New insights into the genetic etiology of Alzheimer's disease and related dementias.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

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

Polyaniline: Application as an Anode and Cathode Material in Rechargeable Batteries Employing Aqueous Electrolytes.

Recent studies have shown that polyaniline exhibits interesting characteristics when used as an electrode-active material in an aqueous electrolyte. It can be synthesized easily from aniline by either chemical or electrochemical oxidation in aqueous solution. Polyaniline is believed to exist in the four extreme idealized forms

On the relevance of kinking to reversible hysteresis in MAX phases

This paper examines the idea that reversible hysteresis in MAX phases is caused by the formation, growth and collapse of unstable, or incipient, kink bands. In situ X-ray diffraction of polycrystalline Ti3SiC2 in compression showed that residual elastic lattice strains developed during the first loading cycle and remained approximately constant afterwards. These residual strains were compressive in grains with a low Schmid factor and tensile in grains with a high Schmid factor, consistent with previous observations of plastically deformed hexagonal metals. In contrast, incipient kink bands would be expected to collapse completely, without any residual strain. Elastoplastic self-consistent simulations showed that reversible hysteresis is predicted if some grains yield by slip on the basal plane, while others remain predominantly elastic, giving both the experimentally observed magnitude of the work dissipated and its dependence on the maximum applied stress. The reversible hysteresis in single crystals was studied by cyclically indenting thin films of Ti3SiC2 and Ti3SiC2/TiC multilayers on Al2O3 substrates. The work dissipated in the multilayer films was greater than in Ti3SiC2 alone, despite the reduction in volume fraction of Ti3SiC2. Reversible hysteresis was also observed during indentation of single-crystal cubic MgO, demonstrating that this behaviour can occur if there are insufficient slip systems to accommodate the strain around the indentation. These results show that reversible hysteresis is associated with conventional dislocation flow, without the need for unstable kinking

On the relevance of kinking to reversible hysteresis in MAX phases

This paper examines the idea that reversible hysteresis in MAX phases is caused by the formation, growth and collapse of unstable, or incipient, kink bands. In situ X-ray diffraction of polycrystalline Ti3SiC2 in compression showed that residual elastic lattice strains developed during the first loading cycle and remained approximately constant afterwards. These residual strains were compressive in grains with a low Schmid factor and tensile in grains with a high Schmid factor, consistent with previous observations of plastically deformed hexagonal metals. In contrast, incipient kink bands would be expected to collapse completely, without any residual strain. Elastoplastic self-consistent simulations showed that reversible hysteresis is predicted if some grains yield by slip on the basal plane, while others remain predominantly elastic, giving both the experimentally observed magnitude of the work dissipated and its dependence on the maximum applied stress. The reversible hysteresis in single crystals was studied by cyclically indenting thin films of Ti3SiC2 and Ti3SiC2/TiC multilayers on Al2O3 substrates. The work dissipated in the multilayer films was greater than in Ti3SiC2 alone, despite the reduction in volume fraction of Ti3SiC2. Reversible hysteresis was also observed during indentation of single-crystal cubic MgO, demonstrating that this behaviour can occur if there are insufficient slip systems to accommodate the strain around the indentation. These results show that reversible hysteresis is associated with conventional dislocation flow, without the need for unstable kinking