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Abstract A two-dimensional tube bundles fluid–structure coupling model was developed using the CFD approach, with a rigid body motion equation and the Newmark integral method. The numerical simulations were performed to determine the vibration coupling properties between various tube bundles of stiffness. Take the corner square tube bundles with a pitch ratio of 1.28 as the research object. The influence of adjacent tubes with different stiffness on the vibration of the central target tube was analyzed. The research results show that the vibration characteristic of tube bundles is affected by the flow field dominant frequency and the inherent frequency of tube bundles. The vibration of adjacent tube bundles significantly impacts the amplitude and frequency of the central target tube. The equal stiffness and large stiffness tubes upstream or downstream inhibit the vibration displacement of the target tube to some extent. The low-stiffness tubes upstream or downstream significantly enhanced the amplitude of the target tube. The findings can be used to provide a basis for reasonable design and vibration suppression of shell-and-tube heat exchangers.

ABSTRACTT cell immunity is critical for human defensive immune response. Exploring the key molecules during the process provides new targets for T cell-based immunotherapies. CMC1 is a mitochondrial electron transport chain (ETC) complex IV chaperon protein. By establishing in-vitro cell culture system and Cmc1 gene knock out mice, we evaluated the role of CMC1 in T cell activation and differentiation. The B16-OVA tumor model was used to test the possibility of targeting CMC1 for improving T cell anti-tumor immunity. We identified CMC1 as a positive regulator in CD8+T cells activation and terminal differentiation. Meanwhile, we found that CMC1 increasingly expressed in exhausted T (Tex) cells. Genetic lost of Cmc1 inhibits the development of CD8+T cell exhaustion in mice. Instead, deletion of Cmc1 in T cells prompts cells to differentiate into metabolically and functionally quiescent cells with increased memory-like features and tolerance to cell death upon repetitive or prolonged T cell receptor (TCR) stimulation. Further, the in-vitro mechanistic study revealed that environmental lactate enhances CMC1 expression by inducing USP7, mediated stabilization and de-ubiquitination of CMC1 protein, in which a mechanism we propose here that the lactate-enriched tumor microenvironment (TME) drives CD8+TILs dysfunction through CMC1 regulatory effects on T cells. Taken together, our study unraveled the novel role of CMC1 as a T cell regulator and its possibility to be utilized for anti-tumor immunotherapy.

Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH. Methods: The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression. Results: Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model. Conclusions: Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

AbstractContext Schisandrin B (Sch B), an active ingredient from Schisandrae chinensis (Turcz.) Baill. (Schisandraceae) Fructus, possesses diverse pharmacological activities including antitumor, anti-inflammation, and hepatoprotection.Objective To explore the effect of Sch B on activated HSCs senescence in hepatic fibrosis and the mechanisms implicated.Materials and methods ICR mice with CCl4-induced hepatic fibrosis were supplemented with Sch B (40 mg/kg) for 30 d and LX2 cells were treated with Sch B (5, 10 and 20 μM) for 24 h. Cellular senescence was assessed by senescence-related indicators senescence-associated β-galactosidase (SA-β-gal) activity and the expression of p16, p21, p53, γ-H2AX, H3K9me3, TERT, TRF1, and TRF2. Ferric ammonium citrate (FAC) and NCOA4 siRNA were used to evaluate the mechanisms underlying Sch B’s regulation of cellular senescence.Results Sch B (40 mg/kg) reduced serum levels of AST and ALT (53.2% and 63.6%), alleviated hepatic collagen deposition, and promoted activated HSCs senescence in mice. Treatment with Sch B (20 μM) decreased cell viability to 80.38 ± 4.87% and elevated SA-β-gal activity, with the levels of p16, p21 and p53 increased by 4.5-, 2.9-, and 3.5-fold and the levels of TERT, TRF1 and TRF2 decreased by 2.4-, 2.7-, and 2.6-fold in LX2 cells. FAC (400 μM) enhanced Sch B’s effect mentioned above. NCOA4 siRNA weakened the effects of Sch B on iron deposition and HSCs senescence.Conclusions Sch B could ameliorate hepatic fibrosis through the promotion of activated HSCs senescence, which might be attributed to its induction of NCOA4-mediated ferritinophagy and subsequent iron overload.

In this paper, Cu-BTC derived mesoporous CuS nanomaterial (m-CuS) was synthesized via a two-step process involving carbonization and sulfidation of Cu-BTC for colorimetric glutathione detection. The Cu-BTC was constructed by 1,3,5-benzenetri-carboxylic acid (H3BTC) and Cu2+ ions. The obtained m-CuS showed a large specific surface area (55.751 m2/g), pore volume (0.153 cm3/g), and pore diameter (15.380 nm). In addition, the synthesized m-CuS exhibited high peroxidase-like activity and could catalyze oxidation of the colorless substrate 3,3′,5,5′-tetramethylbenzidine to a blue product. Peroxidase-like activity mechanism studies using terephthalic acid as a fluorescent probe proved that m-CuS assists H2O2 decomposition to reactive oxygen species, which are responsible for TMB oxidation. However, the catalytic activity of m-CuS for the oxidation of TMB by H2O2 could be potently inhibited in the presence of glutathione. Based on this phenomenon, the colorimetric detection of glutathione was demonstrated with good selectivity and high sensitivity. The linear range was 1–20 μM and 20–300 μM with a detection limit of 0.1 μM. The m-CuS showing good stability and robust peroxidase catalytic activity was applied for the detection of glutathione in human urine samples.

Banxia Xiexin decoction (BXD) is a traditional prescription widely used to treat gastrointestinal conditions, including gastric cancer. Through network pharmacology, bioinformatics, and molecular docking analysis, this study aimed to investigate the potential mechanism of the antigastric cancer effect of BXD and pave the way for future research. The network pharmacology analysis used BXD index components to improve reliability and validity. Prognosis-related genes identified through Lasso and Cox regression analysis were considered potential BXD core targets for gastric cancer. Functional enrichment analysis was conducted to uncover the potential mechanism of action of BXD in gastric cancer. In addition, molecular docking of the index components of BXD and the core targets was used to validate the results. The present study obtained six index components of BXD and 155 corresponding antigastric cancer targets. ANXA5, CYP19A1, FGF1, and F2 in the prognostic signature model were identified as core targets of the index components of BXD. Protein-protein interaction networks and functional enrichment analysis indicated that proteoglycans in cancer, PI3K-Akt, and other pathways were involved. According to molecular docking results, six index components showed good-to-strong binding affinities to the core targets. The results indicated that the index components of BXD act on multiple pathways and targets of gastric cancer. Our study paved the way for further investigation of the antigastric cancer activity and mechanisms of BXD.

In unanticipated obstacle scenarios at intersections, the safety and mobility of autonomous vehicles (AVs) are negatively impacted due to the conflict between traffic law compliance and obstacle avoidance. To solve this problem, an obstacle avoidance motion planning algorithm based on artificial potential field (APF) is proposed. An APF-switching logic is utilized to design the motion planning framework. Collision risk and travel delay are quantified as the switching triggers. The intersection traffic laws are digitalized and classified to construct compliance-oriented potential fields. A potential violation cost index (PVCI) is designed according to theories of autonomous driving ethics. The compliance-oriented potential fields are reconfigured according to the PVCI, forming violation cost potential fields. A cost function is designed based on compliance-oriented and violation cost potential fields, integrated with model predictive control (MPC) for trajectory optimization and tracking. The effectiveness of the proposed algorithm is verified through simulation experiments comparing diverse traffic law constraint strategies. The results indicate that the algorithm can help AVs avoid obstacles safely in unanticipated obstacle scenarios at intersections.

Abstract Objective Recurrent pregnancy loss (RPL) and pre‐eclampsia (PE) are immune‐related pregnancy complications that have been linked to CD4+ T cells and their cytokines, which can be influenced by genetic polymorphisms. This meta‐analysis aimed to investigate the relationship between interleukin (IL)‐17 and ‐27 polymorphisms and the susceptibility to RPL and PE. Methods All eligible case‐control studies published up to February 2023 were identified by searching PubMed, EMBASE, Cochrane, Web of Science, and Google Scholar. The risk of recurrent pregnancy loss and PE associated with the IL‐17 rs2275913, IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were estimated for each study. Results The meta‐analysis incorporated a total of 13 studies. The overall analysis indicated that IL‐17 rs2275913, IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were not significantly associated with immune‐related pregnancy complications, including RPL and PE. However, when the analysis was stratified by disease type, the IL‐17 rs2275913 polymorphism was found to be associated with an increased risk of RPL (recessive model AA/GA + GG: OR = 1.68, 95% confidence interval [CI]: 1.13–2.49, p = .01). Conclusions The IL‐17 rs763780, IL‐27 rs153109, and IL‐27 rs17855750 polymorphisms were not significantly associated with RPL and PE, whereas the IL‐17 rs2275913 polymorphism was associated with the susceptibility to recurrent miscarriage.

Designing nanocomposites with heterointerface as bifunctional electrocatalysts is a potential strategy to overcome the intrinsic activity limitation of electrocatalytic water splitting in acidic media, but it remains challenging. Herein, the highly efficient RuO2/Co3O4 electrocatalyst with a uniform nanoflower structure is prepared by hydrothermal growth combined with interface engineering. Benefiting from the unique nanostructure, the migration of electrons and intermediates is optimized by the sufficient exposure of abundant micropores and defects. Moreover, the formation of strong electronic interaction at the RuO2/Co3O4 heterointerfaces boosts the electrochemical active surface area and accelerates the reaction kinetics, which effectively improve the catalytic activity and stability of the catalyst. Based on enhanced intrinsic activity and electron transfer, the as‐synthesized RuO2/Co3O4 displays impressive hydrogen evolution reaction and oxygen evolution reaction activity, which respectively require low overpotentials of 240 and 100 mV to achieve a current density of 10 mA cm−2 in 0.5 m H2SO4. As a bifunctional electrode, RuO2/Co3O4 exhibits a low operating voltage of 1.58 V at 10 mA cm−2 for overall electrochemical water splitting. This study demonstrates the importance of heterostructure engineering in providing an avenue to achieve acid‐stable bifunctional electrocatalysts for energy conversion applications.

IntroductionAlthough multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME.MethodIn this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction.ResultA total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis.ConclusionOur study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.

Approximately 40% of the global population (primarily rural poor) rely on traditional cookstoves, with pernicious social, economic, and health outcomes. The Government of India launched its massive Prime Ministers’ Ujjwala scheme in 2016 to promote liquefied petroleum gas (LPG), a cleaner cooking system, in poor communities. While there has been a surge in adoption, consistent use of LPG has been tepid. We examined the trend of use of LPG for 18 months in 58 poor households of South India. In place of soliciting survey questions on stove usage, we deployed stove use monitoring technologies to accurately measure the use of LPG and traditional stoves. We also analyzed factors characterizing LPG use. None of the households used LPG for more than 55% of their cooking time. LPG refill transportation, perception of faster cooking, and caste were significant predictors of LPG use. The findings highlight that social workers must engage with these communities to improve their awareness and shape their perceptions of cleaner cooking.

The public health harms caused by fine particulate matter (PM2.5) have become a global focus, with PM2.5 exposure recognized as a critical risk factor for global morbidity and mortality. Chronic inflammation is the common pathophysiological feature of respiratory diseases induced by PM2.5 and is the most critical cause of all these diseases. However, presently there is a lack of effective preventive and therapeutic approaches for inflammatory lung injuries caused by PM2.5 exposure. Baicalin is a herb-derived effective flavonoid compound with multiple health benefits. This study established a murine lung inflammatory injury model via inhalation of PM2.5 aerosols. The data showed that after baicalin intervention, lung injury pathological score of baicalin (4.16 ± 0.54, 3.33 ± 0.76, 4.00 ± 0.45) and claricid (3.00 ± 0.78) treatments were markedly lower than PM2.5-treated mice (6.17 ± 0.31), and pathological damage was alleviated. Compared to the PM2.5 group, the spleen and lung indexes in the baicalin and claricid groups were significantly reduced. The inflammatory cytokines of TNF-α, IL-18, and IL-1β in serum, alveolar lavage fluid, and lung tissue were significantly decreased in the baicalin and claricid groups. The expressions of inflammatory pathway-related genes and proteins HMGB1, NLRP3, ASC, and caspase-1 were up-regulated in the PM2.5 group. The expressions of these genes and proteins were significantly decreased following baicalin treatment. The lung function indicators showed that the MV (65.94 ± 8.19 mL), sRaw (1.79 ± 0.08 cm H2O.s), and FRC (0.52 ± 0.01 mL) in the PM2.5 group were higher than in the control and baicalin groups, and respiratory function was improved by baicalin. PM2.5 exposure markedly altered the bacterial composition at the genus level. The dominant flora relative abundances of uncultured_bacterium_f_Muribaculaceae, Streptococcus, and Lactobacillus, were decreased from the control group (9.20%, 8.53%, 6.21%) to PM2.5 group (6.26%, 5.49%, 4.77%), respectively. Following baicalin intervention, the relative abundances were 9.72%, 6.65%, and 3.57%, respectively. Therefore, baicalin could potentially prevent and improve mice lung inflammatory injury induced by PM2.5 exposure. Baicalin might provide a protective role by balancing oropharyngeal microbiota and affecting the expression of the HMGB1/Caspase1 pathway.

Climate change is the main cause of frequent extreme weather and natural disasters. Therefore, effective climate adaptation strategies for urban rail transit (URT) should be adopted to cope with extreme precipitation events (EPEs). This study proposes a decision-making model based on climate change for drainage renovation, which consists of an optimal renovation sequence model and an optimal investment timing model. This study analyzes the inundation risk of each station and its node importance in the URT network and then uses a multi-attribute decision analysis (MADA) to determine the optimal renovation sequence. This study also uses a real options pricing approach to calculate the value of an option in order to defer the renovation project and determine the optimal investment timing. Then, the Beijing Urban Rail Transit (BURT) is taken as an example to conduct an empirical analysis of the proposed model. Considering the uncertainty of climate change and the complexity of the URT network, the model can obtain the optimal renovation sequence and the investment timing of each station, which is expected to provide a decision-making tool for urban governments to formulate an optimal plan that strengthens the prevention of flooding disasters.

This study aimed to explore the effects of different concentrations of indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), and indene-naphthaleneacetic acid (ABT-1) on the rooting and dynamic changes of the endogenous hormone content of Australian Mulberry (vegetable Mulberry) and Kirin mulberry (Fruit Mulberry) hardwood cuttings. As exhibited by the results, the rooting process of both vegetable mulberry and fruit mulberry could be divided into three stages, namely the initiation stage (1–18 days), the callus formation stage (18–28 days), and the adventitious root formation and elongation stage (28–48 days). The two treatments with 1000 mg·L−1 ABT-1 and 500 mg·L−1 ABT-1 achieved the highest rooting efficiencies of vegetable mulberry and fruit mulberry, significantly higher than those of other treatments (p < 0.01), with average rooting rates of 63.3% and 68.7%, and rooting efficiency indices of 25.3 and 34.3, respectively. During the rooting process, the contents of endogenous IAA and zeatin riboside (ZR) and the ratios of IAA/ABA and IAA/ZR presented a trend of decreasing before increasing, while the abscisic acid (ABA) and jasmonic acid (JA) contents exhibited a trend of increasing before decreasing, and the gibberellin (GA3), strigolactone (SL), and IBA contents showed a continuous decreasing trend. Hence, ABT-1 was effective in inducing the synthesis of IAA, IBA, JA, and SL, reducing the contents of ABA, ZR, and GA3, and promoting the rooting of vegetable mulberry and fruit mulberry cuttings. For fruit mulberry and vegetable mulberry cuttings, the optimal concentrations of ABT-1 were 500 mg·L−1 and 1000 mg·L−1, respectively, demonstrating applicability for the efficient propagation of Morus alba L. cuttings.

Purpose: The management of bone defects is a crucial content of total knee revision. This study compared the biomechanical performance of porous Ti6Al4V block and tumor prosthesis UHMWPE block in treating distal femoral bone defects.Methods: The finite element models of AORI type 3 distal femoral bone defect treated with porous Ti6Al4V block and UHMWPE block were established. Sensitivity analysis was performed to obtain the appropriate mesh size. The biomechanical performance of treatment methods in bone defects were evaluated according to the peak stress, the Von Mises stress distribution, and the average stresses of regions of interest under the condition of standing on one foot and flexion of the knee. Statistical analysis was conducted by independent samples t-test in SPSS (p < 0.05).Results: In the standing on one-foot state, the peak stress of the porous Ti6Al4V block was 12.42 MPa and that of the UHMWPE block was 19.97 MPa, which is close to its yield stress (21 MPa). Meanwhile, the stress distribution of the UHMWPE block was uneven. In the flexion state, the peak stress of the porous Ti6Al4V block was 16.28 MPa, while that of the UHMWPE block was 14.82 MPa. Compared with the porous Ti6Al4V block group, the average stress of the region of interest in UHMWPE block group was higher in the standing on one foot state and lower in the flexion state (p < 0.05).Conclusion: More uniform stress distribution was identified in the porous Ti6Al4V block application which could reserve more bone. On the contrary, uneven stress distribution and a larger high-stress concentration area were found in the UHMWPE block. Hence, the porous Ti6Al4V block is recommended for the treatment of AORI type 3 distal femoral bone defect.

Background: Gastric cancer (GC) has a high mortality rate and is particularly prevalent in China. The extracellular matrix protein, prolyl 4-hydroxylase subunit alpha 3 (P4HA3), has been implicated in various cancers. We aimed to assess the diagnostic and prognostic value of P4HA3 in GC and investigate its correlation with immune cell infiltration.Methods: The present study used microarray data from the Cancer Genome Atlas (TCGA) to analyze the association of P4HA3 expression with clinicopathological features. Data from the Gene Expression Omnibus (GEO) were used for validation. Receiver operating characteristic (ROC) and Kaplan–Meier curves were constructed to determine the diagnostic and prognostic value of P4HA3 in GC. Univariate and multivariate regression analyses were performed to assess the impact of P4HA3 on overall survival (OS) rates. A protein–protein interaction (PPI) network was generated and functional enrichment evaluated. Single-sample gene set enrichment analysis (ssGSEA) was conducted to correlate P4HA3 expression with immune cell infiltration. The correlation between P4HA3 and immune check point genes was studied.Results: P4HA3 was over-expressed in GC, along with 15 other types of cancer, including breast invasive carcinoma and cholangiocarcinoma. P4HA3 showed high diagnostic and prognostic value in GC and was an independent prognostic factor. P4HA3, TNM (tumor, node, metastases) stage, pathological stage and age all correlated with OS rates. Genes related to P4HA3 were enriched in the lumen of the endoplasmic reticulum and included procollagen-proline 3-dioxygenase activity. P4HA3 expression correlated with numbers of macrophages, natural killer (NK) cells, immature dendritic cells (iDC), mast cells, eosinophils, effective memory T cells (Tem), T-helper 1 (Th1) cells and dendritic cells (DC). P4HA3 was positively correlated with hepatitis A virus cellular receptor 2 (HAVCR2) and programmed cell death 1 ligand 2 (PDCD1LG2).Conclusion: P4HA3 is a potential independent biomarker for prognosis of GC and may be an immunotherapy target in the treatment of GC.

Recent studies indicated that hepatocyte senescence plays an important role in the development of alcoholic fatty liver disease (AFLD), suggesting that inhibition of hepatocyte senescence might be a potential strategy for AFLD treatment. The present study investigated the effect of curcumol, a component from the root of Rhizoma Curcumae, on hepatocyte senescence in AFLD and the underlying mechanisms implicated. The results showed that curcumol was able to reduce lipid deposition and injury in livers of ethanol liquid diet-fed mice and in ethanol-treated LO2 cells. Both in vivo and in vitro studies indicated that supplementation with curcumol effectively alleviated ethanol-induced cellular senescence as manifested by a decrease in senescence-associated β-galactosidase (SA-β-gal) activity, a downregulated expression of senescence-related markers p16 and p21, and dysfunction of the telomere and telomerase system. Consistently, treatment with curcumol led to a marked suppression of ethanol-induced formation of cytoplasmic chromatin fragments (CCF) and subsequent activation of cGAS-STING, resulting in a significant reduction in senescence-associated secretory phenotype (SASP)-related inflammatory factors’ secretion. Further studies indicated that curcumol’s inhibition of CCF formation might be derived from blocking the interaction of LC3B with lamin B1 and maintaining nuclear membrane integrity. Taken together, these results indicated that curcumol was capable of ameliorating AFLD through inhibition of hepatocyte senescence, which might be attributed to its blocking of LC3B and lamin B1 interaction and subsequent inactivation of the CCF-cGAS-STING pathway. These findings suggest a promising use of curcumol in the treatment of AFLD.

Bisphenol A (BPA) is a widespread endocrine disruptor that induces the impairment of immune cells, but the mechanism remains unknown. Macrophages are one of the most important immune cells in innate and adaptive immunity. In this study, we aimed to probe the effects of BPA on the damage of RAW264.7 cells and its mechanisms of action, especially focusing on the relationship between autophagy and apoptosis. Cells were pretreated with 10 mg/L LPS, or added autophagy activator RAPA, autophagy inhibitor 3-MA or Bcl-2 inhibitor ABT-737, then treated with BPA (0, 10, 100 and 200 μmol/L) for 12 h. Results have shown that BPA decreased the cell viability and disrupted secretory function by promoting pro-inflammatory cytokines TNF-α and IL-6 and reducing anti-inflammatory cytokines IL-10 TGF-β, as well as phagocytic ability. Moreover, autophagy was inhibited by BPA through decreasing p-AMPK/AMPK and increasing p-mTOR/mTOR, and further down-regulating autophagy proteins ATG6, LC3II/I ratio, and up-regulating autophagy flux protein p62. Additionally, BPA significantly increased Bax/Bcl-2 ratio, Caspase-3 expression and apoptosis rate. We found that RAPA ameliorated the cell viability, Bax/Bcl-2 ratio, and macrophage function damage induced by BPA. Intriguingly, ABT-737 might promote ATG6 expression. In summary, our study demonstrated that the effects of BPA on macrophages seemed to be mediated by inhibiting AMPK/mTOR-dependent autophagy and inducing apoptosis via endogenous mitochondrial pathway. Both Bcl-2 and ATG6 were involved in the regulation of apoptosis and autophagy by BPA. These findings provide a broader perspective for understanding the interaction between autophagy and apoptosis in BPA-induced immune cell injury.

Background: Melanoma is a highly malignant and aggressive tumor. The search for new and effective biomarkers facilitates early diagnosis and treatment, ultimately improving the prognosis of melanoma patients. Although the transmembrane protein TMEM176B has been linked to a number of cancers, its role in cancer immunity remains unknown.Methods: Expression levels of TMEM176B in normal tissues and several cancers, including Skin Cutaneous Melanoma (SKCM), were collected from TCGA and GTEx. We used Receiver operating characteristic and Kaplan–Meier survival curves and performed regression analysis to elucidate the link between TMEM176B and clinicopathological features of SKCM in order to determine the prognostic significance of TMEM176B in SKCM. We then used the GEPIA and STRING websites to search for proteins and associated top genes that may interact with TMEM176B and enriched them for analysis. The link between TMEM176B and immune cells infiltration was then investigated using TIMER, CIBERSORT algorithm and GSVA package of R (v3.6.3). Finally, animal tests were conducted to confirm the expression of Tmem176b and its influence on T-cell immune infiltration.Results:TMEM176B expression was considerably elevated in SKCM compared to normal tissues. Particularly, TMEM176B expression was also linked to pathological stage, tumor ulceration and radiation therapy. Patients with elevated TMEM176B expression had a better prognosis, according to the survival analysis. The majority of tumor infiltrating lymphocytes (TILs) especially T cells in SKCM was positively linked with TMEM176B expression. Our animal experiments also verified that the T-cell infiltration was significantly inhibited in local melanoma tissue of Tmem176b knockout mice. At the same time deleting Tmem176b accelerated tumor progress and impaired T cells effector function.Conclusion: Upregulated expression of TMEM176B in SKCM is associated with a better prognosis and it has the potential to serve as a diagnostic and prognostic marker for the disease. It may serve as a target for SKCM immunotherapy by regulating CD8+ T cells although it requires more evidence.

Strabismus occurs in about 2% of children and may result in amblyopia or lazy eyes and loss of depth perception. However, whether/how long-term strabismus shapes the brain structure and functions in children with concomitant strabismus (CS) is still unclear. In this study, a total of 26 patients with CS and 28 age-, sex-, and education-matched healthy controls (HCs) underwent structural and resting-state functional magnetic resonance imaging examination. The cortical thickness and amplitude of low-frequency fluctuation (ALFF) were calculated to assess the structural and functional plasticity in children with CS. Compared with HCs group, patients with CS showed increased cortical thickness in the precentral gyrus and angular gyrus while decreased cortical thickness in the left intraparietal sulcus, parieto-occipital sulcus, superior and middle temporal gyrus, right ventral premotor cortex, anterior insula, orbitofrontal cortex, and paracentral lobule. Meanwhile, CS patients exhibited increased ALFF in the prefrontal cortex and superior temporal gyrus, and decreased ALFF in the caudate and hippocampus. These results show that children with CS have abnormal structure and function in brain regions subserving eye movement, controls, and high-order cognitive functions. Our findings revealed the structural and functional abnormalities induced by CS and may provide new insight into the underlying neural mechanisms for CS.

Bacillus subtilis J-15 is a plant growth-promoting rhizobacteria isolated from the soil rhizosphere of cotton and is resistant to cotton verticillium wilt. This study evaluated the effects of metabolites of J-15 (J-15-Ms), including mycosubtilin, on plant growth using Arabidopsis and cotton plants. The results showed that J-15-Ms promoted Arabidopsis seeding growth at lower concentrations of 0.2 μg/mL but inhibited the growth at higher concentrations, such as 20 μg/mL. Similar results were obtained in cotton. Thus, J-15-Ms-treated plants showed low-concentration-induced growth promotion and high-concentration-induced growth inhibition. The J-15-Ms components were analyzed by liquid chromatography–mass spectrometry. Correlation analysis using the J-15 genomic databases suggested that J-15 may synthesize indoleacetic acid via the indole-3-pymvate pathway and indole-3-acetamide pathway. Treatment with mycosubtilin, a purified peptide from J-15-Ms, showed that the peptide promoted Arabidopsis growth at a low concentration (0.1 μg/mL) and inhibited plant growth at high concentrations (higher than 1 μg/mL), which also significantly increased plant lateral root number. Transcriptomic analysis showed that mycosubtilin might promote lateral root development and inhibit plant primary root growth by regulating the expression of the plant hormone signaling pathway. This study reveals the mechanism of Bacillus subtilis J-15 in affecting plant growth.

Summary: Germline alterations of the NF2 gene cause neurofibromatosis type 2, a syndrome manifested with benign tumors, and Nf2 deletion in mice also results in slow tumorigenesis. As a regulator of the Hippo signaling pathway, NF2 induces LATS1/2 kinases and consequently represses YAP/TAZ. YAP/TAZ oncoproteins are also inhibited by motin family proteins (Motins). Here, we show that the Hippo signaling is fine-tuned by Motins in a NF2-dependent manner, in which NF2 recruits E3 ligase RNF146 to facilitate ubiquitination and subsequent degradation of Motins. In the absence of NF2, Motins robustly accumulate to restrict full activation of YAP/TAZ and prevent rapid tumorigenesis. Hence, NF2 deficiency not only activates YAP/TAZ by inhibiting LATS1/2 but also stabilizes Motins to keep YAP/TAZ activity in check. The upregulation of Motins upon NF2 deletion serves as a strategy for avoiding uncontrolled perturbation of the Hippo signaling and may contribute to the benign nature of most NF2-mutated tumors.

(1) Background: To further improve the rapid reproduction and large-scale application of Catalpa bignonioides. (2) Methods: With young softwood cuttings from a 3-year-old C. bignonioides mother plant used as materials, the effects of indole-3-acetic acid(IAA), indolebutyric acid(IBA) and rhizogenic powder-1(ABT-1) growth regulators at different concentrations on cutting indexes and the dynamic changes in endogenous hormone contents during the rooting of the C. bignonioides cuttings were studied. (3) Results: The rooting of C. bignonioides cuttings could be divided into five stages. There were three types of rooting of adventitious roots. IBA treatment resulted in a high rooting rate and beneficial root morphology. The morphological indexes of the cutting roots after treatment with 1000 mg·L−1 IBA had the best overall quality, which was significantly higher than that of the roots in the control (CK) group (p < 0.05). Although the average longest root length (20.51 cm) under ABT-1 was the longest, its overall average rooting rate was slightly lower than that under IBA. The rooting effect under IAA was generally lower than that under IBA and ABT-1. The endogenous hormone content of the cuttings was found to be closely related to rooting; the IAA and zeatin nucleoside (ZR) content was high, and the ratios of IAA/ABA and IAA/ZR were high. The contents of gibberellin3 (GA3) and abscisic acid (ABA) were low, which had a promoting effect on the rooting of the cuttings. (5) Conclusions: All three kinds of auxin can promote rooting and, of the three treatment groups, the rooting effect of cuttings in the IBA treatment group was the strongest, with 1000 mg·L−1 being the optimum concentration.

Background: A growing number of randomized controlled trials (RCTs) have explored the significance of adjusting constitution for preventive treatment of disease in traditional Chinese medicine (TCM). In this study, we sought to comprehensively analyze the characteristics of these RCTs. Methods: All RCTs related to constitutional adjustment and preventive treatment of disease were included in the study. Literature was screened searching seven databases, including Pubmed, Web of Science, Embase, SinoMed, CNKI, Chongqing VIP, and Wangfang Database, from inception to December 2018. Data pertaining to bibliometrics, participants, and interventions were extracted and analyzed. Results: Two hundred and forty papers were published between 2007 and 2018, involving 240 RCTs with 55 977 total participants. Sample size in these RCTs ranged from 30 to 7800. Among them, 59 RCTs addressed disease prevention prior to onset involving 11 healthy states of participants, mainly for general health or sub-health population (40.68%) using health care and non-drug therapy. In control the development of existing disease (n = 174), 59 diseases were involved. Based on the number of RCTs and sample sizes, diseases including type 2 diabetes mellitus, primary hypertension, nonalcoholic fatty liver disease, and hyperlipoproteinemia accounted for 51.15% of the total patients studied. Drug therapy as an intervention was frequently used. In preventing recurrence after recovery (n = 7), over 4 kinds of health status in participants were involved. Drug therapy combined with health care was mostly used. Most RCTs reported positive outcomes, with only one reporting negative findings (1/240). Conclusion: The number of RCTs of constitutional adjustment on preventive treatment of disease has gradually increased since 2012. Participants and intervention measures from the above-mentioned types of RCTs exhibit their own characteristics. Future systematic reviews or meta-analyses on constitutional adjustment for preventive treatment of disease are warranted. Keywords: Traditional Chinese medicine constitution, Constitutional adjustment, Preventive treatment of disease, Randomized controlled trials, Bibliometrics

Cervical discogenic pain (CDP) is mainly induced by cervical disc degeneration. However, how CDP modulates the functional interactions within the pain network remains unclear. In the current study, we studied the changed resting-state functional connectivities of pain network with 40 CDP patients and 40 age-, gender-matched healthy controls. We first defined the pain network with the seeds of the posterior insula (PI). Then, whole brain and seed-to-target functional connectivity analyses were performed to identify the differences in functional connectivity between CDP and healthy controls. Finally, correlation analyses were applied to reveal the associations between functional connectivities and clinical measures. Whole-brain functional connectivity analyses of PI identified increased functional connectivity between PI and thalamus (THA) and decreased functional connectivity between PI and middle cingulate cortex (MCC) in CDP patients. Functional connectivity analyses within the pain network further revealed increased functional connectivities between bilateral PI and bilateral THA, and decreased functional connectivities between left PI and MCC, between left postcentral gyrus (PoCG) and MCC in CDP patients. Moreover, we found that the functional connectivities between right PI and left THA, between left PoCG and MCC were negatively and positively correlated with the visual analog scale, respectively. Our findings provide direct evidence of how CDP modulates the pain network, which may facilitate understanding of the neural basis of CDP.

Mutations in the enzyme isocitrate dehydrogenase 1/2 (IDH1/2) are the most common somatic mutations in low-grade glioma (LGG). The Hippo signaling pathway is known to play a key role in organ size control, and its dysregulation is involved in the development of diverse cancers. Large tumor suppressor 1/2 (LATS1/2) are core Hippo pathway components that phosphorylate and inactivate Yes-associated protein (YAP), a transcriptional co-activator that regulates expression of genes involved in tumorigenesis. A recent report from The Cancer Genome Atlas (TCGA) has highlighted a frequent hypermethylation of LATS2 in IDH-mutant LGG. However, it is unclear if LATS2 hypermethylation is associated with YAP activation and prognosis of LGG patients. Here, we performed a network analysis of the status of the Hippo pathway in IDH-mutant LGG samples and determined its association with cancer prognosis. Combining TCGA data with our biochemical assays, we found hypermethylation of LATS2 promoter in IDH-mutant LGG. LATS2 hypermethylation, however, did not translate into YAP activation but highly correlated with IDH mutation. LATS2 hypermethylation may thus serve as an alternative for IDH mutation in diagnosis and a favorable prognostic factor for LGG patients.

Cervical discogenic pain (CDP) is a clinically common pain syndrome caused by cervical disk degeneration. A large number of studies have reported that CDP results in brain functional impairments. However, the detailed dynamic brain functional abnormalities in CDP are still unclear. In this study, using resting-state functional magnetic resonance imaging, we explored the neural basis of CDP with 40 CDP patients and 40 age-, gender-matched healthy controls to delineate the changes of the voxel-level static and dynamic amplitude of low frequency fluctuations (ALFF). We found increased static ALFF in left insula (INS) and posterior precuneus (PCu), and decreased static ALFF in left precentral/postcentral gyrus (PreCG/PoCG), thalamus (THA), and subgenual anterior cingulate cortex in CPD patients compared to healthy controls. We also found decreased dynamic ALFF in left PreCG/PoCG, right posterior middle temporal gyrus, and bilateral THA. Moreover, we found that static ALFF in left PreCG/PoCG and dynamic ALFF in THA were significantly negatively correlated with visual analog scale and disease duration, respectively. Our findings provide the neurophysiological basis for CDP and facilitate understanding the neuropathology of CDP.

Abstract Background Exhausted T cells and regulatory T cells (Tregs) comprise diverse subsets of tumor immunosuppressive microenvironment that play key roles in tumor progress. Understanding subset diversity in T cells is a critical question for developing cancer immunotherapy. Methods A total of 235 specimens from surgical resections of hepatocellular carcinoma (HCC) patients were examined for infiltration of exhausted T cell (Tex) in tumor and adjacent tissue. We conducted deep single‐cell targeted immune profiling on CD3+ cells collected from tumor tissues, adjacent normal tissues (ANTs) and peripheral blood of HCC patients. Total 10 cell clusters were identified with distinct distributions and characteristics. Results We observed transitional differentiation of exhausted CD8+T cells and Tregs increasingly enriched in tumor tissue. The accumulation and location of Tex were related to the differences in the long‐term clinical outcome of HCC. Furthermore, data of single‐cell RNA‐seq showed that (1) cells transforming from effector CD8+ T cells to exhausted CD8+ T cells simultaneously expressed upregulated effector molecules and inhibitory receptors, (2) indicated alteration of gene expression related to stress response and cell cycle at early exhaustion stage, and (3) immunosuppressive Treg had profound activation in comparison to resting Tregs. Conclusions T cell exhaustion is a progressive process, and the gene‐expression profiling displayed T cell exhaustion and anergy are different. Accordingly, it is possible that functional exhaustion is caused by the combination effects of passive defects and overactivation in stress response. The results help to understand the dynamic framework of T cells function in cancer which is important for designing rational cancer immunotherapies.

Background: We aimed to evaluate the risk factors of the daily mortality associated with air pollution causing acute lower respiratory tract infections. Methods: We applied a short time series analysis to the air pollution record, meteorological data and 133 non-accidental death data in Shengyang, China, in 2013-2015. After controlling the seasonality, day of week and weather conditions, the group employed an over-dispersed Possion generalized addictive model to discuss the associations among different variables, then performed the stratified analysis according to age, gender, and season. Results: Mean concentrations of particulate matter with aerodynamic diameters of < 10 μm (PM10) and < 2.5 μm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3) were 122.4, 74.8, 79.4, 47.7, and 86.2 μg/m3, respectively. An increase of 10 μg/m3 in the 8-day moving average concentrations of PM10, PM2.5, SO2, NO2, and O3 corresponded to 0.18% (95% confidence interval [CI]: 0.10%, 0.26%), 0.21% (95% CI: 0.11%, 0.31%), 0.16% (95% CI: 0.04%, 0.30%), 0.43% (95% CI: 0.07%, 0.90%), and 0.10% (95% CI: -0.08%, 0.31%) increase in the daily mortality. The effects of air pollution lasted 9 days (lag 0-8), and they were more statistically significant in the elderly than in other age groups. Conclusion: These findings clarified the burden of air pollution on the morbidity of acute lower respiratory tract infections and emphasized the urgency of the control and prevention of air pollution and respiratory diseases in China.

Bipolar disorder is a common and severe mental illness with unsolved pathophysiology. A genome-wide association study (GWAS) has been used to find a number of risk genes, but it is difficult for a GWAS to find genes indirectly associated with a disease. To find core hub genes, we introduce a network analysis after the GWAS was conducted. Six thousand four hundred fifty eight single nucleotide polymorphisms (SNPs) with p < 0.01 were sifted out from Wellcome Trust Case Control Consortium (WTCCC) dataset and mapped to 2045 genes, which are then compared with the protein–protein network. One hundred twelve genes with a degree >17 were chosen as hub genes from which five significant modules and four core hub genes (FBXL13, WDFY2, bFGF, and MTHFD1L) were found. These core hub genes have not been reported to be directly associated with BD but may function by interacting with genes directly related to BD. Our method engenders new thoughts on finding genes indirectly associated with, but important for, complex diseases.

Many children suffer from nutritional deficiencies that may negatively affect their academic performance. This cluster‐randomized controlled trial aimed to test the effects of micronutrient‐fortified milk in Chinese students. Participants received either micronutrient‐fortified (n = 177) or unfortified (n = 183) milk for six months. Academic performance, motivation, and learning strategies were estimated by end‐of‐term tests and the Motivated Strategies for Learning Questionnaire. Blood samples were analyzed for micronutrients. In total, 296 students (82.2%) completed this study. Compared with the control group, students in the intervention group reported higher scores in several academic subjects (p < 0.05), including languages, mathematics, ethics, and physical performance at the end of follow‐up. Students in the intervention group showed greater self‐efficacy and use of cognitive strategies in learning, and reported less test anxiety (p < 0.001). Moreover, vitamin B2 deficiency (odds ratio (OR) = 0.18, 95% confidence interval (CI): 0.11~0.30) and iron deficiency (OR = 0.34, 95% CI: 0.14~0.81) were less likely in the students of the intervention group, whereas vitamin D, vitamin B12, and selenium deficiencies were not significantly different. “Cognitive strategy” had a partial mediating effect on the test scores of English (95% CI: 1.26~3.79) and Chinese (95% CI: 0.53~2.21). Our findings suggest that micronutrient‐fortified milk may improve students’ academic performance, motivation, and learning strategies.