Start codon variant in LAG3 is associated with decreased LAG-3 expression and increased risk of autoimmune thyroid disease.

Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported.

Physical and cognitive impact following SARS-CoV-2 infection in a large population-based case-control study.

Background: Persistent symptoms are common after SARS-CoV-2 infection but correlation with objective measures is unclear.

Methods: We invited all 3098 adults who tested SARS-CoV-2 positive in Iceland before October 2020 to the deCODE Health Study. We compared multiple symptoms and physical measures between 1706 Icelanders with confirmed prior infection (cases) who participated, and 619 contemporary and 13,779 historical controls.

A small-molecule PI3Kα activator for cardioprotection and neuroregeneration.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling.

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca entry is involved in Ca homeostasis in PASMCs, but its properties in PAH are unclear.

Molecular benchmarks of a SARS-CoV-2 epidemic.

A pressing concern in the SARS-CoV-2 epidemic and other viral outbreaks, is the extent to which the containment measures are halting the viral spread. A straightforward way to assess this is to tally the active cases and the recovered ones throughout the epidemic. Here, we show how epidemic control can be assessed with molecular information during a well characterized epidemic in Iceland.

Humoral Immune Response to SARS-CoV-2 in Iceland.

Background: Little is known about the nature and durability of the humoral immune response to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We measured antibodies in serum samples from 30,576 persons in Iceland, using six assays (including two pan-immunoglobulin [pan-Ig] assays), and we determined that the appropriate measure of seropositivity was a positive result with both pan-Ig assays. We tested 2102 samples collected from 1237 persons up to 4 months after diagnosis by a quantitative polymerase-chain-reaction (qPCR) assay.

Enantioselective Redox-Divergent Chiral Phosphoric Acid Catalyzed Quinone Diels-Alder Reactions.

An efficient enantioselective construction of tetrahydronaphthalene-1,4-diones as well as dihydronaphthalene-1,4-diols by a chiral phosphoric acid catalyzed quinone Diels-Alder reaction with dienecarbamates is reported. The nature of the protecting group on the diene is key to the success of achieving high enantioselectivity. The divergent "redox" selectivity is controlled by using an adequate amount of quinones.

Real-Life Efficacy of Osimertinib in Pretreated Octogenarian Patients with T790M-Mutated Advanced Non-small Cell Lung Cancer.

Background: The resistance mutation T790M is reported in 50-60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare.

Objective: The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients.

Muscular dystrophy with arrhythmia caused by loss-of-function mutations in .

Objective: To study the genetic and phenotypic spectrum of patients harboring recessive mutations in .

Methods: We performed whole-exome sequencing in a multicenter cohort of 1929 patients with a suspected hereditary myopathy, showing unexplained limb-girdle muscular weakness and/or elevated creatine kinase levels. Immunohistochemistry and mRNA experiments on patients' skeletal muscle tissue were performed to study the pathogenicity of identified loss-of-function (LOF) variants in .

Chiral phosphoric acid-catalyzed enantioselective construction of structurally diverse benzothiazolopyrimidines.

A highly efficient catalytic enantioselective [4+2] cycloaddition was developed between 2-benzothiazolimines and enecarbamates. A wide range of benzothiazolopyrimidines bearing three contiguous stereogenic centers was obtained in high to excellent yields and with excellent diastereo- and enantioselectivities (d.r.

Enantioselective Brønsted Acid Catalysis as a Tool for the Synthesis of Natural Products and Pharmaceuticals.

Synthesis of biologically active molecules (whether at laboratory or industrial scale) remains a highly appealing area of modern organic chemistry. Nowadays, the need to access original bioactive scaffolds goes together with the desire to improve synthetic efficiency, while reducing the environmental footprint of chemical activities. Long neglected in the field of total synthesis, enantioselective organocatalysis has recently emerged as an environmentally friendly and indispensable tool for the construction of relevant bioactive molecules.

Enantioselective Three-Component Amination of Enecarbamates Enables the Synthesis of Structurally Complex Small Molecules.

The control of asymmetric synthesis tools represents a major challenge, especially when it comes to the synthesis of bioactive molecules. In this context, the asymmetric synthesis of 1,2-diamines through amination of enecarbamates has been proposed as a highly efficient and tunable approach. Indeed, reactivity of the latter species could be exploited to realize a double functionalization via an electrophilic amination followed by nucleophilic trapping.

Regio-, Diastereo-, and Enantioselective Nitroso-Diels-Alder Reaction of 1,3-Diene-1-carbamates Catalyzed by Chiral Phosphoric Acids.

Chiral phosphoric acid-catalyzed asymmetric nitroso-Diels-Alder reaction of nitrosoarenes with carbamate-dienes afforded cis-3,6-disubstituted dihydro-1,2-oxazines in high yields with excellent regio-, diastereo-, and enantioselectivities. Interestingly, we observed that the catalyst is able not only to control the enantioselectivity but also to reverse the regioselectivity of the noncatalyzed nitroso-Diels-Alder reaction. The regiochemistry reversal and asynchronous concerted mechanism were confirmed by DFT calculations.

Oxidative Stress Biomarkers and Incidence of Postoperative Atrial Fibrillation in the Omega-3 Fatty Acids for Prevention of Postoperative Atrial Fibrillation (OPERA) Trial.

Background: Animal study results point to oxidative stress as a key mechanism triggering postoperative atrial fibrillation (PoAF), yet the extent to which specific biomarkers of oxidative stress might relate to PoAF risk in humans remains speculative.

Methods And Results: We assessed the association of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans, and F3-isoprostanes) in plasma and urine, with incident PoAF among 551 cardiac surgery patients. Biomarkers were measured at enrollment, the end of surgery, and postoperative day 2.

Infective endocarditis after transcatheter aortic valve implantation: results from a large multicenter registry.

Background: We aimed to determine the incidence, predictors, clinical characteristics, management, and outcomes of infective endocarditis (IE) after transcatheter aortic valve implantation (TAVI).

Methods And Results: This multicenter registry included 53 patients (mean age, 79±8 years; men, 57%) who suffered IE after TAVI of 7944 patients after a mean follow-up of 1.1±1.

Resveratrol treatment of mice with pressure-overload-induced heart failure improves diastolic function and cardiac energy metabolism.

Background: Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload-induced HF and identified physiological and molecular mechanisms contributing to this.

Methods And Results: C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF.

Hairy root transformation using Agrobacterium rhizogenes as a tool for exploring cell type-specific gene expression and function using tomato as a model.

Agrobacterium rhizogenes (or Rhizobium rhizogenes) is able to transform plant genomes and induce the production of hairy roots. We describe the use of A. rhizogenes in tomato (Solanum spp.