Long-term exposure to solar ultraviolet radiation as a risk factor for age-related macular degeneration

A clinical epidemiological study has been conducted as apart of research project investigating chronic exposure to solar ultraviolet radiation (UVR) as a factor contributing to the onset of age-related macular degeneration (ARMD). The study included 623 subjects older than 50 from two different geographic areas, one with high solar radiation (the island of Solta - Region 1) and the other (Zagreb and its surroundings - Region 2) with low solar radiation. Individual exposure to UVR was assessed according to global exposure to sunlight, on the basis detailed history of life-long exposure to sunlight, with special reference to professional history and geophysical specificities of the respective areas. Different grades of ARMD were based on the fundus photographs and flourescein angiography. Statistically significant relation was found between ARMD and mean daily exposure (in hours) to solar radiation in Region 1 (chi2 = 186.22; p = 0.000), Region 2 (chi2 = 25.66; p = 0.000) and in both regions together (chi2 = 216.43; p = 0.000). ARMD is more frequent in the subjects belonging to the Region 1 and with the same exposure to sunlight (8 hours and more) which goes in favor of their increased UVR exposure. The results support a relationship between long-term sunlight exposure and increased risk of ARMD.     

Sequencing and G-Quadruplex Folding of the Canine Proto-Oncogene KIT Promoter Region: Might Dog Be Used as a Model for Human Disease?

Downregulation of gene expression by induction of non-canonical DNA structures at promotorial level is a novel attractive anticancer strategy. In human, two guanine-rich sequences (h_kit1 and h_kit2) were identified in the promotorial region of oncogene KIT. Their stabilization into G-quadruplex structures can find applications in the treatment of leukemias, mastocytosis, gastrointestinal stromal tumor, and lung carcinomas which are often associated to c-kit mis-regulation. Also the most common skin cancer in domestic dog, mast cell tumor, is linked to a mutation and/or to an over-expression of c-kit, thus supporting dog as an excellent animal model. In order to assess if the G-quadruplex mediated mechanism of regulation of c-kit expression is conserved among the two species, herein we cloned and sequenced the canine KIT promoter region and we compared it with the human one in terms of sequence and conformational equilibria in physiologically relevant conditions. Our results evidenced a general conserved promotorial sequence between the two species. As experimentally confirmed, this grants that the conformational features of the canine kit1 sequence are substantially shared with the human one. Conversely, two isoforms of the kit2 sequences were identified in the analyzed dog population. In comparison with the human counterpart, both of them showed an altered distribution among several folded conformations.     

Genetic structure of a group of capybaras, Hydrochoerus hydrochaeris (Rodentia: Hydrocheridae) in the Colombian Eastern Llanos

The capybaras are the biggest rodents in the world but, however, there are not extensive population genetics studies on them. In the current work, we studied the genetic structure of a troop of 31 capybaras (Hydrochoerus hydrochaeris) sampled in Hato Corozal, Casanare Department at the Colombian Eastern Llanos, by means of five microsatellite markers. The gene diversity was 0.61 and the average allele number was 5.2, which is a medium-low level for markers of this nature. Out five markers employed, three were in Hardy-Weinberg equilibrium meanwhile one showed a significant homozygote excess and other presented a significant heterozygote excess. There were not significant genetic differences between males and females inside this troop. The application of different procedures to determine possible historical demographic changes (population expansions or bottlenecks) clearly showed that the population analyzed crossed over a very narrow recent bottleneck. The illegal hunt is the possibly cause of this strong genetic bottleneck.     

AMPK phosphorylation of raptor mediates a metabolic checkpoint

AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.     

Rat inositol 1,4,5-trisphosphate receptor isoform 2 interacts with itself in its C-terminal portion and upstream of the first transmembrane domain.

In response to stimulation at the plasma membrane, hepatocellular Ca(2+) signals are fast and precise and lead to rapid local changes in cytoplasmic free Ca(2+) concentration. These changes result from the opening of the inositol 1,4,5-trisphosphate receptor (InsP(3)R), which is a four-subunit intracellular InsP(3)-gated channel that releases Ca(2+) from the stores. To investigate the molecular mechanism underlying interactions between the InsP(3)R subunits, we cloned the predominant hepatocellular isoform, InsP(3)R isoform 2 (InsP(3)R2), and screened for interactions using the yeast two-hybrid assay. We found that the C-terminal domain of rat InsP(3)R2 interacts with itself, and that the cytoplasmic part preceding the first transmembrane domain, a region near a Ca(2+)-binding site, also interacts with itself. These interactions were confirmed by pull-down experiments. The C-terminal domain of InsP(3)R2 is also able to interact with the C-termini of rat InsP(3)R1 and InsP(3)R3. These results advance our understanding of the molecular mechanisms that underlie the oligomerization and interactions of the InsP(3)R subunits during the opening/closing of the Ca(2+) channel.