Mechanistic insight into the sensing of nitroaromatic compounds by metal-organic frameworks

There has been extensive research on the sensing of explosive nitroaromatic compounds (NACs) using fluorescent metal-organic frameworks (MOFs). However, ambiguity in the sensing mechanism has hampered the development of efficient explosive sensors. Here we report the synthesis of a hydroxyl-functionalized MOF for rapid and efficient sensing of NACs and examine in detail its fluorescence quenching mechanisms. In chloroform, quenching takes place primarily by exciton migration to the ground-state complex formed between the MOF and the analytes. A combination of hydrogen-bonding interactions and ??????? stacking interactions are responsible for fluorescence quenching, and this observation is supported by single-crystal structures. In water, the quenching mechanism shifts toward resonance energy transfer and photo-induced electron transfer, after exciton migration as in chloroform. This study provides insight into florescence-quenching mechanisms for the selective sensing of NACs and reduces the ambiguity regarding the nature of interactions between the MOF and NACs

Description and validation of a Markov model of survival for individuals free of cardiovascular disease that uses Framingham risk factors

BACKGROUND: Estimation of cardiovascular disease risk is increasingly used to inform decisions on interventions, such as the use of antihypertensives and statins, or to communicate the risks of smoking. Crude 10-year cardiovascular disease risk risks may not give a realistic view of the likely impact of an intervention over a lifetime and will underestimate of the risks of smoking. A validated model of survival to act as a decision aid in the consultation may help to address these problems. This study aims to describe the development of such a model for use with people free of cardiovascular disease and evaluates its accuracy against data from a United Kingdom cohort. METHODS: A Markov cycle tree evaluated using cohort simulation was developed utilizing Framingham estimates of cardiovascular risk, 1998 United Kingdom mortality data, the relative risk for smoking related non-cardiovascular disease risk and changes in systolic blood pressure and serum total cholesterol total cholesterol with age. The model's estimates of survival at 20 years for 1391 members of the Whickham survey cohort between the ages of 35 and 65 were compared with the observed survival at 20-year follow-up. RESULTS: The model estimate for survival was 75% and the observed survival was 75.4%. The correlation between estimated and observed survival was 0.933 over 39 subgroups of the cohort stratified by estimated survival, 0.992 for the seven 5-year age bands from 35 to 64, 0.936 for the ten 10 mmHg systolic blood pressure bands between 100 mmHg and 200 mmHg, and 0.693 for the fifteen 0.5 mmol/l total cholesterol bands between 3.0 and 10.0 mmol/l. The model significantly underestimated mortality in those people with a systolic blood pressure greater than or equal to 180 mmHg (p = 0.006). The average gain in life expectancy from the elimination of cardiovascular disease risk as a cause of death was 4.0 years for all the 35 year-old men in the sample (n = 24), and 1.8 years for all the 35 year-old women in the sample (n = 32). CONCLUSIONS: This model accurately estimates 20-year survival in subjects from the Whickham cohort with a systolic blood pressure below 180 mmHg

Embryology and bony malformations of the craniovertebral junction

BACKGROUND: The embryology of the bony craniovertebral junction (CVJ) is reviewed with the purpose of explaining the genesis and unusual configurations of the numerous congenital malformations in this region. Functionally, the bony CVJ can be divided into a central pillar consisting of the basiocciput and dental pivot and a two-tiered ring revolving round the central pivot, comprising the foramen magnum rim and occipital condyles above and the atlantal ring below. Embryologically, the central pillar and the surrounding rings descend from different primordia, and accordingly, developmental anomalies at the CVJ can also be segregated into those affecting the central pillar and those affecting the surrounding rings, respectively. DISCUSSION: A logical classification of this seemingly unwieldy group of malformations is thus possible based on their ontogenetic lineage, morbid anatomy, and clinical relevance. Representative examples of the main constituents of this classification scheme are given, and their surgical treatments are selectively discussed

Evolution of Salmonella enterica Virulence via Point Mutations in the Fimbrial Adhesin

Whereas the majority of pathogenic Salmonella serovars are capable of infecting many different animal species, typically producing a self-limited gastroenteritis, serovars with narrow host-specificity exhibit increased virulence and their infections frequently result in fatal systemic diseases. In our study, a genetic and functional analysis of the mannose-specific type 1 fimbrial adhesin FimH from a variety of serovars of Salmonella enterica revealed that specific mutant variants of FimH are common in host-adapted (systemically invasive) serovars. We have found that while the low-binding shear-dependent phenotype of the adhesin is preserved in broad host-range (usually systemically non-invasive) Salmonella, the majority of host-adapted serovars express FimH variants with one of two alternative phenotypes: a significantly increased binding to mannose (as in S. Typhi, S. Paratyphi C, S. Dublin and some isolates of S. Choleraesuis), or complete loss of the mannose-binding activity (as in S. Paratyphi B, S. Choleraesuis and S. Gallinarum). The functional diversification of FimH in host-adapted Salmonella results from recently acquired structural mutations. Many of the mutations are of a convergent nature indicative of strong positive selection. The high-binding phenotype of FimH that leads to increased bacterial adhesiveness to and invasiveness of epithelial cells and macrophages usually precedes acquisition of the non-binding phenotype. Collectively these observations suggest that activation or inactivation of mannose-specific adhesive properties in different systemically invasive serovars of Salmonella reflects their dynamic trajectories of adaptation to a life style in specific hosts. In conclusion, our study demonstrates that point mutations are the target of positive selection and, in addition to horizontal gene transfer and genome degradation events, can contribute to the differential pathoadaptive evolution of Salmonella

Antioxidant supplementation enhances erythrocyte antioxidant status and attenuates cyclosporine-induced vascular dysfunction

The aim of this study was to determine the effects of dietary antioxidant supplementation with a-tocopherol and a-lipoic acid on cyclosporine induced alterations to erythrocyte and plasma redox balance, and cyclosporine-induced endothelial and smooth muscle dysfunction. Rats were randomly assignedto either control, antioxidant, cyclosporine or cyclosporine + antioxidant treatments. Cyclosporine A was administered for 10 days after an 8-week feeding period. Plasma was analyzed for a-tocopherol, total antioxidant capacity, malondialdehyde and creatinine. Erythrocytes were analyzed for glutathione, methemoglobin, superoxide dismutase, catalase, glutathione peroxidase, glucose-6-phosphate dehydrogenase, a-tocopherol and malondialdehye. Vascular endothelial and smooth muscle function was determined in vitro. Antioxidant supplementation resulted in significant increases in erythrocyte a-tocopherol concentration and glutathione peroxidase activity in both of the antioxidant-supplemented groups. Cyclosporine administration caused significant decreases in glutathione concentration, methemoglobin concentration and superoxide dismutase activity. Antioxidant supplementation attenuated the cyclosporine-induced decrease in superoxide dismutase activity. Cyclosporine therapy impaired both endothelium-independent and -dependent relaxation of the thoracic aorta, and this was attenuated by antioxidant supplementation. In summary, dietary supplementation with a-tocopherol and a -lipoic acid attenuated the cyclosporine-induced decrease in erythrocyte superoxide dismutase activity and attenuated cyclosporine-induced vascular dysfunction