Decreased riboflavin formation in mutants of Aerobacter (Enterobacter) aerogenes deficient in the butanediol pathway

Riboflavin concentration increased linearly for more than 60 h in wild type cultures, whereas in three mutants deficient in the formation of acetoin and 2,3-butanediol the production ceased at the end of exponential growth.     

Pleiotropic and Sex-Specific Effects of Cancer GWAS SNPs on Melanoma Risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Background

Several regions of the genome show pleiotropic associations with multiple cancers. We sought to evaluate whether 181 single-nucleotide polymorphisms previously associated with various cancers in genome-wide association studies were also associated with melanoma risk.

Methods

We evaluated 2,131 melanoma cases and 20,353 controls from three studies in the Population Architecture using Genomics and Epidemiology (PAGE) study (EAGLE-BioVU, MEC, WHI) and two collaborating studies (HPFS, NHS). Overall and sex-stratified analyses were performed across studies.

Results

We observed statistically significant associations with melanoma for two lung cancer SNPs in the TERT-CLPTM1L locus (Bonferroni-corrected p<2.8x10^-4), replicating known pleiotropic effects at this locus. In sex-stratified analyses, we also observed a potential male-specific association between prostate cancer risk variant rs12418451 and melanoma risk (OR=1.22, p=8.0x10^-4). No other variants in our study were associated with melanoma after multiple comparisons adjustment (p>2.8e^-4).

Conclusions

We provide confirmatory evidence of pleiotropic associations with melanoma for two SNPs previously associated with lung cancer, and provide suggestive evidence for a male-specific association with melanoma for prostate cancer variant rs12418451. This SNP is located near TPCN2, an ion transport gene containing SNPs which have been previously associated with hair pigmentation but not melanoma risk. Previous evidence provides biological plausibility for this association, and suggests a complex interplay between ion transport, pigmentation, and melanoma risk that may vary by sex. If confirmed, these pleiotropic relationships may help elucidate shared molecular pathways between cancers and related phenotypes.     

Use of Modern Family Planning Methods in Fishing Communities of Lake Victoria,Uganda

Introduction

Fishing communities (FCs) in Uganda have high HIV infection rates but poor access to health services including family planning (FP). Although FP is a cost-effective public health intervention, there is a paucity of data on knowledge and use of modern FP in FCs. This study determined knowledge and use of modern FP methods in FCs of Uganda.

Methods

Data were accrued from a 12-month follow up of 1,688 HIV-uninfected individuals, 18–49 years from 8 FCs along Lake Victoria, between September 2011 and March 2013. Data on knowledge and use of modern FP were collected through a semi-structured questionnaire. Prevalence Risk Ratios with corresponding 95% CIs were used to determine factors associated with Modern FP knowledge and use.

Results

The mean age was 31.4 years, with nearly half (48.8%) being females while more than half (58.6%) had attained up to primary education level. Knowledge of modern FP was high, 87.5% (1477/1688); significantly higher among females [adj. PRR = 4.84 (95% CI; 3.08, 7.61)], among older respondents (25–29 years) [adj. PRR = 1.83 (95% CI; 1.12, 2.99)] compared to younger ones (18–24 years) and among those conducting business [adj. PRR = 2.42(95% CI; 1.02, 5.74)] relative to those primarily in fishing. Just over a third (35.2%, 595/1688) reported use of at least one modern FP method. Use of modern FP methods was significantly higher among females [adj. PRR = 2.04 (95% CI; 1.56, 2.65, and among those reporting multiple sexual partnerships [adj. PRR = 2.12, 95% CI; 1.63, 2.76)]. Nonuse of modern methods was mostly due to desire for more children (30.6%), fear of side effects (12.2%) and partner refusal (5.2%).

Conclusion

Despite their high knowledge of FP, FCs have low use of modern FP methods. Key barriers to use of modern FP methods were high fertility desires, fear of perceived side effects and partner refusal of methods.     

Cα torsion angles as a flexible criterion to extract secrets from a molecular dynamics simulation

A multipolar, polarizable electrostatic method for future use in a novel force field is described. Quantum Chemical Topology (QCT) is used to partition the electron density of a chemical system into atoms, then the machine learning method Kriging is used to build models that relate the multipole moments of the atoms to the positions of their surrounding nuclei. The pilot system serine is used to study both the influence of the level of theory and the set of data generator methods used. The latter consists of: (i) sampling of protein structures deposited in the Protein Data Bank (PDB), or (ii) normal mode distortion along either (a) Cartesian coordinates, or (b) redundant internal coordinates. Wavefunctions for the sampled geometries were obtained at the HF/6-31G(d,p), B3LYP/apc-1, and MP2/cc-pVDZ levels of theory, prior to calculation of the atomic multipole moments by volume integration. The average absolute error (over an independent test set of conformations) in the total atom-atom electrostatic interaction energy of serine, using Kriging models built with the three data generator methods is 11.3 kJ mol^-1 (PDB), 8.2 kJ mol^-1 (Cartesian distortion), and 10.1 kJ mol^-1 (redundant internal distortion) at the HF/6-31G(d,p) level. At the B3LYP/apc-1 level, the respective errors are 7.7 kJ mol^-1, 6.7 kJ mol^-1, and 4.9 kJmol^-1, while at the MP2/cc-pVDZ level they are 6.5 kJ mol^-1, 5.3 kJ mol^-1, and 4.0 kJmol^-1. The ranges of geometries generated by the redundant internal coordinate distortion and by extraction from the PDB are much wider than the range generated by Cartesian distortion. The atomic multipole moment and electrostatic interaction energy predictions for the B3LYP/apc-1 and MP2/cc-pVDZ levels are similar, and both are better than the corresponding predictions at the HF/6-31G(d,p) level.     

Changes in Seroadaptive Practices from before to after Diagnosis of Recent HIV Infection among Men Who Have Sex with Men

Objective

We assessed changes in sexual behavior among men who have sex with men (MSM), before and for several years after HIV diagnosis, accounting for adoption of a variety of seroadaptive practices.

Methods

We collected self-reported sexual behavior data every 3 months from HIV-positive MSM at various stages of HIV infection. To establish population level trends in sexual behavior, we used negative binomial regression to model the relationship between time since diagnosis and several sexual behavior variables: numbers of (a) total partners, (b) potentially discordant partners (PDP; i.e., HIV-negative or unknown-status partners), (c) PDPs with whom unprotected anal intercourse (UAI) occurred, and (d) PDPs with whom unprotected insertive anal intercourse (uIAI) occurred.

Results

A total of 237 HIV-positive MSM contributed 502 interviews. UAI with PDPs occurred with a mean of 4.2 partners in the 3 months before diagnosis. This declined to 0.9 partners/3 months at 12 months after diagnosis, and subsequently rose to 1.7 partners/3 months at 48 months, before falling again to 1.0 partners/3 months at 60 months. The number of PDPs with whom uIAI occurred dropped from 2.4 in the pre-diagnosis period to 0.3 partners/3 months (an 87.5% reduction) by 12 months after enrollment, and continued to decline over time.

Conclusion

Within months after being diagnosed with HIV, MSM adopted seroadaptive practices, especially seropositioning, where the HIV-positive partner was not in the insertive position during UAI, resulting in a sustained decline in the sexual activity associated with the highest risk of HIV transmission.     

Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation

Production of pathogenic Abs contributes to disease progression in many autoimmune disorders. The immunosuppressant agent mycophenolic acid (MPA) has shown clinical efficacy for patients with autoimmunity. The goal of these studies was to elucidate the mechanisms of action of MPA on B cells isolated from healthy individuals and autoimmune patients. In this study, we show that MPA significantly inhibited both proliferation and differentiation of primary human B cells stimulated under various conditions. Importantly, MPA did not globally suppress B cell responsiveness or simply induce cell death, but rather selectively inhibited early activation events and arrested cells in the G0/G1 phase of the cell cycle. Furthermore, MPA blocked expansion of both naive and memory B cells and prevented plasma cell (PC) differentiation and Ab production from healthy controls and individuals with rheumatoid arthritis. Finally, whereas MPA potently suppressed Ig secretion from activated primary B cells, terminally differentiated PCs were not susceptible to inhibition by MPA. The target of MPA, IMPDH2, was found to be downregulated in PCs, likely explaining the resistance of these cells to MPA. These results suggest that MPA provides benefit in settings of autoimmunity by directly preventing activation and PC differentiation of B cells; however, MPA is unlikely to impact autoantibody production by preexisting, long-lived PCs.     

Osteoblasts and osteocytes respond differently to oscillatory and unidirectional fluid flow profiles

Bone cells subjected to mechanical loading by fluid shear stress undergo significant architectural and biochemical changes. The models of shear stress used to analyze the effects of loading bone cells in vitro include both oscillatory and unidirectional fluid shear profiles. Although the fluid flow profile experienced by cells within bone is most likely oscillatory in nature, to date there have been few direct comparisons of how bone cells respond to these two fluid flow profiles. In this study we evaluated morphologic and biochemical responses to a time course of unidirectional and oscillatory fluid flow in two commonly used bone cell lines, MC3T3-E1 osteoblasts and MLO-Y4 osteocytes. We determined that stress fibers formed and aligned within osteoblasts after 1 h of unidirectional fluid flow, but this response was not observed until greater than 5 h of oscillatory fluid flow. Despite the delay in stress fiber formation, oscillatory and unidirectional fluid flow profiles elicited similar temporal effects on the induction of both cyclooxygenase-2 (Cox-2) and osteopontin protein expression in osteoblasts. Interestingly, MLO-Y4 osteocytes formed organized stress fibers after exposure to 24 h of unidirectional shear stress, while the number of dendritic processes per cell increased along with Cox-2 protein levels after 24 h of oscillatory shear stress. Despite these differences, both flow profiles significantly altered osteopontin levels in MLO-Y4 osteocytes. Together these results demonstrate that the profile of fluid shear can induce significantly different responses from osteoblasts and osteocytes.