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Protoporphyrinogen oxidase (PPO) is an important target for discovering new herbicides that interfere with the synthesis of porphyrin. In order to discover new PPO inhibitor herbicides with improved biological activity, a series of new diphenyl ethers containing tetrahydrophthalimide are designed and synthesized. Among them, J6.1 (IC50=4.7 nM) and J6.3 (IC50=30.0 nM) show higher maize (Zea mays L.)PPO inhibitory activity than the commercial herbicides, i.e., oxyfluorfen (IC50=117.9 nM) and flumioxazin (IC50=157.1 nM). The greenhouse herbicidal activity of J6.3 is comparable to that of oxyfluorfen, and it is greater than that of flumioxazin. Even at a dose of 300 g active ingredients/hectare (a.i/ha), cotton (Gossypium hirsutum L.) and peanut (Arachis hypogaea L.) show greater tolerance to J6.3, suggesting that J6.3 could be used for further development of new herbicide candidates in those fields. In addition, molecular docking has been used to further study its mechanism of action. The results show that the introduction of nitro group and tetrahydrophthalimide into the diphenyl ether structure is beneficial to biological activity.
Combination olanzapine and samidorphan (OLZ/SAM), in development for schizophrenia and bipolar I disorder, is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. OLZ/SAM safety, tolerability, and efficacy from a 52-week open-label extension study in patients with schizophrenia are reported.
Patients previously completing the 4-week, double-blind ENLIGHTEN-1 study switched from OLZ/SAM, olanzapine, or placebo to OLZ/SAM. Assessments included adverse events (AEs), weight, vital signs, Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression-Severity (CGI-S) scores. Baseline was prior to first dose of OLZ/SAM in the extension study.
In total, 281 patients enrolled, 277 received ≥1 OLZ/SAM dose, and 183 (66.1%) completed 52 weeks. Reasons for discontinuation included patient withdrawal (15.5%), loss to follow-up (6.9%), AEs (5.8%), and lack of efficacy (1.8%). AEs were reported in 136 (49.1%) patients; increased weight (13%) and somnolence (8%) were most common. Ten serious AEs were reported in eight patients (2.9%); none were considered treatment related. There were no deaths. Mean (SD) baseline weight was 79.1 (17.8) kg. Mean weight change from baseline to week 52 was 1.86 kg (2.79% increase). PANSS total and CGI-S scores continued to decline over 52 weeks (mean [95% CI] changes from baseline to week 52: −16.2 [−18.5, −14.0] and −0.9 [−1.0, −0.8], respectively).
OLZ/SAM was generally well tolerated in this extension study; most patients completed the 52-week treatment period with sustained improvement in schizophrenia symptoms. Mean increases in weight stabilized by week 6 with limited subsequent change through end of treatment.
To determine whether ambient air pollutants and meteorological variables are associated with daily COVID-19 incidence.
A retrospective cohort from January 25 to February 29, 2020.
Cities of Wuhan, Xiaogan, and Huanggang, China.
The COVID-19 cases detected each day.
We collected daily data of COVID-19 incidence, 8 ambient air pollutants (particulate matter of ≤2.5 µm [PM2.5], particulate matter ≤10 µm [PM10], sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and maximum 8-h moving average concentrations for ozone [O3-8h]) and 3 meteorological variables (temperature, relative humidity, and wind) in China’s 3 worst COVID-19–stricken cities during the study period. The multivariate Poisson regression was performed to understand their correlation.
Daily COVID-19 incidence was positively associated with PM2.5 and humidity in all cities. Specifically, the relative risk (RR) of PM2.5 for daily COVID-19 incidences were 1.036 (95% confidence interval [CI], 1.032–1.039) in Wuhan, 1.059 (95% CI, 1.046–1.072) in Xiaogan, and 1.144 (95% CI, 1.12–1.169) in Huanggang. The RR of humidity for daily COVID-19 incidence was consistently lower than that of PM2.5, and this difference ranged from 0.027 to 0.111. Moreover, PM10 and temperature also exhibited a notable correlation with daily COVID-19 incidence, but in a negative pattern The RR of PM10 for daily COVID-19 incidence ranged from 0.915 (95% CI, 0.896–0.934) to 0.961 (95% CI, 0.95–0.972, while that of temperature ranged from 0.738 (95% CI, 0.717–0.759) to 0.969 (95% CI, 0.966–0.973).
Our data show that PM2.5 and humidity are substantially associated with an increased risk of COVID-19 and that PM10 and temperature are substantially associated with a decreased risk of COVID-19.
To estimate the current evidence regarding the association between gestational acrylamide (AA) exposure and offspring’s growth.
Systematic review and meta-analysis.
A systematic literature search for relevant publications was conducted using PubMed, Medline, Embase, Web of Science databases from inception to 26 April 2019. The standardised mean difference (SMD) or OR with 95 % CI was selected as the effect sizes and was calculated using a random effects model.
Five cohort studies including 54 728 participants were identified. Offspring’s birth weight was significantly lower in high AA exposure group than in low AA exposure group (SMD –0·05, 95 % CI –0·09, –0·02, P = 0·005). There was also an association between maternal AA exposure and small for gestational age (OR 1·14, 95 % CI 1·06, 1·23, P < 0·001). In addition, pooled ORs suggested that children had a high risk of developing overweight/obesity in the future in maternal high AA exposure group (OR 1·14, 95 % CI 1·08, 1·21, P < 0·001 at age 3; OR 1·13, 95 % CI 1·07, 1·19, P < 0·001 at age 5; OR 1·09, 95 % CI 1·02, 1·16, P = 0·020 at age 8).
These findings have important implications for conducting health education, providing guidance on maternal diet and developing an appropriate dietary strategy for pregnant women to reduce dietary AA exposure.
Dietary salt intake may vary depending on different lifestyles. We aimed to estimate the different salt intakes and evaluate the knowledge and self-awareness about salt among people speaking the Teochew, Teochew–Hakka and Hakka dialects in the Chaoshan region of southern China.
The study followed a cluster sampling of residents in Chaoshan region. General characteristics, lifestyles, health status as well as knowledge and self-awareness related to salt intake were investigated using a questionnaire. Anthropometric variables as well as Na and K excretion in a 24-h urine collection were measured.
Chaoshan region of China.
Four hundred fifteen adults who spoke only one of these three dialects.
The salt intake of adults who spoke the Teochew, Teochew–Hakka and Hakka dialects was 7·19 (interquartile range (IQR) 5·29–10·17), 9·03 (IQR 6·62–11·54) and 10·12 (IQR 7·61–12·82) g/d, respectively, with significant differences between Teochew and Teochew–Hakka speakers and between Teochew and Hakka speakers (both P < 0·05). The Na:K ratio for adults who spoke the three dialects was 3·00 (IQR 2·00–4·11), 3·50 (IQR 2·64–4·82) and 4·52 (IQR 3·35–5·97), respectively, and differed significantly among the groups (all P < 0·05). Multiple linear regression analysis showed increased Na:K ratio associated with hypertension (β = 0·71, P = 0·043) in Hakka speakers. Knowledge and self-awareness about salt intake were poor in this population.
Salt intake was closely related to lifestyles and was higher than the upper limit (5 g/d) recommended by the WHO in adults of Chaoshan, especially those speaking the Hakka dialect.
Opioid antagonists may mitigate medication-associated weight gain and/or metabolic dysregulation. ENLIGHTEN-2 evaluated a combination of olanzapine and the opioid antagonist samidorphan (OLZ/SAM) vs olanzapine for effects on weight gain and metabolic parameters over 24 weeks in adults with stable schizophrenia.
This phase 3, double-blind study (ClinicalTrials.gov: NCT02694328) enrolled adults 18–55 yo with stable schizophrenia, randomized 1:1 to once-daily OLZ/SAM or olanzapine. Co-primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. Waist circumference and fasting metabolic parameters were also measured. Completers could enter a 52-week open-label safety extension.
561 patients were randomized: 550 were dosed, 538 had ≥1 post-baseline weight assessment, and 352 (64%) completed; 10.9% discontinued due to AEs. At week 24, least squares mean (SE) percent weight change from baseline was 4.21 (0.68)% with OLZ/SAM and 6.59 (0.67)% with olanzapine (difference, −2.38 [0.76]%; P=0.003). Fewer patients treated with OLZ/SAM (17.8%) had ≥10% weight gain vs olanzapine (29.8%; odds ratio=0.50; P=0.003). The change from baseline in waist circumference was significantly smaller with OLZ/SAM (P<0.001). Common AEs (≥10%) with OLZ/SAM and olanzapine were weight increased (24.8%, 36.2%), somnolence (21.2%, 18.1%), dry mouth (12.8%, 8.0%), and increased appetite (10.9%, 12.3%), respectively. Metabolic parameter changes were generally small and remained stable with long-term OLZ/SAM treatment.
OLZ/SAM treatment limited weight gain associated with olanzapine. Metabolic parameter changes were generally small, similar between groups over 24 weeks, and remained stable over an additional 52 weeks of open-label OLZ/SAM treatment.
A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.
Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.
Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).
In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.
Social attention ability is crucial for human adaptive social behaviors and interpersonal communications, and the malfunction of which has been implicated in autism spectrum disorder (ASD), a highly genetic neurodevelopmental disorder marked by striking social deficits.
Using a classical twin design, the current study investigated the genetic contribution to individual variation in social and non-social attention abilities, and further probed their potential genetic linkage. Moreover, individual autistic traits were further measured in an independent group of non-twin participants to examine the hypothetical link between the core social attention ability and ASD.
We found reliable genetic influences on the social attentional effects induced by two distinct cues (eye gaze and walking direction), with 91% of their covariance accounted for by common genetic effects. However, no evidence of heritability or shared genetic effects was observed for the attentional effect directed by a non-social cue (i.e. arrow direction) and its correlation with the social attention ability. Remarkably, one's autistic traits could well predict his/her heritable core social attention ability extracted from the conventional social attentional effect.
These findings together suggest that human social attention ability is supported by unique genetic mechanisms that can be shared across different social, but not non-social, processing. Moreover, they also encourage the identification of ‘social attention genes’ and highlight the critical role of the core human social attention ability in seeking the endophenotypes of social cognitive disorders including ASD.
Density functional theory (DFT) has proved to be exceptionally successful in rationalizing trends in activity and functionality for electrochemical functional materials. With continued increases in computing power, there has been an increased interest in “high-throughput” materials discovery and design based on a few descriptors to scan the phase space en masse for thousands of potential candidates, which could be made technologically and commercially viable. However, given fundamental accuracy limitations associated with DFT, the success of high-throughput material discovery efforts has been limited. In this review, we suggest an additional dimension to aid in high-throughput material discovery related to uncertainty quantification and propagation, which provides a more realistic picture of the likelihood of new candidate materials to improve upon known materials. We demonstrate the approach and its utility through two case studies: (1) electrocatalyst materials for their activity and selectivity for the oxygen reduction reaction, and (2) cathode materials for Li-ion batteries based on Ni-Mn-Co oxides. The ease with which uncertainty quantification and propagation can be incorporated into traditional high-throughput material discovery with almost no additional computational cost allows for its proposed wide usage.
This article provides an overview of emerging directions in the materials science of biointegrated electronic and microfluidic systems, as defined by technologies that are capable of supporting long-term, intimate, physical interfaces to living organisms. Here, deterministic hard/soft composite structures, including those that leverage concepts in fractal mathematics, serve as the materials foundations for diverse devices of this type. Examples of “epidermal” or skin-like electronic systems for biophysical tracking of patient conditions that range from stroke to hydrocephalus illustrate the engineering maturity and operational sophistication that is now possible. Recent ideas in soft, skin-mounted, microfluidic lab-on-a-chip systems extend the capabilities of such platforms to include biochemical assessments of physiological status via capture, storage, manipulation, and in situ detection of biomarkers in microliter volumes of sweat, collected as it emerges from the surface of the skin. The article concludes with a description of mechanically guided assembly schemes that provide access to three-dimensional, open-mesh constructs, as a frontier area of materials development in this broader area of biointegrated systems.