33 research outputs found
HLA tapasin independence: broader peptide repertoire and HIV control.
Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines
Tephrochronology of core PRAD 1-2 from the Adriatic Sea: insights into Italian explosive volcanism for the period 200–80 ka
Core PRAD 1-2, located on the western flank of the Mid-Adriatic Deep, was investigated for tephra content within the part of the sequence assigned on biostratigraphic and sapropel-layer stratigraphy to MIS 5 and 6 (ca. 80–200 ka BP). A total of 11 discrete tephra layers are identified, 8 visible and 3 cryptotephra layers. 235 geochemical measurements obtained from individual glass shards using WDS-EPMA enabled 8 of the 11 tephras to be correlated to known eruption events, 5 of which are represented in the Lago Grande di Monticchio (LGdM) regional tephra archive sequence. Three of these layers are recognised ultra-distally for the first time, extending their known distributions approximately 210 km further north. The results provide an independent basis for establishing an age-depth profile for the MIS 5–6 interval in the PRAD 1-2 marine record. This approach allowed age estimates to be interpolated for the tephra layers that could not be correlated to known events. It also provides an independent test of, and support for, the broad synchroneity of sapropel-equivalent (S-E) events in the Adriatic Sea with the better-developed sapropel layers of the eastern Mediterranean, proposed by Piva et al. (2008a)
Parasitology in an archaeological context: analysis of medieval burials in Nivelles, Belgium
Whole-genome sequencing reveals host factors underlying critical COVID-19
Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease
Genetic variation in South Pacific Islanders
SIGLEAvailable from British Library Document Supply Centre- DSC:D96233 / BLDSC - British Library Document Supply CentreGBUnited Kingdo