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Abstract Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2β rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2β controls the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which reduces Mi-2β ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

BackgroundStroke is the leading cause of acquired disability and the second leading cause of death worldwide. Its rate of incidence, disability, mortality, and recurrence is high, and the patients experience various symptoms of discomfort, which not only affect their rehabilitation function but also reduce their ability to perform daily activities and their quality of life. Nowadays, with the improvement of China’s medical standards, patients are increasingly attentive to their quality of life and health status. However, diagnostic techniques and effective treatments for patients with stroke are still limited but urgently required. ObjectiveThis study aimed to evaluate the quality of life during hospitalization using a stroke patient-reported outcomes (PROs) scale and additionally to recognize potential factors and risk indicators that may impact recurrent events, facilitating early intervention measures. MethodsThis is a registry-based, retrospective observational cross-sectional study on patients with stroke. A convenient sampling method was used to select various indicators of patients. The Stroke-PRO scale was then used to assess patients’ conditions across physical, psychological, social, and therapeutic domains. Multiple linear regression analysis was applied to identify factors influencing stroke PROs, while correlation analysis was conducted to explore the relationship between these outcomes and blood lipid levels. ResultsThe mean Stroke-PRO score in this study was 4.09 (SD 0.29) points. By multiple linear regression analysis, residence, occupation, physical exercise, Barthel index, Braden scale, National Institutes of Health Stroke Scale scores at admission, and stroke type were the risk factors for reported outcomes of patients with stroke (P

Exciton dissociation and charge transport are important processes in the photoelectric conversion of organic solar cells (OSCs), directly affecting the performance of OSCs. In order to facilitate exciton dissociation, phase separation size should be as small as possible. However, for the sake of continuous charge transport, a large phase separation size is also necessary. To balance these two conflicting needs, it is of utmost importance to regulate the phase separation of the active layer. This Review mainly elaborated the smart tactics commonly adopted to phase separation optimization, aiming to understand how these treatments affect both the active layer phase separation and the performance of OSCs. Furthermore, we present an outlook on the new opportunities of phase separation regulation of the active layer. Finally, this Review may provide some reference for the researchers engaged in the research of OSCs.

Plant-derived natural compounds are desired for their anti-inflammatory properties. We investigated the chemical composition and the anti-inflammatory effects of the essential oil obtained from leaves of the Chinese medicinal plant Artemisia annua L. Artemisia annua L. essential oil (AO) was obtained by hydrodistillation; the extraction yield was approximately 1.2%. Gas chromatography–mass spectrometry (GC–MS) revealed the presence of 13 compounds in AO; the major compounds were caryophyllene (32.16%), eucalyptol (28.62%), α-pinene (19.08%), and β-pinene (14.72%). Cell counting kit-8 (CCK8) assay revealed that AO did not show in vitro cytotoxicity toward RAW264.7 cells and suppressed the expression of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 cells. Pretreatment with AO significantly reduced xylene-induced inflammation in the ears of Kunming mice. AO inhibited inflammatory cell infiltration, decreased epidermis thickness in the ear, and suppressed expression of TNF-α in the serum. The in vivo anti-inflammatory activity of AO was similar to that of the positive control compound Di Song Zhang Bo Cream. Overall, AO was observed to be an effective anti-inflammatory agent. These results provide an experimental basis for commercializing AO-derived external preparations for pharmacological and cosmetic industries.

Hematite is one of the most promising photoanode materials for the study of photoelectrochemical (PEC) water splitting because of its ideal bandgap with sufficient visible light absorption and stability in alkaline electrolytes. However, owing to the intrinsically high electron-hole recombination, the PEC performance of hematite is still far below that expected. The efficient charge separation can be achieved via growth of FeOOH on hematite photoanode. In this study, hematite nanostructures were successfully grown on the surface of iron foil by the simple immersion deposition method and thermal oxidation treatment. Furthermore, cocatalyst FeOOH was successfully added to the hematite nanostructure surface to improve charge separation and charge transfer, and thus promote the photoelectrochemical water splitting. By utilizing the FeOOH overlayer as a cocatalyst, the photocurrent density of hematite exhibited a substantial 86% increase under 1.5 VRHE, while the onset potential showed an apparent shift towards the cathodic direction. This can be ascribed to the high reaction area for the nanostructured morphology and high electrocatalytic activity of FeOOH that enhanced the amount of photogenerated holes and accelerated the kinetics of water splitting.

BackgroundPeople age at different rates. Biological age is a risk factor for many chronic diseases independent of chronological age. A good lifestyle is known to improve overall health, but its association with biological age is unclear.MethodsThis study included participants from the UK Biobank who had undergone 12-lead resting electrocardiography (ECG). Biological age was estimated by a deep learning model (defined as ECG-age), and the difference between ECG-age and chronological age was defined as Δage. Participants were further categorized into an ideal (score 4), intermediate (scores 2 and 3) or unfavorable lifestyle (score 0 or 1). Four lifestyle factors were investigated, including diet, alcohol consumption, physical activity, and smoking. Linear regression models were used to examine the association between lifestyle factors and Δage, and the models were adjusted for sex and chronological age.ResultsThis study included 44,094 individuals (mean age 64 ± 8, 51.4% females). A significant correlation was observed between predicted biological age and chronological age (correlation coefficient = 0.54, P

BackgroundHuman voice has increasingly been recognized as an effective indicator for the detection of cognitive disorders. However, the association of acoustic features with specific cognitive functions and mild cognitive impairment (MCI) has yet to be evaluated in a large community-based population. ObjectiveThis study aimed to investigate the association between acoustic features and neuropsychological (NP) tests across multiple cognitive domains and evaluate the added predictive power of acoustic composite scores for the classification of MCI. MethodsThis study included participants without dementia from the Framingham Heart Study, a large community-based cohort with longitudinal surveillance for incident dementia. For each participant, 65 low-level acoustic descriptors were derived from voice recordings of NP test administration. The associations between individual acoustic descriptors and 18 NP tests were assessed with linear mixed-effect models adjusted for age, sex, and education. Acoustic composite scores were then built by combining acoustic features significantly associated with NP tests. The added prediction power of acoustic composite scores for prevalent and incident MCI was also evaluated. ResultsThe study included 7874 voice recordings from 4950 participants (age: mean 62, SD 14 years; 4336/7874, 55.07% women), of whom 453 were diagnosed with MCI. In all, 8 NP tests were associated with more than 15 acoustic features after adjusting for multiple testing. Additionally, 4 of the acoustic composite scores were significantly associated with prevalent MCI and 7 were associated with incident MCI. The acoustic composite scores can increase the area under the curve of the baseline model for MCI prediction from 0.712 to 0.755. ConclusionsMultiple acoustic features are significantly associated with NP test performance and MCI, which can potentially be used as digital biomarkers for early cognitive impairment monitoring.

Background: Psoriasis is a chronic and immune-mediated inflammatory skin disease. Many studies have shown that curcumin (CUR) has strong anti-inflammatory effects and can improve psoriasis; however, its efficacy and safety have not been confirmed, and the specific mechanism remains to be elucidated.Objective: To evaluate the efficacy, safety, and possible mechanisms of CUR in the treatment of psoriasis.Methods: The Cochrane Library, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP (China Science and Technology Journal Database) were systematically searched for clinical trials and preclinical studies on the use of CUR in psoriasis treatment. All databases were searched from inception to January 2022. The meta-analysis was performed using RevMan 5.3 software.Results: Our meta-analysis included 26 studies, comprising seven clinical randomized controlled trials and 19 preclinical studies. A meta-analysis of clinical trials showed that both CUR monotherapy and combination therapy improved Psoriasis Area and Severity Index (PASI) scores in patients compared to controls (standard mean difference [std.MD]: −0.83%; 95% confidence interval [CI]: −1.53 to 0.14; p = 0.02). In preclinical studies, CUR showed better performance in improving the phenotype of psoriatic dermatitis mice compared to controls, including total PASI score (std.MD: 6.50%; 95% CI: 10.10 to −2.90; p = 0.0004); ear thickness (p = 0.01); and the expression of inflammatory cytokines such as interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-17F, and IL-22 (p < 0.05). In cell studies, CUR inhibited cell proliferation (p = 0.04) and the cell cycle (p = 0.03) and downregulated the inflammatory cytokines IL-6 and IL-8 (p < 0.05).Conclusions: CUR has excellent efficacy and broad potential to treat psoriasis in multiple ways. Its use also plays a crucial role in improving the psoriasis phenotype and reducing the inflammatory microenvironment. In conclusion, our findings suggest that CUR alone or in combination with other conventional treatments can effectively treat psoriasis.

Abstract Variants in the melanocortin-1 receptor (MC1R) gene, encoding a trimeric G-protein-coupled receptor and activated by α-melanocyte-stimulating hormone (α-MSH), are frequently associated with red or blonde hair, fair skin, freckling, and skin sensitivity to ultraviolet (UV) light. Several red hair color variants of MC1R are also associated with increased melanoma risk. MC1R variants affect melanoma risk independent of phenotype. Here, we demonstrated that MC1R is a critical factor in chromosome stability and centromere integrity in melanocytes. α-MSH/MC1R stimulation prevents melanocytes from UV radiation-induced damage of chromosome stability and centromere integrity. Mechanistic studies indicated that α-MSH/MC1R-controlled chromosome stability and centromeric integrity are mediated by microphthalmia-associated transcription factor (Mitf), a transcript factor needed for the α-MSH/MC1R signaling and a regulator in melanocyte development, viability, and pigment production. Mitf directly interacts with centromere proteins A in melanocytes. Given the connection among MC1R variants, red hair/fair skin phenotype, and melanoma development, these studies will help answer a question with clinical relevance “why red-haired individuals are so prone to developing melanoma”, and will lead to the identification of novel preventive and therapeutic strategies for melanomas, especially those with redheads.

Summary: Engineering a versatile platform that enables to separate both oil/water and oil/oil mixtures and remove dye from water is not easy. To address this challenge, we have developed an Ag/polydopamine-coated textile (Ag/PDA@textile) by chemically depositing Ag particles on the textile surface using polydopamine as the binder layer. The obtained Ag/PDA@textile attracts water but repels oil in the air, underwater, and when immersed into the oil. Exploiting its water-attracting and oil resistance, the Ag/PDA@textile is acted as a separation membrane to separate oil/water mixtures with enhanced separation efficiency. The Ag/PDA@textile also possesses opposite wetting behavior to oils with different polarities, allowing it to separate oil/oil mixtures efficiently. Thanks to the catalytic performance of the Ag particle, organic dyes can be decomposed effectively by our Ag/PDA@textile under UV illustration or in the presence of NaBH4. Our Ag/PDA@textile may be valuable for applications in water purification and oil sewage treatment.

Cardiovascular disease (CVD) and cancer are the leading causes of death worldwide. With an increasing number of the elderly population, and early cancer screening and treatment, the number of cancers cases are rising, while the mortality rate is decreasing. However, the number of cancer survivors is increasing yearly. With the prolonged life span of cancer patients, the adverse effects of anti-tumor therapy, especially CVD, have gained enormous attention. The incidence of cardiovascular events such as cardiac injury or cardiovascular toxicity is higher than malignant tumors' recurrence rate. Numerous clinical studies have also shifted their focus from the study of a single disease to the interdisciplinary study of oncology and cardiology. Previous studies have confirmed that anti-tumor therapy can cause CVD. Additionally, the treatment of CVD is also related to the tumors incidence. It is well established that the increased incidence of CVD in cancer patients is probably due to an unmodified unhealthy lifestyle among cancer survivors or cardiotoxicity caused by anti-cancer therapy. Nevertheless, some patients with CVD have a relatively increased cancer risk because CVD and malignant tumors are highly overlapping risk factors, including gender, age, hypertension, diabetes, hyperlipidemia, inflammation, and obesity. With advancements in the diagnosis and treatment, many patients simultaneously suffer from CVD and cancer, and most of them have a poor prognosis. Therefore, clinicians should understand the relationship between CVD and tumors, effectively identify the primary and secondary prevention for these diseases, and follow proper treatment methods.

Pigment production is a unique character of melanocytes. Numerous factors are linked with melanin production, including genetics, ultraviolet radiation (UVR) and inflammation. Understanding the mechanism of melanogenesis is crucial to identify new preventive and therapeutic strategies in the treatment of melanoma. Here, we reviewed the current available literatures on the mechanisms of melanogenesis, including the signaling pathways of UVR-induced pigment production, MC1R’s central determinant roles and MITF as a master transcriptional regulator in melanogenesis. Moreover, we further highlighted the role of targeting BRAF, NRAS and MC1R in melanoma prevention and treatment. The combination therapeutics of immunotherapy and targeted kinase inhibitors are becoming the newest therapeutic option in advanced melanoma.

Melanocortin-1 receptor is a palmitoylated protein and variants of the receptor are associated with red hair colour and susceptibility to melanoma. Here, the authors describe a method to enhance the palmitoylation of the receptor, which can inhibit melanomagenesis in mice.

Abstract Programmed cell death 1 ligand 1 (PD-L1) is a ligand of programmed cell death 1 (PD-1) that functions as an immune checkpoint by down-regulating immune responses. To determine whether PD-L1 is a therapy target in vitiligo treatment, Pmel-1 vitiligo mice were treated with a PD-L1 fusion protein. Treatment with this fusion protein significantly reversed/suppressed depigmentation development in adult Pmel-1 mice. Mechanistically, enrichment of regulatory T cells (Treg) in the skin was detected after PD-L1 fusion protein treatment in Pmel-1 mice. Furthermore, Tregs abundance was also increased in both the spleen and circulation of Pmel-1 mice treated with PD-L1. These data indicate that PD-L1 protein therapy inhibits the immune response and reverses depigmentation development in Pmel-1 vitiligo mice.

Abstract We have produced a superconducting binary-elements intercalated graphite, CaxSr1−xCy, with the intercalation of Sr and Ca in highly-oriented pyrolytic graphite; the superconducting transition temperature, T c, was ~3 K. The superconducting CaxSr1−xCy sample was fabricated with the nominal x value of 0.8, i.e., Ca0.8Sr0.2Cy. Energy dispersive X-ray (EDX) spectroscopy provided the stoichiometry of Ca0.5(2)Sr0.5(2)Cy for this sample, and the X-ray powder diffraction (XRD) pattern showed that Ca0.5(2)Sr0.5(2)Cy took the SrC6-type hexagonal-structure rather than CaC6-type rhombohedral-structure. Consequently, the chemical formula of CaxSr1−xCy sample could be expressed as ‘Ca0.5(2)Sr0.5(2)C6’. The XRD pattern of Ca0.5(2)Sr0.5(2)C6 was measured at 0–31 GPa, showing that the lattice shrank monotonically with increasing pressure up to 8.6 GPa, with the structural phase transition occurring above 8.6 GPa. The pressure dependence of T c was determined from the DC magnetic susceptibility and resistance up to 15 GPa, which exhibited a positive pressure dependence of T c up to 8.3 GPa, as in YbC6, SrC6, KC8, CaC6 and Ca0.6K0.4C8. The further application of pressure caused the rapid decrease of T c. In this study, the fabrication and superconducting properties of new binary-elements intercalated graphite, CaxSr1−xCy, are fully investigated, and suitable combinations of elements are suggested for binary-elements intercalated graphite.

Background: Transmembrane tumor necrosis factor (TNF) receptors are involved in inflammatory, apoptotic, and proliferative processes. In the bloodstream, soluble TNF receptor II (sTNFR2) can modify the inflammatory response of immune cells and is predictive of cardiovascular disease risk. We hypothesize that sTNFR2 is associated with epigenetic modifications of circulating leukocytes, which may relate to the pathophysiology underlying atherogenic risk.Methods: We conducted an epigenome-wide association study of sTNFR2 levels in the Framingham Heart Study Offspring cohort (examination 8; 2005–2008). sTNFR2 was quantitated by enzyme immunoassay and DNA methylation by microarray. The concentration of sTNFR2 was loge-transformed and outliers were excluded. We conducted linear mixed effects models to test the association between sTNFR2 level and methylation at over 400,000 CpGs, adjusting for age, sex, BMI, smoking, imputed cell count, technical covariates, and accounting for familial relatedness.Results: The study sample included 2468 participants (mean age: 67 ± 9 years, 52% women, mean sTNFR2 level 2661 ± 1078 pg/ml). After accounting for multiple testing, we identified 168 CpGs (P < 1.2 × 10-7) that were differentially methylated in relation to sTNFR2. A substantial proportion (27 CpGs; 16%) are in the major histocompatibility complex region and in loci overrepresented for antigen binding molecular functions (P = 1.7 × 10-4) and antigen processing and presentation biological processes (P = 1.3 × 10-8). Identified CpGs are enriched in active regulatory regions and associated with expression of 48 cis-genes (±500 kb) in whole blood (P < 1.1 × 10-5) that coincide with genes identified in GWAS of diseases of immune dysregulation (inflammatory bowel disease, type 1 diabetes, IgA nephropathy).Conclusion: Differentially methylated loci in leukocytes associated with sTNF2 levels reside in active regulatory regions, are overrepresented in antigen processes, and are linked to inflammatory diseases.

Background/Aims: To assess the antiviral efficacy of lamivudine (LAM), entecavir (ETV), telbivudine (LDT), and lamivudine and adefovir dipivoxil (CLA) combination in previously untreated hepatitis B patients at different time points during a 52-week treatment period. Patients and Methods: A total of 164 patients were included in this prospective, open-label, head-to-head study. Serum levels of alanine transaminase (ALT), hepatitis B virus (HBV) DNA, and hepatitis B e antigen (HBeAg) were measured at baseline, and at 12, 24, and 52 weeks of treatment. Results: Median reductions in serum HBV DNA levels at 52 weeks (log 10 copies/mL) were as follows: LAM, 3.98; ETV, 3.89; LDT, 4.11; and CLA, 3.36. The corresponding HBV DNA undetectability rates were 83%, 96%, 91%, and 89%, respectively. These two measures showed no significant intergroup differences. Clinical efficacy appeared related to HBV DNA level reduction after 24 weeks of therapy. Patients were divided into three groups based on HBV DNA levels at week 24: Undetectable (10 4 copies/mL. Patients with levels below quantitation limit (QL) were analyzed at 52 weeks for HBV DNA undetectability rate (94%), ALT normalization rate (83%), and viral breakthrough rate (0%). The corresponding values in the QL-10 4 copies/mL group were 50%, 75%, and 13%, whereas those in the above 10 4 copies/mL group were 53%, 65%, and 18%. There were significant differences at week 52 for HBV DNA levels and viral breakthrough rate between the three groups. Conclusions: Different nucleos(t)ide (NUC) analogues tested exhibited no significant differences in effectiveness for Chinese NUC-naive HBV patients during 1-year treatment period.

China is a large import and export economy in global terms, and the carbon dioxide emissions and carbon leakage arising from trade have great significance for China’s foreign trade and its economy. On the basis of trade data for China’s 20 industrial sectors, we first built a panel data model to test the effect of trade on carbon dioxide emissions and the presence of carbon leakage for all industrial sectors. Second, we derived a single-region input–output model for open economies based on the industrial sectors’ diversity and carbon dioxide emissions, and performed an empirical test. We estimated the net carbon intensity embodied in export, which is 0.237tCO2/ten thousand RMB, to divide all sectors (ACSs) into high-carbon sectors (HCSs) and low-carbon sectors (LCSs). The results show that higher trade openness leads to a reduction in the intensity of CO2 emissions and gross emissions and that there are obvious structural differences in different sectors with different carbon emission intensity. The coefficient of trade openness for LCSs is −0.073 and is statistically significant at the 1% level, so higher trade openness for LCSs leads to a reduction in the CO2 emissions intensity. However, the coefficient for HCSs is 0.117 and is statistically significant at the 10% level, indicating that higher trade openness increases the CO2 emissions’ intensity for HCSs. The difference is that higher trade openness in LCSs can help reduce the CO2 emissions’ intensity without the problem of carbon leakage and with the existence of the environmental Kuznets curve (EKC), whereas there is no EKC for HCSs and carbon leakage may happen. We introduced dummy variables and found that a “pollution haven„ effect exists in HCSs. The test results in HCSs and LCSs are exactly the opposite of each other, which shows that the carbon leakage of ACSs cannot be determined. The message that can be drawn for policy makers is that China does not need to worry about the adverse impact on the environment of trade opening up and should, in fact, increase the opening up of trade, while becoming acclimatized to environmental regulation of a new trade mode and new standards. This will help amplify the favorable impact of trade opening up on the environment and improve China’s international reputation. The policies related to trade should encourage structural adjustment between the sectors via the formulation of differential policies and impose a restraint on sectors that have high levels of CO2 emissions embodied in export.

Zinc (Zn) is an important nutrient that is involved in various physiological metabolisms. Zn dyshomeostasis is often associated with various pathogeneses of chronic diseases, such as metabolic syndrome, diabetes, and related complications. Zn is present in ocular tissue in high concentrations, particularly in the retina and choroid. Zn deficiencies have been shown to affect ocular development, cataracts, age-related macular degeneration, and even diabetic retinopathy. However, the mechanism by which Zn deficiency increases the prevalence of diabetic retinopathy remains unclear. In addition, due to the negative effect of Zn deficiency on the eye, Zn supplementation should prevent diabetic retinopathy; however, limited available data do not always support this notion. Therefore, the goal of this paper was to summarize these pieces of available information regarding Zn prevention of diabetic retinopathy. Current theories and possible mechanisms underlying the role of Zn in the eye-related diseases are discussed. The possible factors that affect the preventive effect of Zn supplementation on diabetic retinopathy were also discussed.

Zinc (Zn) deficiency often occurs in the patients with diabetes. Effects of Zn deficiency on diabetes-induced hepatic injury were investigated.Type 1 diabetes was induced in FVB mice with multiple low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with and without Zn chelator, N,N,N',N'-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN), at 5 mg/kg body-weight daily for 4 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level and liver histopathological and biochemical changes.Hepatic Zn deficiency (lower than control level, p

Introduction: An early substantial loss of basal forebrain cholinergic neurons (BFCNs) is a common property of Alzheimer's disease and the degeneration of functional BFCNs is related to learning and memory deficits. As a biocompatible and conductive scaffold for growth of neural stem cells, three-dimensional graphene foam (3D-GF) supports applications in tissue engineering and regenerative medicine. Although its effects on differentiation have been demonstrated, the effect of 3D-GF scaffold on the generation of BFCNs still remains unknown. Methods: In this study, we used 3D-GF as a culture substrate for neural progenitor cells (NPCs) and demonstrated that this scaffold material promotes the differentiation of BFCNs while maintaining excellent cell viability and proliferation. Results: Immunofluorescence analysis, real-time polymerase chain reaction, Western blotting, and ELISA revealed that the proportion of BFCNs at 21 days of differentiation reached approximately 30.5% on 3D-GF compared with TCPS group that only presented 9.7%. Furthermore, a cell adhesion study suggested that 3D-GF scaffold enhances the expression of adhesion proteins including vinculin, integrin, and N-cadherin. These findings indicate that 3D-GF scaffold materials are preferable candidates for the differentiation of BFCNs from NPCs. Conclusions: These results suggest new opportunities for the application of 3D-GF scaffold as a neural scaffold for cholinergic neurons therapies based on NPCs. [ABSTRACT FROM AUTHOR]