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Pubertal timing is highly variable and is associated with long-term health outcomes. Phenotypes associated with pubertal timing include age at menarche, age at voice break, age at first facial hair and growth spurt, and pubertal timing seems to have a shared genetic architecture between the sexes. However, puberty phenotypes have primarily been assessed separately, failing to account for shared genetics, which limits the reliability of the purported health implications. Here, we model the common genetic architecture for puberty timing using a multivariate GWAS, with an effective population of 514,750 European participants. We find 266 independent variants in 197 loci, including 18 novel variants. Transcriptomic, proteome imputation and fine-mapping analyses reveal genes causal for pubertal timing, including KDM4C , LEPR , CCNC , ACP1 , and PCSK1 . Linkage disequilibrium score regression and Mendelian randomisation analysis establish causal associations between earlier puberty and both accelerated ageing and the risk of developing cardiovascular disease and osteoporosis. We find that alanine aminotransferase, glycated haemoglobin, high-density lipoprotein cholesterol and Parabacteroides levels are mediators of these relationships, and establish that controlling oily fish and retinol intake may be beneficial for promoting healthy pubertal development. Zhou et al. present a multivariate GWAS on pubertal timing, identifying 18 novel variants. The results suggest associations of earlier puberty with accelerated ageing and higher risks of cardiovascular disease and osteoporosis.

Background Ambient air pollutants have been suggested to affect pubertal development. Nevertheless, current studies indicate inconsistent effects of these pollutants, causing precocious or delayed puberty onset. This study aimed to explore the associations between long-term exposure to particulate matter with aerodynamic diameters ≤ 2.5 μm (PM 2.5 ) along with its components and menarche timing among Chinese girls. Method Self-reported age at menarche was collected among 855 girls from China Health and Nutrition Survey 2004 to 2015. The pre-menarche annual average concentrations of PM 2.5 and its components were calculated on the basis of a long-term (2000–2014) high-resolution PM 2.5 components dataset. Generalized linear models (GLM) and logistic regression models were used to analyze the associations of exposure to a single pollutant (PM 2.5 , sulfate, nitrate, ammonium, black carbon and organic matter) with age at menarche and early menarche (< 12 years), respectively. Weighted quantile sum methods were applied to examine the impacts of joint exposure on menarche timing. Results In the adjusted GLM, per 1 µg/m 3 increase of annual average concentrations of nitrate and ammonium decreased age at menarche by 0.098 years and 0.127 years, respectively (all P  < 0.05). Every 1 µg/m 3 increase of annual average concentrations of PM 2.5 (OR: 1.04, 95% CI: 1.00-1.08), sulfate (OR: 1.23, 95% CI: 1.01–1.50), nitrate (OR: 1.23, 95% CI: 1.06–1.43) and ammonium (OR: 1.32, 95% CI: 1.06–1.66) were significantly positively associated with early menarche. Higher level of joint exposure to PM 2.5 and its components was associated with 11% higher odds of early menarche ( P  = 0.04). Additionally, the estimated weight of sulfate was the largest among the mixed pollutants. Conclusions Long-term exposure to PM 2.5 and its components could increase the risk of early menarche among Chinese girls. Moreover, sulfate might be the most critical components responsible for this relationship. Our study provides foundation for targeted prevention of PM 2.5 components.

The role of diet in depression is becoming increasingly acknowledged. This umbrella review aimed to summarize comprehensively the current evidence reporting the effects of dietary factors on the prevention and treatment of depression. PubMed, Embase, and the Cochrane Library were searched up to June 2021 to identify relevant meta-analyses of prospective studies. Twenty-eight meta-analyses, with 40 summary estimates on dietary patterns (n = 8), food and beverages (n = 19), and nutrients (n = 13) were eligible. The methodological quality of most meta-analyses was low (50.0%) or very low (25.0%). Quality of evidence was moderate for inverse associations for depression incidence with healthy diet [risk ratio (RR): 0.74, 95% confidential interval (CI), 0.48–0.99, I2 = 89.8%], fish (RR: 0.88, 95% CI, 0.79–0.97, I2 = 0.0%), coffee (RR: 0.89, 95% CI, 0.84–0.94, I2 = 32.9%), dietary zinc (RR: 0.66, 95% CI 0.50–0.82, I2 = 13.9%), light to moderate alcohol (<40 g/day, RR: 0.77, 95% CI, 0.74–0.83, I2 = 20.5%), as well as for positive association with sugar-sweetened beverages (RR: 1.05, 95% CI, 1.01–1.09, I2 = 0.0%). For depression treatment, moderate-quality evidence was identified for the effects of probiotic [standardized mean difference (SMD): −0.31, 95% CI, −0.56 to −0.07, I2 = 48.2%], omega-3 polyunsaturated fatty acid (SMD: −0.28, 95% CI, −0.47 to −0.09, I2 = 75.0%) and acetyl-l-carnitine (SMD: −1.10, 95% CI, −1.65 to −0.56, I2 = 86.0%) supplementations. Overall, the associations between dietary factors and depression had been extensively evaluated, but none of them were rated as high quality of evidence, suggesting further studies are likely to change the summary estimates. Thus, more well-designed research investigating more detailed dietary factors in association with depression is warranted.

The understanding of the macro- and micro-structure, particle spectrum parameters, and their evolutions in different parts of stratocumulus clouds based on aircraft observation data, is important basic data for the development of cloud microphysical parameterization schemes and the quantitative retrieval of cloud-precipitation by radar and satellite detections. In this study, a total of ten vertical measurements during three aircraft observations were selected to analyze the vertical distribution of cloud microphysical properties in different parts of stratocumulus clouds in Hebei, North China. It was found that the downdraft in the cumulus cloud area was stronger than that in the stratiform cloud area, with the temperature at the same height higher than that in the stratiform cloud area, and the height of the 0 °C layers was correspondingly higher. In terms of particle spectrum parameters, the intercept and slope parameters of particle spectrum below melting levels in the cumulus part were higher than those in stratiform clouds area in the same weather process. In different vertical detection, it was found that the ice particles have begun to melt in the negative temperature layer near 0 °C level, and there might be sublimation, fragmentation, and aggregation in the melting process of ice phase particles. In addition, the melting process changed the spectral parameters greatly and also changed the correlation between the intercept and slope of the particle spectrum. The slope below the 0 °C level increased with the increase of intercept, which was greater than that above the 0 °C level. The relationship obtained between the intercept parameter of the particle’s spectrum and temperature, and the correlation between the maximum diameter and slope parameter of the particle spectrum, have certain reference significance for cloud physical parameterization and the quantitative retrieval of cloud precipitation by radar and satellite in North China and similar climate background areas.

In turn, oxidative stress could increase Aβ production. [...]antioxidant therapy is becoming a popular strategy for treating AD. Furthermore, HαSS significantly increased the expression of nuclear factor-E2-related factor 2 (Nrf2) and p21, which are key factors in regulating oxidative stress and the cell cycle (P < 0.05), suggesting that the antioxidant activity of HαSS was mediated via the Nrf2 signaling pathway. [...]animal experiments are necessary to explore the effects and mechanisms of HαSS on AD. [...]the results from this study demonstrated that HαSS alleviated Aβ-induced intracellular oxidative stress, inhibited autophagy, and reduced hyperphosphorylation of tau, supporting the neuroprotective effects of HαSS.

PurposeCombination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers.MethodsTwo pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice.ResultsThe developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy..ConclusionThe results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer.

Isoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown. In current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects. IATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo. IATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

[4] However, there are few studies evaluating the mechanism of NaB on T2DM-related AD. [...]we used mouse neuroblastoma-derived N2a cells (serial TCM29, obtained from National Collection of Authenticated Cell Cultures of China), a cell model extensively used for studying AD-related signal transduction, to investigate the potential impact and mechanism of NaB on high glucose-induced amyloidogenesis. [...]our study found that high glucose treatment decreased activated Akt, which activated GSK-3β and enhanced APP processing, suggesting that high glucose induces amyloidogenesis via GSK-3β signaling. [...]we found the involvement of the Akt/GSK-3β pathway in NaB-mediated anti-amyloidogenesis effect in neuronal cells under high glucose conditions. [...]humans could obtain NaB supplementation by consuming dietary carbohydrates, and diets rich in fiber were reported to decrease brain Aβ and improve memory in AD models and older adults.

In the GO functional and KEGG pathway enrichment analyses, pathways highlighted by FUSION included the behavioral response to nicotine, the carboxylic acid catabolic process, and the response to hypoxia [Figure 1C and Supplementary Table 3, http://links.lww.com/CM9/B347], and the summary of the enrichment analysis in DisGeNET mainly involved smoking behavior and forced expiratory volume function [Figure 1D and Supplementary Table 3, http://links.lww.com/CM9/B347]. Calcium and integrin binding family member 2 (encoded by CIB2) was found to block the translocation of sphingosine kinase 1 (encoded by SPHK1) and inhibit downstream signaling. Since SPHK1 is a cell survival regulator and its overexpression is observed in lung cancer, the association between CIB2 and COPD merits further evaluation. In agreement with previous GWAS in European populations and case-control study in Chinese populations, we identified EGLN2 as a potential candidate gene in East Asian COPD patients. BRAP was demonstrated to modulate NF-κB activity by enhancing the activity of histone deacetylase, suggesting that BRAP is an important regulator of immune and inflammatory responses in the human airway epithelium, providing a target for understanding the pathogenesis of COPD.

We aim to explore the relationship between nocturnal sleep duration (NSD) and midday nap duration (MND) with body composition among Southwest Chinese adults. Data on sleep duration of 3145 adults in Southwest China (59.4% women) were obtained between 2014 and 2015 through questionnaires. Height, weight, and waist circumference (WC) were measured to calculate body composition (body mass index (BMI), percentage of body fat (%BF), and fat mass index (FMI)). Linear regression models were used to assess gender-specific associations between NSD and body composition. The relationship between MND with the odds of overweight and central obesity has been evaluated by logistic regression models. NSD has the inverse relation with males' BMI, WC, %BF and FMI after adjusting for all covariates (all P <0.0007), exclusive of females' (all P >0.4). After adjustment for potential confounders, compared to the subjects in the no midday nap group, the subjects who napped 0.1-1 hour were independently associated with a less prevalence of overweight in both women (OR: 0.72, 95%CI: 0.55-0.95) and men (OR: 0.71, 95%CI: 0.52-0.98). MND was not associated with central obesity. Among Southwest Chinese adults, lower NSD might be related to higher BMI, WC, %BF and FMI among men. Additionally, MND is associated with overweight in adults.