Recurrent dominant mutations affecting two adjacent residues in the motor domain of the monomeric kinesin KIF22 result in skeletal dysplasia and joint laxity.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (lepto-SEMDJL, aka SEMDJL, Hall type), is an autosomal dominant skeletal disorder that, in spite of being relatively common among skeletal dysplasias, has eluded molecular elucidation so far. We used whole-exome sequencing of five unrelated individuals with lepto-SEMDJL to identify mutations in KIF22 as the cause of this skeletal condition. Missense mutations affecting one of two adjacent amino acids in the motor domain of KIF22 were present in 20 familial cases from eight families and in 12 other sporadic cases. The skeletal and connective tissue phenotype produced by these specific mutations point to functions of KIF22 beyond those previously ascribed functions involving chromosome segregation. Although we have found Kif22 to be strongly upregulated at the growth plate, the precise pathogenetic mechanisms remain to be elucidated.

Risk reduction practices in men who have sex with men in Switzerland: serosorting, strategic positioning, and withdrawal before ejaculation.

The aim of this study was to identify predictors of intentional use of the HIV risk reduction practices of serosorting, strategic positioning, and withdrawal before ejaculation during unprotected anal intercourse (UAI) with casual partners. A cross-sectional survey pertaining to the Swiss HIV behavioral surveillance system, using an anonymous self-administered questionnaire, was conducted in 2007 in a self-selected sample of men having sex with other men (MSM). Analysis was restricted to participants with UAI with casual partner(s) (N = 410). Logistic regression was used to estimate factors associated with intentional use of serosorting, strategic positioning, and withdrawal before ejaculation. In the previous 12 months, 71% of participants reported having UAI with a casual partner of different or unknown HIV-status. Of these, 47% reported practicing withdrawal, 38% serosorting, and 25% strategic positioning. In the 319 participants with known HIV-status, serosorting was associated with frequent Internet use to find partners (OR = 2.32), STI (OR = 2.07), and HIV testing in the past 12 months (OR = 1.81). Strategic positioning was associated with HIV-status (OR = 0.13) and having UAI with a partner of different or unknown HIV-status (OR = 3.57). Withdrawal was more frequently practiced by HIV-negative participants or participants reporting high numbers of sexual partners (OR = 2.48) and having UAI with a partner of unknown or different serostatus (OR = 2.08). Risk reduction practices are widely used by MSM, each practice having its own specificities. Further research is needed to determine the contextual factors surrounding harm reduction practices, particularly the strategic or opportunistic nature of their use.

Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts.

TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3-null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype.

The Hippo Transducer YAP1 Transforms Activated Satellite Cells and Is a Potent Effector of Embryonal Rhabdomyosarcoma Formation.

The role of the Hippo pathway effector YAP1 in soft tissue sarcomas is poorly defined. Here we report that YAP1 activity is elevated in human embryonal rhabdomyosarcoma (ERMS). In mice, sustained YAP1 hyperactivity in activated, but not quiescent, satellite cells induces ERMS with high penetrance and short latency. Via its transcriptional program with TEAD1, YAP1 directly regulates several major hallmarks of ERMS. YAP1-TEAD1 upregulate pro-proliferative and oncogenic genes and maintain the ERMS differentiation block by interfering with MYOD1 and MEF2 pro-differentiation activities. Normalization of YAP1 expression reduces tumor burden in human ERMS xenografts and allows YAP1-driven ERMS to differentiate in situ. Collectively, our results identify YAP1 as a potent ERMS oncogenic driver and a promising target for differentiation therapy.

Liddle's syndrome caused by a novel missense mutation (P617L) of the epithelial sodium channel beta subunit.

OBJECTIVE: The aim of the study was to search for mutations of SCNN1B and SCNN1G in an Italian family with apparently dominant autosomal transmission of a clinical phenotype consistent with Liddle's syndrome. METHODS: Genetic analysis was performed in the proband, his relatives, and 100 control subjects. To determine the functional role of the mutation identified in the proband, we expressed the mutant or wild-type epithelial sodium channel in Xenopus laevis oocytes. RESULTS: A novel point mutation, causing an expected substitution of a leucine residue for the second proline residue of the conserved PY motif (PPP x Y) of the beta subunit was identified in the proband. The functional expression of the mutant epithelial sodium channel in X. laevis oocytes showed a three-fold increase in the amiloride-sensitive current as compared with that of the wild-type channel. CONCLUSION: This newly identified mutation adds to other missense mutations of the PY motif of the beta subunit of the epithelial sodium channel, thus confirming its crucial role in the regulation of the epithelial sodium channel. To our knowledge, this is the first report of Liddle's syndrome in the Italian population, confirmed by genetic and functional analysis, with the identification of a gain-of-function mutation not previously reported.

Rein et tabac : revue de la littérature et mise au point [Kidney and smoking: literature review and focus].

Smoking remains a major public health problem. It is associated with a considerable number of deaths in the world's population. Smoking is just like high blood pressure, an independent predictor of progression to any primary renal disease and renal transplant patients. It seems that smoking cessation slows the progression of kidney disease in smokers. The literature data are sometimes contradictory about it because of some methodological weaknesses. However, experimental models highlight the harmful effects of tobacco by hemodynamic and non-hemodynamic factors. The conclusion is that a major effort should be further produced by the nephrology community to motivate our patients to stop smoking.

Human immunodeficiency virus type 1 fitness is a determining factor in viral rebound and set point in chronic infection.

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

Development of a system for 3D high-resolution seismic reflection profiling on lakes

A high-resolution three-dimensional (3D) seismic reflection system for small-scale targets in lacustrine settings has been developed. Its main characteristics include navigation and shot-triggering software that fires the seismic source at regular distance intervals (max. error of 0.25 m) with real-time control on navigation using differential GPS (Global Positioning System). Receiver positions are accurately calculated (error < 0.20 m) with the aid of GPS antennas attached to the end of each of three 24-channel streamers. Two telescopic booms hold the streamers at a distance of 7.5 m from each other. With a receiver spacing of 2.5 m, the bin dimension is 1.25 m in inline and 3.75 m in crossline direction. To test the system, we conducted a 3D survey of about 1 km(2) in Lake Geneva, Switzerland, over a complex fault zone. A 5-m shot spacing resulted in a nominal fold of 6. A double-chamber bubble-cancelling 15/15 in(3) air gun (40-650 Hz) operated at 80 bars and 1 m depth gave a signal penetration of 300 m below water bottom and a best vertical resolution of 1.1 m. Processing followed a conventional scheme, but had to be adapted to the high sampling rates, and our unconventional navigation data needed conversion to industry standards. The high-quality data enabled us to construct maps of seismic horizons and fault surfaces in three dimensions. The system proves to be well adapted to investigate complex structures by providing non-aliased images of reflectors with dips up to 30 degrees.

Mise au point et validation d'un fantôme spécifique pour asssurer le suivi des mesures quantitatives en tomographie par émission de positons.

L'index de consommation du glucose, SUV pour standardized uptake value, est largement utilisé en tomographie par émission de positons (TEP) pour quantifier la concentration relative de [18F]2-fluoro-2-désoxy-D-glucose (18F-FDG) dans les tissus. Cependant, cet indice dépend de nombreux facteurs méthodologiques et biologiques et son utilisation fait débat. Il est donc primordial d'instaurer un contrôle qualité régulier permettant d'assurer la stabilité de la mesure des indices quantitatifs. Dans cette optique, un fantôme spécifique avec inserts cylindriques de différentes tailles a été développé. L'objectif de cette étude est de montrer la sensibilité et l'intérêt de ce fantôme. Méthodes. - La sensibilité du fantôme a été étudiée à travers la mesure des SUV et des coefficients de recouvrement (RC). Plusieurs méthodes de mesure ont été utilisées. Les données ont été reconstruites en utilisant les algorithmes de routine clinique. Nous avons étudié la variation des RC en fonction de la taille des cylindres et le changement relatif de fixation, en utilisant des activités différentes. Le fantôme a ensuite été testé sur l'appareil d'un autre centre. Résultats. - Pour toutes les méthodes de mesure, une forte variation des RC avec la taille des cylindres, de l'ordre de 50 %, a été obtenue. Ce fantôme a également permis de mesurer un changement relatif de fixation qui s'est révélé être indépendant de la méthode de mesure. Malgré un étalonnage des deux systèmes TEP/TDM, des différences de quantification d'environ 20 % ont subsisté. Conclusion. - Les résultats obtenus montrent l'intérêt de ce fantôme dans le cadre du suivi des mesures quantitatives.