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Background: Bone loss is the most common reason for broken bones among the elderly. An ideal agent for the treatment of bone loss should have both osteoclast inhibitory and osteoblast stimulatory functions. Leucine-rich repeat kinase 1 (LRRK1) is a novel target for alternative antiresorptive drugs to treat osteoporosis and osteoporotic fractures. Recently a chemical IN04, Methyl 3-[(([5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-thio-acetyl)-amino]-benzoate, has been identified as a potential LRRK1 inhibitor. Objective: The aim of this work is to investigate how the chemical IN04 interacts with LRRK1 and inhibits its activity. Methods: A structural model of the LRRK1 kinase domain was constructed with SWISS-MODEL. The human protein kinase ROCO4 (PDB ID: 4YZN) was chosen as the template based on sequence homology, structural and phylogenetic analysis. In addition, a homology model of the LRRK1 ROC domain was also prepared based on the LRRK2 ROC domain structure (PDB ID: 2ZEJ). The interactions of IN04 with the active sites in the LRRK1 kinase domain and ROC domain were investigated by SwissDock. Results: IN04 was docked into the active site of the LRRK1 kinase domain with similar interactions as ATP comparable to the ligand bound to homologous kinases. Many rational binding modes of IN04 to LRRK1 kinase domain were investigated and the most likely binding pose containing multiple hydrogen bonds and a salt bridge was discovered. However, IN04 cannot fit into the GDP-binding site of the ROC domain. Conclusion: Chemical IN04 inhibits LRRK1 by binding to the active site of the kinase domain but not the ROC domain.

Antibiotic and antimicrobial resistance is a continually growing challenge in the treatment of various bacterial infections worldwide. New drugs and new drug targets are necessary to curb the threat of infectious diseases caused by multidrug-resistant pathogens. The tryptophan biosynthesis pathway is essential for bacterial growth but is absent in higher animals and humans. Drugs that can inhibit the bacterial biosynthesis of tryptophan offer a new class of antibiotics. In this work, we combined a structure-based strategy using in silico docking screening and molecular dynamics (MD) simulations to identify compounds targeting the α subunit of tryptophan synthase with experimental methods involving the whole-cell minimum inhibitory concentration (MIC) test, solution state NMR, and crystallography to confirm the inhibition of L-tryptophan biosynthesis. Screening 1800 compounds from the National Cancer Institute Diversity Set I against α subunit revealed 28 compounds for experimental validation; four of the 28 hit compounds showed promising activity in MIC testing. We performed solution state NMR experiments to demonstrate that Compound 1 binds to the α subunit. We also report a crystal structure of Salmonella enterica serotype Typhimurium tryptophan synthase in complex with one successful inhibitor, 3-amino-3-imino-2-phenyldiazenylpropanamide (Compound 1) which revealed a binding site at the αβ interface of the dimeric enzyme. MD simulations were carried out to examine two binding sites for the compound. Our results show that this small molecule inhibitor could be a promising lead for future drug development. This article is protected by copyright. All rights reserved.

Mitochondrial membrane potential (ΔΨm) is a key indicator of cell health or injury due to its vital roles in adenosine 5'-triphosphate synthesis. Thus, monitoring ΔΨm is of great significance for the assessment of cell status, diagnosis of diseases, and medicament screening. Cationic fluorescent probes suffer from severe photobleaching or false positive signals due to the luminescence of the probe on non-mitochondria. Herein, we report a lipophilic cationic fluorescent probe [1-methyl-2-(4-(1,2,2-triphenylvinyl)styryl)-β-naphthothiazol-1-ium trifluoromethanesulfonate (TPE-NT)] with the features of aggregation-induced emission and intramolecular charge transfer for imaging ΔΨm in live cells. TPE-NT is enriched on the surface of the mitochondrial inner membrane due to the negative ΔΨm, and its fluorescence is activated in the high-viscosity microenvironment. The false positive signals of emission from TPE-NT on non-mitochondria are therefore effectively eliminated. Moreover, TPE-NT exhibits a Stokes shift of >200 nm, near-infrared (∼675 nm) emission, excellent photostability, and low cytotoxicity, which facilitate real-time imaging in live cells. Cell imaging confirmed that the probe can rapidly and reliably report mitochondrial depolarization (decrement of ΔΨm) during cell damage caused by CCCP and H2O2 as well as mitochondrial polarization (increment of ΔΨm) by oligomycin. Furthermore, the probe successfully detected the reduction of ΔΨm in these cell models of hypoxia, heat damage, acidification, aging, inflammation, mitophagy, and apoptosis caused by hypoxia, heatstroke, lactate/pyruvate, doxorubicin, lipopolysaccharide, rapamycin, monensin, and nystatin, respectively.

In the past few years, the all-solid lithium battery has attracted worldwide attentions, the ionic conductivity of some all-solid lithium-ion batteries has reached 10−3–10−2 S/cm, indicating that the transport of lithium ions in solid electrolytes is no longer a major problem. However, some interface issues become research hotspots. Examples of these interfacial issues include the electrochemical decomposition reaction at the electrode-electrolyte interface; the low effective contact area between the solid electrolyte and the electrode etc. In order to solve the issues, researchers have pursued many different approaches. The addition of a buffer layer between the electrode and the solid electrolyte has been at the center of this endeavor. In this review paper, we provide a systematic summarization of the problems on the electrode-solid electrolyte interface and detailed reflection on the latest works of buffer-based therapies, and the review will end with a personal perspective on the improvement of buffer-based therapies.

The wear and corrosion resistance of Ni-based niobium carbide (NbC) coatings were investigated via scanning electron microscopy, energy dispersive spectrometry, particle size analysis, X-ray diffraction, electrochemical polarization, electrochemicl impedance spectroscopy, digital microhardness testing and wear testing. The results showed that the substrate was mainly composed of a γ-Cr (Fe) solid solution, and the composite coating was composed of FeNi, NbC, and Ni. In addition, the hardness of the coating increased gradually with increasing NbC content. The optimal corrosion resistance and wear resistance of the coating were realized at an NbC content of 20%.

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

Exosomes derived from cancer cells have emerged as important mediators of malignant phenotypes of tumors, being involved in the transmission of biological signals between cells. Herein, we intended to clarify the role of exosome-mediated transfer of oncogenic microRNA-27a (miR-27a) in angiogenesis of renal clear cell carcinoma (RCCC). Through bioinformatics analysis, we identified the differentially expressed genes of RCCC and predicted miRNAs targeting SFRP1. We manipulated the expression of miR-27a and/or SFRP1 in RCCC cells to explore their roles in angiogenesis through Cell Counting Kit-8 (CCK-8), Transwell, and Matrigel tubule formation assays. miR-27a loaded in exosomes was overexpressed and downregulated in vitro and in vivo to verify its effect on angiogenesis. SFRP1 was poorly expressed and miR-27a was highly expressed in RCCC tissues, showing a negative correlation. Dual-luciferase assay verified that miR-27a targeted and downregulated SFRP1 expression. Notably, miR-27a enhanced angiogenesis by downregulating SFRP1 expression. miR-27a-loaded exosomes can be delivered from RCCC cells to human umbilical vein endothelial cells (HUVECs). In vitro and in vivo experiments substantiated that miR-27a-loaded exosomes from RCCC cells repressed SFRP1, augmenting the viability, migration, and angiogenesis of RCCC cells. Together, RCCC-derived miR-27a-loaded exosomes inhibit SFRP1 expression and accelerate tumor angiogenesis in RCCC., Graphical Abstract, Renal clear cell carcinoma cell-derived exosomal miR-27a shuttled into human umbilical vein endothelial cells binds to and suppresses SFRP1 expression, thereby inhibiting angiogenesis and ultimately tumor growth.

Elucidating the intrinsic relationship between diseases and lipid droplet (LD) polarity remains a great challenge owing to the lack of the research on multiple disease models. Until now, the visualization of abnormal LD polarity in models of inflammation and clinical cancer patient samples has not been achieved. To meet the urgent challenge, we facilely synthesized a robust LD-specific and polarity-sensitive fluorescent probe (LD-TTP), which consists of a triphenylamine segment as an electron-donor group (D) and a pyridinium as an electron-acceptor moiety (A), forming a typical D-π-A molecular configuration. Owing to the unique intramolecular charge transfer effect, LD-TTP exhibits high sensitivity to polarity change in the linear range from Δf = 0.258 to 0.312, with over 278-fold fluorescence enhancement. Moreover, we revealed that LD-TTP possessed satisfactory ability for sensitively monitoring LD-polarity changes in living cells. Using LD-TTP, we first demonstrated the detection of LD-polarity changes in fatty liver tissues and inflammatory living mice via confocal laser scanning fluorescence imaging. Surprisingly, the visualization of LD polarity has been achieved not only at the cellular levels and living organs but also in surgical specimens from cancer patients, thus holding great potential in the clinical diagnosis of human cancer. All these features render LD-TTP an effective tool for medical diagnosis of LD polarity-related diseases.

Heat stroke is a fatal condition which usually results in central nervous system dysfunction, organism damage and even death. The relationship between heat stroke and mitochondria is still relatively unknown due to a lack of suitable tools. Herein, an aggregation-induced emission (AIE) probe CSP, by introducing a pyridinium cation as the mitochondria-targeted group to an AIE active core cyanostilbene skeleton, is highly sensitive to viscosity changes due to the restriction of intramolecular motion (RIM) and inhibition of twisted intramolecular charge transfer (TICT) in high-viscosity systems. As expected, with the viscosity increasing from 0.903 cP (0% glycerol) to 965 cP (99% glycerol), CSP exhibited a significant enhancement (more than 117-fold) in fluorescence intensity at 625 nm, with an excellent linear relationship between log I 625 nm and log η (R2 = 0.9869, slope as high as 0.6727). More importantly, using CSP we have successfully monitored the decreased mitochondrial viscosity during heat stroke for the first time. All these features render the probe a promising candidate for further understanding the mechanism underlying mitochondria-associated heat stroke.

Supramolecular drug self-delivery systems (SDSDSs) involving active drugs as building blocks linked by supramolecular interactions have been well defined as an advanced chemotherapy strategy. However, the lack of detecting release of drugs from SDSDSs at specific tumor sites inevitably leads to unsatisfactory therapeutic effects, owing to the lack of information regarding the administration of these drugs. In this work, predesigned platinum-containing supramolecular drug self-delivery nanomicelles (SDSDNMs) were employed to synchronously realize drug monitoring by computed tomography imaging, immediately reflecting the evolution of drug release and real-time treatment at the tumor site. The appropriate administration dosage (1.2 mg mL-1,100 μL) and the injection interval (once every 3 days) needed to guide the antitumor activity of SDSDNMs were then defined, thereby attaining the aim of efficient synergistic combination chemotherapy. In vivo tumor inhibition and histological analyses showed that SDSDNMs exhibited a strong tumor inhibition effect and good safety with respect to normal organs. Such a supramolecular drug self-delivery strategy with monitored functions may offer new potential opportunities for application in the field of synergistic combination chemotherapy.

In the current work, cost-effective, high efficiency, eco-friendly and biodegradable absorption adsorbents were prepared by loading rhodamine onto the surface of poly (butylene succinate) (PBS) electrostatic spinning film for the water purification. The adsorbability to heavy metal ions (such as: Hg(II) and Ag(I)) and dyes (such as: Congo red(CR), Crystal violet(CV)) were investigated. After the coating, it was found that PBS fibrous membranes exhibited better adsorption capacity toward these metal ions and dyes. Based on surface complex and electrostatic interaction mechanisms, the maximum adsorption capacity of Hg(II), Ag(I) CR and CV were 122.3, 91.2 138.5 and 109.4 mg/g respectively. Then the dynamic adsorption was tested of CR and CV by the suction filter, and the adsorption capacity of CR and CV were 111.2 and 83.0 mg/g within 10 s. What’s more, studies on adsorption kinetics and adsorption isotherms showed that the adsorption behavior of the modified PBS fibrous membrane could be well described by the pseudo second-order model, which means the adsorption process transform from physical adsorption (pure PBS) to chemisorptions (rhodamine/PBS). This study provides the eco-friendly method to fabricate polymer adsorbent to remove heavy metal ions and organic dyes from wastewater.

In this study, three series of quinazolinone derivatives containing hydrazone structures were designed and synthesized. Bioactivity assays indicated that these compounds showed good antitumour activities towards human lung cancer cells (A549) and human prostate cancer cells (PC-3) and no apparent toxicity towards those nontumorigenic rat renal tubular epithelial cells (NRK-52E). In particular, compound 7n showed potent inhibitory activity towards A549 and PC-3 with IC50 of 7.36 and 7.73 μmol L−1, respectively. Subsequently, the relationships between the compound structures and numerous biological activities are discussed. A good predictive three-dimensional quantitative structure–activity relationship (3D-QSAR) model was constructed via CoMFA to direct the future structural units. The present results strongly show that 7n with the introduction of 2-fluorobenzoyl should be considered as a lead compound to develop novel antitumour agents.

Objective To reduce the toxicity and side effects of arsenic trioxide (ATO) and provide a new approach for the treatment of primary liver cancer, a folic acid-modified calcium arsenite liposomal “target-controlled” drug delivery system (FA-LP-CaAs) was fabricated using the reverse microemulsion method. Methods A Malvern particle size analyzer and a transmission electron microscope were employed to determine the particle size, distribution, zeta potential and morphology of FA-LP-CaAs. Further, inductively coupled plasma emission spectrometry was employed to determine the drug loading capacity, entrapment efficiency, and in vitro release behavior of FA-LP-CaAs. To determine its toxicity in human hepatoma cells (HepG2) and human normal hepatocytes (LO2) and its effect on HepG2 cell cycle and apoptosis, the MTT method was used. Laser confocal and flow cytometry were also employed to determine the uptake of FA-LP-CaAs by cells. After establishing a mouse liver cancer model, the in vivo distribution of the drug included in the formulation was investigated using in vivo fluorescence. To evaluate the liver cancer targeting and anti-tumor effects of FA-LP-CaAs in vivo, the distribution of ATO in tissues and changes in tumor volume and body weight after liposomal administration were investigated using hematoxylin-eosin (HE)-stained tumor sections. Results The particle size, zeta potential and PDI of FA-LP-CaAs were (122.67 ± 2.18) nm, (12.81 ± 0.75) mV and 0.22 ± 0.01, respectively, while its drug loading capacity was 18.49% ± 1.14%. In vitro experimental results revealed that FA-LP-CaAs had a strong killing effect on HepG2 cells. Further, the cell uptake capacity of this formulation was found to improve. Based on in vivo assessments, FA-LP-CaAs could significantly increase the distribution of ATO in tumor sites and inhibit tumor growth. Conclusions Herein, an FA-LP-CaAs formulation was successfully fabricated. This liposomal drug delivery system had a round appearance, uniform particle size, good polydispersity coeffi-cient, evident “core-shell” structure, high drug loading capacity and pH response, tumor targeted drug delivery and sustained drug release. These findings support further research and the application of ATO as an anti-liver cancer prodrug and provide a new method for the treatment of liver cancer.

Background. Colitis-associated colorectal cancer (CAC) develops from active colonic inflammation, which is characterized by the production of proinflammatory cytokines that can induce mutations. IL-6 is produced by multiple cell types located within the tumor microenvironment including tumor-infiltrating immune cells, stromal cells, and the tumor cells themselves. The aim of our study was to explore the mechanism of Feng-Liao-Chang-Wei-Kang (FLCWK) and 5-fluorouracil (5-FU) in treating CAC. Method. HCT116 cells were treated with 5-FU in the absence or presence of FLCWK. Cell proliferation was assayed by MTT assays. Apoptosis and the cell cycle phases were detected by flow cytometry. Western blotting and Q-PCR assays were used to detect the expression levels of proteins and genes related to the IL-6/STAT3 signalling pathway. A mouse model for CAC was established by treating animals with 12.5 mg/kg azoxymethane (AOM) followed by 3 cycles of 2.5% dextran sodium sulphate (DSS). The associated pathological changes were determined after haematoxylin and eosin (H&E) staining. The expression of related proteins and genes in various tissues was examined using immunofluorescence techniques. Results. FLCWK enhanced the ability of 5-FU to promote apoptosis by inhibiting the proliferation of HCT116 cells and blocking the IL-6/STAT3 pathway. FLCWK combined with 5-FU reduced the number and size of colon tumors in mice with CAC and significantly increased their survival rate. In the CAC model, FLCWK synergized with 5-FU to inhibit the phosphorylation of STAT3, preventing IL-6/STAT3 signal transduction and thus further inducing apoptosis and inhibition of colon cancer cell proliferation. Conclusion. FLCWK can inhibit the activation of STAT3 by reducing the production of IL-6, thereby increasing the occurrence of colitis-related colorectal cancer with 5-FU.

Nucleotide excision repair (NER) removes various DNA lesions caused by UV light and chemical carcinogens. The DNA helicase XPB plays a key role in DNA opening and coordinating damage incision by nucleases during NER, but the underlying mechanisms remain unclear. Here, we report crystal structures of XPB from Sulfurisphaera tokodaii (St) bound to the nuclease Bax1 and their complex with a bubble DNA having one arm unwound in the crystal. StXPB and Bax1 together spirally encircle 10 base pairs of duplex DNA at the double-/single-stranded (ds–ss) junction. Furthermore, StXPB has its ThM motif intruding between the two DNA strands and gripping the 3′-overhang while Bax1 interacts with the 5′-overhang. This ternary complex likely reflects the state of repair bubble extension by the XPB and nuclease machine. ATP binding and hydrolysis by StXPB could lead to a spiral translocation along dsDNA and DNA strand separation by the ThM motif, revealing an unconventional DNA unwinding mechanism. Interestingly, the DNA is kept away from the nuclease domain of Bax1, potentially preventing DNA incision by Bax1 during repair bubble extension.

Lithium sulfur battery (LSB) is widely considered as a next-generation battery system due to its high theoretical energy density of 2567 Wh kg−1. However, several inherent issues obstruct the business application of LSB. To address these issues, we assemble core–shell structure Fe3O4@C nanodots with 5 nm diameter as a valid sulfur host via a convenient organic pyrolysis treatment followed by calcination. The nanosized Fe3O4 particles could expose more chemisorption sites and inhibit the polysulfides shuttle. Moreover, the carbon layer could not only increase the conductivity but also ensure structural integrity during cyclic process. Furthermore, the mesoporous channels around Fe3O4@C could supply sufficient space to load sulfur and physically restrict the shuttle of polysulfides. Thus, the resultant S/Fe3O4@C cathode shows a highly initial capacity of 1089 mAh g−1 at 0.2 C, even retains 655 mAh g−1 over 200 cycles at 1 C.

An l -cysteine-bioinspired calcium phosphate (Ca-P) coating is prepared upon magnesium alloy AZ31 in a water bath at 60 °C. FE–SEM, FTIR, XRD, electrochemical characterization, hydrogen evolution tests and XPS were used to evaluate the microstructure, chemistry and corrosion performance of the samples. Results indicate that l -cysteine promotes the nucleation process of the coating and significantly increases its thickness. This can be attributed to the complexation of the carboxyl group and mercapto group of l -cysteine with calcium ions. Indeed, the obtained Ca-P coating possesses higher corrosion resistance than that prepared in l -cysteine-free bath.

Aim: Search for a new class of potential antidiabetic agents. Methodology: A series of novel peptidomimetics bearing the p-aminobenzoic acid moiety (TM3–TM6) were designed and synthesized. For all synthetic target molecules, the peroxisome proliferator response element (PPRE) activated activities have been evaluated and the toxicity were computed. Results & discussion: 46 new p-aminobenzoic acid derivatives have been characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). The results of in vitro PPRE-activated activity, molecular docking study and toxicity prediction revealed that these compounds had potential antidiabetic activities and low toxicity. In particular compound 3b had up to 87% PPRE-activated activity compared with pioglitazone. This discovery may provide new insights for finding novel PPRE lead compound.

Basically, Mg–Al layered double hydroxide (LDH) coatings are prepared on the surface of micro-arc oxidation (MAO) coated magnesium (Mg) alloys at a high temperature or a low pH value. This scenario leads to the growth rate of LDH coating inferior to the dissolution rate of the MAO coating. This in turn results in limited corrosion resistance of the composite coating. In this study, a Mg–Al LDH coating on MAO-coated Mg alloy AZ31 is prepared through a water bath with a higher pH (13.76) at a lower temperature (60 °C). FE-SEM, EDS, XRD, XPS, and FT-IR are applied to analyze the surface morphology, chemical compositions, and growth process. Electrochemical polarization, electrochemical impedance spectroscopy (EIS) and hydrogen evolution tests are employed to evaluate the corrosion resistance of the samples. The results disclose that the MAO coating is completely covered by the nanosheet-structured LDH coating with a thickness of approximately 3.8 μm. The corrosion current density of the MAO-LDH composite coating is decreased four orders of magnitude in comparison to its substrate; the presence of a wide passivation region in anodic polarization branch demonstrates its strong self-healing ability, indicating the hybrid coating possesses excellent corrosion resistance. The formation mechanism of the LDH coating on the MAO-coated Mg alloy is proposed. Furthermore, the cytocompatibility is assessed via an indirect extraction test for MC3T3-E1 pre-osteoblasts, which indicates an acceptable cytocompatibility of osteoblasts for the composite coating., Graphical abstract Image 1, Highlights • High pH and low temperature balance MAO dissolution rate and LDH growth rate. • EDTA-2Na accelerates the growth of LDH. • MAO-LDH coating shows a wider passivation zone and a seal-healing ability. • MAO-LDH coating has an acceptable biocompatibility for MC3T3-E1 osteoblasts. • The growth mechanism of MAO-LDH coating is proposed.

Backbone assignments for the isolated α-subunit of Salmonella typhimurium tryptophan synthase (TS) are reported based on triple resonance solution-state NMR experiments on a uniformly (2)H,(13)C,(15)N-labeled sample. From the backbone chemical shifts, secondary structure and random coil index order parameters (RCI-S(2)) are predicted. Titration with the 3-indole-D-glycerol 3’-phosphate analog, N-(4’-trifluoromethoxybenzenesulfonyl)-2-aminoethyl phosphate (F9), leads to chemical shift perturbations indicative of conformational changes from which an estimate of the dissociation constant is obtained. Comparisons of the backbone chemical-shifts, RCI-S(2) values, and site-specific relaxation times with and without F9 reveal allosteric changes including modulation in secondary structures and loop rigidity induced upon ligand binding. A comparison is made to the X-ray crystal structure of the α-subunit in the full TS αββα bi-enzyme complex and to two new X-ray crystal structures of the isolated TS α-subunit reported in this work.

Nucleotide excision repair (NER) is a major DNA repair pathway for a variety of DNA lesions. XPB plays a key role in DNA opening at damage sites and coordinating damage incision by nucleases. XPB is conserved from archaea to human. In archaea, XPB is associated with a nuclease Bax1. Here we report crystal structures of XPB in complex with Bax1 from Archaeoglobus fulgidus (Af) and Sulfolobus tokodaii (St). These structures reveal for the first time four domains in Bax1, which interacts with XPB mainly through its N-terminal domain. A Cas2-like domain likely helps to position Bax1 at the forked DNA allowing the nuclease domain to incise one arm of the fork. Bax1 exists in monomer or homodimer but forms a heterodimer exclusively with XPB. StBax1 keeps StXPB in a closed conformation and stimulates ATP hydrolysis by XPB while AfBax1 maintains AfXPB in the open conformation and reduces its ATPase activity. Bax1 contains two distinguished nuclease active sites to presumably incise DNA damage. Our results demonstrate that protein-protein interactions regulate the activities of XPB ATPase and Bax1 nuclease. These structures provide a platform to understand the XPB-nuclease interactions important for the coordination of DNA unwinding and damage incision in eukaryotic NER.

The chemical composition of the volatile oils obtained from the flowers, leaves, and stems of Triadica sebifera were examined. The oil samples were obtained by hydrodistillation of plant materials,...

Nickel-based composite coatings reinforced by spherical tungsten carbide were deposited on 42CrMo alloy steel using plasma transfer arc welding (PTAW) process. Their electrochemical corrosion properties in NaCl solution under atmospheric and high pressure were studied by polarization curve, electrochemical impedance spectroscopy. The corrosion and erosion resistance of the coatings were also investigated by salt spray corrosion and erosion corrosion tests. The results show that the self-corrosion potential of the composite coatings increased with the increase of tungsten carbide content, and the Cr element in Ni60 sample formed a stable and compact passivation film. Compared with corrosion at atmospheric pressure, the adsorption and penetration of Cl- on the coating surface enhanced due to the increase of Cl- activity under pressure, thereby to weaken the corrosion resistance. The Samples that passivated in salt spray environment, cannot completely hinder the corrosion of the coating, just only to slow down the corrosion. This study can provide theoretical basis for deep-sea oil drilling and production engineering equipment.

Fe-based coatings reinforced by spherical tungsten carbide were deposited on 304 stainless steel using plasma transferred arc (PTA) technology. The composition and phase microstructure of the coatings were evaluated using scanning electron microscopy (SEM), energy dispersive spectrometer (EDS) and X-ray diffraction (XRD). The corrosion behaviors of the coatings in 0.5 mol/L HCl solution were studied using polarization curve and electrochemical impedance spectroscopy (EIS) measurements. The experimental results shows that the tungsten carbide improves the corrosion resistance of the Fe-based alloy coating, but increase in the mass fraction of tungsten carbide leads to increasing amount of defects of holes and cracks, which results in an adverse effect on the corrosion resistance. The defects are mainly present on the tungsten carbide but also extend to the Fe-based matrix. The tungsten carbide, acting as a cathode, and binding material of Fe-based alloy, acting as an anode, create a galvanic corrosion cell. The binding material is preferentially corroded and causes the degradation of the coating.

Black TiO₂-graphene oxide (GO) nanocomposites are synthesized via the pulsed laser ablating TiO₂ powders and GO in deionized water. The simple process enables the preparation of black TiO₂ nanoparticles and anchors them onto the GO sheet in one step. The TiO₂-GO nanocomposites exhibit greatly enhancement for photocatalytic degradation of Rhodamine B (RB) dye in comparison with the pristine and the ablated black TiO₂. The heterojunction structure plays an important role in efficient charge separation, which reduces the recombination of photogenerated electrons and holes. The unique two-dimensional structure of GO enables the composite to have a large specific surface area, and prevents the agglomeration of TiO₂ nanoparticles, which are beneficial to the photocatalytic performance of the composite.

Metalaxyl is broadly applied in agriculture to control peronosporales-caused diseases in plant. To investigate the toxic effects, zebrafish embryos were exposed to metalaxyl at 5, 50 and 500 ng/L for 72 h, the development of larvae were assessed. A significant decreased survival rate, body length, hatching rate (48 h post-fertilization), and a significant increased spinal curvature rate were observed in the 500 ng/L treatment. The lengths of lower jaw, upper jaw and hyomandibular were significantly decreased in the 5, 50 and 500 ng/L groups; while the lower jaw width was significantly increased in the 500 ng/L group. The lengths of palatoquadrate, ceratohyal and ethmoid plate were reduced. Though cyp26a1 mRNA levels showed no significant change, the transcription of bmp2b (in the 500 ng/L group), ihh (in the 50 and 500 ng/L groups), shh (in the 5, 50 and 500 ng/L groups) were significantly up-regulated, which may be related to the abnormal development of the skeleton.

The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and other risk factors remain unclear.To investigate the incidence of high on-treatment platelet reactivity in coronary heart disease patients following clopidogrel therapy by analyzing the correlation between genetic polymorphisms and high on-treatment platelet reactivity.This study was conducted in the Chinese People's Liberation Army (PLA) general hospital.578 patients with coronary heart disease undergoing percutaneous transluminal coronary intervention treatment were enrolled. They received dual antiplatelet therapy with aspirin (300 mg) plus clopidogrel (300 mg) over 24 h, or aspirin (100 mg/day) and clopidogrel (75 mg/day) over 3 days. Patients were divided into two groups according to the adenosine diphosphate inhibition rate. The follow-up lasted at least 12 months and adverse endpoint events were recorded.The single nucleotide polymorphisms were detected by MassArray genotyping system.The incidence of HTPR was 15.74% in total, being higher in females than in males (24.29% vs. 13.01%, P 0.01). Diabetes mellitus, homocysteine and high sensitivity C-reactive protein (hs-CRP) levels were significantly higher in the HTPR group than those in the non-HTPR group (P 0.05). Polymorphisms of rs1057910 (OR 2.90, P = 0.003), rs2246709 (OR 0.69, P = 0.039), and rs776746 (OR 0.66, P = 0.034) were associated with the incidence of high on-treatment platelet reactivity. Female patients were prone to polymorphisms of rs1057910 (OR 3.24, P = 0.004) and rs776746 (OR 0.57, P = 0.025). Compared to non-high on-treatment platelet reactivity group, no differences in high reactivity group were observed with coexisting single nucleotide polymorphisms (14.6% vs. 14.8%, P 0.05). The adverse endpoint events were significantly higher in the high on-treatment platelet reactivity group than in the non-treatment reactivity group. The survival analysis showed that high on-treatment platelet reactivity was significantly associated with the risk of the endpoint events (P = 0.0219).Gender (female), diabetes mellitus, high levels of homocysteine and hs-CRP were risk factors for high on-treatment platelet reactivity, and high reactivity was a strong predictor for adverse endpoint events in the coronary heart disease patients. The polymorphism of rs1057910 was a risk factor of high on-treatment platelet reactivity while rs2246709 and rs776746 polymorphisms were protective factors, and coexisting single nucleotide polymorphisms didn't increase the incidence of high on-treatment platelet reactivity.

The dual (pH- and temperature-) responsive core-shell structured mesoporous nanomaterial P@BMMs were prepared using bimodal mesoporous silica as a core and poly(N-isopropylacrylamide-co-acrylic acid) P(NIPAM-co-AA) copolymer as a shell. Ibuprofen (IBU) was used as a model drug, and the effects of copolymer-coated shell thickness on drug loading and controlled release behavior were investigated by means of N2 sorption isotherms, dynamic light scattering measurements, X-ray diffraction patterns, Fourier transform infrared spectra, scanning electron and transmission electron microscopy, thermogravimetric profiles, and elemental analysis techniques. Particularly, their fractal evolutions in the drug delivery durations were explored via small angle X-ray scattering methods, demonstrating that the resultant P@BMMs before IBU-loading and after releasing possess the typical fractal features with spherical morphology. Meanwhile, the estimation for shell thickness of P@BMMs coating in different time intervals indicated that the drug-loaded capacity was improved with the increasing shell thickness, but drug-released rate varies, strongly depending on both shell thickness and release conditions. The drug delivery mechanism was preliminarily explored, following the Korsmeyer-Peppas model. Finally, cytotoxicity in cell and pharmacokinetic of released-IBU from hybrid nanocomposite in mice via intravenously injection were preliminarily explored. Keywords: Fractal, Mesoporous SiO2, Core-shell structures, SAXS, Dual (pH- and temperature-) responsive

[Image: see text] Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1′ that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1′. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate.

Polyaniline (PANI) is a conductive polymer that allows cellulose aerogels to achieve high electrical conductivity. However, aerogels containing PANI alone display a low mechanical stability. Graphene nanosheets (GNS) display high conductivity and mechanical strength but are prone to agglomeration, hindering their electroactive sites. To avoid shortcomings of the individual components, a composite aerogel was prepared via addition of graphene nanosheets (GNS) and PANI to a suspension of cellulose nanofibril (CNF). Transmission electron microscopy and scanning electron microscopy were used to analyze the structural morphology of the CNF/GNS/PANI aerogel. The electrochemical properties were analyzed using a four-probe conductivity meter, cyclic voltammetry, galvanostatic charge-discharge tests, and electrochemical impedance spectroscopy. A 2:2:1 ratio of CNF/GNS/PANI provided optimal structural and electrochemical results. Incorporation of PANI through in-situ polymerization for 6 h resulted in uniform mixing of the three components. The CNF/GNS/PANI composite aerogel displayed a high electrical conductivity with a specific capacitance of 375 Fg-1 at a current density of 0.2 Ag-1. As a base binder and dispersant, CNF made use of PANI as a conductive medium and of GNS as a conductive reinforcing medium to form a flexible nanocellulose composite conductive material with increased stability and improved performance.

Background Chondrocyte apoptosis activated by the mitochondrial dependent pathway serves a crucial role in cartilage degeneration of osteoarthritis (OA). In the present study, the protective effects of CMCS against sodium nitroprusside (SNP)-induced chondrocyte apoptosis were evaluated and the underlying molecular mechanisms were elucidated. Methods Chondrocytes were isolated from articular cartilage of SD rats and identified by type II collagen immunohistochemistry. The chondrocytes stimulated with or without SNP to induce apoptosis, were treated by CMCS for various concentrations. The cell viability were determined by MTT and LDH assays. Cell apoptotic ratio was determined by Annexin V-FITC/PI staining. Mitochondrial membrane potential (ΔΨm) was detected by using Rhodamine123 (Rho123) staining. To understand the mechanism, the mRNA expression levels of Bcl-2, Bax, cytochrome c (Cyt c) and cleaved caspase-3 were detected by real-time PCR and western blot analysis, respectively. Results It was shown using the MTT and LDH assays that CMCS protected the viability of chondrocyte against SNP damage. Annexin V-FITC/PI and Rho123 staining showed that CMCS not only inhibited the cell apoptosis but also restored the reduction of the ΔΨm in chondrocytes. In SNP-induced chondrocytes, CMCS down-regulated the expression of Bax, Cyt c and cleaved caspase-3 but upregulated the expression of Bcl-2, as shown by real-time PCR and western blot. Conclusions Taken together, these results indicated that CMCS has the protective effect on chondrocytes against SNP-induced apoptosis, at least partly, via inhibiting the mitochondrial dependent apoptotic pathway. Thus, CMCS may be potentially used as a biological agent for prevention and treatment of OA.

A mitochondrial pH sensing fluorescent probe namely 2-(2-(6-hydroxynaphthalen-2-yl)vinyl)-3-(6-(triphenyl-phosphonio)hexyl)benzothiazol-3-ium bromide (HTBT2) was designed and facilely synthesized via the Knoevenagel condensation reaction. HTBT2 displayed a linear fluorescence enhancement at 612 nm in response to pH changes between 8.70 and 7.20. The pKa value was determined to be 8.04 ± 0.02, which might be ideal for mitochondrial pH (pHmito ∼8.0) detection. HTBT2 also exhibited a remarkable large Stokes shift of 176 nm, which could diminish the interference of excitation light. The results of live cell imaging studies suggested that HTBT2 showed excellent targeting ability for mitochondria. Importantly, it was successfully applied to visualize mitochondrial pH changes in live cells and differentiate the pHmito difference between cancer cell lines and normal cell lines. Our results consistently supported that HTBT2 held practical promise for the investigation of physiological processes related to pHmito changes and clinical potential for cancer cell differentiation.

Introduction: High serum sodium is associated with increased blood pressure (BP) in dialysis patients, which is a risk factor for cardiovascular (CV) disease. However, the interaction between serum sodium and BP and their association with clinical outcomes in peritoneal dialysis (PD) patients is uncertain. Methods: We analyzed a retrospective cohort of 1,656 incident PD patients from January 2006 to December 2013, who were followed up until December 2018. Cox proportional hazards regression models were used to evaluate the association of serum sodium and BP with all-cause and CV mortality. A priori interaction between serum sodium and systolic BP (SBP) was explored, and a subgroup analysis was performed by stratifying SBP into the following 3 groups: 130 mm Hg. Results: Mean baseline serum sodium was 140.2 ± 3.6 mmol/L, mean SBP was 137 ± 20 mm Hg, and diastolic BP was 85 ± 14 mm Hg. During a median (range) follow-up time of 46.5 (2.6–154.3) months, 507 patients died, 252 of whom died due to CV disease. SBP did not predict all-cause and CV mortality when BP was assessed as a continuous variable. However, SBP >130 or p for interaction = 0.016). In subgroup analysis, among those with SBP >130 mm Hg, the risk of all-cause mortality was elevated in those with serum sodium ≥140 mmol/L (adjusted hazard ratio [aHR] 1.45 [95% confidence interval (CI): 1.07–1.98]), but not for those with serum sodium p for interaction = 0.028). Conclusion: The association of BP with mortality was modified by serum sodium levels in PD patients. Further studies are needed to evaluate whether individualized BP control based on serum sodium levels contributes to improve patient outcomes.

In this work, corn starch (St) was firstly grafted with polyacrylamide (PAM) to obtain StAM, which was subsequently immobilized with arginine to obtain a guanidine-containing starch-based resin, StAM-Arg. The synthesized products were characterized

Hypoxia in solid tumors is directly linked to the elevated levels of endogenous nitroreductase (NTR). We present a novel fluorescent probe, namely NTNO, for nitroreductase-specific detection based on the NTR-catalyzed reduction of the nitro unit to an amine functionality, and demonstrated its application for hypoxia imaging. NTNO was designed by incorporating a nitro unit as the NTR response site into a benzothiazole derivative. Upon reacting with NTR in the presence of reduced nicotinamide adenine dinucleotide (NADH), the fluorescence of the probe was strongly and sensitively turned on, with a good linearity in the NTR concentration range of 0.5-8.0 μg mL-1 and a detection limit of 48 ng mL-1. Most notably, NTNO has been successfully used for imaging hypoxia levels in living cells, tumor tissues and zebrafish, making it of great potential to monitor NTR in biological systems.

Hypocrellins, as natural pigments from Shiraia bambusicola, have extensive applications in the agricultural, cosmetic, food, and feed industries, and play a vital role in photodynamic therapy for anticancer and antiviral treatments. However, environmental stresses are always the bottlenecks for increasing hypocrellin yield during the process of fermentation. Pre-mRNA alternative splicing (AS) is an essential mechanism in the defense of abiotic stresses in the animal and plant kingdom, but is seldom involved in fungi. In this study, AS from genome-wide sequencing and RNA-seq data for S. bambusicola was analyzed for the first time. Interestingly, the proportion of AS in S. bambusicola was 38.44% (most of them participated in metabolic processes, covering pigmentation and response to stimulus), a much higher ratio than seen in that of other fungal species (1.3-18%). Here, we identified the relationship of AS and secondary metabolic (SM) biosynthesis under a series of abiotic stresses. Suitable fungicides suppressed hypocrellin production significantly, and AS occurred in key functional genes (sbFLO, sbMFS, sbPKS) of hypocrellin biosynthesis. In contrast, H2O2 improved the yield of hypocrellins, but AS were not found in the corresponding gene cluster. A further study showed that overexpressing an isoform of sbPKS (sbPKSa) in Shiraia bambusicola could dramatically down-regulate the expression of the original gene sbPKS and nearly inhibit the production of hypocrellins. Altogether, our study strongly supported the hypothesis that AS had a vital role in the regulation of hypocrellin biosynthesis under stresses, and initially explored whether SM functional genes were relevant for fungi.

With the increasing application of polyvinyl alcohol (PVA) films in the field of food packaging, it is important to improve its mechanical and antibacterial properties. This paper focuses on the preparation of PVA nanocomposite films and how their properties are affected by a silver-loaded nanocellulose solution. Cellulose nanocrystals (CNCs) were used as both the carrier and the dispersant of silver nanoparticles (AgNPs) prepared using glucose as the reducing agent. Ag+ was stabilized by the many hydroxyl groups located in the CNCs, and then the Ag+ was reduced to AgNPs in situ. After addition of silver-loaded nanocellulose, the tensile strength of the CNC-PVA-AgNP films increased from 47 MPa to 73 MPa, and the nanocomposite films displayed reduced moisture absorption and good antibacterial properties.

This study developed a model involving the energy balance and decomposition at the ablated interface due to the heat transport, optical decomposition and activation energy in Acrylonitrile Butadiene Styrene/PolyVinyl Chloride (ABS/PVC). The prediction for ablation depth obtained from this study is compared with the available experimental data. The predicted results agree with the measured data. The effects of laser processing parameters, optical and thermal properties of ABS/PVC on the variation of the laser-ablated depth with the laser fluences are also discussed. The results validate that the pulsed-laser ablation rate at the initial short period is dominated by optical penetration absorption for laser and is linearly proportional to the logarithm of the laser fluence by a ratio factor “optical absorption length” (i.e., the ablation rate follows Beer’s law at the initial short period).

The main goal of this study was to explore the dose-effect relationship of ilaprazole.Ilaprazole is a kind of benzimidazole proton-pump inhibitor, which was confirmed efficacious and safe in treatment of duodenal ulcer (DU). However, the dose-effect relationship of ilaprazole was not clear.This was a double-blind, parallel, randomized study. Patients aged above 18 years with at least one endoscopically confirmed active nonmalignant DU were treated with rabeprazole 10 mg or ilaprazole 10 mg/5 mg for 4 weeks. Healing of ulcer was determined by its resolution from active to scarring stage. Symptoms relief was evaluated using a graded score. Safety and tolerability were evaluated on basis of clinical assessments.A total of 390 patients completed the study finally. Ulcers were successfully healed in 75.38%, 77.86%, and 83.72% of patients after 4-week treatment with rabeprazole 10 mg, ilaprazole 5 mg, and ilaprazole 10 mg, respectively. The 4-week healing rate difference between rabeprazole 10 mg and ilaprazole 5 mg was 2.48% (95% confidence interval: -7.79% to 12.74%) leading to accept the noninferiority hypothesis. Logistic regression model suggested that ilaprazole 10 mg was superior to ilaprazole 5 mg at week 2 (odds ratio, 1.92; 95% confidence interval: 1.02, 3.59; P=0.04). Most patients (80%) became asymptomatic after treatment. At the dosages administered, the 3 drug groups exhibited similar efficacy and a similar safety profile.Ilaprazole 5 mg is not inferior to rabeprazole 10 mg in treating DU, and a dose-effect relationship have been revealed between 5 mg and 10 mg of ilaprazole.

Structure and defect control are widely accepted effective strategies to manipulate the activity and stability of catalysts. On a freestanding hierarchically porous carbon microstructure, the tuning of oxygen vacancy in the embedded hollow cobaltosic oxide (Co3 O4 ) nanoparticles is demonstrated through the regulation of nanoscale Kirkendall effect. Starting with the embedded cobalt nanoparticles, the concentration of oxygen-vacancy defect can vary with the degree of Kirkendall oxidation, thus regulating the number of active sites and the catalytic performances. The optimized freestanding catalyst shows among the smallest reversible oxygen overpotential of 0.74 V for catalyzing oxygen reduction/evolution reactions in 0.1 m KOH. Moreover, the catalyst shows promise for substitution of noble metals to boost cathodic oxygen reactions in portable zinc-air batteries. This work provides a strategy to explore catalysts with controllable vacancy defects and desired nano-/microstructures.

Discovering effective combinational components (ECCs) and quality control markers of TCMs is still facing challenges because the holistic healing system comprises hundreds of compounds. Here, taking Yindan Xinnaotong soft capsule (YDXNT), a TCMs preparation composed by 8 herbs, as a case, a strategy that integrated multiple chromatographic analysis and bioactivity assay was proposed for potential ECCs of neuroprotection discovery. Firstly, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF MS) and gas chromatography-mass spectrometry (GC-MS) were applied for comprehensive profiling of the chemical constituents in YDXNT. Given the fact that the complex matrix interference makes it more difficult to identify potentially active compounds, we proposed a structure-diagnostic ions-oriented strategy to remove interference ions from the raw UHPLC-MS data. The proposed strategy consisted of different filtering methods, including diagnostic fragment ions filtering (DFIF), mass defect filtering (MDF) and neutral loss (NL). Using this strategy, a total of 124 compounds were rapidly identified. Among them, 62 non-volatile and 5 volatile constituents in 30 batches of YDXNT were quantified by UHPLC tandem triple quadrupole mass spectrometry (QQQ-MS) and GC-MS methods, respectively. In order to facilitate the quality control of YDXNT, candidate ECCs were selected based on the threshold setting of absolute -contents, and their neuroprotective effects were examined. Finally, a combination of 16 compounds, accounts for 2.80% (w/w) of original YDXNT, was identified as its potential ECCs, which could be considered for the improvement of quality standardization of YDXNT.

Overexpressed P-glycoprotein (P-gp), as the key factor in multidrug resistance (MDR), can greatly reduce intracellular drug levels as a result of chemotherapeutic drug efflux out of cancer cells. Although various P-gp antagonists have been developed to circumvent the MDR effect, the common strategies of physical entrapment or chemical conjugation of anticancer drugs may inevitably induce unstable circulation in vivo or poor response in cancer cells, greatly limiting the therapeutic efficacy. Herein a double-drug-based supramolecular complex (DDSC) was first constructed based on the host-guest interactions between two active drugs, curcumin (Cur)-bridged bis(β-cyclodextrin) and ferrocene-linked camptothecin (CPT). Supramolecular dual drug nanomicelles (SDDNMs) formed by the DDSC self-assembly are proposed to work against the MDR effect, in which Cur as a P-gp antagonist in combination with CPT realized stable transport in vivo and efficient stimuli-responsiveness in cells. In vitro and in vivo studies further confirmed that SDDNMs effectively circumvented the drug efflux induced by the MDR effect and remarkably enhanced the synergistic therapeutic effects.

During development, neurites and synapses segregate into specific neighborhoods or layers within nerve bundles. The developmental programs guiding placement of neurites in specific layers, and hence their incorporation into specific circuits, are not well understood. We implement novel imaging methods and quantitative models to document the embryonic development of the C. elegans brain neuropil, and discover that differential adhesion mechanisms control precise placement of single neurites onto specific layers. Differential adhesion is orchestrated via developmentally regulated expression of the IgCAM SYG-1, and its partner ligand SYG-2. Changes in SYG-1 expression across neuropil layers result in changes in adhesive forces, which sort SYG-2-expressing neurons. Sorting to layers occurs, not via outgrowth from the neurite tip, but via an alternate mechanism of retrograde zippering, involving interactions between neurite shafts. Our study indicates that biophysical principles from differential adhesion govern neurite placement and synaptic specificity in vivo in developing neuropil bundles.

Scanning electron microscopy (SEM) plays a crucial role in the characterization of nanoparticles. Unfortunately, due to the limited resolution, existing imaging techniques are insufficient to display all detailed characteristics at the nanoscale. Hardware-oriented techniques are troubled with costs and material properties. Computational approaches often prefer blurry results or produce a less meaningful high-frequency noise. Therefore, we present a staged loss-driven neural networks model architecture to transform low-resolution SEM images into super-resolved ones. Our approach consists of two stages: first, residual channel attention network (RCAN) with mean absolute error (MAE) loss was used to get a better peak signal-to-noise ratio (PSNR). Then, discriminators with adversarial losses were activated to reconstruct high-frequency texture features. The quantitative and qualitative evaluation results indicate that compared with other advanced approaches, our model achieves satisfactory results. The experiment in AgCl@Ag for photocatalytic degradation confirms that our proposed method can bring realistic high-frequency structural detailed information rather than meaningless noise. With this approach, high-resolution SEM images can be acquired immediately without sample damage. Moreover, it provides an enhanced characterization method for further directing the preparation of nanoparticles.

It has been reported that knockdown of circular RNA (circ) ATPase class II type 9B (Atp9b) can reduce lipopolysaccharide (LPS)-induced inflammation, which plays a notable role in ulcerative colitis (UC). The present study aimed to explore the role of circAtp9b in UC. The expression levels of Atp9b and PTEN in the plasma of patients with UC (n=60) and healthy controls (n=60) were determined via reverse transcription-quantitative PCR. Overexpression of circAtp9b and PTEN were achieved in human colonic epithelial cells (HCnEpCs) to explore the relationship between circAtp9b and PTEN. The role of circAtp9b and PTEN in regulating the apoptosis of HCnEpCs under LPS treatment was evaluated using flow cytometry. The present study revealed that circAtp9b was upregulated in UC and that it was positively correlated with PTEN. In HCnEpCs, LPS treatment resulted in upregulation of circAtp9b in a dose-dependent manner. Moreover, overexpression of circAtp9b mediated the upregulation of PTEN in HCnEpCs, while silencing of circAtp9b decreased the expression levels of PTEN. Apoptosis analysis demonstrated that overexpression of circAtp9b and PTEN promoted the apoptosis of HCnEpCs. In addition, silencing of circAtp9b suppressed apoptosis. Moreover, overexpression of PTEN reduced the effects of silencing of circAtp9b. In conclusion, overexpression of circAtp9b in UC was induced by LPS and it positively upregulated PTEN to promote the apoptosis of HCnEpCs induced by LPS.

AIMS/INTRODUCTION We aimed to explore the clinical factors associated with glycemic variability (GV) assessed with flash glucose monitoring (FGM), and investigate the impact of FGM on glycemic control among Chinese type 1 diabetes mellitus patients in a real-life clinical setting. MATERIALS AND METHODS A total of 171 patients were included. GV was assessed from FGM data. A total of 110 patients wore FGM continuously for 6 months (longitudinal cohort). Hemoglobin A1c (HbA1c), fasting and 2-h postprandial C-peptide, and glucose profiles were collected. Changes in HbA1c and glycemic parameters were assessed during a 6-month FGM period. RESULTS Individuals with high residual C-peptide (HRCP; 2-h postprandial C-peptide >200 pmol/L) had less GV than patients with low residual C-peptide ( 2-h postprandial C-peptide ≤200 pmol/L; P

Stimuli-responsive nanomachines are attractive tools for biosensing, imaging, and drug delivery. Herein, we demonstrate that the orientation of macromolecules and subsequent dynamic interactions at the biomolecule-nanoparticle (bio-nano) interfaces can be rationally controlled to engineer stimuli-responsive DNA nanomachines. The success of this design principle was demonstrated by engineering a series of antibody-responsive DNA walkers capable of moving persistently on a three-dimensional track made of DNA functionalized gold nanoparticles. We show that drastically different responses to antibodies could be achieved using DNA walkers of identical sequences but with varying number or sites of modifications. We also show that multiple interfacial factors could be combined to engineer stimuli-responsive DNA nanomachines with high sensitivity and modularity. The potential of our strategy for practical uses was finally demonstrated for the amplified detection of antibodies and small molecules in both buffer and human serum samples. Unlike many DNA-based nanomachines, the performance of which could be significantly hindered by the matrix of serum, our system shows a matrix-enhanced sensitivity as a result of the engineering approach at the bio-nano interface.