Synthesis of fucose derivatives with thiol motifs towards suicide inhibition of helicobacter pylori

The syntheses of six thiol-exhibiting monosaccharides towards suicide inhibition of Helicobacter pylori are reported. Blood group Antigen Binding Adhesin (BabA), a bacterial membrane-bound lectin, binds to human ABO and Lewis b blood group structures displayed on the surface of host epithelial cells. Crystal structures of the carbohydrate-recognition domain revealed a conserved disulfide bonded loop that anchors a critical fucose residue in these blood group structures. Disruption of this loop by N-acetylcysteine results in reduced BabA-mediated adherence to human gastric tissue sections and attenuated virulence in Lewis b-expressing transgenic mice. With a view of creating specific inhibitors of the lectin, we designed and successfully synthesised six fucose-derived compounds with thiol motifs to engage in a thiol-disulfide exchange with this disulfide bond of BabA and form a glycan-lectin disulfide linkage. Branching and extending the fucose backbone with 2- and 3-carbon thiol motifs delivered a range of candidates to be tested for biological activity against BabA

Simulation Modeling of Population Expansion for Introduced Mountain Goats in the Olympic Mountains of Washington State

Mountain goats (Oreamnos americanus) are not native to the Olympic Peninsula as they are to other regions of Washington State. A total of eleven or twelve animals were translocated from Alaska and British Columbia between 1925 and 1929 then released in the foothills of Mount Storm King. By 1970 these founding goats had colonized the entire Olympic range and concerns about the management of this introduced species developed as damage to alpine soil and vegetation was noted. An aerial census of the Olympic range conducted in July 1983 estimated the mountain goat population at 1,175 (95% CI 840 – 1510). A series of removals reduced the population to 389 (95% CI 181 – 597) goats by 1990, with a period of stasis occurring during the following decade. The most recent two aerial surveys (2011 and 2016) indicate positive growth, and a variety of efforts to mitigate damage to fragile alpine ecosystems are again under consideration. I parameterized an existing population model, CDPOP, for use with mountain goats. CDPOP is a simulation program that uses individual-based movement (including dispersal), reproduction, and mortality to predict the influence of landscape heterogeneity on population dynamics and genetic exchange. Population parameters for the model were derived from published literature. I successfully calibrated the model and simulated the population trajectory for Olympic mountain goats from establishment through the 1983 census. Modeled population dispersal closely tracked anecdotal reports of dispersal. However, observed heterozygosity for the modeled population did not align with previous research. I suspect genetic diversity for the true founding goats was not as great as that of the individuals used to initialize the model. Sensitivity analyses showed that changes in annual reproductive rate had the greatest influence on population trajectories, followed by juvenile mortality and v adult female mortality, respectively. These findings differ from those in two related studies, likely due to the early primiparity within the modeled population. I validated the model by simulating the period from 1990 to 2016. The modeled population showed that approximately 75% to 80% of the total animals removed during the 1980’s needed to be female in order for the observed population stasis to occur. Finally, I discuss avenues for future model development and applications. This model could be utilized to inform current management decisions regarding the impact of removals from the Olympic mountain goat population and proposals to use these animals to augment reduced native populations in the Cascade Mountain Range

A detailed picture of a protein–carbohydrate hydrogen-bonding network revealed by NMR and MD simulations

Cyanovirin-N (CV-N) is a cyanobacterial lectin with antiviral activity towards HIV and several other viruses. Here, we identify mannoside hydroxyl protons that are hydrogen bonded to the protein backbone of the CV-N domain B binding site, using NMR spectroscopy. For the two carbohydrate ligands Manα(1→2)ManαOMe and Manα(1→2) Manα(1→6)ManαOMe five hydroxyl protons are involved in hydrogen-bonding networks. Comparison with previous crystallographic results revealed that four of these hydroxyl protons donate hydrogen bonds to protein backbone carbonyl oxygens in solution and in the crystal. Hydrogen bonds were not detected between the side chains of Glu41 and Arg76 with sugar hydroxyls, as previously proposed for CV-N binding of mannosides. Molecular dynamics simulations of the CV-N/Manα(1→2)Manα(1→6)ManαOMe complex confirmed the NMR-determined hydrogen-bonding network. Detailed characterization of CV-N/mannoside complexes provides a better understanding of lectin-carbohydrate interactions and opens up to the use of CV-N and similar lectins as antiviral agents

Cryptococcus neoformans capsular GXM conformation and epitope presentation: a molecular modelling study

The pathogenic encapsulated Cryptococcus neoformans fungus causes serious disease in immunosuppressed hosts. The capsule, a key virulence factor, consists primarily of the glucuronoxylomannan polysaccharide (GXM) that varies in composition according to serotype. While GXM is a potential vaccine target, vaccine development has been confounded by the existence of epitopes that elicit non-protective antibodies. Although there is evidence for protective antibodies binding conformational epitopes, the secondary structure of GXM remains an unsolved problem. Here an array of molecular dynamics simulations reveal that the GXM mannan backbone is consistently extended and relatively inflexible in both C. neoformans serotypes A and D. Backbone substitution does not alter the secondary structure, but rather adds structural motifs: bDGlcA and bDXyl side chains decorate the mannan backbone in two hydrophillic fringes, with mannose-6-O-acetylation forming a hydrophobic ridge between them. This work provides mechanistic rationales for clinical observations—the importance of O-acetylation for antibody binding; the lack of binding of protective antibodies to short GXM fragments; the existence of epitopes that elicit non-protective antibodies; and the self-aggregation of GXM chains—indicating that molecular modelling can play a role in the rational design of conjugate vaccines

Evidence for Concurrent Effects of Exposure to Environmental Cadmium and Lead on Hepatic CYP2A6 Phenotype and Renal Function Biomarkers in Nonsmokers

We examined the interrelationships between phenotype of hepatic cytochrome P450 2A6 (CYP2A6), nephropathy, and exposure to cadmium and lead in a group of 118 healthy Thai men and women who had never smoked. Their urinary Cd excretion ranged from 0.05 to 2.36 μg/g creatinine, whereas their urinary Pb excretion ranged from 0.1 to 12 μg/g creatinine. Average age and Cd burden of women and men did not differ. Women, however, on average showed a 46% higher urinary Pb excretion (p < 0.001) and lower zinc status, suggested by lower average serum Zn and urinary Zn excretion compared with those in men. Cd-linked nephropathy was detected in both men and women. However, Pb-linked nephropathy was seen only in women, possibly because of higher Pb burden coupled with lower protective factors, notably of Zn (p < 0.001), in women compared with men. In men, Pb burden showed a negative association with CYP2A6 activity (adjusted β= −0.29, p = 0.003), whereas Cd burden showed a positive association with CYP2A6 activity (adjusted β= 0.38, p = 0.001), suggesting opposing effects of Cd and Pb on hepatic CYP2A6 phenotype. The weaker correlation between Cd burden CYP2A6 activity in women despite similarity in Cd burden between men and women is consistent with opposing effects of Pb and Cd on hepatic CYP2A6 phenotypic expression. A positive correlation between Cd-linked nephropathy (urinary N-acetyl-β-d-glucosaminidase excretion) and CYP2A6 activity in men (r = 0.39, p = 0.002) and women (r = 0.37, p = 0.001) suggests that Cd induction of hepatic CYP2A6 expression and Cd-linked nephropathy occurred simultaneously

Dissociation constants and thermodynamic properties of amino acids used in CO2 absorption from (293 to 353) K

The second dissociation constants of the amino acids βalanine, taurine, sarcosine, 6-aminohexanoic acid, DL-methionine, glycine, L-phenylalanine, and L-proline and the third dissociation constants of L-glutamic acid and L-aspartic acid have been determined from electromotive force measurements at temperatures from (293 to 353) K. Experimental results are reported and compared to literature values. Values of the standard state thermodynamic properties are derived from the experimental results and compared to the values of commercially available amines used as absorbents for CO 2 capture.

Willingness to pay for municipality hospital services in rural Japan: a contingent valuation study

<p>Abstract</p> <p>Background</p> <p>The Japanese healthcare system has undergone reforms to address the struggles that municipality hospitals face. Reform guidelines clearly define criteria for administrative improvement. However, criteria to evaluate the demand for healthcare provisions in rural Japan, including the needs of rural residents for municipality hospitals in particular have not been specified. The purpose of this paper is to measure residents' willingness to pay (WTP) for municipality hospital services using the contingent valuation method, and to evaluate municipality hospital valuation on the basis of WTP. K town, located in the Hokkaido prefecture of Japan, was selected as the location for this study. Participants were recruited by a town hall healthcare administrator, hospital and clinic staff, and a local dentist. Participants were asked what amount they would be willing to pay as taxes to continue accessing the services of the municipality hospital for one year by using open-ended questions in face-to-face interviews.</p> <p>Findings</p> <p>Forty-eight residents were initially recruited, and 40 participants were selected for the study (response rate 83%). As compared to K town's population, this data slanted toward the elderly, although there was no significant difference in frequency among the characteristics. The median WTP was estimated at 39,484 yen ($438.71), with a 95$308.95-615.96). Logistic regression revealed no significant factors affecting WTP.</p> <p>Conclusions</p> <p>If the total amount of residents' WTP for the municipality hospital were to be estimated by this result, it would calculate with 129,586,000 yen ($1,439,844). This is approximately equal to the amount of money to be transferred from the general account of the government of K town, more than one-half of the town tax of K town, and about two-fold in comparison to Japan as a whole. This showed that K town's residents placed a high valuation on the municipality hospital, which nearly equalled the amount that the K town government provided to the municipality hospital to cover its annual deficit. K town residents had come to expect not only general clinical practice, but also emergency medical services and night practice provided by their own town's municipality hospital. WTP can be used as a measure of hospital evaluation because it reflects the importance of the hospital to the residents in its region.</p