ABCG2 is a secretory efflux uric acid transporter of the kidney proximal tubule and gut that plays a key role in uric acid excretion. Genetic defect in ABCG2 leads to significant increases in serum urate levels (SUA) causing hyperuricemia and gout. A single common variant, Q141K, is responsible for the majority of ABCG2 associated gout risk. The Q141K mutation is a loss of function mutation associated with a severe reduction in protein abundance and transport function. Previously we hypothesized the Q141K mutation leads to instability in the nucleotide‐binding domain and here we present the specific molecular mechanism of the defect and a proof of concept of its correction using small molecules. We found using a ABCG2 structural model and targeted amino acid substitutions that the Q141K mutations leads to a localized disruption in packing that affects abundance and can be partially rescued with a secondary substitution at H155A. However the use of the signature motif suppressor mutation, G188E, provides full rescue of the Q141K abundance by stabilizing the NBD dimer sandwich, a finding consistent with a Q141K defect in NBD dimer formation. Finally we show that a small molecule, VRT‐325, known to bind directly to the NBD of ABC transporters can rescue both abundance and function of Q141K ABCG2.
BackgroundPlasmodium vivax and Plasmodium falciparum cause a significant illness burden in Peru. Anopheline indices for populated communities in the peri-Iquitos region of Loreto have been reported to be remarkably low, with entomological inoculation rates (EIR) estimated at one to 30 infective bites per year based on a few studies in close proximity to the urban centre of Iquitos and surrounding deforested areas. Local reports suggest that a large number of the reported cases are contracted outside of populated communities in undeveloped riverine areas frequented by loggers and fishermen.MethodsTo better understand vectorial capacity in suspected high malaria transmission zones in a rural district near Iquitos, Peru, mosquito collections were conducted at different points in the seasonality of malaria transmission in 21 sites frequented by occupational labourers. Prevalence of Plasmodium spp in vectors was determined by circumsporozoite protein ELISA on individual mosquitoes. Slide surveillance was performed for humans encountered in the zone.ResultsIn total, of 8,365 adult female mosquitoes examined, 98.5% were identified as Anopheles darlingi and 117 (1.4%) tested positive for sporozoites (P. falciparum, P. vivax VK210 or P. vivax VK247). Measured human biting rates at these sites ranged from 0.102 to 41.13 bites per person per hour, with EIR values as high as 5.3 infective bites per person per night. Six percent of the 284 blood films were positive for P. vivax or P. falciparum; however, 88% of the individuals found to be positive were asymptomatic at the time of sampling.ConclusionsThe results of this study provide key missing indices of prominent spatial and temporal heterogeneity of vectorial capacity in the Amazon Basin of Peru. The identification of a target human subpopulation as a principal reservoir and dispersion source of Plasmodium species has important implications for vaccine development and the delivery of effective targeted malaria control strategies.
Objective To examine the relationship between measures of sleep quality and cognitive performance in HIV+ individuals stable on combination anti-retroviral therapy. Design Multi-method assessments of sleep quality, patterns, and cognitive performance were assessed in a predominantly Black HIV+ cohort. Methods Sleep quality and patterns were characterized in 36 subjects by: polysomnogram, two-week actigraphy monitoring, and validated sleep questionnaires. Cognitive performance was assessed with a battery of neuropsychological tests. Results The majority of participants were cognitively impaired [based on Frascati (75%) criteria]. Self-reported mean scores on the Pittsburgh Sleep Quality Index and the Insomnia Severity Scale suggested poor sleep quality. Better cognitive performance, particularly on tasks of attention, frontal/executive function, and psychomotor/motor speed, was associated with polysomnogram sleep indices (i.e., reduced wake-after-sleep (WASO), greater sleep efficiency, greater sleep latency, and greater total sleep time). Thirty-seven percent of participants had sleep patterns suggestive of chronic partial sleep deprivation which was associated with significantly worse performance on the Digit Symbol test (p = 0.006), non-dominant pegboard (p = 0.043), and verbal fluency tests (p = 0.044). Conclusion Our results suggest that compromised sleep quality and duration may have a significant impact on cognitive performance in HIV+ individuals. Future studies are warranted to determine the utility of sleep quality and quantity indices as potential predictive biomarkers for development and progression of future HIV-associated neurocognitive disorder.
Costimulation blockade (CoB) via belatacept is a lower morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept, and increased adhesion molecule expression. One such molecule is Leukocyte Function Associated Antigen (LFA)-1. LFA-1 exists in two forms, a commonly expressed, low-affinity form, and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 irrespective of its configuration are effective in eliminating memory T cells, but at the cost of impaired protective immunity. Here we test two novel agents, Leukotoxin A and AL-579, each of which targets the high affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity prior to efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB resistant rejection.
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