Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response

Genomic Dissection of Bipolar Disorder and Schizophrenia, Including 28 Subphenotypes

Schizophrenia and bipolar disorder are two distinct diagnoses that share symptomology. Understanding the genetic factors contributing to the shared and disorder-specific symptoms will be crucial for improving diagnosis and treatment. In genetic data consisting of 53,555 cases (20,129 bipolar disorder [BD], 33,426 schizophrenia [SCZ]) and 54,065 controls, we identified 114 genome-wide significant loci implicating synaptic and neuronal pathways shared between disorders. Comparing SCZ to BD (23,585 SCZ, 15,270 BD) identified four genomic regions including one with disorder-independent causal variants and potassium ion response genes as contributing to differences in biology between the disorders. Polygenic risk score (PRS) analyses identified several significant correlations within case-only phenotypes including SCZ PRS with psychotic features and age of onset in BD. For the first time, we discover specific loci that distinguish between BD and SCZ and identify polygenic components underlying multiple symptom dimensions. These results point to the utility of genetics to inform symptomology and potential treatment

Shaping Amine-Based Solid CO₂ Adsorbents: Effects of Pelletization Pressure on the Physical and Chemical Properties

Amine-based solid adsorbents are promising candidates for the separation of CO₂ from dilute gas streams. Here we report the effect of pelletization pressure on the physical and chemical properties of an array of supported amine adsorbents, based on mesoporous silica and γ-alumina supports. The virgin powders based on poly(ethyleneimine) (PEI) and 3-aminopropyltrimethoxysilane (APS) functionalized oxides are pressed at 1000 and 5000 psig pressure to form self-supporting pellets and their physical and chemical properties are compared. No change in chemical structure of the adsorbents is observed after pelletization, though the porosity of each material changes to some degree. Of the three mesoporous supports examined in this study, the commercial porous silica is the most stable support for both class 1 and class 2 adsorbents, whereas lab synthesized mesoporous SBA-15 silica and lab synthesized mesoporous γ-alumina are found to be the least stable supports for class 1 and class 2 adsorbents, respectively. The CO₂ uptake results show a significant drop in equilibrium capacity for the pellets pressed at 5000 psig, regardless of the support used, while the 1000 psig pellets retain their capacity and show comparable performance to their powder counterparts. CO₂ breakthrough experiments suggest an increase in mass transfer resistance for the pellet samples as compared with virgin powders, resulting in the dispersion of the concentration fronts during CO₂ breakthrough using a fixed bed. These findings suggest that shaping solid supported amine adsorbents into binderless pellets requires pressing the powders at low to moderate pressures to ensure that these materials retain their performance in processes that require pelletized samples

Disinfection of Contaminated Water by Using Solar Irradiation

Contaminated water causes an estimated 6 to 60 billion cases of gastrointestinal illness annually. The majority of these cases occur in rural areas of developing nations where the water supply remains polluted and adequate sanitation is unavailable. A portable, low-cost, and low-maintenance solar unit to disinfect unpotable water has been designed and tested. The solar disinfection unit was tested with both river water and partially processed water from two wastewater treatment plants. In less than 30 min in midday sunlight, the unit eradicated more than 4 log(10) U (99.99%) of bacteria contained in highly contaminated water samples. The solar disinfection unit has been field tested by Centro Panamericano de Ingenieria Sanitaria y Ciencias del Ambiente in Lima, Peru. At moderate light intensity, the solar disinfection unit was capable of reducing the bacterial load in a controlled contaminated water sample by 4 log(10) U and disinfected approximately 1 liter of water in 30 min

Ester Formation and Hydrolysis during Wet–Dry Cycles: Generation of Far-from-Equilibrium Polymers in a Model Prebiotic Reaction

Biopolymers exist within living cells as far-from-equilibrium metastable polymers. Living systems must constantly invest energy for biopolymer synthesis. In the earliest stages of life on Earth, the complex molecular machinery that contemporary life employs for the synthesis and maintenance of polymers did not exist. Thus, a major question regarding the origin of life is how the first far-from-equilibrium polymers emerged from a prebiotic “pool” of monomers. Here, we describe a proof-of-principle system, in which l-malic acid monomers form far-from-equilibrium, metastable oligoesters via repeated, cyclic changes in hydration and temperature. Such cycles would have been associated with day–night and/or seasonal cycles on the early Earth. In our model system, sample heating, which promotes water evaporation and ester bond formation, drives polymerization. Even though periodic sample rehydration and heating in the hydrated state promotes ester bond hydrolysis, successive iterations of wet–dry cycles result in polymer yields and molecular weight distributions in excess of that observed after a single drying cycle. We term this phenomenon a “polymerization ratchet”. We have quantitatively characterized the “ratchet” of our particular system. Ester bond formation rates and oligoester hydrolysis rates were determined for temperatures ranging from 60 to 95 °C. Based on these rates, a mathematical model was developed using polycondensation kinetics, from which conditions were predicted for oligoester growth. This model was verified experimentally by the demonstration that l-malic acid monomers subjected to multiple wet–dry cycles form oligoesters, which reach a steady-state concentration and mean length after several cycles. The concentration of oligoesters that persist between subsequent steady-state cycles depends on the temperature and durations of the dry and wet phases of the cycle. These results provide insights regarding the potential for very simple systems to exhibit features that would have been necessary for initiation of polymer evolution, before the emergence of genomes or enzymes

Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.

BackgroundNVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America.MethodsWe conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed.ResultsOf the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose.ConclusionsNVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)