A network map of Interleukin-10 signaling pathway

Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is primarily secreted by antigen-presenting cells such as activated T-cells, monocytes, B-cells and macrophages. In biologically functional form, it exists as a homodimer that binds to tetrameric heterodimer IL-10 receptor and induces downstream signaling. IL-10 is associated with survival, proliferation and anti-apoptotic activities of various cancers such as Burkitt lymphoma, non-Hodgkins lymphoma and non-small scell lung cancer. In addition, it plays a central role in survival and persistence of intracellular pathogens such as Leishmania donovani, Mycobacterium tuberculosis and Trypanosoma cruzi inside the host. The signaling mechanisms of IL-10 cytokine are not well explored and a well annotated pathway map has been lacking. To this end, we developed a pathway resource by manually annotating the IL-10 induced signaling molecules derived from literature. The reactions were categorized under molecular associations, activation/inhibition, catalysis, transport and gene regulation. In all, 37 molecules and 76 reactions were annotated. The IL-10 signaling pathway can be freely accessed through NetPath, a resource of signal transduction pathways previously developed by our group.     

Racial differences in subcutaneous fat patterns in children aged 7–15 years

In a stratified random sample of 278 children aged 7–15 years of an entire biracial community, skinfold measurements were taken on six standard body sites. We found that white children had generally thicker skinfolds than blacks for the same body weight, with a consistent exception: the subscapular skinfold was relatively thicker in blacks. It is suggested that this racial difference in distribution of fat may manifest a genetic adaptive trait developed under circumstances demanding both a caloric reserve and facilitation of convective heat loss in tropical climates.     

Photodynamic action of merocyanine 540 on carcinoma of cervix cells

Results of the studies carried out on localization and photodynamic action of merocyanine 540 (MC540) on carcinoma of cervix (HeLa) cells are presented. Fluorescence microscopic study showed that when HeLa cells were incubated with MC540 in dark, the dye localized in plasma membrane of cells. Photoirradiation of cells in presence of MC540 led to enhancement of dye uptake, intracellular localization of dye and a dose dependent decrease in cell survival. Clonogenic assay showed 96% cell killing at a light dose of 42 kJ/m2. Photosensitization of cells resulted in loss of membrane integrity, decrease in plasma membrane fluidity and reduction in mitochondrial dehydrogenase activity as measured by tetrazolium reduction (MTT) assay. At a given light dose, the relative change in plasma membrane properties was higher than the reduction in activity of mitochondrial enzyme. These results suggest plasma membrane is a primary target of photosensitization of HeLa cells by MC540.     

Bacteriorhodopsin conjugates as anchors for supported membranes

The sophistication of supported lipid bilayer membranes has increased steadily as new applications are being explored. In general, tethered lipids are used to anchor the lipid bilayer to the substrate. Here we describe a new type of anchoring system for supported lipid bilayers that is based on biotin-PEG3400-bacteriorhodopsin conjugates. Amine-based coupling was used to construct the polymer conjugates, followed by fluorophore labeling to enable confocal imaging. The bacteriorhodopsin-based anchoring system was used to construct solid-supported vesicles from streptavidin-coated microspheres. This method could provide a new route for the stability enhancement of supported lipid bilayer membrane assemblies.     

Time Preferences Predict Mortality among HIV-Infected Adults Receiving Antiretroviral Therapy in Kenya

Background

Identifying characteristics of HIV-infected adults likely to have poor treatment outcomes can be useful for targeting interventions efficiently. Research in economics and psychology suggests that individuals’ intertemporal time preferences, which indicate the extent to which they trade-off immediate vs. future cost and benefits, can influence various health behaviors. While there is empirical support for the association between time preferences and various non-HIV health behaviors and outcomes, the extent to which time preferences predict outcomes of those receiving antiretroviral therapy (ART) has not been examined previously.

Methods

HIV-infected adults initiating ART were enrolled at a health facility in Kenya. Participants’ time preferences were measured at enrollment and used to classify them as having either a low or high discount rate for future benefits. At 48 weeks, we assessed mortality and ART adherence, as measured by Medication Event Monitoring System (MEMS). Logistic regression models adjusting for socio-economic characteristics and risk factors were used to determine the association between time preferences and mortality as well as MEMS adherence ≥90%.

Results

Overall, 44% (96/220) of participants were classified as having high discount rates. Participants with high discount rates had significantly higher 48-week mortality than participants with low discount rates (9.3% vs. 3.1%; adjusted odds ratio 3.84; 95% CI 1.03, 14.50). MEMS adherence ≥90% was similar for participants with high vs. low discount rates (42.3% vs. 49.6%, AOR 0.70; 95% CI 0.40, 1.25).

Conclusion

High discount rates were associated with significantly higher risk of mortality among HIV-infected patients initiating ART. Greater use of time preference measures may improve identification of patients at risk of poor clinical outcomes. More research is needed to further identify mechanisms of action and also to build upon and test the generalizability of this finding.     

The Relationship between Alcohol Outlets,HIV Risk Behavior,and HSV-2 Infection among South African Young Women: A Cross-Sectional Study

BackgroundAlcohol consumption has a disinhibiting effect that may make sexual risk behaviors and disease transmission more likely. The characteristics of alcohol-serving outlets (e.g. music, dim lights, lack of condoms) may further encourage risky sexual activity. We hypothesize that frequenting alcohol outlets will be associated with HIV risk.MethodsIn a sample of 2,533 school-attending young women in rural South Africa, we performed a cross-sectional analysis to examine the association between frequency of alcohol outlet visits in the last six months and four outcomes related to HIV risk: number of sex partners in the last three months, unprotected sex acts in the last three months, transactional sex with most recent partner, and HSV-2 infection. We also tested for interaction by alcohol consumption.ResultsVisiting alcohol outlets was associated with having more sex partners [adjusted odds ratio (aOR), one versus zero partners (95% confidence interval (CI)): 1.51 (1.21, 1.88)], more unprotected sex acts [aOR, one versus zero acts (95% CI): 2.28 (1.52, 3.42)], higher levels of transactional sex [aOR (95% CI): 1.63 (1.03, 2.59)], and HSV-2 infection [aOR (95% CI): 1.30 (0.88, 1.91)]. In combination with exposure to alcohol consumption, visits to alcohol outlets were more strongly associated with all four outcomes than with either risk factor alone. Statistical evidence of interaction between alcohol outlet visits and alcohol consumption was observed for all outcomes except transactional sex.ConclusionsFrequenting alcohol outlets was associated with increased sexual risk in rural South African young women, especially when they consumed alcohol. Sexual health interventions targeted at alcohol outlets may effectively reach adolescents at high risk for sexually transmitted infections like HIV and HSV-2.

Trial Registration

HIV Prevention Trials Network HPTN 068     

Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis

Background

Potential biomarkers to aid diagnosis and therapy need to be identified for Amyotrophic Lateral Sclerosis, a progressive motor neuronal degenerative disorder. The present study was designed to identify the factor(s) which are differentially expressed in the cerebrospinal fluid (CSF) of patients with sporadic amyotrophic lateral sclerosis (SALS; ALS-CSF), and could be associated with the pathogenesis of this disease.

Results

Quantitative mass spectrometry of ALS-CSF and control-CSF (from orthopaedic surgical patients undergoing spinal anaesthesia) samples showed upregulation of 31 proteins in the ALS-CSF, amongst which a ten-fold increase in the levels of chitotriosidase-1 (CHIT-1) was seen compared to the controls. A seventeen-fold increase in the CHIT-1 levels was detected by ELISA, while a ten-fold elevated enzyme activity was also observed. Both these results confirmed the finding of LC-MS/MS. CHIT-1 was found to be expressed by the Iba-1 immunopositive microglia.

Conclusion

Elevated CHIT-1 levels in the ALS-CSF suggest a definitive role for the enzyme in the disease pathogenesis. Its synthesis and release from microglia into the CSF may be an aligned event of neurodegeneration. Thus, high levels of CHIT-1 signify enhanced microglial activity which may exacerbate the process of neurodegeneration. In view of the multifold increase observed in ALS-CSF, it can serve as a potential CSF biomarker for the diagnosis of SALS.     

Immunomodulatory effects of cytokine-induced expansion of cytotoxic lymphocytes in a mouse model of lupus-like disease

Background aimsCertain therapies (e.g., daclizumab) that promote expansion of natural killer (NK) cells are associated with clinical amelioration of disease in the context of multiple sclerosis and associated mouse models. The clinical benefits are putatively attributable to an enhanced capacity of NK cells to kill activated pathogenic T cells. Whether a parallel approach will also be effective in systemic lupus erythematosus (lupus), a multi-organ autoimmune disease driven by aberrant responses of self-reactive T and B cells, is unclear.MethodsIn the present study, the authors assess the therapeutic impact of IL-2- and IL-15-based strategies for expanding NK cells on measures of lupus-like disease in a mouse model.ResultsUnexpectedly, cytokine-mediated expansion of cytotoxic lymphocytes aggravated immunological measures of lupus-like disease. Depletion studies revealed that the negative effects of these cytokine-based regimens can largely be attributed to expansion of CD8 T cells rather than NK cells.ConclusionsThese results provoke caution in the use of cytokine-based therapeutics to treat co-morbid cancers in patients with lupus and highlight the need for new methods to selectively expand NK cells to further assess their clinical value in autoimmune disease.