Conformational effects on the pro-S hydrogen abstraction reaction in cyclooxygenase-1: an integrated QM/MM and MD study

A key step in the cyclooxygenase reaction cycle of cyclooxygenase 1 (COX-1) is abstraction of the pro-S hydrogen atom of the arachidonic acid by a radical that is formed at the protein residue Tyr-385. Here we investigate this reaction step by a quantum-mechanics/molecular-mechanics approach in combination with molecular-dynamics simulations. The simulations identify the hydrogen abstraction angle as a crucial geometric determinant of the reaction, thus revealing the importance of the cyclooxygenase active site for calculating the potential energy surface of the reaction

Can uptake length in strams be determined by nutrient addition experiments? Results from an interbiome comparison study

Nutrient uptake length is an important parnmeter tor quantifying nutrient cycling in streams. Although nutrient tracer additions are the preierred method for measuring uptake length under ambient nutrient concentrations, short-term nutrient addition experiments have more irequently been used to estimate uptake length in streams. Theoretical analysis of the relationship between uptake length determined by nutrient addition experiments (Sw\u27) and uptake length determined by tracer additions (Sw)predicted that Sw\u27 should be consistently longer than 5, , and that the overestimate of uptake length by Sw( should be related to the level of nutrient addition above ambient concentrations and the degree of nutrient limitation. To test these predictions, we used data irom an interbiorne study of NH,- uptake length in which 15NH,- tracer and short-term NH,-a ddition experiments were performed in 10 streams using a uniform experimental approach. The experimental results largely contirmed the theoretical predictions: sw\u27 was consistently longer than Sw and Sw\u27:Sw ratios were directly related to the level of NH,- addition and to indicatvrs of N limitation. The experimentally derived Sw\u27:Sw, ratios were used with the theoretical results to infer the N limitation status of each stream. Together, the theoretical and experimental results showed the tracer experiments should be used whenever possible to determine nutrient uptake length in streams. Nutrient addition experiments may be useful for comparing uptake lengths between different streams or cliiferent times in the same stream. however, provided that nutrient additions are kept as low as possible and of similar miagnitude

Cervical Cancer Prevention Through HPV Vaccination in Low- and Middle-Income Countries in Asia

Cervical cancer is ranked the first or second most common cancer in women of low- and middle-income countries (LMICs) in Asia. Cervical cancer is almost exclusively caused by human papillomavirus (HPV), and majority of the cases can be prevented with the use of HPV vaccines. The HPV vaccines have demonstrated high vaccine efficacies against HPV infection and cervical cancer precursors in clinical and post-marketing studies, and are in use in most high-income countries. However, their use in LMICs are limited mainly due to the high costs and logistics in delivering multiple doses of the vaccine. Other issues such as the safety of the vaccines, social and cultural factors, as well as poor knowledge and awareness of the virus have also contributed to the low uptake of the vaccine. This mini-review focuses on the need for HPV vaccine implementation in Asia given the substantial disease burden and underuse of HPV vaccines in LMICs in this region. In addition, the progress towards HPV vaccine introduction, and barriers preventing further rollout of these essential, life-saving vaccines are also discussed in this article

Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection.

Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)₂D₃, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)₂D₃ significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1β as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)₂D₃ may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels

Objective Impulse control disorders are commonly associated with dopaminergic therapy in Parkinson's disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [11C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [123I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. Methods The [123I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Results Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Conclusions Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications

Factors affecting ammonium uptake in streams - an inter-biome perspective

The Lotic Intersite Nitrogen experiment (LINX) was a coordinated study of the relationships between North American biomes and factors governing ammonium uptake in streams. Our objective was to relate inter-biome variability of ammonium uptake to physical, chemical and biological processes. 2. Data were collected from 11 streams ranging from arctic to tropical and from desert to rainforest. Measurements at each site included physical, hydraulic and chemical characteristics, biological parameters, whole-stream metabolism and ammonium uptake. Ammonium uptake was measured by injection of \u275~-ammonium and downstream measurements of 15N-ammonium concentration. 3. We found no general, statistically significant relationships that explained the variability in ammonium uptake among sites. However, this approach does not account for the multiple mechanisms of ammonium uptake in streams. When we estimated biological demand for inorganic nitrogen based on our measurements of in-stream metabolism, we found good correspondence between calculated nitrogen demand and measured assimilative nitrogen uptake. 4. Nitrogen uptake varied little among sites, reflecting metabolic compensation in streams in a variety of distinctly different biomes (autotrophic production is high where allochthonous inputs are relatively low and vice versa). 5. Both autotrophic and heterotrophic metabolism require nitrogen and these biotic processes dominate inorganic nitrogen retention in streams. Factors that affect the relative balance of autotrophic and heterotrophic metabolism indirectly control inorganic nitrogen uptake

Environmental foundations of typhoid fever in the Fijian residential setting

Proximal characteristics and conditions in the residential setting deserve greater attention for their potential to influence typhoid transmission. Using a case-control design in Central Division, Republic of Fiji, we examined bacterial (coliform and Escherichia coli) contamination and chemical composition of water and soil as potential vehicles of exposure to Salmonella Typhi, combining observational analysis of residential living conditions, geospatial analysis of household locations, and factor analysis to explore multivariate associations with the risk of developing typhoid fever. Factors positively associated with typhoid infection related to drainage [phosphate (OR 4.235, p = 0.042) and E. coli concentrations (OR 2.248, p = 0.029) in toilet drainage soil, housing [external condition (OR 3.712, p \u3c 0.001)], drinking water contamination (OR 2.732, p = 0.003) and sanitary condition (OR 1.973, p = 0.031). These five factors explained 42.5% of the cumulative variance and were significant in predicting typhoid infection. Our results support the hypothesis that a combination of spatial and biophysical attributes of the residential setting influence the probability of typhoid transmission; in this study, factors associated with poor drainage, flooding, and sanitary condition increase local exposure to contaminated water and soil, and thereby infection. These findings extend testing of causal assumptions beyond the immediate domestic domain, enhance the scope of traditional case control epidemiology and allow greater specificity of interventions at the scale of the residential setting

Author Correction: Combining CRISPRi and metabolomics for functional annotation of compound libraries

No abstract available

Repeat pneumococcal polysaccharide vaccine in Indigenous Australian adults is associated with decreased immune responsiveness.

BACKGROUND: Indigenous adults residing in the Northern Territory of Australia experience elevated rates of invasive pneumococcal disease despite the routine use of 23-valent pneumococcal polysaccharide vaccine (23vPPV). We hypothesised that the limited protection from 23vPPV may be due to hyporesponsiveness as a result of vaccine failure from repeated vaccination. To explore this possibility, we evaluated the immune response to a first and second dose of 23vPPV in Indigenous adults and a first dose of 23vPPV in non-Indigenous adults. METHODS: Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline and at one month post-vaccination. Individuals were considered to have an adequate immune response if paired sera demonstrated either: a four-fold rise in antibody concentration; a two-fold rise if the post vaccination antibody was >1.3μg/ml but 4.0μg/ml for at least half of the serotypes tested (12/23). Our per-protocol analysis included the comparison of outcomes for three groups: Indigenous adults receiving a second 23vPPV dose (N=20) and Indigenous (N=60) and non-Indigenous adults (N=25) receiving their first 23vPPV dose. RESULTS: All non-Indigenous adults receiving a first dose of 23vPPV mounted an adequate immune response (25/25). There was no significant difference in the proportion of individuals with an adequate response using our definition (primary endpoint), with 88% of Indigenous adults mounted an adequate response following first dose 23vPPV (53/60) compared to 70% having an adequate response following a second dose of 23vPPV (14/20; p=0.05). The risk difference between Indigenous participants receiving first dose compared to non-Indigenous participants receiving first dose was significant when comparing a response threshold of at least 70% (-27%, 95% CI: -43% to -11%; p=0.01) and 90% (-38%, 95% CI: -60% to -16%; p=0.006) of serotypes with a positive response. CONCLUSION: Indigenous participants demonstrated a poorer response to a first dose 23vPPV compared to their non-Indigenous counterparts, with lower IgG following a second 23vPPV dose. These findings highlight the critical need to evaluate the efficacy of future pneumococcal vaccine programs in the Australian Indigenous populations that recommend repeated doses of 23vPPV