Medical Research Council

About: Medical Research Council is a government organization based out in London, United Kingdom. It is known for research contribution in the topics: Population & Malaria. The organization has 16430 authors who have published 19150 publications receiving 1475494 citations.

Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits.

Abstract: We show that three of the eleven genes of the nematode Caenorhabditis elegans that mediate resistance to the nematocide levamisole and to other cholinergic agonists encode nicotinic acetylcholine receptor (nAChR) subunits. unc-38 encodes an alpha subunit while lev-1 and unc-29 encode non-alpha subunits. The nematode nAChR subunits show conservation of many mammalian nAChR sequence features, implying an ancient evolutionary origin of nAChR proteins. Expression in Xenopus oocytes of combinations of these subunits that include the unc-38 alpha subunit results in levamisole-induced currents that are suppressed by the nAChR antagonists mecamylamine, neosurugatoxin, and d-tubocurarine but not alpha-bungarotoxin. The mutant phenotypes reveal that unc-38 and unc-29 subunits are necessary for nAChR function, whereas the lev-1 subunit is not. An UNC-29-GFP fusion shows that UNC-29 is expressed in body and head muscles. Two dominant mutations of lev-1 result in a single amino acid substitution or addition in or near transmembrane domain 2, a region important to ion channel conductance and desensitization. The identification of viable nAChR mutants in C. elegans provides an advantageous system in which receptor expression and synaptic targeting can be manipulated and studied in vivo.

Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

Abstract: BackgroundThe RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. MethodsWe used polymerase chain reaction–based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. ResultsIn the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine...

The Virginia Twin Study of Adolescent Behavioral Development: Influences of Age, Sex, and Impairment on Rates of Disorder

Abstract: Background: The Virginia Twin Study of Adolescent Behavioral Development is a cohort-longitudinal epidemiological study that uses the genetic twin design to study the development and maintenance of child psychiatric disorders. We determined the rates of DSM-III-R disorders, disorders with impairment, and age, sex, and co-morbidity effects. Methods: Families of 2762 white twins aged 8 to 16 years participated. Twins and their parents were asked systematically about risk factors and current psychiatric symptoms by means of investigator-based psychiatric interviews and questionnaires. The DSM-III-R diagnoses were made for major depressive disorder, separation anxiety, overanxious disorder, simple phobia, social phobia, agoraphobia, oppositional defiant disorder, conduct disorder, and attention deficit hyperactivity disorder. Results: The 3-month point prevalence for any DSM-III-R disorders was 413 per 1000, and that for disorders with associated impairment was 142 per 1000. Emotionnal disorders with impairment occurred in 89 per 1000, with girls being more commonly affected; behavioral disorders had a prevalence of 71 per 1000, with boys being more frequently affected. The proportion with disorder who also had functional impairment varied across disorders; anxiety and phobic disorders were particularly likely not to be accompanied by impairment. Rates of emotional and behavioral disorders increased over the age range. There was extensive comorbidity among disorders. Conclusions: The prevalence rates and patterns of findings from this study of twins are consistent with those of other epidemiological studies, supporting previous findings of few differences in rates of psychiatric disorder between twins and singletons. The importance of including measures of functional impairment is evident by its effect on rates of disorder and patterns of comorbidity.

Association of Serotype with Risk of Death Due to Pneumococcal Pneumonia: A Meta-Analysis

Abstract: Streptococcus pneumoniae, or pneumococcus, is an important cause of pneumonia, meningitis, otitis media, and septicemia and is associated with significant morbidity and mortality worldwide. There are 92 known pneumococcal serotypes, and each produces a unique polysaccharide capsule that protects the bacterium against host immune effectors [1]. Serotype affects many aspects of pneumococcal epidemiology. The rank orders of serotypes found in nasopharyngeal carriage [2] and invasive disease [3, 4] are similar worldwide with a few exceptions. Likewise, the invasiveness of a serotype, or the frequency with which it causes invasive disease per carriage episode, is a stable property [5]. There is an inverse relationship between the carriage prevalence of a serotype and its invasiveness [5] and between disease severity and invasiveness [6]. The outcome of a case of invasive pneumococcal disease (IPD) can be affected both by bacterial factors, such as serotype, and by host characteristics, such as old age, very young age, low socioeconomic status, quality of care, alcoholism, immunodeficiency, and other underlying conditions[7–10]. Some studies have found that even after controlling for relevant host factors, certain serotypes are independently associated with more severe outcomes [11–13]. Likewise, experimental studies in mice have shown that serotypes differ in their ability to cause severe disease [14], and strains with larger capsules are more virulent in animals than strains of the same serotype with smaller capsules [15, 16]. It was long ago noted that differences in polysaccharide production between types 1, 2, and 3 correlated with the case-fatality ratios (CFR) for these serotypes in humans [7, 17]. While a number of studies have investigated the relationship between serotype and disease outcome, they differ in the kinds of clinical syndromes included, the age of the populations studied, and the covariates included when deriving effect estimates. As a result, published studies differ in the magnitude and direction of effect estimates for certain serotypes, and these studies have not previously been compared to determine whether stable patterns of virulence exist. We performed a systematic review and meta-analysis of IPD outcome by serotype to evaluate the stability of these estimates between studies. We found that clinical outcome in bacteremic pneumonia, like carriage prevalence and invasiveness, is a stable serotype-associated property, and we hypothesize about the biological reasons for these patterns.