Role of prostaglandin E2 and its receptors in chronic liver disease.

Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E2 (PGE2), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE2 are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE2 and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE2 and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE2-EP receptors system in treating CLD with various etiologies.

Lysine Deprivation Suppresses Adipogenesis in 3T3-L1 Cells: A Transcriptome Analysis.

Growing evidence proves that amino acid restriction can reverse obesity by reducing adipose tissue mass. Amino acids are not only the building blocks of proteins but also serve as signaling molecules in multiple biological pathways. The study of adipocytes' response to amino acid level changes is crucial. It has been reported that a low concentration of lysine suppresses lipid accumulation and transcription of several adipogenic genes in 3T3-L1 preadipocytes. However, the detailed lysine-deprivation-induced cellular transcriptomic changes and the altered pathways have yet to be fully studied. Here, using 3T3-L1 cells, we performed RNA sequencing on undifferentiated and differentiated cells, and differentiated cells under a lysine-free environment, and the data were subjected to KEGG enrichment. We found that the differentiation process of 3T3-L1 cells to adipocytes required the large-scale upregulation of metabolic pathways, mainly on the mitochondrial TCA cycle, oxidative phosphorylation, and downregulation of the lysosomal pathway. Single amino acid lysine depletion suppressed differentiation dose dependently. It disrupted the metabolism of cellular amino acids, which could be partially reflected in the changes in amino acid levels in the culture medium. It inhibited the mitochondria respiratory chain and upregulated the lysosomal pathway, which are essential for adipocyte differentiation. We also noticed that cellular interleukin 6 (IL6) expression and medium IL6 level were dramatically increased, which was one of the targets for suppressing adipogenesis induced by lysine depletion. Moreover, we showed that the depletion of some essential amino acids such as methionine and cystine could induce similar phenomena. This suggests that individual amino acid deprivation may share some common pathways. This descriptive study dissects the pathways for adipogenesis and how the cellular transcriptome was altered under lysine depletion.

Pre-extinction activation of hippocampal AMPK prevents fear renewal in mice.

As a type of fear relapse, fear renewal compromises the efficacy of fear extinction, which serves as the laboratory analog of exposure therapy (a therapeutic strategy for anxiety disorders). Interventions aiming to prevent fear renewal would thus benefit exposure therapy. To date, it remains unknown whether central adenosine monophosphate (AMP)-activated protein kinase (AMPK) activation could produce inhibitory effects on fear renewal. Here, using pharmacological approach and virus-mediated gene overexpression technique, we demonstrated that activation of AMPK in dorsal hippocampus shortly before fear extinction training completely abolished subsequent fear renewal in male mice without affecting other types of fear relapse, including spontaneous recovery of fear and fear reinstatement. Furthermore, we also found that metformin, a first-line antidiabetic drug, was capable of preventing fear renewal in male mice by stimulating AMPK in dorsal hippocampus. Collectively, our study provides insight into the role of hippocampal AMPK in regulation of fear renewal and indicates that increasing activity of hippocampal AMPK can prevent fear renewal, thus enhancing the potency of exposure therapy.

The microneedles carrying cisplatin and IR820 to perform synergistic chemo-photodynamic therapy against breast cancer.

BACKGROUNDS: Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. METHODS: In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. RESULTS: The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone-vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. CONCLUSIONS: Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.

Preparation, characterization and in vitro-in vivo evaluation of bortezomib supermolecular aggregation nanovehicles.

BACKGROUNDS: Intolerable toxicity and unsatisfactory therapeutic effects are still big problems retarding the use of chemotherapy against cancer. Nano-drug delivery system promised a lot in increasing the patients' compliance and therapeutic efficacy. As a unique nano-carrier, supermolecular aggregation nanovehicle has attracted increasing interests due to the following advantages: announcing drug loading efficacy, pronouncing in vivo performance and simplified production process. METHODS: In this study, the supermolecular aggregation nanovehicle of bortezomib (BTZ) was prepared to treat breast cancer. RESULTS: Although many supermolecular nanovehicles are inclined to disintegrate due to the weak intermolecular interactions among the components, the BTZ supermolecules are satisfying stable. To shed light on the reasons behind this, the forces driving the formation of the nanovehicles were detailed investigated. In other words, the interactions among BTZ and other two components were studied to characterize the nanovehicles and ensure its stability. CONCLUSIONS: Due to the promising tumor targeting ability of the BTZ nanovehicles, the supermolecule displayed promising tumor curing effects and negligible systemic toxicity.

Sulforaphane suppresses EMT and metastasis in human lung cancer through miR-616-5p-mediated GSK3ß/ß-catenin signaling pathways.

Sulforaphane is a common antioxidant selectively abundant in cruciferous plants, which exhibits effective anti-cancer actions in control of tumorigenesis or progression of various cancers. A recent study has shown that sulforaphane attenuates the EGFR signaling pathway in non-small cell lung cancer (NSCLC), suggesting its potential anti-metastatic effects. In this study we assessed the involvement of sulforaphane and miR-616-5p in epithelial-mesenchymal transition (EMT) and NSCLC metastasis. Sulforaphane suppressed the cell proliferation in human NSCLC cell lines H1299, 95C and 95D with IC50 values of 9.52±1.23, 9.04±1.90 and 17.35±2.03 µmol/L, respectively. At low concentrations (1-5 µmol/L), sulforaphane dose-dependently inhibited the migration and invasion of 95D and H1299 cells with relatively high metastatic potential. The anti-metastatic action of sulforaphane was confirmed in 95D and H1299 cell xenografts in vivo. In fresh NSCLC tissue samples from 179 patients, miR-616-5p levels were upregulated in late-stage NSCLCs, and strongly correlated with risk of NSCLC recurrence and metastasis. Consistent with the clinic observation, miR-616-5p levels in the 3 NSCLC cell lines were correlated with their metastatic ability, and were decreased by sulforaphane treatment. Silencing miR-616-5p markedly suppressed the migration and invasion of 95D cells in vitro and NSCLC metastasis in vivo. Further studies revealed that miR-616-5p directly targeted GSK3ß and decreased its expression, whereas sulforaphane decreased miR-616-5p levels by histone modification, and followed by inactivation of the GSK3ß/ß-catenin signaling pathway and inhibition of EMT, which was characterized by loss of epithelial markers and acquisition of a mesenchymal phenotype in NSCLC cells. Our findings suggest that sulforaphane is a potential adjuvant chemotherapeutic agent for the prevention of NSCLC recurrence and metastasis, and miR-616-5p can be clinically utilized as a biomarker or therapeutic target to inhibit metastasis.

[Obstructive sleep apnea affects the sexual function of the male patient].

OBJECTIVE: To explore the factors influencing the sexual function of the male patients with obstructive sleep apnea (OSA). METHODS: Using Arizona Sexual Experience Scale (ASEX) and Epworth Sleepiness Scale (ESS), we conducted a questionnaire investigation among 81 male patients with OSA aged 40.5 ± 8.6 years and 35 healthy volunteers aged 38.8 ± 10 years. According to the sex drive (SD) score in ASEX, we divided the OSA patients into an SD reduction group (SD score = 4, n = 32) and a non-SD reduction group (SD score <4, n = 49), compared the clinical data and polysomnographic (PSG) indexes, and analyzed the factors influencing SD by evaluating the association of the PSG indexes with the SD score. RESULTS: The OSA patients scored significantly higher than the healthy controls in ESS (8 ± 5 vs 5 ± 4, P <0.05) and ASEX (15 ± 4 vs 10 ± 2, P <0.05), and so did the patients of the SD reduction group than those of the non-SD reduction group in ESS (9 ± 5 vs 6 ± 5, P <0.05) and saturation impair time below 90% (SIT90) (41.01 ± 26.95 vs 21.87 ± 19.03, P <0.05). Multivariate regression analysis revealed that the SD score was significantly correlated with age (ß = 0.25, P <0.001) and SIT90 (ß = 0.4, P <0.001) in the OSA patients. CONCLUSIONS: OSA affects various aspects of the sexual function, particularly SD, of the patient. The duration of hypoxia and age of the patient are independent risk factors for SD reduction, which can be considered as a main clinical symptom of OSA.

[Effects of Xiangsha Liujunzi decoction on TLR signal pathway in gastric mucosa tissues of rats with Helicobacter pylori-induced chronic atrophic gastritis].

To explore the effects and mechanism of Xiangsha Liujunzi decoction on TLR signal pathway in gastric mucosa tissues of rats with Helicobacter pylori-related gastritis, sixty SD rats were randomly divided into control group, model group, high concentration of Xiangsha Liujunzi decoction group, moderate concentration of Xiangsha Liujunzi decoction group, low concentrations of Xiangsha Liujunzi decoction group and SB203580-treated group, with 10 rats in each group. SD rats of Hp-associated chronic atrophic gastritis models were established by intragastric gavage of Helicobacter pylori (HP) suspension. Changes in the gastric mucosa of rats were assessed by histopathology. ELISA was applied to detect the expressions of TNF-α and IL-6 in the serum, and the activity of iNOS in gastric mucosa. The content of NO in the gastric mucosa was tested by nitrate reductive enzymatic. The expressions of TLR2, TLR4, P38MAPK, NF-κB were detected by QPCR and Western-blot. The results indicated that the clinical symptoms of rats and pathological changes of gastric mucosa were improved in Xiangsha Liujunzi decoction group. Compared with normal control group, the protein expressions of TLR2, TLR4, p-P38MAPK and NF-κB in gastric mucosa of model group rats increased (P<0.01) with the levels of TNF-α and IL-6 in the serum, and the activity of iNOS and the content of NO in gastric mucosa increased. Compared with model group, the expressions decreased in Xiangsha Liujunzi decoction group, especially in the high concentration of Xiangsha Liujunzi decoction group(P<0.01), with gradually increased rate of HP eradication and decreased pathological grades of chronic atrophic gastritis. The serum level of TNF-α and IL-6 decreased from (24.313±2.261) µg•L ⁻¹ to (15.195±1.235) µg•L-1(P<0.01) and from (77.416±8.095) µg•L ⁻¹ to (33.150±2.532) µg•L ⁻¹ (P<0.01), and the activity of iNOS and the content of NO in gastric mucosa decreased from (1.530±0.206) U•mg ⁻¹ to (0.802±0.091) U•mg ⁻¹ (P<0.01) and from (0.907±0.032) mmol•g ⁻¹ to (0.335±0.026) mmol•g ⁻¹ (P<0.01) after the treatment of high concentration of Xiangsha Liujunzi decoction. All the effects increased with the increasing dosage of Xiangsha Liujunzi decoction from 0.324 g•mg ⁻¹ to 1.296 g•mg ⁻¹. The protein expressions of NF-κB decreased in the gastric mucosa after treated with P38MAPK specific inhibitor-SB203580. In the rats model, HP infection results in chronic atrophic gastritis through the activation of TLR2, TLR4/MAPK/NF-κB/iNOS/NO signal pathway. Xiangsha Liujunzi decoction can eradicate H. pylori and alleviate chronic atrophic gastric mucosal inflammation. The treatment is effective and safe to cure HP-induced chronic atrophic gastritis.

The value of CT-based radiomics in predicting hemorrhagic transformation in acute ischemic stroke patients without recanalization therapy.

Objective: The aim of this study is to investigate the clinical value of radiomics based on non-enhanced head CT in the prediction of hemorrhage transformation in acute ischemic stroke (AIS). Materials and methods: A total of 140 patients diagnosed with AIS from January 2015 to August 2022 were enrolled. Radiomic features from infarcted areas on non-enhanced CT images were extracted using ITK-SNAP. The max-relevance and min-redundancy (mRMR) and the least absolute shrinkage and selection operator (LASSO) were used to select features. The radiomics signature was then constructed by multiple logistic regressions. The clinicoradiomics nomogram was constructed by combining radiomics signature and clinical characteristics. All predictive models were constructed in the training group, and these were verified in the validation group. All models were evaluated with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). Results: Of the 140 patients, 59 experienced hemorrhagic transformation, while 81 remained stable. The radiomics signature was constructed by 10 radiomics features. The clinicoradiomics nomogram was constructed by combining radiomics signature and atrial fibrillation. The area under the ROC curve (AUCs) of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the training group were 0.64, 0.86, and 0.86, respectively. The AUCs of the clinical model, radiomics signature, and clinicoradiomics nomogram for predicting hemorrhagic transformation in the validation group were 0.63, 0.90, and 0.90, respectively. The DCA curves showed that the radiomics signature performed well as well as the clinicoradiomics nomogram. The DCA curve showed that the clinical application value of the radiomics signature is similar to that of the clinicoradiomics nomogram. Conclusion: The radiomics signature, constructed without incorporating clinical characteristics, can independently and effectively predict hemorrhagic transformation in AIS patients.

Cardiac hypertrophy is positively regulated by MicroRNA miR-23a.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that mediate post-transcriptional gene silencing. Myocardial hypertrophy is frequently associated with the development of heart failure. A variety of miRNAs are involved in the regulation of cardiac hypertrophy, however, the molecular targets of miRNAs in the cardiac hypertrophic cascades remain to be fully identified. We produced miR-23a transgenic mice, and these mice exhibit exaggerated cardiac hypertrophy in response to the stimulation with phenylephrine or pressure overload by transverse aortic banding. The endogenous miR-23a is up-regulated upon treatment with phenylephrine, endothelin-1, or transverse aortic banding. Knockdown of miR-23a attenuates hypertrophic responses. To identify the downstream targets of miR-23a, we found that transcription factor Foxo3a is suppressed by miR-23a. Luciferase assay indicates that miR-23a directly inhibits the translation activity of Foxo3a 3' UTR. Introduction or knockdown of miR-23a leads to the alterations of Foxo3a protein levels. Enforced expression of the constitutively active form of Foxo3a counteracts the provocative effect of miR-23a on hypertrophy. Furthermore, we observed that miR-23a is able to alter the expression levels of manganese superoxide dismutase and the consequent reactive oxygen species, and this effect is mediated by Foxo3a. In addition, our results show that miR-23a and Foxo3a bi-transgenic mice exhibit a reduced hypertrophic response compared with the miR-23a transgenic mice alone. Our present study reveals that miR-23a can mediate the hypertrophic signal through regulating Foxo3a. They form an axis in hypertrophic machinery and can be targets for the development of hypertrophic treatment.

Stroke risk study based on deep learning-based magnetic resonance imaging carotid plaque automatic segmentation algorithm.

Introduction: The primary factor for cardiovascular disease and upcoming cardiovascular events is atherosclerosis. Recently, carotid plaque texture, as observed on ultrasonography, is varied and difficult to classify with the human eye due to substantial inter-observer variability. High-resolution magnetic resonance (MR) plaque imaging offers naturally superior soft tissue contrasts to computed tomography (CT) and ultrasonography, and combining different contrast weightings may provide more useful information. Radiation freeness and operator independence are two additional benefits of M RI. However, other than preliminary research on MR texture analysis of basilar artery plaque, there is currently no information addressing MR radiomics on the carotid plaque. Methods: For the automatic segmentation of MRI scans to detect carotid plaque for stroke risk assessment, there is a need for a computer-aided autonomous framework to classify MRI scans automatically. We used to detect carotid plaque from MRI scans for stroke risk assessment pre-trained models, fine-tuned them, and adjusted hyperparameters according to our problem. Results: Our trained YOLO V3 model achieved 94.81% accuracy, RCNN achieved 92.53% accuracy, and MobileNet achieved 90.23% in identifying carotid plaque from MRI scans for stroke risk assessment. Our approach will prevent incorrect diagnoses brought on by poor image quality and personal experience. Conclusion: The evaluations in this work have demonstrated that this methodology produces acceptable results for classifying magnetic resonance imaging (MRI) data.

[Research progress on influenza antiviral small RNAs].

Worldwide influenza caused by influenza virus is a respiratory disease which threats the public health by seasonal epidemics or global influenza outbreak. Vaccines and drugs are current therapies, but there are many restricted factors such as neurotoxicity, side effects of gastrointestinal, and drug resistance. New technologies, particularly RNAi mediated by small RNAs, has become a potential and robust method in influenza antiviral research for its high efficiency, specific, and speedy. Following the spread and epidemic of the influenza virus, application of small RNAs into influenza antiviral research has been reported increasingly. The small RNAs, PA-2087, NP-1496, and M-950, which targets PA, NP, and M2 genes, respectively, are the most effective anti-influenza siRNAs up to now. siRNA of targeting conservative region of different influenza viral genes has broader effect on virus inhibition. The combination of siRNAs of targeting different genes can achieve better virus inhibition. In this review, we mainly described the progress of siRNAs and miRNAs for anti-influenza virus, and the prospects and hurdles of influenza RNAi therapy as well.

Association between vaccine dose and risk of hepatitis B virus infection in Fujian Province, China.

The increased dose of hepatitis B vaccine has been adopted for newborns since 2013 in Fujian, China. However, little is known about the impact of this measure on hepatitis B virus (HBV) prevention. We used the seroepidemiological surveys conducted in 2014 and 2020 to address the concern. Compared with subjects who received a 5 µg hepatitis B vaccine, participants who took a 10 µg hepatitis B vaccine were associated with a lower risk of HBV infection (adjusted odds ratio [OR] 0.26, 95% confidence interval [CI]: 0.10-0.68) and a marginal reduction risk of anti-HBc positive (OR, 0.37; 95% CI: 0.13-1.08; P = .07), but not for HBsAg carrier risk. The relation between vaccine dose and risk of anti-HBc positive (OR, 0.20; 95% CI: 0.05-0.81) became slightly stronger and significant among children investigated in 2020 who probably received universal vaccination. No significant association was found for subjects whose mothers were positive for HBsAg. The current 10 µg hepatitis B vaccines for universal vaccination for newborns are reasonable and effective in HBV prevention. More measures should be taken to reduce the risk of HBsAg carriers for infants whose mothers are positive for HBsAg.

Prognostic Significance of NLR, PLR, LMR and Tumor Infiltrating T Lymphocytes in Patients Undergoing Surgical Resection for Hilar Cholangiocarcinoma.

Objective: This study evaluated the prognostic significance of preoperative neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR) and tumor-infiltrating lymphocytes (TILs), and whether these preoperative blood inflammatory indicators were associated with TILs in hilar cholangiocarcinoma (HCCA). Methods: A total of 76 patients with HCCA who underwent radical resection were included. Data on their clinicopathologic characteristics, perioperative features, and survival outcomes were analyzed. The optimal cutoff levels for the NLR, PLR and LMR were defined by using the web application Cut-off Finder. The densities of specific immune cells (CD3+, CD4+, CD8+) within the tumor microenvironment were examined by immunohistochemical. The association of the number of CD3+, CD4+ and CD8+ T cells infiltration in the local tumor microenvironment with preoperative NLR, PLR and LMR level was analyzed. Survival curves were calculated using the Kaplan-Meier estimate. Univariate and multivariate logistic regression models were used to identify factors associated with overall survival. Results: The optimal cutoff value of preoperative NLR, PLR and LMR was 2.00, 117.60, and 4.02, respectively. NLR was significantly negatively correlated with CD3+ and CD8+ T cell infiltration, but not with CD4+ T cells. PLR had no correlation with CD3+, CD4+, or CD8+ T cell infiltration, while LMR had a significantly positive correlation with CD3+ T cells infiltration but not with CD4+ or CD8+ T cells. In the multivariate logistic regression model, T stage, lymph node metastasis, CA19-9 and LMR were independent risk factors associated with overall survival (OS). Survival curves indicated that HCCA patients with low CD3+ T cells infiltration and low preoperative LMR live shorter than others. Conclusions: LMR played as an independent factor for predicting the survival in patients with HCCA after R0 radical resection. A high LMR was associated with an accumulation of CD3+ T cells in HCCA.

Comparison of Safety of Different Vaccine Boosters Following Two-Dose Inactivated Vaccines: A Parallel Controlled Prospective Study.

A vaccine booster to maintain high antibody levels and provide effective protection against COVID-19 has been recommended. However, little is known about the safety of a booster for different vaccines. We conducted a parallel controlled prospective study to compare the safety of a booster usingfour common vaccines in China. In total, 320 eligible participants who had received two doses of an inactivated vaccine were equally allocated to receive a booster of the same vaccine (Group A), a different inactivated vaccine (Group B), an adenovirus type-5 vectored vaccine (Group C), or a protein subunit vaccine (Group D). A higher risk of adverse reactions, observed up to 28 days after injection, was found in Groups C and D, compared to Group A, with odds ratios (OR) of 11.63 (95% confidence interval (CI): 4.22-32.05) and 4.38 (1.53-12.56), respectively. Recipients in Group C were more likely to report ≥two reactions (OR = 29.18, 95% CI: 3.70-229.82), and had a higher risk of injection site pain, dizziness, and fatigue. A gender and age disparity in the risk of adverse reactions was identified. Despite the majority of reactions being mild, heterologous booster strategies do increase the risk of adverse reactions, relative to homologous boosters, in subjects who have had two doses of inactive vaccine.

Association of vaccine policy with virus infection and awareness of hepatitis B in Fujian, China.

China has regulated its hepatitis B vaccination policy. However, data on the prevalence of hepatitis B virus (HBV) infection have not been updated since 2014. In addition, the impact of the policy on awareness of hepatitis B is limited, especially in Fujian Province where HBV infection is highly prevalent. We conducted a sero-epidemiological survey in five national monitoring counties to address these concerns. A total of 5,873 subjects were included and classified into four birth cohorts according to the policy time nodes (1981, 1992, and 2002). The HBsAg carrier rate for the general population was 8.6% (95% confidence interval [CI]: 7.9-9.3). Compared with those born before 1981, adjusted odds ratios (OR) for HBV infection were 0.51 (95% CI: 0.43-0.62), 0.10 (0.08-0.12), and 0.015 (0.01-0.023) among the 1981-1991, 1992-2001, and ≥2002 birth cohorts, respectively; while the OR was 1.26 (1.00-1.57), 0.39 (0.26-0.58), and 0.019 (0.006-0.06) for HBsAg carriage, respectively. Among the 4865 residents aged ≥15 years, hepatitis B awareness has been declining since the introduction of the hepatitis B vaccine into the immunization program (ß = -0.25, SE = 0.08, P = .001, and ß = -0.20, SE = 0.08, P = .017 for 1992-2001 and ≥2002 birth cohort, respectively). This decline was obvious for the initiation time of the first dose of the hepatitis B vaccine. Although the hepatitis B vaccination policies have helped reduce the infection, the awareness has declined. More measures on the target population are warranted to improve the public's awareness of hepatitis B vaccination in the context of great achievements.

[Prediction of the pharmacokinetic drug-drug interaction of pravastatin and pitavastatin with cyclosporine by a digital liver model based on metabolism and transporter].

Information of metabolic enzymes and transporters, physiological parameters of animals and demography of Chinese people were integrated to establish a digital liver model (DLM) based on metabolism and transporter and coded with VBA. Clearance and drug-drug interaction (DDI) of candidate drugs in animal and human could be predicted based on the pharmacokinetic data obtained from in vitro and in vivo experiments. Pravastatin and pitavastatin were selected as the samples to examine this model, where their clearance and their DDI with cyclosporine were predicted. The results showed that the predicted values of median parameters in same species were within twofold of observed values for 83.3% (5/6). The program's successful prediction in DDI tendency might indicate its application in optimizing the dosage regimen and reducing the risk of clinical trial.

IL-6 and INF-γ levels in patients with brucellosis in severe epidemic region, Xinjiang, China.

BACKGROUND: The incidence of brucellosis, which is caused by the Brucella species of bacteria, is rapidly rising worldwide; however, few studies have investigated the immune response to this pathogen and clinical biochemical features. In this paper, we examined the levels of various cytokines and inflammatory factors as well as clinical course characteristics in patients with brucellosis, in order to provide evidence for the diagnosis, assessment, and prognosis of this infectious disease. METHODS: A total of 191 brucellosis inpatients (50 acute cases and 141 chronic cases), as well as 60 healthy control subjects, were included in the analysis. We investigated changes in the levels of six cytokines (IL-4, IL-6, IL-10, IL-17, TNF-α, INF-γ) and related clinical biochemical markers in patients with acute and chronic brucellosis in Xinjiang, China. Possible factors were statistically analyzed using the t test, χ2 test, z test and a multivariate logistic stepwise regression test. RESULTS: We found that IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α levels were higher in those with brucellosis than in controls (P <  0.05). With regard to disease progression, procalcitonin (PCT) and C-reactive protein (CRP) levels were significantly higher in those with an acute infection compared to chronic cases (P <  0.05). We found that the expression of all six cytokines tested was closely related to the degree of brucellosis using univariate logistic regression; however, only IL-6 and INF-γ levels were independent factors associated with the severity of brucellosis. CONCLUSIONS: Assessing cytokine levels in patients with acute and chronic brucellosis is not only useful for detecting the immune response, but can also be indicative of the severity of brucellosis. In particular, we propose IL-6 and INF-γ levels may be useful independent predictive factors in the clinical evaluation and diagnosis of brucellosis.

Ultrathin Densified Carbon Nanotube Film with "Metal-like" Conductivity, Superior Mechanical Strength, and Ultrahigh Electromagnetic Interference Shielding Effectiveness.

Flexible and lightweight high-performance electromagnetic interference shielding materials with minimal thickness, excellent mechanical properties, and outstanding reliability are highly desired in the field of fifth-generation (5G) communication, yet remain extremely challenging to manufacture. Herein, we prepared an ultrathin densified carbon nanotube (CNT) film with superior mechanical properties and ultrahigh shielding effectiveness. Upon complete removal of impurities in pristine CNT film, charge separation in individual CNTs induced by polar molecules leads to strong CNT-CNT attraction and film densification, which significantly improve the electrical conductivity, shielding performance, and mechanical strength. The tensile strength is up to 822 ± 21 MPa, meanwhile the electrical conductivity is as high as 902,712 S/m, and the density is only 1.39 g cm-3. Notably, the shielding effectiveness is over 51 dB with a thickness of merely 1.85 µm in the broad frequency range of 4-18 GHz, and it reaches to ∼82 dB at 6.36 µm and ∼101 dB at 14.7 µm, respectively. Further, such CNT film exhibits excellent reliability after an extended period in strong acid/alkali, high temperature, and high humidity. It demonstrates the best overall performance among representative shielding materials by far, representing a critical breakthrough in the preparation of shielding film toward applications in wearable electronics and 5G communication.

Novel cardiac apoptotic pathway: the dephosphorylation of apoptosis repressor with caspase recruitment domain by calcineurin.

BACKGROUND: Apoptosis repressor with caspase recruitment domain (ARC) is abundantly expressed in cardiomyocytes. Protein kinase CK2 can phosphorylate ARC at threonine-149, thereby enabling ARC to antagonize apoptosis. ARC phosphorylation occurs in a constitutive manner. Nevertheless, cardiomyocytes still undergo apoptosis that is related to cardiac diseases such as myocardial infarction and heart failure. Whether the occurrence of apoptosis is related to the loss of protection by ARC under pathological conditions remains unknown. METHODS AND RESULTS: ARC phosphorylation levels are decreased in cardiomyocytes treated with isoproterenol or aldosterone. We explored the molecular mechanism by which ARC phosphorylation levels are decreased. Our results reveal that either direct incubation or coexpression with calcineurin leads to a decrease in ARC phosphorylation levels. Inhibition of calcineurin can attenuate the reduction in ARC phosphorylation levels on treatment with isoproterenol or aldosterone. These data indicate that the reduction in ARC phosphorylation levels is related to its dephosphorylation by calcineurin. Our results further reveal that ARC can prevent isoproterenol- and aldosterone-induced apoptosis, but this function depends on its phosphorylation status. Isoproterenol and aldosterone upregulate Fas ligand expression, and Fas ligand and caspase-8 are required for isoproterenol and aldosterone to induce apoptosis. However, phosphorylated but not dephosphorylated ARC is able to inhibit caspase-8-mediated apoptosis. Phosphorylated ARC exerts its effects against caspase-8 by directly associating with procaspase-8 and inhibiting its interaction with Fas-associated protein with death domain. CONCLUSIONS: Our study identifies a novel cardiac apoptotic pathway in which ARC is dephosphorylated by calcineurin. This pathway could be a component in the cardiac apoptotic machinery.