NS4B Self-Interaction through Conserved C-Terminal Elements Is Required for the Establishment of Functional Hepatitis C Virus Replication Complexes.

Hepatitis C virus (HCV) is an important human pathogen, persistently infecting more than 170 million individuals worldwide. Studies of the HCV life cycle have become possible with the development of cell culture systems supporting the replication of viral RNA and the production of infectious virus. However, the exact functions of individual proteins, especially of nonstructural protein 4B (NS4B), remain poorly understood. NS4B triggers the formation of specific, vesicular membrane rearrangements, referred to as membranous webs, which have been reported to represent sites of HCV RNA replication. However, the mechanism of vesicle induction is not known. In this study, a panel of 15 mutants carrying substitutions in the highly conserved NS4B C-terminal domain was generated. Five mutations had only a minor effect on replication, but two of them enhanced assembly and release of infectious virus. Ten mutants were replication defective and used for selection of pseudoreversions. Most of the pseudoreversions also localized to the highly conserved NS4B C-terminal domain and were found to restore replication competence upon insertion into the corresponding primary mutant. Importantly, pseudoreversions restoring replication competence also restored heterotypic NS4B self-interaction, which was disrupted by the primary mutation. Finally, electron microscopy analyses of membrane alterations induced by NS4B mutants revealed striking morphological abnormalities, which were restored to wild-type morphology by the corresponding pseudoreversion. These findings demonstrate the important role of the C-terminal domain in NS4B self-interaction and the formation of functional HCV replication complexes.

Metallogenic model of the Trepca Pb-Zn-Ag skarn deposit, Kosovo: Evidence from fluid inclusions, Rare Earth Elements, and stable isotope data

The Trepca Pb-Zn-Ag skarn deposit (29 Mt of ore at 3.45% Pb, 2.30% Zn, and 80 g/t Ag) is located in the Kopaonik block of the western Vardar zone, Kosovo. The mineralization, hosted by recrystallized limestone of Upper Triassic age, was structurally and lithologically controlled. Ore deposition is spatially and temporally related with the postcollisional magmatism of Oligocene age (23-26 Ma). The deposit was formed during two distinct mineralization stages: an early prograde closed-system and a later retrograde open-system stage. The prograde mineralization consisting mainly of pyroxenes (Hd(54-100)Jo(0-45)Di(0-45)) resulted from the interaction of magmatic fluids associated with Oligocene (23-26 Ma) postcollisional magmatism. Whereas there is no direct contact between magmatic rocks and the mineralization, the deposit is classified as a distal Pb-Zn-Ag skarn. Abundant pyroxene reflects low oxygen fugacity (<10(-31) bar) and anhydrous environment. Fluid inclusion data and mineral assemblage limit the prograde stage within a temperature range between 390 degrees and 475 degrees C. Formation pressure is estimated below 900 bars. Isotopic composition of aqueous fluid, inclusions hosted by hedenbergite (delta D = -108 to -130 parts per thousand; delta O-18 = 7.5-8.0 parts per thousand), Mn-enriched mineralogy and high REE content of the host carbonates at the contact with the skarn mineralization suggest that a magmatic fluid was modified during its infiltration through the country rocks. The retrograde mineral assemblage comprises ilvaite, magnetite, arsenopyrite, pyrrhotite, marcasite, pyrite, quartz, and various carbonates. Increases in oxygen and sulfur fugacities, as well as a hydrous character of mineralization, require an open-system model. The opening of the system is related to phreatomagmatic explosion and formation of the breccia. Arsenopyrite geothermometer limits the retrograde stage within the temperature range between 350 degrees and 380 degrees C and sulfur fugacity between 10(-8.8) and 10(-7.2) bars. The principal ore minerals, galena, sphalerite, pyrite, and minor chalcopyrite, were deposited from a moderately saline Ca-Na chloride fluid at around 350 degrees C. According to the isotopic composition of fluid inclusions hosted by sphalerite (delta D = -55 to -74 parts per thousand; delta O-18 = -9.6 to -13.6 parts per thousand), the fluid responsible for ore deposition was dominantly meteoric in origin. The delta S-31 values of the sulfides spanning between -5.5 and +10 parts per thousand point to a magmatic origin of sulfur. Ore deposition appears to have been largely contemporaneous with the retrograde stage of the skarn development. Postore stage accompanied the precipitation of significant amount of carbonates including the travertine deposits at the deposit surface. Mineralogical composition of travertine varies from calcite to siderite and all carbonates contain significant amounts of Mn. Decreased formation temperature and depletion in the REE content point to an influence of pH-neutralized cold ground water and dying magmatic system.

Critères de diagnostic de la fibromyalgie [Fibromyalgia diagnostic criteria].

Fibromyalgia is nowadays an object of controversy. It is the most significant painful and chronic pathology, with a prevalence of 2 to 4% in the general population and a ratio of 3.5% of women for 0.5% of men. Since 1990, fibromyalgia has been defined according to the criteria of the American College of Rheumatology (ACR). The use of these criteria in practice has proved to be controversial and a wide range of studies has shown that an important percentage of patients with fibromyalgia are diagnosed without the criteria of the ACR. This article describes an alternative method for the diagnosis of fibromyalgia.

Diagnostic imaging modalities of osteoblastic metastases

Methods to quantify radiograph images are needed to improve the identification of metastases

Diagnostic performance of CT-arthrography and 1.5T MR-arthrography for the assessment of glenohumeral joint cartilage: a comparative study with arthroscopic correlation.

PURPOSE: To compare the diagnostic performance of multi-detector CT arthrography (CTA) and 1.5-T MR arthrography (MRA) in detecting hyaline cartilage lesions of the shoulder, with arthroscopic correlation. PATIENTS AND METHODS: CTA and MRA prospectively obtained in 56 consecutive patients following the same arthrographic procedure were independently evaluated for glenohumeral cartilage lesions (modified Outerbridge grade ≥2 and grade 4) by two musculoskeletal radiologists. The cartilage surface was divided in 18 anatomical areas. Arthroscopy was taken as the reference standard. Diagnostic performance of CTA and MRA was compared using ROC analysis. Interobserver and intraobserver agreement was determined by κ statistics. RESULTS: Sensitivity and specificity of CTA varied from 46.4 to 82.4 % and from 89.0 to 95.9 % respectively; sensitivity and specificity of MRA varied from 31.9 to 66.2 % and from 91.1 to 97.5 % respectively. Diagnostic performance of CTA was statistically significantly better than MRA for both readers (all p ≤ 0.04). Interobserver agreement for the evaluation of cartilage lesions was substantial with CTA (κ = 0.63) and moderate with MRA (κ = 0.54). Intraobserver agreement was almost perfect with both CTA (κ = 0.94-0.95) and MRA (κ = 0.83-0.87). CONCLUSION: The diagnostic performance of CTA and MRA for the detection of glenohumeral cartilage lesions is moderate, although statistically significantly better with CTA. KEY POINTS: ? CTA has moderate diagnostic performance for detecting glenohumeral cartilage substance loss. ? MRA has moderate diagnostic performance for detecting glenohumeral cartilage substance loss. ? CTA is more accurate than MRA for detecting cartilage substance loss.

Construct validity of the French version of the PRWE (Patient Rated Wrist Evaluation) with the French version of the DASH (Disabilities Arm Shoulder and Hand) is good to very good in a population of patients with wrist injuries in an inpatient rehabilitation unit

Objective.- The Patient-Rated Wrist Evaluation is a specific questionnaire for the wrist [1]. It consists of 15 questions with a total score of 100. It was recently translated into French [2]. However, its validity has not been tested in this language. The Disabilities Arm Shoulder and Hand (DASH), with well-established psychometric properties, is considered as the reference questionnaire for the evaluation of upper extremities. The objective of this study is to measure the construct validity of the PRWE-F with the DASH-F in patients with wrist pathology.Patients and methods.- Fifty-one patients (40 m, 11 w, mean age 42 years), 25 fractures of the radius and 26 lesions of the carpus.Questionnaires PRWE-F and DASH-F at entry and at discharge (0 to 100). Calculation of the construct validity of the PRWE-F comparing with the DASH-F with Pearson correlation coefficients (r) at entry and at discharge. Level of significance (alpha) was set at 5%.Results.- Correlation DASH/PRWE at entry: r = 0.799 (95% CI 0.671 to 0.881), P < 0.0001. Correlation DASH/PRWE at discharge: r = 0.847 (95% CI: 0.745 to 0.910), P < 0.0001.Discussion.- The construct validity of the two instruments indicates that they measure the same concept. Our correlation between DASH-F and PRWE-F, going from 0.799 to 0.847, are comparable to those published in different languages (0.71 to 0.84) [3,4]. The questionnaires PRWE-F can thus be used in rehabilitation patients presenting with wrist pathologies; it is comparable to the DASH but described by MacDermid [1] to be more specific. Compared to the DASH it has the advantage of consisting of two dimensions. Its construct validity is excellent. This questionnaire should be evaluated in other populations, and it should be compared with hand questionnaires more specific than the DASH.

Elements traça en esfalerites i galenes del dipòsit de Cierco (Pb-Zn). Alta Ribagorça, Pirineu Central

El diposit consisteix en dos filons E-W, tallats per un altre N-S. El rebliment filonia ès zonat amb esfalerita- galena-calcita als nivells profunds i galena-baritina als superiors. Els elements traça en esfalerites i galenes, plenament separades, han estat analitzats mitjancant fluorescència de raigs X. Els resultats mostren que l'esfalerita concentra la majoria d'elements traça, preferentment Fe, Co, Cd, Sn, Sb, Ga, Cu, Ge i Ag, amb una bona correlació entre els sis primers. La galena concentra únicament Sb, Ag i As, amb bona correlació entre els dos primers. Els continguts en elements traça estan homogèniament distribuits en tot el diposit.

Elements pedagògics de la concepció metodològica del disseny

Visió dels processos de la labor projectual del disseny com exemple de la possibilitat de l'autocrítica de la seva lògica i per la seva utilitat a l'ensenyament del disseny

MAR elements regulate the probability of epigenetic switching between active and inactive gene expression.

Gene expression often cycles between active and inactive states in eukaryotes, yielding variable or noisy gene expression in the short-term, while slow epigenetic changes may lead to silencing or variegated expression. Understanding how cells control these effects will be of paramount importance to construct biological systems with predictable behaviours. Here we find that a human matrix attachment region (MAR) genetic element controls the stability and heritability of gene expression in cell populations. Mathematical modeling indicated that the MAR controls the probability of long-term transitions between active and inactive expression, thus reducing silencing effects and increasing the reactivation of silent genes. Single-cell short-terms assays revealed persistent expression and reduced expression noise in MAR-driven genes, while stochastic burst of expression occurred without this genetic element. The MAR thus confers a more deterministic behavior to an otherwise stochastic process, providing a means towards more reliable expression of engineered genetic systems.

A prospective study of predictors of poststroke depression.

OBJECTIVE: To investigate the association between early depressive behavior after stroke onset and occurrence of poststroke depression (PSD) at 3- and 12-month follow-up evaluations. METHODS: The study prospectively included 273 patients with first-ever single uncomplicated ischemic stroke. In the stroke unit, nurses scored crying, overt sadness, and apathy daily using an observational method to include patients with comprehension deficits. The Barthel Index was used to assess disability. Follow-up evaluation at months 3 and 12 included psychiatric assessment based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition. RESULTS: Crying (19.8%), overt sadness (50.5%), and apathy (47.6%) were observed. Of the patients observed crying, 4 showed pathologic crying, 19 emotionalism, and 12 catastrophic reactions. Crying and overt sadness, but not apathy, were associated with a subjective experience of depression (p < 0.05). Thirty of 52 (58%) patients observed crying, 12 of 19 (63%) patients with emotionalism, and 5 of 12 (41%) patients with catastrophic reactions developed PSD within the first year. Multiple logistic regression analysis showed that only severe functional disability (odds ratio [OR], 4.31; 95% CI, 2.41 to 7.69), crying behaviors (OR, 2.66; 95% CI, 1.35 to 5.27), and an age <68 years (OR, 2.32; 95% CI, 1.30 to 4.13) were (p < 0.05) predictors of late PSD development (13% of the variance). CONCLUSIONS: In the stroke unit, crying and overt sadness are more reliable indicators of depressed mood than apathy. In patients with first-ever stroke, crying behaviors soon after stroke, a younger age, and severe disability are predictors of poststroke depression occurrence within the first year after stroke onset.

Level shifts in a panel data based unit root test : an application to the rate of unemployment

Several unit root tests in panel data have recently been proposed. The test developed by Harris and Tzavalis (1999 JoE) performs particularly well when the time dimension is moderate in relation to the cross-section dimension. However, in common with the traditional tests designed for the unidimensional case, it was found to perform poorly when there is a structural break in the time series under the alternative. Here we derive the asymptotic distribution of the test allowing for a shift in the mean, and assess the small sample performance. We apply this new test to show how the hypothesis of (perfect) hysteresis in Spanish unemployment is rejected in favour of the alternative of the natural unemployment rate, when the possibility of a change in the latter is considered.

An analysis of inflation rates in the European Union using wavelets : strong evidence against unit roots

In this paper we assume inflation rates in European Union countries may in fact be fractionally integrated. Given this assumption, we obtain estimations of the order of integration by means a method based on wavelets coefficients. Finally, results obtained allow reject the unit root hypothesis on inflation rates. It means that a random shock on the rate of inflation in these countries has transitory effects that gradually diminish with the passage of time, that this, said shock hasn¿t a permanent effect on future values of inflation rates

New evidence of the real interest rate parity for OECD countries using panel unit root tests with breaks

This paper tests for real interest parity (RIRP) among the nineteen major OECD countries over the period 1978:Q2-1998:Q4. The econometric methods applied consist of combining the use of several unit root or stationarity tests designed for panels valid under cross-section dependence and presence of multiple structural breaks. Our results strongly support the fulfilment of the weak version of the RIRP for the studied period once dependence and structural breaks are accounted for.