Synchronized Optical and Electronic Detection of Biomolecules Using a Low Noise Nanopore Platform

In the past two decades there has been a tremendous amount of research into the use of nanopores as single molecule sensors, which has been inspired by the Coulter counter and molecular transport across biological pores. Recently, the desire to increase structural resolution and analytical throughput has led to the integration of additional detection methods such as fluorescence spectroscopy. For structural information to be probed electronically high bandwidth measurements are crucial due to the high translocation velocity of molecules. The most commonly used solid-state nanopore sensors consist of a silicon nitride membrane and bulk silicon substrate. Unfortunately, the photoinduced noise associated with illumination of these platforms limits their applicability to high-bandwidth, high-laser-power synchronized optical and electronic measurements. Here we present a unique low-noise nanopore platform, composed of a predominately Pyrex substrate and silicon nitride membrane, for synchronized optical and electronic detection of biomolecules. Proof of principle experiments are conducted showing that the Pyrex substrates have substantially lowers ionic current noise arising from both laser illumination and platform capacitance. Furthermore, using confocal microscopy and a partially metallic pore we demonstrate high signal-to-noise synchronized optical and electronic detection of dsDNA

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni

Comprehensive and Medically Appropriate Food Support Is Associated with Improved HIV and Diabetes Health

Food insecurity is associated with negative chronic health outcomes, yet few studies have examined how providing medically appropriate food assistance to food-insecure individuals may improve health outcomes in resource-rich settings. We evaluated a community-based food support intervention in the San Francisco Bay Area for people living with HIV and/or type 2 diabetes mellitus (T2DM) to determine the feasibility, acceptability, and potential impact of the intervention on nutritional, mental health, disease management, healthcare utilization, and physical health outcomes. The 6-month intervention provided meals and snacks designed to comprise 100% of daily energy requirements and meet nutritional guidelines for a healthy diet. We assessed paired outcomes at baseline and 6 months using validated measures. Paired t tests and McNemar exact tests were used with continuous and dichotomous outcomes, respectively, to compare pre-post changes. Fifty-two participants (out of 72 initiators) had both baseline and follow-up assessments, including 23 with HIV, 24 with T2DM, and 7 with both HIV and T2DM. Median food pick-up adherence was 93%. Comparing baseline to follow-up, very low food security decreased from 59.6% to 11.5% (p < 0.0001). Frequency of consumption of fats (p = 0.003) decreased, while frequency increased for fruits and vegetables (p = 0.011). Among people with diabetes, frequency of sugar consumption decreased (p = 0.006). We also observed decreased depressive symptoms (p = 0.028) and binge drinking (p = 0.008). At follow-up, fewer participants sacrificed food for healthcare (p = 0.007) or prescriptions (p = 0.046), or sacrificed healthcare for food (p = 0.029). Among people with HIV, 95% adherence to antiretroviral therapy increased from 47 to 70% (p = 0.046). Among people with T2DM, diabetes distress (p < 0.001), and perceived diabetes self-management (p = 0.007) improved. Comprehensive, medically appropriate food support is feasible and may improve multiple health outcomes for food-insecure individuals living with chronic health conditions. Future studies should formally test the impact of medically appropriate food support interventions for food-insecure populations through rigorous, randomized controlled designs