Lipoprotein genotype and conserved pathway for exceptional longevity in humans

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans.     

Role of protein-tyrosine phosphatase SHP2 in focal adhesion kinase down-regulation during neutrophil cathepsin G-induced cardiomyocytes anoikis

Inflammatory cells and their proteases contribute to tissue reparation at site of inflammation. Although beneficial at early stages, excessive inflammatory reaction leads to cell death and tissue damage. Cathepsin G (Cat.G), a neutrophil-derived serine protease, has been shown to induce neonatal rat cardiomyocyte detachment and apoptosis by anoikis through caspase-3 dependent pathway. However the early mechanisms that trigger Cat.G-induced caspase-3 activation are not known. This study identifies focal adhesion kinase (FAK) tyrosine dephosphorylation as an early mechanism that regulates Cat.G-induced anoikis in cardiomyocytes. Both FAK tyrosine phosphorylation at Tyr-397 and kinase activity decrease rapidly upon Cat.G treatment and was associated with a decrease of FAK association with adapter and cytoskeletal proteins, p130(Cas) and paxillin, respectively. FAK-decreased tyrosine phosphorylation is required for Cat.G-induced myocyte anoikis as concurrent expression of phosphorylation-deficient FAK mutated at Tyr-397 or pretreatment with a protein-tyrosine phosphatase (PTP) inhibitor, pervanadate, blocks Cat.G-induced FAK tyrosine dephosphorylation, caspase-3 activation and DNA fragmentation. Analysis of PTPs activation shows that Cat.G treatment induces an increase of SHP2 and PTEN phosphorylation; however, only SHP2 forms a complex with FAK in response to Cat.G. Expression of dominant negative SHP2 mutant markedly attenuates FAK tyrosine dephosphorylation induced by Cat.G and protects myocytes to undergo apoptosis. In contrast, increased SHP2 expression exacerbates Cat.G-induced FAK tyrosine dephosphorylation and myocyte apoptosis. Taken together, these results show that Cat.G induces SHP2 activation that leads to FAK tyrosine dephosphorylation and promotes cardiomyocyte anoikis.     

Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases

When appended to the epidermal growth factor receptor (EGFR), ubiquitin serves as a sorting signal for lysosomal degradation. Here we demonstrate that the ubiquitin ligase of EGFR, namely c-Cbl, also mediates receptor modification with the ubiquitin-like molecule Nedd8. EGF stimulates receptor neddylation, which enhances subsequent ubiquitylation, as well as sorting of EGFR for degradation. Multiple lysine residues, located within the tyrosine kinase domain of EGFR, serve as attachment sites for Nedd8. A set of clathrin coat-associated binders of ubiquitin also bind Nedd8, but they undergo ubiquitylation, not neddylation. We discuss the emerging versatility of the concerted action of ubiquitylation and neddylation in the process that desensitizes growth factor-activated receptor tyrosine kinases.     

Mating factor linkage and genome evolution in basidiomycetous pathogens of cereals

Sex in basidiomycete fungi is controlled by tetrapolar mating systems in which two unlinked gene complexes determine up to thousands of mating specificities, or by bipolar systems in which a single locus (MAT) specifies different sexes. The genus Ustilago contains bipolar (Ustilago hordei) and tetrapolar (Ustilago maydis) species and sexual development is associated with infection of cereal hosts. The U. hordei MAT-1 locus is unusually large (approximately 500 kb) and recombination is suppressed in this region. We mapped the genome of U. hordei and sequenced the MAT-1 region to allow a comparison with mating-type regions in U. maydis. Additionally the rDNA cluster in the U. hordei genome was identified and characterized. At MAT-1, we found 47 genes along with a striking accumulation of retrotransposons and repetitive DNA; the latter features were notably absent from the corresponding U. maydis regions. The tetrapolar mating system may be ancestral and differences in pathogenic life style and potential for inbreeding may have contributed to genome evolution.     

Genome assembly of bell pepper endornavirus from small RNA

The family Endornaviridae infects diverse hosts, including plants, fungi, and oomycetes. Here we report for the first time the assembly of bell pepper endornavirus by next-generation sequencing of viral small RNA. Such a population of small RNA indicates the activation of the viral immunity silencing machinery by this cryptic virus, which probably encodes a novel silencing suppressor.     

Presence and persistence of Salmonella enterica serotype typhimurium in the phyllosphere and rhizosphere of spray-irrigated parsley

Salmonella enterica is one of the major food-borne pathogens associated with ready-to-eat fresh foods. Although polluted water might be a significant source of contamination in the field, factors that influence the transfer of Salmonella from water to the crops are not well understood, especially under conditions of low pathogen levels in water. The aim of this study was to investigate the short- and long-term (1 h to 28 days) persistence of Salmonella enterica serotype Typhimurium in the phyllosphere and the rhizosphere of parsley following spray irrigation with contaminated water. Plate counting and quantitative real-time PCR (qRT-PCR)-based methods were implemented for the quantification. By applying qRT-PCR with enrichment, we were able to show that even irrigation with water containing as little as ～300 CFU/ml resulted in the persistence of S. Typhimurium on the plants for 48 h. Irrigation with water containing 8.5 log CFU/ml resulted in persistence of the bacteria in the phyllosphere and the rhizosphere for at least 4 weeks, but the population steadily declined with a major reduction in bacterial counts, of ～2 log CFU/g, during the first 2 days. Higher levels of Salmonella were detected in the phyllosphere when plants were irrigated during the night compared to irrigation during the morning and during winter compared to the other seasons. Further elucidation of the mechanisms underlying the transfer of Salmonella from contaminated water to crops, as well as its persistence over time, will enable the implementation of effective irrigation and control strategies.     

Earliest record of Platychoerops (Primates,Plesiadapidae), a new species from Mouras Quarry,Mont de Berru,France

Plesiadapids are extinct relatives of extant euarchontans (primates, dermopterans, and scandentians), which lived in North America and Europe during the Paleocene and Early Eocene. The only genus of plesiadapid whose species are absent from Paleocene strata is Platychoerops. Further, Platychoerops is the only group found in sediments post‐dating the Paleocene‐Eocene boundary (PEB) by a substantial period of time based on large samples. It is also substantially different from other plesiadapids in dental features thought to reflect ecology. Its evolution has been linked to the rapid global climate change and faunal turnover marking the PEB. Platychoerops and Plesiadapis tricuspidens have been reconstructed as members of a single lineage by some authors. We describe a specimen (right p3‐m3) that we attribute to a new species, Platychoeropsantiquus, from the unequivocally Paleocene (MP6) Mouras Quarry of Mont de Berru, France. It has strong morphological affinities to Platychoerops daubrei yet co‐occurs with many specimens of Plesiadapis tricuspidens, as well as the plesiadapid Chiromyoides campanicus. The existence of a species of Platychoerops prior to the PEB decouples the evolution of Platychoerops from the climate change and faunal turnover event associated with the PEB. Furthermore, the co‐occurrence of Platychoerops with P. tricuspidens refutes the idea of a single lineage for these taxa. Instead, Platychoerops may be more closely related to North American Plesiadapis cookei (a previous alternate hypothesis). We suggest character displacement in a Paleocene immigrant population of P. cookei resulting from competition with sympatric P. tricuspidens, as a likely scenario for the evolution of Platychoerops. Am J Phys Anthropol, 2012. © 2012 Wiley Periodicals, Inc.     

Backbone and side chain NMR assignments for the intrinsically disordered cytoplasmic domain of human neuroligin-3

Neuroligins act as heterophilic adhesion molecules at neuronal synapses. Their cytoplasmic domains interact with synaptic scaffolding proteins, and have been shown to be intrinsically disordered. Here we report the backbone and side chain ¹H, ¹³C and ¹⁵N resonance assignments for the cytoplasmic domain of human neuroligin 3.