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Abstract Kesterite Cu2ZnSn(S, Se)4 is considered one of the most competitive photovoltaic materials due to its earth-abundant and nontoxic constituent elements, environmental friendliness, and high stability. However, the preparation of high-quality Kesterite absorbers for photovoltaics is still challenging for the uncontrollability and complexity of selenization reactions between metal element precursors and selenium. In this study, we propose a solid-liquid/solid-gas (solid precursor and liquid/vapor Se) synergistic reaction strategy to precisely control the selenization process. By pre-depositing excess liquid selenium, we provide the high chemical potential of selenium to facilitate the direct and rapid formation of the Kesterite phase. The further optimization of selenium condensation and subsequent volatilization enables the efficient removal of organic compounds and thus improves charge transport in the absorber film. As a result, we achieve high-performance Kesterite solar cells with total-area efficiency of 13.6% (certified at 13.44%) and 1.09 cm2-area efficiency of 12.0% (certified at 12.1%).

Abstract Background Hepatic ischemia–reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. Methods Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. Results Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). Conclusions Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Abstract Background Spindle and kinetochore-associated complex subunit 3 (SKA3) plays an important role in cell proliferation by regulating the separation of chromosomes and their division into daughter cells. Previous studies demonstrated that SKA3 was strongly implicated in tumor development and progression. However, the roles of SKA3 in cholangiocarcinoma (CCA) and the underlying mechanisms remain unclear. Methods Next-generation sequencing (NGS) was performed with paired CCA tissues and normal adjacent tissues (NATs). SKA3 was chose to be the target gene because of its remarkably upregulation and unknown function in cholangiocarcinoma in TCGA datasets, GSE107943 datasets and our sequencing results. RT-PCR and immunohistochemistry staining were used to detect the expression of SKA3 in paired CCA tissues and normal adjacent tissues. The SKA3 knockdown and overexpression cell line were constructed by small interfering RNA and lentivirus vector transfection. The effect of SKA3 on the proliferation of cholangiocarcinoma under hypoxic conditions was detected by experiments in vitro and in vivo. RNA-seq was used to find out the differentially expressed pathways in cholangiocarcinoma proliferation under hypoxia regulated by SKA3. IP/MS analysis and Western blot assays were used to explore the specific mechanism of SKA3 in regulating the expression of HIF-1a under hypoxia. Results SKA3 was up-regulated in NGS, TCGA and GSE107943 databases and was associated with poor prognosis. Functional experiments in vitro and in vivo showed that hypoxia-induced SKA3 promoted cholangiocarcinoma cell proliferation. RNA-sequencing was performed and verified that SKA3 enhanced fatty acid synthesis by up-regulating the expression of key fatty acid synthase, thus promoting cholangiocarcinoma cell proliferation under hypoxic conditions. Further studies indicated that under hypoxic conditions, SKA3 recruited PARP1 to bind to HIF-1a, thus enhancing the poly ADP-ribosylation (PARylation) of HIF-1a. This PARylation enhanced the binding between HIF-1a and USP7, which triggered the deubiquitylation of HIF-1a under hypoxic conditions. Additionally, PARP1 and HIF-1a were upregulated in CCA and promoted CCA cell proliferation. SKA3 promoted CCA cell proliferation and fatty acid synthesis via the PARP1/HIF-1a axis under hypoxic conditions. High SKA3 and HIF-1a expression levels were associated with poor prognosis after surgery. Conclusion Hypoxia-induced SKA3 promoted CCA progression by enhancing fatty acid synthesis via the regulation of PARylation-dependent HIF-1a deubiquitylation. Furthermore, increased SKA3 level enhanced chemotherapy-resistance to gemcitabine-based regimen under hypoxic conditions. SKA3 and HIF-1a could be potential oncogenes and significant biomarkers for the analysis of CCA patient prognosis.

Abstract Hypoxic-ischemic encephalopathy (HIE) at high-altitudes leads to neonatal mortality and long-term neurological complications without effective treatment. Acer truncatum Bunge Seed extract (ASO) is reported to have effect on cognitive improvement, but its molecular mechanisms on HIE are unclear. In this study, ASO administration contributed to reduced neuronal cell edema and improved motor ability in HIE rats at a simulated 4500-meter altitude. Transcriptomics and WGCNA analysis showed genes associated with lipid biosynthesis, redox homeostasis, neuronal growth, and synaptic plasticity regulated in the ASO group. Targeted and untargeted-lipidomics revealed decreased free fatty acids and increased phospholipids with favorable ω-3/ω-6/ω-9 fatty acid ratios, as well as reduced oxidized glycerophospholipids (OxGPs) in the ASO group. Combining multi-omics analysis demonstrated FA to FA-CoA, phospholipids metabolism, and lipid peroxidation were regulated by ASO treatment. Our results illuminated preliminary metabolism mechanism of ASO ingesting in rats, implying ASO administration as potential intervention strategy for HIE under high-altitude.

In order to reduce the low mass discrimination effect of the miniaturized ion funnel, a method of gradient descent radio frequency (RF) signal application was proposed. The RF signals with decreasing amplitude were applied on the outlet electrodes of the ion funnel, which would improve the transmission efficiency of low mass-to-charge ratio ions. The ion transmission performance of the miniature ion funnel with the gradient descent RF signal applying was studied by simulation software SIMION and ion trajectory simulation software AXSIM. When the gradient descent RF voltage was applied, the potential line around the outlet electrodes of miniaturized ion funnel was sparse, and the effective potential was shallower, then it could significantly reduce the axial effective potential of the terminal electrode. The simulation results showed that the gradient descent RF application method could effectively reduce the low mass discrimination, while the transmission efficiency of high mass ions was not affected. As revealed by the simulation, when the initial RF voltage amplitude V1 was 120 V and 80 V, respectively, the corresponding optimal descent gradient σ was 6 V and 3 V, and the ion transmission efficiency could achieve 60% and 62% for the ions at m/z 20, while it still maintained nearly 100% efficiency in high mass range (m/z≥200). Not only that, at lower mass segments (m/z≤20), a lower mass-to-charge ratio cutoff was obtained in the gradient descent RF signal application mode, which demonstrated that this new RF signal application method could significantly extend the low mass range. The influence of RF frequency and direct current (DC) field gradient parameter with the gradient descent RF application method on the ion transmission efficiency was studied in detail, indicating that a RF frequency of 1 MHz and a DC field gradient parameter of 10 V/cm were the optimal value of obtaining a high ion transmission efficiency. Further, the gradient descent RF signal application method was simplified. The ion transfer efficiency achieved by the simplified method decreased slightly, but it was still better than that achieved by the traditional RF application method. An ion transmission efficiency (at m/z 20) of 56.6% was achieved in the simplified gradient descent RF signal application mode, which was decreased by 5.7% compared with that before simplification and improved by 57.2% compared to conventional RF application mode. The simulation result illustrated that the simplified gradient descent RF application mode can reduce low mass discrimination effect to adequate extent. The simplification method can reduce the difficulty of operation and improve the feasibility of the scheme implementation.

Abstract Background Extracellular vesicles (EVs) are membranous structures that are formed during pathophysiology, host-parasite interactions and parasite motility. Typically, apicomplexan-infected host cells secrete EVs which traverse local and systemic strata of the host as the parasites develop. Methods Extracellular vesicles were isolated from the caecum and serum of Eimeria falciformis-infected mice during oocyst ingestion (0 h post-infection [0 hpi]), merozont stages 1 and 2 (68 and 116 hpi), oocyst shedding (7 days post-infection [7 dpi]) and host recovery (10 dpi) and subsequently characterized and profiled by tandem mass tag (TMT). Results With the progression of E. falciformis life stages, subpopulation of EVs bearing EV biomarkers, including CD9, CD82, heat shock protein 70 (HSP70) and major histocompatibility complex (MHC) molecules, increased. A total of 860 and 1024 differentially expressed proteins were identified in serum EVs (sEVs) and caecum EVs (cEVs), respectively. Identified immune-related molecules (such as cytokines, receptors, immunoglobins, complements, hormones, inflammasomes), ion exchange and cell death-associated proteins were significantly expressed, at least during the E. falciformis first and second merozont stages. Bioinformatics assessment indicated that sEV proteins were at all time points implicated in antigen processing and presentation as well as natural killer cell-mediated cytotoxicity (68 hpi), complement activation/blood coagulation (116 hpi/10 dpi) and catabolic activities (7 dpi). In contrast, cEV proteins were involved in catabolic process, ion transport and antigen presentation (68 and 116 hpi). Host response to E. falciformis infection was similar to intestinal bacterium at 7 dpi and cell adhesion and intercellular protein transport at 10 dpi. In both systems, ferroptosis and necroptosis were common across the parasite’s infectious cycle while apoptosis occurred at 68 hpi. Conclusion The proteomic data indicate that E. falciformis infection co-opts cellular and humoral responses through EV secretions, and that, host cell death and ionic imbalance are associated with E. falciformis infection. This study offers additional insight into host-parasite interactions and host regulatory EV proteins as potential disease indicators or diagnostic molecules. Graphical Abstract

Abstract Background Hypertension is a risk factor for cholangiocarcinoma (CCA). The effect of anti-hypertensive drugs on the prognosis of CCA is not clear. Methods This is a retrospective study of 102 patients (56.9% males, median age 66 years) diagnosed with CCA and hypertension concurrently and received radical surgery (R0), with a median follow-up of 36.7 months. Kaplan-Meier analysis, Cox regressions, and propensity score (PS) matching were applied for statistical analysis. Results Results of multivariable cox analysis showed that renin-angiotensin system inhibitors (RASis) usage was a protective factor for progression-free survival (PFS) (hazard ratio [HR] = 0.55, 95% confidence interval [95% CI]: 0.32–0.96) and overall survival (OS) (HR = 0.40, 95% CI: 0.20–0.79), respectively. Calcium channel blockers, diuretics, and β-blockers didn’t show significant associations. The association of RASis usage and PFS and OS was derived by PS matching, with a cohort of 28 RASis users and 56 RASis non-users. The median PFS and OS of RASis users (PFS, 17.6 months (9.2–34.4); OS, 24.8 months (16.5–42.3)) were longer than RASis non-users (PFS, 10.5 months (4.1–24.1); OS, 14.6 months (10.6–28.4)). The 1 year, 2 years, and 3 years’ survival rates of RASis users (89.1%, 77.0%, and 65.5%) were higher than RASis non-users (70.9%, 54.0%, and 40.0%). Conclusions RASis usage improves the survival of patients with CCA and hypertension concurrently.

Background: The high disability rate of osteoarthritis (OA), a joint disease with an insidious onset and widespread effects, places a heavy financial burden on patients, families, and society. Traditional diagnostic approaches, including radiology and physical examination, cannot achieve early-stage screening of OA and thus, miss early intervention for patients. Therefore, the need of biomarkers for the early diagnosis of OA is crucial. Results: A total of 390 differentially expressed genes (DEGs) were identified from the training set, and 1077 key module genes were found by constructing a weighted gene co-expression network, and 161 key genes were obtained as a result. Four diagnostic marker genes highly associated with OA were screened for key genes using machine learning algorithms, and the resulting nomogram model showed excellent predictive power and clinical value. After further background studies, immune infiltration and functional enrichment analysis, we found that FKBP5 may play an important role in the prognosis and immune infiltration of multiple cancers, and this hypothesis was verified by pan-cancer analysis. Conclusions: We screened four diagnostic marker genes (FKBP5, EPYC, KLF9 and PDZRN4) that are highly associated with OA. And this led to a diagnostic model, which was assessed to have good predictive power and clinical value. FKBP5 may be a potential intervention target for human diseases such as osteoarthritis and tumors. How to cite: Xiao Y, Wang Y, Xu X, et al. Integrated analysis reveals potential significance of FKBP5 in the prognosis and immunity of osteoarthritis and pan-cancer. Electron J Biotechnol 2023;65. https://doi.org/10.1016/j.ejbt.2023.05.002.

Effective economic dispatch for the integrated energy system (IES) can improve energy efficiency and promote renewable energy accommodation. Tradition IES economic dispatch are based on model-based methods that rely on accurate system parameters and uncertainty prediction. This paper proposes a data-driven fast economic dispatch method based on deep reinforcement learning (DRL) in an integrated electricity and natural gas system (IEGS). Unlike other DRL-based studies that spend a lot of computation time to calculate power flow, we employ DNNs to learn the complex nonlinear relationship existing in the IEGS, namely IEGSNet. Then, the economic dispatch problem is formulated as a Markov decision process, and solved by the soft actor–critic​ (SAC) algorithm. Simulation results illustrate that the proposed method achieves the similar operation cost to the tradition DRL-based dispatch method, but takes almost one tenth of the training time. Additionally, the computation time of the proposed method for 10-day dataset is at least two orders of magnitudes shorter that the model-based optimization algorithm.

Objective: The aim of this study was to optimize the formulation of a C60-modified self-microemulsifying drug delivery system loaded with triptolide (C60-SMEDDS/TP) and evaluate the cytoprotective effect of the C60-SMEDDS/TP on normal human cells. Results: The C60-SMEDDS/TP exhibited rapid emulsification, an optimal particle size distribution of 50 ± 0.19 nm (PDI 0.211 ± 0.049), and a near-neutral zeta potential of −1.60 mV. The release kinetics of TP from the C60-SMEDDS/TP exhibited a sustained release profile and followed pseudo-first-order release kinetics. Cellular proliferation and apoptosis analysis indicated that the C60-SMEDDS/TP (with a mass ratio of TP: DSPE-PEG-C60 = 1:10) exhibited lower toxicity towards L02 and GES-1 cells. This was demonstrated by a higher IC50 (40.88 nM on L02 cells and 17.22 nM on GES-1 cells) compared to free TP (21.3 nM and 11.1 nM), and a lower apoptosis rate (20.8% on L02 cells and 26.3% on GES-1 cells, respectively) compared to free TP (50.5% and 47.0%) at a concentration of 50 nM. In comparison to the free TP group, L02 cells and GES-1 cells exposed to the C60-SMEDDS/TP exhibited a significant decrease in intracellular ROS and an increase in mitochondrial membrane potential (ΔψM). On the other hand, the C60-SMEDDS/TP demonstrated a similar inhibitory effect on BEL-7402 cells (IC50 = 28.9 nM) and HepG2 cells (IC50 = 107.6 nM), comparable to that of the free TP (27.2 nM and 90.4 nM). The C60-SMEDDS/TP group also exhibited a similar intracellular level of ROS and mitochondrial membrane potential compared to the SMEDDS/TP and free TP groups. Method: Fullerenol-Grafted Distearoyl Phosphatidylethanolamine-Polyethylene Glycol (DSPE-PEG-C60) was synthesized and applied in the self-microemulsifying drug delivery system. The C60-SMEDDS/TP was formulated using Cremophor EL, medium-chain triglycerides (MCT), PEG-400, and DSPE-PEG-C60, and loaded with triptolide (TP). The toxicity and bioactivity of the C60-SMEDDS/TP were assessed using normal human liver cell lines (L02 cells), normal human gastric mucosal epithelial cell lines (GES-1 cells), and liver cancer cell lines (BEL-7402 cells and HepG2 cells). The production of reactive oxygen species (ROS) after the C60-SMEDDS/TP treatment was assessed using 2′,7′-dichlorofluorescein diacetate (DCFDA) staining. The alterations in mitochondrial membrane potential (ΔψM) were assessed by measuring JC-1 fluorescence. Conclusions: The cytoprotection provided by the C60-SMEDDS/TP favored normal cells (L02 and GES-1) over tumor cells (BEL-7402 and HepG2 cells) in vitro. This suggests a promising approach for the safe and effective treatment of TP.

In order to ascertain the impact of working water flow rate and inlet pressure on the performance of the liquid–gas jet pump with square nozzle, the pumping volume ratio and efficiency of the liquid–gas jet pump with square nozzle were experimentally investigated at different inlet pressures and working water flow rates. Furthermore, the internal flow characteristics of the liquid–gas jet pump with square nozzle were explored through the utilization of visualization technology in the self-designed square-nozzle liquid–gas jet pump experimental setup. The findings indicate that the pumping ratio of the liquid–gas jet pump increases in conjunction with an elevation in the inlet pressure. Liquid–gas jet pump efficiency is higher at lower inlet pressures, up to 42.48%, and drops rapidly as inlet pressure increases. The pumping volume ratio of the liquid–gas jet pump increases significantly as the working water flow rate increases, and the working water flow rate exerts a minimal effect on the working efficiency of the liquid–gas jet pump. In the context of extreme vacuum conditions, a considerable number of droplets undergo substantial reflux in the posterior section of the throat, with a notable absence of bubbles in the diffusion tube. The size and number of bubbles diminish gradually along the axial direction. The objective of this paper is to provide a reference point for determining the optimal operational parameters for a square-nozzle liquid–gas jet pump in a practical context.

The operating state of axle box bearings is crucial to the safety of high-speed trains, and the vibration acceleration signal is a commonly used bearing-health-state monitoring signal. In order to extract hidden characteristic frequency information from the vibration acceleration signal of axle box bearings for fault diagnosis, a method for extracting the fault characteristic frequency based on principal component analysis (PCA) fusion and the optimal bandpass filtered denoising signal analytic energy operator (AEO) demodulation spectrum is proposed in this paper. PCA is used to measure the dimension reduction and fusion of three-direction vibration acceleration, reducing the interference of irrelevant noise components. A new type of multi-channel bandpass filter bank is constructed to obtain filtering signals in different frequency intervals. A new, improved average kurtosis index is used to select the optimal filtering signals for different channel filters in a bandpass filter bank. A dimensionless characteristic index characteristic frequency energy concentration coefficient (CFECC) is proposed for the first time to describe the energy prominence ability of characteristic frequency in the spectrum and can be used to determine the bearing fault type. The effectiveness and applicability of the proposed method are verified using the simulation signals and experimental signals of four fault bearing test cases. The results demonstrate the effectiveness of the proposed method for fault diagnosis and its advantages over other methods.

Panax notoginseng is a highly valued perennial medicinal herb in China and is widely used in clinical treatments. The main purpose of this study was to elucidate the changes in the composition of P. notoginseng saponins (PNSs), which are the main bioactive substances, triggered by arbuscular mycorrhizal fungi (AMF) via ultrahigh-performance liquid chromatography–electrospray ionization–tandem mass spectrometry (UPLC–ESI–MS/MS). A total of 202 putative terpenoid metabolites were detected, of which 150 triterpene glycosides were identified, accounting for 74.26% of the total. Correlation analysis, principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS–DA) of the metabolites revealed that the samples treated with AMF (group Ce) could be clearly separated from the CK samples. In total, 49 differential terpene metabolites were identified between the Ce and CK groups, of which 38 and 11 metabolites were upregulated and downregulated, respectively, and most of the upregulated differentially abundant metabolites were mainly triterpene glycosides. The relative abundances of the two major notoginsenosides (MNs), ginsenosides Rd and Re, and 13 rare notoginsenosides (RNs), significantly increased. The differential saponins, especially RNs, were more easily clustered into one branch and had a high positive correlation. It could be concluded that the biosynthesis and accumulation of some RNs share the same pathways as those triggered by AMF. This study provides a new way to obtain more notoginsenoside resources, particularly RNs, and sheds new light on the scientization and rationalization of the use of AMF agents in the ecological planting of medicinal plants.

Objective To explore the correlation between different flora and colorectal polyp via comparing the gut microbiota between patients with colorectal polyp and healthy population. Methods A cross-sectional study was conducted on 75 patients with colorectal polyp (polyp group) and 73 patients with no abnormal colonoscopy (control group) indicated by colonoscopy from Department of Gastroenterology of 5 Class-A tertiary hospitals in Southwest China from February 2021 to February 2022.16S rRNA gene sequence analysis was used to compare the bacterial flora in stool samples before colonoscopy between the 2 groups. The metabolic pathway information with significant differences was analyzed by comparing the data of Kyoto Encyclopedia of Genes and Genomes(KEGG). The random forest method was used to analyze the species with significant difference of flora and its predictive effect. Results There were no significant differences in age, sex and body mass index (BMI) between these 2 groups. There were significant differences in gut microbiota structure between the polyp group and control group (Bray-curtis, weighted unifrac, P < 0.05), and Faecalibacterium (P < 0.001) and Ruminococcus_2 (P < 0.05) in the polyp group significantly decreased, while Pseudomonas was significantly increased (P < 0.05). Gut microbiota function analysis showed that the function of aminoacyl-tRNA biosynthesis (P < 0.05), ribosome synthesis (P < 0.01), mismatch repair (P < 0.05) and homologous recombination (P < 0.01) was significantly reduced in polyp group. Random forest analysis showed that gut microbiota could predict the occurrence of colorectal polyp (AUC=0.756) and Faecalibacterium had the strongest prediction effect. Conclusion Patients with colorectal polyp show the changed features of gut microbiota compared with normal people. The difference of Faecalibacterium is the most significant, Which may be related to the formation of colorectal polyp.

Abstract Background Autopolyploidy is a valuable model for studying whole-genome duplication (WGD) without hybridization, yet little is known about the genomic structural and functional changes that occur in autopolyploids after WGD. Cyclocarya paliurus (Juglandaceae) is a natural diploid–autotetraploid species. We generated an allele-aware autotetraploid genome, a chimeric chromosome-level diploid genome, and whole-genome resequencing data for 106 autotetraploid individuals at an average depth of 60 × per individual, along with 12 diploid individuals at an average depth of 90 × per individual. Results Autotetraploid C. paliurus had 64 chromosomes clustered into 16 homologous groups, and the majority of homologous chromosomes demonstrated similar chromosome length, gene numbers, and expression. The regions of synteny, structural variation and nonalignment to the diploid genome accounted for 81.3%, 8.8% and 9.9% of the autotetraploid genome, respectively. Our analyses identified 20,626 genes (69.18%) with four alleles and 9191 genes (30.82%) with one, two, or three alleles, suggesting post-polyploid allelic loss. Genes with allelic loss were found to occur more often in proximity to or within structural variations and exhibited a marked overlap with transposable elements. Additionally, such genes showed a reduced tendency to interact with other genes. We also found 102 genes with more than four copies in the autotetraploid genome, and their expression levels were significantly higher than their diploid counterparts. These genes were enriched in enzymes involved in stress response and plant defense, potentially contributing to the evolutionary success of autotetraploids. Our population genomic analyses suggested a single origin of autotetraploids and recent divergence (~ 0.57 Mya) from diploids, with minimal interploidy admixture. Conclusions Our results indicate the potential for genomic and functional reorganization, which may contribute to evolutionary success in autotetraploid C. paliurus.

Abstract Future climate changes are projected to adversely affect mortality risk of cardiovascular disease (CVD) in urbanized regions. However, future temperature-related excess CVD hospitalizations in rural residents with poorer socioeconomic status is not well understood. Moreover, influence of aging and declining rural population are rarely considered. Using CVD hospitalizations in rural residents during 2010–2016 in eight regions in southeastern China, the region-specific temperature-CVD associations were estimated by generalized additive models, which were combined by a meta-regression. We projected excess CVD hospitalizations due to temperature using regional associations for 27 climate models under scenarios of climate change for 2010–2099. To reveal the influences of aging and declining rural population, age-specific associations and future population change ratio were used to estimate age-specific number of temperature-related hospitalizations. We found that heat-related hospitalizations in rural residents from ischemic stroke, ischemic heart disease and cerebrovascular disease are projected to increase in the 2090 s, although the excess CVD hospitalizations associated with future temperature in rural residents will reduce in the 2090 s. Rural population aging amplifies temperature-related CVD burden by >2.34-fold under SSPs in the 2050 s compared to scenarios with only population declining, although rural population reduction will reduce the temperature-related CVD hospitalizations in the 2090 s. The elderly, male and those lived in Longyan and Sanming could be more affected. These findings suggest that future heat is projected to increase hospitalizations of some CVD subcategories. Policies are needed to mitigate increasing temperature and baseline hospitalization rate. The impact of population aging is noteworthy.

Abstract Background Sorafenib resistance greatly reduces the efficacy of treatments in advanced hepatocellular carcinoma (HCC) patients, but the underlying mechanisms are not thoroughly understood. All-trans retinoic acid (ATRA), an anti-leukaemia agent, has attracted considerable attention due to its role in sensitizing cells to other anticancer treatments. We aimed to investigate the combined effect of ATRA and Sorafenib on HCC and the underlying mechanisms. Methods CCK-8, cell sphere formation, trans-well migration, and wound-healing assays were used to analyse the biological behaviours of HCC cells in vitro. Western blotting and qRT-PCR analysis were conducted to measure the expression of p21 activated kinase 1 (PAK1) and phospho-p21 activated kinase 1 (pPAK1). Xenograft models were established to confirm the synergistic effects of ATRA and Sorafenib in vivo. TUNEL assays and immunohistochemistry were utilized to determine apoptosis, proliferation, PAK1 and pPAK1 levels in tumour tissues. Results We observed that PAK1 was overexpressed in HCC, and its expression was negatively correlated with the survival of patients. PAK1 promoted the proliferation, self-renewal and epithelial-mesenchymal transition of HCC cells. Correlation analysis indicated that the IC50 of Sorafenib was positively correlated with the level of pPAK1 in HCC cell lines. ATRA inhibited the progression of HCC and sensitized HCC response to Sorafenib by downregulation of PAK1, as shown by the calculated coefficient of drug interaction and the data obtained from xenograft models. Conclusions Our findings indicated that instead of treatment with Sorafenib alone, the combination of ATRA and Sorafenib provides a more effective treatment for HCC patients. Video Abstract

Background: Natural plants as well as traditional Chinese medicine have made outstanding contributions to the health and reproduction of human beings and remain the basis and major resource for drug innovation. Carrier-free nanoplatforms completely self-assembled by pure molecules or therapeutic components have attracted increasing attention due to their advantages of improved pharmacodynamics/pharmacokinetics, reduced toxicity, and high drug loading. In recent years, carrier-free nanoplatforms produced by self-assembly from natural plants have contributed to progress in a variety of therapeutic modalities. Notably, these nanoplatforms based on the interactions of components from different natural plants improve efficiency and depress toxicity. Aim of Review: In this review, different types of self-assembled nanoplatforms are first summarized, mainly including nanoassemblies of pure small molecules isolated from different plants, extracellular vesicles separated from fresh plants, charcoal nanocomponents obtained from charred plants, and nanoaggregates from plants formulae decoctions.Key Scientific Concepts of Review: We mainly focus on composition, self-assembly mechanisms, biological activity and modes of action. Finally, a future perspective of existing challenges with respect to the clinical application of plant-based carrier-free nanoplatforms is discussed, which may be instructive to further develop effective carrier-free nanoplatforms from natural plants in the future.

The development and application of ambient ionization and miniature mass spectrometry have become the current research hotpot, which is capable of rapid, sensitive, on-site and real-time analysis of samples without complex sample pretreatment. In this study, a rapid on-site method using dielectric barrier discharge ionization (DBDI) and a miniature mass spectrometer was developed for the screening of prohibited substances in spray cosmetics. Helium gas was used as the discharge gas and 1 mm thick quartz glass was used as the dielectric barrier in a custom-made DBDI ion source. The two brass electrodes were 10 mm apart, both mounted outside the quartz glass. The inner diameter of the glass tube at the gas inlet and outlet was 1 mm. When the experiment was carried out, the DBDI ion source was placed 3 cm in front of the discontinuous atmospheric pressure interface (DAPI) of the miniature mass spectrometer. The spray cosmetic sample was placed 8 cm directly above the plasma beam generated by the DBDI. Without any sample pretreatment, once the sample spray valve was pressed, the sample microdroplets generated in the vertical direction collided with the plasma beam generated in the horizontal direction. In the region between the DBDI and the miniature mass spectrometer, the target substances were ionized by energy and charge transfer with the plasma beam, and then detected by the miniature mass spectrometer. The helium flow rate was set at an optimum value of 220 mL/min by a gas mass flow controller. Coupled with the miniature mass spectrometer, four prohibited colorants in disposable hair dye spray and four prohibited fragrances in spray lotion were screened. Based on the observed signal-to-noise ratio (S/N) of the most intense MS/MS fragment peaks and using S/N=3 as a criterion, the limits of detection (LODs) were estimated between 10 and 50 μg/kg for the eight prohibited substances. The entire analysis procedure could be completed within 1 min. The simplified analytical protocol can effectively solve the disadvantages of traditional analytical methods that are cumbersome and time-consuming. The proposed method is simple, rapid, sensitive, efficient, and suitable for rapid on-site screening of prohibited substances in spray cosmetics.

Functional gait disorder (FGD) is a common subtype of functional movement disorder (FMD), mainly characterized by instability, lameness and Parkinson's gait. The clinical manifestations of FGD are the same as those of other types of gait disorder, with the possibility of misdiagnosis. However, there are significant differences in the treatment principles between them, so clear diagnosis and accurate treatment are crucial to improve patients' symptoms and prognosis. This paper aims to systematically review the epidemiological characteristics, clinical manifestations, auxiliary examination, diagnosis and differential diagnosis, treatment and prognosis of FGD, in order to improve the understanding of clinicians.

Abstract In this study, we aim to develop and validate a radiomics model for pretreatment prediction of RPS6K expression in hepatocellular carcinoma (HCC) patients, thus helping clinical decision-making of mTOR-inhibitor (mTORi) therapy. We retrospectively enrolled 147 HCC patients, who underwent curative hepatic resection at First Affiliated Hospital Zhejiang University School of Medicine. RPS6K expression was determined with immunohistochemistry staining. Patients were randomly split into training or validation cohorts on a 7:3 ratio. Radiomics features were extracted from T2-weighted and diffusion-weighted images. Machine learning algorithms including multiple logistic regression (MLR), supporting vector machine (SVM), random forest (RF), and artificial neural network (ANN) were applied to construct the predictive model. A nomogram was further built to visualize the possibility of RPS6K expression. The area under the receiver operating characteristic (AUC) was used to evaluate the performance of diagnostic models. 174 radiomics features were confirmed correlated with RPS6K expression. Amongst all built models, the ANN-based hybrid model exhibited best predictive ability with AUC of 0.887 and 0.826 in training and validation cohorts. ALB was identified as the key clinical index, and the nomogram displayed further improved ability with AUC of 0.917 and 0.845. In this study, we proved MRI-based radiomics model and nomogram can accurately predict RPS6K expression non-invasively, thus providing help for clinical decision making for mTORi therapy.