Heritable transcriptional defects from aberrations of nuclear architecture.

Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1-3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.

PDIA3 orchestrates effector T cell program by serving as a chaperone to facilitate the non-canonical nuclear import of STAT1 and PKM2.

Dysregulated T cell activation underpins the immunopathology of rheumatoid arthritis (RA), yet the machineries that orchestrate T cell effector program remain incompletely understood. Herein, we leveraged bulk and single-cell RNA sequencing data from RA patients and validated protein disulfide isomerase family A member 3 (PDIA3) as a potential therapeutic target. PDIA3 is remarkably upregulated in pathogenic CD4 T cells derived from RA patients and positively correlates with C-reactive protein level and disease activity score 28. Pharmacological inhibition or genetic ablation of PDIA3 alleviates RA-associated articular pathology and autoimmune responses. Mechanistically, T cell receptor signaling triggers intracellular calcium flux to activate NFAT1, a process that is further potentiated by Wnt5a under RA settings. Activated NFAT1 then directly binds to the Pdia3 promoter to enhance the expression of PDIA3, which complexes with STAT1 or PKM2 to facilitate their nuclear import for transcribing T helper 1 (Th1) and Th17 lineage-related genes, respectively. This non-canonical regulatory mechanism likely occurs under pathological conditions, as PDIA3 could only be highly induced following aberrant external stimuli. Together, our data support that targeting PDIA3 is a vital strategy to mitigate autoimmune diseases, such as RA, in clinical settings.

Integrated analysis of single-cell RNA-seq and bulk RNA-seq unravels the molecular feature of M2 macrophages of head and neck squamous cell carcinoma.

The connection between head and neck squamous cell carcinoma (HNSC) and M2 tumour-associated macrophages is not yet fully understood. We gathered gene expression profiles and clinical data from HNSC patients in the TCGA database. Using Consensus Clustering, we categorized these patients into M2 macrophage-related clusters. We developed a M2 macrophage-related signature (MRS) through statistical analyses. Additionally, we assessed gene expression in HNSC cells using single-cell sequencing data (GSE139324). We identified three distinct M2 macrophage-related clusters in HNSC, each with different prognostic outcomes and immune characteristics. Patients with different MRS profiles exhibited variations in immune infiltration, genetic mutations and prognosis. FCGR2A may play a role in creating an immunosuppressive tumour microenvironment and could potentially serve as a therapeutic target for HNSC. Our study demonstrated that M2 macrophage-related genes significantly impact the development and progression of HNSC. The M2 macrophage-related model offered a more comprehensive assessment of HNSC patient prognosis, genetic mutations and immune features. FCGR2A was implicated in immunosuppressive microenvironments and may hold promise for the development of novel immunotherapeutic strategies for HNSC.

Fluvoxamine inhibits Th1 and Th17 polarization and function by repressing glycolysis to attenuate autoimmune progression in type 1 diabetes.

BACKGROUND: Fluvoxamine is one of the selective serotonin reuptake inhibitors (SSRIs) that are regarded as the first-line drugs to manage mental disorders. It has been also recognized with the potential to treat inflammatory diseases and viral infection. However, the effect of fluvoxamine on autoimmune diseases, particularly type 1 diabetes (T1D) and the related cellular and molecular mechanisms, are yet to be addressed. METHOD: Herein in this report, we treated NOD mice with fluvoxamine for 2 weeks starting from 10-week of age to dissect the impact of fluvoxamine on the prevention of type 1 diabetes. We compared the differences of immune cells between 12-week-old control and fluvoxamine-treated mice by flow cytometry analysis. To study the mechanism involved, we extensively examined the characteristics of CD4+ T cells with fluvoxamine stimulation using RNA-seq analysis, real-time PCR, Western blot, and seahorse assay. Furthermore, we investigated the relevance of our data to human autoimmune diabetes. RESULT: Fluvoxamine not only delayed T1D onset, but also decreased T1D incidence. Moreover, fluvoxamine-treated NOD mice showed significantly attenuated insulitis coupled with well-preserved ß cell function, and decreased Th1 and Th17 cells in the peripheral blood, pancreatic lymph nodes (PLNs), and spleen. Mechanistic studies revealed that fluvoxamine downregulated glycolytic process by inhibiting phosphatidylinositol 3-kinase (PI3K)-AKT signaling, by which it restrained effector T (Teff) cell differentiation and production of proinflammatory cytokines. CONCLUSION: Collectively, our study supports that fluvoxamine could be a viable therapeutic drug against autoimmunity in T1D setting.

Alcohol Advertising Exposure and Drinking Habits Among Chinese Adolescents in 2021: A National Survey.

Objectives. To assess the exposure of Chinese adolescents to proalcohol advertising and explore its association with alcohol consumption. Methods. A nationally and regionally representative school-based survey was conducted in mainland China in 2021 among students in grades 7 through 12, aged 13 to 18 years. We assessed adolescent exposure to proalcohol advertising and its association with alcohol consumption. Results. A total of 57 336 students participated in the survey, and the exposure percentage of proalcohol advertising was 66.8%, with no difference between boys and girls or between urban and rural areas. The top 3 exposure channels were television (51.8%), the Internet (43.6%), and outdoor billboards (42.0%). The exposure was higher among students who had consumed alcohol in the past 30 days (80.1% vs 65.1%; adjusted odds ratio [AOR] = 1.29) and in the past 12 months (77.3% vs 61.7%; AOR = 1.30). However, no significant correlation was observed between advertising exposure and drunkenness. Conclusions. Approximately two thirds of Chinese adolescents have been exposed to proalcohol advertising in the past 30 days, with television, the Internet, and outdoor billboards being the most prevalent channels. Exposure to proalcohol advertising exhibits a positive correlation with drinking. (Am J Public Health. 2024;114(8):814-823. https://doi.org/10.2105/AJPH.2024.307680).

Single-cell and bulk RNA-sequencing reveals mitosis-involved gene HAUS1 is a promising indicator for predicting prognosis and immune responses in prostate adenocarcinoma (PRAD).

It was imperative to identify latent biomarkers pertinent to malignancies, given the pivotal role targeted molecular therapies play in tumor treatment investigations. This study aimed to assess the validity of HAUS1 as an indicator for survival prognosis and immune responses in prostate adenocarcinoma (PRAD) via single-cell and bulk RNA-sequencing. Related data on HAUS1 expression in PRAD were obtained from online databases, followed by comprehensive analyses to delineate its associations with survival prognosis, implicated pathways, and immune responses. Besides, the expression pattern of HAUS1 in PRAD was also verified in vitro, by using qRT-PCR, Western blot analysis, and immunohistochemistry. We found HAUS1 was downregulated in PRAD compared with normal tissues, as verified in vitro by qRT-PCR, Western blot, and immunohistochemistry (p < 0.05). Single-cell RNA-sequencing analysis indicated that HAUS1 had relatively higher expressions in B cells, Mono/Macro cells, and Endothelial cells compared with other cell types. Cox regression analysis revealed HAUS1 could serve as an independent indicator for the overall survival prognosis of PRAD (p < 0.05). Spearman correlation analyses revealed HAUS1 was closely related to the tumor microenvironment, immune cell infiltration levels, immune checkpoints, and immune cell pathways (p < 0.05). Furthermore, HAUS1 expression was found to be closely related to the immunotherapeutic response of patients receiving clinical intervention (p < 0.05). Collectively, our findings underscored the significant role of HAUS1 in PRAD prognosis and immune response, thereby presenting a novel and promising avenue for investigating the clinical utility of immunotherapy in PRAD.

Nuclear envelope assembly defects link mitotic errors to chromothripsis.

Defects in the architecture or integrity of the nuclear envelope are associated with a variety of human diseases1. Micronuclei, one common nuclear aberration, are an origin for chromothripsis2, a catastrophic mutational process that is commonly observed in cancer3-5. Chromothripsis occurs after micronuclei spontaneously lose nuclear envelope integrity, which generates chromosome fragmentation6. Disruption of the nuclear envelope exposes DNA to the cytoplasm and initiates innate immune proinflammatory signalling7. Despite its importance, the basis of the fragility of the micronucleus nuclear envelope  is not known. Here we show that micronuclei undergo defective nuclear envelope assembly. Only 'core' nuclear envelope proteins8,9 assemble efficiently on lagging chromosomes, whereas 'non-core' nuclear envelope proteins8,9, including nuclear pore complexes (NPCs), do not. Consequently, micronuclei fail to properly import key proteins that are necessary for the integrity of the nuclear envelope and genome. We show that spindle microtubules block assembly of NPCs and other non-core nuclear envelope proteins on lagging chromosomes, causing an irreversible defect in nuclear envelope assembly. Accordingly, experimental manipulations that position missegregated chromosomes away from the spindle correct defective nuclear envelope assembly, prevent spontaneous nuclear envelope disruption, and suppress DNA damage in micronuclei. Thus, during mitotic exit in metazoan cells, chromosome segregation and nuclear envelope assembly are only loosely coordinated by the timing of mitotic spindle disassembly. The absence of precise checkpoint controls may explain why errors during mitotic exit are frequent and often trigger catastrophic genome rearrangements4,5.

Metabolic disparities between obese and non-obese patients with polycystic ovary syndrome: implications for endometrial receptivity indicators.

OBJECTIVE: To investigate the differences in the metabolic indicators and sex hormones between obese and non-obese patients with polycystic ovary syndrome (PCOS), and their impacts on endometrial receptivity (ER). METHODS: We selected 255 individuals with PCOS, and categorized them into the obese groups, including the OP group (obese patients with PCOS) and the ON group (obese patients without PCOS), and selected 64 individuals who were categorized in the non-obese groups, namely, the control groups, which comprise the NP group (non-obese patients with PCOS) and the NN group(non-obese patients without PCOS). The one-way analysis of variance (ANOVA) and Mann-Whitney U tests were used to compare the metabolic indicators, and sex hormone-associated and ER-associated indicators between the groups. The correlation between the aforementioned clinical markers and ER was analyzed using the Pearson's correlation coefficient. RESULTS: (1) In comparison with the NP group, the OP group exhibited higher levels (p < .01) of free androgen index (FAI), anti-müllerian hormone (AMH), fasting insulin (FINS), insulin level within 60 min, 120 min, and 180 min-60minINS, 120minINS, and 180minINS, respectively, fasting blood glucose (FBG), blood glucose level within two hours (2hGlu), homeostatic model assessment for insulin resistance (HOMA-IR), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), waist-to-hip ratio (WHR), waist circumference, hip circumference, the ratio of the maximum blood flow velocity of the uterine artery during systole to the blood flow velocity of the uterine artery at the end of diastole (uterine artery S/D), and blood flow resistance index (RI) of the uterine artery. In comparison with the NP group, the OP group exhibited lower levels (p < .01) of sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA), high molecular weight adiponectin (HMWA), and high-density lipoprotein cholesterol (HDL-C). (2) In the PCOS group, RI was significantly positively correlated with FAI, FINS, 120minINS, HOMA-IR, and WHR (p < .01), and significantly negatively correlated with SHBG, HDL-C, and HMWA (p < .01); uterine artery S/D was significantly positively correlated with FAI, FINS, 2hGlu, HOMA-IR, LDL-C, and WHR (p < .01), significantly positively correlated with 120minINS and FBG (p < .05), and significantly negatively correlated with SHBG and HMWA (p < .01). CONCLUSION: (1) The OP group exhibited obvious metabolic disorders and poor ER, which was manifested as low levels of SHBG and HMWA, and high levels of FAI, HOMA-IR, WHR, uterine artery S/D, and RI. (2) In patients with PCOS, there was a substantial correlation between ER-associated indicators RI and uterine artery S/D and FAI, FINS, 120minINS, HOMA-IR, WHR, SHBG, and HMWA.

miR-708-3p targetedly regulates LSD1 to promote osteoblast differentiation of hPDLSCs in periodontitis.

Periodontitis (PD) is a multifactorial inflammatory disease associated with periodontopathic bacteria. Lysine-specific demethylase 1 (LSD1), a type of histone demethylase, has been implicated in the modulation of the inflammatory response process in oral diseases by binding to miRNA targets. This study investigates the molecular mechanisms by which miRNA binds to LSD1 and its subsequent effect on osteogenic differentiation. First, human periodontal ligament stem cells (hPDLSCs) were isolated, cultured, and characterized. These cells were then subjected to lipopolysaccharide (LPS) treatment to induce inflammation, after which osteogenic differentiation was initiated. qPCR and western blot were employed to monitor changes in LSD1 expression. Subsequently, LSD1 was silenced in hPDLSCs to evaluate its impact on osteogenic differentiation. Through bioinformatics and dual luciferase reporter assay, miR-708-3p was predicted and confirmed as a target miRNA of LSD1. Subsequently, miR-708-3p expression was assessed, and its role in hPDLSCs in PD was evaluated through overexpression. Using chromatin immunoprecipitation (ChIP) and western blot assay, we explored the potential regulation of osterix (OSX) transcription by miR-708-3p and LSD1 via di-methylated H3K4 (H3K4me2). Finally, we investigated the role of OSX in hPDLSCs. Following LPS treatment of hPDLSCs, the expression of LSD1 increased, but this trend was reversed upon the induction of osteogenic differentiation. Silencing LSD1 strengthened the osteogenic differentiation of hPDLSCs. miR-708-3p was found to directly bind to and negatively regulate LSD1, leading to the repression of OSX transcription through demethylation of H3K4me2. Moreover, overexpression of miR-708-3p was found to promote hPDLSCs osteogenic differentiation in inflammatory microenvironment. However, the protective effect was partially attenuated by reduced expression of OSX. Our findings indicate that miR-708-3p targetedly regulates LSD1 to enhance OSX transcription via H3K4me2 methylation, ultimately promoting hPDLSCs osteogenic differentiation.

Medical waste incineration fly ash-based magnesium potassium phosphate cement: Calcium-reinforced chlorine solidification/stabilization mechanism and optimized carbon reduction process strategy.

The traditional solidification/stabilization (S/S) technology, Ordinary Portland Cement (OPC), has been widely criticized due to its poor resistance to chloride and significant carbon emissions. Herein, a S/S strategy based on magnesium potassium phosphate cement (MKPC) was developed for the medical waste incineration fly ash (MFA) disposal, which harmonized the chlorine stabilization rate and potential carbon emissions. The in-situ XRD results indicated that the Cl- was efficiently immobilized in the MKPC system with coexisting Ca2+ by the formation of stable Ca5(PO4)3Cl through direct precipitation or intermediate transformation (the Cl- immobilization rate was up to 77.29%). Additionally, the MFA-based MKPC also demonstrated a compressive strength of up to 39.6 MPa, along with an immobilization rate exceeding 90% for heavy metals. Notably, despite the deterioration of the aforementioned S/S performances with increasing MFA incorporation, the potential carbon emissions associated with the entire S/S process were significantly reduced. According to the Life Cycle Assessment, the potential carbon emissions decreased to 8.35 × 102 kg CO2-eq when the MFA reached the blending equilibrium point (17.68 wt.%), while the Cl- immobilization rate still remained above 65%, achieving an acceptable equilibrium. This work proposes a low-carbon preparation strategy for MKPC that realizes chlorine stabilization, which is instructive for the design of S/S materials.

The construction of elastin-like polypeptides and their applications in drug delivery system and tissue repair.

Elastin-like polypeptides (ELPs) are thermally responsive biopolymers derived from natural elastin. These peptides have a low critical solution temperature phase behavior and can be used to prepare stimuli-responsive biomaterials. Through genetic engineering, biomaterials prepared from ELPs can have unique and customizable properties. By adjusting the amino acid sequence and length of ELPs, nanostructures, such as micelles and nanofibers, can be formed. Correspondingly, ELPs have been used for improving the stability and prolonging drug-release time. Furthermore, ELPs have widespread use in tissue repair due to their biocompatibility and biodegradability. Here, this review summarizes the basic property composition of ELPs and the methods for modulating their phase transition properties, discusses the application of drug delivery system and tissue repair and clarifies the current challenges and future directions of ELPs in applications.

Effect of LSD1 on osteogenic differentiation of human periodontal ligament stem cells in periodontitis.

OBJECTIVE: Periodontitis is a chronic inflammation of periodontal tissues. This study is expected to assess the effect of LSD1 on the osteogenic differentiation of hPDLSCs in periodontitis. METHODS: hPDLSCs were separated, cultivated, and identified, and then treated by LPS to induce inflammatory microenvironment and subjected to osteogenic differentiation. Subsequently, LSD1 expression was determined, and then silenced to assess its effect on hPDLSCs. Next, the binding relation between LSD1 and miR-590-3p was analyzed. miR-590-3p expression was detected and then overexpressed to evaluate its role in hPDLSCs in periodontitis. Afterward, the relation between LSD1 and OSX was analyzed. H3K4me2 level and OSX transcription were measured, and the role of H3K4me2 was determined. Additionally, the role of OSX in hPDLSCs was verified. RESULTS: LSD1 was poorly expressed after osteogenic differentiation of hPDLSCs while it was rescued upon LPS induction. The osteogenic differentiation of hPDLSC in periodontitis was strengthened upon LSD1 downregulation. Besides, miR-590-3p targeted LSD1 transcription, and LSD1 inhibited OSX transcription via H3K4me2 demethylation. miR-590-3p overexpression improved osteogenic differentiation of hPDLSCs in periodontitis. But this improvement was annulled by OSX inhibition. CONCLUSION: miR-590-3p targeted LSD1 transcription and upregulated H3K4me2 methylation to promote OSX transcription, thereby encouraging osteogenic differentiation of hPDLSCs in periodontitis.

Wire Rope Defect Recognition Method Based on MFL Signal Analysis and 1D-CNNs.

The quantitative defect detection of wire rope is crucial to guarantee safety in various application scenes, and sophisticated inspection conditions usually lead to the accurate testing of difficulties and challenges. Thus, a magnetic flux leakage (MFL) signal analysis and convolutional neural networks (CNNs)-based wire rope defect recognition method was proposed to solve this challenge. Typical wire rope defect inspection data obtained from one-dimensional (1D) MFL testing were first analyzed both in time and frequency domains. After the signal denoising through a new combination of Haar wavelet transform and differentiated operation and signal preprocessing by normalization, ten main features were used in the datasets, and then the principles of the proposed MFL and 1D-CNNs-based wire rope defect classifications were presented. Finally, the performance of the novel method was evaluated and compared with six machine learning methods and related algorithms, which demonstrated that the proposed method featured the highest testing accuracy (>98%) and was valid and feasible for the quantitative and accurate detection of broken wire defects. Additionally, the considerable application potential as well as the limitations of the proposed methods, and future work, were discussed.

A new dimeric (-)-5-methylmellein from cultures of the basidiomycete Inonotus sinensis.

(-)-5-Methylmellein (1) and its new dimer (2) were isolated from cultures of the basidiomycete Inonotus sinensis. Their structures were elucidated on the basis of extensive spectroscopic methods including UV, IR, HR-EI-MS, 1D NMR and 2D NMR. The structure of Compound 2 was determined by single-crystal X-ray crystallographic analysis. Compound 2 was tested for the cytotoxicities against five human cancer cell lines.

Recent advances in the research on effects of micro/nanoplastics on carbon conversion and carbon cycle: A review.

Massive production and spread application of plastics have led to the accumulation of numerous plastics in the global environment so that the proportion of carbon storage in these polymers also increases. Carbon cycle is of fundamental significance to global climate change and human survival and development. With the continuous increase of microplastics, undoubtedly, there carbons will continue to be introduced into the global carbon cycle. In this paper, the impact of microplastics on microorganisms involved in carbon transformation is reviewed. Micro/nanoplastics affect carbon conversion and carbon cycle by interfering with biological fixation of CO2, microbial structure and community, functional enzymes activity, the expression of related genes, and the change of local environment. Micro/nanoplastic abundance, concentration and size could significantly lead to difference in carbon conversion. In addition, plastic pollution can further affect the blue carbon ecosystem reduce its ability to store CO2 and marine carbon fixation capacity. Nevertheless, problematically, limited information is seriously insufficient in understanding the relevant mechanisms. Accordingly, it is required to further explore the effect of micro/nanoplastics and derived organic carbon on carbon cycle under multiple impacts. Under the influence of global change, migration and transformation of these carbon substances may cause new ecological and environmental problems. Additionally, the relationship between plastic pollution and blue carbon ecosystem and global climate change should be timely established. This work provides a better perspective for the follow-up study of the impact of micro/nanoplastics on carbon cycle.

Mixed cropping with duck co-culture: an agroecological system to improve grain quality and farm profitability.

BACKGROUND: Previous studies found that mixed cropping combined with duck co-culture (MCDC) system could improve the efficiency of grain production and positively affect soil nutrient contents. However, the effects on grain quality, and profitable income have not been evaluated yet. In this study, a field experiment with four combinations of different rice varieties and ducks was conducted during both the early and late rice growing seasons. RESULTS: The field survey demonstrated that MCDC system significantly decreased the grain appearance of chalky rice rate and the chalkiness degree with an average of 56.82%, and 54.28%, respectively. Leaf SPAD value, photosynthetic rate, and aboveground dry weight were all improved in the MCDC and mixed-cropping systems, relative to the mono-cropping system. The net income obtained from the mono-cropping, mixed cropping (no ducks), and MCDC (with ducks) systems (from grain and ducks' meat) was 581.2 USD ha-1 yr-1 , 1001.8 USD ha-1 yr-1 , and 5242.1 USD ha-1 yr-1 in both growing seasons, respectively. CONCLUSION: Planting genetically diverse rice varieties and co-culture with ducks increased rice growth rates, productivity and grain quality. The MCDC system would provide more ecological and economic benefits compared with the conventional mono-cropping system. © 2022 Society of Chemical Industry.

Molecular Dipole Engineering of Carbonyl Additives for Efficient and Stable Perovskite Solar Cells.

Carbonyl functional materials as additives are extensively applied to reduce the defects density of the perovskite film. However, there is still a lack of comprehensive understanding for the effect of carbonyl additives to improve device performance. In this work, we systematically study the effect of carbonyl additive molecules on the passivation of defects in perovskite films. After a comprehensive investigation, the results confirm the importance of molecular dipole in amplifying the passivation effect of additive molecules. The additive with strong molecular dipole possesses the advantages of enhancing the efficiency and stability of perovskite solar cells (PSCs). After optimization, the companion efficiency of PSCs is 23.20 %, and it can maintain long-term stability under harsh conditions. Additionally, a large-area solar cell module-modified DLBA was 20.18 % (14 cm2 ). This work provides an important reference for the selection and designing of efficient carbonyl additives.

Understanding the Role of Fluorine Groups in Passivating Defects for Perovskite Solar Cells.

Introducing fluorine (F) groups into a passivator plays an important role in enhancing the defect passivation effect for the perovskite film, which is usually attributed to the direct interaction of F and defect states. However, the interaction between electronegative F and electron-rich passivation groups in the same molecule, which may influence the passivation effect, is ignored. We herein report that such interactions can vary the electron cloud distribution around the passivation groups and thus changing their coordination with defect sites. By comparing two fluorinated molecules, heptafluorobutylamine (HFBM) and heptafluorobutyric acid (HFBA), we find that the F/-NH2 interaction in HFBM is stronger than the F/-COOH one in HFBA, inducing weaker passivation ability of HFBM than HFBA. Accordingly, HFBA-based perovskite solar cells (PSCs) provide an efficiency of 24.70 % with excellent long-term stability. Moreover, the efficiency of a large-area perovskite module (14.0 cm2 ) based on HFBA reaches 21.13 %. Our work offers an insight into understanding an unaware role of the F group in impacting the passivation effect for the perovskite film.

Trends in smoking prevalence in urban and rural China, 2007 to 2018: Findings from 5 consecutive nationally representative cross-sectional surveys.

BACKGROUND: Tobacco smoking is a leading cause of premature death in China, especially among adult men. Since the implementation of the Framework Convention on Tobacco Control in 2005, nationwide tobacco control has been strengthened, but its long-term impact on smoking prevalence is unclear. METHODS AND FINDINGS: Five nationally representative surveys of the China Chronic Disease and Risk Factor Surveillance (CCDRFS) were conducted in 2007, 2010, 2013, 2015, and 2018. A total of 624,568 adults (278,605 men and 345,963 women) aged 18 to 69 years were randomly selected from 31 provinces (or equivalent) in China. Temporal changes in smoking prevalence and patterns (e.g., percentages of those smoking manufactured cigarettes, amount smoked, and age at smoking initiation) were analyzed, overall and by sex, urban or rural residence, year of birth, education and occupation, using linear regression methods. Among men, the standardized prevalence of current smoking decreased from 58.4% (95% confidence interval [CI]: 56.1 to 60.7) to 50.8% (95% CI: 49.1 to 52.5, p < 0.001) between 2007 and 2018, with annual decrease more pronounced in urban (55.7% [95% CI: 51.2 to 60.3] to 46.3% [95% CI: 43.7 to 49.0], p < 0.001) than rural men (59.9% [95% CI: 57.5 to 62.4] to 54.6% [95% CI: 52.6 to 56.6], p = 0.05) and in those born before than after 1980. Among rural men born after 1990, however, the prevalence increased from 40.2% [95% CI: 34.0 to 46.4] to 52.1% ([95% CI: 45.7 to 58.5], p = 0.007), with the increase taking place mainly before 2015. Among women, smoking prevalence remained extremely low at around 2% during 2007 to 2018. No significant changes of current smoking prevalence (53.9% to 50.8%, p = 0.22) were observed in male patients with at least 1 of major chronic diseases (e.g., hypertension, diabetes, myocardial infarction, stroke, chronic obstructive pulmonary disease (COPD)). In 2018, 25.6% of adults aged ≥18 years smoked, translating into an estimated 282 million smokers (271 million men and 11 million women) in China. Across 31 provinces, smoking prevalence varied greatly. The 3 provinces (Yunnan, Guizhou, and Hunan) with highest per capita tobacco production had highest smoking prevalence in men (68.0%, 63.4%, and 61.5%, respectively), while lowest prevalence was observed in Shanghai (34.8%). Since the children and teenage groups were not included in the surveys, we could not assess the smoking trends among youths. Furthermore, since the smoking behavior was self-reported, the smoking prevalence could be underestimated due to reporting bias. CONCLUSIONS: In this study, we observed that the smoking prevalence has decreased steadily in recent decades in China, but there were diverging trends between urban and rural areas, especially among men born after 1980. Future tobacco control strategies should target rural young men, regions with high tobacco production, and patients suffering from chronic diseases.

Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain.

Delta opioid receptor (DOR) agonists alleviate nociceptive behaviors in various chronic pain models, including neuropathic pain, while having minimal effect on sensory thresholds in the absence of injury. The mechanisms underlying nerve injury-induced enhancement of DOR function are unclear. We used a peripheral nerve injury (PNI) model of neuropathic pain to assess changes in the function and localization of DORs in mice and rats. Intrathecal administration of DOR agonists reversed mechanical allodynia and thermal hyperalgesia. The dose-dependent thermal antinociceptive effects of DOR agonists were shifted to the left in PNI rats. Administration of DOR agonists produced a conditioned place preference in PNI, but not in sham, animals, whereas the DOR antagonist naltrindole produced a place aversion in PNI, but not in sham, mice, suggesting the engagement of endogenous DOR activity in suppressing pain associated with the injury. GTPγS autoradiography revealed an increase in DOR function in the dorsal spinal cord, ipsilateral to PNI. Immunogold electron microscopy and in vivo fluorescent agonist assays were used to assess changes in the ultrastructural localization of DORs in the spinal dorsal horn. In shams, DORs were primarily localized within intracellular compartments. PNI significantly increased the cell surface expression of DORs within lamina IV-V dendritic profiles. Using neonatal capsaicin treatment, we identified that DOR agonist-induced thermal antinociception was mediated via receptors expressed on primary afferent sensory neurons but did not alter mechanical thresholds. These data reveal that the regulation of DORs following PNI and suggest the importance of endogenous activation of DORs in regulating chronic pain states.