Further characterization of the putative human isopeptidase T catalytic site

AbstractThe human isopeptidase T (isoT) is a zinc-binding deubiquitinating enzyme involved in the disassembly of free K48-linked polyubiquitin chains into ubiquitin monomers. The catalytic site of this enzyme is thought to be composed of Cys335, Asp435, His786 and His795. These four residues were site-directed mutagenized. None of the mutants were able to cleave a peptide-linked ubiquitin dimer. Similarly, C335S, D435N and H795N mutants had virtually no activity against a K48-linked isopeptide ubiquitin dimer, which is an isoT-specific substrate that mimics the K48-linked polyubiquitin chains. On the other hand, the H786N mutant retained a partial activity toward the K48-linked substrate, suggesting that the His786 residue might not be part of the catalytic site. None of the mutations significantly affected the capacity of isoT to bind ubiquitin and zinc. Thus, the catalytic site of UBPs could resemble that of other cysteine proteases, which contain one Cys, one Asp and one His

Stress and strain patterns, kinematics and deformation mechanisms in a basement-cored anticline: Sheep Mountain Anticline, Wyoming

International audienceIn order to characterize and compare the stress-strain record prior to, during, and just after folding at the macroscopic and the microscopic scales and to provide insights into stress levels sustained by folded rocks, we investigate the relationship between the stress-strain distribution in folded strata derived from fractures, striated microfaults, and calcite twins and the development of the Laramide, basement-cored Sheep Mountain Anticline, Wyoming. Tectonic data were mainly collected in Lower Carboniferous to Permian carbonates and sandstones. In both rock matrix and veins, calcite twins recorded three different tectonic stages: the first stage is a pre-Laramide (Sevier) layer-parallel shortening (LPS) parallel to fold axis, the second one is a Laramide LPS perpendicular to the fold axis, and the third stage corresponds to Laramide late fold tightening with compression also perpendicular to the fold axis. Stress and strain orientations and regimes at the microscale agree with the polyphase stress evolution revealed by populations of fractures and striated microfaults, testifying for the homogeneity of stress record at different scales through time. Calcite twin analysis additionally reveals significant variations of differential stress magnitudes between fold limbs. Our results especially point to an increase of differential stress magnitudes related to Laramide LPS from the backlimb to the forelimb of the fold possibly in relation with motion of an underlying basement thrust fault that likely induced stress concentrations at its upper tip. This result is confirmed by a simple numerical model. Beyond regional implications, this study highlights the potential of calcite twin analyses to yield a representative quantitative picture of stress and strain patterns related to folding

Paleostress magnitudes in folded sedimentary rocks

International audienceUsing Sheep Mountain Anticline (Wyoming, USA) as a case study, we propose a new approach to quantify effective paleo-principal stress magnitudes in the uppermost crust. The proposed mechanical scenario relies on a well-documented kinematic and chronological sequence of development of faults, fractures and microstructures in the folded strata. Paleostress orientations and regimes as well as differential stress magnitudes based on calcite twinning paleopiezometry are combined with rock mechanics data in a Mohr construction to derive principal stress magnitudes related to the successive steps of layer-parallel shortening and to late stage fold tightening. Such quantification also provides original insights into the evolution of the fluid (over)pressure and amount of syn-folding erosion

Quasi-nuclear and quark model baryonium: historical survey

We review ideas and speculations concerning possible bound states or resonances coupled to the nucleon-antinucleon channel.Comment: 7 pages, no figure, Latex with espcrc2.sty, Talk at QCD99, Montpellier, France, July 1999, to appear in the Proceedings, ed. S. Nariso

Contrôle du remplissage détritique tardiglaciaire à holocène d'une haute vallée alpine par les dynamiques de versant : l'exemple de la moyenne Maurienne (Savoie).

Les cônes de déjection constituent le trait morphologique majeur de l'étroite vallée de l'Arc (Savoie), entre les ombilics de Saint-Jean-de-Maurienne et Saint-Michel-de-Maurienne. Une reconstitution géométrique des différents corps sédimentaires constitutifs de ces cônes a été rendue possible grâce à la corrélation de données géomorphologiques, à la synthèse des données de forages de diverses campagnes de reconnaissance pour EDF et Alpetunnel et à l'utilisation de données géophysiques. Un calage stratigraphique a été établi à partir de datations de bois fossilisés puis une évolution paléogéographique est proposée. Elle montre que, dans cette gorge de raccordement, le remplissage tardiglaciaire à holocène est fortement contrôlé par les dépôts torrentiels latéraux, des coulées boueuses, des écroulements rocheux massifs et glissements de terrain. En barrant cette étroite vallée, ces dépôts gravitaires favorisent localement une sédimentation lacustre

Is Impact of Statin Therapy on All-Cause Mortality Different in HIV-Infected Individuals Compared to General Population? Results from the FHDH-ANRS CO4 Cohort

French Hospital Database on HIVInternational audienceBackgroundThe effect of statins on all-cause mortality in the general population has been estimated as 0.86 (95%CI 0.79-0.94) for primary prevention. Reported values in HIV-infected individuals have been discordant. We assessed the impact of statin-based primary prevention on all-cause mortality among HIV-infected individuals.MethodsPatients were selected among controls from a multicentre nested case-control study on the risk of myocardial infarction. Patients with prior cardiovascular or cerebrovascular disorders were not eligible. Potential confounders, including variables that were associated either with statin use and/or death occurrence and statin use were evaluated within the last 3 months prior to inclusion in the case-control study. Using an intention to continue approach, multiple imputation of missing data, Cox’s proportional hazard models or propensity based weighting, the impact of statins on the 7-year all-cause mortality was evaluated.ResultsAmong 1,776 HIV-infected individuals, 138 (8%) were statins users. During a median follow-up of 53 months, 76 deaths occurred, including 6 in statin users. Statin users had more cardiovascular risk factors and a lower CD4 T cell nadir than statin non-users. In univariable analysis, the death rate was higher in statins users (11% vs 7%, HR 1.22, 95%CI 0.53-2.82). The confounders accounted for were age, HIV transmission group, current CD4 T cell count, haemoglobin level, body mass index, smoking status, anti-HCV antibodies positivity, HBs antigen positivity, diabetes and hypertension. In the Cox multivariable model the estimated hazard ratio of statin on all-cause mortality was estimated as 0.86 (95%CI 0.34-2.19) and it was 0.83 (95%CI 0.51-1.35) using inverse probability treatment weights.ConclusionThe impact of statin for primary prevention appears similar in HIV-infected individuals and in the general population

Evidence for pre-folding vein development in the Oligo-Miocene Asmari Formation in the Central Zagros Fold Belt, Iran

International audienceIn order to understand the interplay between vein development and folding in the carbonates of the Oligo-Miocene Asmari Formation (one of the main hydrocarbon reservoir rocks) in Iran, several anticlines have been investigated in the central part of the Zagros folded belt. Combining observations of relative chronology between veins based on calcite-filling phases and crosscutting/abutting relationships, as well as aerial/satellite image interpretation on several anticlines allowed proposing a tectonic model highlighting the widespread development of veins and other extensional micro/meso-structures in the Central Zagros folded belt. Our data suggest that most of the veins affecting the Asmari formation predated the main Miocene-Pliocene folding episode. An early regional vein set striking N50° marked the onset of collisional stress build-up in the region. Then, N150° and N20° trending vein sets were initiated in response to local extension caused by large-scale flexure/drape folds above N-S and N140° basement faults reactivated under the regional NE compression. At the onset and during Miocene-Pliocene folding of the sedimentary cover, the early formed veins were reactivated (reopened and/or sheared) while duplexes, low angle reverse faults and thrusts formed. Beyond regional implications, this study puts emphasis on the need of carefully considering regional/local vein development predating folding as well as influence of underlying basement faults in models of folded-fractured reservoirs in fold-thrust belts

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

<p>Abstract</p> <p>Background</p> <p>Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool.</p> <p>Methods</p> <p>We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3).</p> <p>Results</p> <p>Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel.</p> <p>Conclusions</p> <p>Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.</p

Eight previously unidentified mutations found in the OA1 ocular albinism gene

BACKGROUND: Ocular albinism type 1 (OA1) is an X-linked ocular disorder characterized by a severe reduction in visual acuity, nystagmus, hypopigmentation of the retinal pigmented epithelium, foveal hypoplasia, macromelanosomes in pigmented skin and eye cells, and misrouting of the optical tracts. This disease is primarily caused by mutations in the OA1 gene. METHODS: The ophthalmologic phenotype of the patients and their family members was characterized. We screened for mutations in the OA1 gene by direct sequencing of the nine PCR-amplified exons, and for genomic deletions by PCR-amplification of large DNA fragments. RESULTS: We sequenced the nine exons of the OA1 gene in 72 individuals and found ten different mutations in seven unrelated families and three sporadic cases. The ten mutations include an amino acid substitution and a premature stop codon previously reported by our team, and eight previously unidentified mutations: three amino acid substitutions, a duplication, a deletion, an insertion and two splice-site mutations. The use of a novel Taq polymerase enabled us to amplify large genomic fragments covering the OA1 gene. and to detect very likely six distinct large deletions. Furthermore, we were able to confirm that there was no deletion in twenty one patients where no mutation had been found. CONCLUSION: The identified mutations affect highly conserved amino acids, cause frameshifts or alternative splicing, thus affecting folding of the OA1 G protein coupled receptor, interactions of OA1 with its G protein and/or binding with its ligand