Hearing loss is one of the most common neurosensory disorders in humans,severely affecting pa-tients'quality of life with lack of ideal treatments.Its pathogenesis is related to oxidative stress,inflammation and apoptosis in the inner ear.Recent studies have demonstrated that members of the signal transducer and activator of transcriptions(STATs)family are involved in regulating gene expression in auditory cells during inner ear develop-ment and physiological activities such as apoptosis,oxidative stress,inflammation and autophagy during auditory disorders.In this paper,we review the research on STATs in inner ear development and hearing loss,and elucidate their specific molecular mechanisms,aiming to provide theoretical guidance and direction for the prevention and treatment of hearing loss.

Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results. To fundamentally overcome these issues and accelerate drug discovery, a new combined-structure RBFE (CS-FEP) calculation strategy was proposed, which solved the existing issues by constructing a new alchemical pathway, smoothed the alchemical transformation, increased the phase-space overlap between adjacent states, and thus significantly increased the convergence and accelerated the relative binding free energy calculations. This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1 (PDE1). Starting from a PDE1 inhibitor (compound 9, IC₅₀ = 16.8 μmol/L), the CS-FEP guided hit-to-lead optimizations resulted in a promising lead (11b and its mesylate salt formulation 11b-Mesylate, IC₅₀ = 7.0 nmol/L), with ∼2400-fold improved inhibitory activity. Further experimental studies revealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.

Heterotypic cell-in-cell structures (heCICs) are closely related to tumor development and progression, and have become a new frontier in life science research. Ras-related C3 botulinum toxin substrate 1 (Rac1) belongs to the classic Rho GTPase, which plays a key role in regulating the cytoskeleton and cell movement. To investigate the role and mechanism of Rac1 in the formation of heCICs, tumor cells and immune killer cells were labeled with cell-tracker, respectively, to establish the heCICs model. Upon treatment with the Rac1 inhibitor NSC23766, the formation of heCICs between tumor and immune cells was significantly reduced. The plasmid pQCXIP-Rac1-EGFP constructed by gene cloning was packaged into pseudoviruses that subsequently infect tumor cells to make cell lines stably expressing Rac1. As a result, the formation of heCICs was significantly increased upon Rac1 overexpression. These results demonstrated a promotive role of Rac1 in heCICs formation, which may facilitate treating cell-in-cell related diseases, such as tumors, by targeting Rac1.

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated in vitro and in vivo by a potent and selective PDE1 inhibitor 4a. Also, the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of 4a, especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate 5f, with a potent IC₅₀ value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-κB transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.

ObjectiveTo evaluate the effect and safety of Buyang Huanwutang in treatment of connective tissue disease-associated pulmonary fibrosis in the patients with syndrome of Qi deficiency and blood stasis and explore the possible anti-fibrosis mechanism of Buyang Huanwutang. MethodSixty-six patients with connective tissue disease-associated pulmonary fibrosis with syndrome of Qi deficiency and blood stasis were randomized to receive either Buyang Huanwutang combined with routine therapy or routine therapy for 4 weeks. The primary outcome indicator was change in forced vital capacity （FVC） from the baseline， and the secondary outcome indicators included the changes in percentage of predicted forced vital capacity （FVC%pred）， percentage of forced expiratory volume in first second to predicted value （FEV₁%pred）， King's Brief Interstitial Lung Disease （K-BILD） total score， 6 minute walking distance （6MWD）， hydroxyproline （HYP）， matrix metalloproteinase （MMP）， tissue inhibitor of metalloproteinase-1 （TIMP-1）， and transforming growth factor-β （TGF-β） from baseline. Patients in line with the inclusion criteria were included in the primary analysis， and sensitivity analysis was performed after multiple imputation of missing data. Safety set was adopted for safety analysis. ResultThe 66 patients （included in the sensitivity analysis） meeting the inclusion criteria included 34 in the observation group and 32 in the control group， and 60 patients finally received the whole trial intervention （included for primary analysis）. Compared with the baseline， the FVC increased in the observation group and decreased in the control group after intervention （P<0.01）， which was consistent between the sensitivity analysis and the primary analysis. The changes in FVC%pred， FEV₁%pred， 6MWD， and K-BILD total score from baseline in the observation group were superior to those in the control group （P<0.01）， with consistent results between the sensitivity analysis and the primary analysis. TIMP-1 in the observation group decreased compared with baseline （P<0.05）， while TIMP-1 in the two groups showed no significant changes from the baseline The observation group outperformed the control group in the changes in HYP， MMP-9， and TGF-β from baseline （P<0.05）. The common adverse events were cough， diarrhea， nausea， rash， and upper gastrointestinal tract infection， the incidence of which showed no statistical difference between the two groups. ConclusionBuyang Huanwutang can improve lung function， motor function， and quality of life in patients with connective tissue disease-associated pulmonary fibrosis and has good safety. The mechanism may be related to the reduction of TGF-β， MMP-9， and TIMP-1 levels and maintaining of MMP-9/TIMP-1 balance.

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC₅₀ = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.

Objective:To analyze the current level and dynamic change of the salary and income satisfaction rate of doctors in Chinese tertiary public hospitals in recent years.Methods:In January 2018, March 2019 and March 2021, the project team of " the third party evaluation of the China Healthcare Improvement Initiative" conducted a questionnaire survey among doctors of 136 tertiary public hospitals in 31 provinces. The first-line clinicians were investigated by stratified sampling method. The salary level and satisfaction of doctors were investigated by questionnaire. Chi square test was used for comparison between groups.Results:The sample size of the three surveys was 20 786, 23 289 and 22 836 respectively. The median value of doctors′ actual income after tax in 2017, 2018 and 2020 was 100 800 yuan, 120 000 yuan, 150 000 yuan respectively, and the median expected annual income after tax was 196 000 yuan, 250 000 yuan and 250 000 yuan. The proportion of doctors satisfied with the current income was 16.5%, 17.8% and 26.9% respectively. The salary and satisfaction rate of doctors had an upward trend, but the overall level was still low.Conclusions:In recent years, the salary of doctors in tertiary public hospitals in China has been improved to a certain extent, but on the whole, it is at a low level, and there is still much room for improvement. In the future, the government needs to improve the hospital salary system and increase the salary of doctors continuously, especially needs to pay attention to the doctors with high education level and intermediate titles.

Objective:To analyze the salary level, change trend and salary satisfaction of nurses in tertiary public hospitals in China.Methods:The data was derived from three round third-party evaluation of the China Healthcare Improvement Initiative at 136 tertiary public hospitals from December 2017 to January 2018, March 2019 and January to March 2021. The self-reported salary, expected salary and salary satisfaction rate of nurses were analyzed.Results:The sample sizes of the three evaluations were 27 575, 27 568 and 25 197, representing the salary situation in 2017, 2018 and 2020 respectively. In 2017, 2018 and 2020, the actual average annual salary of nurses was 81 600 yuan, 100 000 yuan and 110 000 yuan respectively, the expected average annual salary was 140 000 yuan, 160 000 yuan and 160 000 yuan respectively, and the ratio of expected salary to actual salary was 1.72, 1.60 and 1.45 respectively. In 2017, 2018 and 2020, the proportion of nurses satisfied with their current income was 34.0%, 33.7% and 43.6% respectively. In 2020, nurses in the eastern region, other specialized hospitals, senior professional titles and graduate degrees had highest annual salary.Conclusions:The salary level and satisfaction rate of nurses in tertiary public hospitals in China show a slow growth trend, and the gap between actual salary and expected salary is gradually narrowing.

Objective:To understand the changes in the practice environment from the perspective of doctors in 136 tertiary public hospitals, and to provide evidence for formulating strategies and measures to improve the practice environment of doctors.Methods:The data was collected from five rounds of China Healthcare Improvement Evaluation Survey from December 2015 to March 2021. The sample size was 17 945, 19 774, 20 786, 23 289, and 22 836, with a total of 104 630. The self-designed questionnaire on four dimensions of doctor-patient relationship, workload, administrative logistics support and professional identity was performed.Results:From the 1st to the 5th survey, the approval ratio of " the administrative and logistics department of this hospital is highly efficient" showed the characteristics of " U-shaped distribution" , and the approval ratio of " approve or encourage children to continue to engage in medical work" increased from 13.38% to 23.91%.From the 2nd to the 5th survey, the percentage of doctors who experienced doctor-patient disputes dropped from 28.96% to 23.20%, and the percentage of doctors agreeing that the relationship between doctors and patients in this hospital was improving continued to increase from 33.20% to 60.45%.From the 3rd to the 5th survey, the proportion of doctors experiencing medical troubles dropped from 15.10% to 14.19%, and the recognition rate of " the cafeteria of this hospital provided medical staff with nutritious and delicious meals" increased from 36.25% to 47.52%, and the approval proportion of " my current work load is heavy" dropped from 61.55% to 45.24%. The results of the 5th survey showed that there were significant differences in the approval ratios of each dimension in different genders, job titles and hospital types( P<0.001). Conclusions:From the perspective of doctor-patient relationship, workload, administrative logistics support, and professional identity, the improvement of doctors′ practice environment is still insufficient. Hospital administrators should continue to focus on the improvement of the doctor-patient relationship, and take necessary measures to reduce doctors′ workload and improve doctors′ professional identity.

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor