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Background: Fibrosis is a significant pathological feature of chronic skeletal muscle injury, profoundly affecting muscle regeneration. Fibro-adipogenic progenitors (FAPs) have the ability to differentiate into myofibroblasts, acting as a primary source of extracellular matrix (ECM). the process by which FAPs differentiate into myofibroblasts during chronic skeletal muscle injury remains inadequately explored. Method: mouse model with sciatic nerve denervated was constructed and miRNA expression profiles between the mouse model and uninjured mouse were analyzed. qRT/PCR and immunofluorescence elucidated the effect of miR-27b-3p on fibrosis in vivo and in vitro. Dual-luciferase reporter identified the target gene of miR-27b-3p, and finally knocked down or overexpressed the target gene and phosphorylation inhibition of Smad verified the influence of downstream molecules on the abundance of miR-27b-3p and fibrogenic differentiation of FAPs. Result: FAPs derived from a mouse model with sciatic nerves denervated exhibited a progressively worsening fibrotic phenotype over time. Introducing agomiR-27b-3p effectively suppressed fibrosis both in vitro and in vivo. MiR-27b-3p targeted Transforming Growth Factor Beta Receptor 1 (TGF-βR1) and the abundance of miR-27b-3p was negatively regulated by TGF-βR1/Smad. Conclusion: miR-27b-3p targeting the TGF-βR1/Smad pathway is a novel mechanism for regulating fibrogenic differentiation of FAPs. Increasing abundance of miR-27b-3p, suppressing expression of TGF-βR1 and inhibiting phosphorylation of smad3 presented potential strategies for treating fibrosis in chronic skeletal muscle injury. [ABSTRACT FROM AUTHOR]

Interface tissue repair requires the construction of biomaterials with integrated structures of multiple protein types. Hydrogels that modulate internal porous structures provide a 3D microenvironment for encapsulated cells, making them promise for interface tissue repair. Currently, reduction of intrinsic immunogenicity and increase of bioactive extracellular matrix (ECM) secretion are issues to be considered in these materials. In this study, gelatin methacrylate (GelMA) hydrogel is used to encapsulate chondrocytes and construct a phase transition 3D cell culture system (PTCC) by utilizing the thermosensitivity of gelatin microspheres to create micropores within the hydrogel. The types of bioactive extracellular matrix protein formation by chondrocytes encapsulated in hydrogels are investigated in vitro. After 28 days of culture, GelMA PTCC forms an extracellular matrix predominantly composed of collagen type II, collagen type I, and fibronectin. After decellularization, the protein types and mechanical properties are well preserved, fabricating a decellularized tissue‐engineered extracellular matrix and GelMA hydrogel interpenetrating network hydrogel (dECM‐GelMA IPN) consisting of GelMA hydrogel as the first‐level network and the ECM secreted by chondrocytes as the second‐level network. This material has the potential to mediate the repair and regeneration of tendon–bone interface tissues with multiple protein types. [ABSTRACT FROM AUTHOR]

Nitro-m-xylenes (NMX) was synthesized in semi-batch mode via m-xylene nitration using nitric acid-acetic anhydride (HNO 3 -Ac 2 O) as nitrating reagent in this work. The nitration process was optimized by response surface methodology. The yield of NMX could reach 92.40% under the optimal conditions of jacket temperature of 20 °C, 0.15 mol of HNO 3 and 0.19 mol of Ac 2 O. Corresponding large reaction enthalpy (Δ H =240.9 kJ/mol) and adiabatic temperature rise (Δ T ad,r =398.1 K) indicated the serious hazards of nitration in a thermal runaway scenario. Pyrolysis of nitration products occurred at about 320–400 °C by differential scanning calorimetry tests. The reaction order of the pyrolysis was determined to be 1.2 by adiabatic kinetic analysis. Thermal risk of the nitration process was assessed to be acceptable and level 1 via the risk matrix and Stoessel criticality diagram analyses, respectively. Furthermore, detailed nitration mechanisms for NO 2 + generation and aromatic substitution were presented. The activation free enthalpy and free energy parameters for each step were calculated by density functional theory (DFT). These findings can help understand the exothermic sources of m-xylene nitration and guide the intrinsically safer design and scale-up of the process. [ABSTRACT FROM AUTHOR]

1,1-Di (tert-butylperoxy) cyclohexane (1, 1-DTBCH), as an important organic peroxide, is commonly used as initiator, curing agent and crosslinking agent in the chemical industry. Due to the presence of peroxy bonds, the thermal instability of 1, 1-DTBCH may incur a decomposition reaction and cause further thermal runaway. The thermal decomposition characteristics and runaway reaction characteristics of 1, 1-DTBCH were investigated by differential scanning calorimetry (DSC) and accelerated rate calorimetry (ARC). The kinetic triplet and thermal safety parameters were calculated by using non-isothermal method. The gaseous products and pyrolysis products of 1, 1-DTBCH was investigated by thermogravimetric and infrared spectroscopy (TG-FTIR) and gas chromatography/mass spectrometry (GC/MS). The thermal decomposition pathway of 1, 1-DTBCH was explored with density functional theory (DFT). The exothermic dominant reaction in the thermal decomposition process of 1, 1-DTBCH was explored by combining experiment and theoretical calculation. The corresponding safety control measures were provided to reduce the thermal runaway hazard of 1, 1-DTBCH. [ABSTRACT FROM AUTHOR]

Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost‐saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro‐inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM‐CoFe PBA enables ROS clearance through multi‐nanomase activity. In addition, CCM‐CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC. [ABSTRACT FROM AUTHOR]

The exothermic pattern of m-xylene nitration with mixed acid in semi-batch mode was studied by reaction calorimetry. Adiabatic temperature rise (Δ T ad) and reaction enthalpy (∆ H) were obtained to identify the thermal hazard. Process conditions including stirring rate, reaction temperature and strength of mixed acid were studied to optimize the reaction. Optimal yield (95.5%) was reached under the conditions of sufficient stirring rate, 70% strength of mixed acid and reaction temperature of 40 °C. Meanwhile, the thermal stability of nitration products was investigated by differential scanning calorimetry (DSC) and accelerating rate calorimetry (ARC). Pyrolysis kinetic parameters were calculated under non-isothermal and adiabatic conditions. Furthermore, the maximum temperature of the runaway system for synthesis reaction (MTSR) was determined to analyze the reaction hazard. The thermal risk of nitration of m-xylene was also assessed by the risk matrix and Stoessel criticality diagram. In addition, the nitration mechanism of m-xylene was presented. The active site for the electrophilic reaction of m-xylene was predicted via theoretical approach which was in consistent with the selectivity obtained by the experiment. These findings provide guidance for the safe operation of m-xylene nitration and can be used for further scale-up. [ABSTRACT FROM AUTHOR]

A bifunctional TPE-based fluorescent sensor (TPE-Q) for both liquid viscosity and amyloid β (Aβ) has been synthesized straightforwardly by the introduction of an ethylene glycol chain and quaternary ammonium to the classical tetraphenyl ethylene core. Due to the rotation of the intramolecular restriction (RIR) effect of TPE-Q, the sensor displayed liquid viscosity sensing capability with a promising linear relationship within 37 to 609 cp. The fluorescence enhancement was around 11.77 folds. On the other hand, TPE-Q showed both in vitro and in vivo Aβ sensing capabilities. By mixing with Aβ1−42 solution, TPE-Q showed a maximum fluorescence enhancement of 21.60 folds, with a detection limit of 160 nM. In addition, fluorescence colocalization experiments revealed a good merging of TPE-Q and commercial Th T, proving the in vivo imaging capability of TPE-Q in Aβ1−42 over-expressing Caenorhabditis elegans (C. elegans, CL4176). Furthermore, computational docking prediction revealed the binding pattern of TPE-Q towards Aβ aggregates. [ABSTRACT FROM AUTHOR]

A gelatin/sodium alginate-based hydrogel microsphere has been fabricated after reaction condition optimization. Macrophages (RAW246.7) and adipose mesenchymal stem cells (ADSC) have been subsequently encapsulated in the microsphere in order to construct a 3D paracrine system for wound healing treatment. The synthesized microsphere displayed neglectable cytotoxicity toward both encapsulated cells until 10 days of incubation, indicating promising biocompatibility of the microsphere. A qRT-PCR and ELISA experiment revealed positive regulation of cytokines (Arg-1, IL-6, IL-8, IL-10, bFGF, HGF, VEGF, TLR-1, and CXCL13) expression regarding macrophage phenotype transformation and anti-inflammatory performance both inside the microsphere and in the microenvironment of established in vitro inflammatory model. Additionally, positive tendency of cytokine expression benefit wound healing was more pronounced in a fabricated 3D paracrine system than that of a 2D paracrine system. Furthermore, the 3D paracrine system exhibited more efficiently in the wound healing rate compared to the 2D paracrine system in an in vitro model. These results suggested the current paracrine system could be potentially used as a robust wound healing dressing. [ABSTRACT FROM AUTHOR]

Combinations of multi-sensor remote sensing images and machine learning have attracted much attention in recent years due to the spectral similarity of wetland plant canopy. However, the integration of hyperspectral and quad-polarization synthetic aperture radar (SAR) images for classifying marsh vegetation has still been faced with the challenges of using machine learning algorithms. To resolve this issue, this study proposed an approach to classifying marsh vegetation in the Honghe National Nature Reserve, northeast China, by combining backscattering coefficient and polarimetric decomposition parameters of C-band and L-band quad-polarization SAR data with hyperspectral images. We further developed an ensemble learning model by stacking Random Forest (RF), CatBoost and XGBoost algorithms for marsh vegetation mapping and evaluated its classification performance of marsh vegetation between combinations of hyperspectral and full-polarization SAR data and any of the lone sensor images. Finally, this paper explored the effect of different polarimetric decomposition methods and wavelengths of radar on classifying wetland vegetation. We found that a combination of ZH-1 hyperspectral images, C-band GF-3, and L-band ALOS-2 quad-polarization SAR images achieved the highest overall classification accuracy (93.13%), which was 5.58–9.01% higher than that only using C-band or L-band quad-polarization SAR images. This study confirmed that stacking ensemble learning provided better performance than a single machine learning model using multi-source images in most of the classification schemes, with the overall accuracy ranging from 77.02% to 92.27%. The CatBoost algorithm was capable of identifying forests and deep-water marsh vegetation. We further found that L-band ALOS-2 SAR images achieved higher classification accuracy when compared to C-band GF-3 polarimetric SAR data. ALOS-2 was more sensitive to deep-water marsh vegetation classification, while GF-3 was more sensitive to shallow-water marsh vegetation mapping. Finally, scattering model-based decomposition provided important polarimetric parameters from ALOS-2 SAR images for marsh vegetation classification, while eigenvector/eigenvalue-based and two-component decompositions produced a great contribution when using GF-3 SAR images. [ABSTRACT FROM AUTHOR]

This study discusses the multidimensional functionally graded materials (MFGMs) for spacers in high voltage direct current gas-insulated transmission lines and switchgears (HVDC GILs/GISs). The effects of surface conductance graded materials ($\sigma $ -SFGMs) and bulk permittivity graded materials ($\varepsilon $ -FGMs) on the electric field distributions along the basin-type spacer are investigated under dc stationary and transient conditions. Results show that the $\sigma $ -SFGM spacer can effectively regulate the steady-state electric field, but the regulation effect on the transient electric field is limited when its time constant is longer than the transient time of the applied voltage. The $\varepsilon / \sigma $ -MFGM spacer with both bulk permittivity and surface conductance gradients has the same relaxation effect on the stationary electric field as the $\sigma $ -SFGM spacer and the same effect on the transient electric field as the $\varepsilon $ -FGM spacer, which can coordinately regulate the electric field distribution under multiple operating conditions in HVDC GIL/GIS. Compared to the uniform spacer, the $\varepsilon / \sigma $ -MFGM spacer can reduce the maximum electric field strengths under steady state, switching-on, and dc-impulse conditions by 38.9%, 18.6%, and 28.2%, respectively. [ABSTRACT FROM AUTHOR]

• The effects of twelve organic solvents on the reaction selectivity of m-xylene nitration were investigated. • Thermal safety parameters of m-xylene nitration were calculated to evaluate process hazards. • Solubility of m-xylene under twelve organic solvents was analyzed by MPI. • Interaction energy and visualization analysis between HNO 3 and solvents were studied. • The promoting effects of acetic and propionic anhydrides on NO 2 + production were revealed theoretically. Selection of appropriate solvents is of great significance for achieving efficient and safe m-xylene nitration. In this study, the exothermic behavior of m-xylene nitration under twelve organic solvents were studied by reaction calorimetry. The process hazards were assessed by calculation of thermal safety parameters. The reaction selectivity was quantified. The anhydrides exhibited the prominent promotion as water absorbent and active reagent in nitration, followed by selected aliphatic hydrocarbons, chlorinated hydrocarbons. While acetic acid, propionic acid and ethyl acetate had negative effects. The maximum yield of 95.6 % was achieved in nitric acid-acetic anhydride (HNO 3 -Ac 2 O) system. The thermal weight loss of the products appeared at around 150−230 °C by thermogravimetry experiments. The activation energy was determined to be 192.9 kJ/mol through adiabatic kinetic calculations. Furthermore, the solvent effects were analyzed by calculating the solvent polarity and its interaction energy with HNO 3. The different action mechanisms of Ac 2 O and Pc 2 O on NO 2 + generation were revealed. The density functional theory calculations were in agreement with the experimental results. These findings can provide guidance for understanding of the solvent effect on the reaction hazards and selectivity of m-xylene nitration, and provide experimental and theoretical basis for solvent screening for the nitration of similar aromatic compounds. [ABSTRACT FROM AUTHOR]

This study proposed a novel multiscale prediction strategy, including mesoscale and macroscale damage evolution modeling, to investigate the effective properties and progressive damage failure behavior of plain-woven reinforced composites (PWRCs) under various external loads (tension, compression). A high-precision mesoscale representative volume element (RVE) that could accurately describe the local mechanical behavior of PWRCs was developed by combining experimental characterization (scanning electron microscope and X-ray computed tomography) and numerical simulation. To solve the problem of inaccurate prediction results caused by multiscale characteristics and complex stress changes in the damaged area of PWRCs, the strain-based 3D Hashin failure criterion and the multiscale damage models were used to predict the damage initiation and evolution of mesoscale reinforcement (bamboo fiber yarn bundle) and macroscale composites, respectively. Considering the damage evolution law of isotropic materials, a damage model based on the Von Mises criterion was used to characterize the damage initiation and evolution of mesoscale matrix epoxy resin (EP) under external loading. The effective properties and mechanical behavior of the PWRCs were transferred from mesoscale to macroscale through the progressive homogenization method. The bilinear constitutive relationship of the mixed-mode cohesive element was used to characterize the interlaminar failure of the PWRCs. Finally, the corresponding mechanical characterization (tension, compression) of the PWRCs was carried out. Moreover, the experimental results were highly consistent with the simulation results, verifying the reliability of the novel multiscale prediction strategy in investigating the mechanical response of the PWRCs at multiple scales and revealing the damage mechanism of the PWRCs. [Display omitted] • A novel strategy can precisely predict the multiscale mechanical response of natural fiber-reinforced composites. • A high-precision mesoscale model is used to capture the local mechanical behavior of plain-woven reinforced composites. • Strain-based failure criterion and multiscale damage models can accurately predict the progressive damage behavior. • The dynamic coupling of mesoscale and macroscale accurately predicts the macroscale mechanical behavior. [ABSTRACT FROM AUTHOR]

This study discusses the application of the surface conductivity gradient materials ($\sigma $ -SFGMs) for relaxing the electric field concentration around the epoxy-based spacer in high-voltage direct current gas-insulated transmission lines (HVDC GIL). Based on the ±500-kV HVDC GIL model, the iterative method is applied to optimize the thickness gradients of the $\sigma $ -SFGM layers on convex and concave surfaces of the basin-type spacer. It is proven that the $\sigma $ -SFGM layers can significantly suppress the electric field distortion around the high voltage electrode by increasing the homopolar charges and reducing the heteropolar charges on both spacer surfaces. To fabricate the $\sigma $ -SFGM spacer, a thickness-graded layer of high conductivity is formed on a truncated cone-type spacer by electrospinning. Experimental test results show that the application of $\sigma $ -SFGM exhibits a promoting effect of about 11.5% on the dc flashover voltage of the cone-type spacer. The $\sigma $ -SFGM spacer can withstand over ten thermal-shock cycles, indicating that the $\sigma $ -SFGM layer fabricated by electrospinning is more reliable than that fabricated by dip coating. [ABSTRACT FROM AUTHOR]

• Duocarmycins and analogues are DNA-alkylators highly cytotoxic to cancer cells. • Up to now, none of duocarmycins have not been approved for oncological practice. • Novel features make duocarmycins an ideal payload for targeted drug delivery. • Various duocarmycin-based antibody-drug conjugates are in clinical development. • An emerging era of duocarmycin-based anticancer biotherapeutics is in the horizon. Duocarmycins are a class of DNA minor-groove-binding alkylating molecules. For the past decade, various duocarmycin analogues have been used as payloads in the development of antibody–drug conjugates (ADCs). Currently, more than 15 duocarmycin-based ADCs have been studied preclinically, and some of them such as SYD985 have been granted Fast-Track Designation status. Nevertheless, progress in duocarmycin-based ADCs also faces challenges, with setbacks including the termination of BMS-936561/MDX-1203. In this review, we discuss issues associated with the efficacy, pharmacokinetic profile, and toxicological activity of these biotherapeutics. Furthermore, we summarize the latest advances in duocarmycin-based ADCs that have different target specificities and linker chemistries. Evidence from preclinical and clinical studies has indicated that duocarmycin-based ADCs are promising biotherapeutics for oncological application in the future. [ABSTRACT FROM AUTHOR]

Nonylphenol ethoxylate-n (NPnEO) is a nonionic surfactant, and can be degraded in chemical and biological ways for short-chain NPnEO with n ≤ 10. However, when n is >10, the degradation of NPEO in wastewater was seldom reported. In this study, the electrochemical oxidation of long-chain NP40EO at high saline wastewater was investigated. The main influencing factors such as current density, plate distance, initial pH, salt type, and salt concentration on electrochemical degradation of high saline NP40EO wastewater were evaluated. The chemical oxygen demand (COD) removal efficiency increased with the increase of current density and reached 73.4% at 45 mA/cm2 after 6 h electrolysis. Plate distance had no effect on the COD removal. As compared with sodium sulfate (Na2SO4), sodium chloride (NaCl) solution led to better COD removal. A high COD removal efficiency was obtained at lower initial pH value. A possible electrochemical degradation pathway of NP40EO was proposed. The energy consumption increased with increasing current density, plate distance, initial pH value, and decreasing NaCl concentration. Based on the energy consumption analysis, the optimal operating parameters were obtained at current density of 30 mA/cm2, plate distance of 2.0 cm, NaCl concentration of 0.50 M, and initial pH value of 3.0. This result indicated that electrochemical advanced oxidation process is a feasible way for the treatment of long-chain NP40EO wastewater at high saline conditions. [ABSTRACT FROM AUTHOR]

Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a μ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are μ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications. • BUP does not restrict the growth of hCOs as MTD does. • κ-receptor antagonism prevents the growth-suppressive effect of MTD in hCOs. • BUP shows milder inhibitory effect on neural network activity than MTD in hCOs. • BUP lacks NMDA antagonism of MTD and causes less suppression on neuronal activity. [ABSTRACT FROM AUTHOR]

The electrochemical technique has been increasingly used for the detection of heavy metal ions in the water system. However, the process for determining the optimum experimental conditions was cumbersome, time-consuming, and unsynchronized, resulting in unsatisfactory detection efficiency. Herein, a new machine learning (ML) strategy combined with BiFeO 3 /Ti 3 C 2 MXene (BiFeO 3 /MXene) was used to fabricate a simple but efficient electrochemical Pb2+ sensor. The interconnected BiFeO 3 /MXene composites prepared by a hydrothermal method possessed an interconnected conductive framework, abundant active sites, and a large surface area, which gave them excellent electronic conductivity and high accumulation of Pb2+. Meanwhile, ML methods such as back-propagation artificial neural network (BPANN) and genetic algorithm (GA) combined with orthogonal experimental design (OED) were used to optimize sensor parameters such as the pH of the supporting electrolyte, the BiFeO 3 /MXene content, deposition potential, and deposition time. Compared with OED and the one factor at a time (OFAT) methods, the OED-ML method greatly simplified the experimental procedures and improved the electrochemical detection performance. The developed sensor showed superior detection performance for Pb2+ with a detection limit of 0.0001 μg L−1 using the OED-ML method, which was much lower than that of the OED and OFAT methods (0.0003 μg L−1). In addition, the sensor showed good repeatability, reproducibility, stability, and interference capability. The feasibility of the method was verified by detecting Pb2+ in lake samples with recoveries ranging from 98.79% to 101.3%. To our knowledge, the ML strategy was introduced for the first time in an electrochemical sensor for Pb2+ detection, which proved the feasibility and practicality of ML. Machine learning strategy-incorporated BiFeO 3 /Ti 3 C 2 MXene electrochemical sensor for simple, rapid and highly sensitive detection of Pb2+. [Display omitted] • BiFeO 3 /MXene composite was designed as electrochemical platform for Pb2+ detection. • BiFeO 3 /MXene presented good conductivity and high enrichment capability for Pb2+. • OED-ML method made efficient parameters optimization for the sensor. • The obtained sensor exhibited an extremely low detection limit down to 0.0001 μg L−1. • The proposed method was successfully used to determine Pb2+ in lake water. [ABSTRACT FROM AUTHOR]

• Cancerous MET overexpression is a common pathological feature manifested by genetic, molecular, and cellular abnormalities. • Conventional therapeutic antibodies targeting MET, under clinical trials for almost 10 years, have made little progress with various setbacks. • Novel biotherapeutics, such as bispecific antibodies, antibody-drug conjugates, and their combination, are under anti-MET clinical trials. • Amivantamab, a MET/EGFR bispecific antibody, has been granted the Breakthrough Therapy Designation status for treatment of advanced NSCLC. • An emerging era of antibody-based biotherapeutics for treatment of cancer overexpressing MET is in the horizon. Aberrant expression of the MET receptor, defined by immunohistochemical (IHC) staining and manifested through amplification, mutation, alternative exon splicing, and abnormal protein metabolism, has led to the development of small-molecule kinase inhibitors (SMKIs) and conventional therapeutic monoclonal antibodies (TmAbs) for targeted cancer therapy. SMKIs have been approved for clinical application. However, conventional anti-MET TmAbs, although under clinical trials for 10 years, have made little progress, with various setbacks, raising uncertainty about their usefulness. In this review, we discuss the relevance of MET overexpression and the latest development of bispecific antibodies, antibody–drug conjugates (ADCs), and their combined products for clinical development. Evidence from preclinical and clinical studies highlights the potential of these novel MET-targeted biotherapeutics for cancer therapy in the future. Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality. [ABSTRACT FROM AUTHOR]

• Aberrant RON expression is a pathogenic feature in breast cancer including TNBC. • Antibody-drug conjugates targeting RON for TNBC therapy is a novel strategy. • Anti-RON ADCs eradicate TNBC xenografts with favorable pharmacokinetic profiles and manageable toxicological activities. • The efficacy of anti-RON ADCs warrants their transition into clinical trials. Treatment of triple-negative breast cancer (TNBC) is a challenge to oncologists. Currently, the lack of effective therapy has fostered a major effort to discover new targets and therapeutics to combat this disease. The recepteur d'origine nantais (RON) receptor has been implicated in the pathogenesis of TNBC. Clinical studies have revealed that aberrant RON expression is crucial in regulating TNBC malignant phenotypes. Increased RON expression also has prognostic value for breast cancer progress. These features provide the rationale to target RON for TNBC treatment. In this review, we discuss the importance of RON in TNBC tumorigenesis and the development of anti-RON antibody–drug conjugates (ADCs) for clinical application. The findings from preclinical studies lay the foundation for clinical trials of this novel biotherapeutic for TNBC therapy. Discovery of novel targets and therapeutics, such as antibody–drug conjugates, targeting RON hold the promise to effectively combat triple-negative breast cancer in the future. [ABSTRACT FROM AUTHOR]

Boronate-functionalized surface imprinted nanoparticles that function under physiological pH would be highly desirable for specific enrichment of target glycoproteins. In this work, magnetic molecularly imprinted polymers integrated with low pKa teamed boronate affinity (Fe 3 O 4 @PGMA-TBA/MIPs) were fabricated for selective separation of glycoprotein at pH = 7.4. The teamed boronate affinity (TBA) was formed by boron-nitrogen (B-N) coordination between 1,6-hexamethylenediamine and 3-aminophenylboronic acid, and then was fixed on the surface of magnetic poly(glycidyl methacrylate) (Fe 3 O 4 @PGMA) through ring-opening reaction. After immobilizing the template glycoproteins (ovalbumin, OVA), surface imprinting layer was deposited onto Fe 3 O 4 @PGMA-TBA surface via redox polymerization of aniline, and Fe 3 O 4 @PGMA-TBA/MIPs with obvious core–shell-shell structure were prepared by removing template. Fe 3 O 4 @PGMA-TBA/MIPs were demonstrated with an imprinted polymer film (10–20 nm) and exhibited superparamagnetic property ( M s  = 32 emu g −1 ) and magnetic stability after multiple regenerations. Besides, the results of 11 B MAS NMR spectrum and zeta potentials confirmed the presence of TBA resulting from B-N coordination. Additionally, taking advantage of surface imprinting and TBA, as-prepared Fe 3 O 4 @PGMA-TBA/MIPs posed high binding capacity (190.7 mg g −1 ) and fast capture kinetics (50 min) toward OVA under physiological pH. More importantly, because of the TBA was electroneutral at pH = 7.4, Fe 3 O 4 @PGMA-TBA/MIPs not only exhibited superior specific recognition toward OVA (imprinting factor IF = 7.51), but also maintained the activity of OVA from practical samples analysis. Therefore, this work opened up a universal route for developing intelligent controllability molecular imprinting materials for the specific separation of glycoproteins in biomedical filed under physiological pH. [ABSTRACT FROM AUTHOR]

Chronic Mountain Sickness (CMS) occurs in high-altitude residents with major neurological symptoms such as migraine headaches, dizziness and cognitive deficits. Recent work demonstrated that highlanders have increased intracellular pH (pH i ) in their brain cells, perhaps for the sake of adaptation to hypoxemia and help to facilitate glycolysis, DNA synthesis, and cell cycle progression. Since there are well adapted (non-CMS) and maladapted (CMS) high-altitude dwellers, it is not clear whether pH i is differently regulated in these two high-altitude populations. In this work, we obtained induced pluripotent stem cell (iPSC)-derived astrocytes from both CMS and non-CMS highlanders who live in the Peruvian Andes (>14,000 ft) and studied pH i regulation in these astrocytes using pH-sensitive dye BCECF. Our results show that the steady-state pH i (ss pH i ) is lower in CMS astrocytes compared with non-CMS astrocytes. In addition, the acid extrusion following an acid loading is faster and the pH i dependence of H + flux rate becomes steeper in CMS astrocytes. Furthermore, the Na + dependency of ss pH i is stronger in CMS astrocytes and the Na + /H + exchanger (NHE) inhibitors blunted the acid extrusion in both CMS and non-CMS astrocytes. We conclude that (a) NHE contributes to the ss pH i stabilization and mediates active acid extrusion during the cytosolic acidosis in highlanders; (b) acid extrusion becomes less pH i sensitive in non-CMS (versus CMS) astrocytes which may prevent NHE from over-activated in the hypoxia-induced intracellular acidosis and render the non-CMS astrocytes more resistant to hypoxemia challenges. [ABSTRACT FROM AUTHOR]

Chronic mountain sickness (CMS) or Monge’s disease is a disease in highlanders. These patients have a variety of neurologic symptoms such as migraine, mental fatigue, confusion, dizziness, loss of appetite, memory loss and neuronal degeneration. The cellular and molecular mechanisms underlying CMS neuropathology is not understood. In the previous study, we demonstrated that neurons derived from CMS patients’ fibroblasts have a decreased expression and altered gating properties of voltage-gated sodium channel. In this study, we further characterize the electrophysiological properties of iPSC-derived astrocytes from CMS patients. We found that the current densities of the inwardly rectifying potassium (Kir) channels in CMS astrocytes (−5.7 ± 2.2 pA/pF at −140 mV) were significantly decreased as compared to non-CMS (−28.4 ± 3.4 pA/pF at −140 mV) and sea level subjects (−28.3 ± 5.3 pA/pF at −140 mV). We further demonstrated that the reduced Kir current densities in CMS astrocytes were caused by their decreased protein expression of Kir4.1 and Kir2.3 channels, while single channel properties (i.e., P o , conductance) of Kir channel in CMS astrocytes were not altered. In addition, we found no significant differences of outward potassium currents between CMS and non-CMS astrocytes. As compared to non-CMS and sea level subjects, the K + uptake ability in CMS astrocytes was significantly decreased. Taken together, our results suggest that down-regulation of Kir channels and the resulting decreased K + uptake ability in astrocytes could be one of the major molecular mechanisms underlying the neurologic manifestations in CMS patients. [ABSTRACT FROM AUTHOR]

Glucosamine (GA) is an important cartilage matrix precursor for the glycosaminoglycan biochemical synthesis, and has positive effects on cartilage regeneration, particularly in osteoarthritis therapy. However, it has not been used as a bioactive group in scaffolds for cartilage repair widely. In this study, we synthesized modified polyethylene glycol (PEG) hydrogel with glucosamine and then encapsulated human bone mesenchymal stem cells (hBMSCs) in the hydrogel to induce the differentiation of hBMSCs into chondrocytes in three-dimensional culture. The GA-modified PEG hydrogels promoted the chondrogenesis of hBMSCs, particularly in the concentration of 5 mM and 10 mM. The subcutaneous transplantation of 10 mM GA-modified hydrogels with hBMSCs formed cartilage-like blocks in vivo for 8 weeks. Importantly, with glucosamine increase, the modified hydrogels down-regulated the fibrosis and hypertrophic cartilage markers in protein level. Therefore, glucosamine modified PEG hydrogels facilitated the chondrogenesis of hBMSCs, which might represent a new method for cartilage repair using a tissue-engineering approach. [ABSTRACT FROM AUTHOR]

The sodium bicarbonate co-transporter (NBC) is the major bicarbonate-dependent acid–base transporter in mammalian astrocytes and has been implicated in ischemic brain injury. A malfunction of astrocytes could have great impact on the outcome of stroke due to their participation in the formation of blood-brain barrier, synaptic transmission, and electrolyte balance in the human brain. Nevertheless, the role of NBC in the ischemic astrocyte death has not been well understood. In this work, we obtained skin biopsies from healthy human subjects and had their fibroblasts grown in culture and reprogrammed into human-induced pluripotent stem cells (hiPSCs). These hiPSCs were further differentiated into neuroprogenitor cells (NPCs) and then into human astrocytes. These astrocytes express GFAP and S100β and readily propagate calcium waves upon mechanical stimulation. Using pH-sensitive dye BCECF [2′,7′-bis-(carboxyethyl)-5-(and-6)-carboxyfluorescein] and qPCR technique, we have confirmed that these astrocytes express functional NBC including electrogenic NBC (NBCe). In addition, astrocytes exposed to an ischemic solution (IS) that mimics the ischemic penumbral environment enhanced both mRNA and protein expression level of NBCe1 in astrocytes. Using IS and a generic NBC blocker S0859, we have studied the involvement of NBC in IS-induced human astrocytes death. Our results show that a 30 μM S0859 induced a 97.5 ± 1.6% ( n = 10) cell death in IS-treated astrocytes, which is significantly higher than 43.6 ± 4.5%, ( n = 10) in the control group treated with IS alone. In summary, a NBC blocker exaggerates IS-induced cell death, suggesting that NBC activity is essential for astrocyte survival when exposed to ischemic penumbral environment. [ABSTRACT FROM AUTHOR]

Early epilepsy is a prominent feature in patients with CDKL5-deficiency disorder (CDD). The underlying mechanism for excessive excitability in CDD is largely unknown. The brain organoid model has been recently developed to resemble many critical features of early human brain development. Here, we used a brain organoid model to investigate the cellular electrophysiological basis for hyper-excitability in CDD patients. Our study employed cortical organoids derived from two CDD patients harboring the same CDKL5 mutation (R59X) and two controls from their healthy parents. Whole-cell patch-clamp recordings revealed higher action potential (AP) firing rate and lower rheobase in both CDD organoids, indicating increased intrinsic neuronal excitability. We further found dysfunction of voltage-gated ion channels in CDD neurons that leads to hyperexcitability, including higher Na+ and K+ current densities and a negative shift in Na+ channel activation. In contrast to neuronal properties, we found that glutamatergic neurotransmission and the electrophysiological properties of glial cells were not altered in CDD organoids. In support of our CDD findings, we further discovered similar electrophysiologic properties in cortical organoids derived from a Rett syndrome (RTT) patient, including alterations in AP firings and Na+ and K+ channel function suggesting a convergent mechanism. Together, our study suggests a critical role of intrinsic neuronal hyperexcitability and ion channel dysfunction, seen in early brain development in both CDD and RTT disorders. This investigation provides potential novel drug targets for developing treatments of early epilepsy in such disorders. • Characterization of AP firings and rheobase showed increased excitability in organoids derived from CDD patients. • Neuronal hyperexcitability in CDD organoids is due to dysfunction of Na+ and K+ channels. • RTT or CDD organoids exhibited similar electrophysiological phenotypes, indicating convergent mechanisms for CDD and RTT patients. • Excitatory synaptic transmission was not altered in CDD or RTT organoids. [ABSTRACT FROM AUTHOR]

Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirus∆VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD. © 2015 The Author(s) Published by S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Summary Objectives In the winter of 2013, people were facing the risk of human-to-human transmission of the re-emerging influenza A(H7N9) virus. We report herein information on the clinical features of two patients from the same family infected with this virus, the genomic sequences of the viruses harbored, and antiviral drug sensitivity. Methods Clinical and epidemiological data of two patients from the same family were collected and analyzed. Sequencing was done for the viruses isolated from these two patients and one epidemiologically related chicken, and the sequences of the eight gene segments of the viruses were analyzed phylogenetically. The sensitivity of the viruses to antiviral drug treatment was determined by neuraminidase inhibitor susceptibility test. Results The two patients from one family cluster shared the same symptoms but had different outcomes, and had a strong epidemiological link. Three strains, two from these two patients and one from the chicken, were isolated. Genome sequencing and analyses of phylogenetic trees demonstrated that the two viruses were almost identical. We noted the presence of the PB2 E627K amino acid substitution that was not present in isolates from the first wave, as well as two new mutations in the NA gene and six in the PB2 gene. Drug sensitivity testing showed that the new isolates were resistant to oseltamivir but sensitive to peramivir. Conclusions The two patients from one family cluster were probable human-to-human transmission cases. The new isolates were sensitive to peramivir but showed reduced sensitivity to oseltamivir. [ABSTRACT FROM AUTHOR]

Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Since the discovery of MSP (macrophage-stimulating protein; also known as MST1 and hepatocyte growth factor-like (HGFL)) as the ligand for the receptor tyrosine kinase RON (also known as MST1R) in the early 1990s, the roles of this signalling axis in cancer pathogenesis has been extensively studied in various model systems. Both in vitro and in vivo evidence has revealed that MSP-RON signalling is important for the invasive growth of different types of cancers. Currently, small-molecule inhibitors and antibodies blocking RON signalling are under investigation. Substantial responses have been achieved in human tumour xenograft models, laying the foundation for clinical validation. In this Review, we discuss recent advances that demonstrate the importance of MSP-RON signalling in cancer and its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether Toll-like receptor (TLR) 7 and TLR9-mediated interferon α (IFN-α) production in plasmacytoid dendritic cells (pDCs) is compromised in patients with chronic hepatitis B virus (HBV) infection. Materials and methods: Peripheral blood mononuclear cells (PBMCs) were prepared from 32 chronic HBV patients and 13 healthy volunteers, and treated with loxoribine or cytidine phosphate guanosine (CpG) oligodeoxynucleotides (ODN). Interferon α in the supernatant was measured by sandwich ELISA. PDC frequency and the expression levels of TLR7 and TLR9 in pDCs were quantified by flow cytometry. The serum viral load of HBV was quantified using a highly sensitive real-time PCR kit. Results: Compared to cells from healthy control group, PBMCs and pDCs from the HBV group showed significantly decreased production of IFN-α in response to ligand for TLR7 (loxoribine) and TLR9 (CpG ODN, P < 0.05). Mechanistically, the number of pDCs in peripheral blood, and the expression of pDC-associated TLR7 and TLR9 were significantly lower in HBV group than in the healthy control group ( P < 0.05). In addition, the number of pDCs and the expression of TLR9 on pDCs were correlated inversely with the serum load of HBV. Conclusion: Impaired IFN-α production from pDC may contribute to the immunopathogenesis of chronic HBV infection, which may be the result of a reduced amount of pDCs as well as decreased expression of TLR7 and TLR9 on pDCs. [ABSTRACT FROM AUTHOR]

In pursuit of reducing environmental impact during battery manufacture, the utilization of nontoxic and renewable materials is essential for building a sustainable future. As one of the most intensively investigated biomaterials, proteins have recently been applied in various high‐performance rechargeable batteries. In this review, the opportunities and challenges of using protein‐based materials for high‐performance energy storage devices are discussed. Recent developments of directly using proteins as active components (e.g., electrolytes, separators, catalysts or binders) in rechargeable batteries are summarized. The advantages and disadvantages of using proteins are compared with the traditional counterparts, and the working mechanisms when using proteins to improve the electrochemical performances of rechargeable batteries are elucidated. Finally, the future development of applying biomaterials to build better batteries is predicted. [ABSTRACT FROM AUTHOR]

Abstract: Based on polyaniline/silica gel composites (PAS) as support and functional monomer, the surface imprinted polymers (MIP–PAS) were synthesized for the selective adsorption of 2,6-dichlorophenol (2,6-DCP) from aquatic environment. The MIP–PAS was characterized by FTIR spectroscopy, scanning electron microscopy, nitrogen adsorption–desorption analysis, particle-size and EDX analysis. The effects of pH, initial analyte concentration, contact time and temperature of medium on the adsorption were studied. Equilibrium data, at various temperatures, can be described well by the Langmuir isotherm model. Kinetic can be described by the pseudo-first-order model, pseudo-second-order model, and by an intraparticle diffusion equation. A diffusion-controlled process as the essential adsorption rate-controlling step was also obtained. Moreover, intraparticle diffusion coefficient (k i) and pore diffusion coefficient (D 2) for MIP–PAS elevated with the increased of 2,6-DCP concentration and temperature of medium, while increase in 2,6-DCP concentration was found to reduce film diffusion. Furthermore, the values of film diffusion coefficient (D 1) were lower than those of D 2, indicating the diffusion process was controlled by film diffusion. Thermodynamics parameters (positive values for delta H° and delta S°, negative values of delta G°) indicated that the process is endothermic and spontaneous. The selectivity of the imprint also demonstrates high affinity for 2,6-DCP over related phenolic compounds and over non-imprinted polymers (NIP). [Copyright &y& Elsevier]

Abstract: The chitosan/fly-ash-cenospheres/γ-Fe2O3 (CTS/γ-Fe2O3/FACs) magnetic composites were prepared by microemulsion process. The resulting composites were charcterized by XRD, FT-IR, SEM, TGA, DTG and VSM, and the results indicated that CTS/γ-Fe2O3/FACs exhibited magnetic property (M s =6.553emug−1) and thermal stability, and composed of chitosan wrapping magnetic γ-Fe2O3 and fly-ash-cenospheres (thickness of the cross-linked chitosan was about 5.2μm). Then the CTS/γ-Fe2O3/FACs were employed as adsorbents for the fast removal of bisphenol A (BPA) and 2,4,6-trichlorophenol (TCP) from aqueous solutions. The adsorption performances of CTS/γ-Fe2O3/FACs were investigated by batch mode experiments with respect to pH, temperature, initial concentration, contact time and binary solution system. The Langmuir isotherm model was fitted to the equilibrium data better than the Freundlich model, and the kinetic properties were well described by the pseudo-second-order equation. The effects of binary solution systems also demonstrated that BPA adsorption onto CTS/γ-Fe2O3/FACs was more affected by the simultaneous presence of competitive phenolic compound than that of TCP. In addition, the resulting composite reusability without obviously deterioration in performance was demonstrated by at least three repeated cycles. [Copyright &y& Elsevier]

The potential molecular mechanism of Brucea javanica oil in the induction of apoptosis of T24 bladder cancer cells was investigated in vitro. T24 cells were divided into two groups: one, treated with B. javanica oil and the other, untreated. The cells were maintained in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal calf serum (FCS) and 4 mM glutamine. The morphological characteristics of T24 cells were examined microscopically at the 2nd and 5th day of the culture. The drug toxicity spectrum (IC50) was estimated by the MTT assay, and viability of T24 cells was assessed on the basis of the percentage of T24 apoptotic cells, as determined by Annexin/PI staining and flow cytometric analysis. The expression of caspase-3, capase-9, NF-κB p65, and COX-2 was analyzed by Western blotting. Morphological characteristics of the cells on the 2nd day showed apoptosis of the treated T24 cells; it was more apparent in the cells on the 5th day. B. javanica oil decreased the cell viability at the testing concentrations spectrum (5–0.156 mg/ml), and this viability was significantly higher as compared to the control group. In this concentration spectrum, B. javanica oil also induced apoptosis of T24 cells, which was analyzed by annexin/PI staining and flow cytometric analysis. These results were also statistically significant as compared to those of the control group. The expressions of caspase-3 and caspase-9 were low in the control T24 cells, while the expressions of NF-κB and COX-2 were high in normal T24 cells. Treatment with B. javanica oil significantly induced the expressions of caspase-3 and caspase-9 proteins in T24 cells, whereas the expressions of NF-κB and COX-2 proteins were inhibited. B. javanica oil significantly reduced the viability of T24 cells and induced T24 cell apoptosis. The molecular mechanism underlying these effects may be the activation of caspase apoptotic pathway by upregulation of the expression of caspase-3 and caspase-9 proteins and inhibition of the expression of NF-κB and COX-2 proteins. [ABSTRACT FROM AUTHOR]

• The pyrolysis and thermal runaway behavior of tetrazolo[1,5-a]pyridine were evaluated. • The kinetic parameters under dynamic heating and adiabatic conditions were obtained. • The thermal safety parameters were calculated. • The major gasous pyrolysis products were N 2 , HCN and C 2 H 2 by TG-MS and DFT methods. • The most likely pyrolysis mechanism of tetrazolo[1,5-a]pyridine was proposed. The pyrolysis characteristics of tetrazolo[1,5-a]pyridine were investigated by thermogravimetric analysis (TG) and differential scanning calorimetry (DSC). The apparent activation energy (E α) was estimated with DSC and various kinetic analysis methods, and it was determined that the decomposition of tetrazolo[1,5-a]pyridine follows the Avarami-Erofeve (A 2) reaction pattern. The thermal safety and thermodynamic parameters were calculated. In addition, the thermal runaway behavior and kinetic parameters under adiabatic conditions were studied by employing an adiabatic accelerating calorimeter (ARC). Thermogravimetric-photoionization mass spectrometry (TG-MS) was used to identify the vapor phase products of the pyrolysis process. The different decomposition pathways were analyzed by density functional theory (DFT). The main decomposition products were N 2 , C 2 H 2 and HCN according to TG-MS experiments and theoretical calculations. The most likely proposed decomposition mechanism proceeded through the opening of the tetrazole ring to dissociate N 2 and the rupturing of the pyridine ring to release C 2 H 2 and HCN. The findings of these experiments and theoretical calculations can contribute to the determination of safety precautions for possible heat hazard accidents during the handling, transportation, use and storage of tetrazolo[1,5-a]pyridine. [ABSTRACT FROM AUTHOR]

Lipid metabolism influences membrane proteins, including ion channels, in health and disease. Fatty acid esters of CoA are important intermediates in fatty acid metabolism and lipid biosynthesis. In the present study, we examined the effect of acyl-CoAs on hSlo BK currents. Arachidonoyl-CoA (C20-CoA) induced β2-dependent inhibition of hSlo-α current when applied intracellularly but not extracellularly. This action was also mimicked by other long-chain acyl-CoAs such as oleoyl-CoA (C18-CoA) and palmitoyl-CoA (C16-CoA), but not acetyl-CoA (C2-CoA, shorter chain), suggesting that the length of acyl chains, rather than CoA headgroups, is critical. When hSlo-α inactivation was induced by a free synthetic cationic β2 NH2-terminus inactivation ball peptide, long-chain acyl-CoAs inhibited hSlo-α current and facilitated inactivation. The precursor fatty acids also facilitated the ball peptide-induced inactivation in a chain length-dependent manner, whereas sphingosine (positively charged) slowed this inactivation. When the β2-induced inactivation was compared with that of the ball peptide, there was a negative shift in the steady state inactivation, slower recovery, and a reduced voltage-dependence of inactivation onset. These data suggest that electrostatic interactions with the cytosolic inactivation domain of β2 mediate acyl-CoA modulation of BK currents. BK channel inactivation may be a specific target for lipid modulation in physiological and pathophysiological conditions. [ABSTRACT FROM AUTHOR]

Abstract: Aberrant expression of the RON (Recepteur d’Origine Nantais) receptor tyrosine kinase, accompanied by generation of multiple splicing or truncated variants, contributes to pathogenesis of epithelial cancers. Currently, six variants including RONΔ170, Δ165, Δ160, Δ155, Δ110, and Δ55 with various deletions or truncations in the extracellular or intracellular regions have been identified. The extracellular sequences contain functional structures such as sema domain, PSI motif, and IPT units. The deletion or truncation results in constitutive phosphorylation and increased kinase activities. Oncogenic RONΔ160, generated by exclusion of the first IPT unit, is a typical example. In contrast, the deletion adjacent to the conserved MET1254 in the kinase domain converts RON into a dominant negative agent. Among three mechanisms underlying isoform production, the switch from constitutive to alternative pre-mRNA splicing is the major event in producing RON variants in cancer cells. Most of the RON variants have the ability to activate multiple signaling cascades with a different substrate specificity and phosphorylation profile. They regulate cell migration, invasion, and proliferation, which contribute to the invasive phenotype and promote the malignant progression. Thus, determining the pathogenesis of RON variants is critical in understanding the mechanisms underlying cancer initiation and progression. Targeting oncogenic signals elicited by RON or its variants by special antibody or small interfering RNA could provide a novel strategy for the treatment of malignant epithelial cancers. [Copyright &y& Elsevier]

In focal ischemia, the fate of penumbral cells is closely linked to the infarcted tissue. Because of the release of cytosolic material from damaged cells, the biochemical and ionic alterations within the core are dramatic. Hence, adjacent cells ( infarct rim) are generally exposed to these changes and may be deleteriously affected. To mimic such conditions in vitro, we have employed a slice culture system and used an ischemic solution (IS) that resembles the milieu in the territory of infarct rim. In contrast to normal artificial cerebral spinal fluid, IS is characterized by low O2, glucose, pH; excitotoxic levels of glutamate; and ionic alterations. In organotypic hippocampal slice cultures, we examined cell injury/death using propidium iodide following exposure to IS. Our data show significant cell injury starting at ∼8 h following IS exposure with cell injury spreading as a function of exposure duration. We further studied the effect of each component in the IS separately, i.e., acidosis, hypoxia, ionic shifts or glutamate exitotoxicity and were able to isolate the contribution of each of these effectors to the IS-induced cell death. Our results suggest that in IS, acidosis exacerbates the potential for injury while ionic shifts, especially those of K+ and Na+, alleviate the potential for cell death. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation.Methods: We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence.Results: Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK-STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression.Conclusions: Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression. [ABSTRACT FROM AUTHOR]

• Bismuth-rich Bi 4 O 5 I 2 nanosheets were prepared through progressive hydrolysis of urea in a facile solvothermal route. • Adjusting the sufficient and progressive hydrolysis of urea in ethylene glycol is vital step. • Resulted Bi 4 O 5 I 2 nanosheets exhibited superior visible-light photoreduction activity of Cr (VI). Bismuth-rich Bi 4 O 5 I 2 nanosheets were prepared through progressive hydrolysis of urea in a facile solvothermal route, which is different from the conventional strategies of pH adjusting or calcination. To promote the hydrolysis of urea for the formation of Bi 4 O 5 I 2 nanosheets, the type of solvents and urea concentration were the distinctive roles. Especially, urea concentration over 1.0 g but less than 3.0 g in the solvent of ethylene glycol could boost the formation of Bi 4 O 5 I 2 nanosheets. Furthermore, the resulted Bi 4 O 5 I 2 nanosheets possessing more negative conductive band level of −1.02 eV showed superior visible-light photoreduction activity of Cr (VI) due to the efficient separation of charge carriers. [ABSTRACT FROM AUTHOR]

Advanced epithelial cancers such as gastric, lung, and pancreatic tumors are featured by invasive proliferation, distant metastasis, acquired chemoresistance, and tumorigenic stemness. For the last decade, molecular-targeted therapies using therapeutic antibodies, small molecule kinase inhibitors and immune-checkpoint blockades have been applied for these diseases with significant clinical benefits. Nevertheless, there is still a large gap to achieve curative outcomes. MET (mesenchymal-epithelial transition protein), a receptor tyrosine kinase, is a tumorigenic determinant that regulates epithelial cancer initiation, progression, and malignancy. Increased MET expression also has prognostic value for cancer progression and patient survival. These features provide the rationale to target MET for cancer treatment. In this review, we discuss the importance of MET in epithelial tumorigenesis and the development of antibody-based biotherapeutics, including bispecific antibodies and antibody-drug conjugates, for clinical application. The findings from both preclinical and clinical studies highlight the potential of MET-targeted biotherapeutics for cancer therapy in the future. [ABSTRACT FROM AUTHOR]

Advanced colorectal adenocarcinoma (CRAC), featured by distinctive histopathological appearance, distant organ metastasis, acquired chemoresistance, and tumorigenic stemness is a group of heterogeneous cancers with unique genetic signatures and malignant phenotypes. Treatment of CRAC is a daunting task for oncologists. Currently, various strategies including molecular targeting using therapeutic monoclonal antibodies, small molecule kinase inhibitors and immunoregulatory checkpoint therapy have been applied to combat this deadly disease. However, these therapeutic modalities and approaches achieve only limited success. Thus, there is a pharmaceutical need to discover new targets and develop novel therapeutics for CRAC therapy. MET and RON receptor tyrosine kinases have been implicated in CRAC pathogenesis. Clinical studies have revealed that aberrant MET and/or RON expression and signaling are critical in regulating CRAC progression and malignant phenotypes. Increased MET and/or RON expression also has prognostic value for CRAC progression and patient survival. These features provide the rationale to target MET and RON for clinical CRAC intervention. At present, the use of small molecule kinase inhibitors targeting MET for CRAC treatment has achieved significant progress with several approvals for clinical application. Nevertheless, antibody-based biotherapeutics, although under clinical trials for more than 8 years, have made very little progress. In this review, we discuss the importance of MET and/or RON in CRAC tumorigenesis and development of anti-MET, anti-RON, and MET and RON-dual targeting antibody-drug conjugates for clinical application. The findings from both preclinical studies and clinical trials highlight the potential of this novel type of biotherapeutics for CRAC therapy in the future. [ABSTRACT FROM AUTHOR]

• Thermokinetic characteristics of H4-PTZ-methylene tetrazole were explored. • Thermal safety parameters of H4-PTZ-methylene tetrazole were calculated. • The initial decomposition mechanism of H4-PTZ was investigated and elucidated. 5-(4-Pyridyl)tetrazolate-methylene tetrazole (H4-PTZ-methylene tetrazole) was prepared. Thermokinetic characteristics of H4-PTZ-methylene tetrazole were described through differential scanning calorimetry (DSC). Ozawa method, Kissinger method, and isoconversional approach were used to calculate the kinetic parameters. Thermal safety parameters, such as self-accelerated decomposition temperature (SADT) and thermal ignition temperature (T TIT), were evaluated from experimental results. The initial decomposition process was investigated using experimental and theoretical calculations. Geometric optimisation, Mulliken charges, electrostatic potentials, and decomposition pathways were explored using Gaussian 16. The simultaneous dissociation of C7–N8 and N9–N10 bonds (DM1) and of C13–N17 and N15–N16 bonds (DM2) had lower energy barriers. The theoretical apparent activation energy was higher than the experimental one. As a novel finding, the exothermic process observed through DSC was primarily because of the reaction that opened the tetrazole ring, which released nitrogen. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with poor prognosis and high mortality. Molecular aberrations associated with PDAC pathogenesis and progression have been extensively investigated. Nevertheless, these findings have not been translated into clinical practice. Lack of therapeutics for PDAC treatment is another challenge. Recent application of molecularly targeted and immunoregulatory therapies appears to be disappointing. Thus, discovery of new targets and therapeutics is urgently needed to combat this malignant disease. The RON receptor tyrosine kinase is a tumorigenic determinant in PDAC malignancy, which provides the rationale to target RON for PDAC treatment. In this review, we summarize the latest evidence of RON in PDAC pathogenesis and the development of anti-RON antibody-drug conjugates for potential PDAC therapy. The finding that anti-RON antibody-drug conjugates show efficacy in preclinical animal models highlights the potential of this novel class of anti-cancer biotherapeutics in future clinical trials. [ABSTRACT FROM AUTHOR]

Fine‐grained visual classification is challenging due to the inherently subtle intra‐class object variations. To solve this issue, a novel framework named channel attention and progressive multi‐granularity training network, is proposed. It first exploits meaningful feature maps through the channel attention module and captures multi‐granularity features by the progressive multi‐granularity training module. For each feature map, the channel attention module is proposed to explore channel‐wise correlation. This allows the model to re‐weight the channels of the feature map according to the impact of their semantic information on performance. Furthermore, the progressive multi‐granularity training module is introduced to fuse features cross multi‐granularity. And the fused features pay more attention to the subtle differences between images. The model can be trained efficiently in an end‐to‐end manner without bounding box or part annotations. Finally, comprehensive experiments are conducted to show that the method achieves state‐of‐the‐art performances on the CUB‐200‐2011, Stanford Cars, and FGVC‐Aircraft datasets. Ablation studies demonstrate the effectiveness of each part in our module. [ABSTRACT FROM AUTHOR]

PtII based organometallic photosensitizers (PSs) have emerged as novel potent photodynamic inactivation (PDI) reagents through their enhanced intersystem crossing (ISC) processes. Currently, few PtII PSs have been investigated as antibacterial materials, with relatively poor performances reported and with structure‐activity relationships not well described. Herein, a pair of configurational isomers are reported of Bis‐BODIPY (4,4‐difluoro‐boradizaindacene) embedded PtII PSs. The cis‐isomer (cis‐BBP) displayed enhanced 1O2 generation and better bacterial membrane anchoring capability as compared to the trans‐isomer (trans‐BBP). The effective PDI concentrations (efficiency > 99.9%) for cis‐BBP in Acinetobacter baumannii (multi‐drug resistant (MDR)) and Staphylococcus aureus are 400 nM (12 J cm−2) and 100 nM (18 J cm−2), respectively; corresponding concentrations and light doses for trans‐BBP in the two bacteria are 2.50 µM (30 J cm−2) and 1.50 µM (18 J cm−2), respectively. The 50% and 90% minimum inhibitory concentration (MIC50 and MIC90) ratio of trans‐BBP to cis‐BBP is 22.22 and 24.02 in A. baumannii (MDR); 21.29 and 22.36 in methicillin resistant S. aureus (MRSA), respectively. Furthermore, cis‐BBP displays superior in vivo antibacterial performance, with acceptable dark and photoinduced cytotoxicity. These results demonstrate cis‐BBP is a robust light‐assisted antibacterial reagent at sub‐micromolecular concentrations. More importantly, configuration of PtII PSs should be an important issue to be considered in further PDI reagents design. [ABSTRACT FROM AUTHOR]

Locus coeruleus (LC) dysfunction is involved in the pathophysiology of depression; however, the neural circuits and specific molecular mechanisms responsible for this dysfunction remain unclear. Here, it is shown that activation of tyrosine hydroxylase (TH) neurons in the LC alleviates depression‐like behaviors in susceptible mice. The dorsolateral septum (dLS) is the most physiologically relevant output from the LC under stress. Stimulation of the LCTH‐dLSSST innervation with optogenetic and chemogenetic tools bidirectionally can regulate depression‐like behaviors in both male and female mice. Mechanistically, it is found that brain‐derived neurotrophic factor (BDNF), but not norepinephrine, is required for the circuit to produce antidepressant‐like effects. Genetic overexpression of BDNF in the circuit or supplementation with BDNF protein in the dLS is sufficient to produce antidepressant‐like effects. Furthermore, viral knockdown of BDNF in this circuit abolishes the antidepressant‐like effect of ketamine, but not fluoxetine. Collectively, these findings underscore the notable antidepressant‐like role of the LCTH‐dLSSST pathway in depression via BDNF‐TrkB signaling. [ABSTRACT FROM AUTHOR]

A water soluble diacrylate decorated aggregation induced emission (AIE) fluorophore (tetraphenyl ethylene decorated with diacrylate, TPE‐D) has been synthesized via straight forward synthetical route. The compound displayed promising liquid viscosity sensing capability. Upon increasing the liquid viscosity, the fluorescence emission intensity was observed to enhance. By polymerization with diacrylate‐PEG, a novel mechanical parameter self‐characterizing fluorescent hydrogel has been constructed. Taking advantages of AIE nature of TPE‐D, the viscosity, elastic modulus and viscous modulus, in addition to the liquid viscosity, of the as‐constructed hydrogel can be reflected by fluorescent intensity. We wish this novel hydrogel can be further applied as 3D cell culture to disclose the mechanical influence on disease related cellular behavior. [ABSTRACT FROM AUTHOR]

In this research, pendimethalin was synthesized by a two-step reaction with N-(1-Ethylpropyl)− 3,4-dimethylaniline as raw material and nitric acid as nitration reagent. The research focused on the second-step reaction, which was far more dangerous than the first-step. The effects of reaction temperature (T p), feeding time (t), stirring rate (SR) and nitric acid concentration (φ) on the yield and thermal hazard of the second step reaction were explored by experiments. The optimal process conditions were obtained. In addition, concentration variation of each component during the reaction were monitored by using HPLC for intermediate sampling. Combined with the theoretical calculation, the possible reaction mechanism was deduced. The reaction can be divided into two main paths according to the sequence of nitro substitution. In one of these paths the nitro group replaced the H first at position 2 and then at position 6, while in the other path it was completely reversed. Both paths eventually produced pendimethalin. Finally, the thermal hazard was analyzed by Stoessel criticality diagram. The risk levels for the two-step reaction were level 1 and level 3, respectively. This study provides theoretical support for the safe production of the nitration and synthesis of pendimethalin. [ABSTRACT FROM AUTHOR]