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Abstract Distant metastasis is a primary cause of mortality and contributes to poor surgical outcomes in cancer patients. Before the development of organ-specific metastasis, the formation of a pre-metastatic niche is pivotal in promoting the spread of cancer cells. This review delves into the intricate landscape of the pre-metastatic niche, focusing on the roles of tumor-derived secreted factors, extracellular vesicles, and circulating tumor cells in shaping the metastatic niche. The discussion encompasses cellular elements such as macrophages, neutrophils, bone marrow-derived suppressive cells, and T/B cells, in addition to molecular factors like secreted substances from tumors and extracellular vesicles, within the framework of pre-metastatic niche formation. Insights into the temporal mechanisms of pre-metastatic niche formation such as epithelial-mesenchymal transition, immunosuppression, extracellular matrix remodeling, metabolic reprogramming, vascular permeability and angiogenesis are provided. Furthermore, the landscape of pre-metastatic niche in different metastatic organs like lymph nodes, lungs, liver, brain, and bones is elucidated. Therapeutic approaches targeting the cellular and molecular components of pre-metastatic niche, as well as interventions targeting signaling pathways such as the TGF-β, VEGF, and MET pathways, are highlighted. This review aims to enhance our understanding of pre-metastatic niche dynamics and provide insights for developing effective therapeutic strategies to combat tumor metastasis.

Abstract Cancer-associated fibroblasts (CAFs) are the major components of the tumor microenvironment and are related to tumor proliferation, metastasis, relapse, and drug resistance. With the development of sequencing technologies, single-cell RNA sequencing has become a popular method for identifying CAFs in the tumor microenvironment. Whereas the drawbacks of CAFs, such as the lack of a spatial landscape, still exist, recent research has utilized spatial transcriptomics combined with single-cell RNA sequencing to address this issue. These multiomics analyses can resolve the single-cell resolution problem in spatial transcriptomics. In this review, we summarized the recent literature regarding the targeting of CAFs to address drug resistance, angiogenesis, metabolic reprogramming and metastasis in tumor tissue.

Abstract Introduction There is a high morbidity and mortality rate in mechanical trauma (MT)-induced hepatic injury. Currently, the molecular mechanisms underlying liver MT are largely unclear. Exploring the underlying mechanisms and developing safe and effective medicines to alleviate MT-induced hepatic injury is an urgent requirement. The aim of this study was to reveal the role of mitochondria-associated ER membranes (MAMs) in post-traumatic liver injury, and ascertain whether melatonin protects against MT-induced hepatic injury by regulating MAMs. Methods Hepatic mechanical injury was established in Sprague–Dawley rats and primary hepatocytes. A variety of experimental methods were employed to assess the effects of melatonin on hepatic injury, apoptosis, MAMs formation, mitochondrial function and signaling pathways. Results Significant increase of IP3R1 expression and MAMs formation were observed in MT-induced hepatic injury. Melatonin treatment at the dose of 30 mg/kg inhibited IP3R1-mediated MAMs and attenuated MT-induced liver injury in vivo. In vitro, primary hepatocytes cultured in 20% trauma serum (TS) for 12 h showed upregulated IP3R1 expression, increased MAMs formation and cell injury, which were suppressed by melatonin (100 μmol/L) treatment. Consequently, melatonin suppressed mitochondrial calcium overload, increased mitochondrial membrane potential and improved mitochondrial function under traumatic condition. Melatonin’s inhibitory effects on MAMs formation and mitochondrial calcium overload were blunted when IP3R1 was overexpressed. Mechanistically, melatonin bound to its receptor (MR) and increased the expression of phosphorylated ERK1/2, which interacted with FoxO1 and inhibited the activation of FoxO1 that bound to the IP3R1 promoter to inhibit MAMs formation. Conclusion Melatonin prevents the formation of MAMs via the MR-ERK1/2-FoxO1-IP3R1 pathway, thereby alleviating the development of MT-induced liver injury. Melatonin-modulated MAMs may be a promising therapeutic therapy for traumatic hepatic injury. Graphical Abstract

Circulating cell‐free DNA (cfDNA) fragmentomics, which encompasses the measurement of cfDNA length and short nucleotide motifs at the ends of cfDNA molecules, is an emerging field for cancer diagnosis. The utilization of cfDNA fragmentomics for the diagnosis of patients with hepatocellular carcinoma (HCC) caused by hepatitis B virus (HBV) is currently limited. In this study, we utilized whole‐genome sequencing data of cfDNA in samples from patients with HCC (n = 197) and HBV (n = 187) to analyze the association of fragment size selection (

As a vital adipokine, Adipsin is closely associated with cardiovascular risks. Nevertheless, its role in the onset and development of cardiovascular diseases remains elusive. This study was designed to examine the effect of Adipsin on survival, cardiac dysfunction and adverse remodeling in the face of myocardial infarction (MI) injury. In vitro experiments were conducted to evaluate the effects of Adipsin on cardiomyocyte function in the face of hypoxic challenge and the mechanisms involved. Our results showed that Adipsin dramatically altered expression of proteins associated with iron metabolism and ferroptosis. In vivo results demonstrated that Adipsin upregulated levels of Ferritin Heavy Chain (FTH) while downregulating that of Transferrin Receptor (TFRC) in peri-infarct regions 1 month following MI. Adipsin also relieved post-MI-associated lipid oxidative stress as evidenced by decreased expression of COX2 and increased GPX4 level. Co-immunoprecipitation and immunofluorescence imaging prove a direct interaction between Adipsin and IRP2. As expected, cardioprotection provided by Adipsin depends on the key molecule of IRP2. These findings revealed that Adipsin could be efficiently delivered to the heart by exosomes derived from pericardial adipose tissues. In addition, Adipsin interacted with IRP2 to protect cardiomyocytes against ferroptosis and maintain iron homeostasis. Therefore, Adipsin-overexpressed exosomes derived from pericardial adipose tissues may be a promising therapeutic strategy to prevent adverse cardiac remodeling following ischemic heart injury.

Pain is one of the most serious problems plaguing human health today. Pain is not an independent pathophysiological condition and is associated with a high impact on elevated disability and organ dysfunction. Several lines of evidence suggested the associations of pain with cardiovascular diseases, especially myocardial ischemia-reperfusion (I/R) injury, while the role of pain in I/R injury and related mechanisms are not yet comprehensively assessed. In this review, we attempted to explore the role of pain in myocardial I/R injury, and we concluded that acute pain protects myocardial ischemia-reperfusion injury and chronic pain aggravates cardiac ischemia-reperfusion injury. In addition, the construction of different pain models and animal models commonly used to study the role of pain in myocardial I/R injury were discussed in detail, and the potential mechanism of pain-related myocardial I/R injury was summarized. Finally, the future research direction was prospected. That is, the remote regulation of pain to cardiac function requires peripheral pain signals to be transmitted from the peripheral to the cardiac autonomic nervous system, which then affects autonomic innervation during cardiac ischemia-reperfusion injury and finally affects the cardiac function.

Imbalanced mitochondrial dynamics including inhibited mitochondrial fusion is associated with cardiac dysfunction as well as tumorigenesis. This study sought to explore the effects of promoting mitochondrial fusion on doxorubicin(Dox)-induced cardiotoxicity and its antitumor efficacy, with a focus on the underlying metabolic mechanisms. Herein, the inhibition of Mfn2-mediated mitochondrial fusion was identified as a key phenotype in Dox-induced cardiotoxicity. Restoration of Mfn2-mediated mitochondrial fusion enhanced mitochondrial oxidative metabolism, reduced cellular injury/apoptosis and inhibited mitochondria-derived oxidative stress in the Dox-treated cardiomyocytes. Application of lentivirus expressing Drp1 (mitochondrial fusion inhibitor) or Rote/Anti A (mitochondrial complex I/III inhibitors) blunted the above protective effects of Mfn2. Cardiac-specific Mfn2 transgenic mice showed preserved mitochondrial fusion and attenuated myocardial injury upon Dox exposure in vivo. The suppression of Mfn2-mediated mitochondrial fusion was induced by Dox-elicited upregulation of FoxO1, which inhibited the transcription of Mfn2 by binding to its promoter sites. In the B16 melanoma, Mfn2 upregulation not only attenuated tumor growth alone but also further delayed tumor growth in the presence of Dox. Mechanistically, Mfn2 synergized with the inhibitory action of Dox on glycolysis metabolism in the tumor cells. One common feature in both cardiomyocytes and tumor cells was that Mfn2 increased the ratio of oxygen consumption rate to extracellular acidification rate, suggesting Mfn2 triggered a shift from aerobic glycolysis to mitochondrial oxidative metabolism. In conclusion, targeting Mfn2-mediated mitochondrial fusion may provide a dual therapeutic advantage in Dox-based chemotherapy by simultaneously defending against Dox-induced cardiotoxicity and boosting its antitumor potency via metabolic shift.

Abstract Background Colorectal cancer (CRC) is one of the causes of cancer-related death worldwide. The aim of our study was to disclose the expression pattern and underlying molecular mechanism of circular RNA TADA2A (circTADA2A) in CRC. Methods The levels of circTADA2A, transcriptional adaptor 2A (TADA2A), microRNA-374a-3p (miR-374a-3p) and Kruppel like factor 14 (KLF14) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Xenograft tumor assay was used to uncover the function of circTADA2A in vivo. The miRNA targets of circTADA2A were searched using circbank and starbase softwares, while DIANA TOOL was used to explore miR-374a-3p-mRNA interactions. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were performed to validate the target relationship of circTADA2A/miR-374a-3p/KLF14 axis. Cell cycle and apoptosis were analyzed by flow cytometry. The glycolysis of CRC cells was determined by Seahorse XFe 96 Extracellular Flux Analyzer, Glucose Uptake Colorimetric Assay kit, Lactate Assay Kit II and ATP Colorimetric Assay kit. KLF14 protein level was measured by Western blot assay. Results CircTADA2A was abnormally down-regulated in CRC tissues and cell lines. CircTADA2A overexpression impeded CRC tumor growth in vivo. MiR-374a-3p was verified as a target of circTADA2A in CRC cells, and circTADA2A inhibited the malignant potential of CRC cells through targeting miR-374a-3p. MiR-374a-3p interacted with KLF14 messenger RNA (mRNA), and miR-374a-3p deteriorated CRC through down-regulating KLF14. CircTADA2A enhanced the abundance of KLF14 through targeting miR-374a-3p in CRC cells. Conclusion CircTADA2A functioned as a tumor suppressor in CRC to inhibit the glycolysis and cell cycle and potentiate the apoptosis of CRC cells via miR-374a-3p/KLF14 axis.

Diabetes disrupts mitochondrial function and often results in diabetic cardiomyopathy (DCM). Paeonol is a bioactive compound that has been reported to have pharmacological potential for cardiac and mitochondrial protection. This study aims to explore the effects of paeonol on mitochondrial disorderes in DCM and the underlying mechanisms. We showed that paeonol promoted Opa1-mediated mitochondrial fusion, inhibited mitochondrial oxidative stress, and preserved mitochondrial respiratory capacity and cardiac performance in DCM in vivo and in vitro. Knockdown of Opa1 blunted the above protective effects of paeonol in both diabetic hearts and high glucose-treated cardiomyocytes. Mechanistically, inhibitor screening, siRNA knockdown and chromatin immunoprecipitation experiments showed that paeonol-promoted Opa1-mediated mitochondrial fusion required the activation of Stat3, which directly bound to the promoter of Opa1 to upregulate its transcriptional expression. Moreover, pharmmapper screening and molecular docking studies revealed that CK2α served as a direct target of paeonol that interacted with Jak2 and induced the phosphorylation and activation of Jak2-Stat3. Knockdown of CK2α blunted the promoting effect of paeonol on Jak2-Stat3 phosphorylation and Opa1-mediated mitochondrial fusion. Collectively, we have demonstrated for the first time that paeonol is a novel mitochondrial fusion promoter in protecting against hyperglycemia-induced mitochondrial oxidative injury and DCM at least partially via an Opa1-mediated mechanism, a process in which paeonol interacts with CK2α and restores its kinase activity that subsequently increasing Jak2-Stat3 phosphorylation and enhancing the transcriptional level of Opa1. These findings suggest that paeonol or the promotion of mitochondrial fusion might be a promising strategy for the treatment of DCM.

Abstract Background This study was designed to test the hypothesis that κ-opioid receptor (κ-OR) stimulation reduces palmitate-induced HUVECs apoptosis and to investigate its mechanisms. Methods HUVECs were subjected to sodium palmitate, apoptosis and cell viability were determined, HUVECs were treated with specific inhibitors to PI3K, Akt, eNOS and siRNAs targeting κ-OR and Akt. Groups were divided as follows: the control group, the sodium palmitate group, the sodium palmitate+U50,488H (a selective κ-OR agonist) group and the sodium palmitate+U50,488H + nor-BNI (a selective κ-OR antagonist) group. Results Treatment with sodium palmitate significantly reduced cell viability and increased apoptosis rate which were significantly alleviated by pretreatment with U50,488H, the effect of U50,488H was abolished by nor-BNI. Phosphorylation of Akt and eNOS, as well as NO production were attenuated and accompanied by an increased expression of caspase 3 when HUVECs were subjected to sodium palmitate, and all these changes were restored by pretreatment with U50,488H, the effects of U50,488H were abolished by nor-BNI, and specific inhibitors to PI3K, Akt, eNOS, respectively. SiRNAs targeting κ-OR or Akt abolished the effects of U50,488H on phosphorylation of Akt and eNOS as well as the expressions of caspase 3, Bax and Bcl-2. SiRNAs targeting Akt elicited no effect on the expression of κ-OR. Conclusion This study provides the evidence for the first time that κ-OR stimulation possesses anti-palmitate-induced apoptosis effect, which is mediated by PI3K/Akt/eNOS signaling pathway.

Cardiac remodeling and dysfunction are responsible for the high mortality after myocardial infarction (MI). We assessed the potential for Shank3 to alleviate the post-infarction cardiac dysfunction. The experimental MI mice model was constructed by left anterior descending coronary artery ligation. Shank3 knockout aggravated cardiac dysfunction after MI, while Shank3 overexpression alleviated it. The histological examination showed that the infarct size was significantly increased in the acute phase of MI in the Shank3 knockout group, and the cardiac dysfunction of the Shank3 knockout group was even more severe than the Shank3 overexpression group, revealed by echocardiography analyses. In vitro, cultured neonatal cardiomyocytes were subjected to simulated MI. Shank3 downregulation curbed LC3 expression and autophagosome-lysosome fusion. Furthermore, Shank3 downregulation increased cardiomyocyte apoptosis. In contrast, Shank3 upregulation induced autophagy, and inhibited apoptosis under hypoxia. In vivo, western blot analysis showed decreased levels of Atg7, Beclin1, LC3-II, and Bcl-2 as well as increased expression of p62, cleaved caspase-3, and cleaved caspase-9 in the Shank3 knockout group which suffered from MI. On the other hand, it also revealed that Shank3 overexpression induced autophagy and inhibited apoptosis after MI. Shank3 may serve as a new target for improving cardiac function after MI by inducing autophagy while inhibiting apoptosis.

κ-opioid receptor (κ-OR) plays a key role in preventing hypoxic pulmonary hypertension (HPH) development after activated by exogenous agonist U50,488H. Calcium sensing receptor (CaSR) activation induces HPH by promoting vasoconstriction and vascular remodeling. The activated κ-OR is reported to inhibit the expression of CaSR in pulmonary artery smooth muscle cells (PASMCs). Thus, in this study, we aimed to explore the effect of activated κ-OR on the role of CaSR in preventing HPH development. An HPH rat model was constructed using Sprague-Dawley rats. Changes in mean pulmonary arterial pressure (mPAP) and right ventricular pressure (RVP) mediated by κ-OR agonist U50,488H and CaSR inhibitor NPS2143 were observed. The effects of CaSR agonist spermine and inhibitor NPS2143 on pulmonary artery tension were tested. The expression and localization of κ-OR and CaSR were measured in isolated PASMCs. A cell-counting kit-8 assay was performed to evaluate the effect of spermine in PASMC proliferation. Expression of proliferating cell nuclear antigen (PCNA), Erk, and p-Erk was evaluated by western blot analysis. Results showed that κ-OR and CaSR were co-expressed and colocalized in PASMCs under normoxic and hypoxic conditions. Interactions between κ-OR and CaSR were also observed. Spermine improved vasoconstriction in the pulmonary artery in HPH rats, which was abolished by U50,488H. RVP and mPAP were significantly increased in HPH rats under CaSR stimulation, but were significantly reduced when the rats were pretreated with U50,488H and NPS2143 (P < 0.01). Spermine treatment significantly promoted PASMC proliferation, which was significantly inhibited by U50,488H, p38 inhibitor SB203580, JNK inhibitor SP600125, Erk inhibitor SCH772984, and MEK inhibitor U0126, especially Erk inhibitor (P < 0.01). Spermine significantly increased PCNA and P-Erk expression in hypoxic conditions, which was inhibited by U50,488H and NPS2143. κ-OR stimulation prevented HPH development via the CaSR/MAPK signaling pathway.

Abstract Background Hemodynamic overload causes cardiac hypertrophy leading to heart failure. Wnt signaling pathway was reported activated in heart failure. Secreted frizzled related protein 1 (Sfrp1) is a suppressor of Wnt signaling activation. The aim of the present study was to investigate the protective effect of Sfrp1 on hemodynamic overload- induced cardiac dysfunction. Methods A mice transverse aortic constriction (TAC)- induced heart failure model was established. A recombinant adeno-associated virus 9 (AAV9) vector was used to deliver Sfrp1 gene into myocardium. Fluorescence and immunohistochemistry staining was used to evaluate the effectiveness of viral vector delivery. Invasive hemodynamic examination was used to evaluate cardiac systolic and diastolic functions. Myocardium apoptosis was detected by TUNEL assay. The expression levels of Sfrp1, β-catenin, caspase3, Bax, Bcl-2 and c-Myc were measured by Western blotting. Results Increased mean arterial pressure and impaired cardiac function confirmed the establishment of TAC model. Sfrp1 protein expression was effectively increased in myocardium of mice treated with AAV9-Sfrp1 viral vector. The viral vector administration improved both systolic and diastolic cardiac functions by reducing myocardial apoptosis in TAC mice. The expression levels of β-catenin, caspase3 and Bax were significantly reduced while the expression levels of Bcl-2 and c-Myc were dramatically increased in myocardium by the viral vector treatment in TAC mice. Conclusions AAV9 viral vector delivered sfrp1 expression gene into myocardium, which attenuated TAC-induced cardiac dysfunction by inhibiting Wnt signaling pathway activation- mediated apoptosis.

Background/Aims: In a previous study, we showed that κ-opioid receptor stimulation with the selective agonist U50,488H ameliorated hypoxic pulmonary hypertension (HPH). However, the roles that pulmonary arterial smooth muscle cell (PASMC) proliferation, apoptosis, and autophagy play in κ-opioid receptor-mediated protection against HPH are still unknown. The goal of the present study was to investigate the role of autophagy in U50,488H-induced HPH protection and the underlying mechanisms. Methods: Rats were exposed to 10% oxygen for three weeks to induce HPH. After hypoxia, the mean pulmonary arterial pressure (mPAP) and the right ventricular pressure (RVP) were measured. Cell viability was monitored using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected by flow cytometry and Western blot. Autophagy was assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay and by Western blot. Results: Inhibition of autophagy by the administration of chloroquine prevented the development of HPH in the rat model, as evidenced by significantly reduced mPAP and RVP, as well as decreased autophagy. U50,488H mimicked the effects of chloroquine, and the effects of U50,488H were blocked by nor-BNI, a selective κ-opioid receptor antagonist. In vitro experiments showed that the inhibition of autophagy by chloroquine was associated with decreased proliferation and increased apoptosis of PASMCs. Under hypoxia, U50,488H also significantly inhibited autophagy, reduced proliferation and increased apoptosis of PASMCs. These effects of U50,488H were blocked by nor-BNI. Moreover, exposure to hypoxic conditions significantly increased AMPK phosphorylation and reduced mTOR phosphorylation, and these effects were abrogated by U50,488H. The effects of U50,488H on PASMC autophagy were inhibited by AICAR, a selective AMPK agonist, or by rapamycin, a selective mTOR inhibitor. Conclusion: Our data provide evidence for the first time that κ-opioid receptor stimulation protects against HPH by inhibiting PASMCs autophagy via the AMPK-mTOR pathway.

Background/Aims: Increasing evidence demonstrates that long non-coding RNAs (lncRNAs) regulate diverse cellular processes and cancer progression. Whether lncRNAs play any functional role in colorectal carcinoma (CRC) remains largely unknown. The aim of this study was to investigate the role of lncRNA CPS1 intronic transcript 1 (CPS1-IT1) in CRC. Methods: Expression of CPS1-IT1 was initially assessed in human CRC tissues and in a series of CRC cell lines. The correlations between CPS1-IT1 levels and survival outcomes were analyzed to elucidate the clinical significance of CPS1-IT1 in CRC. The underlying mechanisms of CPS1-IT1 in CRC were analyzed through in vitro and in vivo functional assays. Results: Expression of CPS1-IT1 was significantly decreased in CRC tissues and cell lines, and patients with low CPS1-IT1 expression had poor survival outcomes. The results of in vitro assays revealed that CPS1-IT1 significantly reduced cell proliferation, migration and invasion capacities and accelerated cell apoptosis, thereby suppressing epithelial-mesenchymal transition (EMT). An in vivo animal model also demonstrated the tumor-suppressive role of CPS1-IT1. Conclusion: In this study, we found that CPS1-IT1 has a tumor-suppressive role in CRC. Our data suggest that CPS1-IT1 could be used as a new prognostic biomarker and therapeutic target for CRC.

The water–rock interactions significantly affect the dissolution and release of dissolved organic matter (DOM) during the reinjection of mine water into the underground reservoir. In this study, the surface characteristics and chemical composition of the natural medium from the open-pit coal mine were characterized. The waste consists mainly of quartz-dominated sandstone (43.64%) and mudstone dominated by sanidine (76.36%). During the 35-day experiment, two protein-like, one humus-like, and one fulvic acid-like substances were identified by PARAFAC. It was observed that the type of aqueous medium significantly affected the variational trend of DOM. Compared to the artificial medium, the fluorescence intensity of waste materials in the waste dump increased significantly during the reinjection process. Therefore, a positive correlation was observed between the fraction of mudstone in the aqueous medium and the DOM composition, mainly due to the dissolution of polycyclic aromatic hydrocarbon substances from the mudstone. The results revealed that the natural water storage medium had a certain water storage feasibility when compared with the expensive artificial medium. However, the fraction of mudstone in the water storage medium should be controlled to minimize the release of organic matter into the environment. HIGHLIGHTS The evolution law of DOM in the underground storage of mine water has been elucidated first.; The water storage medium in sandstone and mudstone was divided, and the influence of mineral composition on the evolution of water quality separately was studied.; The variation patterns of different components of DOM in mine water were scientifically analyzed using three-dimensional fluorescence spectroscopy combined with the parallel factor method.;

Abstract Mine water inflow is an important basis for the formulation of mining plans and the utilization of groundwater resources. The mine water inflow is the result of the combined influence of many factors. The weight value of the influencing factors is calculated by the entropy method, and the order of importance of the factors is: precipitation > mining depth > cumulative mined-out area > aquifer thickness > mining area > mining height. The optimal univariate nonlinear regression model of mine water inflow to each influencing factor is obtained by factor scatter analysis and Matlab function programming. On this basis, combined with the weight values of factors, a multivariate nonlinear regression prediction model of mine water inflow based on weighting is innovatively established, which overcomes the defect that the traditional water inflow prediction method that cannot reflect the relative importance differences of various influencing factors. The multivariate weighted nonlinear regression model is used to predict the mine water inflow of typical coal mines, and the prediction results are compared with the linear regression model and the measured value. The results show that the prediction model of mine water inflow based on weighted multivariate nonlinear regression is accurate higher, with higher practical application value.

Abstract Alzheimer’s disease (AD) is the most common cause of dementia characterized by amyloid-β (Aβ) deposition, tau hyperphosphorylation, and neuroinflammation. Naringenin (NRG), a natural flavonoid widely present in citrus fruits, has been reported can penetrate the blood-brain barrier and exert anti-inflammatory effects in the central nervous system. Here, we investigate the protective effects of long-term NRG treatment on AD. The novel object recognition test and Morris water maze test reveal that NRG treatment can improve the learning and memory ability of APP/PS1 mice. Besides, we find that NRG can significantly reduce Aβ deposition, microglial and astrocytic activation, and pro-inflammatory cytokine levels in APP/PS1 mice. Results further show that NRG effectively decreases pro-inflammatory cytokines in LPS/Aβ-stimulated BV2 cells. Lastly, the molecular mechanistic study reveals that NRG attenuates neuroinflammatory responses via inhibition of the MAPK signaling pathway in vivo and in vitro. Overall, NRG may emerge as a promising compound for the prevention and treatment of AD.

This study aims to develop an environmentally friendly multi-energy system for sustainable production of electricity, cooling and hydrogen. The study introduces a pioneering geothermal-based system, integrating an ejector refrigeration cycle, a dual-loop organic Rankine cycle, and a hydrogen production unit with proton exchange membrane electrolyzers. The study provides a thorough analysis of the system's energy and exergy performance, as well as its economic feasibility. Through sensitivity and parametric analyses, the research identifies key parameters that significantly influence system performance. The system's innovative design promises minimal environmental impact while delivering multifaceted performance: generating 1.38 MW of electricity, supplying 436 kW of cooling load, and producing 5.39 kg/h of hydrogen. In the exergy analysis, Evaporator1 is identified as the primary contributor to exergy loss, representing 34 % of the total exergy destruction. This is followed by the electrolysis unit, the condenser, and the ejector refrigeration cycle, which contribute 18 %, 14 %, and 12 %, respectively. The system achieves optimal efficiency at an organic Rankine cycle turbine1 inlet temperature of 387 K, yielding a power generation of 885.4 kW and an exergy efficiency of 26.7 %. Beyond this temperature, any further increase leads to a decline in power output due to operational disturbances. A multi-criteria optimization using genetic algorithm is applied, resulting in an optimized system with a cost rate of 18.13 $/h and an exergy efficiency of 38.96 %.

Volatile organic compounds (VOCs) pose potential hazards to human health and contribute significantly to odor pollution. This study examined VOC emissions from a representative recycled rubber industry, evaluating the occupational health risks for frontline workers in various workshops. Variables such as gender and workshop-specific concentration variations were considered using Monte Carlo simulation methods. Employees in the five production workshops and office areas face noncarcinogenic health risks with hazard indices (HIs) greater than 1, with the rubber compounding phase presenting the highest risk. Acetaldehyde is identified as the primary noncarcinogenic health risk substance, with hazard quotient (HQ) values exceeding 1 in all workshops. Carcinogenic health risks vary by area, with the highest risks found in compounding and refining workshops. Formaldehyde poses the greatest risk in rubber grinding workshops and offices, with cumulative weights exceeding unacceptable levels of M80.58 % and W77.56 % in grinding and M94.98 % and W92.24 % in the office. Male workers face 4–7 % greater noncarcinogenic VOC health risks than females and 5–14 % greater carcinogenic risks from individual VOCs, increasing their susceptibility to health risks caused by VOCs. Additionally, our analysis of odor identification and intensity classification revealed that 53 VOCs are capable of causing odor pollution, with several substances reaching odor levels of 2 or higher. The predominant perceived odors, as reflected in the odor wheel, include categories such as ''solvent/aromatic'' and ''sweet/fruit,'' with aldehydes being the primary odor-causing substances. In summary, emissions of VOCs from rubber industrial processes not only pose substantial health risks to workers but also contribute significantly to odor pollution. Consequently, enterprises must prioritize optimizing workplace conditions to ensure the occupational health and well-being of their employees.

Abstract Background Appendicular lean mass (ALM) is a good predictive biomarker for sarcopenia. And previous studies have reported the association between ALM and stroke or Alzheimer’s disease (AD), however, the causal relationship is still unclear, The purpose of this study was to evaluate whether genetically predicted ALM is causally associated with the risk of stroke and AD by performing Mendelian randomization (MR) analyses. Methods A two-sample MR study was designed. Genetic variants associated with the ALM were obtained from a large genome-wide association study (GWAS) and utilized as instrumental variables (IVs). Summary-level data for stroke and AD were generated from the corresponding GWASs. We used random-effect inverse-variance weighted (IVW) as the main method for estimating causal effects, complemented by several sensitivity analyses, including the weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods. Multivariable analysis was further conducted to adjust for confounding factors, including body mass index (BMI), type 2 diabetes mellitus (T2DM), low density lipoprotein-C (LDL-C), and atrial fibrillation (AF). Results The present MR study indicated significant inverse associations of genetically predicted ALM with any ischemic stroke ([AIS], odds ratio [OR], 0.93; 95% confidence interval [CI], 0.89–0.97; P = 0.002) and AD (OR, 090; 95% CI 0.85–0.96; P = 0.001). Regarding the subtypes of AIS, genetically predicted ALM was related to the risk of large artery stroke ([LAS], OR, 0.86; 95% CI 0.77–0.95; P = 0.005) and small vessel stroke ([SVS], OR, 0.80; 95% CI 0.73–0.89; P

China is the country with the most complicated coal-forming and occurrence conditions in the world. The roof water disaster, caused by the diversity and complexity of the hydrogeological conditions of the coal seam roof, the mutuality and time-varying coupling of the mining overburden fracture field and the seepage field, and the uniqueness and harmfulness of the coal mine roof water inrush, is one of the main mine disasters in China, especially in the western coal mining area. In order to better understand the roof water disaster, promote the existing technology and explore new technologies to prevent and control such mine disasters, based on the comprehensive analysis of the law of roof water disaster accidents in China’s coal mines in recent years and the occurrence conditions, water inrush mode, dynamic characteristics and mechanical behavior of roof water-filled aquifers, the types and characteristics of roof water disasters are systematically divided. The disaster mechanism of the main categories and the existing prevention and control technologies of roof water disasters are reviewed, and the future development direction of roof water disaster prevention and control is prospected. The study found that: ① The main structure of roof water disaster includes five types: gushing (leaching) water in thick bedrock aquifer, water-sand coupling inrush in weak cementation layer of thin bedrock, water storage and energy storage water inrush in abscission layer space, skylight recharge water inrush, and surrounding rock burning and permeability enhancement. They are concentrated in the north of the Qinling Mountains-Huaihe River. Shaanxi, Inner Mongolia and Ningxia are the main gathering places of roof water disasters. ② Mining-induced “Z” -type separation space is developed in the primary fractures of overlying strata under the super-thick bedrock aquifer, resulting in a large area of water gushing (leaching) in the stope. The fracture conditions of composite key strata are established, and the power source of water-sand coupling inrush disaster in weak cemented layer of thin bedrock is clarified. The critical criterion for assessing the instability of water inrush from bed separation is constructed, and the water inrush from bed separation is divided into three modes: static load disturbance, “dynamic+static” load composite disturbance and repeated disturbance of composite coal seam mining. The lack of laterite aquiclude and the mining-induced deterioration damage in the weak area of laterite are the main causes of skylight leakage recharge. The surrounding rock is burnt to increase permeability and porosity, and a new water-bearing structure is formed after receiving water supplement from adjacent water sources. Under the induction of mining, burnt rock water pours into stope and causes water disaster accidents. ③ The current prevention and control technology system of coal mine roof water disaster “exploration-discharge-treatment” is evaluated, and the future development direction is put forward, such as the conjugate linkage of upper and lower wells, the drilling-mining (excavation) high-level collaborative geological exploration system, the geological guarantee work guided by the “three zones” division of water prevention and control, the green mining and water prevention concept of “coal-water-ecology” multi-objective co-management, and the digital intelligence and transparent mine hydrogeological disaster information maintenance system.

Objective To investigate the current situation of family caregivers' care ability of elderly patients with tuberculosis and analyze the influencing factors. Methods A total of 360 family caregivers from the respiratory ward of the Eighth Affiliated Hospital of Xinjiang Medical University from May to August 2022 were selected as the study subjects by convenience sampling.The general data of family caregivers and the family caregiver care ability scale were used to investigate.Multiple linear regression was used to analyze the influencing factors of family caregiver care ability. Results The results of multiple linear regression model analysis showed that the gender, education level, health status of caregivers and their understanding of tuberculosis were the influencing factors on the care ability of family caregivers(P

Shaanxi province is rich in coal resources and is one of the main coal-producing provinces in China, with a coal production of 746 million tons in 2022. Due to the obvious differences in geological and hydrogeological conditions in the coal mining areas of the province, there are various types of water disasters in its coal mines. With the increase of coal mining intensity in recent years, the frequency of water disasters increases significantly, and the situation of water prevention and control is challenging. On the basis of the overall analysis of the hydrogeological conditions in the coal mining areas of Shaanxi province, combined with the types of water disasters revealed in the mining process of various mining areas in the province, the regional distribution of all kinds of water disas-ters is systematically summarized, and the formation mechanism and characteristics of typical water disasters are discussed. Also, the corresponding prevention and control technology and progress are put forward. The results show that ① the main coal producing areas in Shaanxi province are divided into northern Shaanxi, Huanglong and Weibei. The Jurassic coalfield in northern Shaanxi is mainly affected by the water disaster of roof's loose sand layer, the water disaster of thick sandstone, water and sand burst disaster, and the burnt rock flood exists in some coal mines. The Huanglong coalfield is mainly threatened by roof super-thick sandstone water, separated layer water, mud and sand burst disaster or hidden danger. The Carboniferous-Permian coalfields in northern Shaanxi and Weibei are mainly threatened by the water damage of Ordovician limestone on the coal seam floor. ② The hidden danger of roof flood in the Jurassic coalfield in northern Shaanxi is mainly formed by the disturbance of roof aquifer by mining water diversion fracture zone, which can form a continuous large flow water gushing through sandstone aquifer or loose sand layer, and the water filling intensity is large in some areas. Roof flood occurs when the amount of water exceeds the capacity of the drainage system in a short time, and it can be transformed into water and sand burst disaster when the collapse zone in the thin bedrock area directly leads to the loose sand layer. When the water-conducting fracture zone affects the water-rich area of burnt rock, it can form a flood of burnt rock with large instantaneous water volume and continuous flood. The super-thick sandstone aquifer on the roof of the Huanglong coalfield is swept by the mining water-conducting fracture zone to form a high-intensity continuous water gushing and may form roof flood. When the thickness of the lower aquifer is large, the separated layer water burst disaster may be formed. When the roof strata near the coal seam is soft and easy to collapse, it can be transformed into mud and sand burst disaster. In the Carboniferous-Permian coalfield and the Weibei coalfield in northern Shaanxi, when structures such as coal seam mining floor disturbance failure zones or faults lead to the Ordovician limestone aquifers, they will cause extremely serious floor water inrush disasters, which are characterized by strong sudden occurrence and large instantaneous water volume. ③ The roof water disaster treatment technology in each region mainly includes drilling hole drainage, grouting treatment, mining parameter control and so on, and the floor water damage is mainly treated by regional grouting reinforcement and plugging. Burnt rock water disaster is mainly treated by the combination of curtain grouting and drilling exploration.

Abstract Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals.

In this study, we introduce Light-ESRGAN, a novel cellular image super-resolution reconstruction model utilizing Generative Adversarial Networks (GANs). High-resolution (HR) cellular images are pivotal in pathological research; however, how to caputer critical features such as cell edges during microscopic imaging presents challenges due to hardware limitations and environmental factors. These factors frequently introduce noise and interference. Rapid advancements in deep learning have significantly enhanced the field of image super-resolution reconstruction, demonstrating substantial potential in cellular image processing. Our Light-ESRGAN employs a random degradation modeling process to leverage the GAN architecture for more accurate simulations of real-world degradation. We have also incorporated the Convolutional Block Attention Module (CBAM) into the residual blocks of the generator, thereby enhancing its ability to reconstruct image edges and textures through the fusion of channel and spatial attentions. For the discriminator, a lightweight U-Net structure is adopted, which not only reduces the model’s parameter size but also improves its discriminative capacity. Compared to Real-ESRGAN and A-ESRGAN, Light-ESRGAN has reduced model parameters by 34.7% and 66.4%, respectively. It has demonstrated improved performance on publicly available cellular images, increasing the average Peak Signal-to-Noise Ratio (PSNR) by 1.174 dB and 1.992 dB, the Structural Similarity Index (SSIM) by an average of 1.5% and 9.1%, and reducing the Normalized Root Mean Square Error (NRMSE) by an average of 0.005 and 0.009.

Objective: To demonstrate the surgical techniques employed in the robotic single port (SP) transvaginal natural orifice transluminal endoscopic surgery (RSP-vNOTES) for hysterectomy utilizing a domestically developed robotic system in China. Methods: We performed two cases of RSP-vNOTES hysterectomy for patients presenting with persistent vaginal bleeding resulting in atypical endometrial hyperplasia per endometrial biopsy. Procedures were initiated with traditional TVH and seamlessly transitioned to the robotic platform when necessary to complete the entire process. The robotic docking process was executed smoothly. Two elbowed instruments, a bipolar grasper, a pair of monopolar scissors, and a facing-upward camera were used. The hysterectomies were carried out precisely, without complications. Bilateral salpingo-oophorectomy was performed in the first patient and bilateral salpingectomy in the second. The vaginal cuff was closed continuously through a transvaginal approach after undocking. Results: Both patients were discharged on the third postoperative day, with satisfactory surgical results and no complications. Conclusions: The domestically developed Chinese Robotic SP system demonstrates feasibility for RSP-vNOTES procedures of hysterectomy. This approach amalgamates the advantages of both vaginal and robotic surgeries, incorporating surgical triangulation with an elbowed function that simplifies surgical manipulation. However, further studies with larger sample sizes and potential comparative analyses are essential to validate the merits and safety of adopting this platform.

Transvaginal Natural Orifice Transluminal Endoscopic Surgery (NOTES) has become popular since its inception in 2012, offering advantages by combining vaginal surgery principles with laparoscopic instruments for procedures like hysterectomy and myomectomy. The da Vinci Xi robotic system for transvaginal NOTES has been used successfully in over 300 cases, including advanced surgeries like sacrocolpopexy and endometriosis procedures. The new da Vinci SP platform, designed for single-port surgery, was employed in the first transvaginal NOTES hysterectomy on November 11, 2023, at Baylor College of Medicine. The surgical steps and outcomes of the procedure are detailed in this case report, showcasing the feasibility and success of utilizing the da Vinci SP system for transvaginal NOTES. The patient was discharged on the same day with an unremarkable post-operative course, and pathology results revealed adenomyosis and endometriosis after the comprehensive surgery.

The safety assessment and control of large-diameter pipelines under tunnel blasting at ultrasmall clear distances is a significant problem faced in construction. However, there has been no reference case for the quantitative comparison of the disturbance degree of surrounding rock by using two blasting schemes of non-electric detonator design and electronic detonator design under a similar total blasting charge consumption. In this study, the blasting test was carried out based on the engineering background of drilling and blasting methods to excavate the tunnel under the water pipeline at a close distance. The peak particle velocity (PPV), stress, and deformation responses of the pipeline under the two construction methods of non-electric and electronic detonators were comparatively analyzed. The PPV can be remarkably reduced by 64.2% using the hole-by-hole initiation of the electronic detonators. For the large-diameter pipeline, the PPV on the blasting side was much larger than that on the opposite side because the blasting seismic wave propagated a longer distance and attenuated more rapidly, owing to its greater cavity vibration reduction effect. The PPV of the electronic detonators decayed more slowly than that of the non-electric detonators. The cumulative damage caused by consecutive hole-by-hole blasting using electronic detonators was less than that caused by simultaneous multi-hole initiation using non-electric detonators, with a reduction of about 50.5%. When the nearest peripheral holes away from the pipeline are detonated, the cumulative damage variable D and damage range increase rapidly. The PPV, dynamic tensile strength, and cumulative damage variables were used to evaluate the safety of the pipelines.