Murine model of dextran sulfate sodium-induced colitis reveals Candida glabrata virulence and contribution of β-mannosyltransferases

Candida glabrata, like Candida albicans, is an opportunistic yeast pathogen that has adapted to colonize all segments of the human gastrointestinal tract and vagina. The C. albicans cell wall expresses β-1,2-linked mannosides (β-Mans), promoting its adherence to host cells and tissues. Because β-Mans are also present in C. glabrata, their role in C. glabrata colonization and virulence was investigated in a murine model of dextran sulfate sodium (DSS)-induced colitis. Five clustered genes of C. glabrata encoding β-mannosyltransferases, BMT2-BMT6, were deleted simultaneously. β-Man expression was studied by Western blotting, flow cytometry, and NMR analysis. Mortality, clinical, histologic, and colonization scores were determined in mice receiving DSS and different C. glabrata strains. The results show that C. glabrata bmt2-6 strains had a significant reduction in β-1,2-Man expression and a disappearance of β-1,2-mannobiose in the acid-stable domain. A single gavage of C. glabrata wild-type strain in mice with DSS-induced colitis caused a loss of body weight, colonic inflammation, and mortality. Mice receiving C. glabrata bmt2-6 mutant strains had normal body weight and reduced colonic inflammation. Lower numbers of colonies of C. glabrata bmt2-6 were recovered from stools and different parts of the gastrointestinal tract. Histopathologic examination revealed that the wild-type strain had a greater ability to colonize tissue and cause tissue damage. These results showed that C. glabrata has a high pathogenic potential in DSS-induced colitis, where β-Mans contribute to colonization and virulence.     

Face recognition: lessons from a wasp

The golden paper wasp is a social insect whose colony members have the remarkable ability to recognise each others' faces. New research shows that this species is singularly skilled at learning about faces, opening interesting perspectives on convergent evolution of specialist cognitive abilities in insects and vertebrates.     

Relevance of exocytotic glutamate release from retinal glia

Glial cells release molecules that influence brain?development, function, and disease. Calcium-dependent exocytosis has been proposed as potential release mechanism in astroglia, but the physiological relevance of "gliotransmission" in?vivo remains controversial. We focused on the impact of glial exocytosis on sensory transduction in the retina.?To this end, we generated transgenic mice to block exocytosis by Cre recombinase-dependent expression of the clostridial botulinum neurotoxin serotype?B light chain, which cleaves vesicle-associated membrane protein 1-3. Ubiquitous and neuronal toxin expression caused perinatal lethality and?a reduction of synaptic transmission thus validating transgene function. Toxin expression in Müller cells inhibited vesicular glutamate release and impaired glial volume regulation but left retinal histology and visual processing unaffected. Our model to study gliotransmission in?vivo reveals specific functions of exocytotic glutamate release in retinal glia.     

Sequence variant (CTAGGG)n in the human telomere favors a G-quadruplex structure containing a G·C·G·C tetrad

Short contiguous arrays of variant CTAGGG repeats in the human telomere are unstable in the male germline and somatic cells, suggesting formation of unusual structures by this repeat type. Here, we report on the structure of an intramolecular G-quadruplex formed by DNA sequences containing four human telomeric variant CTAGGG repeats in potassium solution. Our results reveal a new robust antiparallel G-quadruplex fold involving two G-tetrads sandwiched between a G·C base pair and a G·C·G·C tetrad, which could represent a new platform for drug design targeted to human telomeric DNA.     

2,6-Diphenylthiazolo[3,2-b][1,2,4]triazoles as telomeric G-quadruplex stabilizers

The design and synthesis of 2,6-diphenylthiazolo[3,2-b][1,2,4]triazoles characterized by a large aromatic building block bearing cationic side chains are reported. These molecules are evaluated as telomeric G-quadruplex stabilizers and for their selectivity towards duplex DNA by competition experiments. Two compounds (14a, 19) were found active with high selectivity for telomeric G-quadruplex over duplex DNA.     

The endocannabinoid system: Its roles in energy balance and potential as a target for obesity treatment

Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.     

Proteomic characterization of the effects of clofibrate on protein expression in rat liver

Clofibrate is a peroxisome proliferator known to induce liver tumours in rats. A proteomics study was conducted to provide new insights into the molecular mechanisms of clofibrate-induced non-genotoxic hepatocarcinogenesis. Rats were treated with 250 mg/kg day clofibrate orally and sacrificed after 7 days. Proteins extracted from the liver were analysed by 2-DE using DIGE technology. The protein identification performed by MS showed that clofibrate induced up-regulation of 77 proteins and down-regulation of 27 proteins. The highest expression ratios corresponded to proteins involved in a series of biochemical pathways such as lipid metabolism, fatty acid metabolism, amino acid metabolism, protein metabolism, citric acid cycle, xenobiotic detoxification and oxidative stress. Proteins implicated in cell proliferation and apoptosis, such as prohibitin, 10-formyl tetrahydrofolate dehydrogenase, senescence marker protein-30, pyridoxine 5'-phosphate oxidase and vimentin, were also identified as being regulated. These results provide leads for further investigations into the molecular mechanisms of liver tumours induced by clofibrate. In addition, MS results showed that a series of regulated proteins were detected as several spots corresponding to different pI and/or M(r). Differential effects on those variants could result from specific PTM and could be a specific molecular signature of the clofibrate-induced protein expression modulation in rat liver.