Novel Allosteric Sites on Ras for Lead Generation

Aberrant Ras activity is a hallmark of diverse cancers and developmental diseases. Unfortunately, conventional efforts to develop effective small molecule Ras inhibitors have met with limited success. We have developed a novel multi-level computational approach to discover potential inhibitors of previously uncharacterized allosteric sites. Our approach couples bioinformatics analysis, advanced molecular simulations, ensemble docking and initial experimental testing of potential inhibitors. Molecular dynamics simulation highlighted conserved allosteric coupling of the nucleotide-binding switch region with distal regions, including loop 7 and helix 5. Bioinformatics methods identified novel transient small molecule binding pockets close to these regions and in the vicinity of the conformationally responsive switch region. Candidate binders for these pockets were selected through ensemble docking of ZINC and NCI compound libraries. Finally, cell-based assays confirmed our hypothesis that the chosen binders can inhibit the downstream signaling activity of Ras. We thus propose that the predicted allosteric sites are viable targets for the development and optimization of new drugs

Relation between oral health and nutritional condition in the elderly

Oral health is a prerequisite for a good chewing function, which may have an impact on food choices and nutritional well-being. OBJECTIVE: This study was designed to evaluate the relationship between oral health status and nutritional status in the elderly. MATERIAL AND METHODS: In this cross-sectional study, 33 elderly people from the Group for the Elderly Interdisciplinary Geriatrics and Gerontology Program, at Fluminense Federal University, Niteroi, RJ, Brazil, completed a questionnaire to collect information on socioeconomic status, eating habits, physical activity and health habits, undertook a clinical oral examination, blood test, and anthropometric measurements, and were allocated into groups according to age. The oral health status was assessed using the index for decayed, missing and filled teeth (DMFT). The nutritional status was assessed using hemoglobin, hematocrit and albumin concentrations in blood, anthropometric values and the body mass index. RESULTS: Tooth loss was the biggest nuisance to the elderly subjects (57.6%), followed by the use of dentures (30.3%) and ill-fitting dentures (33.3%). 66.6% of patients had difficulty in chewing, and 54.5% reported this to be due to prostheses and 13.6% to the absence of teeth. A significant correlation was found between DMFT and the value of suprailiac skinfold thickness (rho=0.380, p=0.029). CONCLUSION: The results support the temporal association between tooth loss and detrimental changes in anthropometry, which could contribute to increased risk of developing chronic diseases

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

Experimental Study on Sediment Supply-Limited Bedforms in a Coastal Context

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