ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.     

Nitrogen fertilizer and landscape position impacts on CO2 and CH4 fluxes from a landscape seeded to switchgrass

This study was conducted to evaluate the impacts of N fertilizer and landscape position on carbon dioxide (CO₂) and methane (CH₄) fluxes from a US Northern Great Plains landscape seeded to switchgrass (Panicum virgatum L.). The experimental design included three N levels (low, 0 kg N ha⁻¹; medium, 56 kg N ha⁻¹; and high, 112 kg N ha⁻¹) replicated four times. The experiment was repeated at shoulder and footslope positions. Soil CO₂ and CH₄ fluxes were monitored once every 2 weeks from May 2010 to October 2012. The CO₂ fluxes were 40% higher at the footslope than the shoulder landscape position, and CH₄ fluxes were similar in both landscape positions. Soil CO₂ and CH₄ fluxes averaged over the sampling dates were not impacted by N rates. Seasonal variations showed highest CO₂ release and CH₄ uptake in summer and fall, likely due to warmer and moist soil conditions. Higher CH₄ release was observed in winter possibly due to increased anaerobic conditions. However, year to year (2010–2012) variations in soil CO₂ and CH₄ fluxes were more pronounced than the variations due to the impact of landscape positions and N rates. Drought conditions reported in 2012, with higher annual temperature and lower soil moisture than long-term average, resulted in higher summer and fall CO₂ fluxes (between 1.3 and 3 times) than in 2011 and 2010. These conditions also promoted a net CH₄ uptake in 2012 in comparison to 2010 when there was net CH₄ release. Results from this study conclude that landscape positions, air temperature, and soil moisture content strongly influenced soil CO₂ fluxes, whereas soil moisture impacted the direction of CH₄ fluxes (uptake or release). However, a comprehensive life cycle analysis would be appropriate to evaluate environmental impacts associated with switchgrass production under local environmental conditions.     

Expression of protective antigen in transgenic plants: a step towards edible vaccine against anthrax

Protective antigen (PA) is the most potent molecule for vaccination against anthrax. In the present study, we have successfully integrated protective antigen gene in nuclear genome of tobacco plants by Agrobacterium mediated leaf-disc transformation method. Expression of protective antigen gene was detected by immunoblot analysis using antisera raised against purified PA. A distinct band of approximately 83kDa lighted up in the protein extracted from transformed plants while there was no such band in untransformed plants. The plant expressed PA showed biological activity just like native PA, which was demonstrated by cytolytic assay on macrophage like cell lines with lethal factor. This study establishes for the first time expression of PA gene in a plant system and thus marks the first milestone towards developing edible vaccine against anthrax.     

Biophysical aspects and biological implications of the interaction of benzophenanthridine alkaloids with DNA

Benzophenanthridine alkaloids represent a very interesting and significant group of natural products that exhibit a broad range of biological and pharmacological properties. Among this group of alkaloids, sanguinarine, nitidine, fagaronine, and chelerythrine have the potential to form molecular complexes with DNA structures and have attracted recent attention for their possible clinical and pharmacological utility. This review focuses on the interaction of these alkaloids with polymorphic DNA structures (B-form, Z-form, H^L-form, and triple helical form) reported by several research groups employing various physical techniques such as spectrophotometry, spectrofluorimetry, circular dichroism, NMR spectroscopy, thermal melting, viscometry as well as thermodynamic analysis by isothermal titration calorimetry and differential scanning calorimetry to elucidate the mode and mechanism of action at the molecular level to determine the structure-activity relationship. DNA binding properties of these alkaloids are interpreted in relation to their biological activity.     

Impact of ammonia concentration on Spirulina platensis growth in an airlift photobioreactor

Spirulina platensis was cultivated in a bench-scale airlift photobioreactor using synthetic wastewater (total nitrogen 412 mg L(-1), total phosphorous 90 mg L(-1), pH 9-10) with varying ammonia/total nitrogen ratios (50-100% ammonia with balance nitrate) and hydraulic residence times (15-25 d). High average biomass density (3500-3800 mg L(-1)) and productivity (5.1 g m(-2) d(-1)) were achieved when ammonia was maintained at 50% of the total nitrogen. Both high ammonia concentrations and mutual self-shading, which resulted from the high biomass density in the airlift reactor, were found to partially inhibit the growth of S. platensis. The performance of the airlift bioreactor used in this study compared favorably with other published studies. The system has good potential for treatment of high strength wastewater combined with production of algae for biofuels or other products, such as human and animal food, food supplements or pharmaceuticals.     

RNA-based gene therapy for the treatment and prevention of HIV: from bench to bedside

Gene therapy is considered a feasible approach for the treatment and prevention of HIV/AIDS. Targeting both viral genes and host dependency factors can interfere with the viral lifecycle and prevent viral replication. A number of approaches have been taken to target these genes, including ribozymes, aptamers, and RNAi based therapies. A number of these therapies are now beginning to make their way into clinical trials and providing proof of principle that gene therapy is a safe and realistic option for treating HIV. Here, we focus on those therapies that have progressed along the pipeline to preclinical and clinical testing.