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BACKGROUND: Conventional ultrasound (US), which include gray scale US and Doppler US, is the first-line imaging modality for the evaluation of renal allograft; however, conventional US indicators have limitations. OBJECTIVE: To explore the application value of shear-wave elastography (SWE) combined with monochrome superb microvascular imaging (mSMI) in renal allograft chronic rejection (CR). METHODS: From November 2021 to February 2022 in the Lanzhou University Second Hospital, the US features of 54 patients with renal allograft were retrospectively analyzed. Patients were categorized into two groups: stable group(n = 44) and CR group(n = 10), with clinical diagnosis as reference standard. The vascular index (VI) on mSMI and parenchymal stiffness were measured in the middle cortex of all renal allografts and receiver operating characteristic (ROC) curves were drawn to evaluate the feasibility of differentiation. Statistically significant US features and biochemical indicators such as creatinine were scored, and the results of the scores were analyzed by ROC curve. RESULTS: The VI on mSMI of the stable group (49.5±2.0) was significantly greater than that of the CR group (33.8±5.9) (P = 0.028). There was a statistically significant difference in parenchymal stiffness between stable group (16.2kPa±1.2) and CR group (33.9kPa±6.6) (P = 0.027). The sensitivity was 90% and specificity was 81.8% of the scores in the differentiation of stable group from CR group (cut-off value, 2; P = 0.000). CONCLUSION: SWE combined with mSMI may help differentiate stable renal allograft from renal allograft CR and have the potential application value in the diagnosis of renal allograft CR.

Background The effect of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) on mortality was preliminarily explored through the comparison of ACEIs/ARBs with non-ACEIs/ARBs in patients with coronavirus disease 2019 (COVID-19). Reaching a conclusion on whether previous ACEI/ARB treatment should be continued in view of the different ACE2 levels in the comparison groups was not unimpeachable. Therefore, this study aimed to further elucidate the effect of ACEI/ARB continuation on hospital mortality, intensive care unit (ICU) admission, and invasive mechanical ventilation (IMV) in the same patient population. Methods We searched PubMed, the Cochrane Library, Ovid, and Embase for relevant articles published between December 1, 2019 and April 30, 2022. Continuation of ACEI/ARB use after hospitalization due to COVID-19 was considered as an exposure and discontinuation of ACEI/ARB considered as a control. The primary outcome was hospital mortality, and the secondary outcomes included 30-day mortality, rate of ICU admission, IMV, and other clinical outcomes. Results Seven observational studies and four randomized controlled trials involving 2823 patients were included. The pooled hospital mortality in the continuation group (13.04%, 158/1212) was significantly lower than that (22.15%, 278/1255) in the discontinuation group (risk ratio [RR] = 0.45; 95% confidence interval [CI], 0.28–0.72; P = 0.001). Continuation of ACEI/ARB use was associated with lower rates of ICU admission (10.5% versus 16.2%, RR = 0.63; 95% CI 0.5–0.79; P Conclusion Previous ACEI/ARB treatment could be continued since it was associated with lower hospital deaths, ICU admission, and IMV in patients with COVID-19, although the benefits of continuing use were mainly shown in observational studies. More evidence from multicenter RCTs are still needed to increase the robustness of the data. Trial registration PROSPERO (CRD42022341169). Registered 27 June 2022

By analyzing the differences of contrast-enhanced ultrasound (CEUS) features between low- and high-grade of WHO/ISUP grading, to explore the diagnostic value of CEUS in evaluating the prognosis of renal cell carcinoma (RCC).The qualitative and quantitative features of CEUS in 69 patients with RCC confirmed by surgical pathology in the Lanzhou University Second Hospital from March to October 2021 were retrospectively analyzed. Patients were categorized into two groups: low-grade group (n = 22) and high-grade group (n = 47), with surgical pathology as reference standard. The diagnostic performance of statistically significant CEUS features was evaluated by receiver operating characteristic (ROC) curves.There were statistically significant differences in enhancement degree (P = .032) and quantitative features such as slopeCEUS features such as ∆PI, may help differentiate low-grade RCC from high-grade RCC. CEUS has a promising application prospect in preoperative evaluation of the prognosis of RCC.

The major purpose of this study is to provide a proper approach for model identification of the Proton Exchange Membrane Fuel Cells (PEMFCs) to use in different applications. The method introduces a modified version of the Extreme Learning Machine (ELM) model for identification purposes. The modification is based on proposing and designing a new improved metaheuristic, called the developed Arithmetic Optimization Algorithm (dAOA). The algorithm is then verified by various algorithms to demonstrate its effectiveness and is then employed for optimizing the ELM configuration with the aim of minimizing the sum of the square error between the output voltage of the real PEMFC data and the output voltage achieved by the network. Simulation results of the proposed system are validated based on four scenarios that their results are as follows: for 3/5bar with 353.15 K, the maximum training error for dAOA and AOA are 6.01 and 9.899, respectively. For 1/1bar with 343.15 K, the maximum training error for dAOA and AOA are 0.0045 and 0.012, respectively. For 2.5/3bar with 343.15 K, the maximum training error for dAOA and AOA are 0.0132 and 0.0177, respectively, and for 1.5/1.5 bar with 343.15 K, the maximum training error for dAOA and AOA are 0.01and 0.01584, respectively. This shows the better results of the proposed dAOA to provide accurate parameters of the PEMFC stack system.

The fluffy fibers based on nitrocellulose (NC)/ammonium dinitramide (ADN) with high explosives have been fabricated by electrospinning technique. The morphology, thermal stability, combustion behaviors and mechanical sensitivity of NC/ADN-based composite fibers were characterized by means of scanning electron microscope (SEM), transmission electron microscopy (TEM), differentialscanning calorimetry (DSC), gas pressure measurement of thermostatic decomposition, laser ignition and sensitivity test, respectively. The results showed that the prepared fibers with fluffy 3D macrostructure were constructed by the overlap of mirco/nanofibers with the energetic particles imbedded in NC matrix. The addition of ADN can accelerate the thermal decomposition with the peak temperature (Tp) decrease by 10.1 oC and the pressure rise time moving forward. Furthermore, ADN can decrease the ignition delay time of NC-based fibers under atmosphere at room temperature from 33 ms to 9 ms, and enhance the burning strength of NC-based fibers under normal pressure. In addition, the impact sensitivities were reduced from 100–56% for NC-based fibers containing CL-20 and from 88–56% for NC-based fibers containing RDX; the friction sensitivities were reduced from 100–64% for NC-based fibers containing CL-20 and from 84–60% for NC-based fibers containing RDX, respectively.

Huang W, Zhu J, Shi H, Wu Q, Zhang C. Onco Targets Ther. 2021;14:3583–3596. The authors have advised there is an error in Figure 2E on page 3589. The Y axis “Migrative Cells per field” is shown as 0, 20, 40, 60, 80, and 100 and should read 0, 50, 100, 150 and 200. The correct Figure 2 is as follows. Figure 2 Silencing ITGA2 inhibits ESCC cells aggressiveness. (A–E) TE-1 and TE-10 cells were stably transfected with sh-Control or sh-ITGA2. Flow cytometric analysis of apoptosis (A), CCK8 assay (B), colony formation assay (C), wound healing assay (D), invasion and migration assay (E). For (E), displayed invasion and migration images are based on Transwell experiment. Sh-ITGA2 group and sh-Control group were compared. Each bar displays the mean±SD of 3 independent experiments as analyzed by paired two-tailed students, t-test. *p

Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.

Wei Huang,1,2,* Ju Zhu,1,* Haoming Shi,1 Qingchen Wu,1 Cheng Zhang1 1Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qingchen Wu; Cheng ZhangDepartment of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaEmail wuqc6@hotmail.com; zhangcs05223@163.comBackground: Integrin alpha 2 (ITGA2) is highly expressed in various cancers. ITGA2 up regulation promotes tumor proliferation, invasion, migration, and angiogenesis and ITGA2 is a poor prognostic factor in many tumors. However, the mechanism underlying its role in esophageal squamous cell carcinoma (ESCC) is unknown.Methods: The expression profile of ITGA2 in ESCC was analyzed using the Gene expression profiling interactive analysis (GEPIA). ESCC tissues were analyzed by real time PCR (RT-qPCR) and immunohistochemistry to verify ITGA2 expression. The impact of ITGA2 on the clinicopathological characteristics was explored using a chi-square test. Apoptosis, Transwell, colony formation, and wound healing assays were conducted to characterize the roles of ITGA2 in ESCC. Its impact on tumorigenesis was further examined using a tumor xenograft model. The expression of proteins associated with the epithelial-mesenchymal Transition (EMT) and focal adhesion kinase (FAK)/AKT pathway and regulated by ITGA2 was evaluated with Western blot analysis. The Akt inhibitor MK-2206 was used to explore the interaction of ITGA2 with the FAK/Akt pathway.Results: ITGA2 was upregulated in ESCC tissues and related to lymph node metastasis as well as TNM stage. In vitro experimental models revealed that ITGA2 promotes proliferation, invasion, and migration, and inhibits apoptosis. In vivo experiments show that ITGA2 promotes ESCC proliferation. Additionally, Western blot analysis revealed that ITGA2 silencing inhibits FAK/AKT signaling and suppresses EMT, while its overexpression activates FAK/AKT signaling and promotes EMT. Moreover, treatment with the AKT inhibitor MK-2206 successfully repressed the progression of ESCC caused by ITGA2 overexpression.Conclusion: Our findings indicated that in ESCC, ITGA2 promotes proliferation, invasion and migration, while inhibiting apoptosis and promoting EMT in ESCC, possibly via FAK/AKT phosphorylation. These findings highlight the therapeutic value of ITGA2 in ESCC.Keywords: ITGA2, ESCC, FAK/AKT, phosphorylation, EMT

Low or excessively high concentration of S-vacancy (CS-vacancy) is disadvantageous for the hydrogen evolution reaction (HER) activity of MoS2-based materials. Additionally, alkaline water electrolysis is most likely to be utilized in the industry. Consequently, it is of great importance for fine-tuning CS-vacancy to significantly improve alkaline hydrogen evolution. Herein, we have developed a one-step Ru doping coupled to compositing with CoS2 strategy to precisely regulate CS-vacancy of MoS2-based materials for highly efficient HER. In our strategy, Ru doping favors the heterogeneous nucleation and growth of CoS2, which leads to a high crystallinity of Ru-doped CoS2 (Ru-CoS2) and rich heterogeneous interfaces between Ru-CoS2 and Ru-doped MoS2-x (Ru-MoS2-x). This facilitates the electron transfer from Ru-CoS2 to Ru-MoS2-x, thereby increasing CS-vacancy of MoS2-based materials. Additionally, the electron injection effect increases gradually with an increase in the mass of Co precursor (mCo), which implies more S2- leaching from MoS2 at higher mCo. Subsequently, CS-vacancy of the as-synthesized samples is precisely regulated by the synergistic engineering of Ru doping and compositing with CoS2. At CS-vacancy = 17.1%, a balance between the intrinsic activity and the number of exposed Mo atoms (EMAs) to boost highly active EMAs should be realized. Therefore, the typical samples demonstrate excellent alkaline HER activity, such as a low overpotential of 170 mV at 100 mA cm−2 and a TOF of 4.29 s−1 at -0.2 V. Our results show promise for important applications in the fields of electrocatalysis or energy conversion.

Aim: To investigate the value of vesical imaging reporting and data system (VI-RADS) score based on conventional ultrasound and contrast-enhanced ultrasound (CEUS) in differentiating muscle-invasive bladder cancer (MIBC).Material and methods: Thirty-eight patients who underwent conventional ultrasound and CEUS examinations at our ultrasound department between March 2021 and June 2022 were retrospectively included in this study. Two sonographers analyzed the conventional ultrasound and CEUS images of each patient separately and scored them in strict accordance with VI-RADS scoring system based on conventional ultrasound and CEUS. The VI-RADS score of each lesion was compared with the pathological findings to assess the diagnostic performance of VI-RADS. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the VI-RADS score in the diagnosis of MIBC were analyzed when the cutoff values were 3 and 4, respectively. Interobserver agreement was evaluated using the weighted-kappa coefficient (κ).Results: The final pathological results evidenced 25 (65.8%) non-muscle-invasive bladder cancers (NMIBCs) and 13 (34.2%) MIBCs. When the VI-RADSscore ≥ 4, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the VI-RADS score for predicting muscle-invasive bladder cancer were 92.3%, 84.0%, 75.0%, 95.5%, and 86.8%, respectively. The area under the receiver operating curve for the VI-RADS score was 0.882 (95%CI:0.761-1). Inter-reader agreement for VI-RADS scoreswas good.Conclusion: The VI-RADS score based on conventional ultrasound and CEUS is useful in differentiating muscleinvasive bladder cancer.

B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-XL, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy. Recently, an increasing number of Mcl-1-selective small-molecule inhibitors have entered preclinical studies and advanced into clinical trials. In this review, we briefly introduce the role of Mcl-1 in apoptosis and highlight the recent development of Mcl-1 small-molecule inhibitors.

To evaluate the outcomes of refractory/relapsed cHL patients after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) in Beijing Cancer hospital and to identify the prognostic risk factors. We retrospectively analyzed 115 relapsed/refractory cHL patients who accepted HDCT and ASCT in our cancer center and had complete follow-up data from April 2000 to May 2017. Ages of these 115 patients at ASCT ranged from 14 to 63 (median age 28). Forty-four (38.3%) patients achieved CR and 50 (43.5%) patients achieved PR before ASCT. Thirty-seven (48.7%) patients of those 76 patients who did PET-CT before ASCT had negative PET-CT scans. The median follow-up time was 72 months. A total of 23 patients died in our study. The 5-year OS and PFS rates of all patients after ASCT were 78.7% and 53%, respectively. The 5-year OS rates after ASCT of patients who were in CR or PR or less than PR status before ASCT were 92.8%, 68.2%, and 76.2%, respectively (log-rank = 2.913, p = 0.233). And their 5-year PFS rates after ASCT were 69.2%, 54.2%, and 18.5%, respectively (log-rank = 13.615, p = 0.001). Univariate analysis revealed that ECOG (p = 0.010; hazard ratio = 1.578), disease status before ASCT (CR: p = 0.001; hazard ratio = 0.227) and after ASCT (CR: p < 0.001; hazard ratio = 0.154), and PET-CT results after ASCT (p = 0.023; hazard ratio = 0.438) significantly impact patients' PFS while number of pretransplant salvage chemotherapy (p = 0.037; hazard ratio = 2.521), radiotherapy (p = 0.046; hazard ratio = 0.423), and disease status after ASCT (CR: p = 0.010; hazard ratio = 0.197) significantly affected patients' OS. Multivariate analysis shown only disease status before ASCT (p = 0.002) had significant impact on PFS and disease status after ASCT (p = 0.021) had significant impact on OS. R/R HL patients can still obtain long-term PFS after HDCT and ASCT and disease status before ASCT was the most significant prognostic factor for PFS.

The colchicine site inhibitors (CSIs) showed promising prospects as antitumor agents due to their vascular disrupting activities besides antimitotic activities. 1-Phenyl-dihydrobenzoindazole was found as a novel scaffold of CSI without the cis−trans isomerization problem. The X-ray co-crystal structure of the lead compound with tubulin was determined, which revealed the binding mode including special water-bridged hydrogen bonds. The structure also provided guidance for the structural optimization of this type of CSI, which led to the discovery of the most potent inhibitor A3, with growth IC50 lower than 1 nM against human colon cancer cell lines and tubulin polymerization IC50 of 1.6 μM. In addition, its water-soluble prodrug B1 showed good in vivo antitumor activity on two human colon cancer xenograft nude mice models, encouraging further study of this type of antitumor compound.

Focusing on the characteristics of public participation and large group decision making of major livelihood projects, this paper proposes a multi-agent linguistic-style large group decision-making method with the consideration of public expectations. Firstly, based on the discrimination degree of evaluating information, the comprehensive weight of each attribute is calculated with the principle of maximum entropy. Secondly, the expert preference information for different alternatives is clustered and several aggregations are formed. Thirdly, the preference conflict level of experts' group for each alternative is calculated, and a conflict-oriented experts' aggregation weight optimization model is constructed to ensure the effectiveness of conflict resolution. Fourthly, the public group's satisfaction is determined with the expectation distribution of public’s and the expert group's preference, so as to obtain the sorting result of the decision alternatives. Finally, the effectiveness and applicability of the proposed method are verified by method comparison.

Background: Non-small cell lung cancer (NSCLC) survivors are at an increased risk of developing second primary malignancies, such as small cell lung cancer. This paper sought to establish a prognostic nomogram to assess overall survival (OS) in patients with second primary small cell lung cancer (SPSCLC) after NSCLC.Methods: 420 patients who developed SPSCLC after NSCLC were randomly split into the training and validation groups. A nomogram was established by stepwise regression. Area under the curve (AUC) and calibration plots were applied to assess the prognostic performance of the nomogram. Concordance index (C-index), integrated discrimination improvement (IDI), net reclassification index (NRI) and decision curve analysis (DCA) were performed to compare the nomogram with the American Joint Committee on Cancer (AJCC) 8th staging system. Survival risk classification was constructed based on the nomogram.Results: Five variables were chosen to construct the nomogram. The AUC showed that it had a satisfactory discrimination ability. All calibration plots displayed good concordance between nomogram and observation. The C-index, IDI, NRI and DCA showed the nomogram was superior to the AJCC 8th staging system. The Kaplan-Meier curves suggested huge differences in prognosis among the three risk groups.Conclusions: This study build a nomogram and risk stratification system for predicting probabilities of OS in patients with SPSCLC after NSCLC, which can help clinicians in individualized survival assessment and treatment decisions.

Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1

Despite the growing knowledge of T cell responses in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Here, with a predicted peptide library from SARS-CoV-2 S and N proteins, restricted to three of the most prominent HLA-A alleles in the Asian population, we found that specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients (15/20). A total of 15 SARS-CoV-2 epitopes from the S and N proteins were identified, and among them, 3 dominant epitopes were further characterized. We found that an epitope from the N protein, N361-369 (KTFPPTEPK), was the most dominant epitope from our selected peptide library. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity that were independent of the CD8 co-receptor. These TCRs exhibited complementary cross-reactivity to several presently reported N361-369 mutant variants, as to the wild-type epitope. Further, the natural functions of these TCRs in the cytotoxic immunity against SARS-CoV-2 were determined with dendritic cells (DCs) and the lung organoid model. We found that the N361-369 epitope could be normally processed and endogenously presented by these different types of antigen presenting cells, to elicit successful activation and effective cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, and illuminated potential ways of viral clearance in COVID-19 patients. These results indicate that utilizing CD8-independent TCRs against SARS-CoV-2-associated antigens may provide functional superiority that is beneficial for the adoptive cell immunotherapies based on natural or genetically engineered T cells. Additionally, this information is highly relevant for the development of the next-generation vaccines with protections against continuously emerged SARS-CoV-2 mutant strains.

Human epidermal growth factor receptor 2 (HER-2) is an essential member of the receptor tyrosine kinase (RTK) superfamily and has been reported as a critical method for treating HER-2 positive breast cancer. Here, we retained (E)-4-methyl-2-(4-(trifluoromethyl)styryl)oxazole, a fragment of HER-2 inhibitor Mubritinib, and synthesized 32 novel compounds from it. We screened out the most potential compound Q7j with HER-2 positive breast cancer cells through MTT assays, which possessed low toxicity on normal cells (MCF7-10A). Subsequently, wound healing, transwell, western blotting, and immunofluorescence experiments were performed, and it was found that compound Q7j could suppress cell migration by inhibiting the phosphorylation of HER-2 and affecting the expression of EMT-related proteins. Moreover, the SKBR3 orthotopic xenograft model confirmed that compound Q7j was more effective than Mubritinib in inhibiting the proliferation of cancer cells. In general, compound Q7j was a potential HER-2 inhibitor in treating breast cancer, which may be of great significance for developing and improving HER-2 small molecule inhibitors.

In the last two decades, with the wide use of azoles, antifungal resistance among Candida parapsilosis has considered a matter of concern worldwide. The aim of this study is to evaluate the antifungal potentials of tetrandrine (TET) alone and in combination with fluconazole (FLC)/voriconazole (VRC) against C. parapsilosis. Susceptibility tests were performed by microdilution method, checkerboard assay, time-kill test, spot assay. Subsequently, rhodamine 6G efflux test and the expressions of transporter related genes, namely CDR1 and MDR1 for C. parapsilosis were analyzed by qRT-PCR. The susceptibility test showed that TET presented strong synergism with FLC and VRC with fractional inhibitory concentration index (FICI) in a range of 0.094-0.562. The susceptibility results were also confirmed by spot assay and time-kill studies. With TET treatment, a vast quantity of rhodamine 6G could not be pumped out from the cells as considerably intracellular red fluorescence was accumulated. Meanwhile, the expressions of efflux-associated genes presented varying degrees of inhibition. These results indicated that TET was a decent antifungal synergist to promote the antifungal efficacy of FLC/VRC, and the underlying antifungal mechanism might be associated with the inhibition of efflux pump and the elevation of intracellular drug content.

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an important enzyme response for the metabolism or detoxification of toxic aldehydes, in particular acetaldehyde and 4-hydroxynonenal (4-HNE), which were important risk factors for acute alcoholism and stroke respectively. A special variant ALDH2∗2 with reduced enzymatic activity was carried by a high percentage of East Asians, especially Han Chinese, and that could increase the risk of these diseases further. Therefore, ALDH2 activators had important potential clinical values. N-benzylbenzamide compounds represented by Alda-1 were the only ALDH2-specific activators that have been reported so far. In this study, three new classes of compounds were modified from Alda-1 to improve their water-solubility and then drug-like properties. The results showed that all compounds had increased water solubility and two classes of compounds exhibited good activation activity. Among them, compound I-6 showed the best activity. Keywords: Mitochondrial aldehyde dehydrogenase 2, Activators, Synthesis, Biological evaluation

Background/aim: This article analyzes the incidence and characteristics of peripheral neuropathy in patients with impaired glucose regulation (IGR).Materials and methods: A total of 120 IGR patients and 60 healthy controls were enrolled. All subjects underwent nerve conduction study (NCS) of large fibers and skin sympathetic response (SSR) and contact heat pain evoked potential (CHEP) testing of small fibers with a Medtronic Keypoint machine (Medoc Ltd., Israel). IGR patients were evaluated using the Michigan Neuropathy Screening Instrument (MNSI).Results: The abnormal rates (MNSI >2) in IGR patients and NCS and SSR evaluations were 18.3%, 22.5%, and 39.2%, respectively. All abnormal NCS findings were accompanied with abnormal SSR findings. Compared with the control group, the sensory nerve action potential wave of the posterior tibial and sural nerve was decreased in the IGR group (P = 0.01, P = 0.00), the SSR wave was reduced in the upper and lower limbs (P = 0.002, P = 0.00), and the CHEP wave was decreased in opisthenar and shank (P = 0.00). Compared with the control group, the CHEP wave was decreased in the shank in the normal SSR group (P < 0.05) and in the opisthenar and shank in the normal NCS group (P < 0.05).Conclusion: : IGR patients have peripheral neuropathy characterized by impaired functions of large and small fibers focused on small fiber and lower limb sensory nerves. CHEP can detect small fiber damage earlier than SSR and NCS.

Multiple myeloma (MM) is the second most common haematological malignancy and remains an incurable disease, with most patients relapsing and requiring further treatment. Augmenter of liver regeneration (ALR) is a vital protein affecting fundamental processes such as energy transduction, cell survival and regeneration. Silencing ALR inhibits cell proliferation and triggers apoptosis in human MM U266 cells. However, little is known about the role of 15-kDa-ALR on MM. In the present study, the role of 15-kDa-ALR in human MM cells was investigated. Blocking extracellular 15-kDa-ALR with an anti-ALR monoclonal antibody (McAb) decreased the proliferation and viability of U266 cells. However, the results of flow cytometry revealed no changes in apoptosis, and the expression levels of Bax, Bcl-2, caspase-3 and cleaved caspase-3 were not affected. However, combined treatment with anti-ALR McAb and epirubicin increased the apoptosis of U266 cells. RNA sequencing results indicated that the ERK1/2, JNK-MAPK and STAT3 signaling pathways, as well as the cell cycle, were associated with the mechanism of action of the anti-ALR McAb, and PCR, western blotting and cell cycle analysis confirmed these results. The present findings suggested that blocking extracellular 15-kDa-ALR in U266 cells with an anti-ALR McAb decreased cell proliferation via the MAPK, STAT3 and cell cycle signaling pathways without increasing apoptosis. Thus, 15-kDa-ALR may be a new therapeutic target for myeloma.

The rapid development of intelligent manufacturing provides strong support for the intelligent medical service ecosystem. Researchers are committed to building Wise Information Technology of 120 (WIT 120) for residents and medical personnel with the concept of simple smart medical care and through core technologies such as Internet of Things, Big Data Analytics, Artificial Intelligence, and microservice framework, to improve patient safety, medical quality, clinical efficiency, and operational benefits. Among them, how to use computers and deep learning technology to assist in the diagnosis of tongue images and realize intelligent tongue diagnosis has become a major trend. Tongue crack is an important feature of tongue states. Not only does change of tongue crack states reflect objectively and accurately changed circumstances of some typical diseases and TCM syndrome but also semantic segmentation of fissured tongue can combine the other features of tongue states to further improve tongue diagnosis systems’ identification accuracy. Although computer tongue diagnosis technology has made great progress, there are few studies on the fissured tongue, and most of them focus on the analysis of tongue coating and body. In this paper, we do systematic and in-depth researches and propose an improved U-Net network for image semantic segmentation of fissured tongue. By introducing the Global Convolution Network module into the encoder part of U-Net, it solves the problem that the encoder part is relatively simple and cannot extract relatively abstract high-level semantic features. Finally, the method is verified by experiments. The improved U-Net network has a better segmentation effect and higher segmentation accuracy for fissured tongue image dataset. It can be used to design a computer-aided tongue diagnosis system.

To determine the effects of Chinese medicine (CM) involving triple rehabilitation therapy on the progression of knee osteoarthritis (KOA).A total of 722 patients recruited from 38 community health service centers located in China from March 2013 to March 2017 were randomly divided into treatment and control groups equally, using a cluster randomization design. Health education combined with CM involving triple rehabilitation therapy for KOA (electro-acupuncture, Chinese medicinal herb fumigating-washing, and traditional exercises) was administered in the treatment group while conventional rehabilitation therapy (physical factor therapy, joint movement training, and muscle strength training) was administered in the control group. Patients with a visual analog scale (VAS) scores ≽4 were treated with dispersible meloxicam tablets (7.5 mg, once daily). The Lequesne index scores, VAS scores, range of motion (ROM), lower limb muscle strength, knee joint circumference, quantitative scores of KOA symptoms, and the short-form 36 item health survey questionnaire (SF-36) scores were measured for each patient at 5 checkpoints (before treatment, at the 2nd week and the 4th week during the 4-week treatment period, at 1 month and 3 months after end of treatment), and adverse reactions were observed also.A total of 696 patients completed the entire process, with 351 in the treatment group and 345 in the control group. At all treatment checkpoints, the treatment group demonstrated better outcomes than the control group with regard to the total Lequesne index scores, effective rate and improvement rate of the total Lequesne index scores, VAS scores, lower limb muscle strength, knee circumference, quantitative scores of KOA symptoms, and SF-36 scores as well (P0.05 or P0.01). No adverse reactions were encountered in this study.CM involving triple rehabilitation therapy can alleviate KOA-related pain and swelling, improve lower limb muscle strength, promote flexion and activity of the knee and improve the quality of life in patients undergoing KOA. It is suitable for patients with early or mid-stage KOA. (Registration No. ChiCTR-TRC-12002538).

To study the effects ofEighty SD male rats were randomly divided into eight groups: control group(A), exercise group(B), exercise + alpha-asarone low, middle and high dose treatment group (C, D, E), exercise +The escape latency and MDA content in hippocampus of rats in groups E and H were lower than those in groups B, C, D, F and G and the numbers of Plateau crossing, SOD and NOS activities and the expression levels of nNOS protein in hippocampus of rats were higher than those in groups B, C, D, F and G(目的: 研究石菖蒲及其活性成分-α-细辛醚改善疲劳运动大鼠学习记忆的作用及其机制。方法: 80只SD大鼠随机分为正常对照组(A)、单纯运动组(B)、运动+α-细辛醚低、中、高剂量组(C、D、E)、运动+石菖蒲低、中、高剂量治疗组(F、G、H),每组10只。并在疲劳运动开始前2 h分别以0.10、0.50 和 1.00 mg α-细辛醚,灌胃C、D、E组,以0.12、1.20和4.80 g. kg

Despite the growing knowledge of T cell responses and their epitopes in COVID-19 patients, there is a lack of detailed characterizations for T cell-antigen interactions and T cell functions. Using a peptide library predicted with HLA class I-restriction, specific CD8+ T cell responses were identified in over 75% of COVID-19 convalescent patients. Among the 15 SARS-CoV-2 epitopes identified from the S and N proteins, N361-369 (KTFPPTEPK) was the most dominant epitope. Importantly, we discovered 2 N361-369-specific T cell receptors (TCRs) with high functional avidity, and they exhibited complementary cross-reactivity to reported N361-369 mutant variants. In dendritic cells (DCs) and the lung organoid model, we found that the N361-369 epitope could be processed and endogenously presented to elicit the activation and cytotoxicity of CD8+ T cells ex vivo. Our study evidenced potential mechanisms of cellular immunity to SARS-CoV-2, illuminating natural ways of viral clearance with high relevancy in the vaccine development.

Oxidative stress from the trophoblasts is one of the possible pathological mechanisms of Preeclampsia (PE). This study aimed at exploring the potential effects of astaxanthin (ATX) on oxidative stress damaged placental trophoblast cell line HTR-8/SVneo. Oxidative stress-induced damaged through H

Aldehyde dehydrogenase 2 (ALDH2) plays important role in ethanol metabolism, and also serves as an important shield from the damage occurring under oxidative stress. A special inactive variant was found carried by 35–45% of East Asians. The variant carriers have recently been found at the higher risk for the diseases related to the damage occurring under oxidative stress, such as cardiovascular and cerebrovascular diseases. As a result, ALDH2 activators may potentially serve as a new class of therapeutics. Herein, N-benzylanilines were found as novel allosteric activators of ALDH2 by computational virtual screening using ligand-based and structure-based screening parallel screening strategy. Then a structural optimization was performed and has led to the discovery of the compound C6. It has good activity in vitro and in vivo, which could reduce infarct size by ∼70% in ischemic stroke rat models. This study provided good lead compounds for the further development of ALDH2 activators.

Ischemia–reperfusion (I/R) is the most common cause of acute kidney injury (AKI) and can induce apoptosis in renal epithelial tubule cells. Mitochondrial dysfunction is one of the main reasons for I/R-induced apoptosis. Accumulating evidence suggests that PINK1/Parkin-mediated mitophagy possibly plays a renoprotective role in kidney disease by removing impaired mitochondria and preserving a healthy population of mitochondria. Our previous study showed that augmenter of liver regeneration (ALR) alleviates tubular epithelial cells apoptosis in rats with AKI, although the specific mechanism remains unclear. In this study, we investigated the role of ALR in I/R-induced mitochondrial pathway of apoptosis. We knocked down ALR with short hairpin RNA lentiviral and established an I/R model in human kidney proximal tubular (HK-2) cells in vitro. We observed that the knockdown of ALR aggravated mitochondrial dysfunction and increased the mitochondrial reactive oxygen species (ROS) levels, leading to an increase in cell apoptosis via inhibition of mitophagy. We also found that the PINK1/Parkin pathway was activated by I/R via confocal microscopy and Western blot. Furthermore, the knockdown of ALR suppressed the activation of PINK1 and Parkin. These findings collectively indicate that ALR may protect HK-2 cells from I/R injury by promoting mitophagy, and the mechanism by which ALR regulates mitophagy seems to be related to PINK1 and Parkin. Consequently, ALR may be used as a potential therapeutic agent for AKI in the future.

While the effect of increasing tidewater inundation caused by sea-level rise on carbon cycling had been well studied in saltmarshes, little is known about the effect of increasing tidewater inundation on CO

To investigate the effects of Acorus tatarinowii Schott and its active component 5- hydroxymethyl furfural (HMF) on learning and memory and ERK/CREB signal in hippocampus of rats with exercise-induced fatigue.SD rats were randomly divided into normal group (A), exercise group (B), exercise + HMF low, middle and high dose treatment group (C, D, E), exercise + acorus tatarinowii Schott low, middle and high dose treatment group (F, G, H), with ten rats in each group. The rats in group C, D and E were treated with HMF at the doses of 0.10, 1.00 and 3.00 mg. kgThe escape latencies of E and H groups were lower than those of groups B, C, D, F and G; and the numbers of plateau crossing were more than those of groups B, C, D, F and G and the expression levels of p-ERK1/2, p-CREB protein were higher than those of groups B, C, D, F and G , respectively(P ＜ 0.01). There was no significant difference in the above indexes among groups A, E and H(P＞0.05) except that the expression levels of p-ERK2 protein in group E were lower than those in group A and H (P＜0.05).Acorus tatarinowii and its active component- HMF can improve the learning and memory of rats with exercise-induced fatigue, and the mechanism is related to the up-regulation of ERK / CREB signal in hippocampus of rats with exercise-induced fatigue.