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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]

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]

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]

• 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]

• 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]

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]

One of the current challenges in burn wound care is the development of multifunctional dressings that can protect the wound from bacteria or organisms and promote skin regeneration and tissue reconstitution. To this end, we report the design and fabrication of a composite electrospun membrane, comprised of electrospun polylactide: poly(vinyl pyrrolidone)/polylactide: poly(ethylene glycol) (PLA:PVP/PLA:PEG) core/shell fibers loaded with bioactive agents, as a functionally integrated wound dressing for efficient burns treatment. Different mass ratios of PLA:PVP in the shell were screened to optimize mechanical, physicochemical, and biological properties, in addition to controlled release profiles of loaded antimicrobial peptides (AMPs) from the fibers for desirable antibacterial activity. Fibroblasts were shown to readily adhere and proliferate when cultured on the membrane, indicating good in vitro cytocompatibility. The introduction of PLA beads by electrospraying on one side of the membrane resulted in biomimetic micro-nanostructures similar to those of lotus leaves. This designer structure rendered the composite membranes with superhydrophobic property to inhibit the adhesion/spreading of exogenous bacteria and other microbes. The administration of the resulting composite fibrous membrane on burnt skin in an infected rat model led to faster healing than a conventional product (sterile silicone membrane) and control detailed herein. These composite fibrous membranes loaded with bioactive drugs provide an integrated strategy for promoting burn wound healing and skin regeneration. To address an urgent need in complex clinical requirements on developing a new generation of wound dressings with integrated functionalities. This article reports research work on a hierarchical fiber/bead composite membranes design, which combines a lotus-leaf-like superhydrophobic surface with drugs preloaded in the core and shell of fibers for effective burn treatment. This demonstrates a balance between simplified preparation processes and increased multifunctionality of the wound dressings. The creation of hierarchically structured surfaces can be readily achieved by electrospinning, and the composite dressings possessed a considerable mechanical strength, effective wound exudate absorption and permeability, good biocompatibility, broad antibacterial ability and promoting wound healing etc. Thus, our work unveils a promising strategy for the development of functionally integrated wound dressings for burn wound care. [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]

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]

The function and regulation of different heterogeneous reactive states of astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic reactive (A1-like) astrocytes are strongly induced, prior to behavioral impairments and dendritic atrophy, in depression-like mice. More interestingly, global or microglia-specific knockout of Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific Nlrp3 depletion is ineffective. Microglial Nlrp3 ablation also alleviates the neuronal dysfunction induced by A1-like astrocytes both in vitro and in vivo. We further show that in microglia the NF-κB pathway activates the NLRP3 inflammasome which in turn activates caspase-1 to induce the secretion of A1 inductors, leading to the production of A1-like astrocytes. Altogether, this study reveals the function of microglial NLRP3 inflammasome in the induction of neurotoxic astrocytes via activating neuroinflammatory caspase-1 pathway in response to chronic stress and suggests a potential therapeutic strategy for depression. [Display omitted] • Neurotoxic A1-like astrocytes are enhanced in the CMS depression mouse model • NLRP3 inflammasome in microglia but not in astrocytes induces A1-like astrocytes • NLRP3 inflammasome activates microglia and promotes A1 cocktail secretion • NF-κB and caspase-1 pathways are involved in NLRP3-induced astrocyte reactivity Li et al. report that microglial NLRP3 inflammasome induces neurotoxic A1-like astrocytes and neuronal dysfunction in response to chronic mild stress in mice through pro-A1 astrocyte cytokines, involving upstream NF-κB pathway and downstream caspase-1 pathway. Their results suggest crucial roles of microglial NLRP3 in neurotoxic astrocyte reactivity in major depression. [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]

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]

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]

• 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]

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]

In this study, diphenyl sulfoxide was prepared by oxidizing diphenyl sulfide with hydrogen peroxide using phosphotungstic acid as catalyst in semi-batch mode. In order to optimize the synthesis process, a four-factor three-level Box-Behnken design was adopted. The result showed that under the optimal condition, namely catalyst concentration 0.19 mmol/mol, oxygen-sulfur ratio 1.08, reaction temperature 30 ºC, and dosing time 15 min, the yield of diphenyl sulfoxide could reach up to 79.05%. In addition, the thermal behavior of synthesis process was systematically investigated using a reaction calorimeter (EasyMax 102) equipped with a situ FTIR monitoring. The receivable mechanism is that H 2 O 2 is activated by the catalyst and subsequently reacts with diphenyl sulfide to produce oxidized product. H 2 O 2 was relatively stable when PTA was used as catalyst. Thermal risk index was used to assess the thermal hazard of H 2 O 2 & PTA. Furthermore, risk matrix method as well as Stoessel criticality diagram was used to assess the thermal risk of the process and an unacceptable risk was obtained. One of the main hidden dangers was the potential chemical splatter caused by decomposition of H 2 O 2. It should be equipped with a pre-set quench or sufficient emergency discharge to avoid further loss. The results of this work proposed a solid foundation for the safe operation of this process and can be further used for scale-up. [ABSTRACT FROM AUTHOR]