Scutellarein derivatives with histamine H3 receptor antagonism and cholinesterase inhibitory potency as multi target-directed ligands for possible Alzheimer's disease therapy.

A series of scutellarein 7-l-amino acid carbamate-4'-cycloalkylamine propyl ether conjugates were designed and synthesized for the first time as multifunctional agents for Alzheimer's disease (AD) therapy. The designed compounds exhibited more balanced and effective multi-target potency. Among them, compound 11l, l-Valine carbamate derivative of scutellarein cycloheptylamine ether, exhibited the most potent inhibition of electric eel AChE enzymes and human AChE enzymes, with an IC50 values of 7.04 µM and 9.73 µM, respectively. Moreover, 11l exhibited more potent H3R antagonistic activities than clobenpropit, with an IC50 value of 1.09 nM. Compound 11l not only displayed excellent inhibition of self- and Cu2+-induced Aß1-42 aggregation (95.48 % and 88.63 % inhibition, respectively) but also induced the disassembly of self- and Cu2+-induced Aß fibrils (80.16 % and 89.30 % disaggregation, respectively). Moreover, 11l significantly reduced tau protein hyperphosphorylation induced by Aß25-35. It exhibited effective antioxidant activity and neuroprotective potency, and inhibited RSL3-induced PC12 cell ferroptosis. Assays of hCMEC/D3 and hPepT1-MDCK cell line permeability indicated that 11l would have optimal blood-brain barrier permeability and intestinal absorption characteristics. In addition, in vivo studies revealed that compound 11l significantly attenuated learning and memory impairment in an AD mouse model. Finally, a pharmacokinetic characterization of 11l indicated favorable druggability and pharmacokinetic properties. Taken together, our results suggest that 11l is a potential candidate for AD treatment and merits further investigation.

Research Progress on the Degradation of Organic Pollutants in Wastewater via Ultrasound/Periodate Systems: A Review.

In recent years, the efficient removal of organic pollutants from wastewater has emerged as a critical area of global research interest. Against this backdrop, an array of innovative technologies for wastewater treatment has been developed. Among numerous advanced oxidation processes (AOPs), periodate (PI), an emerging oxidizing agent in AOPs, has garnered significant attention from researchers. Particularly, the integration of ultrasound (US)-activated PI systems has been recognized as an exceptionally promising approach for the synergistic degradation of organic pollutants in wastewater. In this paper, we conducted a thorough analysis of the mechanisms underlying the degradation of organic pollutants using the US/PI system. Furthermore, we comprehensively delineated the effects of ultrasonic power, periodate concentration, temperature, pH, coexisting inorganic ions, and dissolved organic matter on the removal efficiency of organic pollutants and summarized application cases of the US/PI system for the degradation of different pollutants. Finally, we also offered prospective discussions on the future trajectories of US/PI technology development.

Degradation of tetracycline by heat/peroxymonosulfate and ultrasound/peroxymonosulfate systems: performance and kinetics.

In recent decades, water pollution caused by emerging contaminants such as pharmaceuticals, has attracted much attention. Antibiotics are commonly used pharmaceuticals, and their residue in water may accelerate the development of antibiotic resistance genes, which can produce resistance to the treatment of diseases. In this study, two energy-based systems, heat/peroxymonosulfate (PMS) and ultrasound (US)/PMS were chosen to treat the typical antibiotic tetracycline (TC) in water. The influencing factors and kinetic equations of TC degradation by heat/PMS and US/PMS were investigated and the rates of TC degradation by the two systems were compared. The results showed that the optimal PMS concentration required for TC degradation in both systems was 0.3 mM, and neither system was affected by solution pH. The power of the US in the US/PMS system was as important as the temperature in the heat/PMS system because they provided activation energy. Both heat and US could activate PMS to degrade TC, and US was slightly superior with 80% TC removal under the conditions of [TC] = 20 mg/L, [PMS] = 0.3 mM, pH = 6.4, T = 20 °C, and US power = 550 W. US is considered to be more advantageous in activating PMS to degrade TC.

Design, synthesis and evaluation of tetrahydrocarbazole derivatives as potential hypoglycemic agents.

Two series of tetrahydrocarbazole derivatives have been designed and synthesized based on ZG02, a promising candidate developed in our previous studies. The newly prepared compounds were screened for glucose consumption activity in HepG2 cell lines. Aza-tetrahydrocarbazole compound 12b showed the most potent hypoglycemic activity with a 45% increase in glucose consumption when compared to the solvent control, which had approximately 1.2-fold higher activity than the positive control compounds (metformin and ZG02). An investigation of the potential mechanism indicated that 12b may exhibit hypoglycemic activity via activation of the AMPK pathway. Metabolic stability assays revealed that 12b showed good stability profiles in both artificial gastrointestinal fluids and blood plasma from SD rats. An oral glucose tolerance test (OGTT) was performed and the results further confirmed that 12b was a potent hypoglycemic agent.

Brand equity and the Covid-19 stock market crash: Evidence from U.S. listed firms.

Brand equity has played an important role in firms' stock performance, especially during the stock market crash provoked by Covid-19. Our manuscript investigates how brand equity impacts stock performance during the Covid-19 crash. Firms with top brands should be a particularly attractive "safe harbor" in the crash to investors since consumer loyalty and demand advantages brought by brand equity enable firms to retain stable cash flows and mitigate the macroeconomic shock. Based on U.S. listed firms, we find that firms with top brands experience higher stock returns, lower systematic risk and lower idiosyncratic risk in the Covid-19 crash than other firms. Moreover, our findings are used to distinguish the brand equity effect from the corporate social responsibility (CSR) effect on stock performance during the Covid-19 crash.

The implication of LncRNA MALAT1 in promoting chemo-resistance of laryngeal squamous cell carcinoma cells.

BACKGROUND: This study was aimed to evaluate the involvement of lncRNA MALAT1 in modifying chemo-sensitivity of laryngeal squamous cell carcinoma (LSCC) cell lines. METHODS: Totally 108 pairs of tumor tissues and matched para-tumor normal tissues were gathered from patients who were pathologically confirmed as LSCC. Meanwhile, LSCC cell lines, including TU686, TU177, AMC-HN-8, and LSC-1, were purchased to evaluate their tolerance to cisplatin, 5-fluorouracil, paclitaxel, and vincristine. Additionally, CCK-8 assay, flow cytometry, transwell assay, and wound healing assay were implemented to assess the part of MALAT1 in modulating viability, apoptosis, invasion, and migration of LSCC cell lines. RESULTS: MALAT1 expression was higher in LSCC tissues than in adjacent normal tissues (P < .05), and LSCC patients who carried highly expressed MALAT1 demonstrated poorer 5-year survival than ones with low MALAT1 expression (P < .05). For another, expression of MALAT1 was also unusually elevated within TU686, TU177, AMC-HN-8, and LSC-1 cell lines as relative to NHBEC cell line (P < .05). The TU686 cell line therein excelled in resisting the growth-curbing effects of 5-fluorouracil (IC50 = 20.44 µmol/L), paclitaxel (IC50 = 35.86 µg/L), and vincristine (IC50 = 0.12 µmol/L), when compared with TU177, AMC-HN-8, and LSC-1 cell line (P < .05). Moreover, there seemed great potential for over-expressed MALAT1 to enhance the chemo-resistance of both TU686 and LSC-1 cell lines (P < .05). Not only that, silencing of MALAT1 tended to undermine the proliferative and metastatic power of TU686 and LSC-1 cell lines (P < .05). CONCLUSION: LncRNA MALAT1 counted in triggering tolerance of LSCC against chemo-drugs by boosting metastasis and depressing apoptosis of tumor cells.

Syntheses of coumarin-tacrine hybrids as dual-site acetylcholinesterase inhibitors and their activity against butylcholinesterase, Aß aggregation, and ß-secretase.

Exploring small-molecule acetylcholinesterase (AChE) inhibitors to slow the breakdown of acetylcholine (Ach) represents the mainstream direction for Alzheimer's disease (AD) therapy. As the first acetylcholinesterase inhibitor approved for the clinical treatment of AD, tacrine has been widely used as a pharmacophore to design hybrid compounds in order to combine its potent AChE inhibition with other multi-target profiles. In present study, a series of novel tacrine-coumarin hybrids were designed, synthesized and evaluated as potent dual-site AChE inhibitors. Moreover, compound 1g was identified as the most potent candidate with about 2-fold higher potency (Ki=16.7nM) against human AChE and about 2-fold lower potency (Ki=16.1nM) against BChE than tacrine (Ki=35.7nM for AChE, Ki=8.7nM for BChE), respectively. In addition, some of the tacrine-coumarin hybrids showed simultaneous inhibitory effects against both Aß aggregation and ß-secretase. We therefore conclude that tacrine-coumarin hybrid is an interesting multifunctional lead for the AD drug discovery.

A multistep approach for exploring quality markers of Shengjiang Xiexin decoction by integrating plasma pharmacochemistry-pharmacokinetics-pharmacology.

Shengjiang Xiexin decoction (SXD), a well-known traditional Chinese medicine (TCM), was used to alleviate delayed-onset diarrhea induced by the chemotherapeutic agent irinotecan (CPT-11). Our previous study showed that SXD regulated multidrug resistance-associated protein 2 (Mrp-2) to alter the pharmacokinetics of CPT-11 and its metabolites. However, the pharmacodynamic constituents and the related quality markers of SXD are unclear. In this study, ultra-high performance liquid chromatography coupled with quadrupole orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) was utilized to identify the prototypes and metabolites in rat plasma after oral administration of SXD. The pharmacokinetic markers (PK markers) were screened through quantification and semiquantification of SXD-related xenobiotics in plasma using liquid chromatography-mass spectrometry (LC-MS) combined with statistical analysis. Computational molecular docking was performed to assess the potential binding ability of the PK markers with the target Mrp-2. The results were verified by evaluating the impact on Mrp-2 function using Caco-2 cells. The quality markers were chosen from these PK markers based on the binding affinities with Mrp-2, the specificity and the traceability. As a result, a total of 142 SXD-related exogenous components, including 77 prototypes and 65 metabolites, were detected in rat plasma. Among these, 83 xenobiotics were selected as PK markers due to their satisfactory pharmacokinetic behaviors. Based on the characteristics of quality markers, the prototype-based PK markers were considered the indices of quality control for SXD, including baicalin, baicalein, wogonoside, wogonin, liquiritigenin, isoliquiritigenin, norwogonin, oroxylin A, dihydrobaicalin, chrysin, glycyrrhizic acid, glycyrrhetinic acid, oroxylin A 7-O-glucuronide, liquiritin and isoliquiritin. This study provided an interesting strategy for screening the quality markers involved in the pharmacokinetics of SXD and its action target, which offered important information for the modernization of SXD and other TCM formulae.

Computational gibberellin-binding channel discovery unraveling the unexpected perception mechanism of hormone signal by gibberellin receptor.

Gibberellins (GAs) are phytohormones essential for many developmental processes in plants. In this work, fundamental mechanism of hormone perception by receptor GID1 has been studied by performing computational simulations, revealing a new GA-binding channel of GID1 and a novel hormone perception mechanism involving only one conformational state of GID1. The novel hormone perception mechanism demonstrated here is remarkably different from the previously proposed/speculated mechanism [Murase et al., Nature 2008, 456, 459] involving two conformational states ("OPEN" and "CLOSED") of GID1. According to the new perception mechanism, GA acts as a "conformational stabilizer," rather than the previously speculated "allosteric inducer," to induce the recognition of protein DELLA by GID1. The novel mechanistic insights obtained in this study provide a new starting point for further studies on the detailed molecular mechanisms of GID1 interacting with DELLA and various hormones and for mechanism-based rational design of novel, potent growth regulators that target crops and ornamental plants.

Design and synthesis of 1-(benzothiazol-5-yl)-1H-1,2,4-triazol-5-ones as protoporphyrinogen oxidase inhibitors.

Protoporphyrinogen oxidase (PPO, E.C. 1.3.3.4) is the action target for several structurally diverse herbicides. A series of novel 4-(difluoromethyl)-1-(6-halo-2-substituted-benzothiazol-5-yl)-3-methyl-1H-1,2,4-triazol-5(4H)-ones 2a-z were designed and synthesized via the ring-closure of two ortho-substituents. The in vitro bioassay results indicated that the 26 newly synthesized compounds exhibited good PPO inhibition effects with K(i) values ranging from 0.06 to 17.79 µM. Compound 2e, ethyl 2-{[5-(4-(difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-fluorobenzo-thiazol-2-yl]thio}acetate, was the most potent inhibitor with K(i) value of 0.06 µM against mtPPO, comparable to (K(i)=0.03 µM) sulfentrazone. Further green house assays showed that compound 2f (K(i)=0.24 µM, mtPPO), ethyl 2-{[5-(4-(difluoromethyl)-3-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-6-fluorobenzothiazol-2-yl]thio}propanoate, showed the most promising post-emergence herbicidal activity with broad spectrum even at concentrations as low as 37.5 gai/ha. Soybean exhibited tolerance to compound 2f at the dosages of 150 gai/ha, whereas they are susceptible to sulfentrazone even at 75 gai/ha. Thus, compound 2f might be a potential candidate as a new herbicide for soybean fields.

Piezoelectric polarization coupled with photoinduced catalytic oxidation technology for environmental pollution control: Recent advances and future prospects.

Energy scarcity and environmental pollution concerns have become substantial impediments to sustainable global economic development. The advent of semiconductor photocatalysis technology provides a potential possibility for effectively alleviating excessive energy consumption and maintaining the long-term stability of the aqueous ecosystem. However, the inefficient transmission efficiency of charge carriers and the high recombination rate of photogenerated electron-hole pairs will culminate in the mediocre catalytic performance observed in conventional semiconductor materials. Fortunately, the piezo-photocatalysis ingeniously integrates the piezoelectric properties of piezoelectric crystals with the optoelectronic properties of semiconductors, thus building a theoretical system of photo-electric-chemical three-phase coupled catalysis. Currently, the photo-mechanical energy synergistic catalytic oxidation degradation process, as a cutting-edge technology based on clean renewable energy, has been perceived as a promising environmental remediation strategy. Herein, a critical review of the application of piezo-photocatalysis in environmental pollution control was delivered. We undertook a comprehensive analysis to elucidate the underlying enhancement mechanism of the piezoelectric effect on photocatalysis in terms of charge migration dynamics and pertinent energy band bending phenomena. In addition, we meticulously summarized diverse innovative methods for introducing vibration energy in piezo-photocatalytic degradation systems (ultrasound, fluid mechanical energy, airflow, self-assembled reactors, etc.). Then, state-of-the-art research advances in the field of environmental pollution control and the corresponding environmental decontamination mechanisms were elaborated based on various integration modes of catalysts (single component, noble metal deposition, heterojunction, coupled substrate materials, etc.). Eventually, an in-depth assessment of current limitations and development trends of piezo-photocatalytic degradation technology has been proposed, along with proactive strategies aimed at surmounting the existing challenges.

Synthesis of chitin nanocrystals supported Zn2+ with high activity against tobacco mosaic virus.

Chitin is a kind of natural nitrogenous organic polysaccharide. It contains antibacterial and antiviral properties, and it can induce plant disease resistance and promote plant growth. However, its application is constrained due to its insolubility and intricate molecular structure. Tobacco mosaic disease is caused by tobacco mosaic virus (TMV) infection, which seriously harms tobacco production. Zinc-containing chemical agents are commonly used to control tobacco mosaic disease, but overuse of chemical agents will cause serious environmental pollution. In this study, a novel nanomaterial (ChNC@Zn) was prepared by using chitin nanocrystals loaded with Zn2+, which has the function of inducing disease resistance to plants and reducing virus activity. When the Zn2+ concentration of ChNC@Zn is 105.6 µg/mL, it shows higher resistance to TMV than Lentinan (LNT). ChNC@Zn can improve the enzymes activities of peroxidase (POD) and catalase (CAT) in tobacco, and reduce the damage of reactive oxygen species (ROS) caused by TMV infection, thereby inducing resistance to TMV in tobacco. Besides, it can promote the growth of tobacco. As a result, ChNC@Zn can exhibit strong antiviral activity at low Zn2+ concentration and minimize the pollution of Zn2+ to the environment, which has high potential application value in the control of virus disease.

Identifying novel selective PPO inhibitors through structure-based virtual screening and bio-evaluation.

Protoporphyrinogen oxidase (PPO) is a key enzyme in chlorophyll and heme biosynthesis, and the development of its inhibitors is of great importance both in the pharmaceutical and pesticide industries. However, the currently developed PPO inhibitors have insignificant bio-selectivity and have a serious impact on non-target organisms. In this study, a docking-based virtual screening approach combined with bio-activity testing was used to obtain novel selective inhibitors of PPO. The results of the bio-activity test showed that thirteen compounds showed 10-fold selectivity over human PPO. And the best selective compound, ZINC70338, has a K i value of 2.21 µM for Nicotiana tabacum PPO and >113-fold selectivity for human PPO. The selectivity mechanism of ZINC70338 in different species of PPO was then analyzed by molecular dynamics simulations to provide a design basis and theoretical guidance for the design of novel selective inhibitors.

Quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-ones as human protoporphyrinogen oxidase inhibitors.

Protoporphyrinogen oxidase (Protox, EC 1.3.3.4) has attracted great interest during the last decades due to its unique biochemical characteristics and biomedical significance. As a continuation of our research work on the development of new PPO inhibitors, 23 new 1,3,4-thiadiazol-2(3H)-ones bearing benzothiazole substructure were designed and synthesized. The in vitro assay indicated that the newly synthesized compounds 1a-w displayed good inhibition activity against human PPO (hPPO) with K(i) values ranging from 0.04µM to 245µM. To the knowledge, compound 1a, O-ethyl S-(5-(5-(tert-butyl)-2-oxo-1,3,4-thiadiazol-3(2H)-yl)-6-fluorobenzothiazol-2-yl)carbonothioate, with the K(i) value of 40nM, is so far known as the most potent inhibitor against hPPO. Based on the molecular docking and modified molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) calculations, the quantitative structure-activity relationships of 1,3,4-thiadiazol-2(3H)-ones and 1,3,4-oxadiazol-2(3H)-one derivatives were established with excellent correlation relationships (r(2)=0.81) between the calculated and experimental binding free energies. Some important insights were also concluded for guiding the future rational design of new hPPO inhibitors with improved potency.

Computational study reveals substituted benzimidazole derivatives' binding selectivity to PI3Kδ and PI3Kγ.

Phosphatidylinositol 3-kinase (PI3K) is a key regulatory kinase in the PI3K/AKT/mTOR signaling pathway, which is involved in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. Class IA PI3K isoforms γ and δ share a highly homologous ATP binding site and are distinguished by only a few residues around the binding site. Subtype-selective inhibitors have been proven to have great advantages in tumor treatment. Preliminary studies have obtained PI3K inhibitors bearing a benzimidazole structural motif with a certain selectivity for PI3Kδ and PI3Kγ subtypes. On this basis, we investigated the selective inhibitory mechanism of PI3Kδ and PI3Kγ using four developed inhibitors via molecular docking, molecular dynamics, binding free energy calculations, and residue energy decomposition. This study could provide references for the further development of PI3K-isoform-selective inhibitors.

A coumarin-based fluorescent probe for NIR imaging-guided photodynamic therapy against S. aureus-induced infection in mouse models.

A coumarin-based viscosity-responsive fluorescent probe (HZAU800) was designed and synthesized. The probe, containing a strong electron-donating and rigid group on the 7-position of coumarin and a rhodamine derivative containing an oxonium ion on 3-position, could not only shift the emission wavelength to near-infrared region (NIR, λem = 800 nm) but also deliver a good PDT effect due to its high rigid planarity. The NIR fluorescence of HZAU800 can be lighted up in the S. aureus-infected region due to its high viscous environment. Under the laser's irradiation at 690 nm, the PDT effect was effectively triggered up, and the antibacterial evaluation in vitro and in vivo was successfully carried out. This study not only offers a new strategy for constructing coumarin-based phototherapy agents but also facilitates the exploration of the next generation of antibacterial materials based on coumarin architectures.

Network Pharmacology and Molecular Docking Study of the Chinese Miao Medicine Sidaxue in the Treatment of Rheumatoid Arthritis.

PURPOSE: This study aimed to investigate the molecular mechanisms of Compound Sidaxue (SX), a prescription of Chinese Miao medicine, in treating rheumatoid arthritis (RA) using network pharmacology and in vivo experimental approaches. METHODS: Network pharmacology was adopted to detect the active components of four Traditional Chinese herbal medicine (TCM) of SX, and the key targets and signaling pathways in the treatment of RA were predicted, and the key components and targets were screened for molecular docking. The predicted targets and pathways were validated in bovine type II collagen and incomplete Freund's adjuvant emulsifier-induced rat RA model. RESULTS: In this study, we identified 33 active components from SX, predicted to act on 44 RA-associated targets by network pharmacology. PPI network demonstrated that TNF-α, VEGF-A, IL-2, IL-6, AKT, PI3K, STAT1 may serve as the key targets of SX for the treatment of RA. The main functional pathways involving these key targets include PI3K-AKT signaling pathway, TNF signaling pathway, NF-κB signaling pathway. Molecular docking analysis found that the active components ß-amyrin, cajanin, eleutheroside A have high affinity for TNF-α, VEGFA, IL-2, AKT, and PI3K, etc. SX can improve joint swelling in Collagen-induced arthritis (CIA) rats, reduce inflammatory cell infiltration and angiogenesis in joint synovial tissue, and down-regulate IL-2, IL-6, TNF-α, VEGF, PI3K, AKT, p-AKT, NF-κBp65, the expression of p-NF-κBp65, STAT1, and PTGS2 are used to control the exacerbation of inflammation and alleviate the proliferation of synovial pannus, and at the same time play the role of cartilage protection to achieve the effect of treating RA. CONCLUSION: Through a network pharmacology approach and animal study, we predicted and validated the active compounds of SX and their potential targets for RA treatment. The results suggest that SX can markedly alleviate CIA rat by modulating the VEGF/PI3K/AKT signaling pathway, TNF-α signaling pathway, IL/NF-κB signaling pathway.

Protoporphyrinogen oxidase inhibitor: an ideal target for herbicide discovery.

As the last common enzyme in the biosynthetic pathway leading to heme and chlorophyll, protoporphyrinogen oxidase (PPO; EC 1.3.3.4) is an ideal target for herbicide development. Currently, about 30 PPO inhibitors have been developed as agricultural herbicides. PPO inhibitors have displayed environmentally benign, but advantageous characteristics, including low toxicity, low effective concentration, broad herbicidal spectrum (active against both monocotyledon and dicotyledon weeds), quick onset of action, and long lasting effect. Over the last several years, great achievements have been made in revealing the structural biology of PPO. Five PPO crystal structures, four isolated in enzyme-inhibitor complexes and one in the native form, have been determined, including those from Nicotiana tabacum, Myxococcus Xanthus, Bacillus subtilis, and human. Although PPO inhibitors have been developed for over forty years, we continue to uncover exciting future prospects for novel PPO-inhibiting herbicides. In this review, we have summarized the structures of PPOs from plants, human, and bacteria; the interactions between PPOs and inhibitors; the quantitative structure-activity relationships of PPO inhibitors; and the molecular design of new PPO inhibitors.

Genomic Landscape of Head and Neck Squamous Cell Carcinoma Across Different Anatomic Sites in Chinese Population.

BACKGROUND: The characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated. METHODS: Genomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations. RESULTS: A total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1-4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB, TEX10-NTRK2 fusion, who may benefit from larotrectinib or entrectinib treatment. CONCLUSION: The genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs.

Silent Counterattack: The Impact of Workplace Bullying on Employee Silence.

The purpose of this paper is to explore the relationship between workplace bullying (WB) and employee silence (ES) as well as its mechanism. This paper collects data from 322 employees of three Chinese enterprises in two waves, with a 2 months interval between the two waves. Moreover, this paper uses confirmatory factor analysis, a bootstrapping mediation test, a simple slope test, and other methods to verify the hypothesis. We find that: (1) WB is positively correlated with ES; (2) psychological safety (PS) and affective commitment mediated the relationship between WB and ES, respectively, and these two variables have a chain mediating effect in the above relationship; and (3) a forgiveness climate moderates this chain mediating effect by weakening the negative impact of WB on PS. Our findings can effectively guide organizations to ultimately adjust their management style, pay attention to employees' cognitive and emotional resources, and formulate some measures to curb WB in organizations.