Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin

Determination of Major Ion Concentration and Ionic Strength of Saline Water: A Case Study of Lakes; Nakuru, Bogoria-Kenya and Nata Saltpan Sanctuary –Botswana

Lakes Nakuru, Bogoria and Nata salt pan are of great ecological and economic importance. They are home to one of the world’s renowned bird sanctuaries with over 400 bird species, lesser flamingoes and breeding ground for a host of water birds including pelicans and flamingoes. These aquatic ecosystems are however; threatened by environmental pollution mainly due to anthropogenic activities in the catchment basins. The current study therefore, sought to determine the concentration of individual ions of saline waters and ionic strength in Lake Nakuru, Lake Bogoria (Kenya) and Nata Saltpan Sanctuary (Botswana) so as to form the baseline information for periodic monitoring and remediation of such aquatic saline systems amid the environmental pollution. Identification of individual dissolved ions can also be used as an indicator of the source of pollution. Samples were collected during the dry season by stratified sampling technique using Van Dorn Sampler. Water temperatures were generally high and consistent with the ambient air temperatures and pH values were 10.55±0.09, 10.15±0.18 and 9.97±0.33 for Nakuru, Bogoria and Nata saltpan respectively. Mean conductivity of values of 47.77±0.78, 62.50±0.37 and 12.79±0.33 were recorded for Lakes Nakuru, Bogoria and Nata saltpans respectively. Cation concentration were dominated by Na+ followed by K+, Ca2+ and Mg2+ and significant amount of trace anions in Lake Nakuru, Bogoria and Nata saltpan. Ionic strength for lakes Nakuru, Bogoria and Nata saltpan waters was 0.166, 0.195 and 0.059 M respectively. The findings of the study showed high level of ions in lakes Nakuru and Bogoria compared to Nata Saltpan. This was attributed to high agricultural and industrial activities in the catchment area. Key Words: Salinity, Conductivity, Ionic strength, Pollution, Water

Association of Gestational Opioid Exposure and Risk of Major and Minor Congenital Malformations

Importance: The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. Objective: To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations. Design, Setting, and Participants: This retrospective population-based cohort study evaluated linked Rhode Island Medicaid claims and vital statistics data of live births from January 1, 2008, to December 31, 2016. Data analysis was conducted from May 1, 2019, to May 31, 2020. Women who had a live birth during the study period, but no cancer or opioid use disorder, were followed up from 3 months before pregnancy to the end of pregnancy. Exposures: Data on the mother’s prescription opioid exposure were obtained through pharmacy claims and exposure was defined as dispensing of at least 1 prescription opioid during the first, second, or third trimester. Main Outcomes and Measures: The primary outcome was overall major or minor congenital malformations, defined as 1 or more major or minor congenital malformation. Secondary outcomes were defined as 10 specific categories of congenital malformations classified by organ systems using International Classification of Diseases diagnosis codes. Results: Of 12 424 included pregnancies, 891 mothers (7.2%) received prescription opioids during pregnancy and 3153 infants (25.4%) were diagnosed with major or minor congenital malformations. Comparing prescription opioid exposure vs nonexposure, no excess risk was observed for major birth defects in infants with opioid exposure in trimester 1 (adjusted relative risk [aRR], 1.40; 95% CI, 0.84-2.34), and higher risks were found for overall minor birth defects in trimester 3 (aRR, 1.26; 95% CI, 1.04-1.53) and minor birth defects in the musculoskeletal system in trimester 2 (aRR, 1.50; 95% CI, 1.10-2.03) and trimester 3 (aRR, 1.65; 95% CI, 1.23-2.22). Significant dose responses in selected minor malformations and effects of specific opioids were also identified. Hydrocodone in trimester 2 (aRR, 3.01; 95% CI, 1.80-5.03) and oxycodone in trimester 3 (aRR, 2.43; 95% CI, 1.37-4.02) were associated with plagiocephaly, polydactyly, and other specified congenital deformities of the hip. Conclusions and Relevance: The findings of this study suggest a higher risk of minor congenital malformations associated with use of prenatal prescription opioids in trimester 3, which seems to be dose-dependent. Further investigation is needed to establish causality and explore the physiologic plausibility of the association

Randomized Trial of Interventions to Improve Childhood Asthma in Homes with Wood-Burning Stoves

BACKGROUND: Household air pollution due to biomass combustion for residential heating adversely affects vulnerable populations. Randomized controlled trials to improve indoor air quality in homes of children with asthma are limited, and no such studies have been conducted in homes using wood for heating. OBJECTIVES: Our aims were to test the hypothesis that household-level interventions, specifically improved-technology wood-burning appliances or air-filtration devices, would improve health measures, in particular Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores, relative to placebo, among children living with asthma in homes with wood-burning stoves. METHODS: A three-arm placebo-controlled randomized trial was conducted in homes with wood-burning stoves among children with asthma. Multiple preintervention and postintervention data included PAQLQ (primary outcome), peak expiratory flow (PEF) monitoring, diurnal peak flow variability (dPFV, an indicator of airway hyperreactivity) and indoor particulate matter (PM) PM2.5. RESULTS: Relative to placebo, neither the air filter nor the woodstove intervention showed improvement in quality-of-life measures. Among the secondary outcomes, dPFV showed a 4.1 percentage point decrease in variability [95% confidence interval (CI) = −7.8 to −0.4] for air-filtration use in comparison with placebo. The air-filter intervention showed a 67% (95% CI: 50% to 77%) reduction in indoor PM2.5, but no change was observed with the improved-technology woodstove intervention. CONCLUSIONS: Among children with asthma and chronic exposure to woodsmoke, an air-filter intervention that improved indoor air quality did not affect quality-of-life measures. Intent-to-treat analysis did show an improvement in the secondary measure of dPFV

Towards Efficient Detection of Small Near-Earth Asteroids Using the Zwicky Transient Facility (ZTF)

We describe ZStreak, a semi-real-time pipeline specialized in detecting small, fast-moving near-Earth asteroids (NEAs) that is currently operating on the data from the newly-commissioned Zwicky Transient Facility (ZTF) survey. Based on a prototype originally developed by Waszczak et al. (2017) for the Palomar Transient Factory (PTF), the predecessor of ZTF, ZStreak features an improved machine-learning model that can cope with the $10\times$ data rate increment between PTF and ZTF. Since its first discovery on 2018 February 5 (2018 CL), ZTF/ZStreak has discovered $45$ confirmed new NEAs over a total of 232 observable nights until 2018 December 31. Most of the discoveries are small NEAs, with diameters less than $\sim100$ m. By analyzing the discovery circumstances, we find that objects having the first to last detection time interval under 2 hr are at risk of being lost. We will further improve real-time follow-up capabilities, and work on suppressing false positives using deep learning.Comment: PASP in pres

Understanding the individual to implement the ecosystem approach to fisheries management

Ecosystem-based approaches to fisheries management (EAFMs) have emerged as requisite for sustainable use of fisheries resources. At the same time, however, there is a growing recognition of the degree of variation among individuals within a population, as well as the ecological consequences of this variation. Managing resources at an ecosystem level calls on practitioners to consider evolutionary processes, and ample evidence from the realm of fisheries science indicates that anthropogenic disturbance can drive changes in predominant character traits (e.g. size at maturity). Eco-evolutionary theory suggests that human-induced trait change and the modification of selective regimens might contribute to ecosystem dynamics at a similar magnitude to species extirpation, extinction and ecological dysfunction. Given the dynamic interaction between fisheries and target species via harvest and subsequent ecosystem consequences, we argue that individual diversity in genetic, physiological and behavioural traits are important considerations under EAFMs. Here, we examine the role of individual variation in a number of contexts relevant to fisheries management, including the potential ecological effects of rapid trait change. Using select examples, we highlight the extent of phenotypic diversity of individuals, as well as the ecological constraints on such diversity. We conclude that individual phenotypic diversity is a complex phenomenon that needs to be considered in EAFMs, with the ultimate realization that maintaining or increasing individual trait diversity may afford not only species, but also entire ecosystems, with enhanced resilience to environmental perturbations. Put simply, individuals are the foundation from which population- and ecosystem-level traits emerge and are therefore of central importance for the ecosystem-based approaches to fisheries management

The Relationship Between Physical Activity and Diet and Young Children\u27s Cognitive Development: A Systematic Review

Objective Given the high prevalence of suboptimal nutrition and low activity levels in children, we systematically reviewed the literature on the relationship between physical activity and dietary patterns and cognitive development in early childhood (six months to five years). Methods In February 2016, we conducted two different searches of MEDLINE, PsycINFO, and ERIC. Each search included either physical activity (including gross motor skills) or diet terms, and neurocognitive development outcome terms. Included studies were in English, published since 2005, and of any study design in which the physical activity or diet measure occurred prior to age five. Results For physical activity, twelve studies (5 cross-sectional, 3 longitudinal and 4 experimental) were included. Eleven studies reported evidence suggesting that physical activity or gross motor skills are related to cognition or learning. Both acute bouts and longer term exposures showed benefit. For diet, eight studies were included consisting of secondary analyses from longitudinal cohort studies. A healthier dietary pattern was associated with better cognitive outcomes in all studies, although some of the reported associations were weak and the measures used varied across the studies. Conclusions Physical activity and healthy diets in early childhood are associated with better cognitive outcomes in young children. The paucity of literature and the variability in the type and quality of measures used highlight the need for more rigorous research. Given that the early childhood years are critical for both obesity prevention and neurocognitive development, evidence that the same healthy behaviors could promote both should inform future interventions. Keywords Nutrition; Physical activity; Childhood obesity; Cognitive development; Executive function; Early learnin

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors.

With a resurgence in interest in covalent drugs, there is a need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as a cysteine reactive warhead is employed to target Cys788 in c-KIT, where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification while avoiding some of the limitations generally associated with established moieties