Anti-Cracking TEOS-Based Hybrid Materials as Reinforcement Agents for Paper Relics.

Tetraethoxysilane (TEOS) is the most commonly used silicon-based reinforcement agent for conserving art relics due to its cost-effectiveness and commercial maturity. However, the resulting silica gel phase is prone to developing cracks as the gel shrinks during the sol-gel process, potentially causing severe damage to the objects being treated. In this study, dodecyltrimethoxysilane (DTMS) was introduced into TEOS to minimize this shrinkage by adding elastic long chains to weaken the capillary forces. The gel formed from the DTMS/TEOS hybrid material was transparent and crack-free, featuring a dense microstructure without mesopores or micropores. It exhibited excellent thermal stability, with a glass transition temperature of up to 109.64 °C. Evaluation experiments were conducted on artificially aged, handmade bamboo paper. The TEOS-based hybrid material effectively combined with the paper fibers through the sol-gel process, polymerizing into a network structure that enveloped the paper surface or penetrated between the fibers. The surface of the treated paper displayed excellent hydrophobic properties, with no significant changes in appearance, color, or air permeability. The mechanical properties of the treated bamboo paper improved significantly, with longitudinal and transverse tensile strengths increasing by up to 36.63% and 44.25%, respectively. These research findings demonstrate the promising potential for the application of DTMS/TEOS hybrid materials in reinforcing paper relics.

Eicosapentaenoic acid activates the P62/KEAP1/NRF2 pathway for the prevention of diabetes-associated cognitive dysfunction.

Diabetes-associated cognitive dysfunction (DCD) is a severe complication of diabetes mellitus (DM), threatening the life quality of the diabetic population. However, there is still a lack of effective approaches for its intervention. Eicosapentaenoic acid (EPA) is an omega-3 polyunsaturated fatty acid that was not previously investigated for its effect on DCD. In this study, EPA was found to improve DCD in a mouse model of type 2 DM (T2DM) induced by streptozotocin and a high-fat diet, exhibiting profound protective effects on cognitive dysfunction, neuronal loss, and cerebral oxidative stress and inflammation. While EPA did not attenuate advanced glycation end product-induced neuron injury, we hypothesized that EPA might protect neurons by regulating microglia polarization, the effect of which was confirmed by the co-culture of neurons and lipopolysaccharide-stimulated microglia. RNA sequencing identified nuclear factor-erythroid-2-related factor 2 (NRF2) antioxidant signaling as a major target of EPA in microglia. Mechanistically, EPA increased sequestosome-1 (SQSTM1 or P62) levels that might structurally inhibit Kelch-like ECH associated protein 1 (KEAP1), leading to nuclear translocation of NRF2. P62 and NRF2 predominantly mediated EPA's effect since the knockdown of P62 or NRF2 abolished EPA's protective effect on microglial oxidative stress and inflammation and sequential neuron injuries. Moreover, the regulation of P62/KEPA1/NRF2 axes by EPA was confirmed in the hippocampi of diabetic mice. The present work presents EPA as an effective nutritional approach and microglial P62/KEAP1/NRF2 as molecular targets for the intervention of DCD.

Function of mast cell and bile-cholangiocarcinoma interplay in cholangiocarcinoma microenvironment.

OBJECTIVE: The correlation between cholangiocarcinoma (CCA) progression and bile is rarely studied. Here, we aimed to identify differential metabolites in benign and malignant bile ducts and elucidate the generation, function and degradation of bile metabolites. DESIGN: Differential metabolites in the bile from CCA and benign biliary stenosis were identified by metabonomics. Biliary molecules able to induce mast cell (MC) degranulation were revealed by in vitro and in vivo experiments, including liquid chromatography-mass spectrometry (MS)/MS and bioluminescence resonance energy transfer assays. Histamine (HA) receptor expression in CCA was mapped using a single-cell mRNA sequence. HA receptor functions were elucidated by patient-derived xenografts (PDX) in humanised mice and orthotopic models in MC-deficient mice. Genes involved in HA-induced proliferation were screened by CRISPR/Cas9. RESULTS: Bile HA was elevated in CCA and indicated poorer prognoses. Cancer-associated fibroblasts (CAFs)-derived stem cell factor (SCF) recruited MCs, and bile N,N-dimethyl-1,4-phenylenediamine (DMPD) stimulated MCs to release HA through G protein-coupled receptor subtype 2 (MRGPRX2)-Gαq signalling. Bile-induced MCs released platelet-derived growth factor subunit B (PDGF-B) and angiopoietin 1/2 (ANGPT1/2), which enhanced CCA angiogenesis and lymphangiogenesis. Histamine receptor H1 (HRH1) and HRH2 were predominantly expressed in CCA cells and CAFs, respectively. HA promoted CCA cell proliferation by activating HRH1-Gαq signalling and hastened CAFs to secrete hepatocyte growth factor by stimulating HRH2-Gαs signalling. Solute carrier family 22 member 3 (SLC22A3) inhibited HA-induced CCA proliferation by importing bile HA into cells for degradation, and SLC22A3 deletion resulted in HA accumulation. CONCLUSION: Bile HA is released from MCs through DMPD stimulation and degraded via SLC22A3 import. Different HA receptors exhibit a distinct expression profile in CCA and produce different oncogenic effects. MCs promote CCA progression in a CCA-bile interplay pattern.

Recent advances of novel targeted drug delivery systems based on natural medicine monomers against hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the most prevalent type of liver cancer, is often diagnosed at an advanced stage. Surgical interventions are often ineffective, leading HCC patients to rely on systemic chemotherapy. Unfortunately, commonly used chemotherapeutic drugs have limited efficacy and can adversely affect vital organs, causing significant physical and psychological distress for patients. Natural medicine monomers (NMMs) have shown promising efficacy and safety profiles in HCC treatment, garnering attention from researchers. In recent years, the development of novel targeted drug delivery systems (TDDS) combining NMMs with nanocarriers has emerged. These TDDS aim to concentrate drugs effectively in HCC cells by manipulating the characteristics of nanomedicines, leveraging receptor and ligand interactions, and utilizing endogenous stimulatory responses to promote specific nanomedicines distribution. This comprehensive review presents recent research on TDDS for HCC treatment using NMMs from three perspectives: passive TDDS, active TDDS, and stimuli-responsive drug delivery systems (SDDS). It consolidates the current state of research on TDDS for HCC treatment with NMMs and highlights the potential of these innovative approaches in improving treatment outcomes. Moreover, the review also identifies research gaps in the related fields to provide references for future targeted therapy research in HCC.

Effects of dietary Clostridium butyricum and rumen protected fat on meat quality, oxidative stability, and chemical composition of finishing goats.

BACKGROUND: Clostridium butyricum (CB) is a probiotic that can regulate intestinal microbial composition and improve meat quality. Rumen protected fat (RPF) has been shown to increase the dietary energy density and provide essential fatty acids. However, it is still unknown whether dietary supplementation with CB and RPF exerts beneficial effects on growth performance and nutritional value of goat meat. This study aimed to investigate the effects of dietary CB and RPF supplementation on growth performance, meat quality, oxidative stability, and meat nutritional value of finishing goats. Thirty-two goats (initial body weight, 20.5 ± 0.82 kg) were used in a completely randomized block design with a 2 RPF supplementation (0 vs. 30 g/d) × 2 CB supplementation (0 vs. 1.0 g/d) factorial treatment arrangement. The experiment included a 14-d adaptation and 70-d data and sample collection period. The goats were fed a diet consisted of 400 g/kg peanut seedling and 600 g/kg corn-based concentrate (dry matter basis). RESULT: Interaction between CB and RPF was rarely observed on the variables measured, except that shear force was reduced (P < 0.05) by adding CB or RPF alone or their combination; the increased intramuscular fat (IMF) content with adding RPF was more pronounced (P < 0.05) with CB than without CB addition. The pH24h (P = 0.009), a* values (P = 0.007), total antioxidant capacity (P = 0.050), glutathione peroxidase activities (P = 0.006), concentrations of 18:3 (P < 0.001), 20:5 (P = 0.003) and total polyunsaturated fatty acids (P = 0.048) were increased, whereas the L* values (P < 0.001), shear force (P = 0.050) and malondialdehyde content (P = 0.044) were decreased by adding CB. Furthermore, CB supplementation increased essential amino acid (P = 0.027), flavor amino acid (P = 0.010) and total amino acid contents (P = 0.024) as well as upregulated the expression of lipoprotein lipase (P = 0.034) and peroxisome proliferator-activated receptor γ (PPARγ) (P = 0.012), and downregulated the expression of stearoyl-CoA desaturase (SCD) (P = 0.034). The RPF supplementation increased dry matter intake (P = 0.005), averaged daily gain (trend, P = 0.058), hot carcass weight (P = 0.046), backfat thickness (P = 0.006), concentrations of 16:0 (P < 0.001) and c9-18:1 (P = 0.002), and decreased the shear force (P < 0.001), isoleucine (P = 0.049) and lysine content (P = 0.003) of meat. In addition, the expressions of acetyl-CoA carboxylase (P = 0.003), fatty acid synthase (P = 0.038), SCD (P < 0.001) and PPARγ (P = 0.022) were upregulated due to RPF supplementation, resulting in higher (P < 0.001) content of IMF. CONCLUSIONS: CB and RPF could be fed to goats for improving the growth performance, carcass traits and meat quality, and promote fat deposition by upregulating the expression of lipogenic genes of Longissimus thoracis muscle.

Continuous-Time Decision Transformer for Healthcare Applications.

Offline reinforcement learning (RL) is a promising approach for training intelligent medical agents to learn treatment policies and assist decision making in many healthcare applications, such as scheduling clinical visits and assigning dosages for patients with chronic conditions. In this paper, we investigate the potential usefulness of Decision Transformer (Chen et al., 2021)-a new offline RL paradigm-in medical domains where decision making in continuous time is desired. As Decision Transformer only handles discrete-time (or turn-based) sequential decision making scenarios, we generalize it to Continuous-Time Decision Transformer that not only considers the past clinical measurements and treatments but also the timings of previous visits, and learns to suggest the timings of future visits as well as the treatment plan at each visit. Extensive experiments on synthetic datasets and simulators motivated by real-world medical applications demonstrate that Continuous-Time Decision Transformer is able to outperform competitors and has clinical utility in terms of improving patients' health and prolonging their survival by learning high-performance policies from logged data generated using policies of different levels of quality.