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The environmental threat posed by stibnite is an important geoenvironmental issue of current concern. To better understand stibnite oxidation pathways, aerobic abiotic batch experiments were conducted in aqueous solution with varying δ18OH2O value at initial neutral pH for different lengths of time (15-300 days). The sulfate oxygen and sulfur isotope compositions as well as concentrations of sulfur and antimony species were determined. The sulfur isotope fractionation factor (Δ34SSO4-stibnite) values decreased from 0.8‰ to -2.1‰ during the first 90 days, and increased to 2.6‰ at the 180 days, indicating the dominated intermediate sulfur species such as S2O32-, S0, and H2S (g) involved in Sb2S3 oxidation processes. The incorporation of O into sulfate derived from O2 (∼100%) indicated that the dissociated O2 was only directly adsorbed on the stibnite-S sites in the initial stage (0-90 days). The proportion of O incorporation into sulfate from water (27%-52%) increased in the late stage (90-300 days), which suggested the oxidation mechanism changed to hydroxyl attack on stibnite-S sites promoted by nearby adsorbed O2 on stibnite-Sb sites. The exchange of oxygen between sulfite and water may also contributed to the increase of water derived O into SO42-. The new insight of stibnite oxidation pathway contributes to the understanding of sulfide oxidation mechanism and helps to interpret field data.

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Regulation of the two-photon excited fluorescence (TPEF) emission intensity and wavelength of metal-organic framework (MOF) crystals with similar constitutions presents a significant challenge. In this study, two MOFs, Zn-BTPPA and Cd3-BTPPA, were constructed using tetrakis(1,1'-biphenyl-4-carboxylic acid)-1,4-benzenediamine (H4BTPPA) as the organic ligand and mononuclear Zn and trinuclear Cd3 inorganic nodes, respectively. The incorporation of H4BTPPA within the MOF structures enables effective TPEF emission in both Zn-BTPPA and Cd3-BTPPA. The TPEF results show that Zn-BTPPA and Cd3-BTPPA exhibited strong emissions at 523 and 463 nm, respectively, when excited with a 780 nm laser. Moreover, Zn-BTPPA and Cd3-BTPPA exhibited much higher two-photon absorption cross sections, approximately 4.9 and 5.2 times higher than that of the reported dinuclear MOF, Cd2-BTPPA, with a similar composition, respectively. With different inorganic nodes, the stacking of chromophores, π···π interactions, and ligand geometry were found to correlate with the enhanced TPEF in Cd3-BTPPA and the blue-shifted TPEF in Zn-BTPPA. This work serves as an inspiration for designing efficient TPEF MOF materials based on the structure-property relationship.

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Lysosomes are important cellular structures for human health as centers for recycling, signaling, metabolism and stress adaptation. However, the potential role of lysosomes in stress-related emotions has long been overlooked. Here, it is found that lysosomal morphology in astrocytes is altered in the medial prefrontal cortex (mPFC) of susceptible mice after chronic social defeat stress. A screen of lysosome-related genes revealed that the expression of the mucolipin 1 gene (Mcoln1; protein: mucolipin TRP channel 1) is decreased in susceptible mice and depressed patients. Astrocyte-specific knockout of mucolipin TRP channel 1 (TRPML1) induced depressive-like behaviors by inhibiting lysosomal exocytosis-mediated adenosine 5'-triphosphate (ATP) release. Furthermore, this stress response of astrocytic lysosomes is mediated by the transcription factor EB (TFEB), and overexpression of TRPML1 rescued depressive-like behaviors induced by astrocyte-specific knockout of TFEB. Collectively, these findings reveal a lysosomal stress-sensing signaling pathway contributing to the development of depression and identify the lysosome as a potential target organelle for antidepressants.

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Over the last 15 years, a small number of paediatric artemisinin-based combination therapy products have been marketed. These included Riamet® and Coartem® dispersible tablets, a combination of artemether and lumefantrine, co-developed by the Medicines for Malaria Venture and Novartis. Disappointingly, patient compliance, requirement for high-fat meal, and sporadic drug dissolution behaviours following administration still result in considerable challenges for these products. The first and foremost barrier that needs addressed for successful delivery of the artemether/lumefantrine combination is the poor solubility of lumefantrine within the gastrointestinal fluids. In this work, amorphous solid dispersions of lumefantrine within Soluplus®-based matrices have been manufactured using hot melt extrusion as a potential formulation strategy to achieve enhanced dissolution and apparent solubility. The drug loading capacity of Soluplus® to accommodate amorphous lumefantrine, whilst ensuring improved in-vitro dissolution performance, was investigated. The extrusion process employed a variety of processing parameters, including various temperature profiles and different production scales. The influence of variation in extrusion conditions upon the physical stability of manufactured amorphous solid dispersions was also examined. This allowed for a greater understanding of the role of extrusion processing conditions on the performance of supersaturated amorphous solid dispersions during dissolution and storage. This may allow for the design and manufacture of drug enabled formulations with lower drug dosing and thus a lower risk of adverse effects.

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The effectiveness of Toll-like 9 agonists (CpG) as an adjuvant for tumor immunotherapy is restricted due to their insufficient ability to activate anti-tumor immunity. To address that, the common nutrient metal ions are explored (Mn2+, Cu2+, Ca2+, Mg2+, Zn2+, Fe3+, and Al3+), identifying Mn2+ as a key enhancer of CpG to mediate immune activation by augmenting the STING-NF-κB pathway. Mn2+ and CpG are then self-assembled with epigallocatechin gallate (EGCG) into a nanoadjuvant MPN/CpG. Local delivery of MPN/CpG effectively inhibits tumor growth in a B16 melanoma-bearing mouse model, reshaping the tumor microenvironment (TME) by repolarizing M2-type tumor-associated macrophages (TAMs) to an M1-type and boosting intra-tumoral infiltration of CD8+/CD4+ T lymphocytes and DCs. Furthermore, compared to free CpG, MPN/CpG exhibits heightened accumulation in lymph nodes, enhancing CpG uptake and DC activation, consequently inducing significant antigen-specific cytotoxic CD8+ T cell immune response and humoral immunity. In a prophylactic tumor-bearing mouse model, MPN/CpG vaccination with OVA antigen significantly delays B16-OVA melanoma growth and extends mouse survival. These findings underscore the potential of MPN/CpG as a multifunctional adjuvant platform to drive powerful innate and adaptive immunity and regulate TME against tumors.

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A phytochemical study on the stems and leaves of Cratoxylum cochinchinense (Lour.) Blume resulted in the isolation and characterisation of a new polyprenylated xanthone, cratocochinone (1), as well as seven known analogues, fuscaxanthone K (2), pruniflorone Q (3), 1,3,5,8-tetrahy-droxy- 2-(3-methybut-2-enyl)-4-(3,7-dimethylocta-2,6-dienyl) xanthone (4), cochinensoxanthone (5), cratoxylum-xanthone B (6), cochinchinone I (7) and cochinchinone K (8). The chemical structure of 1 was determined by comprehensive spectral analyses. The known compounds 2 - 8 were identified by comparing their experimental spectroscopic data with those reported data in the literature. The anti-inflammatory and anti-HIV effects of all isolates 1-8 were evaluated. As a result, compounds 1-8 showed remarkable inhibitory effects against nitric oxide (NO) production induced by lipopolysaccharide in mouse macrophage RAW 264.7 cells showing IC50 values ranging from 0.68 ± 0.06 to 10.27 ± 0.18 µM. Meanwhile, compounds 1-8 displayed notable anti-HIV-1 reverse transcriptase (RT) effects with EC50 values ranging from 0.19 to 10.72 µM.

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The immune landscape of distant unablated tumors following insufficient microwave ablation (iMWA) in hepatocellular carcinoma (HCC) remains to be clarified. The objective of this study is to define the abscopal immune landscape in distant unablated tumor before and after iMWA for HCC. Two treatment-naive patients were recruited for tumor tissue sampling, of each with two HCC lesions. Tumor samples were obtained at before and after microwave ablation in distant unablated sites for single-cell RNA sequencing (scRNA-seq). Mouse model with bilateral hepatoma tumors were developed, and distant unablated tumors were analyzed using multicolor immunofluorescence, RNA sequencing and flow cytometry. The scRNA-seq revealed that a reduced proportion of CD8+ T cells and an increased proportion of myeloid-derived suppressor cells (MDSCs) were observed in the distant unablated tumor microenvironment (TME). A notable disruption was observed in the lipid metabolism of tumor-associated immune cells, accompanied by an upregulated expression of CD36 in tumor-infiltrating immune cells in distant unablated tumor. The administration of a CD36 inhibitor has been demonstrated to ameliorate the adverse effects induced by iMWA, primarily by reinstating the anti-tumor responses of T cells in distant unablated tumor. These findings explain the recurrence and progression of tumors after iMWA and provide a new target of immunotherapy for HCC.

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Alemtuzumab induction with belatacept/rapamycin-based maintenance immunotherapy (ABR) prevents kidney allograft rejection and specifically limits early costimulation blockade-resistant rejection (CoBRR). To evaluate the mechanisms by which this regimen alters CoBRR, we characterized the phenotype and functional response of preexisting memory cells to allogeneic endothelial cells using intracellular cytokine staining and flow cytometry. IL-7-induced lymphocyte proliferation in the presence or absence of rapamycin was assessed to characterize the phenotype of proliferating cells. Lymphocytes from 40 recipients who underwent transplant using the ABR regimen were studied longitudinally. The rapid immunoresponses of preexisting alloreactive cells to allogeneic endothelial cells were predominantly CD8+TNF-α+/IFN-γ+ cells. These cells were effector memory (TEM) and terminally differentiated effector memory cells lacking CD28 expression, and most were CD57+PD1-. Neither rapamycin nor belatacept directly inhibited these cells. IL-7, a cytokine induced during lymphopenia postdepletion, provoked dramatic CD8+ TEM cell proliferation and a low level of CD8+CD57+PD1- cell expansion in vitro. The IL-7 stimulation induced CD8+ cell mTOR phosphorylation, and rapamycin treatment markedly inhibited IL-7-induced TEM and CD57+PD1- cell expansion. This effect was evident in patients receiving the ABR in that the repopulation of CD8+CD57+PD1- TEM cells was substantially suppressed for at least 36 mo after transplant. These findings help define one mechanism by which a costimulation blockade/rapamycin-based therapy following alemtuzumab induction minimizes CoBRR, namely that in the presence of rapamycin, costimulation-resistant alloreactive cells are disproportionately ineffective at repopulating following post-transplant T cell depletion.

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SASH1 (SAM and SH3 domain containing 1) has been increasingly reported as a tumor suppressor gene. However, there is limited research on the role of SASH1 in breast cancer. This manuscript aims to investigate the mechanism of SASH1 in the occurrence, development, and prognosis of breast cancer. Firstly, we obtained RNA-sequencing data of the tumors from the Genomic Data Commons data portal website, along with the corresponding clinical information of patients. Pan-cancer analysis was performed to analyze the expression of SASH1 across all tumors. Univariate Cox regression analysis was used to assess the correlation between SASH1 expression and the prognosis of breast cancer patients. Then, immunohistochemistry was utilized to evaluate the expression levels of SASH1, p-Akt, p-PI3K, and p-mTOR in breast cancer tissue. Finally, a cell assay was employed to analyze the impact of SASH1 on the proliferation and invasion of breast cancer cells (MDA-MB-231). The results revealed that SASH1 expression is decreased in BRCA, LUSC, LUAD, CESC, ESCA, and COAD. Meta-analysis also found that SASH1 is downregulated in most tumor tissues, and the expression level of SASH1 in breast cancer was significantly lower than that in the control group (OR = 0.14, 95% CI = 0.08-0.25; P < 0.001). Further experimental validation showed that SASH1 expression is significantly downregulated in breast cancer tissue (38.33%, 23/60), and the overexpression of SASH1 can inhibit the proliferation and invasion of breast cancer cells accompanied by the suppression of PI3K-Akt-mTOR signaling pathway. Additionally, SASH1 overexpression can improve OS and RFS of breast cancer patients.

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A C-H functionalizing annulation reaction of boron-doped polycyclic aromatic hydrocarbons (PAHs) with alkynes is described. This metal-free π-extension provides a new synthetic route to fusion atom B-doped polycyclic aromatic hydrocarbons (PAHs) that is demonstrated with the synthesis of a family of new, functionalized, structurally constrained 6a,15a-diborabenzo[tuv]naphtho[2,1-b]picenes. These annulation products exhibit deep LUMO energy levels, strong visible-range absorptions, and sterically accessible π-systems that can adopt herringbone or π-stacked solid-state structures based on choice of substituents. From regioselectivity and DFT calculations, we propose an annulation mechanism involving intramolecular electrophilic aromatic substitution of a zwitterionic intermediate.

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Chirality plays a pivotal role in both the origin of life and the self-assembly of materials. However, the governing principles behind chirality transfer in hierarchical self-assembly across multiple length scales remain elusive. Here, we propose a concise and versatile simulation strategy using the patchy particle chain model to investigate the self-assembly of rods interacting through chiral and aggregation interactions. We reveal that chiral interaction possessing an entropic nature, amplifies the fluctuations and twists in the alignment of rods, while aggregation interaction serves as a foundational platform for aggregation and assembly. When both interactions exhibit moderate absolute and relative values, their synergistic interplay facilitates the chirality transfer from rods to assemblies, resulting in the formation of chiral mesoscale ordered structures. Furthermore, we observe a two-step chirality transfer process by monitoring the formation kinetics of the twisted assemblies. This work not only provides a comprehensive insight into chirality transfer mechanisms, but also introduces a versatile mesoscale simulation framework for exploring the role of chirality in hierarchical self-assembly.

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The purpose of this research was to assess the association between sleep disorders and coronary heart disease (CHD) using data from the National Health and Nutrition Examination Survey (NHANES) database. This cross-sectional study included 9886 eligible participants with valid data on sleep disorders and CHD from the NHANES from 2011 to 2014. The complex NHANES sampling led to use of sample weights in analyses. Various statistical methods and covariates were utilized. Significance was set at P < .05. Receiver operating characteristic curves were used to assess the diagnostic efficacy of sleep disorders in relation to CHD. Sleep disorders were significantly associated with CHD (P < .001). In the model corrected for age, sex, race, hypertension, diabetes, and uric acid as covariates, sleep disorders and CHD remained significantly associated (P < .001, odds ratio = 1.83 [95% confidence interval: 1.31-2.58]). The correlation between sleep disorders and CHD varies by age and gender. Sleep disorders have some predictive value for CHD (0.5 < area under curve ≤ 0.7). Sleep disorders were associated with and predictive of CHD risk, warranting consideration in clinical assessments.

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Lung squamous cell carcinoma (LUSC), a subset of non-small cell lung cancer (NSCLC), accounts for about 30% of all lung cancers (LC) and exhibits a dismal response to current therapeutic protocols. Existed studies have indicated that aberrations in fibroblast growth factor receptors (FGFRs) play a pivotal role in the progression of LUSC, rendering them as attractive targets for therapeutic intervention in this cancer type. This study found that Erdafitinib (Erda), a novel pan-FGF receptor tyrosine kinase inhibitor (TKI), exerted a cytotoxic effect on LUSC cells. However, STAT3, the downstream target of FGFRs, remained still activated despite Erdafitinib treatment. Then, a STAT3 inhibitor, Stattic (Sta), was concurrently used with Erdafitinib, and the combined treatment demonstrated a synergistic efficacy in both in vitro and in vivo models of LUSC when compared to that of the treatment of the Erdafitinib or Stattic alone. Further molecular studies showed that such an effect of Erdafitinib and Stattic was associated with their concurrently inhibitory effect on FGFR1 and STAT3 signaling in LUSC cells. Therefore, the findings of this study indicated that the concurrent use of Erdafitinib and Stattic is a promising therapeutic approach for the treatment of FGFR1-positive LUSC.

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Sphingolipids, crucial components of cellular membranes, play a vital role in maintaining cellular structure and signaling integrity. Disruptions in sphingolipid metabolism are increasingly implicated in cancer development. Key bioactive sphingolipids, such as ceramides, sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glycosphingolipids, profoundly impact tumor biology. They influence the behavior of tumor cells, stromal cells, and immune cells, affecting tumor aggressiveness, angiogenesis, immune modulation, and extracellular matrix remodeling. Furthermore, abnormal expression of sphingolipids and their metabolizing enzymes modulates the secretion of tumor-derived extracellular vesicles (TDEs), which are key players in creating an immunosuppressive tumor microenvironment, remodeling the extracellular matrix, and facilitating oncogenic signaling within in situ tumors and distant pre-metastatic niches (PMNs). Understanding the role of sphingolipids in the biogenesis of tumor-derived extracellular vesicles (TDEs) and their bioactive contents can pave the way for new biomarkers in cancer diagnosis and prognosis, ultimately enhancing comprehensive tumor treatment strategies.

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For nonlinear systems with uncertain state time delays, an adaptive neural optimal tracking control method based on finite time is designed. With the help of the appropriate LKFs, the time-delay problem is handled. A novel nonquadratic Hamilton-Jacobi-Bellman (HJB) function is defined, where finite time is selected as the upper limit of integration. This function contains information on the state time delay, while also maintaining the basic information. To meet specific requirements, the integral reinforcement learning method is employed to solve the ideal HJB function. Then, a tracking controller is designed to ensure finite-time convergence and optimization of the controlled system. This involves the evaluation and execution of gradient descent updates of neural network weights based on a reinforcement learning architecture. The semi-global practical finite-time stability of the controlled system and the finite-time convergence of the tracking error are guaranteed.

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In this study, an antimicrobial component, silk protease inhibitors (SPIs), was extracted from discarded silkworm cocoons, and a suitable degumming method for obtaining regenerated silk fibroin (SF) was screened. An edible antimicrobial coating was prepared by mixing SPIs with SF for evaluation of potential in strawberries preservation. Results demonstrated that SPI could effectively inhibit mycelial growth and spore germination. The alkaline protease method exhibited the highest degumming rate of 24.4 %. The SPI-SF coating exhibited excellent mechanical properties, high water vapor permeability, and easy washability. Within 10 days, seedlings treatment with SPI-SF coating solution showed a germination rate of 94.3 %, and exhibited good biocompatibility with HepG2 cells. Coating with SPI-SF led to increase in the storage period of strawberries to 10-14 days, concurrent with considerable reduction in decay rate at room temperature. Conclusively, this study demonstrates the potential of SPI-SF edible coating in strawberries preservation.

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The vegetable leafminer (Liriomyza sativae) is a devastating invasive pest of many vegetable crops and horticultural plants worldwide, causing serious economic loss. Conventional control strategy against this pest mainly relies on the synthetic chemical pesticides, but widespread use of insecticides easily causes insecticide resistance development and is harmful to beneficial organisms and environment. In this context, a more environmentally friendly pest management strategy based on RNA interference (RNAi) has emerged as a powerful tool to control of insect pests. Here we report a successful oral RNAi in L. sativae after feeding on pak choi (Brassica rapa ssp. chinensis) that transiently express hairpin RNAs targeting vital genes in this pest. First, potentially lethal genes are identified by searching an L. sativae transcriptome for orthologs of the widely used V-ATPase A and actin genes, then expression levels are assessed during different life stages and in different adult tissues. Interestingly, the highest expression levels for V-ATPase A are observed in the adult heads (males and females) and for actin in the abdomens of adult females. We also assessed expression patterns of the target hairpin RNAs in pak choi leaves and found that they reach peak levels 72 h post agroinfiltration. RNAi-mediated knockdown of each target was then assessed by letting adult L. sativae feed on agroinfiltrated pak choi leaves. Relative transcript levels of each target gene exhibit significant reductions over the feeding time, and adversely affect survival of adult L. sativae at 24 h post infestation in genetically unmodified pak choi plants. These results demonstrate that the agroinfiltration-mediated RNAi system has potential for advancing innovative environmentally safe pest management strategies for the control of leaf-mining species.

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Phytochemical study on the stems and leaves of Artocarpus tonkinensis led to the isolation of a new 2-arylbenzofuran, artocartone (1), as well as seven known 2-arylbenzofurans (2-8). The chemical structure of 1 was established by means of comprehensive spectroscopic analyses and the known compounds were determined by comparing their MS and NMR data with those reported data in literature. The antiproliferative activities of all isolates 1-8 against five human cancer cell lines: HL-60, SMMC-7721, A-375, MCF-7 and SW480 in vitro were evaluated. As a result, compounds 1- 8 displayed notable antiproliferative activities against various human cancer cell lines with IC50 values in the range of 0.28 ± 0.05-26.89 ± 0.18 µM.