IFT80 negatively regulates osteoclast differentiation via association with Cbl-b to disrupt TRAF6 stabilization and activation.

Excess bone loss due to increased osteoclastogenesis is a significant clinical problem. Intraflagellar transport (IFT) proteins have been reported to regulate cell growth and differentiation. The role of IFT80, an IFT complex B protein, in osteoclasts (OCs) is completely unknown. Here, we demonstrate that deletion of IFT80 in the myeloid lineage led to increased OC formation and activity accompanied by severe bone loss in mice. IFT80 regulated OC formation by associating with Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) to promote protein stabilization and proteasomal degradation of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6). IFT80 knockdown resulted in increased ubiquitination of Cbl-b and higher TRAF6 levels, thereby hyperactivating the receptor activator of nuclear factor-κß (NF-κß) ligand (RANKL) signaling axis and increased OC formation. Ectopic overexpression of IFT80 rescued osteolysis in a calvarial model of bone loss. We have thus identified a negative function of IFT80 in OCs.

Environmental effects and their impact on yield in adjacent experimental plots of high-stem and short-stem wheat varieties.

BACKGROUND: In regional wheat trials, when short-stem wheat varieties and high-stem wheat varieties are planted adjacent to each other in small plots, changes in their marginal plot environment can lead to bias in yield evaluation. Currently, there is no relevant research revealing the degree of their mutual influence. RESULTS: In a regional wheat experiment, when high-stem wheat varieties and short-stem wheat varieties were planted adjacent to one another, there was no significant change in soil temperature or humidity in the high-stem wheat variety experimental plot from November to May compared to the control plot, while the soil humidity in the short-stem wheat variety experimental plot was greater than that in the control plot. In May, the soil temperature of the short-stem wheat varieties in the experimental plot was lower than that in the control plot. Illumination of the wheat canopy in the high-stem wheat variety experimental plot had a significant positive effect in April and May, while illumination of the wheat canopy in the short-stem wheat variety experimental plot had a negative effect. The chlorophyll fluorescence parameters of flag leaves in the high-stem wheat variety experimental plots showed an overall increasing trend, while the chlorophyll fluorescence parameters of flag leaves in the experimental plots of short-stem wheat varieties showed a decreasing trend. The analysis of the economic yield, biological yield, and yield factors in each experimental plot revealed that the marginal effects of the economic yield and 1000-grain weight were particularly significant and manifested as positive effects in the high-stem wheat variety experimental plot and as negative effects in the short-stem wheat variety experimental plot. The economic yield of the high-stem wheat variety experimental plot was significantly greater than that of the control plot, the economic yield of the short-stem wheat variety experimental plot was significantly lower than that of the control plot, and the economic yield of the high-stem experimental plot was significantly greater than that of the short-stem experimental plot. When the yield of the control plot of the high-stem wheat varieties was compared to that of the control plot of the short-stem wheat varieties, the yield of the control plot of the short-stem wheat varieties was significantly greater than that of the control plot of the high-stem wheat varieties. CONCLUSIONS: Based on these findings, it is concluded that plots with high-stem and short-stem wheat varieties are adjacent in regional wheat trials, the plots of high-stem wheat varieties are subject to marginal positive effects, resulting in a significant increase in economic yield; the plots of short-stem wheat varieties are subject to marginal negative effects, resulting in a decrease in economic yield. This study reveals the mutual influence mechanism of environment and yield with adjacent planting of high-stem and short-stem wheat varieties in regional wheat trials, providing a useful reference and guidance for optimizing the layout of regional wheat trials.

Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis.

BACKGROUND: Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases. OBJECTIVE: To investigate the abnormal Khib profile and its pathogenic role in psoriasis. METHODS: We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis. RESULTS: The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression. CONCLUSION: Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.

The structure and function of multifunctional protein ErbB3 binding protein 1 (Ebp1) and its role in diseases.

ErbB3-binding protein 1(Ebp1) has two isoforms, p42 Ebp1 and p48 Ebp1, both of which can regulate cell growth and differentiation. But these isoforms often have opposite effects, including contradictory roles in regulation of cell growth in different tissues and cells. P48 Ebp1 belongs to the full-length sequence, while conformational changes in the crystal structure of p42 Ebp1 reveals a lack of an α helix at the amino terminus. Due to the differences in the structures of these two isoforms, they have different binding partners and protein modifications. Ebp1 can function as both an oncogene and a tumor suppressor factor. However, the underlying mechanisms by which these two isoforms exert opposite functions are still not fully understood. In this review, we summarize the genes and the structures of protein of these two isoforms, protein modifications, binding partners and the association of different isoforms with diseases.

The causal relationship between blood cell indices and 28-day mortality in sepsis: a retrospective study and bidirectional Mendelian randomization analysis.

BACKGROUND: Despite emerging evidence linking blood cell indices (BCIs) to sepsis mortality, the inconsistency of observational studies obscures the clarity of these associations. This study aims to clarify the causal influence of BCIs on 28-day mortality rates in sepsis patients. METHODS: Utilizing univariable and multivariable Mendelian randomization (MR) analyses, we examined the impact of BCIs on sepsis mortality by analyzing data from extensive genome-wide association studies. The inverse-variance weighted (IVW) method was our primary analytic tool, complemented by several robustness checks to mitigate pleiotropy, including weighted median, mode-based estimates, MR-Egger regression, and MR-PRESSO. Subsequently, we conducted a retrospective study to further explore the correlation between platelet indices and 28-day mortality of sepsis using real-world data. RESULTS: Our findings highlight a significant causal relationship between platelet distribution width (PDW) and 28-day mortality in sepsis, with the univariable Mendelian randomization approach yielding an odds ratio of 1.12 (95% CI, 1.06-1.26; P < 0.05). Multivariable analysis further substantiated PDW's robust association with mortality risk (OR 1.23; 95% CI, 1.03-1.48; P < 0.05). Conversely, our analysis did not uncover significant correlations between the genetic predispositions to other BCIs-including red blood cell count, erythrocyte distribution width, platelet count, mean platelet volume, white blood cell count, neutrophil count, neutrophil percentage, lymphocyte count, and lymphocyte percentage-and 28-day mortality in sepsis. Additionally, an inverse MR analysis did not establish a causal impact of 28-day mortality in sepsis on PDW (OR 1.00; 95% CI, 1.00-1.07; P = 0.29). Moreover, a similar result was observed in the retrospective study. CONCLUSIONS: The study underscores the independent causal role of PDW in predicting 28-day mortality in sepsis, suggesting its potential utility in early patient assessment, risk stratification, and tailoring of therapeutic interventions.

Non-invasive assessment of response to transcatheter arterial chemoembolization for hepatocellular carcinoma with the deep neural networks-based radiomics nomogram.

BACKGROUND: Transcatheter arterial chemoembolization (TACE) is a mainstay treatment for intermediate and advanced hepatocellular carcinoma (HCC), with the potential to enhance patient survival. Preoperative prediction of postoperative response to TACE in patients with HCC is crucial. PURPOSE: To develop a deep neural network (DNN)-based nomogram for the non-invasive and precise prediction of TACE response in patients with HCC. MATERIAL AND METHODS: We retrospectively collected clinical and imaging data from 110 patients with HCC who underwent TACE surgery. Radiomics features were extracted from specific imaging methods. We employed conventional machine-learning algorithms and a DNN-based model to construct predictive probabilities (RScore). Logistic regression helped identify independent clinical risk factors, which were integrated with RScore to create a nomogram. We evaluated diagnostic performance using various metrics. RESULTS: Among the radiomics models, the DNN_LASSO-based one demonstrated the highest predictive accuracy (area under the curve [AUC] = 0.847, sensitivity = 0.892, specificity = 0.791). Peritumoral enhancement and alkaline phosphatase were identified as independent risk factors. Combining RScore with these clinical factors, a DNN-based nomogram exhibited superior predictive performance (AUC = 0.871, sensitivity = 0.844, specificity = 0.873). CONCLUSION: In this study, we successfully developed a deep learning-based nomogram that can noninvasively and accurately predict TACE response in patients with HCC, offering significant potential for improving the clinical management of HCC.

Cumulative radiation exposure from multimodality recurrent imaging of CT, fluoroscopically guided intervention, and nuclear medicine.

OBJECTIVES: To assess cumulative effective dose (CED) over a 4-year period in patients undergoing multimodality recurrent imaging at a major hospital in the USA. METHODS: CED from CT, fluoroscopically guided intervention (FGI), and nuclear medicine was analyzed in consecutive exams in a tertiary care center in 2018-2021. Patients with CED ≥ 100 mSv were classified by age and body habitus (underweight, healthy weight, overweight, obese), as per body mass index percentiles < 5th, 5th to < 85th, 85th to < 95th, and ≥ 95th (age 2-19 years), and its ranges < 18.5, 18.5-24.9, 25-29.9, and ≥ 30 (≥ 20 years), respectively. RESULTS: Among a total of 205,425 patients, 5.7% received CED ≥ 100 mSv (mean 184 mSv, maximum 1165 mSv) and their ages were mostly 50-64 years (34.1%), followed by 65-74 years (29.8%), ≥ 75 years (19.5%), 20-49 years (16.3%), and ≤ 19 years (0.29%). Body habitus in decreasing occurrence was obese (38.6%), overweight (31.9%), healthy weight (27.5%), and underweight (2.1%). Classification by dose indicated 172 patients (≥ 500 mSv) and 3 (≥ 1000 mSv). In comparison, 5.3% of 189,030 CT patients, 1.6% of 18,963 FGI patients, and 0.19% of 41,401 nuclear-medicine patients received CED ≥ 100 mSv from a single modality. CONCLUSIONS: The study of total dose from CT, FGI, and nuclear medicine of patients with CED ≥ 100 mSv indicates major (89%) contribution of CT to CED with 70% of cohort being obese and overweight, and 64% of cohort aged 50-74 years. CLINICAL RELEVANCE STATEMENT: Multimodality recurrent exams are common and there is a lack of information on patient cumulative radiation exposure. This study attempts to address this lacuna and has the potential to motivate actions to improve the justification process for enhancing patient safety. KEY POINTS: • In total, 5.7% of patients undergoing multimodality recurrent imaging (CT, fluoroscopically guided intervention, nuclear medicine) incurred a dose of ≥ 100 mSv. • Mean dose was 184 mSv, with 15 to 18 times contribution from CT than that from fluoroscopically guided intervention or nuclear medicine. • In total, 70% of those who received ≥ 100mSv were either overweight or obese.

CT image quality evaluation in the age of deep learning: trade-off between functionality and fidelity.

OBJECTIVE: To quantitatively compare DLIR and ASiR-V with realistic anatomical images. METHODS: CT scans of an anthropomorphic phantom were acquired using three routine protocols (brain, chest, and abdomen) at four dose levels, with images reconstructed at five levels of ASiR-V and three levels of DLIR. Noise power spectrum (NPS) was estimated using a difference image by subtracting two matching images from repeated scans. Using the max-dose FBP reconstruction as the ground truth, the structure similarity index (SSIM) and gradient magnitude (GM) of difference images were evaluated. Image noise magnitude (σ), frequency location of the NPS peak (fpeak), mean SSIM (MSSIM), and mean GM (MGM) were used as quantitative metrics to compare image quality, for each anatomical region, protocol, algorithm, dose level, and slice thickness. RESULTS: Image noise had a strong (R2 > 0.99) power law relationship with dose for all algorithms. For the abdomen and chest, fpeak shifted from 0.3 (FBP) down to 0.15 mm-1 (ASiR-V 100%) with increasing ASiR-V strength but remained 0.3 mm-1 for all DLIR levels. fpeak shifted down for the brain protocol with increasing DLIR levels. Three levels of DLIR produced similar image noise levels as ASiR-V 40%, 80%, and 100%, respectively. DLIR had lower MSSIM but higher MGM than ASiR-V while matching imaging noise. CONCLUSION: Compared to ASiR-V, DLIR presents trade-offs between functionality and fidelity: it has a noise texture closer to FBP and more edge enhancement, but reduced structure similarity. These trade-offs and unique protocol-dependent behaviors of DLIR should be considered during clinical implementation and deployment. KEY POINTS: • DLIR reconstructed images demonstrate closer noise texture and lower structure similarity to FBP while producing equivalent noise levels comparable to ASiR-V. • DLIR has additional edge enhancement as compared to ASiR-V. • DLIR has unique protocol-dependent behaviors that should be considered for clinical implementation.

n-3 PUFA can reduce IL-6 and TNF levels in patients with cancer.

Current studies on inhibitory effects of n-3 PUFA on pro-inflammatory cytokines have inconsistent results. Thus, a meta-analysis of randomised controlled trials was conducted to identify the effects of n-3 PUFA administration on circulating IL-6 and TNF in patients with cancer. Studies that examined the effects of n-3 PUFA administration on circulating IL-6 and TNF in patients with cancer were identified by searching PubMed and EMBASE from January 1975 to February 2021. Differences in n-3 PUFA administration and control conditions were determined by calculating standardised mean differences (SMD) with 95 % CI. Twenty studies involving 971 patients met the inclusion criteria. The overall SMD were 0·485 (95 % CI 0·087, 0·883) for IL-6 and 0·712 (95 % CI 0·461, 0·962) for TNF between n-3 PUFA administration and control conditions. Sources of heterogeneity were not found through subgroup and meta-regression analyses. Publication bias was observed in TNF with a slight contribution to the effect size. n-3 PUFA can reduce circulating IL-6 and TNF levels in patients with cancer. Results supported the recommendation of n-3 PUFA as adjuvant therapy for patients with cancer, possibly excluding head and neck cancer, owing to their anti-inflammatory properties.

Two Stable Bifunctional Zinc Metal-Organic Frameworks with Luminescence Detection of Antibiotics and Proton Conduction.

Functionalized crystalline solids based on metal-organic frameworks (MOFs) enable efficient luminescence detection and high proton conductivity, making them crucial in the realms of environmental monitoring and clean energy. Here, two structurally and functionally distinct zinc-based MOFs, [Zn(TTDPa)(bodca)]·H2O (1) and [Zn(TTDPb)(bodca)]·H2O (2), were successfully designed and synthesized using 3,6-di(pyridin-4-yl)thieno[3,2-b]thiophene (TTDPa) and 2,5-di(pyridin-4-yl)thieno[3,2-b]thiophene (TTDPb) as ligands, in the presence of bicyclo[2.2.2]octane-1,4-dicarboxylic acid (H2bodca). Both 1 and 2 display a three-dimensional (3D) structure with 5-fold interpenetration, and notably, 2 forms a larger one-dimensional pore measuring 17.16 × 10.81 Å2 in size. Fluorescence experiments demonstrate that 1 and 2 can function as luminescent sensors for nitrofurantoin (NFT) and nitrofurazone (NFZ) with low detection limits, remarkable selectivity, and good recyclability. A comprehensive analysis was conducted to investigate the differing sensing effects of compounds 1 and 2 and to explore potential sensing mechanisms. Additionally, at 328 K and 98% relative humidity, 1 and 2 exhibit proton conductivity values of 2.13 × 10-3 and 4.91 × 10-3 S cm-1, respectively, making them suitable proton-conducting materials. Hence, the integration of luminescent sensing and proton conductivity in monophasic 3D Zn-MOFs holds significant potential for application in intelligent multitasking devices.

Reaction mechanism of nickel sulfide atomic layer deposition using bis(N,N'-di-tert-butylacetamidinato)nickel(II) and hydrogen sulfide.

As a unique nanofabrication technology, atomic layer deposition (ALD) has been used in the microelectronics, catalysis, environmental and energy fields. As an energy and catalytic material, nickel sulfide has excellent electrochemical and catalytic activities and has attracted extensive attention. In this work, the reaction mechanism for nickel sulfide ALD from an amidine metal precursor was investigated using density functional theory (DFT) calculations. The results show that the first amidine ligand of bis(N,N'-di-tert-butylacetamidinato)nickel(II) [Ni(tBu-MeAMD)2] can be easily eliminated on the sulfhydrylated surface. The second amidine ligand can also react with the adjacent sulfhydryl group to generate the N,N'-di-tert-butylacetamidine (tBu-MeAMD-H) molecule, which can strongly interact with the Ni atom on the surface and be difficult to be desorbed. In the subsequent H2S reaction, the tBu-MeAMD-H molecule can be exchanged with the H2S precursor. Ultimately, the tBu-MeAMD-H molecule can be desorbed and H2S can be dissociated to form two sulfhydrylated groups on the surface. Meanwhile, the -SH of a H2S molecule can be exchanged with the second tBu-MeAMD ligand. These insights into the reaction mechanism of nickel sulfide ALD can provide theoretical guidance to design the metal amidinate precursors and improve the ALD process for metal sulfides.

Anti-Neuroinflammatory Meroterpenoids from a Chinese Collection of the Brown Alga Sargassum siliquastrum.

Nine new chromane-type meroterpenoids, including the rare nor-meroterpenoid sargasilol A (1) and the eight meroditerpenoids sargasilols B-I (2-9), were isolated from a China Sea collection of the brown alga Sargassum siliquastrum, together with six known analogues (10-15). The structures of the new chromanes were identified by extensive spectroscopic analysis and by comparison with previously reported data. Compounds 1-3 and 6-15 exhibited inhibition against LPS-induced NO production in BV-2 microglial cells, and 1, with a shorter carbon chain, was the most active one. Compound 1 was established as an anti-neuroinflammatory agent through targeting the IKK/IκB/NF-κB signaling pathway. As such, the chromanes from brown algae could provide promising anti-neuroinflammatory lead compounds for further structural modification.

Self-polymerized platinum (II)-Polydopamine nanomedicines for photo-chemotherapy of bladder Cancer favoring antitumor immune responses.

Systemic administration of platinum-based drugs has obvious limitations in the treatment of advanced bladder cancer (BC) owing to lower tumor accumulation and uncontrolled release of chemotherapeutics. There is an urgent need for advanced strategies to overcome the current limitations of platinum-based chemotherapy, to achieve maximal therapeutic outcomes with reduced side effects. In this study, self-polymerized platinum (II)-polydopamine nanocomplexes (PtPDs) were tailored for efficient chemo-photoimmunotherapy of BC. PtPDs with high Pt loading content (11.3%) were degradable under the combination of a reductive tumor microenvironment and near-infrared (NIR) light irradiation, thus controlling the release of Pt ions to achieve efficient chemotherapy. In addition, polydopamine promoted stronger photothermal effects to supplement platinum-based chemotherapy. Consequently, PtPDs provided effective chemo-photothermal therapy of MB49 BC in vitro and in vivo, strengthening the immunogenic cell death (ICD) effect and robust anti-tumoral immunity response. When combined with a PD-1 checkpoint blockade, PtPD-based photochemotherapy evoked systemic immune responses that completely suppressed primary and distant tumor growth without inducing systemic toxicities. Our work provides a highly versatile approach through metal-dopamine self-polymerization for the precise delivery of metal-based chemotherapeutic drugs, and may serve as a promising nanomedicine for efficient and safe platinum-based chemotherapy for BC.

Thermal process of a silicon wafer under a CW laser and 100-10000 Hz pulsed laser irradiation.

The thermal process of a (001) silicon wafer subjected to a continuous-wave (CW) laser and 100-10000 Hz pulsed laser irradiation is investigated experimentally and numerically. The temperature evolution of the spot center is measured using an infrared radiation pyrometer. The waveforms of the temperature evolution curves provide valuable information about melting, solidification, vaporization, and fracture. To gain a better understanding of the thermal process, a three-dimensional finite element model is established, and numerical simulations are conducted to analyze the temperature, stress, and dislocation field. The results show that the 10 kHz laser exhibits the highest heating efficiency before vaporization, but the lowest ablation efficiency after vaporization due to the shielding effect of vapor. The diffusion time of vapor is found to be more than 50 µs. Fracture occurs during 1 kHz laser irradiation. The motion of liquid may play a significant role, but it cannot be evidenced by a simulation due to complex dependence of material parameters on dislocation. This issue should be addressed as a priority in future studies.

Potential dynamic changes of single-season rice planting suitability across China.

As an important food crop in China, changes in suitable areas for rice planting are critical to agricultural production. In this study, the maximum entropy model (MaxEnt) was utilized to pick the main climatic factors affecting single-season rice planting distribution and project the potential changes under RCP4.5 and RCP8.5 scenarios. It was clear that rice planting distribution was significantly affected by annual total precipitation, the accumulated temperature during a period in which daily temperature was ≥ 10 °C, the moisture index, total precipitation during April-September, and continuous days during the period of daily temperature ≥ 18 °C, with their contribution being 97.6%. There was a continuous decrease in the area of good and high suitability for rice planting projected from 2021-2040 to 2061-2080, with a respective value ranging from 1.49 × 106 km2 to 0.93 × 106 km2 under the RCP4.5 scenario and from 1.42 × 106 km2 to 0.66 × 106 km2 under RCP8.5 scenarios. In 2081-2100, there was a bit increase in the area of good and high suitability under the RCP4.5 scenario. The most significant increases in good and high suitability were detected in Northeast China, while obvious decreases were demonstrated in the Yangtze River Basin which might be exposed to extreme temperature threat. The spatial potential planting center was characterized by the largest planting area in 25°N-37°N and 98°E-134°E. The north boundary and center of rice cultivation arose to 53.5°N and 37.52°N, respectively. These potential distributions for single-season rice under future climate change can provide a theoretical basis for optimizing rice planting layout, improving cultivation, and adjusting variety and management systems in response to climate change.

[Hesperetin Alleviates Doxorubicin-Induced Cytotoxicity in H9c2 Cells by Activating SIRT1/NRF2 Signaling].

Objective: To investigate whether hesperetin (Hes) alleviates doxorubicin (DOX)-induced cardiomyocytotoxicity by reducing oxidative stress via regulating silent information regulator 1 (SIRT1)/nuclear transcription factor E2-related factor 2 (NRF2) signaling in H9c2 cells. Methods: H9c2 cells were treated with DOX to establish the cardiotoxicity model and were randomly assigned to four groups, a control group (Control) and three treatment groups, receiving respectively DOX (the DOX group), Hes+DOX (the DOX+Hes group), and Hes+SIRT1 inhibitor EX527+DOX (the DOX+Hes+EX527 group). Cellular morphology was observed by the light microscope. Cell viability was evaluated by CCK-8. DOX-induced apoptosis in H9c2 cells was examined by flow cytometry. The levels of reactive oxygen species (ROS) in the H9c2 cells of the four groups were determied with 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD), catalase (CAT), and SIRT1 as well as the malondialdehyde (MDA) content were measured using ELISA kits. The expressions of cleaved caspase-3, cytochrome c, SIRT1, Ac-FOXO1, NRF2, and heme oxygenase 1 (HO-1) were determined by Western blot. Results: Compared with the Control group, the DOX group showed swollen cellular morphology, decreased cell density and viability, and increased LDH activity in the medium ( P<0.01); both apoptosis and the expression of cleaved caspase-3 and cytochrome c increased ( P<0.01); the activities of CAT and SOD decreased while the contents of MDA and ROS increased ( P<0.01); the expression of SIRT1, NRF2, and HO-1 decreased, the activity of SIRT1 decreased, and the expression of Ac-FOXO1 increased ( P<0.01). Compared with the DOX group, the DOX+Hes group showed improved cellular morphology, increased cell density and viability, and decreased LDH activity in the medium ( P<0.01); the apoptosis and the expression of cleaved caspase-3 and cytochrome c decreased ( P<0.01); the activities of CAT and SOD increased while the levels of MDA and ROS decreased ( P<0.01); the expression of SIRT1, NRF2, and HO-1 increased, the activity of SIRT1 increased, and the expression of Ac-FOXO1 decreased ( P<0.01). Comparison of the findings for the DOX+Hes group and the DOX+Hes+EX527 group showed that EX527 could block the protective effects of Hes against DOX-induced cell injury, oxidative stress, and SIRT1/NRF2 signaling. Conclusion: Hes inhibits oxidative stress and apoptosis via regulating SIRT1/NRF2 signaling, thereby reducing DOX-induced cardiotoxicity in H9c2 cells.

EDIL3 influenced the αvß3-FAK/MEK/ERK axis of endothelial cells in psoriasis.

One of the earliest events in the development of psoriatic lesion is a vascular network expansion. The abnormal vascular network is associated with increased endothelial cells (ECs) survival, proliferation, adhesion, migration, angiogenesis and permeability in psoriatic lesion. Our previous study demonstrated that epidermal growth factor-like repeats and discoidin I-like domains 3 (EDIL3) derived from psoriatic dermal mesenchymal stem cells (DMSCs) promoted cell-cell adhesion, migration and angiogenesis of ECs, but the molecular mechanism of upstream or downstream has not been explored. So, this study aimed to explore the association between EDIL3 derived from DMSCs (DMSCs-derived EDIL3) and psoriasis-associated angiogenesis. We injected recombinant EDIL3 protein to mouse model of psoriasis to confirm the roles of EDIL3 in psoriasis. Besides, we employed both short-interference RNA (si-RNA) and lentiviral vectors to explore the molecular mechanism of EDIL3 promoting angiogenesis in psoriasis. In vivo, this research found that after injected recombination EDIL3 protein, the epidermis thickness and microvessel density were both elevated. EDIL3 accelerated the process of psoriasis in the IMQ-induced psoriasis-like mouse model. Additionally, we confirmed that in vitro DMSCs-derived EDIL3 is involved in the tube formation of ECs via αvß3-FAK/MEK/ERK signal pathway. This suggested that DMSCs-derived EDIL3 and αvß3-FAK/MEK/ERK signal pathway in ECs play an important role in the pathogenesis of psoriasis. And the modification of DMSCs, EDIL3 and αvß3-FAK/MEK/ERK signal pathway will provide a valuable therapeutic target to control the angiogenesis in psoriasis.

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.

Inhibition of miR-130b-3p restores autophagy and attenuates intervertebral disc degeneration through mediating ATG14 and PRKAA1.

Oxidative stress-induced autophagy dysfunction is involved in the pathogenesis of intervertebral disc degeneration (IVDD). MicroRNAs (miRNAs) not only have been regarded as important regulators of IVDD but also reported to be related to autophagy. This research was aimed to explore the role of miR-130b-3p in IVDD and its regulation on autophagy mechanism. The miR-130b-3p expression in the patient's degenerative nucleus pulposus (NP) samples and rat NP tissues was detected by qRT-PCR and FISH assay. The miR-130b-3p was knocked down or overexpressed in the human NP cells by lentivirus transfection. TBHP was used to induce oxidative stress in the human NP cells. Apoptosis, senescence, and autophagy were evaluated by flow cytometry, ß-gal staining, immunofluorescence, electron microscopy, and Western blot in the miR-130b-3p knocked down human NP cells under TBHP treatment. The relationship between the miR-130b-3p and ATG14 or PRKAA1 was confirmed by luciferase assay. The siRNA transfection was used to knock down the ATG14 and PRKAA1 expression, and then the human NP cells functions were further determined. In the in vivo experiment, the IVDD rat model was constructed and an adeno-associated virus (AAV)-miR-130b-3p inhibitor was intradiscally injected. After that, MRI and histological staining were conducted to evaluate the role of miR-130b-3p inhibition in the IVDD rat model. We found that the miR-130b-3p was upregulated in the degenerative NP samples from humans and rats. Interestingly, the inhibition of miR-130b-3p rescued oxidative stress-induced dysfunction of the human NP cells, and miR-130b-3p inhibition upregulated autophagy. Mechanistically, we confirmed that the miR-130b-3p regulated the ATG14 and PRKAA1 directly and the knockdown of the ATG14 or PRKAA1 as well as the treatment of autophagy inhibitor blockaded the autophagic flux and reversed the protective effects of miR-130b-3p inhibition in the TBHP-induced human NP cells. Furthermore, the inhibition of the miR-130b-3p via AAV- miR-130b-3p injection ameliorated the IVDD in a rat model. These data demonstrated that the miR-130b-3p inhibition could upregulate the autophagic flux and alleviate the IVDD via targeting ATG14 and PRKAA1.The translational potential of this article: The suppression of miR-130b-3p may become an effective therapeutic strategy for IVDD.

Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004-18.

BACKGROUND: In China, mean body-mass index (BMI) and obesity in adults have increased steadily since the early 1980s. However, to our knowledge, there has been no reliable assessment of recent trends, nationally, regionally, or in certain population subgroups. To address this evidence gap, we present detailed analyses of relevant data from six consecutive nationally representative health surveys done between 2004 and 2018. We aimed to examine the long-term and recent trends in mean BMI and prevalence of obesity among Chinese adults, with specific emphasis on changes before and after 2010 (when various national non-communicable disease prevention programmes were initiated), assess how these trends might vary by sex, age, urban-rural locality, and socioeconomic status, and estimate the number of people who were obese in 2018 compared with 2004. METHODS: We used data from the China Chronic Disease and Risk Factors Surveillance programme, which was established in 2004 with the aim to provide periodic nationwide data on the prevalence of major chronic diseases and the associated behavioural and metabolic risk factors in the general population. Between 2004 and 2018 six nationally representative surveys were done. 776 571 individuals were invited and 746 020 (96·1%) participated, including 33 051 in 2004, 51 050 in 2007, 98 174 in 2010, 189 115 in 2013, 189 754 in 2015, and 184 876 in 2018. After exclusions, 645 223 participants aged 18-69 years remained for the present analyses. The mean BMI and prevalence of obesity (BMI ≥30 kg/m2) were calculated and time trends compared by sex, age, urban-rural locality, geographical region, and socioeconomic status. FINDINGS: Standardised mean BMI levels rose from 22·7 kg/m2 (95% CI 22·5-22·9) in 2004 to 24·4 kg/m2 (24·3-24·6) in 2018 and obesity prevalence from 3·1% (2·5-3·7) to 8·1% (7·6-8·7). Between 2010 and 2018, mean BMI rose by 0·09 kg/m2 annually (0·06-0·11), which was half of that reported during 2004-10 (0·17 kg/m2, 95% CI 0·12-0·22). Similarly, the annual increase in obesity prevalence was somewhat smaller after 2010 than before 2010 (6·0% annual relative increase, 95% CI 4·4-7·6 vs 8·7% annual relative increase, 4·9-12·8; p=0·13). Since 2010, the rise in mean BMI and obesity prevalence has slowed down substantially in urban men and women, and moderately in rural men, but continued steadily in rural women. By 2018, mean BMI was higher in rural than urban women (24·3 kg/m2vs 23·9 kg/m2; p=0·0045), but remained lower in rural than urban men (24·5 kg/m2vs 25·1 kg/m2; p=0·0007). Across all six surveys, mean BMI was persistently lower in women with higher levels of education compared with women with lower levels of education, but the inverse was true among men. Overall, an estimated 85 million adults (95% CI 70 million-100 million; 48 million men [95% CI 39 million-57 million] and 37 million women [31 million-43 million]) aged 18-69 years in China were obese in 2018, which was three times as many as in 2004. INTERPRETATION: In China, the rise in mean BMI among the adult population appears to have slowed down over the past decade. However, we found divergent trends by sex, geographical area, and socioeconomic status, highlighting the need for a more targeted approach to prevent further increases in obesity in the Chinese general population. FUNDING: China National Key Research and Development Program, China National Key Project of Public Health Program, and Youth Scientific Research Foundation of the National Center for Chronic and Noncommunicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention.