Structure-based virtual screening for novel p38 MAPK inhibitors and a biological evaluation

Mitogen-activated protein kinases (MAPKs) are a group of serine-threonine protein kinases that can be activated by extracellular stimuli. MAPK14 (p38α) affects major disease processes, while inhibition of p38α has been shown to have potential therapeutic effects. Many inhibitors targeting p38α have entered clinical trials but have a long development cycle and severe side effects. We developed a multi-step receptor structure-based virtual screening method to screen potential bioactive molecules from SPECS and our MCDB libraries. Compound 10 was identified as a promising p38α inhibitor that may be used in the treatment of p38αMAPK pathway-related diseases, but corollary studies are warranted

Associations of COVID-19 lockdown with birth weight in China

BackgroundDuring the special period of the global spread of COVID-19, pregnant women are sensitive groups to the impacts of COVID-19 epidemic. However, the effects of lockdown measures implemented in response to the COVID-19 on fetal birthweight remain unclear.ObjectivesThis study investigated the associations of COVID-19 lockdown with birth weight in Chinese population.MethodsWe collected 730,153 data of participants from hospitals of five cities in the south of China, we defined the time period of level I response (1/23-2/24/2020) as level I lockdown, and women who were pregnant during level I lockdown as the exposure group. Women who were pregnant during the same calendar month from 2015 to 2019 were defined as the unexposed group. We quantitatively estimate the individual cumulative exposure dose by giving different weights to days with different emergency response levels. Generalized linear regression models were used to estimate the association between COVID-19 lockdown exposure with birth weight and risk of low birth weight (<2,500 g) and macrosomia (>4,000 g).ResultsThe birth weight of the exposed group is heavier than the unexposed group (3,238.52 vs. 3,224.11 g: adjusted β = 24.39 g [95% CI: 21.88, 26.91 g]). The exposed group had a higher risk of macrosomia (2.8% vs. 2.6%; adjusted OR = 1.17 [95% CI: 1.12, 1.22]). More obvious associations were found between COVID-19 lockdown and macrosomia in women who experienced the lockdown in their early pregnancy. Women who experienced the lockdown at their 4–7 weeks of pregnancy showed statistically significant heavier birth weight than unexposed group (after adjustment): β = 1.28 (95% CI: 1.11, 1.46) g. We also observed a positive association between cumulative exposure dose of COVID-19 lockdown in all pregnant women and birth weight, after divided into four groups, Q1: β = 32.95 (95% CI: 28.16, 37.75) g; Q2: β = 18.88 (95% CI: 14.12, 23.64) g; Q3: β = 19.50 (95% CI: 14.73, 24.28) g; Q4: β = 21.82 (95% CI: 17.08, 26.56) g. However, there was no statistically significant difference in the risk of low birth weight between exposed and unexposed groups.ConclusionsThe COVID-19 lockdown measures were associated with a heavier birth weight and a higher risk of macrosomia. Early pregnancy periods may be a more susceptible exposure window for a heavier birth weight and a higher risk of macrosomia. We also observed a positive association between cumulative exposure dose of COVID-19 lockdown and birth weight. The government and health institutions should pay attention to the long-term health of the infants born during the COVID-19 lockdown period, and follow up these mothers and infants is necessary

Structural and Lipidomic Alterations of Striatal Myelin in 16p11.2 Deletion Mouse Model of Autism Spectrum Disorder

Myelin abnormalities have been observed in autism spectrum disorder (ASD). In this study, we seek to discover myelin-related changes in the striatum, a key brain region responsible for core ASD features, using the 16p11.2 deletion (16p11.2±) mouse model of ASD. We found downregulated expression of multiple myelin genes and decreased myelin thickness in the striatum of 16p11.2± mice versus wild type controls. Moreover, given that myelin is the main reservoir of brain lipids and that increasing evidence has linked dysregulation of lipid metabolism to ASD, we performed lipidomic analysis and discovered decreased levels of certain species of sphingomyelin, hexosyl ceramide and their common precursor, ceramide, in 16p11.2± striatum, all of which are major myelin components. We further identified lack of ceramide synthase 2 as the possible reason behind the decrease in these lipid species. Taken together, our data suggest a role for myelin and myelin lipids in ASD development

The association of long-term trajectories of BMI, its variability, and metabolic syndrome: a 30-year prospective cohort study

Background Limited data exists on how early-life weight changes relate to metabolic syndrome (MetS) risk in midlife. This study examines the association between long-term trajectories of body mass index (BMI), its variability, and MetS risk in Chinese individuals. Methods In the Hanzhong Adolescent Hypertension study (March 10, 1987–June 3, 2017), 1824 participants with at least five BMI measurements from 1987 to 2017 were included. Using group-based trajectory modeling, different BMI trajectories were identified. BMI variability was assessed through standard deviation (SD), variability independent of the mean (VIM), and average real variability (ARV). Logistic regression analyzed the relationship between BMI trajectory, BMI variability, and MetS occurrence in midlife (URL: https://www.clinicaltrials.gov; Unique identifier: NCT02734472). Findings BMI trajectories were categorized as low-increasing (34.4%), moderate-increasing (51.8%), and high-increasing (13.8%). Compared to the low-increasing group, the odds ratios (ORs) [95% CIs] for MetS were significantly higher in moderate (4.27 [2.63–6.91]) and high-increasing groups (13.11 [6.30–27.31]) in fully adjusted models. Additionally, higher BMI variabilities were associated with increased MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 2.30 [2.02–2.62], 1.22 [1.19–1.26], and 4.29 [3.38–5.45]). Furthermore, BMI trajectories from childhood to adolescence were predictive of midlife MetS, with ORs in moderate (1.49 [1.00–2.23]) and high-increasing groups (2.45 [1.22–4.91]). Lastly, elevated BMI variability in this period was also linked to higher MetS odds (ORs for SDBMI, VIMBMI, and ARVBMI: 1.24 [1.08–1.42], 1.00 [1.00–1.01], and 1.21 [1.05–1.38]). Interpretation Our study suggests that both early-life BMI trajectories and BMI variability could be predictive of incident MetS in midlife

Big-five personality and BIS/BAS traits as predictors of career exploration: The mediation role of career adaptability

Based on career construction theory, the current research examined whether career adaptability mediates the relations of the personality traits (Five-Factor Model personality traits and behavioral inhibition and activation systems (BIS/BAS)) to career exploration behavior. Results from a survey in Chinese university students (N = 264) showed that career exploration correlated negatively with neuroticism, and positively with openness to experience, extroversion, agreeableness, conscientiousness and BAS. Results of regression analyses further showed that openness to experience, agreeableness, conscientiousness and BAS served as the strongest predictors for career exploration. In addition, career adaptability was shown to be a key mediator for the relationships between personality traits and career exploration behavior. Career concern and career curiosity were the more important dimensions in the mediation model. These findings advance current understandings on how different personality traits predict career exploration behavio

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM