Opioid Coprescription Through Risk Mitigation Guidance and Opioid Agonist Treatment Receipt.

Importance: At the onset of the COVID-19 pandemic, the government of British Columbia, Canada, released clinical guidance to support physicians and nurse practitioners in prescribing pharmaceutical alternatives to the toxic drug supply. These alternatives included opioids and other medications under the risk mitigation guidance (RMG), a limited form of prescribed safer supply, designed to reduce the risk of SARS-CoV-2 infection and harms associated with illicit drug use. Many clinicians chose to coprescribe opioid medications under RMG alongside opioid agonist treatment (OAT). Objective: To examine whether prescription of hydromorphone tablets or sustained-release oral morphine (opioid RMG) and OAT coprescription compared with OAT alone is associated with subsequent OAT receipt. Design, Setting, and Participants: This population-based, retrospective cohort study was conducted from March 27, 2020, to August 31, 2021, included individuals from 10 linked health administrative databases from British Columbia, Canada. Individuals who were receiving OAT at opioid RMG initiation and individuals who were receiving OAT and eligible but unexposed to opioid RMG were propensity score matched at opioid RMG initiation on sociodemographic and clinical variables. Data were analyzed between January 2023 and February 2024. Exposure: Opioid RMG receipt (≥4 days, 1-3 days, or 0 days of opioid RMG dispensed) in a given week. Main Outcome and Measures: The main outcome was OAT receipt, defined as at least 1 dispensed dose of OAT in the subsequent week. A marginal structural modeling approach was used to control for potential time-varying confounding. Results: A total of 4636 individuals (2955 [64%] male; median age, 38 [31-47] years after matching) were receiving OAT at the time of first opioid RMG dispensation (2281 receiving ongoing OAT and 2352 initiating RMG and OAT concurrently). Opioid RMG receipt of 1 to 3 days in a given week increased the probability of OAT receipt by 27% in the subsequent week (adjusted risk ratio, 1.27; 95% CI, 1.25-1.30), whereas receipt of opioid RMG for 4 days or more resulted in a 46% increase in the probability of OAT receipt in the subsequent week (adjusted risk ratio, 1.46; 95% CI, 1.43-1.49) compared with those not receiving opioid RMG. The biological gradient was robust to different exposure classifications, and the association was stronger among those initiating opioid RMG and OAT concurrently. Conclusions and Relevance: This cohort study, which acknowledged the intermittent use of both medications, demonstrated that individuals who were coprescribed opioid RMG had higher adjusted probability of continued OAT receipt or reengagement compared with those not receiving opioid RMG.

Boron-Containing Mesoporous Silica Nanoparticles with Effective Delivery and Targeting of Liver Cancer Cells for Boron Neutron Capture Therapy.

Nanocarriers have been researched comprehensively for the development of novel boron-containing agents in boron neutron capture therapy (BNCT). We designed and synthesized a multifunctional mesoporous silica nanoparticle (MSN)-based boron-containing agent. The latter was coated with a lipid bilayer (LB) and decorated with SP94 peptide (SFSIIHTPILPL) on the surface as SP94-LB@BA-MSN. The latter incorporated boric acid (BA) into hydrophobic mesopores, coated with an LB, and modified with SP94 peptide on the LB. SP94-LB@BA-MSN enhanced nano interface tumor-targeting ability but also prevented the premature release of drugs, which is crucial for BNCT because adequate boron content in tumor sites is required. SP94-LB@BA-MSN showed excellent efficacy in the BNCT treatment of HepG-2 cells. In animal studies with tumor-bearing mice, SP94-LB@BA-MSN exhibited a satisfactory accumulation at the tumor site. The boron content reached 40.18 ± 5.41 ppm in the tumor site 4 h after injection, which was 8.12 and 15.51 times higher than those in mice treated with boronated phenylalanine and those treated with BA. For boron, the tumor-to-normal tissue ratio was 4.41 ± 1.13 and the tumor-to-blood ratio was 5.92 ± 0.45. These results indicated that nanoparticles delivered boron to the tumor site effectively while minimizing accumulation in normal tissues. In conclusion, this composite (SP94-LB@BA-MSN) shows great promise as a boron-containing delivery agent for the treatment of hepatocellular carcinoma using BNCT. These findings highlight the potential of MSNs in the field of BNCT.

Impact of physicochemical properties on biological effects of lipid nanoparticles: Are they completely safe.

Lipid nanoparticles (LNPs) are promising materials and human-use approved excipients, with manifold applications in biomedicine. Researchers have tended to focus on improving the pharmacological efficiency and organ targeting of LNPs, while paid relatively less attention to the negative aspects created by their specific physicochemical properties. Here, we discuss the impacts of LNPs' physicochemical properties (size, surface hydrophobicity, surface charge, surface modification and lipid composition) on the adsorption-transportation-distribution-clearance processes and bio-nano interactions. In addition, since there is a lack of review emphasizing on toxicological profiles of LNPs, this review outlined immunogenicity, inflammation, hemolytic toxicity, cytotoxicity and genotoxicity induced by LNPs and the underlying mechanisms, with the aim to understand the properties that underlie the biological effects of these materials. This provides a basic strategy that increased efficacy of medical application with minimized side-effects can be achieved by modulating the physicochemical properties of LNPs. Therefore, addressing the effects of physicochemical properties on toxicity induced by LNPs is critical for understanding their environmental and health risks and will help clear the way for LNPs-based drugs to eventually fulfill their promise as a highly effective therapeutic agents for diverse diseases in clinic.

Modular Microgel-Based Bioassembly Scaffold Induced Chondrogenic and Osteogenic Differentiation of BMSCs.

Bioactive scaffolds capable of simultaneously repairing osteochondral defects remain a big challenge due to the heterogeneity of bone and cartilage. Currently modular microgel-based bioassembly scaffolds are emerged as potential solution to this challenge. Here, microgels based on methacrylic anhydride (MA) and dopamine modified gelatin (GelMA-DA) are loaded with chondroitin sulfate (CS) (the obtained microgel named GC Ms) or bioactive glass (BG) (the obtained microgel named GB Ms), respectively. GC Ms and GB Ms show good biocompatibility with BMSCs, which suggested by the adhesion and proliferation of BMSCs on their surfaces. Specially, GC Ms promote chondrogenic differentiation of BMSCs, while GB Ms promote osteogenic differentiation. Furthermore, the injectable GC Ms and GB Ms are assembled integrally by bottom-up in situ cross-linking to obtain modular microgel-based bioassembly scaffold (GC-GB/HM), which show a distinct bilayer structure and good porous properties and swelling properties. Particularly, the results of in vivo and in vitro experiments show that GC-GB/HM can simultaneously regulate the expression levels of chondrogenic- and osteogenesis-related genes and proteins. Therefore, modular microgel-based assembly scaffold in this work with the ability to promote bidirectional differentiation of BMSCs and has great potential for application in the minimally invasive treatment of osteochondral tissue defects.

What is the ideal time to begin tapering opioid agonist treatment? A protocol for a retrospective population-based comparative effectiveness study in British Columbia, Canada.

INTRODUCTION: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known. However, ethically, taper plans should acknowledge clients' preferences and autonomy but apply principles of shared informed decision-making regarding safety and efficacy. Linked population-level data capturing real-world tapering practices provide a valuable opportunity to improve existing evidence on when to contemplate starting an OAT taper. Our objective is to determine the comparative effectiveness of alternative times from OAT initiation at which a taper can be initiated, with a primary outcome of taper completion, as observed in clinical practice in British Columbia (BC), Canada. METHODS AND ANALYSIS: We propose a population-level retrospective observational study with a linkage of eight provincial health administrative databases in BC, Canada (01 January 2010 to 17 March 2020). Our primary outcomes include taper completion and all-cause mortality during treatment. We propose a 'per-protocol' target trial to compare different durations to taper initiation on the likelihood of taper completion. A range of sensitivity analyses will be used to assess the heterogeneity and robustness of the results including assessment of effectiveness and safety. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

A Dual Functional Bioinspired Lubricant for Osteoarthritis Treatment and Potential Prevention.

Osteoarthritis (OA), primarily characterized by the deterioration of articular cartilage, is a highly prevalent joint-disabling disease. The pathological onset and progression of OA are closely related to cartilage lubrication dysfunction and synovial inflammation. Synergistic options targeted at restorative lubrication and anti-inflammation are expected to be the most attractive candidates to treat OA and perhaps help prevent it. Herein, a bioinspired lubricant (HA/PA@Lipo) was fabricated by combining anionic hyaluronan-graft-poly(2-acrylamide-2-methylpropanesulfonic acid sodium salt) (HA/PA) with cationic liposomes (Lipo) via electrostatic interaction. HA/PA@Lipo mimicked the lubrication complex located on the outer cartilage surface and was endowed cartilage with excellent cartilage-lubricating performances. After the antioxidant gallic acid (GA) was loaded for dual functionality, HA/PA@Lipo-GA was prepared with added anti-inflammatory properties. HA/PA@Lipo-GA showed favorable biocompatibility with C28/I2 cells, inhibited the production of reactive oxygen, and regulated the expression levels of anabolic genes and proteins. The therapeutic effects of HA/PA@Lipo-GA were evaluated using a sodium iodoacetate-induced OA rat model, and the preventive effects of HA/PA@Lipo-GA were estimated in vivo. The results suggested the robust potential of HA/PA@Lipo-GA with dual functions as a candidate option for OA treatment and prevention.

Stress systems exacerbate the inflammatory response after corneal abrasion in sleep-deprived mice via the IL-17 signaling pathway.

Sleep deprivation (SD) has a wide range of adverse health effects. However, the mechanisms by which SD influences corneal pathophysiology and its post-wound healing remain unclear. This study aimed to examine the basic physiological characteristics of the cornea in mice subjected to SD and determine the pathophysiological response to injury after corneal abrasion. Using a multi-platform water environment method as an SD model, we found that SD leads to disturbances of corneal proliferative, sensory, and immune homeostasis as well as excessive inflammatory response and delayed repair after corneal abrasion by inducing hyperactivation of the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Pathophysiological changes in the cornea mainly occurred through the activation of the IL-17 signaling pathway. Blocking both adrenergic and glucocorticoid synthesis and locally neutralizing IL-17A significantly improved corneal homeostasis and the excessive inflammatory response and delay in wound repair following corneal injury in SD-treated mice. These results indicate that optimal sleep quality is essential for the physiological homeostasis of the cornea and its well-established repair process after injury. Additionally, these observations provide potential therapeutic targets to ameliorate SD-induced delays in corneal wound repair by inhibiting or blocking the activation of the stress system and its associated IL-17 signaling pathway.

Exploring Immune Cell Diversity in the Lacrimal Glands of Healthy Mice: A Single-Cell RNA-Sequencing Atlas.

The lacrimal gland is responsible for maintaining the health of the ocular surface through the production of tears. However, our understanding of the immune system within the lacrimal gland is currently limited. Therefore, in this study, we utilized single-cell RNA sequencing and bioinformatic analysis to identify and analyze immune cells and molecules present in the lacrimal glands of normal mice. A total of 34,891 cells were obtained from the lacrimal glands of mice and classified into 18 distinct cell clusters using Seurat clustering. Within these cell populations, 26 different immune cell subpopulations were identified, including T cells, innate lymphocytes, macrophages, mast cells, dendritic cells, and B cells. Network analysis revealed complex cell-cell interactions between these immune cells, with particularly significant interactions observed among T cells, macrophages, plasma cells, and dendritic cells. Interestingly, T cells were found to be the main source of ligands for the Thy1 signaling pathway, while M2 macrophages were identified as the primary target of this pathway. Moreover, some of these immune cells were validated using immunohistological techniques. Collectively, these findings highlight the abundance and interactions of immune cells and provide valuable insights into the complexity of the lacrimal gland immune system and its relevance to associated diseases.

Boron-Containing MOF Nanoparticles with Stable Metabolism in U87-MG Cells Combining Microdosimetry To Evaluate Relative Biological Effectiveness of Boron Neutron Capture Therapy.

Accurate prediction of the relative biological effectiveness (RBE) of boron neutron capture therapy (BNCT) is challenging. The therapy is different from other radiotherapy; the dynamic distribution of boron-containing compounds in tumor cells affects the therapeutic outcome considerably and hampers accurate measurement of the neutron-absorbed dose. Herein, we used boron-containing metal-organic framework nanoparticles (BMOFs) with high boron content to target U87-MG cells and maintain the concentration of the 10B isotope in cells. The content of boron in the cells could maintain 90% (60 ppm) within 20 min compared with that at the beginning; therefore, the accurate RBE of BNCT can be acquired. The effects of BNCT upon cells after neutron irradiation were observed, and the neutron-absorbed dose was obtained by Monte Carlo simulations. The RBE of BMOFs was 6.78, which was 4.1-fold higher than that of a small-molecule boron-containing agent (boric acid). The energy spectrum of various particles was analyzed by Monte Carlo simulations, and the RBE was verified theoretically. Our results suggested that the use of nanoparticle-based boron carriers in BNCT may have many advantages and that maintaining a stable boron distribution within cells may significantly improve the efficiency of BNCT.

Does carbon emission trading policy has emission reduction effect?-An empirical study based on quasi-natural experiment method.

As an important measure to reduce carbon emissions, carbon emission trading policy has been widely concerned and implemented around the world. The emission reduction effect of carbon emission trading policy has become a hot topic in theoretical researches and empirical explorations. Hence, this study aims to discuss the impact of the implementation of carbon emission trading policy on the reduction of carbon emissions, as well as the potential influencing paths and mechanisms. The quasi-nature experimental design is conducted with the data of 272 prefecture-level cities in China from 2007 to 2019. The propensity score matching (PSM) and difference-in-difference (DID) methods are adopted to explore and verify the causal relationship between carbon emission trading policy and carbon emissions. The results of this study are as follows: (1) the implementation of carbon emission policy can promote the reduction of carbon emission significantly; (2) the heterogeneity analysis results denote that the effect of carbon emission policy on the reduction of carbon emission varies among cities of different geographical locations; (3) mechanism analysis results indicate that technological capability is the main channel for carbon emission policy promotes the reduction of carbon emission; however, the effect of industry structure upgrading mechanisms is not significant. This manuscript responds to the theoretical issues of carbon emission and provides an empirical basis and references for further promoting the implementation of carbon emission policy.

Electroacupuncture Attenuates Ventilator-Induced Lung Injury by Modulating the Nrf2/HO-1 Pathway.

INTRODUCTION: Ventilator-induced lung injury (VILI) is the most common complication associated with mechanical ventilation. Electroacupuncture (EA) has shown potent anti-inflammatory effects. This study aimed to investigate the effects of EA on VILI and explore the underlying mechanisms. METHODS: Male C57BL/6 mice were subjected to high tidal volume ventilation to induce VILI. Prior to mechanical ventilation, mice received treatment with EA, nonacupoint EA, or EA combined with zinc protoporphyrin. RESULTS: EA treatment significantly improved oxygenation, as indicated by increased PaO2 levels in VILI mice. Moreover, EA reduced lung injury score, lung wet/dry weight ratio, and protein concentration in bronchoalveolar lavage fluid. EA also decreased the expression of pro-inflammatory cytokines including interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, IL-18, chemokine keratinocyte chemoattractant, macrophage inflammatory protein 2, and malondialdehyde. Furthermore, EA increased the activities of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase in VILI mice. At the molecular level, EA upregulated the expression of Nrf2 (nucleus) and heme oxygenase -1, while down-regulating the expression of p-NF-κB p65, NLR Family Pyrin Domain Containing 3, Cleaved Caspase-1, and ASC in VILI mice. Notably, the effects of EA were reversed by zinc protoporphyrin treatment, nonacupoint EA did not affect the aforementioned indicators of VILI. CONCLUSIONS: EA alleviates VILI by inhibiting the NLR Family Pyrin Domain Containing three inflammasome through activation of the Nrf2/HO-1 pathway.

Functional nano drug delivery system with dual lubrication and immune escape for treating osteoarthritis.

Local drug delivery via inter-articular injection offers a promising scenario to treat the most common joint disease, osteoarthritis (OA), which is closely associated with the increased friction or cartilage degeneration and the inflammatory syndrome of synovium. Therefore, it is quite necessary to improve the retention of drug delivery system within synovial joint, simultaneously restore the lubrication of degraded cartilage and meanwhile alleviate the inflammation. In this study, we propose a hydrophilic coating modified nano-liposome drug carrier (PMPC-Lipo) to achieve these functions. A modified chain transfer agent was utilized to polymerize 2-methacryloyloxyethyl phosphorylcholine (MPC), the obtained polymer, combined with lecithin and cholesterol, formed a liposome (PMPC-Lipo) where poly (MPC) acted as hydrophilic coating. PMPC-Lipo was found to restore the lubrication of mechanically damage cartilage (mimicking OA conditions) to the level like healthy cartilage due to the hydration lubrication. Additionally, due to the presence of poly (MPC), we also found PMPC-Lipo avoid the recognition of macrophage and thus escape from the phagocytosis to prolong its retention in synovial joint. Furthermore, after encapsulating gallic acid (GA) into PMPC-Lipo, the obtained GA-PMPC-Lipo can effectively scavenge reactive oxygen species and restore the imbalance of matrix secretion in inflammatory chondrocytes. Collectively, the proposed GA-PMPC-Lipo may provide a new idea for osteoarthritis treatment by providing both long-term effective drug action and excellent lubrication properties.

Maternal exposure to sunlight-irradiated graphene oxide induces neurodegeneration-like symptoms in zebrafish offspring through intergenerational translocation and genomic DNA methylation alterations.

The physiochemical properties of graphene oxide may be affected by sunlight irradiation. However, the underlying mechanisms that alter the properties and subsequent intergenerational effects are not sufficiently investigate. Epigenetics is an early sensitive marker for the intergenerational effects of nanomaterial exposure due to the epigenetic memory. In this study, we investigate changes in the physicochemical properties and the intergenerational effects of maternal exposure to simulated sunlight-irradiated polyethyleneimine-functionalized graphene oxide (SL-PEI-GO). Results show that the physicochemical properties of polyethyleneimine-functionalized graphene oxide (PEI-GO) can be altered significantly by the oxidation of carbon atoms with unpaired electrons present in the defects and on the edges of PEI-GO by sunlight. First, the positive charges, sharp edges, defects and disordered structures of SL-PEI-GO make it translocate from maternal zebrafish to offspring, thus catalyzing the production of reactive oxygen species and damaging mitochondria directly. In addition, changes in DNA methylation reduce the expression of protocadherin1a, protocadherin19 and cadherin4, thus destroying cell membrane integrity, cell adhesion and Ca2+ binding. The alteration of DNA methylation induced by maternal exposure activates the Ca2+-CaMKK-brsk2a pathway, which catalyzes the phosphorylation of Tau and eventually results in the appearance of neurodegeneration-like symptoms, including the loss of neurons and neurobehavioral disorders. This study demonstrates that maternal exposure to SL-PEI-GO induces clear neurodegeneration-like symptoms in offspring through both the intergenerational translocation of nanomaterials and differential DNA methylation. These findings may provide new insights into the health risks of nanomaterials altered by nature conditions.

Mitochondria and NLRP3 inflammasome in cardiac hypertrophy.

Cardiac hypertrophy is the main adaptive response of the heart to chronic loads; however, prolonged or excessive hypertrophy promotes myocardial interstitial fibrosis, systolic dysfunction, and cardiomyocyte death, especially aseptic inflammation mediated by NLRP3 inflammasome, which can aggravate ventricular remodeling and myocardial damage, which is an important mechanism for the progression of heart failure. Various cardiac overloads can cause mitochondrial damage. In recent years, the mitochondria have been demonstrated to be involved in the inflammatory response during the development of cardiac hypertrophy in vitro and in vivo. As the NLRP3 inflammasome and mitochondria are regulators of inflammation and cardiac hypertrophy, we explored the potential functions of the NLRP3 inflammasome and mitochondrial dysfunction in cardiac hypertrophy. In particular, we proposed that the induction of mitochondrial dysfunction in cardiomyocytes may promote NLRP3-dependent inflammation during myocardial hypertrophy. Further in-depth studies could prompt valuable discoveries regarding the underlying molecular mechanisms of cardiac hypertrophy, reveal novel anti-inflammatory therapies for cardiac hypertrophy, and provide more desirable therapeutic outcomes for patients with cardiac hypertrophy.

VAMP8 suppresses the metastasis via DDX5/ß-catenin signal pathway in osteosarcoma.

Osteosarcoma is a highly metastatic malignant bone tumor, necessitating the development of new treatments to target its metastasis. Recent studies have revealed the significance of VAMP8 in regulating various signaling pathways in various types of cancer. However, the specific functional role of VAMP8 in osteosarcoma progression remains unclear. In this study, we observed a significant downregulation of VAMP8 in osteosarcoma cells and tissues. Low levels of VAMP8 in osteosarcoma tissues were associated with patients' poor prognosis. VAMP8 inhibited the migration and invasion capability of osteosarcoma cells. Mechanically, we identified DDX5 as a novel interacting partner of VAMP8, and the conjunction of VAMP8 and DDX5 promoted the degradation of DDX5 via the ubiquitin-proteasome system. Moreover, reduced levels of DDX5 led to the downregulation of ß-catenin, thereby suppressing the epithelial-mesenchymal transition (EMT). Additionally, VAMP8 promoted autophagy flux, which may contribute to the suppression of osteosarcoma metastasis. In conclusion, our study anticipated that VAMP8 inhibits osteosarcoma metastasis by promoting the proteasomal degradation of DDX5, consequently inhibiting WNT/ß-catenin signaling and EMT. Dysregulation of autophagy by VAMP8 is also implicated as a potential mechanism. These findings provide new insights into the biological nature driving osteosarcoma metastasis and highlight the modulation of VAMP8 as a potential therapeutic strategy for targeting osteosarcoma metastasis.

Preparation and testing of laterally graded multilayer with a double genetic algorithm and root mean square error optimization in differential deposition.

Lateral graded multilayer can realize reflection, collimation and focusing of hard X-ray, and are currently the research frontier and hotspot of synchrotron radiation and high-performance X-ray sources. To reduce the d-spacing error of graded multilayers, a root mean square error optimization method based on double genetic algorithm (DGA-RMSE) is proposed. The theoretical d-spacing distribution is obtained by optical design, and the range is 1.9 ∼ 3.1 nm. The optimized d-spacing distribution is obtained by convolution of particle beam function and continuous monotonic rate distribution line (RDL) which is constructed in the form of a polynomial. The GA is applied to optimize variables from the polynomial twice, and the RMSE of thickness error is optimized and converged to 0.0065 nm. The final thickness error which is measured by the grazing incidence X-ray reflectivity (GIXRR) is consistent with the theoretical calculation. The results show that DGA-RMSE can precisely select polynomial function of RDL, reducing the error in high-precision magnetron sputtering and mask technology.

Research Advances of Mitochondrial Dysfunction in Perioperative Neurocognitive Disorders.

Perioperative neurocognitive disorders (PND) increases postoperative dementia and mortality in patients and has no effective treatment. Although the detailed pathogenesis of PND is still elusive, a large amount of evidence suggests that damaged mitochondria may play an important role in the pathogenesis of PND. A healthy mitochondrial pool not only provides energy for neuronal metabolism but also maintains neuronal activity through other mitochondrial functions. Therefore, exploring the abnormal mitochondrial function in PND is beneficial for finding promising therapeutic targets for this disease. This article summarizes the research advances of mitochondrial energy metabolism disorder, inflammatory response and oxidative stress, mitochondrial quality control, mitochondria-associated endoplasmic reticulum membranes, and cell death in the pathogenesis of PND, and briefly describes the application of mitochondria-targeted therapies in PND.

Can the Maillard reaction affect the characteristic aroma of Sesame aroma baijiu - A research on the methional during the stacking fermentation stage of jiupei.

In this study, we focused on methional, a characteristic flavor compound of Sesame aroma baijiu, and investigated its production during the stacking fermentation of baijiu jiupei. It has been speculated that the Maillard reaction occurs during the stacking fermentation, which results in the production of methional. This research showed that methional increased during the stacking process, reaching 0.45 mg/kg in the later stage of stacking fermentation. To simulate the stacking fermentation, a Maillard reaction model was established for the first time with conditions determined based on the measured stacking parameters (pH, temperature, moisture, reducing sugars, etc.). Through the analysis of the reaction products, we found that it is highly possible that the Maillard reaction occurs during the stacking fermentation, and a potential formation route of methional during the process was elucidated. These findings provide insights for the study of relevant volatile compounds in baijiu.

miR-137-LAPTM4B regulates cytoskeleton organization and cancer metastasis via the RhoA-LIMK-Cofilin pathway in osteosarcoma.

Osteosarcoma (OS) is a rare malignant bone tumor but is one leading cause of cancer mortality in childhood and adolescence. Cancer metastasis accounts for the primary reason for treatment failure in OS patients. The dynamic organization of the cytoskeleton is fundamental for cell motility, migration, and cancer metastasis. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is an oncogene participating in various biological progress central to cancer biogenesis. However, the potential roles of LAPTM4B in OS and the related mechanisms remain unknown. Here, we established the elevated LAPTM4B expression in OS, and it is essential in regulating stress fiber organization through RhoA-LIMK-cofilin signaling pathway. In terms of mechanism, our data revealed that LAPTM4B promotes RhoA protein stability by suppressing the ubiquitin-mediated proteasome degradation pathway. Moreover, our data show that miR-137, rather than gene copy number and methylation status, contributes to the upregulation of LAPTM4B in OS. We report that miR-137 is capable of regulating stress fiber arrangement, OS cell migration, and metastasis via targeting LAPTM4B. Combining results from cells, patients' tissue samples, the animal model, and cancer databases, this study further suggests that the miR-137-LAPTM4B axis represents a clinically relevant pathway in OS progression and a viable target for novel therapeutics.