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Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000-300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10-10). The risk allele, while ancestral, has a frequency of ~1.4%, suggesting strong negative selection and increases risk for SCD by 1.92-fold per allele (95% CI 1.57-2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006).

Fully automated synthetic chemistry would substantially change the field by providing broad on-demand access to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of C sp 3 –C bonds would expand access to many important types of functional organic molecules 1 . Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of C sp 2 –C sp 2 bonds and were effective building blocks for automating the synthesis of many small molecules 2 , but they are incompatible with stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 3 bond-forming reactions 3 , 4 , 5 , 6 , 7 , 8 , 9 – 10 . Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N -methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis 11 , 12 – 13 revealed that redistribution of electron density increases covalency of the N–B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage 2 , which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled C sp 3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 3 bond formation. These findings will enable increasingly complex C sp 3 -rich small molecules to be accessed via automated assembly. Identification of a hyperstable boronate enables automated lego-like synthesis to access a wider range of three-dimensionally complex small organic molecules rich in C sp 3 –C bonds. 

Ocean acidification (OA) is altering the chemistry of the world's oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4) with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material affected only by saturation state.

Unconventional oil and gas development has generated intense public concerns about potential impacts to groundwater quality. Specific pathways of contamination have been identified; however, overall rates of contamination remain ambiguous. We used an archive of geochemical data collected from 1988 to 2014 to determine the sources and occurrence of groundwater methane in the Denver-Julesburg Basin of northeastern Colorado. This 60,000-km² region has a 60-y-long history of hydraulic fracturing, with horizontal drilling and high-volume hydraulic fracturing beginning in 2010. Of 924 sampled water wells in the basin, dissolved methane was detected in 593 wells at depths of 20–190 m. Based on carbon and hydrogen stable isotopes and gas molecular ratios, most of this methane was microbially generated, likely within shallow coal seams. A total of 42 water wells contained thermogenic stray gas originating from underlying oil and gas producing formations. Inadequate surface casing and leaks in production casing and wellhead seals in older, vertical oil and gas wells were identified as stray gas migration pathways. The rate of oil and gas wellbore failure was estimated as 0.06% of the 54,000 oil and gas wells in the basin (lower estimate) to 0.15% of the 20,700 wells in the area where stray gas contamination occurred (upper estimate) and has remained steady at about two cases per year since 2001. These results show that wellbore barrier failure, not high-volume hydraulic fracturing in horizontal wells, is the main cause of thermogenic stray gas migration in this oil- and gas-producing basin.

Increasing anthropogenic carbon dioxide is altering marine carbonate chemistry through a process called ocean acidification. Many calcium carbonate forming organisms are sensitive to changes in marine carbonate chemistry, especially mollusk bivalve larvae at the initial shell building stage. Rapid calcification, limited energy reserves, and more exposed calcification surfaces, are traits at this stage that increase vulnerability to ocean acidification through our previously argued kinetic-energetic hypothesis. These developmental traits are common to broadcast spawning bivalve species that are the focus of most ocean acidification studies to date. Some oyster species brood their young, which results in slower development of the embryos through the initial shell formation stage. We examined the responses of the brooding Olympia oyster, Ostrea lurida, during their initial shell building stage. We extracted fertilized eggs from, O. lurida, prior to shell development, then exposed developing embryos to a wide range of marine carbonate chemistry conditions. Surprisingly, O. lurida showed no acute negative response to any ocean acidification treatments. Compared to the broadcast spawning Pacific oyster, Crassostrea gigas, calcification rate and standardized endogenous energy lipid consumption rate were nearly 10 and 50 times slower, respectively. Our results suggest that slow shell building may lessen the energetic burden of acidification at this stage and provides additional support for our kinetic-energetic hypothesis. Furthermore, these results may represent an example of exaptation; fitness conveyed by a coopted trait that evolved for another purpose, a concept largely lacking in the current perspective of adaptation and global climate change.

We characterize the overall incidence and risk factors for breakthrough infection among fully vaccinated participants in the North Carolina COVID-19 Community Research Partnership cohort. Among 15,808 eligible participants, 638 reported a positive SARS-CoV-2 test after vaccination. Factors associated with a lower risk of breakthrough in the time-to-event analysis included older age, prior SARS-CovV-2 infection, higher rates of face mask use, and receipt of a booster vaccination. Higher rates of breakthrough were reported by participants vaccinated with BNT162b2 or Ad26.COV2.S compared to mRNA-1273, in suburban or rural counties compared to urban counties, and during circulation of the Delta and Omicron variants.

Background: The Cardiovascular Health Cognition Study has evaluated the determinants of dementia among 3,608 participants that had a magnetic resonance imaging (MRI) of the brain in 1991 and were followed to 1998–1999. Methods: There were 480 incident dementia cases, 330 (69%) were classified as Alzheimer’s disease (AD). Results: In univariate analysis, low scores on the Modified Mini-Mental State Examination (3MSE) and on the Digit Symbol Substitution Test as well as declines in scores over time prior to the development of dementia were significant predictors of dementia. A high ventricular grade on the MRI (atrophy) as well as high white matter grade, a number of brain infarcts on the MRI were all determinants of dementia. Apolipoprotein E Ε4 (Apo E-4 ) was also a powerful predictor of dementia. In a multivariate Cox proportional hazards model controlling for race, gender and grade, the hazard ratios for age (1.1), 3MSE score (0.9), ventricular size (1.4), white matter grade (1.8), presence of large infarcts >3 mm (1.3) and Apo E-4 (2.1) were significant predictors of dementia. The combination of an Apo E-4 genotype, 3MSE score <90, ≧5 ventricular grade, ≧3 white matter grade at the time of the MRI were associated with a 17-fold increased risk (95% CI: 8.6–34.9) of dementia as compared to individuals with none of the above attributes. Conclusions: Measures of cognition, Apo E-4 and MRI of the brain are strong predictors of both dementia and of AD.

Neuroimaging genetics is an emerging field that aims to identify the associations between genetic variants (e.g., single nucleotide polymorphisms (SNPs)) and quantitative traits (QTs) such as brain imaging phenotypes. In recent studies, in order to detect complex multi-SNP-multi-QT associations, bi-multivariate techniques such as various structured sparse canonical correlation analysis (SCCA) algorithms have been proposed and used in imaging genetics studies. However, associations between genetic markers and imaging QTs identified by existing bi-multivariate methods may not be all disease specific. To bridge this gap, we propose an analytical framework, based on three-way sparse canonical correlation analysis (T-SCCA), to explore the intrinsic associations among genetic markers, imaging QTs, and clinical scores of interest. We perform an empirical study using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to discover the relationships among SNPs from AD risk gene APOE , imaging QTs extracted from structural magnetic resonance imaging scans, and cognitive and diagnostic outcomes. The proposed T-SCCA model not only outperforms the traditional SCCA method in terms of identifying strong associations, but also discovers robust outcome-relevant imaging genetic patterns, demonstrating its promise for improving disease-related mechanistic understanding.

ObjectiveTo determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI).Study designCohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks’ postmenstrual age was used to produce adjusted odds ratios (aOR).ResultsCompared with infants in the reference group (22–28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8 and 49 but higher among infants treated at DOL 50–63 (aOR 1.77, 95% CI 1.03–3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44–6.48). The aOR for NDI did not vary significantly by age of PNS exposure.ConclusionFor infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD.

Climate change due to greenhouse gas emissions is predicted to raise the mean global temperature by 1.0-3.5°C in the next 50-100 years. The direct and indirect effects of this potential increase in temperature on terrestrial ecosystems and ecosystem processes are likely to be complex and highly varied in time and space. The Global Change and Terrestrial Ecosystems core project of the International Geosphere-Biosphere Programme has recently launched a Network of Ecosystem Warming Studies, the goals of which are to integrate and foster research on ecosystem-level effects of rising temperature. In this paper, we use meta-analysis to synthesize data on the response of soil respiration, net N mineralization, and aboveground plant productivity to experimental ecosystem warming at 32 research sites representing four broadly defined biomes, including high (latitude or altitude) tundra, low tundra, grassland, and forest. Warming methods included electrical heat-resistance ground cables, greenhouses, vented and unvented field chambers, overhead infrared lamps, and passive nighttime warming. Although results from individual sites showed considerable variation in response to warming, results from the meta-analysis showed that, across all sites and years, 2-9 years of experimental warming in the range 0.3-6.0°C significantly increased soil respiration rates by 20% (with a 95% confidence interval of 18-22%), net N mineralization rates by 46% (with a 95% confidence interval of 30-64%), and plant productivity by 19% (with a 95% confidence interval of 15-23%). The response of soil respiration to warming was generally larger in forested ecosystems compared to low tundra and grassland ecosystems, and the response of plant productivity was generally larger in low tundra ecosystems than in forest and grassland ecosystems. With the exception of aboveground plant productivity, which showed a greater positive response to warming in colder ecosystems, the magnitude of the response of these three processes to experimental warming was not generally significantly related to the geographic, climatic, or environmental variables evaluated in this analysis. This underscores the need to understand the relative importance of specific factors (such as temperature, moisture, site quality, vegetation type, successional status, land-use history, etc.) at different spatial and temporal scales, and suggests that we should be cautious in \"scaling up\" responses from the plot and site level to the landscape and biome level. Overall, ecosystem-warming experiments are shown to provide valuable insights on the response of terrestrial ecosystems to elevated temperature.