Novel human immunodeficiency virus type 1 protease mutations potentially involved in resistance to protease inhibitors

Plasma-derived sequences of human immunodeficiency virus type 1 (HIV-1) protease from 1,162 patients (457 drug-naive patients and 705 patients receiving protease inhibitor [PI]-containing antiretroviral regimens) led to the identification and characterization of 17 novel protease mutations potentially associated with resistance to PIs. Fourteen mutations were positively associated with PIs and significantly correlated in pairs and/or clusters with known PI resistance mutations, suggesting their contribution to PI resistance. In particular, E34Q, K43T, and K55R, which were associated with lopinavir treatment, correlated with mutations associated with lopinavir resistance (E34Q with either L33F or F53L, or K43T with I54A) or clustered with multi-PI resistance mutations (K43T with V82A and I54V or V82A, V32I, and I47V, or K55R with V82A, I54V, and M46I). On the other hand, C95F, which was associated with treatment with saquinavir and indinavir, was highly expressed in clusters with either L90M and I93L or V82A and G48V. K45R and K20T, which were associated with nelfinavir treatment, were specifically associated with D30N and N88D and with L90M, respectively. Structural analysis showed that several correlated positions were within 8 A of each other, confirming the role of the local environment for interactions among mutations. We also identified three protease mutations (T12A, L63Q, and H69N) whose frequencies significantly decreased in PI-treated patients compared with that in drug-naive patients. They never showed positive correlations with PI resistance mutations; if anything, H69N showed a negative correlation with the compensatory mutations M36I and L10I. These mutations may prevent the appearance of PI resistance mutations, thus increasing the genetic barrier to PI resistance. Overall, our study contributes to a better definition of protease mutational patterns that regulate PI resistance and strongly suggests that other (novel) mutations beyond those currently known to confer resistance should be taken into account to better predict resistance to antiretroviral drugs

Physics searches at the LHC

With the LHC up and running, the focus of experimental and theoretical high energy physics will soon turn to an interpretation of LHC data in terms of the physics of electroweak symmetry breaking and the TeV scale. We present here a broad review of models for new TeV-scale physics and their LHC signatures. In addition, we discuss possible new physics signatures and describe how they can be linked to specific models of physics beyond the Standard Model. Finally, we illustrate how the LHC era could culminate in a detailed understanding of the underlying principles of TeV-scale physics.Comment: 184 pages, 55 figures, 14 tables, hundreds of references; scientific feedback is welcome and encouraged. v2: text, references and Overview Table added; feedback still welcom

Proton-hole states in the N=30 neutron-rich isotope K49

Excited states in the N=30 neutron-rich isotope K49 have been studied using multinucleon transfer reactions with thin targets and the PRISMA-CLARA spectrometer combined with thick-target γ-coincidence data from Gammasphere. The d3/2 proton-hole state is located 92 keV above the s1/2 ground state, and the proton-particle f7/2 state is suggested at 2104 keV. Three other levels are established as involving the coupling to 2+ of two neutrons above the N=28 shell. The measured or estimated lifetimes served to reinforce the interpretation of the observed level structure, which is found to be in satisfactory agreement with shell-model calculations

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

Effect of filler type and processing apparatus on the properties of the recycled "light fraction" from municipal post consumer plastics

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