Prediction of electrical properties of GAAFET based on integrated learning model.

As device feature sizes continue to decrease and fin field effect transistors (FinFETs) reach their physical limits, gate all around field effect transistors (GAAFETs) have emerged with larger gate control areas and stackable characteristics for better suppression of second-order effects such as short-channel effects due to their gate encircling characteristics. Traditional methods for studying the electrical characteristics of devices are mostly based on the technology computer-aided design (TCAD). Still, it is not conducive to developing new devices due to its time-consuming and inefficient drawbacks. Deep learning (DL) and machine learning (ML) have been well-used in recent years in many fields. In this paper, we propose an integrated learning model that integrates the advantages of DL and ML to solve many problems in traditional methods. This integrated learning model predicts the direct current characteristics, capacitance characteristics, and electrical parameters of GAAFET better than those predicted by DL or ML methods alone, with a linear regression factor (R2) greater than 0.99 and very small root mean square error (RMSE). The proposed integrated learning model achieves fast and accurate prediction of GAAFET electrical characteristics, which provides a new idea for device and circuit simulation and characteristics prediction in microelectronics. .

Exploring the conformational dynamics and thermodynamics of EGFR S768I and G719X + S768I mutations in non-small cell lung cancer: An in silico approaches.

Non-small cell lung cancer (NSCLC) is often driven by mutations in the epidermal growth factor receptor (EGFR) gene. However, rare mutations such as G719X and S768I lack standard anti-EGFR targeted therapies. Understanding the structural differences between wild-type EGFR and these rare mutants is crucial for developing EGFR-targeted drugs. We performed a systematic analysis using molecular dynamics simulations, essential dynamics (ED), molecular mechanics Poisson-Boltzmann surface area, and free energy calculation methods to compare the kinetic properties, molecular motion, and free energy distribution between wild-type EGFR and the rare mutants' structures G719X-EGFR, S768I-EGFR, and G719X + S768I-EGFR. Our results showed that S768I-EGFR and G719X + S768I-EGFR have higher global and local conformational flexibility and lower thermal and global structural stability than WT-EGFR. ED analysis revealed different molecular motion patterns between S768I-EGFR, G719X + S768I-EGFR, and WT-EGFR. The A-loop and αC-helix, crucial structural elements related to the active state, showed a tendency toward active state development, providing a molecular mechanism explanation for NSCLC caused by EGFR S768I and EGFR G719C + S768I mutations. The present study may be helpful in the development of new EGFR-targeted drugs based on the structure of rare mutations. Our findings may aid in developing new targeted treatments for patients with EGFR S768I and EGFR G719X + S768I mutations.

A bibliometric and thematic analysis of the trends in the research on ginkgo biloba extract from 1985 to 2022.

Background: Ginkgo biloba extract (GBE), a complementary and alternative medicine, has been widely used for disorders such as brain infarction, dementia, and coronary heart disease, in recent decades. Given its widespread clinical use, GBE has always been a vital research topic. However, there are no bibliometric analyses on this topic; furthermore, published reviews of GBE focus only on a specific research field or lack scientific and systematic evaluation. This study combined bibliometrics with thematic reviews by visual analysis to identify the current status of GBE research and to better identify research hotspots and trends in the past 40 years to understand future developments in basic and clinical research. Methods: Articles and reviews on GBE were retrieved by topic from the Web of Science Core Collection from inception to 2022.12.01. Countries, institutions, authors, journals, references, and keywords in the field were visually analyzed using CiteSpace, Scimago Graphica, and VOSviewer software; then, these visualization results for references and keywords were clarified in detail by thematic reviews in subdivisions of the fields. Results: In total, 2015 publications were included. The GBE-related literature has high volumes of publications and citations. The majority of literature is from China, and the USA cooperates most closely with other countries. In GBE research, Christen Yves is the most cited author, Phytotherapy Research is the most prolific journal, and the Journal of Ethnopharmacology is the most co-cited journal. Through a comprehensive analysis of keywords, references, and reviews, the quality of the meta-analysis of randomized controlled clinical trials of GBE in treating dementia was evaluated by the Risk of Bias in Systematic Reviews scale (ROBIS). Current research on GBE focuses on its pharmacological mechanisms, and neuroprotective application in diseases such as Alzheimer's disease, and glaucoma. Randomized controlled trials are the current research hotspot. Conclusion: Research on GBE is flourishing; using bibliometric and thematic analysis, we identified its hotspots and trends. The pharmacological mechanisms and clinical applications of GBE are the focus of present and likely future research.

Endogenous hydrogen sulfide inhibition suppresses tumor growth by promoting apoptosis and pyroptosis in esophageal cancer cells.

BACKGROUND: Hydrogen sulfide (H2S) has been identified as the third gaseous signaling molecule. Endogenous H2S plays a key role in the progression of various types of cancer. However, the effect of endogenous H2S on the growth of esophageal cancer (EC) remains unknown. METHODS: In this study, three kinds of H2S-producing enzymes inhibitors, DL-propargylglycine (PAG, inhibitor of cystathionine-γ-lyase), aminooxyacetic acid (AOAA, inhibitor of cystathionine-ß-synthase), and L-aspartic acid (L-Asp, inhibitor of 3-mercaptopyruvate sulfurtransferase) were used to determine the role of endogenous H2S in the growth of EC9706 and K450 human EC cells. RESULTS: The results indicated that the combination (PAG+AOAA+L-Asp) group showed higher inhibitory effects on the viability, proliferation, migration, and invasion of EC cells than PAG, AOAA, and L-Asp group. Inhibition of endogenous H2S promoted apoptosis via activation of mitogen-activated protein kinase pathway in EC cells. Endogenous H2S suppression triggered pyroptosis of EC cells by activating reactive oxygen species-mediated nuclear factor-κB signaling pathway. In addition, the combine group showed its more powerful growth-inhibitory effect on the growth of human EC xenograft tumors in nude mice without obvious toxicity. CONCLUSION: Our results indicate that inhibition of endogenous H2S production can significantly inhibit human EC cell growth via promotion of apoptosis and pyroptosis. Endogenous H2S may be a promising therapeutic target in EC cells. Novel inhibitors for H2S-producing enzymes can be designed and developed for EC treatment.

[Explorations in and Practice of Integrating Ideological and Political Theories Education in Stomatology Textbooks].

Stomatology textbooks are an important carrier of integrated ideological and political education. The preparation of textbooks for the stomatology specialty in the new era is an important issue of concern for administrators and teachers of higher education institutions. Integrating ideological and political education in the instruction and practice composnents of academic courses on stomatology is an important issue to be resolved. Herein, we introduced the significance of ideological and political education and elaborated on the method of integrating ideological and political education in stomatology courses and textbooks from the perspectives of curriculum design, textbook compilation, teacher training, teaching evaluation, etc. We analyzed the different ways of integrating ideological and political education in stomatology courses and textbooks from the perspectives of classroom instruction, clinical practice, campus culture, social activities, and some other aspects.

CiteSpace-Based Visualization Analysis of Forensic Research in China from 2010 to 2019.

OBJECTIVES: To analyze the research status of forensic medicine in China from 2010 to 2019, obtain the development trend of forensic medicine and explore the hotspots and research frontiers. METHODS: The forensic medical academic papers published on China National Knowledge Infrastructure (CNKI) database from 2010 to 2019 were collected. CiteSpace 5.7.R1, an information visualization analysis software, was used to analyze publication organizations, authors, keywords, and other elements. RESULTS: The majority of the research institutions were universities, provincial and ministerial scientific research and forensic institutions. Forensic pathology was still an important branch of forensic medicine and a popular research direction. The "polymorphism" and "Y chromosome" had been the research hotspots in recent years. "Medical damage" and "standard" were the most novel studies. CONCLUSIONS: In order to provide scientific basis and research direction for forensic research, this paper analyzes the cooperation network, research hotspots and research innovation in forensic research.

Quantitative comparison of the efficacies and safety profiles of three first-line non-platinum chemotherapy regimens for advanced non-small cell lung cancer.

Objectives: The purpose of this study was to quantify the efficacies and safety profiles of the three first-line non-platinum chemotherapy regimens recommended in the National Comprehensive Cancer Network guidelines. Materials and Methods: The PubMed and Cochrane Library databases were searched comprehensively, and clinical trials involving patients with advanced non-small cell lung cancer treated with one of three first-line non-platinum regimens (gemcitabine combined with vinorelbine, gemcitabine combined with docetaxel, or gemcitabine alone) were included in the analysis. A parametric proportional hazard survival model was established to analyze the time course of overall survival (OS). The objective response rate (ORR) and incidence rates of grade 3-4 adverse events (AEs) were summarized using a single-arm meta-analysis with a random-effects model. Results: Seventeen studies met the inclusion criteria. Age and performance status (PS) scores were significant predictors of OS. For each 10-years increase in age, mortality risk increased by 18.5%, and the mortality risk increased by 4% for every 10% increase in the proportion of patients with a PS score of 2. After correcting for the above factors, we found that the three first-line non-platinum chemotherapy regimens did not differ based on OS or toxicity. Conclusion: There was no significant difference in OS or toxicity among the three first-line non-platinum chemotherapy regimens. Age and PS scores were significant predictors of OS, and their heterogeneity across different studies should be considered in cross-study comparisons and sample size estimations when designing clinical trials.

PCNP is a novel regulator of proliferation, migration, and invasion in human thyroid cancer.

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non-tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down-regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/ß-catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion, in vitro and in vivo data demonstrate that PCNP as a tumor suppressor gene may serve as a novel prognostic and potential therapeutic marker in human thyroid cancer.

Exploration of Adherence to the Immunosuppressive Medication in Kidney Transplant Recipients Based on Theory of Planned Behavior.

To investigate adherence to immunosuppressive medication (IM) in kidney transplant recipients (KTRs) and analyze the associated factors using the Theory of Planned Behavior (TPB). Data were collected at Time1 (T1) and 3 months later (T2). T1: the elements of the TPB, past behavior, beliefs about medicines, perceived social support were measured. T2: IM adherence was measured. Structural equation modeling was applied to analyze the associated factors of medication adherence. A total of 246 KTRs were included. The average IM adherence score of KTRs' was 4.86 (SD = 1.63). Of the recipients, 39.43% had one aspect of non-adherence to IM. The model could explain 28.7% of the variance in adherence to IM (R2 = .287, p = .006). TPB is a useful tool for understanding adherence to IM in KTRs. Caregivers can provide effective interventions during follow-up, which should focus on improving medication beliefs as well as provision of other external support especially from outside.

Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren's Syndrome.

This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.

Enhancement of biotransformation of ginsenosides in white ginseng roots by aerobic co-cultivation of Bacillus subtilis and Trichoderma reesei.

In the present work, the biotransformation of ginsenosides in white ginseng roots was innovatively investigated using the aerobic fermentation by the co-cultivation of Bacillus subtilis and Trichoderma reesei. It is found that in the co-cultivation mode, the optimal nitrogen source was corn steep liquor, and the loading of ginseng powder and inoculation proportion of B. subtilis and T. reesei were 15 g/L and 1:4, respectively. The total ginsenoside yield and production of minor ginsenosides in the co-cultivation mode obviously enhanced in comparison to the monoculture mode. Meanwhile, the maximal total ginsenoside yield of 21.79% and high hydrolase activities were achieved using the staged inoculation at the inoculation proportion of 1:4 in the co-cultivation mode, the production of minor ginsenosides such as Rg3 and Rh1, Rh2 was significantly strengthened, and the pharmacological activities of the fermented solution obviously improved. The enhancement of ginsenoside transformation can be mainly attributed to hydrolysis of the produced hydrolases and metabolism of two probiotics. This result clearly reveals that using the staged inoculation in co-cultivation fermentation mode was favor of the ginsenoside biotransformation in ginseng due to non-synchronous cell growth and different metabolic pathways of both probiotics. This work can provide a novel method for enhancing ginsenoside transformation of ginseng.Key points• Co-cultivation fermentation significantly promoted ginsenoside biotransformation.• The staged inoculation in co-culture mode was an optimal operation method.• The pharmacological activity of the co-cultured solution was significantly enhanced.

Role of HPV status and PD-L1 expression in prognosis of laryngeal squamous cell carcinoma.

PURPOSE: Human papillomavirus (HPV) infection has been recognized as a cause of head and neck squamous cell carcinomas (HNSCC). Laryngeal squamous cell carcinoma (LSCC) is one of the most common pathologic types of HNSCC. Clinical trials show that there are differences in response to immunotherapy according to HPV status. It was reported that a high level of programmed cell death-ligand 1 (PD-L1) is correlated with better survival in HPV-positive head and neck cancer. In this study, we investigated the expression of PD-L1 in HPV-positive and HPV-negative LSCC to determine its prevalence and prognostic value. METHODS: 52 cases of LSCC were collected from Tangshan Head and Neck Disease Pathology Research Base. PCR-reverse dot blot hybridization and RNAscope in situ hybridization were used to detect HPV status. PD-L1 expression was evaluated by immunohistochemistry and all cases were followed up for survival. SPSS24.0 was used for data entry and statistical analysis. Kaplan-Meier method and Log-rank time series analysis were used for single factor analysis. Multivariate analysis was performed using Cox proportional hazard regression model, and HR and 95% CI were calculated. RESULTS: Of the 52 LSCC patients, 32.7% (17/52) were HPV-positive by RNAscope in situ hybridization, and 51.9% (27/52) of patients were positive for PD-L1 expression by immunohistochemistry. Regression analysis showed that with a median follow-up period of 69 months, smoking and late stage were associated with poor overall survival (OS), whereas HPV positivity and PD-L1 expression showed a better overall survival outcome. CONCLUSION: Smoking status, tumor stage, HPV status, and PD-L1 expression in tumor cells may represent useful prognostic biomarkers in patients with LSCC.

Kidney Injury Following Ibuprofen and Acetaminophen: A Real-World Analysis of Post-Marketing Surveillance Data.

Background: Although kidney injury has been reported as a serious adverse effect in patients treated with ibuprofen or acetaminophen (APAP), there are still few real-world studies to compare the specific differences in the adverse effects of nephrotoxicity. Methods: Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected kidney injury after using ibuprofen and APAP based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of ibuprofen-associated kidney injury and APAP-associated kidney injury were also investigated. Results: 2,453 reports of ibuprofen-associated kidney injury and 1,288 reports of APAP-associated kidney injury were identified. Ibuprofen appeared to affected more middle-aged patients than elderly ones (27.76 vs 16.53%) while APAP appeared to affected more young patients than middle-aged patients (45.24 vs 29.10%) and elderly patients were fewer (13.99%). Compared to ibuprofen, APAP had the higher association with renal injury based on the higher reporting odds ratio (ROR = 2.45, 95% two-sided CI = 2.36-2.56), proportional reporting ratio (PRR = 2.39, χ 2 = 2002.94) and empirical Bayes geometric mean (EBGM = 2.38, 95% one-sided CI = 2.3). In addition, APAP-associated kidney injury had earlier onset (32.74 vs 115.82 days, p < 0.0001) and a higher fatality rate (44.43 vs 7.36%, p < 0.001) than those of ibuprofen-associated kidney injury. Conclusion: The analysis of FAERS data provides a more accurate profile on the incidence and prognosis of kidney injury after ibuprofen and acetaminophen treatment, enabling continued surveillance and timely intervention in patients at risk of kidney injury using these drugs.

Transplant-related Symptom Clusters in Renal Transplant Recipients.

Renal transplant recipients experience multiple symptoms, but complex relationships among these symptoms remain poorly understood. To explore the existence of symptom clusters in renal transplant recipients. A total of 295 renal transplant recipients were recruited in a hospital in Tianjin from October 2017 to January 2018. The participants completed the symptom questionnaire that assessed three symptom dimensions of 62 symptoms. Exploratory factor analysis was performed to identify symptom clusters. Five symptom clusters were extracted through exploratory factor analysis: emotional-sleep symptom cluster, pain-gastrointestinal symptom cluster, immune-related symptom cluster, lack of energy symptom cluster, and visual dysfunction symptom cluster, which explained 50.53% of the variance of symptom experience. Renal transplant recipients experienced a complex series of symptoms, and some symptoms related to one another formed a symptom cluster. Adopting a symptom cluster approach has the potential to remarkably enhance symptom assessment and nursing care for renal transplant recipients.

A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis.

BACKGROUND: Benvitimod cream, a novel synthetic small molecule, was effective in treating mild-to-moderate plaque psoriasis. We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis. METHODS: We randomly assigned 686 patients (2:1:1) to receive 1% benvitimod cream, 0.005% calcipotriol ointment or placebo twice a day for 12 weeks. The primary efficacy end points were the percentage of patients with a 75% or greater reduction from baseline in the psoriasis area and severity index (PASI 75) score and with a score of 0 or 1 in static physician's global assessment (sPGA) at week 12. RESULTS: The results showed that 50.4% of patients in the benvitimod group achieved PASI 75, which was significantly higher than that in the calcipotriol (38.5%, P < 0.05) and placebo (13.9%, P < 0.05) groups. The proportion of patients achieving an sPGA score 0 or 1 was 66.3% in the benvitimod group and 63.9% in the calcipotriol group, which were both significantly higher than that in the placebo group (34%, P < 0.05). In the long-term follow-up study, 50.8% of patients experienced recurrence. After retreatment with 1% benvitimod, 73.3% of patients achieved an sPGA score of 0 or 1 again at week 52. Adverse events included application site irritation, follicular papules, and contact dermatitis. No systemic adverse reactions were reported. CONCLUSION: During this 12-week study, benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR), ChiCTR-TRC-13003259; http://www.chictr.org.cn/showprojen.aspx?proj=6300.

High risk HPV detection by RNAscope in situ hybridization combined with Cdc2 protein expression by immunohistochemistry for prognosis of oropharyngeal squamous cell carcinoma.

High risk human papillomavirus (HPV) infection is related to the development of head and neck squamous cell carcinoma (HNSCC). Oropharyngeal squamous cell carcinoma (OPSCC) is a common type of HNSCC, and its incidence has increased significantly in recent years. In this study, high risk HPV, the expression of P53, P21, and Cdc2 in OPSCC tissues was detected and the prognostic factors and clinical value of OPSCC were discussed. According to the WHO classification and diagnosis standard for head and neck tumors (2017 Edition), 49 OPSCC cases with complete clinical data were collected from Tangshan Head and Neck Disease Pathology Research Base from January 1, 2012 to December 31, 2018. The E6 and E7 mRNA of HPV 16 and HPV 18 were detected by RNAscope in situ hybridization. The expression of P53, P21, and Cdc2 protein was observed by SP immunohistochemical method and all cases were followed up for survival. Median survival time was analyzed by Kaplan-Meier method. The Log-rank test was used for single factor analysis and Cox regression model was used to analyze multiple prognostic factors. In 49 OPSCC cases the median age was 53 years; 14 were HPV-DNA positive (14/49, 28.6%) while 35 were negative (35/49, 71.4%). E6, E7 mRNA test showed that 20 cases (20/49, 40.8%) were positive for HPV-16. Among them 11 cases were positive for HPV-16 DNA. 2 cases were positive for HPV-18 mRNA (2/49, 4.08%). 27 cases were negative for mRNA16 and 18 (27/49, 55.1%). The prevalence of HPV was 68.8% (11/16) in the non-smoking group, which was higher than that of the smoking group (10/33, 33.3%), (χ2=5.463, P=0.019). There was no significant correlation between HPV detection and gender, age, drinking, tumor differentiation degree, and clinical stage (P > 0.05). The expression rates of P53, P21, and Cdc2 in OPSCC tissues were 63.3% (31/49), 65.3% (32/49), and 67.3% (33/49), respectively. There was no significant correlation between expression of all the three proteins and gender, age, HPV, smoking, drinking, tumor differentiation, and clinical stage (P > 0.05). Cox multifactor regression analysis showed that HPV (HR=0.275, 95% CI: 0.146-0.517), tumor differentiation (HR=1.751, 95% CI: 1.231-2.492), stage (HR=3.268, 95% CI: 1.758-6.074) and expression of Cdc2 protein (HR=1.804, 95% CI: 0.990-3.286) were related to the survival time of patients (P < 0.05). Our findings support that most of the HPV-positive OPSSC patients were non-smokers. The patients with negative HPV, low differentiation, late stage, and Cdc2 positive expression have poor prognosis and need to be followed up.

Persistent Viral Presence Determines the Clinical Course of the Disease in COVID-19.

BACKGROUND: The clinical management of coronavirus disease 2019 (COVID-19) is dependent on understanding the underlying factors that contribute to the disease severity. In the absence of effective antiviral therapies, other host immunomodulatory therapies such as targeting inflammatory response are currently being used without clear evidence of their effectiveness. Because inflammation is an essential component of host antiviral mechanisms, therapies targeting inflammation may adversely affect viral clearance and disease outcome. OBJECTIVE: To understand whether the persistent presence of the virus is a key determinant in the disease severity during COVID-19 and to determine whether the viral reactivation in some patients is associated with infectious viral particles. METHODS: The data for patients were available including the onset of the disease, duration of viral persistence, measurements of inflammatory markers such as IL-6 and C-reactive protein, chest imaging, disease symptoms, and their durations among others. Follow-up tests were performed to determine whether the viral negative status persists after their recovery. RESULTS: Our data show that patients with persistent viral presence (>16 days) have more severe disease outcomes including extensive lung involvement and requirement of respiratory support. Two patients who died of COVID-19 were virus-positive at the time of their death. Four patients demonstrated virus-positive status on the follow-up tests, and these patient samples were sent to viral culture facility where virus culture could not be established. CONCLUSIONS: These data suggest that viral persistence is the key determining factor of the disease severity. Therapies that may impair the viral clearance may impair the host recovery from COVID-19.

Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.

Comparative Efficacy of Drugs for the Treatment of Chronic Constipation: Quantitative Information for Medication Guidelines.

BACKGROUND: Quantitative information is scarce with regard to guidelines for currently prescribed medications for constipation. Furthermore, these guidelines do not reflect the differences in the number of bowel movements caused by each drug. GOALS: In this study, we used a model-based meta-analysis to quantitatively estimate the deviations from the baseline number of spontaneous bowel movements (SBMs) and complete spontaneous bowel movements (CSBMs) associated with pharmacotherapy for chronic constipation to bridge the knowledge gap in the guidelines for current medications. STUDY: A comprehensive survey was conducted using literature databases. In this study, we also included randomized placebo-controlled trials on chronic constipation. Pharmacodynamic models were established to describe the time course of the numbers of SBMs and CSBMs produced by each drug. RESULTS: Data from 20 studies (comprising 9998 participants and 8 drugs) were used to build this model. The results showed that bisacodyl had the greatest effect on increasing the frequency of bowel movements, whereas plecanatide yielded the lowest increase in the number of SBMs and CSBMs. After eliminating the placebo effect, the maximal increase in bowel movement frequency associated with bisacodyl was 6.8 for SBMs (95% confidence interval: 6.1-7.6) and 4.7 for CSBMs (95% confidence interval: 4.3-5.1) per week. These numbers are ∼4 times higher than the number of bowel movements produced by plecanatide. The change in the frequency of SBMs and CSBMs for other drugs, such as sodium picosulfate, velusetrag, linaclotide, elobixibat, lubiprostone, and prucalopride, was similar. The highest increases in the frequency of SBM and CSBM were 2.5 to 4 and 1 to 2.1 per week, respectively. Bisacodyl had the most noticeable loss of efficacy between week 1 and week 4; it reduced the frequencies of SBMs and CSBMs by 2.3 and 2.2, respectively. By contrast, the changes in the frequencies of SBMs and CSBMs were not as great with other drugs. CONCLUSIONS: The data provided in this study may be a valuable supplement to the medication guidelines for the treatment of chronic constipation.

THBS1/CD47 Modulates the Interaction of γ-Catenin With E-Cadherin and Participates in Epithelial-Mesenchymal Transformation in Lipid Nephrotoxicity.

Hyperlipidemia, an important risk factor for cardiovascular and end-stage renal diseases, often aggravates renal injury and compromises kidney function. Here, histological analysis of human kidney samples revealed that high lipid levels induced the development of renal fibrosis. To elucidate the mechanism underlying lipid nephrotoxicity, we used two types of mouse models (Apoe-/- and C57BL/6 mice fed a 45 and 60% high-fat diet, respectively). Histological analysis of kidney tissues revealed high-lipid-induced renal fibrosis and inflammation; this was confirmed by examining fibrotic and inflammatory marker expression using Western blotting and real-time polymerase chain reaction. Oxidized low-density lipoprotein (OX-LDL) significantly induced the fibrotic response in HK-2 tubular epithelial cells. RNA-sequencing and Gene Ontology analysis of differentially expressed mRNAs in OX-LDL-treated HK-2 tubular epithelial cells and real-time PCR validation in Apoe-/- mice showed that the expression of thrombospondin-1 (THBS1) in the high-fat group was significantly higher than that of the other top known genes, along with significant overexpression of its receptor CD47. THBS1 knockdown cells verified its relation to OX-LDL-induced fibrosis and inflammation. Liquid chromatography tandem mass spectrometry and STRING functional protein association network analyses predicted that THBS1/CD47 modulated the interaction between γ-catenin and E-cadherin and was involved in epithelial-mesenchymal transition, which was supported by immunoprecipitation and immunohistochemistry. CD47 downregulation following transfection with small-hairpin RNA in OX-LDL-treated tubular epithelial cells and treatment with anti-CD47 antibody restored the expression of E-cadherin and attenuated renal injury, fibrosis, and inflammatory response in OX-LDL-treated cells and in type 2 diabetes mellitus. These findings indicate that CD47 may serve as a potential therapeutic target in long-term lipid-induced kidney injury.