Pathological Intraplaque Hemorrhage as the Gold Standard to Assess the Efficacy of Ultrasound in Predicting Vulnerable Carotid Plaque Rupture.

OBJECTIVE: To assess the clinical utility of ultrasound in predicting the risk of carotid vulnerable plaque rupture using pathological intraplaque hemorrhage as the gold standard. METHODS: A total of 118 patients who underwent endarterectomy due to symptomatic carotid artery stenosis were enrolled. Conventional ultrasound assessed the plaque thickness, area stenosis rate, echo, and surface morphology. Neovascularization were assessed by contrast-enhanced ultrasound (CEUS) and tracing intraplaque nonenhanced areas. According to neovascularization grade (0-4), plaques were classified as low-, intermediate-, and high risk. Fresh intraplaque hemorrhage within the pathology was adopted as the gold standard for diagnosing plaque rupture risk. Thus, we divided patients into ruptured risk and nonruptured risk groups to assess the value of crucial factors for plaque rupture risk using ultrasound. RESULTS: Of the 118 patients, hypertension accounted for 71.2%, hyperlipidemia 68.6%, diabetes 52.5%, and statin history 64.4%. In the rupture risk group, diabetes, smoking, and stenosis rate were significantly higher than the nonrupture risk group (P < .001); plaque thickness ≥4 mm (P > .05); and mainly hypoechoic with irregular surface morphology (P < .001), nonenhanced areas in the plaques (P < .001), and neovascularization >grade 2 (P < .001). Compared with the low-risk group, plaque rupture risk was 7.219 times higher in the medium-risk group and 18.333 times higher in the high-risk group. The kappa value of the interobserver consistency of crucial ultrasound parameters was >0.75, and the intraclass correlation coefficient was 0.919 (P < .01). CONCLUSIONS: Both conventional ultrasound and CEUS have significant clinical importance in the prediction of rupture risk in vulnerable carotid plaques, thereby enabling stroke risk stratification and the assessment of plaque rupture risk.

Phytochemical Research and Anti-inflammatory Activities of the Ethanol Extract from Anoectochilus roxburghii (Wall.) Lindl.

Anoectochilus roxburghii is a well-known and valuable traditional Chinese herb due to various medicinal and functional benefits. In-depth investigation is necessary to discover active ingredients and expand its application. In this study, four new compounds (1-4) along with ten known compounds (5-14) were isolated from the ethanol extract ofA.roxburghii. Their structures were elucidated by spectroscopic data interpretation. The isolates were screened for their inhibitory activities on the production of NO in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Among them, compounds 5, 6, 9, 10, 12, 13 and 14exhibited significant anti-inflammatory activity through inhibiting the release of NO.

An approach to complex transboundary water management in Central Asia: Evolutionary cooperation in transboundary basins under the water-energy-food-ecosystem nexus.

Water-related issues in transboundary basins are generally complicated by the challenges of climate change, the historical evolution of the basin characteristics, and the different interests of the riparian countries. Therefore, dealing with water-sharing and water cooperation problems among basin countries needs to be based on multi-factor system analysis in the context of regional water, energy, food (land) resources, and ecosystems. In the present study, the Aral Sea basin in Central Asia, where transboundary water problems are extremely prominent and complex, was selected as the research area. Firstly, the characteristics of the water-energy-food-ecosystem nexus of the Aral Sea basin are analyzed. Then, based on the game theory, a multi-objective game model is constructed, and the multi-objective evolutionary game process and evolutionary stable strategies (ESSs) of both the upstream and downstream countries are explored. Finally, the evolutionary stable strategy under the intervention of the basin commission is simulated. The results show that there are obvious reciprocal feedbacks among water, land, energy, and ecosystem in the Aral Sea basin, and the uneven distribution of natural resources, fragile ecosystems, and conflicting demands of multiple actors lead to the unstable evolution of the nexus. Driven by the maximization of upstream and downstream countries' respective interests, the optimal stabilization strategy of the system cannot be realized. Whereas, the introduction of the basin commission intervention and its restraint mechanism is conducive to promoting cooperation and maximizing the overall benefits of the basin. The incentives and penalties of the basin commission have significant effects on whether the system can reach Pareto optimality, and higher incentive coefficient and penalty coefficient help the system converge to the ideal state more quickly. The evolution of the water-energy-food-ecosystem nexus based on the perspective of the whole basin can provide theoretical support for dealing with the transboundary water conflicts, and the cooperation strategy aiming at maximizing the overall benefits of the basin can provide decision-making basis for promoting transboundary water cooperation and synergistic development of the water-energy-food-ecosystem nexus.

An integrated simulation-optimization approach for combined allocation of water quantity and quality under multiple uncertainties.

Multiple uncertainties such as water quality processes, streamflow randomness affected by climate change, indicators' interrelation, and socio-economic development have brought significant risks in managing water quantity and quality (WQQ) for river basins. This research developed an integrated simulation-optimization modeling approach (ISMA) to tackle multiple uncertainties simultaneously. This approach combined water quality analysis simulation programming, Markov-Chain, generalized likelihood uncertainty estimation, and interval two-stage left-hand-side chance-constrained joint-probabilistic programming into an integration nonlinear modeling framework. A case study of multiple water intake projects in the Downstream and Delta of Dongjiang River Basin was used to demonstrate the proposed model. Results reveal that ISMA helps predict the trend of water quality changes and quantitatively analyze the interaction between WQQ. As the joint probability level increases, under strict water quality scenario system benefits would increase [3.23, 5.90] × 109 Yuan, comprehensive water scarcity based on quantity and quality would decrease [782.24, 945.82] × 106 m3, with an increase in water allocation and a decrease in pollutant generation. Compared to the deterministic and water quantity model, it allocates water efficiently and quantifies more economic losses and water scarcity. Therefore, this research has significant implications for improving water quality in basins, balancing the benefits and risks of water quality violations, and stabilizing socio-economic development.

Long-term liming mitigates the positive responses of soil carbon mineralization to warming and labile carbon input.

Liming, as a common amelioration practice worldwide, has the potential to alleviate soil acidification and ensure crop production. However, the impacts of long-term liming on the temperature sensitivity (Q10) of soil organic carbon (SOC) mineralization and its response to labile C input remain unclear. To fill the knowledge gap, soil samples were collected from a long-term (∼10 years) field trial with unlimed and limed (CaO) plots. These soil samples were incubated at 15 °C and 25 °C for 42 days, amended without and with 13C-labeled glucose. Results showed that compared to the unlimed soil (3.6-8.6 mg C g-1 SOC), liming increased SOC mineralization (6.1-11.2 mg C g-1 SOC). However, liming significantly mitigated the positive response of SOC mineralization to warming, resulting in a lower Q10. Long-term liming increased bacterial richness and Shannon diversity as well as their response to warming which were associated with the decreased Q10. Furthermore, the decreased Q10 due to liming was attributed to the decreased response of bacterial oligotrophs/copiotrophs ratio, ß-glucosidase and xylosidase activities to warming. Labile C addition had a strong impact on Q10 in the unlimed soil, but only a marginal influence in the limed soil. Overall, our research highlights that acidification amelioration by long-term liming has the potential to alleviate the positive response of SOC mineralization to warming and labile C input, thereby facilitating SOC stability in agroecosystems, especially for acidic soils in subtropical regions.

αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway.

In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.

Physiological, biochemical and molecular responses associated with drought tolerance in grafted grapevine.

BACKGROUND: Grafting is one of the promising techniques for improving abiotic stress tolerance in horticultural crops, but the underlying regulatory mechanisms of drought on grafted grapevine are largely unexplored. RESULTS: Herein, we investigated the phenotypic, physiologic, biochemical, and drought related genes change of self-rooted 1103P (1103 Paulsen), SM (Shine Muscat) and grafted SM/1103P (SM shoot/1103P root) under drought stress condition. The results indicated that grafted grapevine effectively alleviated drought damage in grape leaves by higher RWC, water potential and free water content. Drought stress led to the alterations of chlorophyll, carotenoid, photosynthetic parameters and chlorophyll fluorescence in grapevine leaves after drought treatment indicated grafted plants improved the photosystem response to drought stress. Moreover, grafted plants under drought stress exhibited higher levels of abscisic acid (ABA), indoleacetic acid (IAA) and soluble protein, but less contents of hydrogen peroxide (H2O2) and malondialdehyde (MDA) both in leaves and roots. Drought stress also increased the activities of antioxidant enzymes (SOD, POD and CAT) and activated the transcript expression of VvCu/ZnSOD, VvPOD4 and VvCAT1) in both leaves and roots. Further expression analysis by real-time PCR indicated that the expression levels of ABA-dependent and ABA-independent related genes could be activated in grafted grape after drought treatment. CONCLUSIONS: Taken together, our findings demonstrated that grafting onto 1103P enhanced tolerance against drought stress in grape by improving water content, photosynthesis and antioxidant defense capacity, which provided a valuable information for understanding the mechanisms of drought tolerance regulated by grafting plants.

Cost-effectiveness analysis of ovarian function preservation with GnRH agonist during chemotherapy in premenopausal women with early breast cancer.

STUDY QUESTION: Is it economically worthwhile to use GnRH agonist (GnRHa) to prevent menopausal symptoms (MS) and protect fertility in premenopausal women with breast cancer (BC) during chemotherapy from the US perspective? SUMMARY ANSWER: It is cost-effective to administer GnRHa during chemotherapy in order to forefend MS in premenopausal patients with BC when the willingness-to-pay (WTP) threshold is $50 000.00 per quality-adjusted life-year (QALY), and to preserve fertility in young patients with BC who undergo oocyte cryopreservation (OC), or no OC, when the WTP thresholds per live birth are $71 333.33 and $61 920.00, respectively. WHAT IS KNOWN ALREADY: Chemotherapy often results in premature ovarian insufficiency (POI) in premenopausal survivors of BC, causing MS and infertility. Administering GnRHa during chemotherapy has been recommended for ovarian function preservation by international guidelines. STUDY DESIGN, SIZE, DURATION: Two decision-analytic models were developed, respectively, for preventing MS and protecting fertility over a 5-year period, which compared the cost-effectiveness of two strategies: adding GnRHa during chemotherapy (GnRHa plus Chemo) or chemotherapy alone (Chemo). PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were early premenopausal women with BC aged 18-49 years who were undergoing chemotherapy. Two decision tree models were constructed: one for MS prevention and one for fertility protection from the US perspective. All data were obtained from published literature and official websites. The models' primary outcomes included QALYs and incremental cost-effectiveness ratios (ICERs). The robustness of the models was tested by sensitivity analyses. MAIN RESULTS AND THE ROLE OF CHANCE: In the MS model, GnRHa plus Chemo resulted in an ICER of $17 900.85 per QALY compared with Chemo, which was greater than the WTP threshold of $50 000.00 per QALY; therefore, GnRHa plus Chemo was a cost-effective strategy for premenopausal women with BC in the USA. Probabilistic sensitivity analysis (PSA) results showed an 81.76% probability of cost-effectiveness in the strategy. In the fertility model, adding GnRHa for patients undergoing OC and those who were unable to undergo OC resulted in ICERs of $67 933.50 and $60 209.00 per live birth in the USA, respectively. PSA indicated that GnRHa plus Chemo was more likely to be cost-effective over Chemo when the WTP for an additional live birth exceed $71 333.33 in Context I (adding GnRHa to preserve fertility in young patients with BC after OC) and $61 920.00 in Context II (adding GnRHa to preserve fertility in young patients with BC who cannot accept OC). LIMITATIONS, REASONS FOR CAUTION: The indirect costs, such as disease-related mental impairment and non-medical costs (e.g. transportation cost) were not included. All data were derived from previously published literature and databases, which might yield some differences from the real world. In addition, the POI-induced MS with a lower prevalence and the specific strategy of chemotherapy were not considered in the MS model, and the 5-year time horizon for having a child might not be suitable for all patients in the fertility model. WIDER IMPLICATIONS OF THE FINDINGS: When considering the economic burden of cancer survivors, the results of this study provide an evidence-based reference for clinical decision-making, showing that it is worthwhile to employ GnRHa during chemotherapy to prevent MS and preserve fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Natural Science Foundation of Fujian Province [2021J02038]; and the Startup Fund for Scientific Research, Fujian Medical University [2021QH1059]. All authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Research on synthesis and property of nano-textured Sc2O3-MgO efficient antibacterial agents.

In order to obtain the inorganic efficient antibacterial agents, the means of ion doping and morphology construction in this research are used to enhance the antibacterial property of nano-MgO, which is according to the "oxidative damage mechanism" and "contact mechanism". In this work, the nano-textured Sc2O3-MgO are synthesized by doping Sc3+ in nano-MgO lattice through calcining at 600 °C. When the Sc3+ content reaches 10%, the nanotextures on the powders surface are pretty clearly visible and uniform, and the specific surface area and the oxygen vacancy are ideal, so that the 10% Sc3+-doped powders (SM-10) has the excellent antibacterial property against E. coli and S. aureus (MBC = 0.03 mg/mL). The efficient antibacterial agents in this research have a better antibacterial effect than the 0% Sc3+-doped powders (SM-0, MBC = 0.20 mg/mL) and the commercial nano-MgO (CM, MBC = 0.40 mg/mL), which have application prospects in the field of antibacterial.

Tea consumption and the risks of osteoporosis and hip fracture: a population-based longitudinal follow-up study.

This population-based longitudinal follow-up study showed a protective effect of tea consumption against osteoporosis, particularly among women and middle-aged people. High tea consumption was also associated with a reduced risk of hip fracture. INTRODUCTION: To investigate the association of tea consumption with the risks of osteoporosis and hip fracture. METHODS: This study used the Keelung Community-based Integrated Screening database and Taiwan's National Health Insurance Research Database. A total of 42,742 subjects aged 45 to 74 years were enrolled. Each was classified as no tea consumption, low tea consumption, and high tea consumption, according to the results of an eating habits questionnaire. The diagnosis of osteoporosis and hip fracture was based on BMD measured by dual-energy X-ray absorptiometry and the X-ray findings. The median follow-up time was 8.5 years. RESULTS: As compared with the no tea consumption group, the osteoporosis HRs for the low tea consumption and high tea consumption groups were 0.88 (95% confidence interval (CI) 0.80-0.96) and 0.87 (95% CI 0.80-0.94), respectively. Among those participants aged 59 or below, the osteoporosis HRs for low tea consumption and high tea consumption (vs. no tea consumption) were 0.85 (95% CI 0.74-0.96) and 0.79 (95% CI 0.69-0.90). The HRs of hip fracture for the low tea consumption and high tea consumption groups (vs. no tea consumption) were 0.85 (95% CI 0.67-1.08) and 0.69 (95% CI 0.55-0.86), respectively. CONCLUSION: Tea consumption was linked to a lower risk of osteoporosis, particularly among women and middle-aged people. High tea consumption was also associated with a reduced risk of hip fracture.

Increased visceral fat area to skeletal muscle mass ratio is positively associated with the risk of cardiometabolic diseases in a Chinese natural population: A cross-sectional study.

AIMS: Visceral adiposity and skeletal muscle loss may be positively correlated with cardiometabolic outcomes. This study aimed to explore the associations between the visceral fat area to skeletal muscle mass ratio (VSR) and the risk of cardiometabolic diseases in a Chinese natural population. MATERIALS AND METHODS: A total of 5158 participants were included in this study. Body composition, anthropometrical, and biochemical measurements were performed. Body composition was assessed via the direct segmental multi-frequency bioelectrical impedance analysis method. The associations between VSR and metabolic associated fatty liver disease (MAFLD), hyperglycemia, hypertension, dyslipidemia, and hyperuricemia were analysed. RESULTS: With the increase of VSR by one quartile, the odds ratio (OR) increased significantly for all five cardiometabolic diseases in both genders (ptrend  < 0.001). With regard to the highest versus the lowest quartile of VSR, the ORs for cardiometabolic diseases were significantly higher in women than in men. Restricted cubic splines showed that there were significant non-linear relationships between VSR and the risk of MAFLD, dyslipidemia, hyperglycemia, and hypertension in both genders (p for non-linearity <0.05). The risk was relatively flat until VSR reached 3.078 cm2 /kg in men and 4.750 cm2 /kg in women and started to increase rapidly afterwards. In men, however, the risk slowed down after the VSR value reached around 4 cm2 /kg. CONCLUSIONS: VSR was positively associated with cardiometabolic diseases regardless of gender. As VSR increased, the risk of cardiometabolic diseases was significantly higher in women than in men. TRIAL REGISTRATION: www.chictr.org.cn (Registration number: ChiCTR2100044305).

Nrf2 plays protective role during intermittent hypoxia-induced ferroptosis in rat liver (BRL-3A) cells.

PURPOSE: Ferroptosis is reported to be involved in the chronic intermittent hypoxia (CIH)-related liver damage in vivo. Nuclear factor E2-related factor 2 (Nrf2) has an essential role in the regulation of ferroptosis. This study tested the hypothesis that intermittent hypoxia (IH) could lead to hepatocyte ferroptosis in vitro and the function of Nrf2 in IH-induced hepatocyte ferroptosis. METHODS: BRL-3A cells (rat liver cells) were exposed to normoxia or IH. The protocol of IH consisted of 32 cycles of 60-min hypoxic exposure with 30-min reoxygenation phase (nadir of 1% oxygen to peak of 20% oxygen). Ferroptosis was evaluated by cell viability, iron concentration, lipid reactive oxygen species (ROS), protein content of ferritin heavy chain (FTH1), and glutathione peroxidase 4 (GPX4). Both ferrostatin-1 (a ferroptosis inhibitor) and Nrf2 interfering RNA were applied to treat BRL-3A cells, respectively. RESULTS: IH exposure induced ferroptosis in BRL-3A cells with decreased cell viability and increased total iron content and lipid ROS levels. The protein contents of GPX4 and FTH1 in IH group were markedly lower than that in normoxic control. Ferroptosis inhibitor ferrostatin-1 alleviated IH-induced ferroptosis in BRL-3A cells. IH treatment enhanced expression of Nrf2, and Nrf2 knockdown augmented IH-induced ferroptosis in BRL-3A cells. CONCLUSIONS: The results revealed that Nrf2 played a protective role during IH-induced ferroptosis in BRL-3A cells. The finding provides a therapeutic target for obstructive sleep apnea-related liver injury.

MdMYB66 Is Associated with Anthocyanin Biosynthesis via the Activation of the MdF3H Promoter in the Fruit Skin of an Apple Bud Mutant.

Skin color is an important trait that is mainly determined by the content and composition of anthocyanins in apples. In this study, a new bud mutant (RM) from 'Oregon Spur II' (OS) of Red Delicious apple was obtained to reveal the mechanism underlying red color formation. Results showed that the total anthocyanin content in RM was significantly higher than that in OS with the development of fruit. Through widely-targeted metabolomics, we found that cyanidin-3-O-galactoside was significantly accumulated in the fruit skin of RM. Transcriptome analysis revealed that the structural gene MdF3H and MdMYB66 transcription factor were significantly up-regulated in the mutant. Overexpression of MdMYB66 in apple fruit and apple callus significantly promoted anthocyanin accumulation and significantly increased the expression level of MdMYB66 and structural genes related to anthocyanin synthesis. Y1H and LUC analysis verified that MdMYB66 could specifically bind to the promoter of MdF3H. The results of the double luciferase activity test showed that MdMYB66 activated MdF3H 3.8 times, which led to increased anthocyanin contents. This might explain the phenotype of red color in RM at the early stage. Taken together, these results suggested that MdMYB66 was involved in regulating the anthocyanin metabolic pathways through precise regulation of gene expression. The functional characterization of MdMYB66 provides insight into the biosynthesis and regulation of anthocyanins.

Preparation and Properties of (Sc2O3-MgO)/Pcl/Pvp Electrospun Nanofiber Membranes for the Inhibition of Escherichia coli Infections.

Due to their high porosity, large specific surface area, and structural similarity with the extracellular matrix (ECM), electrospun nanofiber membranes are often endowed with the antibacterial properties for biomedical applications. The purpose of this study was to synthesize nano-structured Sc2O3-MgO by doping Sc3+, calcining at 600 °C, and then loading it onto the PCL/PVP substrates with electrospinning technology with the aim of developing new efficient antibacterial nanofiber membranes for tissue engineering. A scanning electron microscope (SEM) and energy dispersive X-ray spectrometer (EDS) were used to study the morphology of all formulations and analyze the types and contents of the elements, and an X-ray diffraction (XRD), thermogravimetric analysis (TGA), and Fourier transform attenuated total reflection infrared spectroscopy (ATR-FTIR) were used for further analysis. The experimental results showed that the PCL/PVP (SMCV-2.0) nanofibers loaded with 2.0 wt% Sc2O3-MgO were smooth and homogeneous with an average diameter of 252.6 nm; the antibacterial test indicated that a low load concentration of 2.0 wt% Sc2O3-MgO in PCL/PVP (SMCV-2.0) showed a 100% antibacterial rate against Escherichia coli (E. coli).

SDF-1 inhibits the dedifferentiation of islet ß cells in hyperglycaemia by up-regulating FoxO1 via binding to CXCR4.

Islet ß cell dedifferentiation is one of the most important mechanisms in the occurrence and development of diabetes. We studied the possible effects of chemokine stromal cell-derived factor-1 (SDF-1) in the dedifferentiation of islet ß cells. It was noted that the number of dedifferentiated islet ß cells and the expression of SDF-1 in pancreatic tissues significantly increased with diabetes. In islet ß cell experiments, inhibition of SDF-1 expression resulted in an increase in the number of dedifferentiated cells, while overexpression of SDF-1 resulted in a decrease. This seemed to be contradicted by the effect of diabetes on the expression of SDF-1 in pancreatic tissue, but it was concluded that this may be related to the loss of SDF-1 activity. SDF-1 binds to CXCR4 to form a complex, which activates and phosphorylates AKT, subsequently increases the expression of forkhead box O1 (FOXO1), and inhibits the dedifferentiation of islet ß cells. This suggests that SDF-1 may be a novel target in the treatment of diabetes.

OTUB1 stabilizes mismatch repair protein MSH2 by blocking ubiquitination.

DNA mismatch repair (MMR) maintains genome stability primarily by correcting replication errors. MMR deficiency can lead to cancer development and bolsters cancer cell resistance to chemotherapy. However, recent studies have shown that checkpoint blockade therapy is effective in MMR-deficient cancers, thus the ability to identify cancer etiology would greatly benefit cancer treatment. MutS homolog 2 (MSH2) is an obligate subunit of mismatch recognition proteins MutSα (MSH2-MSH6) and MutSß (MSH2-MSH3). Precise regulation of MSH2 is critical, as either over- or underexpression of MSH2 results in an increased mutation frequency. The mechanism by which cells maintain MSH2 proteostasis is unknown. Using functional ubiquitination and deubiquitination assays, we show that the ovarian tumor (OTU) family deubiquitinase ubiquitin aldehyde binding 1 (OTUB1) inhibits MSH2 ubiquitination by blocking the E2 ligase ubiquitin transfer activity. Depleting OTUB1 in cells promotes the ubiquitination and subsequent degradation of MSH2, leading to greater mutation frequency and cellular resistance to genotoxic agents, including the common chemotherapy agents N-methyl-N'-nitro-N-nitrosoguanidine and cisplatin. Taken together, our data identify OTUB1 as an important regulator of MSH2 stability and provide evidence that OTUB1 is a potential biomarker for cancer etiology and therapy.

Reactivation of occult hepatitis B virus infection in a renal transplant recipient.

We report a case of hepatitis B virus (HBV) reactivation in a renal transplant recipient. Reactivation manifested as an occult infection with detectable HBV-DNA and negativity for hepatitis B surface antigen (HBsAg). The anti-HBs antibody titre was above the protective threshold and continued to rise, to 951.36 mIU/ml, after HBV reactivation. Sequencing revealed multiple vaccine- and diagnostic-escape mutations in the major hydrophilic region of HBsAg. This case demonstrates both reactivation of an HBV escape mutant in a vaccinated patient and host immunity after virus mutation.

ELISPOT assay of interferon-γ secretion for evaluating human cytomegalovirus reactivation risk in allo-HSCT recipients.

Human cytomegalovirus (HCMV) is a common cause of significant morbidity and mortality in transplant recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We evaluated interferon-γ (IFN-γ) secretion by HCMV NLV-specific CD8+ T cells in HCMV-reactivated allo-HSCT recipients using an enzyme-linked immunospot (ELISPOT) assay at 3 months post-transplantation. Blood samples from 47 recipients were tested for HCMV DNAemia, HCMV pp65 antigenemia, and anti-HCMV immunoglobulins (IgG/IgM) over 3 months post-transplantation. Of the 47 transplant recipients, 26 were HLA-A*02 positive and 21 were HLA-A*02 negative. The results were essentially consistent between the 47 transplant recipients and the HLA-A*02-positive recipients. HCMV DNAemia was not linearly correlated with IFN-γ spot-forming cells (SFCs) counts; IFN-γ SFCs counts did not differ significantly between the HCMV DNAemia-positive and -negative groups, whereas the HCMV-DNA virus loads were inversely correlated with the IFN-γ SFCs counts. HCMV pp65 antigenemia was not linearly correlated with IFN-γ SFCs counts; IFN-γ SFCs counts in the HCMV pp65 antigenemia-positive and -negative groups were similar. More IFN-γ SFCs counts were detected in transplant recipients with high anti-HCMV-IgG antibody titers than in those with low anti-HCMV-IgG titers pre-transplantation in the 47 recipients. Anti-HCMV-IgG antibody titers were positively linearly correlated with IFN-γ SFCs counts in HLA-A*02-positive recipients. The HCMV infection indicators used to monitor HCMV reactivation had different values in transplant recipients. The use of the IFN-γ SFCs counts measured by ELISPOT to evaluate the risk of HCMV reactivation needs further study.

Visceral fat area to appendicular muscle mass ratio as a predictor for nonalcoholic fatty liver disease independent of obesity.

OBJECTIVE: Obesity and sarcopenia are known to be closely related to nonalcoholic fatty liver disease (NAFLD). We attempted to explore the combined influence of fat and muscle tissue on NAFLD by using visceral fat area to appendicular muscle mass ratio (VAR) as a novel parameter. MATERIAL AND METHODS: In this cross-sectional study, a total of 3255 adults (1399 men and 1856 women) coming for a health examination were enrolled. NAFLD was diagnosed using ultrasound and VAR was measured by bioelectrical impedance analyzer. RESULTS: The prevalence of NAFLD was 46.5% in men and 26.6% in women. VAR differed significantly between subjects with and without NAFLD (4.27 vs. 3.26 in men, 7.89 vs. 5.01 in women, respectively, p < .001). Logistic regression analysis determined VAR as a risk factor for NAFLD, and the multivariable-adjusted odds ratios in the highest VAR quartile was 9.57 (95%CI: 5.98-15.30) for men and 12.37 (95%CI: 6.37-24.05) for women. From the receiver operating characteristic analysis, the area under the curve was 0.767 and 0.834, with the suitable cut-off VAR value of 3.469 and 6.357 for men and women, respectively. To control the influence of obesity, all subjects were stratified according to their BMI. For each BMI group, individuals with VAR above the cut-off value had significant higher prevalence and risk of NAFLD, with odds ratios ranging from 1.76 to 4.75. CONCLUSIONS: Increased VAR is strongly associated with higher risk of NAFLD in both sexes independent of obesity and can serve as a screening reference for NAFLD.

New dammarane-type glycosides from Gynostemma pentaphyllum and their lipid-lowering activity.

Gynostemma pentaphyllum (Thunb.) Makino has a long history as food and diary supplement in China. At present, there are some products for hyperlipidemia in the market, including G. pentaphyllum tea, healthy wine and healthy food. In order to discover proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, fourteen new triterpenoid saponins named gypenoside LXXXVIII-CI (1-14) along with six known compounds (15-20) were isolated from G. pentaphyllum. Their structures were elucidated by means of various spectroscopic techniques. Eight isolates were evaluated the inhibitory effect on PCSK9 in HepG2 cells. The results showed that three dammarane-type glycosides (2, 3, 15) remarkably reduced PCSK9 expression at 10 µM concentration. These findings suggested that G. pentaphyllum was worthy of further investigation to find small molecule PCSK9 inhibitors and facilitate their utilization as functional food ingredients.