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Adverse Childhood Experiences (ACEs) may have an impact on cognitive disability through multiple pathways. Frequent Mental Distress (FMD) could result in cognitive disability through different aspects, but the potential mediating role of FMD in the associations remained unclear. So we aimed to investigate not only the association between self-reported ACEs and cognitive disability, but also the mediating effect of FMD between ACEs and cognitive disability. A cross-sectional analysis of respondents aged 18–25 years old in the 2020 and 2021 Behavioral Risk Factor Surveillance System (BRFSS) was performed. Weighted multivariate logistic regression models were used to assess the association of ACEs with FMD and cognitive disability. Mediation effects were used to investigate FMD as mediation between ACEs and cognitive disability in emerging adults. Among the 10,309 respondents, the prevalence of cognitive disability was 15.8%, and 71.6% of them experienced ACEs. We found experienced ACEs, self-reported FMD were significantly associated with 4.05 and 5.61 times increased risk of cognitive disability, respectively. The more types of ACEs respondents experienced, the higher risks of cognitive disability. And mediating effect analysis found FMD mediated the associations between ACEs and cognitive disability. Our study indicated a strong association between ACEs and cognitive disability in emerging adults. Furthermore, FMD plays a mediating role in the associations.

The evidence regarding the effects of blood pressure changes on older individuals remains inconclusive, and the impact of frailty throughout the life course is not known. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality. Participants included 7335 persons from 2008 to 2014 of the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Change in blood pressure was calculated as the difference between follow-up and baseline. Frailty was evaluated using a 40-item frailty index. Mortality status was ascertained up to December 31, 2014. The mean age of participants was 82.6 ± 10.7 years. The optimal blood pressure level (SBP, 130-150 mmHg; DBP, 70-90 mmHg) was associated with the lowest risk of frailty while decreasing follow-up SBP and DBP were significantly correlated with frailty. Lower baseline blood pressure levels (SBP < 130 mmHg; DBP < 70 mmHg) were associated with decreased mortality risk when participants increased their blood pressure to optimal levels during follow-up SBP and DBP (0.78, 0.63-0.98), compared to maintaining a steady low SBP (< 130 mmHg) and DBP (< 70 mmHg). For those with DBP around 70-90 mmHg, decreasing follow-up DBP (< 70 mmHg) was associated with higher mortality (1.23, 1.07-1.42) compared to maintaining stable follow-up DBP (70-90 mmHg). These results remain significant after adjusting for frailty. Optimal blood pressure levels were associated with the lowest risk of frailty. The association between lower blood pressure and increased mortality risk persisted even after accounting for frailty. We used a nationally representative longitudinal cohort study by using 2008-2014 of the Chinese Longitudinal Healthy Longevity in China. Change in blood pressure was calculated as the difference between follow-up and baseline. We investigated the associations of different change patterns of blood pressure during 3-year intervals with frailty and mortality.

HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC.

Scaffold hopping is a key strategy in drug discovery. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. We present here a distinct scaffold hopping strategy for the skeletal editing of pyrimidines into a wide range of heteroarenes through the addition of nucleophiles, ring-opening, fragmentation, and ring-closing (ANROFRC) processes. This method features the in situ generation of a vinamidinium salt intermediate, which serves as a unique N-C-C-C four-atom (A4) synthon that reacts with A1 and A2 synthons. Mechanistic studies reveal that C4-aryl substituents play a crucial role in stabilizing the vinamidinium salt intermediate. This work provides a powerful tool for the systematic construction and modification of nitrogen heterocycles, thereby expanding conventional molecular editing techniques. While one-to-one scaffold hopping strategies are thriving and evolving, one-to-multiple strategies remain challenging to design. Here, the authors report a scaffold hopping strategy for the skeletal editing of pyrimidines into a wide range of heteroarenes through the addition of nucleophiles, ring-opening, fragmentation, and ring-closing processes.

Electron-deficient nitrogen-containing aromatic heterocycles, particularly pyridine derivatives, can be converted into all-carbon aromatic frameworks via the ANRORC (Addition of Nucleophile, Ring-Opening, and Ring-Closing) skeletal editing process, providing a convenient tool for molecular diversification. However, reported methods are mainly limited to nucleophilic modification of ring-opening species. Herein, we report a distinct electrophilic modification method, smoothly converting pyridines into arene-1,3-dialdehydes or naphthalene-1,3-dialdehydes. Electron-deficient nitrogen-containing aromatic heterocycles can be converted into all-carbon aromatic frameworks via skeletal editing but reported methods are mainly limited to nucleophilic modification of ring-opening species. Here the authors report an electrophilic modification method which converts pyridines into arene-1,3-dialdehydes or naphthalene-1,3-dialdehydes.

NR0B1 is frequently activated in hepatocellular carcinoma (HCC). However, the role of NR0B1 is controversial in HCC. In this study, we observed that NR0B1 was an independent poor prognostic factor, negatively correlated with the overall survival of HCC and the relapse‐free survival of patients treated with sorafenib. Meanwhile, NR0B1 promoted the proliferation, migration, and invasion of HCC cells, inhibited sorafenib‐induced apoptosis, and elevated the IC50 of sorafenib in HCC cells. NR0B1 was further displayed to increase sorafenib‐induced autophagic vesicles and activate Beclin1/LC3‐II‐dependent autophagy pathway. Finally, NR0B1 was revealed to transcriptionally suppress GSK3β that restrains AMPK/mTOR‐driven autophagy and increases BAX‐mediated apoptosis. Collectively, our study uncovered that the ectopic expression of NR0B1 augmented sorafenib‐resistance in HCC cells by activating autophagy and inhibiting apoptosis. Our findings supported that NR0B1 was a detrimental factor for HCC prognosis. Our bioinformatic analysis firstly suggested that the ectopic expression of NR0B1 was negatively correlated with the relapse‐free survival (RFS) of patients treated with sorafenib. We found that NR0B1 promotes proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells and augments sorafenib resistance in HCC cells. We further revealed that NR0B1 inhibited sorafenib‐induced apoptosis and promoted autophagy through transcriptionally repressing GSK3β expression. The downregulated GSK3β activity enhanced the autophagic pathway of AMPK/mTOR/Beclin1/LC3‐II whereas suppressed the BAX‐apoptosis pathway. Importantly, our study proposed that the nuclear factor of NR0B1 was a detrimental factor for HCC prognosis and a new target related to sorafenib resistance.

Objective: To study the extraction process of agarwood active ingredients (AA) and investigate the safety and effectiveness of AA in the treatment of insomnia rats by nasal administration. Method: A β-cyclodextrin (β-CD) inclusion compound (a-β-CD) was prepared from agarwood essential oil (AEO), and the preparation process was optimized and characterized. The safety of AA in nasal mucosa was evaluated through Bufo gargarizans maxillary mucosa and rat nasal mucosa models. Insomnia animal models were replicated by injecting p-chlorophenylalanine (PCPA), conducting behavioral tests, and detecting the expression levels of monoamine neurotransmitters (NE and 5-HT) and amino acids (GABA/Glu) in the rat hypothalamus. Results: The optimum inclusion process conditions of β-CD were as follows: the feeding ratio was 0.35:1.40 (g:g), the inclusion temperature was 45 °C, the inclusion time was 2 h, and the ICY% and IEO% were 53.78 ± 2.33% and 62.51 ± 3.21%, respectively. The inclusion ratio, temperature, and time are the three factors that have significant effects on the ICY% and IEO% of a-β-CD. AA presented little damage to the nasal mucosa. AA increased the sleep rate, shortened the sleep latency, and prolonged the sleep time of the rats. The behavioral test results showed that AA could ameliorate depression in insomnia rats to a certain extent. The effect on the expression of monoamine neurotransmitters and amino acids in the hypothalamus of rats showed that AA could significantly reduce NE levels and increase the 5-HT level and GABA/Glu ratio in the hypothalamus of insomnia rats. Conclusion: The preparation of a-β-CD from AEO can reduce its irritation, improve its stability, increase its curative effect, and facilitate its storage and transport. AA have certain therapeutic effects on insomnia. The mechanism of their effect on rat sleep may involve regulating the expression levels of monoamine neurotransmitters and amino acids in the hypothalamus.

Tumor-associated macrophages (TAMs) occupy an important position in the tumor microenvironment (TME), they are a highly plastic heterogeneous population with complex effects on tumorigenesis and development. TAMs secrete a variety of cytokines, chemokines, and proteases, which promote the remodeling of extracellular matrix, tumor cell growth and metastasis, tumor vessel and lymphangiogenesis, and immunosuppression. TAMs with different phenotypes have different effects on tumor proliferation and metastasis. TAMs act a pivotal part in occurrence and development of tumors, and are very attractive target to inhibit tumor growth and metastasis in tumor immunotherapy. This article reviews the interrelationship between TAMs and tumor microenvironment and its related applications in tumor therapy.

In this study, systematic soil methane cycle geochemical monitoring was carried out in a typical gas hydrate region in the Qinghai-Tibet Plateau. Soil gas samples were collected for hydrocarbon components and carbon isotope analysis. Meanwhile, soil-methane fluxes from the upper active layer (20–30 cm) were monitored during six months of one year. The results of this research provide evidence of a new source of methane emission from wetland soils in permafrost regions: gas hydrate release. Sites with large methane emissions were found using flux monitoring, the characteristics of thermogenic methane were identified using carbon isotope tracing, and the relationship between emission by soils and effusion from gas hydrates was determined through correlation analyses of soil-adsorbed hydrocarbons. Seasonal variation of methane emissions are also discussed by considering the emission of bacterial methane, thermogenic methane, and the absorption of methane from the soil active layer. These comprehensive findings provide valuable information for carbon cycle research of wetlands in permafrost regions.

Melanoma is one of the most common malignant tumors. The anti-PD-1 antibody is used for the treatment of metastatic melanoma. Treatment success is only 35-40% and a range of immune-related adverse reactions can occur. Combination of anti-PD1 antibody therapy with other oncology therapies has been attempted. Herein, we assessed whether chlorogenic acid liposomes modified with sialic acid (CA-SAL) combined with anti-PD1 antibody treatment was efficacious as immunotherapy for melanoma. CA-SAL liposomes were prepared and characterized. In a mouse model of B16F10 tumor, mice were treated with an anti-PD1 antibody, CA-SAL, or combination of CA-SAL + anti-PD1 antibody, and compared with no treatment controls. The tumor inhibition rate, tumor-associated macrophages (TAMs) phenotype, T-cell activity, and safety were investigated. We observed a significant decrease in the proportion of M2-TAMs and CD4 + Fop3 + T cells, while there was a significant increase in the proportion of M1-TAMs and CD8 + T cells, and in the activity of T cells, and thus in the tumor inhibition rate. No significant toxicity was observed in major organs. CA-SAL and anti-PD1 Ab combination therapy presented synergistic anti-tumor activity, which enhanced the efficacy of the PD-1 checkpoint blocker in a mouse model of melanoma. In summary, combination immunotherapy of CA-SAL and anti-PD1 Ab has broad prospects in improving the therapeutic effect of melanoma, and may provide a new strategy for clinical treatment.