Efficacy of Behavioral Intervention, Text Messaging, and Extended Intervention to Address Alcohol Misuse in Sexual Minority Men with HIV: A Factorial Randomized Clinical Trial.

This clinical trial examined the individual and combined effects of three different approaches to reducing alcohol misuse among a sample of sexual minority men (SMM) with HIV. Specifically, we used a 2 × 2 × 2 randomized factorial design to compare: (a) behavioral intervention based in motivational interviewing (MI) vs. brief intervention (BI), (b) interactive text messaging (ITM) for alcohol use vs. no ITM, and (c) extended intervention (EI) length of nine months vs. a one-month intervention duration. Participants (N = 188) were SMM with HIV and alcohol misuse recruited in Miami, FL, and Boston, MA. Participants were randomized to one of eight intervention combinations and assessed at 6- and 12-month follow-ups. Large reductions of over 50% in drinks per week and heavy drinking days were observed in all conditions at follow-up. Those who received ITM, compared to those who did not, reported significantly lower drinks consumed per week at 6 and 12 months (incidence rate ratios = 0.73 [95% CI = 0.57, 0.90] and 0.72 [95% CI = 0.56, 0.87], respectively), and increased odds of cessation of alcohol misuse at 12 months, odds ratio = 1.46, 95% CI = 1.03, 2.08. Results provided no evidence of better alcohol use outcomes for either MI or EI relative to their comparison conditions, and no specific combination of intervention components demonstrated a notable benefit. This study suggests a two-session BI can effectuate substantial reductions in alcohol use in SMM with HIV and that adding one month of ITM can yield further improvements. Clinical Trials Number: NCT02709759.

Marine ecological security shelter in China: Concept, policy framework, mechanism and implementation obstacles.

Building a marine ecological security shelter (MESS) has become the main strategy to adapt marine ecological threats in China. As China's marine policy lacks a robust framework document, it is necessary to consider whether the policy system can effectively support the construction of MESS. However, the linkage between the construction measures of MESS and related policies is not clear. Therefore, the purpose of this paper is to clarify the concept of MESS and its connection with policy, by adopting the policy content analysis method to analyze the evolution process of MESS-related policy system. The legislative shortcomings and implementation obstacles of the MESS-related policy system are then summarized and discussed. The results show that from 1981 to 2021 the MESS-related policy system has been continuously improved. However, the policy system's support and guarantee capacity for building MESS still needs to be improved. (1) Due to the lack of basic laws and special laws, the coordination among governance subjects and among policies lacks legislative guarantee. (2) The construction of MESS continues the inter-regional and inter-department administrative barriers in collaborative governance of marine environment. To establish an effective collaborative governance model, it is essential to improve the governance structure and mechanism. (3) The government-led governance pattern faces the problem of mechanism failure. The command and control instrument accounts for more than 82%, and the public and enterprises lack strong policy guarantees to participate in marine governance. (4) The policy system's adaptability to emerging threats must be improved. Marine policies rarely involve emerging threats such as climate change and new pollutants. Meanwhile, the real-time supervision and monitoring mechanism is weak. The real-time supervision is only accounting for about 10%. Generally speaking, as a complex and long-term system engineering, the construction of MESS will inevitably encounter contradictions in politics, culture, and economy. China should deepen the construction of marine ecological civilization and form a governance concept based on ecosystems. Overall, this paper helps to understand the internal connection between MESS and policy comprehensively and provides a new perspective for improving China's marine governance capacity.

Bithiophene-Functionalized Infrared Two-Photon Absorption Metal Complexes as Single-Molecule Platforms for Synergistic Photodynamic, Photothermal, and Chemotherapy.

A planar conjugated ligand functionalized with bithiophene and its Ru(II), Os(II), and Ir(III) complexes have been constructed as single-molecule platform for synergistic photodynamic, photothermal, and chemotherapy. The complexes have significant two-photon absorption at 808 nm and remarkable singlet oxygen and superoxide anion production in aqueous solution and cells when exposed to 808 nm infrared irradiation. The most potent Ru(II) complex Ru7 enters tumor cells via the rare macropinocytosis, locates in both nuclei and mitochondria, and regulates DNA-related chemotherapeutic mechanisms intranuclearly including DNA topoisomerase and RNA polymerase inhibition and their synergistic effects with photoactivated apoptosis, ferroptosis and DNA cleavage. Ru7 exhibits high efficacy in vivo for malignant melanoma and cisplatin-resistant non-small cell lung cancer tumors, with a 100 % survival rate of mice, low toxicity to normal cells and low residual rate. Such an infrared two-photon activatable metal complex may contribute to a new generation of single-molecule-based integrated diagnosis and treatment platform to address drug resistance in clinical practice and phototherapy for large, deeply located solid tumors.

Neuroprotective Effect of Hydrogen Sulfide Subchronic Treatment Against TBI-Induced Ferroptosis and Cognitive Deficits Mediated Through Wnt Signaling Pathway.

Emerging evidence shows that targeting ferroptosis may be a potential therapeutic strategy for treating traumatic brain injury (TBI). Hydrogen sulfide (H2S) has been proven to play a neuroprotective role in TBI, but little is known about the effects of H2S on TBI-induced ferroptosis. In addition, it is reported that the Wnt signaling pathway can also actively regulate ferroptosis. However, whether H2S inhibits ferroptosis via the Wnt signaling pathway after TBI remains unclear. In this study, we first found that in addition to alleviating neuronal damage and cognitive impairments, H2S remarkably attenuated abnormal iron accumulation, decreased lipid peroxidation, and improved the expression of glutathione peroxidase 4, demonstrating the potent anti-ferroptosis action of H2S after TBI. Moreover, Wnt3a or liproxstatin-1 treatment obtained similar results, suggesting that activation of the Wnt signaling pathway can render the cells less susceptible to ferroptosis post-TBI. More importantly, XAV939, an inhibitor of the Wnt signaling pathway, almost inversed ferroptosis inactivation and reduction of neuronal loss caused by H2S treatment, substantiating the involvement of the Wnt signaling pathway in anti-ferroptosis effects of H2S. In conclusion, the Wnt signaling pathway might be the critical mechanism in realizing the anti-ferroptosis effects of H2S against TBI. TBI induces ferroptosis-related changes characterized by iron overload, impaired antioxidant system, and lipid peroxidation at the chronic phase after TBI. However, NaHS subchronic treatment reduces the susceptibility to TBI-induced ferroptosis, at least partly by activating the Wnt signaling pathway.

The impact of online reviews in the presence of customer returns.

We develop a duopoly model to examine how online reviews influence the decisions of two competing online sellers who sell products of differentiated quality under different returns policies. We derive the competing sellers' optimal decisions on price and returns policy with and without online reviews, and we find that online reviews have greater impact on the high-quality seller than on the low-quality seller. If the salvage value of the product is relatively low, the seller has less opportunity to benefit from online reviews when it offers an MBG, as compared to a no-refund policy. The impact of online reviews on the competition between the two sellers has a "symmetric effect area," where reviews may either weaken or intensify the price competition between the two sellers when they both offer a no-refund policy, but always intensify the competition if they both offer an MBG. We have identified the conditions under which online reviews lead to a win-win, or benefit one seller, or present a prisoner's dilemma for the two online sellers. We also show that MBGs at both sellers help mitigate the prisoner's dilemma if the net salvage value at both sellers is sufficiently high.

Small molecule nAS-E targeting cAMP response element binding protein (CREB) and CREB-binding protein interaction inhibits breast cancer bone metastasis.

Bone is the most common metastatic site for breast cancer. The excessive osteoclast activity in the metastatic bone lesions often produces osteolysis. The cyclic-AMP (cAMP)-response element binding protein (CREB) serves a variety of biological functions including the transformation and immortalization of breast cancer cells. In addition, evidence has shown that CREB plays a key role in osteoclastgenesis and bone resorption. Small organic molecules with good pharmacokinetic properties and specificity, targeting CREB-CBP (CREB-binding protein) interaction to inhibit CREB-mediated gene transcription have attracted more considerations as cancer therapeutics. We recently identified naphthol AS-E (nAS-E) as a cell-permeable inhibitor of CREB-mediated gene transcription through inhibiting CREB-CBP interaction. In this study, we tested the effect of nAS-E on breast cancer cell proliferation, survival, migration as well as osteoclast formation and bone resorption in vitro for the first time. Our results demonstrated that nAS-E inhibited breast cancer cell proliferation, migration, survival and suppressed osteoclast differentiation as well as bone resorption through inhibiting CREB-CBP interaction. In addition, the in vivo effect of nAS-E in protecting against breast cancer-induced osteolysis was evaluated. Our results indicated that nAS-E could reverse bone loss induced by MDA-MB-231 tumour. These results suggest that small molecules targeting CREB-CBP interaction to inhibit CREB-mediated gene transcription might be a potential approach for the treatment of breast cancer bone metastasis.

TRAF6 neddylation drives inflammatory arthritis by increasing NF-κB activation.

Neddylation is a process similar to ubiquitination, and is critical in various inflammatory diseases; however, its importance in the pathogenesis of inflammatory arthritis is not well understood. Here, we investigated the role of neddylation in collagen-induced arthritis (CIA) and its clinical relevance. We showed that neddylation-related genes, including NEDD8 and CULLIN-1, were significantly upregulated in inflamed arthritic synovia. Functionally, neddylation activation was crucial for synovitis of CIA, as the inhibition of neddylation by MLN4924 significantly suppressed synovial cell proliferation and inflammatory responses. Mechanistically, neddylation mediated inflammatory arthritis by regulating NF-κB activation in fibroblast-like synovial cells (FLSs). Furthermore, TNF receptor-associated factor 6 (TRAF6) neddylation at Lys124 was essential for IL-17A-induced NF-κB activation. Replacing the Lys-124 residue with Arg (K124R) resulted in significantly impaired conjugation of NEDD8 to TRAF6, as well as markedly attenuated IL-17A-induced NF-κB activity. Therefore, the pathogenic role of neddylation in CIA as well as its mechanism of action demonstrated here provides a new insight into understanding the role of post-transcriptional modifications in the arthritis inflammatory response.

The prevention of latanoprost on osteoclastgenesis in vitro and lipopolysaccharide-induced murine calvaria osteolysis in vivo.

Identification of agents that inhibit osteoclast formation and function is important for the treatment of osteolytic diseases which feature excessive osteoclast formation and bone resorption. Latanoprost (LTP), an analog of prostaglandin F2α, is a medication which works to lower pressure inside the eyes. Prostaglandin F2α was reported to regulate bone metabolism, however, the effect of LTP in osteoclastogenesis is still unknown. Here, we found that LTP suppressed RANKL-induced osteoclastogenesis in a dose-dependent manner as illustrated by TRAP activity and TRAP staining. In addition, the osteoclast function was also reduced by LTP treatment, as indicated in less osteoclastic resorption pit areas. Furthermore, LTP inhibited the mRNA expressions of osteoclast marker genes such as TRAP and cathepsin K. In order to illustrate its molecular mechanism, we examined the changing of mRNA and protein levels of NFATc1 and c-fos by LTP treatment, as well as the phosphorylation of ERK, AKT, JNK, and p38. The results suggested that LTP inhibited RANKL-induced osteoclastgenesis and function by inhibiting ERK, AKT, JNK, and p38 cascade, following by the c-fos/NFATc1 pathway. In agreement with in vitro results, using an in vivo lipopolysaccharide-induced murine calvaria osteolysis mouse model, we found that administration of LTP was able to reverse the lipopolysaccharide-induced bone loss. Together, these data demonstrated that LTP attenuated the bone loss in lipopolysaccharide-induced murine calvaria osteolysis mice through inhibiting osteoclast formation and function. Our study thus provided the evidences that LTP was a potential treatment option against osteolytic bone diseases.

Diagnostic accuracy of alpha-defensin in periprosthetic joint infection: a systematic review and meta-analysis.

BACKGROUND: Alpha-defensin, a novel biomarker, has shown great potential for the accurate diagnosis of periprosthetic joint infection (PJI) in recent years: many published studies have presented encouraging results. Nevertheless, the diagnostic accuracy of alpha-defensin is inconsistent across published studies. Moreover, the optimum value of the diagnostic threshold urgently needs to be ascertained. This meta-analysis sought to estimate the precision of alpha-defensin for the diagnosis of PJI and, where possible, to confirm the threshold. METHOD: We systematically searched PubMed, Embase, Cochrane, Web of Knowledge, and ClinicalTrials.gov for relevant literature on alpha-defensin in the diagnosis of PJI (searching publications from the inception of each database until February 2017, with no language restriction). Pooled sensitivity, specificity, diagnostic odds ratios, and likelihood ratios were the indexes used for assessment, with the use of a random-effects model. RESULT: Eleven of the 426 studies that evaluated the diagnostic accuracy of alpha-defensin in periprosthetic joint infection (PJI) were included in this analysis. The pooled diagnostic sensitivity of alpha-defensin for PJI was 0.96 (95% confidence interval [CI], 0.87 to 0.99) and the specificity was 0.95 (95% CI, 0.91 to 0.97). Since there was substantial heterogeneity among studies, based on the inconsistency index (I2), threshold, site of arthroplasty, study design and techniques for the alpha-defensin test, subgroup analyses were performed to estimate the impacts of these variables on heterogeneity. CONCLUSION: In summary, this meta-analysis clearly lends support to the conclusion that alpha-defensin is a promising addition to the current methods for diagnosis of PJI.

Poor performance of Enduron polyethylene liner in total hip arthroplasty: a minimum ten-year follow up and ultra-morphological analysis of wear particles.

PURPOSE: The aim of the present study was to investigate the long-term outcome and the wear characteristics of two distinct types of ultra-high molecular weight polyethylene (UHMWPE) liners in total hip arthroplasty (THA). METHODS: We conducted a retrospective clinical study on patients which were treated with total hip arthroplasty using either Enduron polyethylene (Enduron PE) or Trilogy polyethylene (Trilogy PE) liners based on a minimum of ten year follow up data. Morphological analyses of wear particles from tissue samples, which were harvested during revision surgeries, were also performed. RESULTS: A total of 79 THAs in the Enduron group and 55 THAs in the Trilogy group were available for analysis. Kaplan-Meier survival with revision for wear-related complications as the endpoint of the Enduron PE liners was lower than that of Trilogy PE liners at ten years (93.5 % and 100 %, P = 0.03). The Enduron group had higher mean linear wear rate than that of the Trilogy group (0.20 ± 0.09 and 0.09 ± 0.03 mm/year, P < 0.01). The incidence of osteolysis for the Enduron group was higher than that of the Trilogy group (33.3 % and 12 %, P = 0.04). Under transmission electron microscopy, the Enduron group had more than 82 % of the particles less than 1.0 µm in size and more than 57 % of the particles less than 0.5 µm. CONCLUSION: The long-term performance of Enduron liners was worse than that of Trilogy liners. Further clinical follow-up may be necessary in patients with Enduron PE liners in order to avoid catastrophic complications.

Mesenchymal stem cells-derived exosomes alleviate liver fibrosis by targeting Hedgehog/SMO signaling.

BACKGROUND & AIMS: Despite increasing knowledge regarding the cellular and molecular mechanisms of liver fibrogenesis, there is currently no approved drug for the treatment of liver fibrosis. Mesenchymal stem cells (MSCs) are multipotent progenitor cells representing an attractive therapeutic tool for tissue damage and inflammation. This study was designed to determine the protective effect and underlying mechanism of human umbilical cord-derived MSCs (UC-MSCs) on thioacetamide-induced liver fibrosis. METHODS: Liver fibrosis was induced in mice by intraperitoneal injection of thioacetamide (TAA). Some mice were then given injection of UC-MSCs or UC-MSCs-derived exosomes (UC-MSCs-Exo) via the tail vein. Liver tissues were collected for histologic analysis. RESULTS: We found that administration of UC-MSCs significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels, and attenuated hepatic inflammation and fibrosis. Moreover, the therapeutic effect of UC-MSCs-derived exosomes was similar to that of UC-MSCs. Intriguingly, UC-MSCs-Exo treatment downregulated the expression of smoothened (SMO), a fundamental component of Hedgehog signaling which plays a critical role in fibrogenesis, and subsequently inhibited the activation of hepatic stellate cells, a central driver of fibrosis in experimental and human liver injury. Furthermore, the anti-inflammatory and anti-fibrotic effects of UCMSCs- Exo was reversed by the SMO agonist SAG treatment in mice. CONCLUSION: Our findings suggest that UC-MSCs-Exo exert therapeutic effects on liver fibrosis, at least in part, through inhibiting the Hedgehog/SMO signaling pathway.

2-[(5'-Chloro-1,1':3',1''-terphenyl-4'-yl)imino]-acenaphthylen-1(2H)-one.

The title compound, C30H18ClNO, is a product of the condensation reaction of acenaphthyl-ene-1,2-dione and 5'-chloro-1,1':3',1''-terphenyl-4'-amine. The acenaphthyl-ene fragment and two terminal phenyl rings are rotated relative to the central benzene ring by 72.2 (3), 43.2 (3) and 41.2 (3)°, respectively. This mol-ecular conformation is supported by weak C-H⋯π inter-actions. In the crystal, mol-ecules form centrosymmetric dimers by the stacking inter-actions between two neighboring acenaphthyl-ene fragments, with an inter-planar distance of 3.365 (3) Å. The dimers are bound to each other by weak C-H⋯N and C-H⋯π inter-actions, forming a three-dimensional framework.

The relationship between student interaction with generative artificial intelligence and learning achievement: serial mediating roles of self-efficacy and cognitive engagement.

Generative artificial intelligence (GAI) shocked the world with its unprecedented ability and raised significant tensions in the education field. Educators inevitably transition to an educational future that embraces GAI rather than shuns it. Understanding the mechanism between students interacting with GAI tools and their achievement is important for educators and schools, but relevant empirical evidence is relatively lacking. Due to the characteristics of personalization and real-time interactivity of GAI tools, we propose that the students-GAI interaction would affect their learning achievement through serial mediators of self-efficacy and cognitive engagement. Based on questionnaire surveys that include 389 participants as the objective, this study finds that: (1) in total, there is a significantly positive relationship between student-GAI interaction and learning achievement. (2) This positive relationship is mediated by self-efficacy, with a significant mediation effect value of 0.015. (3) Cognitive engagement also acts as a mediator in the mechanism between the student-GAI interaction and learning achievement, evidenced by a significant and relatively strong mediating effect value of 0.046. (4) Self-efficacy and cognitive engagement in series mediate this positive association, with a serial mediating effect value of 0.011, which is relatively small in comparison but also shows significance. In addition, the propensity score matching (PSM) method is applied to alleviate self-selection bias, reinforcing the validity of the results. The findings offer empirical evidence for the incorporation of GAI in teaching and learning.

Magnetic nanoagent assisted deciphering of heterogeneous glycans in extracellular vesicles of varied cellular origins.

Extracellular vesicles bear a rich glycome that presents versatile functions in diverse biological processes. Leverage polydopamine modified magnetic particles to serve as nanosized agents for rapid and robust EV capture and manipulation, we here integrated the easy magnetic actuation with specific lectin-glycan binding and enzyme-mediated fluorescence amplification and thus proposed a facile approach to efficiently decipher a broad spectrum of glycans in EVs. Termed magnetic nanoagent assisted extracellular vesicle glycan deciphering (MAEG), the developed assay utilized a magnet as the assistant operation tool and realized fast (∼1 h) and sensitive (a limit of detection of ∼0.7 µg/mL vesicles) EV glycan analysis in a simple low-cost (around 2.27 Chinese Yuan for one test) manner without requirement of any sophisticated platforms. With robust performance for different sample species, the assay achieved to depict the comprehensive glycosylation landscapes for varied EVs derived from eight cell lines focusing on non-small-cell lung cancer. Systematic analyses clearly revealed the high heterogeneity in glycan features of EVs of varied cellular origins. Using an established difference network method, unique glycan features in different EVs were sifted out and further compiled to construct lectin-denoted patterns as dedicated glycosylation fingerprints, potentially expanding EV-based clinical applications.

Vascularized polypeptide hydrogel modulates macrophage polarization for wound healing.

Wound repair involves a sophisticated process that includes angiogenesis, immunoregulation and collagen deposition. However, weak revascularization performance and the lack of biochemical cues to trigger immunomodulatory function currently limit biomaterial applications for skin regeneration and tissue engineering. Herein, we fabricate a new bioactive polypeptide hydrogel (QK-SF) constituted by silk fibroin (SF) and a vascular endothelial growth factor mimetic peptide KLTWQELYQLKYKGI (QK) for tissue regeneration by simultaneously promoting vascularization and macrophage polarization. Our results showed that this QK-SF hydrogel can be prepared via an easy manufacturing process, and exhibited good gel stability and low cytotoxicity to cultured human umbilical vein endothelial cells (HUVECs) via both live/dead and cell counting kit-8 assays. Importantly, this QK-SF hydrogel triggered macrophage polarization from M1 into M2, as exemplified by the enhanced expression of the M2 marker and decreased expression of the M1 marker in RAW264.7 cells. Furthermore, the QK-SF hydrogel showed high capacity for inducing endothelial growth, migration and angiogenesis, which were proved by increased expression of angiogenesis-related genes in HUVECs. Consistent with in vitro findings, in vivo data show that the QK-SF hydrogel promoted M2 polarization, keratinocyte differentiation, and collagen deposition in the mouse skin wound model in immunohistochemistry assay. Furthermore, this QK-SF hydrogel can reduce inflammation, induce angiogenesis and promote wound healing as exemplified by the increased vessel formation and decreased wound area in the mouse skin wound model. Altogether, these results indicate that the bioactive QK-SF hydrogel plays dual functional roles in promoting angiogenesis and immunoregulation for tissue regeneration. STATEMENT OF SIGNIFICANCE: The QK-SF hydrogel plays dual functional roles in promoting angiogenesis and immunoregulation for tissue repair and wound healing. The QK-SF hydrogel can be prepared via an easy manufacturing process, and exhibited good gel stability and low cytotoxicity to cultured HUVECs. The QK-SF hydrogel triggered macrophage polarization from M1 into M2. The QK-SF hydrogel showed high capacity for inducing endothelial growth, migration and angiogenesis. The QK-SF hydrogel promoted M2 polarization, keratinocyte differentiation, and collagen deposition.

Self-Assembled Nanospheres with Enhanced Interfacial Lubrication for the Treatment of Osteoarthritis.

Osteoarthritis is associated with an increase in mechanical friction of the joint, which causes irreversible damage to articular cartilage. Consequently, it is crucial to restore joint lubrication for effectively treating osteoarthritis. In the present study, hyaluronic acid (HA)-based zwitterionic nanospheres with phosphocholine groups on the surface were synthesized, which achieved excellent lubrication behavior due to the hydration lubrication mechanism. Specifically, HA was initially thiolated and modified with hexadecylamine based on an amidation reaction, then it was grafted with 2-methacryloyloxyethyl phosphocholine (MPC) by the thiol-ene click reaction, and finally self-assembled into nanospheres (HA-MPC) by hydrophobic interaction and cross-linking of the thiol group. The lubrication test demonstrated that the HA-MPC nanospheres improved lubrication under shear force, with a 40% reduction in the friction coefficient compared with HA. The in vitro experiment indicated that the HA-MPC nanospheres had excellent biocompatibility, and they upregulated the cartilage anabolic gene and downregulated cartilage catabolic proteases as well as the pain-related gene. The in vivo test showed that the injection of HA-MPC nanospheres to the joint cavity could inhibit the development of osteoarthritis, which was examined based on histological staining and also morphological evaluation. In conclusion, the new self-assembled zwitterionic HA-MPC nanospheres may be intra-articularly injected for the effective treatment of osteoarthritis by restoring joint lubrication.

Notch-activated mesenchymal stromal/stem cells enhance the protective effect against acetaminophen-induced acute liver injury by activating AMPK/SIRT1 pathway.

BACKGROUND: Notch signaling plays important roles in regulating innate immunity. However, little is known about the role of Notch in mesenchymal stromal/stem cell (MSC)-mediated immunomodulation during liver inflammatory response. METHODS: Notch activation in human umbilical cord-derived MSCs was performed by a tissue culture plate coated with Notch ligand, recombinant human Jagged1 (JAG1). Mice were given intravenous injection of Notch-activated MSCs after acetaminophen (APAP)-induced acute liver injury. Liver tissues were collected and analyzed by histology and immunohistochemistry. RESULTS: MSC administration reduced APAP-induced hepatocellular damage, as manifested by decreased serum ALT levels, intrahepatic macrophage/neutrophil infiltration, hepatocellular apoptosis and proinflammatory mediators. The anti-inflammatory activity and therapeutic effects of MSCs were greatly enhanced by Notch activation via its ligand JAG1. However, Notch2 disruption in MSCs markedly diminished the protective effect of MSCs against APAP-induced acute liver injury, even in the presence of JAG1 pretreatment. Strikingly, Notch-activated MSCs promoted AMP-activated protein kinase (AMPKα) phosphorylation, increased the sirtuins 1 (SIRT1) deacetylase expression, but downregulated spliced X-box-binding protein 1 (XBP1s) expression and consequently reduced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation. Furthermore, SIRT1 disruption or XBP1s overexpression in macrophages exacerbated APAP-triggered liver inflammation and augmented NLRP3/caspase-1 activity in MSC-administrated mice. Mechanistic studies further demonstrated that JAG1-pretreated MSCs activated Notch2/COX2/PGE2 signaling, which in turn induced macrophage AMPK/SIRT1 activation, leading to XBP1s deacetylation and inhibition of NLRP3 activity. CONCLUSIONS: Activation of Notch2 is required for the ability of MSCs to reduce the severity of APAP-induced liver damage in mice. Our findings underscore a novel molecular insights into MSCs-mediated immunomodulation by activating Notch2/COX2/AMPK/SIRT1 pathway and thus provide a new strategy for the treatment of liver inflammatory diseases.

Construction of Active Protein Materials: Manipulation on Morphology of Salmon Calcitonin Assemblies with Enhanced Bone Regeneration Effect.

The effect of protein drugs is always limited by their relatively low stability and fast degradation property; thus, various elegant efforts have been made to improve the bioactivity and biocompatibility of the protein drugs. Here, an alternative way is proposed to solve this problem. By simply adding a limited amount of small-molecular regulator, which tunes the subtle balance of protein-protein interactions (PPIs) and disulfide bond formation, the self-assembly property of the protein drug can be regulated, forming an "active protein material" itself. This means that, the resulting biomaterial is dominated by the protein drug and water, with significantly enhanced bone regeneration effect compared to the virgin protein in vitro and in vivo, through multivalent effect between the protein and receptor and the retarded degradation of the assembled proteins. In this active protein material, the protein drug is not only the active drug, but also the drug carrier, which greatly increases the drug-loading efficiency of the biomaterial, indicating the advantages of the easy preparation, high efficiency, and low cost of the active protein material with a bright future in biomedical applications.

The Antecedents of Thriving at Work: A Meta-Analytic Review.

In this study, a systematic and comprehensive meta-analysis of the relationship between thriving at work and its antecedents is conducted. The antecedents in terms of the characteristics of unit contextual features, the resources produced at work, agentic work behaviors, and personality traits are illustrated according to the socially embedded model of thriving described by Spreitzer and research. Additionally, we examine possible cultural influence on the relationship between thriving and its antecedents at different levels of individualistic culture. According to 67 independent samples (N = 28,097), our findings reveal the correlations between thriving at work and the antecedents such as those in the form of unit contextual features, the resources produced at work, agentic work behaviors, and personality traits. Furthermore, we find that individualism moderate the relationships between certain antecedents and thriving at work. Finally, we discuss the theoretical and practical implications of this study as well as the directions for future research.

Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation.

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFß/Smad, Notch, Wnt/ß-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.