Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells

Protein regulators of G protein signaling (RGS proteins) were discovered as negative regulators of heterotrimeric G protein-mediated signal transduction in yeast and worms. Experiments with purified recombinant proteins in vitro have established that RGS proteins accelerate the GTPase activity of certain G protein α subunits (the reaction responsible for their deactivation); they can also act as effector antagonists. We demonstrate herein that either of two such RGS proteins, RGS4 or GAIP, attenuated signal transduction mediated by endogenous receptors, G proteins, and effectors when stably expressed as tagged proteins in transfected mammalian cells. The pattern of selectivity observed in vivo was similar to that seen in vitro. RGS4 and GAIP both attenuated G_i-mediated inhibition of cAMP synthesis. RGS4 was more effective than GAIP in blocking G_q-mediated activation of phospholipase Cβ.     

RGS4 and GAIP are GTPase-activating proteins for Gqα and block activation of phospholipase Cβ by γ-thio-GTP-Gqα

RGS proteins constitute a newly appreciated and large group of negative regulators of G protein signaling. Four members of the RGS family act as GTPase-activating proteins (GAPs) with apparent specificity for members of the G_iα subfamily of G protein subunits. We demonstrate here that two RGS proteins, RGS4 and GAIP, also act as GAPs for G_qα, the G_α protein responsible for activation of phospholipase Cβ. Furthermore, these RGS proteins block activation of phospholipase Cβ by guanosine 5′-(3-O-thio)triphosphate-G_qα. GAP activity does not explain this effect, which apparently results from occlusion of the binding site on G_α for effector. Inhibitory effects of RGS proteins on G protein-mediated signaling pathways can be demonstrated by simple mixture of RGS4 or GAIP with plasma membranes.     

High degree of Plasmodium vivax diversity in the Peruvian Amazon demonstrated by tandem repeat polymorphism analysis

Molecular tools to distinguish strains of Plasmodium vivax are important for studying the epidemiology of malaria transmission. Two sets of markers-tandem repeat (TR) polymorphisms and MSP3α-were used to study Plasmodium vivax in patients in the Peruvian Amazon region of Iquitos. Of 110 patients, 90 distinct haplotypes were distinguished using 9 TR markers. An MSP3α polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using HhaI and AluI revealed 8 and 9 profiles, respectively, and 36 profiles when analyzed in combination. Combining TR and PCR-RFLP markers, 101 distinct molecular profiles were distinguished among these 110 patients. Nine TR markers arrayed along a 100 kB stretch of a P. vivax chromosome containing the gene for circumsporozoite protein showed non-linear linkage disequilibrium (I(SA) = 0.03, P = 0.001). These findings demonstrate the potential use of TR markers for molecular epidemiology studies.     

Rapid Implementation of New TB Diagnostic Tests: Is It Too Soon for a Global Roll-Out of Xpert MTB/RIF?

In 2011 the World Health Organization approved Xpert MTB/RIF for tuberculosis diagnosis and recommended its rapid implementation. Xpert MTB/RIF is accurate: sensitivity is 72.5–98.2% (smear-negative and -positive cases, respectively) and specificity 99.2%. Benefits include same-day diagnosis and simultaneous detection of rifampicin resistance. However, the test has some shortcomings and has not had time for thorough evaluation. Cost-effectiveness studies are difficult to perform and few have been completed. Existing data suggest cost-effectiveness in some, but not all, settings. The urgent need for better diagnostics is evident. Yet, serial implementation of new technologies causes ineffective spending and fragmentation of services. How new tests are incorporated into existing diagnostic algorithms affects both outcomes and costs. More detailed data on performance, effect on patient-important outcomes, and costs when used with adjunct tests are needed for each setting before implementation. While awaiting further clarification it seems prudent to slow its implementation among resource-constrained tuberculosis control programs.     

Transmission of Enterocytozoon bieneusi between a child and guinea pigs

An unusual Enterocytozoon bieneusi genotype was found in seven guinea pigs and a 2-year-old child in the same household. The genetic uniqueness of the parasite, its wide occurrence in other guinea pigs in the community, and its absence in other children in the community suggest the possibility of zoonotic transmission of the infection to the study child.     

Attitudes,health lifestyle behaviors and cardiometabolic risk factors among relatives of individuals with type 2 diabetes mellitus

ObjectiveTo describe and compare attitudes, lifestyle behaviors, and cardiometabolic risk factors between individuals with and without a relative with type 2 diabetes mellitus (T2DM) living in the same household.MethodsA secondary analysis of baseline data from an implementation study in Peru was conducted. The outcomes were attitudes towards changing lifestyle behaviors (e.g. intentions towards losing weight, increasing physical activity, reducing salt consumption, etc), profiles of health lifestyle behaviors (e.g. daily smoking, heavy drinking, and physical activity), and cardiometabolic risk factors (e.g., overweight [body mass index ≥25 kg/m²] and hypertension); whereas the exposure was the presence of at least one relative with known diagnosis of T2DM living in the same household. Multilevel logistic mixed effect regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI).ResultsA total of 2298 records, 1134 (49.4%) males, mean age 43.3 (SD: 17.2) years, were analyzed. There was no evidence of a difference in lifestyle-changing attitudes, smoking, alcohol drinking, physical activity levels, and hypertension between individuals with and without relatives with T2DM. Overweight was 63% more common among individuals having a relative with a T2DM in multivariable model (OR = 1.63; 95% CI: 1.03–2.61).ConclusionsIndividuals with relatives with T2DM have higher probabilities of being overweight compared to those who did not have relatives with T2DM in the same household. The absence of differences on lifestyle-related attitudes and behaviors highlight the need of involving relatives of patients with T2DM on intervention strategies to further enhance diabetes prevention and management efforts.