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Aberrant activation of eIF4E contributes to gastric cancer growth and resistance. MAPK‐interacting kinases (MNKs) regulate eIF4E phosphorylation and activity in tumor but not normal cells and are potentially safe targets for the treatment of various cancers. Our work reveals that tomivosertib, a potent and highly selective dual MNK1/2 inhibitor, preferentially sensitizes gastric cancer to chemotherapy via suppressing MNK‐eIF4E‐β‐catenin. We firstly demonstrate that tomivosertib displays higher efficacy than other MNK inhibitors in inhibiting gastric cancer cells. In addition, tomivosertib significantly augments the inhibitory effects of 5‐FU and paclitaxel but not everolimus, suggesting that tomivosertib preferentially sensitizes gastric cancer to chemotherapy. We next show that eIF4E overexpression and phosphorylation coordinately regulate β‐catenin signaling in gastric cancer. Rescue studies confirm that tomivosertib inhibits gastric cancer via targeting MNK‐ eIF4E‐β‐catenin. Finally, we demonstrate that the in vitro functional and mechanism observations are translatable to in vivo gastric cancer model in mice. Tomivosertib is now in Phase 2 clinical trials. Our study provides preclinical evidence to initialize clinical trials for gastric cancer using tomivosertib in combination with chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: The longitudinal influence of parental leisure‐time physical activity (LTPA) on their offspring's LTPA is poorly understood. This study examined the longitudinal associations between parental LTPA and offspring's LTPA at two‐time intervals. Method: Child (offspring) participants (N = 3596) were enrolled from the Cardiovascular Risk in Young Finns Study in 1980. Their LTPA was self‐rated through nine phases from baseline to 2018 and categorized by year into youth (1980‒1986) and adult (1992‒2018) LTPA. Parental LTPA was assessed with a single self‐reported question at three phases from 1980 to 1986. Latent growth curve modeling stratified by gender was fitted to estimate the potential pathways between parental LTPA and offspring's youth and adult LTPA. Results: Higher initial levels of paternal and maternal LTPA were independently associated with greater initial levels of youth and adult LTPA of offspring in both genders, respectively, except maternal LTPA, which did not associate with male offspring's adult LTPA. The initial levels of paternal LTPA were directly related to changes in male offspring's youth LTPA after adjusting for age, residential place, paternal education and occupation, having siblings, and offspring's body mass index. Conclusion: Our study demonstrates that the initial levels of parental LTPA are directly linked to the initial levels of offspring's LTPA during youth and adulthood, while changes in parental LTPA are unrelated to changes in offspring's youth and adult LTPA for either gender over time. These results imply that higher initial levels of LTPA in parents may serve as a predictor of offspring's LTPA across life stages. [ABSTRACT FROM AUTHOR]

Earth's water resources are critical for supporting livelihoods and food security but are being increasingly overexploited to support global agriculture. Diversifying cropping systems could potentially resolve unsustainable water use but trade‐offs with other aspects of sustainability and food security have not yet been assessed. We performed a detailed analysis of 31 different field crop rotations conducted during 1990–2019 in the North China Plain, to assess the potential impact of crop diversification on actual evapotranspiration (ETa), changes in regional groundwater table, grain yield, economic output, and water use efficiency (WUE) and to identify configurations that can achieve co‐benefits across multiple dimensions. We found that a combination of lowering the cropping index (i.e., harvest frequency), incorporating fallow periods, and introducing higher‐value crops into the currently dominant winter wheat–summer maize double cropping system can reduce growing season ETa by as much as 31%, mitigate groundwater decline by 19% or more, and increased economic output and economic WUE by more than 11% and 3%, respectively. We also found that multiple diversified wheat‐maize–based rotations—all with rotation lengths greater than 2 years—achieve co‐benefits across all evaluated dimensions. This study provides new empirical evidence of the opportunities for diversified crop rotations to balance the multiple objectives of food production, sustainable groundwater use, and farmer profitability. Extending this solution to other water‐stressed agricultural regions could be an effective strategy in achieving more sustainable food production system globally. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?The aim was to investigate the function of microRNA‐188 in the biological characteristics of lung cancer stem cells and the molecular mechanisms involved.What is the main finding and its importance?This study highlights a new molecular mechanism involving microRNA‐188, MDK and the Hippo signalling pathway that plays a suppressive role in biological activity of lung cancer stem cells. This finding might offer new insights into gene‐based therapy for lung cancer. MicroRNAs (miRNAs) have been implicated in lung cancer and reported as new promising diagnostic and therapeutic tools for cancer control. Here, we investigated the action of microRNA‐188 (miR‐188) in lung cancer stem cells. We first tested miR‐188 expression in clinical samples of lung cancer patients, and a low expression profile of miR‐188 was found. Next, we analysed the role of miR‐188 in lung cancer stem cells with cell growth assays. To verify the in vitro results, we used a xenograft model to validate the capability of miR‐188 in tumorigenesis. Overexpression of miR‐188 reduced viability and metastasis of cancer stem cells. Similar results were reproduced in vivo, where overexpression of miR‐188 retarded tumour growth in mice. We also identified MDK as a target of miR‐188, and overexpression of MDK was found in lung cancer samples. Overexpressed MDK promoted the malignant behaviours of lung cancer stem cells. In addition, the Hippo pathway was found to be inactivated in lung cancer tissues, presenting as increased levels of YAP and TAZ. Suppression of the Hippo pathway also enhanced lung cancer stem cell activity and promoted the growth of xenograft tumours. To sum up, our results reveal that miR‐188 inhibits the malignant behaviours of lung cancer stem cells and the growth of xenograft tumours. This study might offer new insights into gene‐based therapies for cancer. [ABSTRACT FROM AUTHOR]

Purpose: The long‐term effects of sociodemographic and health characteristics on television viewing (TV) time changes have not been identified in adulthood. We aimed to examine the modifiable and non‐modifiable determinants of changes in TV‐time in young adults over 10 years. Methods: Participants (N = 2929) aged 24‐39 years were recruited between 2001 and 2011 from the Cardiovascular Risk in Young Finns Study. Data were collected using questionnaires and a medical examination. The determinants of changes in TV‐time were estimated using latent growth modeling for men and women separately. Results: For men, inverse associations with initial levels of TV‐time were observed for students becoming employed and already has children, and direct associations were observed for both those who stayed a smoker and those who stayed overweight/obese. Increasing attention to health habits was inversely associated with a slope of TV‐time, whereas age and becoming unemployed were positively associated with the slope of TV‐time. For women, inverse associations with the levels of TV‐time were found for age, staying in non‐manual work, and paying consistently high and increasing attention to health habits, and direct associations were found for staying unemployed, smoking and overweight/obese, and becoming employed, single and non‐smoking. Increasing physical activity, becoming employed, motherhood, and normal weight were inversely associated with the slope of TV‐time, whereas age and staying in non‐manual work were positively associated with the slope of TV‐time. Conclusions: This suggests several gender‐specific determinants of changes in TV‐time that can help identify potential targets for interventions to prevent excessive TV‐time in adulthood. [ABSTRACT FROM AUTHOR]

A novel capacitor mismatch calibration method is presented to compensate the capacitor mismatches in a successive approximation register (SAR) ADC. The method features a new weight‐balancing split capacitive DAC which allows automatic extraction and calibration of the capacitor mismatches by itself. As a result, the ADC's resolution can be substantially improved with minimum area and power penalty. The calibration method was verified and implemented in a 14 bit, 10 kS/s SAR ADC, fabricated in a 0.13 µm standard CMOS process. The measured signal‐to‐noise‐plus‐distortion and spurious‐free dynamic range are 72.7 and 86 dB after calibration with 13.6 and 21.8 dB improvements, respectively. The total power consumption is 15.2 µW at a 1.2 V supply voltage. [ABSTRACT FROM AUTHOR]

Summary: In this meta‐analysis, we aim to evaluate the risk of gallbladder and biliary disease of weight management strategies and investigate the association between weight reduction and risk of gallbladder or biliary disease. Randomized controlled trials (RCTs) with a duration of at least 12 weeks that compare antiobesity medications (AOMs) with placebo or bariatric surgery with less intensive weight management strategy were concluded. Weight management strategy was associated with a significant increased risk of gallbladder or biliary disease (OR 1.361, 95% CI 1.147 to 1.614, P < 0.001, I2 = 3.5%), cholelithiasis, cholecystitis, and cholecystectomy compared with placebo or controls. The increased risk of gallbladder or biliary disease was observed both in pharmacotherapies subgroup and bariatric surgery subgroup. With regards of specific pharmacotherapies, an increased risk of gallbladder or biliary disease was observed in trials with glucagon‐like peptide 1 receptor agonist (GLP‐1 RA) treatments. In addition, trials with indication of obesity and overweight treatment and trials with higher doses showed significant higher risk of gallbladder or biliary disease compared with placebo or controls. In conclusion, weight management strategy was associated with an increased risk of gallbladder or biliary disease when compared with placebo or control groups. [ABSTRACT FROM AUTHOR]

Aims: Rasd1 has been reported to be correlated with neurotoxicity, metabolism, and rhythm, but its effect in case of subarachnoid hemorrhage (SAH) remained unclear. White matter injury (WMI) and ferroptosis participate in the early brain injury (EBI) after SAH. In this work, we have investigated whether Rasd1 can cause ferroptosis and contribute to SAH‐induced WMI. Methods: Lentivirus for Rasd1 knockdown/overexpression was administrated by intracerebroventricular (i.c.v) injection at 7 days before SAH induction. SAH grade, brain water content, short‐ and long‐term neurobehavior, Western blot, real‐time PCR, ELISA, biochemical estimation, immunofluorescence, diffusion tensor imaging (DTI), and transmission electron microscopy (TEM) were systematically performed. Additionally, genipin, a selective uncoupling protein 2(UCP2) inhibitor, was used in primary neuron and oligodendrocyte co‐cultures for further in vitro mechanistic studies. Results: Rasd1 knockdown has improved the neurobehavior, glia polarization, oxidative stress, neuroinflammation, ferroptosis, and demyelination. Conversely, Rasd1 overexpression aggravated these changes by elevating the levels of reactive oxygen species (ROS), inflammatory cytokines, MDA, free iron, and NCOA4, as well as contributing to the decrease of the levels of UCP2, GPX4, ferritin, and GSH mechanistically. According to the in vitro study, Rasd1 can induce oligodendrocyte ferroptosis through inhibiting UCP2, increasing reactive oxygen species (ROS), and activating NCOA4‐mediated ferritinophagy. Conclusions: It can be concluded that Rasd1 exerts a modulated role in oligodendrocytes ferroptosis in WMI following SAH. [ABSTRACT FROM AUTHOR]

Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) are typical causes of developmental delay and refractory epilepsy. G‐protein‐coupled receptor 30 (GPR30) is a specific estrogen receptor that is critical in neurodevelopment, neuroinflammation, and neuronal excitability, suggesting that it plays a potential role in the epilepsy of patients with FCDIIb and TSC. Therefore, we investigated the role of GPR30 in patients with FCDIIb and TSC. We found that the expression of GPR30 and its downstream protein kinase A (PKA) pathway were decreased and negatively correlated with seizure frequency in female patients with FCDIIb and TSC, but not in male patients. GPR30 was widely distributed in neurons, astrocytes, and microglia, and its downregulation was especially notable in microglia. The GPR30 agonist G‐1 increased the expression of PKA and p‐PKA in cultured cortical neurons, and the GPR30 antagonist G‐15 exhibited the opposite effects of G‐1. The NF‐κB signaling pathway was also activated in the specimens of female patients with FCDIIb and TSC, and was regulated by G‐1 and G‐15 in cultured cortical neurons. We also found that GPR30 regulated cortical neuronal excitability by altering the frequency of spontaneous excitatory postsynaptic currents and the expression of NR2A/B. Further, the relationship between GPR30 and glycometabolism was evaluated by analyzing the correlations between GPR30 and 18F‐FDG PET‐CT values (standardized uptake values, SUVs). Positive correlations between GPR30 and SUVs were found in female patients, but not in male patients. Intriguingly, GPR30 expression and SUVs were significantly decreased in the epileptogenic tubers of female TSC patients, and ROC curves indicated that SUVs could predict the localization of epileptogenic tubers. Taken together, our results suggest a potential protective effect of GPR30 in the epileptogenesis of female patients with FCDIIb and TSC. [ABSTRACT FROM AUTHOR]

This study examined longitudinal associations between parenthood‐related factors and physical activity from young adulthood to midlife over a 19‐year follow‐up period. Participants (n = 761) at the ongoing Cardiovascular Risk in Young Finns Study responded to a self‐report questionnaire in their adulthood (in 1992, 2001, 2007, and 2011). Participants were classified as meeting or not meeting an aerobic physical activity recommendation. Parenthood‐related factors included the age of having their first child and the number and age of the children. Analyses of generalized estimation equations were performed and adjusted for several demographic and health‐related covariates. Both mothers and fathers with children under 6 years were less likely to be involved in physical activity than participants without children. However, meeting the aerobic physical activity recommendations did not differ between parents with a youngest child who was 6 years old or older as compared to the childless participants. The older the youngest child was, the more likely the parents were to be physically active. Participants who became a parent relatively late, at the age of 30 or older, seemed less likely to meet the aerobic physical activity recommendation during follow‐up than those who had their first child at the age of 26–29. The results indicate that parenthood does not seem to have a long‐lasting negative impact on adults' physical activity, and the individuals reached a similar level of physical activity in midlife than they had before parenthood. [ABSTRACT FROM AUTHOR]

Background: Focal cortical dysplasia type IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation, which promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. To explore the potential roles of formyl peptide receptor 2 (FPR2), which is a key regulator of inflammation resolution, in epilepsy caused by FCDIIb and TSC, we examined the expression and cellular distribution of FPR2. Method: The expression of FPR2 and nuclear factor‐κB (NF‐κB) signaling pathway was examined by real‐time PCR, western blots, and analyzed via one‐way analysis of variance. The distribution of FPR2 was detected using immunostaining. The expression of resolvin D1 (RvD1, the endogenous ligand of FPR2) was observed via enzyme‐linked immunosorbent assay. Pearson's correlation test was used to evaluate the correlation between the expression levels of FPR2 and RvD1 and the clinical variants. Results: The expression of FPR2 was significantly lower in FCDIIb (p =.0146) and TSC (p =.0006) cortical lesions than in controls, as was the expression of RvD1 (FCDIIb: p =.00431; TSC: p =.0439). Weak FPR2 immunoreactivity was observed in dysmorphic neurons (DNs), balloon cells (BCs), and giant cells (GCs) in FCDIIb and TSC tissues. Moreover, FPR2 was mainly distributed in dysplastic neurons; it was sparse in microglia and nearly absent in astrocytes. The NF‐κB pathway was significantly activated in patients with FCDIIb and TSC, and the protein level of NF‐κB was negatively correlated with the protein level of FPR2 (FCDIIb: p =.00395; TSC: p =.0399). In addition, the protein level of FPR2 was negatively correlated with seizure frequency in FCDIIb (p =.0434) and TSC (p =.0351) patients. Conclusion: In summary, these results showed that the expression and specific distribution of FPR2 may be involved in epilepsy caused by FCDIIb and TSC, indicating that downregulation of FPR2 mediated the dysfunction of neuroinflammation resolution in FCDIIb and TSC. [ABSTRACT FROM AUTHOR]

Provides information on a study that examined the clinical phenotype of individuals characterized by normal or low insulin receptor substrate-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Methodology of the study; Results and discussion on the study.