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.

A Mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis.

Abstract: Toll-like receptors (TLRs) and members of their signaling pathway are important in the initiation of the innate immune response to a wide variety of pathogens. The adaptor protein Mal (also known as TIRAP), encoded by TIRAP (MIM 606252), mediates downstream signaling of TLR2 and TLR4 (refs. 4-6). We report a case-control study of 6,106 individuals from the UK, Vietnam and several African countries with invasive pneumococcal disease, bacteremia, malaria and tuberculosis. We genotyped 33 SNPs, including rs8177374, which encodes a leucine substitution at Ser180 of Mal. We found that heterozygous carriage of this variant associated independently with all four infectious diseases in the different study populations. Combining the study groups, we found substantial support for a protective effect of S180L heterozygosity against these infectious diseases (N = 6,106; overall P = 9.6 x 10(-8)). We found that the Mal S180L variant attenuated TLR2 signal transduction.

Prediction of human errors by maladaptive changes in event-related brain networks.

Abstract: Humans engaged in monotonous tasks are susceptible to occasional errors that may lead to serious consequences, but little is known about brain activity patterns preceding errors. Using functional MRI and applying independent component analysis followed by deconvolution of hemodynamic responses, we studied error preceding brain activity on a trial-by-trial basis. We found a set of brain regions in which the temporal evolution of activation predicted performance errors. These maladaptive brain activity changes started to evolve ≈30 sec before the error. In particular, a coincident decrease of deactivation in default mode regions of the brain, together with a decline of activation in regions associated with maintaining task effort, raised the probability of future errors. Our findings provide insights into the brain network dynamics preceding human performance errors and suggest that monitoring of the identified precursor states may help in avoiding human errors in critical real-world situations.

Model for signal sequence recognition from amino-acid sequence of 54K subunit of signal recognition particle

Abstract: PROTEIN targeting to the endoplasmic reticulum in mammalian cells is catalysed by signal recognition particle (SRP)1,2. Cross-linking experiments have shown that the subunit of relative molecular mass 54,000 (Mr 54K; SRP54) interacts directly with signal sequences as they emerge from the ribosome3,4. Here we present the sequence of a complementary DNA clone of SRP54 which predicts a protein that contains a putative GTP-binding domain and an unusually methionine-rich domain. The properties of this latter domain suggest that it contains the signal sequence binding site. A previously uncharacterized Escherichia coli protein has strong homology to both domains. Closely homologous GTP-binding domains are also found in the α-subunit of the SRP receptor (SRα, docking protein) in the endoplasmic reticulum membrane5-8 and in a second E. coli protein, ftsY, which resembles SRα. Recent work has shown that SRα is a GTP-binding protein and that GTP is required for the release of SRP from the signal sequence and the ribosome on targeting to the endoplasmic reticulum membrane9. We propose that SRP54 and SRα use GTP in sequential steps of the targeting reaction and that essential features of such a pathway are conserved from bacteria to mammals.

Mutations in the myosin VIIA gene cause non-syndromic recessive deafness.

Abstract: Genetic hearing impairment affects around 1 in every 2,000 births. The bulk (approximately 70%) of genetic deafness is non-syndromic, in which hearing impairment is not associated with any other abnormalities. Over 25 loci involved in non-syndromic deafness have been mapped and mutations in connexin 26 have been identified as a cause of non-sydromic deafness. One locus for non-syndromic recessive deafness, DFNB2 (ref. 4), has been localized to the same chromosomal region, 11q14, as one of the loci, USH1B, underlying the recessive deaf-blind syndrome. Usher syndrome type 1b, which is characterized by profound congenital sensorineural deafness, constant vestibular dysfunction and prepubertal onset of retinitis pigmentosa. Recently, it has been shown that a gene encoding an unconventional myosin, myosin VIIA, underlies the mouse recessive deafness mutation, shaker-1 (ref. 5) as well as Usher syndrome type 1b. Mice with shaker-1 demonstrate typical neuroepithelial defects manifested by hearing loss and vestibular dysfunction but no retinal pathology. Differences in retinal patterns of expression may account for the variance in phenotype between shaker-1 mice and Usher type 1 syndrome. Nevertheless, the expression of MYO7A in the neuroepithelium suggests that it should be considered a candidate for non-syndromic deafness in the human population. By screening families with non-syndromic deafness from China, we have identified two families carrying MYO7A mutations.