysis suggests that the ancestral distribution of the different lineages was restricted to Africa, and that an explanation of current distribution of the species requires three different dispersal events. Main conclusions Our results support the idea of a very recent colonization of south‐western Europe and the Canary Islands from Morocco. South‐western Europe has been colonized at least twice: once from northern Morocco probably to the Mediterranean coast of France and once from the western coast of Morocco to southern Iberia. Human transport is a likely explanation for at least one of these events. Within Morocco, the pattern of diversity is consistent with a model of mountain refugia during hyperarid periods within the Pleistocene. Evaluation of the phylogenetic relationships of Tunisian haplotypes will require an approach involving the other related hylid taxa in the area.     

Post-synthesis incorporation of a lipidic side chain into a peptide on solid support.

A new strategy for the synthesis of lipopeptides has been developed. Using Weinreb (N-methoxy, N-methyl) amide as an aldehyde function precursor on the side chains of Asp or Glu residues, this new strategy avoids the synthesis of a lipidic amino acid residue before its incorporation in the peptide sequence. The aldehyde generated on the solid support can react with ylides leading to unsaturated or saturated side chains or with various nucleophiles to yield non-coded amino acid residues incorporated into the sequence.     

Drinking Pattern,Abstention and Problem Drinking as Risk Factors for Depressive Symptoms: Evidence from Three Urban Eastern European Populations

Purpose

To examine whether the frequency and amount of alcohol consumed in binge drinking sessions, total annual volume of alcohol consumed, problem drinking and abstaining from alcohol are associated with depressive symptoms in Eastern Europe.

Subjects and Methods

Cross-sectional data from a total of 24,381 participants from general population samples of the Czech Republic (N = 7,601), Russia (N = 6,908) and Poland (N = 9,872) aged 45–69 years in 2002–2005. Depressive symptoms were defined as ≥16 points on the Centre for Epidemiological Studies – Depression (CES-D) scale. Several alcohol related measures were derived using responses from the graduated frequency questionnaire. Binge drinking was defined at several sex-specific thresholds (ranging from 60+ to 140+ g of ethanol) and two frequencies (at least monthly or weekly). Total annual alcohol intake in grams was also extracted. Problem drinking was defined as ≥2 positive answers on the CAGE questionnaire.

Results

Problem drinking was consistently associated with approximately a 2-fold increase in odds of depressive symptoms across all countries and in both sexes. Abstaining from alcohol was typically associated with increased odds of depressive symptoms. Analyses separating lifelong abstainers and former drinkers in the Russian cohort revealed that this increased odds was driven by former drinkers. Amongst men, heavy frequent binge drinking was associated with increased odds of depressive symptoms in the Czech Republic and Poland. In women, heavy infrequent binge drinking was associated with increased odds of depressive symptoms in Russia and Poland. Only in Polish men was higher annual volume of alcohol intake associated with increased odds of depressive symptoms.

Conclusion

Abstaining from alcohol and problem drinking were associated with increased odds of depressive symptoms in these Eastern European populations. Annual volume of alcohol intake as well as frequency and amount of alcohol consumed in a binge drinking session were less consistently associated with depressive symptoms.     

Idiopathic pulmonary fibrosis: new insights in its pathogenesis

Idiopathic pulmonary fibrosis (IPF) is a unique type of chronic fibrosing lung disease of unknown etiology. The sequence of the pathogenic mechanisms is unknown, but the disease is characterized by epithelial injury and activation, the formation of distinctive subepithelial fibroblast/myofibroblast foci, and excessive extracellular matrix accumulation. These pathological processes usually lead to progressive and irreversible changes in the lung architecture resulting in progressive respiratory insufficiency and an almost universally terminal outcome in a relatively short period of time. While research has largely focused on inflammatory mechanisms for initiating the fibrotic response, recent evidence strongly suggests that disruption of the alveolar epithelium is an underlying pathogenic event. Although treatment to date has proved largely ineffective, this new approach has opened up several promising therapeutic avenues.