Reversible Photochromic Phenomenon of Plasmonic Metal/Semiconductor Heterostructures via Photoinduced Electron Storage.

The transfer and migration process of the photogenerated charge carriers in plasmonic metal/semiconductor heterostructures not only affects their photocatalytic performance but also triggers some captivating phenomena. Here, a reversible photochromic behavior is observed on the Au/CdS heterostructures when they are investigated as photocatalysts for hydrogen production. The photochromism takes place upon excitation of the CdS component, in which the photogenerated holes are rapidly consumed by ethanol, while the electrons are transferred and stored on the Au cores, resulting in the blue shift of their localized surface plasmon resonance. The colloidal solution can restore its initial color after pumping with air, and the photochromic behavior can be cycled five times without obvious degradation. The finding represents great progress toward the photochromic mechanism of metal/semiconductor heterostructures and also reveals the importance of understanding the dynamic process of the photogenerated charge carriers in these heterostructures.

Tumor burden score and carcinoembryonic antigen predict outcomes in patients with intrahepatic cholangiocarcinoma following liver resection: a multi­institutional analysis.

BACKGROUND: The prognostic significance of tumor burden score (TBS) in relation to carcinoembryonic antigen (CEA) has not been investigated among patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC). This study aimed to develop and validate a simplified model, a combination of TBS and CEA (CTC grade), for predicting the long-term outcomes of postoperative ICC patients. METHODS: Patients who underwent curative - intent resection of ICC between 2011 and 2019 were identified from a large multi - institutional database. The impact of TBS, CEA, and the CTC grade on overall survival (OS) and recurrence - free survival (RFS) was evaluated in both the derivation and validation cohorts. The receiver operating characteristic curve was utilized for assessing the predictive accuracy of the model. Subgroup analyses were performed across 8th TNM stage system stratified by CTC grade to assess the discriminatory capacity within the same TNM stage. RESULTS: A total of 812 patients were included in the derivation cohort and 266 patients in the validation cohort. Survival varied based on CEA (low: 36.7% vs. high: 9.0%) and TBS (low: 40.3% vs. high: 17.6%) in relation to 5 - year survival (both p < 0.001). As expected, patients with low CTC grade (i.e., low TBS/low CEA) were associated with the best OS as well as RFS, while high CTC grade (i.e., high TBS/high CEA) correlated to the worst outcomes. The model exhibited well performance in both the derivation cohort (area under the curve of 0.694) and the validation cohort (0.664). The predictive efficacy of the CTC grade system remains consistently stable across TNM stages I and III/IV. CONCLUSION: The CTC grade, a composite parameter derived from the combination of TBS and CEA levels, served as an easy - to - use tool and performed well in stratifying patients with ICC relative to OS and RFS.

Prognostic implications of alpha-fetoprotein and C-reactive protein elevation in hepatocellular carcinoma following resection (PACE): a large cohort study of 2770 patients.

BACKGROUND: Routine clinical staging for hepatocellular carcinoma (HCC) incorporates liver function, general health, and tumor morphology. Further refinement of prognostic assessments and treatment decisions may benefit from the inclusion of tumor biological marker alpha-fetoprotein (AFP) and systemic inflammation indicator C-reactive protein (CRP). METHODS: Data from a multicenter cohort of 2770 HCC patients undergoing hepatectomy were analyzed. We developed the PACE risk score (Prognostic implications of AFP and CRP Elevation) after initially assessing preoperative AFP and CRP's prognostic value. Subgroup analyzes were performed in BCLC cohorts A and B using multivariable Cox analysis to evaluate the prognostic stratification ability of the PACE risk score and its complementary utility for BCLC staging. RESULTS: Preoperative AFP ≥ 400ng/mL and CRP ≥ 10 mg/L emerged as independent predictors of poorer prognosis in HCC patients who underwent hepatectomy, leading to the creation of the PACE risk score. PACE risk score stratified patients into low, intermediate, and high-risk groups with cumulative 5-year overall (OS) and recurrence-free survival (RFS) rates of 59.6%/44.9%, 43.9%/38.4%, and 20.6%/18.0% respectively (all P < 0.001). Increased PACE risk scores correlated significantly with early recurrence and extrahepatic metastases frequency (all P < 0.001). The multivariable analysis identified intermediate and high-risk PACE scores as independently correlating with poor postoperative OS and RFS. Furthermore, the PACE risk score proficiently stratified the prognosis of BCLC stages A and B patients, with multivariable analyses demonstrating it as an independent prognostic determinant for both stages. CONCLUSION: The PACE risk score serves as an effective tool for postoperative risk stratification, potentially supplementing the BCLC staging system.

Synthesis of mitochondria-targeted menadione cation derivatives: Inhibiting mitochondrial thioredoxin reductase (TrxR2) and inducing apoptosis in MGC-803 cells.

Menadione (VK3) is used as a powerful inducer of cellular reactive oxygen species (ROS) for many years and displays the high anti-cancer activities in vivo. Recently, the development of mitochondria-targeted drugs has been more and more appreciated. Here, the thirteen derivatives of VK3 were synthesized, which could localize in mitochondria by the triphenylphosphonium (TPP) cation or the nitrogen-based cation. The results of cytotoxicity from six human cancer cell lines showed that the targeted compounds T1-T13 displayed higher activity than VK3 with the average IC50 value around 1 µM. The results of cytotoxicity indicated that the substitutes on C-2, the linear alkyl chains on C-3 and cation moiety all could affect the cytotoxicity. The mechanistic studies showed that five representative compounds (T2, T3, T5, T8 and T13) could localize in cellular mitochondria, elicit ROS burst and collapse mitochondrial membrane potential (ΔΨm), leading to cytochrome C release and apoptosis in MGC-803 cells. Particularly, they could obviously inhibit mitochondrial thioredoxin reductase TrxR2 expression, thus leading to aggravate cellular oxidative stress.

Synthesis of mitochondria-targeted ferulic acid amide derivatives with antioxidant, anti-inflammatory activities and inducing mitophagy.

The seventeen ferulic acid amide derivatives were synthesized by coupling mitochondrial carrier coumarin-3-carboxamide with acrylic acids. The results of cellular antioxidant activity and inhibitory effects on NO production against LPS-stimulated RAW264.7 macrophages indicated four compounds (8c, 8d, 9c, 9d) showed the higher dual-activities of antioxidant and anti-inflammatory. The structure-activity relationship was deduced. In regard to mechanism research, the most potent compound 8d which mainly distributed in mitochondria suppressed the secretion of inflammatory cytokines IL-6 and TNF-α, enhancing mitophagy to alleviate inflammatory response. Besides, the dual-activities were diminished by removal of coumarin carrier in 8d, suggesting the enrichment in mitochondria might be important for activities. This study showed that development of mitochondria-targeted antioxidants could be a feasible strategy to resist inflammation.

Feedforward Control of Piezoelectric Ceramic Actuators Based on PEA-RNN.

Multilayer perceptron (MLP) has been demonstrated to implement feedforward control of the piezoelectric actuator (PEA). To further improve the control accuracy of the neural network, reduce the training time, and explore the possibility of online model updating, a novel recurrent neural network named PEA-RNN is established in this paper. PEA-RNN is a three-input, one-output neural network, including one gated recurrent unit (GRU) layer, seven linear layers, and one residual connection in the linear layers. The experimental results show that the displacement linearity error of piezoelectric ceramics reaches 8.96 µm in the open-loop condition. After using PEA-RNN compensation, the maximum displacement error of piezoelectric ceramics is reduced to 0.465 µm at the operating frequency of 10 Hz, which proves that PEA-RNN can accurately compensate piezoelectric ceramics' dynamic hysteresis nonlinearity. At the same time, the training epochs of PEA-RNN are only 5% of the MLP, and fewer training epochs provide the possibility to realize online updates of the model in the future.

Circ_0084043 Facilitates High Glucose-Induced Retinal Pigment Epithelial Cell Injury by Activating miR-128-3p/TXNIP-Mediated Wnt/ß-Catenin Signaling Pathway.

ABSTRACT: Diabetic retinopathy is a frequent complication of diabetes mellitus and one of the common causes of blindness. Circular RNAs (circRNAs) can modulate various biological behaviors of human diseases. Circ_0084043 is a novel circRNA, and its function in diabetic retinopathy progression is unclear. Adult retinal pigment epithelial cells (ARPE-19) were treated with high glucose (HG). RNA levels of circ_0084043, microRNA-128-3p (miR-128-3p), and thioredoxin-interacting protein (TXNIP) were detected by quantitative real-time polymerase chain reaction. 3-(4, 5-dimethylthiazole-2-y1)-2, 5-diphenyl tetrazolium bromide and flow cytometry were, respectively, used to examine cell viability and apoptosis. Apoptotic and TNXIP relative protein levels were measured by Western blot. The combination between targets was analyzed through dual-luciferase reporter assay or RNA immunoprecipitation assay. Results showed that HG induced the upregulation of circ_0084043 and the downregulation of miR-128-3p in ARPE-19 cells. Circ_0084043 knockdown or miR-128-3p overexpression mitigated the HG-mediated cell viability inhibition, apoptosis promotion, and inflammatory response. Circ_0084043 targeted miR-128-3p and miR-128-3p inhibitor returned the regulation of si-circ_0084043 in HG-treated cells. TXNIP was the target gene of miR-128-3p and TXNIP overexpression abolished the miR-128-3p-mediated effects after HG treatment. Circ_0084043 regulated the TXNIP expression to activate Wnt/ß-catenin signal pathway by targeting miR-128-3p. Our findings unraveled that circ_0084043 promoted the HG-induced retinal pigment epithelial cell injury through activating the Wnt/ß-catenin signal pathway by the miR-128-3p/TXNIP axis. Circ_0084043 might be an available biomarker in diabetic retinopathy diagnosis and therapy.

Synthesis of mitochondria-targeted coumarin-3-carboxamide fluorescent derivatives: Inhibiting mitochondrial TrxR2 and cell proliferation on breast cancer cells.

Targeting specific mitochondrial alterations to kill cancer cells without affecting their normal counterparts emerges as a feasible strategy. Coumarin derivatives have demonstrated the potential anti-breast cancer activities. By coupling coumarin-3-carboxamide derivatives with mitochondria carrier triphenylphosphonium, mitocoumarins 15a-c were produced and tested as the anti-breast cancer fluorescence agents. Among them, 15b as the amide-based drug potently suppressed the cell growth in MCF-7, MDA-231, SK-BR-3 breast cancer cells with the IC50 values from 3.0 to 4.1 µM, including the lower cytotoxicity to normal MCF-10A cells with the IC50 value around 45.30 ± 2.45 µM. In mechanistic study for 15b in MDA-MB-231 cells, it could localize in mitochondria to elicit ROS burst and collapse Δψm. Besides, it could deplete GSH by an irreversible alkylation process and moderately inhibit mitochondrial thioredoxin reductase TrxR2, thus leading to aggravate cellular oxidative stress. This study reported 15b might be useful for the further development into a mitochondria-targeted anti-triple negative breast cancer drug.

Inhibition of TIM-4 protects against cerebral ischaemia-reperfusion injury.

TIM-4 plays an important role in ischaemia-reperfusion injury of liver and kidney; however, the effects of TIM-4 on cerebral ischaemia-reperfusion injury (IRI) are unknown. The purpose of the present study was to investigate the potential role of TIM-4 in experimental brain ischaemia-reperfusion injury. In this study, cerebral ischaemia reperfusion was induced by transient middle cerebral artery occlusion (MCAO) for 1 hour in C57/BL6 mice. The TIM-4 expression was detected in vivo or vitro by real-time quantitative polymerase chain reaction, Western blot and flow cytometric analysis. In vivo, the administration of anti-TIM-4 antibodies significantly suppressed apoptosis, inhibited inflammatory cells and enhanced anti-inflammatory responses. In vitro, activated microglia exhibited reduced cellular proliferation and induced IRI injury when co-cultured with neurons; these effects were inhibited by anti-TIM-4 antibody treatment. Similarly, microglia transfected with TIM-4 siRNA and stimulated by LPS + IFN-γ alleviated the TIM-4-mediated damage to neurons. Collectively, our data indicate that the inhibition of TIM-4 can improve the inflammatory response and exerts a protective effect in cerebral ischaemia-reperfusion injury.

Highly Branched Gradient Glycopolymer: Enzyme-Assisted Synthesis and Enhanced Bacteria-Binding Ability.

A one-pot strategy was applied to synchronize enzymatic monomer transformation with reversible addition fragmentation chain transfer (RAFT) polymerization for the synthesis of glycopolymers with highly branched gradient architectures. Also, the linear analogues, block glycopolymers, and gradient glycopolymers were also synthesized for comparison. The binding ability of glycopolymers toward bacteria was then studied by optical density (OD) test, confocal laser scanning microscopy (CLSM), and quartz crystal microbalance with dissipation (QCM-D). The results show that the highly branched gradient glycopolymers have the most remarkable bacteria-binding ability compared with the two linear analogues, gradient glycopolymers, and block glycopolymers. The highly branched glycopolymers were further used as inhibitors in the anti-infection test, demonstrating a significant inhibitory effect on preventing bacteria from infecting the cells.

Ultralow Crosslinked Microgel Brings Ultrahigh Catalytic Efficiency.

Microgel nanoreactors maintain the stability of metallic nanoparticles and regulate their catalytic activity. However, limited by the synthetic method, the recycling ability and long-lasting stability of microgel nanoreactors are challenged. Herein, a brand-new nanoparticle carrier, ultralow crosslinked poly(N-isopropylacrylamide-b-methacrylic acid) (P(NIPAm-b-MAA)) microgel, is synthesized based on the reversible addition-fragmentation chain transfer polymerization method and the self-crosslinking mechanism of PNIPAm. This carrier enables the easy preparation, low cost, long-lasting stability, and high catalytic efficiency of nanoreactors. As far as it is known, the catalytic reduction rates of several dye models used in this work are the highest ones in similar systems. In addition, the presence of the MAA block leads to the agglomeration and dispersion of the microgels under different pH conditions, thus realizing rapid recycling of the nanoreactors. This novel carrier has great potential for a wide range of applications in catalysis.

Confined-walking mode for an elliptical polarized undulator and its application.

Elliptical polarized undulators (EPUs) are broadly used in the soft X-ray energy range. They have the advantage of providing photons with both varied energy and polarization through adjustments to the value of the gap and/or shift magnet arrays in an undulator. Yet these adjustments may create a disturbance on the stability of the electron beam in a storage ring. To correct such a disturbance, it is necessary to establish a feed-forward table of key nodes in the gap-shift-defined two-dimensional parameter space. Such a table can only be scanned during machine-study time. For a free-walking mode, whereby an undulator is allowed to manoeuvre in the whole gap-shift space, all the key nodes need to be scanned at the expense of a large amount of machine-study time. This will greatly delay the employment of a full-polarization capable undulator (especially circularly polarized). By analyzing data-collecting patterns of user experiments, this paper defines a reduced set of key nodes in gap-shift parameter space, with the number of key nodes to be scanned for feed-forwarding scaled down to one-third of the original; and introduces a new walking mode for EPUs: confined-walking mode, whereby the undulator is manoeuvred only within the reduced set of key nodes. Such a mode is firstly realized on the EPUs at the DREAMLINE beamline at Shanghai Synchrotron Radiation Facility (SSRF). Under confined-walking mode, the undulator movements are stable and there is no obvious disturbance to the electron beam with the feed-forward system in operation. Successful experiments have been carried out using the circularly polarized light obtained via the new walking mode. This mode is expected to be applied to future EPUs at SSRF with the increasing requirements for various polarization modes.

[Roles and mechanism of microRNAs in the regulation of skeletal muscle insulin resistance].

Insulin resistance is a common pathophysiological mechanism of obesity and type 2 diabetes mellitus. Skeletal muscle is one of the major target organs of insulin-mediated glucose uptake, metabolism and utilization, and it is the earliest and most important site of insulin resistance. Studies have shown that the impairments of glucose uptake, insulin signaling pathway and mitochondrial biosynthesis are closely related to skeletal muscle insulin resistance. When insulin resistance develops in skeletal muscle, multiple microRNAs (miRNAs) are up-regulated (miR-106b, miR-23a, miR-761, miR-135a, Let-7 and miR-29a) or down-regulated (miR-133a, miR-149 and miR-1). They participate in the regulation of skeletal muscle glucose uptake, insulin signaling pathway and mitochondrial biogenesis, and thus play important roles in the occurrence and development of skeletal muscle insulin resistance. Therefore, these miRNAs may serve as potential targets for the treatment of skeletal muscle insulin resistance or diabetes.

[Signaling pathways controlling skeletal muscle mass].

The skeletal muscle mass accounts for more than 40% of the body weight of healthy adults. The skeletal muscle not only plays an important role in physical activities but also affects the function of other organs as a secretory organ secreting multiple muscle factors. Therefore, it is important to maintain the normal quantity and function of skeletal muscle. Skeletal muscle mass is the basis of skeletal muscle function and is often affected by many factors such as exercise and disease. Resistance exercise training induces increased protein synthesis in skeletal muscle cells, while limb disuse, chronic obstructive pulmonary disease, heart failure, chronic kidney disease, cachexia, Duchenne muscular dystrophy and many other pathological conditions lead to decreased protein synthesis or enhanced protein degradation of skeletal muscle cells. The process of skeletal muscle hypertrophy involves changes in multiple signaling pathways, such as IGF-1/PI3K/Akt, myostatin and G protein. On the other hand, activations of the ubiquitin-proteasome system, IGF-1/Akt/FoxO, autophagy-lysosomal pathway, NF-κB, and the glucocorticoid-mediated signaling pathways play important roles in regulating muscle atrophy. These signaling pathways regulate skeletal muscle mass and are modulated by some different conditions. This review briefly summarizes the signaling pathways of skeletal muscle mass control.

High speed and small footprint silicon micro-ring modulator assembly for space-division-multiplexed 100-Gbps optical interconnection.

We designed and fabricated a 4-channel silicon micro-ring modulator (MRM) assembly chip with arrayed grating couplers for space-division-multiplexed optical interconnection. Only 4 channels out of 7 have been utilized with the consideration of popular multi-source-agreements (MSA) compatibility with respect to a 7-core multi-core-fiber (MCF). Experimental modulations at 10, 15, 20 and 25 Gbps have been carried out for all the four channels with clearly opened eye-diagrams which indicates a single-fiber aggregate capacity of 100 Gbps with only one laser input for SDM optical interconnection. The silicon MRM assembly demonstrated in this work is advantageous for practical applications due to its simplified modulation solution (NRZ-OOK) with high capacity (100-Gbps), small footprint (0.45 mm2) and long reach (1 km).

Target ROS to induce apoptosis and cell cycle arrest by 5,7-dimethoxy-1,4-naphthoquinone derivative.

The 1,4-naphthoquinone derivatives bearing 5,7-dimethoxyl moiety were designed, synthesized, and tested as the antitumor agents against five human cancer cell lines (A549, Hela, HepG2, NCI-H460 and HL-60). All the compounds are described herein for the first time. The structure-activity relationships indicated that the presence of chlorine atom at the 2-position was crucial for the antiproliferative activity. Further, the electrochemical properties of the representative compounds (7e, 8e and 9e) were evaluated and a definite correlation between the redox potential and the antiproliferative activity. The most potent compound 9e displayed significant anti-leukemic activity with IC50 value of 3.8 µM in HL-60 cells and weak cytotoxicity with IC50 of 40.7 µM in normal cells WI-38. In mechanistic study for 9e, the increased numbers of apoptotic cells and increased cell population at G2/M phase correlated with ROS generation. Together, our results suggested that the derivatives of 2-chlorine-1,4-naphthoquinone might be the promising candidates for the treatment of promyelocytic leukemia.

Anti-acute myeloid leukemia activity of 2-chloro-3-alkyl-1,4-naphthoquinone derivatives through inducing mtDNA damage and GSH depletion.

2-Chloro-3-alkyl-1,4-naphthoquinone derivatives were synthesized and tested as the anti-acute myeloid leukaemia agents. The compound 9b (2-chloro-3-ethyl-5,6,7-trimethoxy-1,4-naphthoquinone) was the most potent toward HL-60 leukaemia cells. In mechanistic study for 9b, the protein levels of mtDNA-specific DNA polymerase γ (poly-γ) and mtDNA transcription factor A (mt-TFA) were decreased after the 24 h treatment, showing the occurrence of mtDNA damage. And 9b triggered cell cycle arrest at S phase accompanied by a secondary block in G2/M phase which had a direct link to the process of mtDNA damage. The dissipations of mitochondrial membrane potential and ATP also proceeded. On the other hand, 9b promoted the generation of ROS and resulted in the oxidation of intracellular GSH to GSSG. This process was coupled to the formation of adduct between 9b and GSH, detected by the UV-Vis spectrum and HRMS analysis. Depletion of GSH by buthionine sulfoximine enhanced ROS level and produced higher cytotoxicity, suggesting GSH was involved in the anti-leukemic mechanism of 9b. Together, our results provide new insights on the molecular mechanism of the derivatives of 2-chloro-1,4-naphthoquinone and 9b might be useful for the further development into an anti-leukemia agent.

[Fat deposition in skeletal muscle and its regulation].

Under normal condition, there are a few lipid droplets in skeletal muscle. But in skeletal muscle acute injury, muscular dystrophy, muscle atrophy, obesity, diabetes and other pathological conditions, the fat deposition in skeletal muscle increases, which implicate that the fat deposition may play an important role in the pathogenesis of these diseases. However, the mechanisms of development and regulation of fat deposition in skeletal muscle are not clear. Clarifying the key signaling pathways and regulatory factors that affect fat deposition in skeletal muscle, and exploring new ways to improve the fat deposition in skeletal muscle will not only help to deepen our understanding of the pathogenesis of these diseases, but also provide new ideas for the treatment of these diseases. This paper reviews the research progresses and main mechanisms of fat deposition in skeletal muscle.

Molecular mechanism of R-bicalutamide switching from androgen receptor antagonist to agonist induced by amino acid mutations using molecular dynamics simulations and free energy calculation.

R-bicalutamide, a first generation antiandrogen, was used to treat prostate cancer for decades. Although it is very effective at the beginning, resistance appears after 2-3 years of treatment. Mutation of androgen receptor (AR) is considered a main reason for drug resistance. It is reported that AR W741C, W741L, W741C_T877A, T877A, F876L, F876L_T877A and L701H mutations can convert R-bicalutamide from AR antagonist to agonist, but the switching mechanisms are not clear. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to analyze the interaction mechanisms between R-bicalutamide and wild type/mutant ARs. The results indicate that helix H12, which lies on the top of AR LBD like a cover, plays a vital role in R-bicalutamide binding. When interacting with AR, the B-ring of R-bicalutamide pushes H12 aside, distorting the coactivator binding site (AF2) resulting in the inactivation of transcription. Several residue mutations appear to enlarge the distance between the B-ring of R-bicalutamide and H12, reducing steric clash, which is conducive to a closed H12 conformation, leading to the formation of the coactivator binding site AF2 and increased transcription. Hydrogen bond and per-residue free energy decomposition analyses are also investigated to explore the interacting mechanisms, and M895 is found to be a key residue in the antagonist mechanism. The obtained molecular mechanisms will aid rational screening and design of novel AR antagonists, even to mutant AR.

[The Role of Hepatocyte Growth Factor in Keletal Muscle Regeneration]

Skeletal muscle repair after injury includes three stages which are inflammation, repair and tissue remodeling. The ability of Skeletal muscle to regenerate in response to injury is solely dependen on the activation, proliferation and differentiation of satellite cells. After skeletal muscle injury, hepatocyte growth factor (HGF) can regular muscle satellite cell function in the manner of autocrine, paracrine or endocrine, thus affecting the regeneration of damaged skeletal muscle. Studies about the mechanism have shown that HGF may bind to its receptor, e-met, to start the relevant signaling pathways involved in skeletal muscle satellite cell activation, proliferation, differentiation and migration, which affects skeletal muscle regeneration process.