Regulation of the megakaryocytic glycoprotein IX promoter by the oncogenic Ets transcription factor Fli-1

Glycoprotein (GP) IX is a subunit of the von Willebrand receptor, GPIb-V-IX, which mediates adhesion of platelets to the subendothelium of damaged blood vessels. Previous characterization of the GPIX promoter identified a functional Ets site that, when disrupted, reduced promoter activity. However, the Ets protein(s) that regulated GPIX promoter expression was unknown. In this study, transient cotransfection of several GPIX promoter/reporter constructs into 293T kidney fibroblasts with a Fli-1 expression vector shows that the oncogenic protein Fli-1 can transactivate the GPIX promoter when an intact GPIX Ets site is present. In addition, Fli-1 binding of the GPIX Ets site was identified in antibody supershift experiments in nuclear extracts derived from hematopoietic human erythroleukemia cells. Comparative studies showed that Fli-1 was also able to transactivate the GPIbalpha and, to a lesser extent, the GPIIb promoter. Immunoblot analysis identified Fli-1 protein in lysates derived from platelets. In addition, expression of Fli-1 was identified immunohistochemically in megakaryocytes derived from CD34(+) cells treated with the megakaryocyte differentiation and proliferation factor, thrombopoietin. These results suggest that Fli-1 is likely to regulate lineage-specific genes during megakaryocytopoiesis.     

Face recognition in schizophrenia: do individual and average ROCs tell the same story?

Introduction. Many studies have shown that recollection process is impaired in patients with schizophrenia, whereas familiarity is generally spared. However, in these studies, the Receiver Operating Characteristic (ROC) presented is average ROC likely to mask individual differences.

Methods. In the present study using a face-recognition task, we computed the individual ROC of patients with schizophrenia and control participants. Each group was divided into two subgroups on the basis of the type of recognition processes implemented: recognition based on familiarity only and recognition based on familiarity and recollection.

Results. The recognition performance of the schizophrenia patients was below that of the control participants only when recognition was based solely on familiarity. For the familiarity-alone patients, the score obtained on the Scale for the Assessment of Positive Symptoms (SAPS) was correlated with the variance of the old-face familiarity. For the familiarity-recollection patients, the score obtained on the Scale for the Assessment of Negative Symptoms (SANS) was correlated with the decision criterion and with the old-face recollection probability.

Conclusions. These results show that one cannot ascribe the impaired recognition observed in patients with schizophrenia to a recollection deficit alone. These results show that individual ROC can be used to distinguish between subtypes of schizophrenia and could serve as a basis for setting up specific cognitive remediation therapy for individuals with schizophrenia.     

The trans/cis photoisomerization in hydrogen bonded complexes with stability controlled by substituent effects: 3-(6-aminopyridin-3-yl)acrylate case study

The association of aminopyridine-based acrylic acid and its salt was studied by NMR titration experiments. The AA (acceptor, acceptor) hydrogen-bonding pattern present in the salt forms a complex readily with a DD (donor, donor) hydrogen-bonding pattern of the substituted ureas even in polar and competitive environment. The double carbon–carbon bond in the acrylic acid derivative is subjected to photoisomerization. This is dependent on the association with substituted urea derivatives. The substituent in ureas influences the trans/cis isomerization kinetics and position of the photostationary state. Two mechanisms that influence the photoisomerization were proposed. To the best of our knowledge, the trans/cis photoisomerization influenced by the substituent in such a hydrogen-bonding pattern has not observed previously. It was shown that interaction with urea derivatives causes lowering of the trans-to-cis photoreaction rates.

The association of aminopyridine-based acrylic acid and its salt was studied by NMR titration experiments.     

Individual QT–R‐R Relationship: Average Stability over Time Does Not Rule Out an Individual Residual Variability: Implication for the Assessment of Drug Effect on the QT Interval

Background: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT–R‐R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT–R‐R relationship stability over time needs to be evaluated. Methods: The present report is part of randomized, double‐dummy, and placebo‐controlled 4‐way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run‐in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the “bin” approach. For each period, individual QT–R‐R relationship were calculated using two different models (linear and parabolic log–log models). Results: The mean intrasubject variability for the α coefficient of the linear modeling (SDintra = 0.011 ± 0.005) reached 28.6 ± 10.2%. When the parabolic model was considered, the SDintra was 0.026 ± 0.009 for the α coefficient. The QT–R‐R relationship variability was in part related to long‐term RR changes (R²= 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT–R‐R coefficients. Moxifloxacin significantly increased the α coefficient of the QT–R‐R relationship from 0.07 ± 0.018 to 0.085 ± 0.019, P < 0.05 (linear model). Conclusions: The individual QT–R‐R relationship shows a residual variability in part related to long‐term autonomic changes. In addition, the QT–R‐R relationship might be modulated by the drug tested. As a consequence, pretherapy QT–R‐R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.     

Comparison of non-invasive liver fibrosis biomarkers in HIV/HCV co-infected patients: the fibrovic study--ANRS HC02

BACKGROUND/AIMS: To compare non-invasive biological liver fibrosis scores, as alternatives to liver biopsy, in HIV/HCV co-infected patients. METHODS: Two hundred and seventy-two HIV/HCV patients, nai ve for HCV treatment, underwent liver biopsy [197 (72%) men, 39.9 years, fibrosis stage (Metavir) F1 (25%), F2 (40%), F3 (25%), F4 (10%), median CD4 486/mm(3) and median HIV viral load 3.5log. Fibrotest (FT), Hepascore (HS), Fibrometer (FM), SHASTA, APRI, Forns index, and Fib-4 were tested in order to differentiate patients with mild to moderate fibrosis (F2) and those with advanced fibrosis (F3). The AUROC and the rate of well-classified patients were compared to liver biopsy. RESULTS: FT, HS, and FM were able to stage liver fibrosis in all patients with AUROCs of 0.78, 0.84 and 0.89 for the diagnosis of F2, respectively. The correlation coefficient indexes were 0.37, 0.46 and 0.48, respectively. The rates of well-classified patients were 62%, 68% and 71%, respectively. Fib-4, APRI and the Forn's index were only able to stage 37-61% of patients and showed lower accuracies. Using a combination of FT, HS and FM did not significantly increase the performance of each test. CONCLUSIONS: In HIV/HCV co-infected patients, Fibrometer, Hepascore and Fibrotest outperformed other non-invasive liver fibrosis biomarkers for the prediction of significant liver fibrosis.