Molecular basis of messenger RNA recognition by the specific bacterial repressing clamp RsmA/CsrA.

Proteins of the RsmA/CsrA family are global translational regulators in many bacterial species. We have determined the solution structure of a complex formed between the RsmE protein, a member of this family from Pseudomonas fluorescens, and a target RNA encompassing the ribosome-binding site of the hcnA gene. The RsmE homodimer with its two RNA-binding sites makes optimal contact with an 5'-A/UCANGGANGU/A-3' sequence in the mRNA. When tightly gripped by RsmE, the ANGGAN core folds into a loop, favoring the formation of a 3-base-pair stem by flanking nucleotides. We validated these findings by in vivo and in vitro mutational analyses. The structure of the complex explains well how, by sequestering the Shine-Dalgarno sequence, the RsmA/CsrA proteins repress translation.

Inverse metamorphic zonation in very low-grade Tibetan zone series of SE Zanskar and its tectonic consequences (NW India, Himalaya)

The metamorphism of the carbonate rocks of the SE Zanskar Tibetan zone has been studied by `'illite crystallinity'' and calcite-dolomite thermometry. The epizonal Zangla unit overlies the anchizonal Chumik unit. This discontinuous inverse zonation demonstrates a late to post-metamorphic thrust of the first unit over the second. The studied area underwent a complex tectonic history: - The tectonic units were stacked from the NE to the SW, generating recumbent folds, NE dipping thrusts and the regional metamorphism. The compressive movements were active under lower temperature conditions, resulting in late thrusts that disturbed the metamorphic zonation. The discontinuous inverse metamorphic zonation dates from this phase. - A NE vergent backfolding phase occurred at lower temperature conditions. It caused the uplift of more metamorphic levels. - A late extensional phase is revealed by the presence of NE dipping low angle normal faults, and a major high angle fault, the Sarchu fault. The low angle normal faults locally run along earlier thrusts (composite tectonic contacts). Their throw has been sufficient to reset a normal stratigraphic superposition (young layers overlying old ones), but insufficient to erase the inverse metamorphic relationship. However, the combined action of backfolding and normal faulting can locally lessen, or even cancel, the inverse metamorphic superposition. After deduction of the normal fault translation, the vertical component of the original thrust displacement through stratigraphy is 400 m, which is a value far too low to explain the temperature difference between the two units. The horizontal component of displacement is therefore far more important than the vertical one. The regional distribution of metamorphism within the Zangla unit points out to an anchizonal front and an epizonal inner part. This fact is in agreement with nappe tectonics.

Paral lelismes lèxics en aragonès xistaví i català: préstec o fenomen de contínuum?

A part de l"ús del pretèrit perifràstic, format amb el verb ir + infinitiu (xistaví) o anar + infinitiu (català), els paral lelismes més interessants entre el xistaví i el català són de tipus lèxic. Tanmateix, sovint no resulta gens fàcil decidir si les formes compartides són préstecs directes o si constitueixen part d"un tresor comú. Determinades paraules com ara sep i boc, amb oclusiva final, i llesca, amb [ʎ] inicial, porten l"empremta d"identitat catalana, així com borde < bord, amb vocal de suport final en aragonès i en castellà, i cotón, sense l"article àrab aglutinat (però amb [n] final en aragonès). La forma mielsa és un catalanisme tan antic que presenta diftongació de la vocal radical en aragonès. A més a més, tancar, que és específic de l"Aragó oriental, sembla ser resultat de l"expansió del català a territoris dialectals veïns. En canvi, bachoca és tan generalitzat també es troba a Múrcia i València que no pot ésser considerat com el cas anterior. En aquest article intentem d"avaluar l"impacte del lèxic català en l"aragonès de Gistaín (xistaví).

Structure and kinematics of the Jungfrau syncline, Faflertal (Valais, Alps), and its regional significance

The formation and structural evolution of the jungrau syncline is described, based on excellent outcrops occurring in the lotschental, in the central alps of switzerland. the quality of the outcrops allows us to demonstrate that the external massifs of the swiss alps have developed due to internal folding. The jungfrau suncline, which separates the autochtonous gastern dome from the aar massif basement gneiss folds, is composed of slivers of basement rocks with their mesozoic sedimentary cover. in the inner faflertal, a side valley of the lotschental, the 200 m thick syncline cp, roses fpir imots, the gastern massif with a reduced mesozoic sedimentary cover in a normal stratigraphic succession, two units of overturned basement rocks with their mesozoic sedimentary cover, and the overturned lower limn of the tschingelhorn gneiss fold of the aar massif with lenses of its sedimentary cover. stratigraphy shows that the lower units, related to the gastern massis, are condensed and that the upper units, deposited farther away from a gastern paleo-high, form a more complete sequence, linked to the doldenhorn meso-cneozoic basin fill. the integration of these local observations with published regional data leads to the following model. on the northern margin of the doldenhorn hbasin, at the northern fringe of the alpine tethuys, the pre-triassic crystalline basement and its mesozoic sedimentary cover were folded by ductile deformation at temperatures above 300 degrees C and in the presence of high fluid pressures, as the helveti c and penninic nappes were overthrusted towards the northwest during the main alpine deformation phase, the visosity contrast between the basement gneisses and the sediments caused the formation of large basement anticlines and tight sedimentary sunclines (mullion-type structures). The edges of basement blocks bounded buy pre-cursor se-dipping normal faults at the northwestern border of the doldenhorn basin were deformed bu simple shear, creating overturned slices of crystalline rocks with their sedimentary cover in what now forms the hungfrau syncline. the localisation of ductile deformation in the vicinity of pre-existing se-dipping faults is thought to have been helped by the circulation of fluids along the faults; these fluids would have been released from the mesozoic sediments by metamorphic dehydration reactions accompanied by creep and dynamic recrystallisation of quartz at temperatures above 300 degrees C. Quantification of the deformation suggests an strain ellipsoid with a ratio (1 + e(1)/+ e(3)) of approximately 1000. The jungfrau suncline was deformed bu more brittle nw-directed shear creating well-developed shear band cleavages at a late stage, after cooling by uplift and erosion. It is suggested that the external massifs of the apls are basement gneiss folds created at temperatures of 300 degrees C by detachment through ductile deformation of the upper crust of the european plate as it was underthrusted below the adriatic plate.

The Hercynian structure of the Catalonian Coastal Ranges (NE Spain)

In the Catalonian Coastal Ranges, Paleozoic sedimentary and meta-sedimentary rocks crop out in severa1 areas, intruded by late tectonic Hercynian granitoids and separated by Mesozoic and Tertiary cover sediments. Large structures are often difficult to recognize, although a general east-west trend can be observed on the geological map. Deformation was accompanied by the development of cleavages and regional metamorphism. Green-schist facies rocks are prominent throughout the Ranges, while amphibolite facies are restricted to small areas. In low-grade areas, the main deformation phase generated south-facing folds with an axial plane cleavage (slaty cleavage in metapelitic rocks). The intersection lineation (Ss/Sl) and the axes of minor folds trend cast-west, as do all mapable structures. Late deformations generated coarse crenulations, small chevrons and kink-bands, all intersecting the slaty cleavage at high angles. In medium- to high-grade areas no major folds have been observed. In these areas, the main foliation is a schistosity and is often folded, giving centimetric to decimetric, nearly isoclinal intrafolial folds. In schists, these folds aremuchmore common than inother lithologies, and can be associated with a crenulation cleavage. All these planar structures in high-grade rocks are roughly parallel. The late Hercynian deformational events, which gave rise to the crenulations and small chevrons, also produced large (often kilometric) open folds which fold the slaty cleavage and schistosity. As aconsequence, alternating belts with opposite dip (north and south) of the main foliation were formed. With respect to the Hercynian orogenic belt, the Paleozoic outcrops of the Catalonian Coastal Ranges are located within the northern branch of the Ibero-Armorican arc, and have a relatively frontal position within the belt. The Carboniferous of the Priorat-Prades area, together with other outcrops in the Castellón Province, the Montalbán massif (Iberian Chain) and the Cantabrian zone (specially the Pisuerga-Carrión Province) probably form part of a wide area of foreland Carboniferous deposition placed at the core of the arc.

Acute creatine ingestion in human: consequences on serum creatine and creatinine concentrations.

The aim of the study was to explore the effect of an acute dose of creatine (Cr) ingestion on serum Cr and serum creatinine (Crn) concentrations. Sixteen healthy subjects ingested a single dose of Cr (20 g) followed by the measurement of serum Cr and Crn concentration for 3 h up to a maximum of 6 h (n=6). In response to Cr ingestion a large rise in serum Cr concentration was observed (by 50 folds) occurring approximately 2 1/2h after the ingestion (peak value of 2.17 +/- 0.66 mmol x l(-1)). We also found a moderate but significant rise in serum Crn concentration averaging 13 % after 3 h (peak value at 99.5 +/- 10.5 micromol x l(-1)). A dose response curve obtained in two case studies, in whom different doses of Cr were ingested (0, 2.5, 5, 10, 15, 20 g and 0, 10, 20, 30 g), showed that serum Cr concentration as well as the peak time increased linearly with Cr ingestion. In addition, acute Crn ingestion (5 g) resulted in a substantial increase in serum Crn concentration (by 10 folds) but led to a minor rise in serum Cr concentration (by 2 folds). These results suggest that when acute doses of Cr are ingested in humans, the degree of conversion of exogenous Cr to Crn in the stomach and the gut can be considered as negligible following the first 6 h of ingestion. However, further studies are required to explore the prolonged effect of Cr on Crn metabolism.

Anatomia funcional de la veu

S'estudien les diferents parts de l'aparell vocal i com interactuen per a produir la veu normal.

Anatomía funcional de la voz

Se estudian las distintas partes del aparato vocal y cómo interactúan para producir la voz.

Osteolytic metastasis detected by F18-FDG PET in a patient with lung carcinoma

We present a 53-year-old man with a vocal cord paralysis observed as a primary manifestation of lung carcinoma. Tc-99m MDP whole body bone scan were performed and resulted a normal scintiscan. The bone scan does not revealed suspicious foci of uptake. The possibility of bone metastasis was taken into consideration. A whole body F18-FDG-PET scan showed intense uptake in the left upper lung corresponding to the primary tumor. A bronchial biopsy confirmed infiltration by small cell lung carcinoma (SCLC). SCLC is composed of poorly differentiated, rapidly growing cells with disease usually occurring centrally rather than peripherally. It metastasizes early. The whole-body F18-FDG-PET scan clearly demonstrated a focus of increased uptake in the second lumbar vertebral body suspicious for osteolytic metastasis. A lytic bone metastasis was confirmed by MRI. The patient then received therapy and underwent follow up abdominal CT. The scan showed blastic changes in the L2 vertebra suggesting response to treatment.

High expression of the HMG box factor sox-13 in arterial walls during embryonic development.

Members of the Sox gene family of transcription factors are defined by the presence of an 80 amino acid homology domain, the High Mobility Group (HMG) box. Here we report the cloning and initial analysis of murine Sox-13 . The 984 amino acids Sox-13 protein contains a single HMG box, a leucine zipper motif and a glutamine-rich stretch. These characteristics are shared with another member of the Sox gene family, Sox-6. High level embryonic expression of Sox-13 occurs uniquely in the arterial walls of 13.5 days post coitum (dpc) mice and later. Low level expression was observed in the inner ear of 13.5 dpc mice and in a limited number of cells in the thymus of 16.5 dpc mice, from which Sox-13 was originally cloned. At 18.5 dpc, Sox-13 is expressed in the tracheal epithelium below the vocal cord and in the hair follicles. The Sox-13 protein binds to the consensus HMG box motif, AACAAAG, but does not transactivate transcription through a concatamer of this motif. Sox-13, like other members of the Sox family likely plays an important role in development.

Une carte des zones de cisaillement ductiles des Alpes Centrales

The main deformation structures due to the Tertiary continental collision in the Western Swiss Alps are ductile shear zones. Four main shear zones can be recognized on the structural map, each characterised by a different shear direction. The first D I shear zone with a X I, SE (transverse) stretching direction has been created during the under-thrusting towards the SE of the European plate under the Adriatic plate. This took place mainly by ductile deformation of the upper part of the European continental basement with the formation of the external massifs basement folds and the Penninic foldnappes. The second D II shear zone (Simplon ductile shear zone) is characterized by a XII stretching, dipping from 0 to 30-degrees to the SW (longitudinal stretching). It is approximately 10 km wide, and crosses the Alpine nappes in an oblique direction. It corresponds to a relative SW transport direction of the upper units together with the Adriatic plate. This dextral transpression zone is also responsible for the stretching parallel to the elongation of the Alpine belt. The third D III shear zone is made of mylonites with a steep stretching direction and corresponds to the hanging wall of the Canavese reverse fault. The D IV shear zones, dextral wrench zones combined with underthrusting movement, are characterised by a W and SW stretching direction. They were formed during and after the S facing backfolding which for instance made the Mischabel fold and the Boggioleto fold. Actually it occupies two narrow areas of more ductile rocks between the Mischabel backfold to the N and the Monte Rosa nappe to the S and allong the Canavese Line. These dextral shear zones represent probably the western continuation of the Tonale Line dextral wrench fault. The D I to IV ductile shear zone were formed under greenschist and amphibolite facies conditions during the Tertiary orogenic metamorphism. Their regional distribution is limited to the metamorphic ductile zone representing the deep part of the Alpine belt, between 10 and 30 km depth. The emplacement and orientation of the shear zones was also directed by the geometry of the boundaries of the European and Adriatic plates. The analysis of the superposed Central Alpine shear zones permits thus to propose a model of the history of the relative convergent and wrench movements which took place between the European and Adriatic plates during the Alpine Tertiary continental collision.

Body fat levels in children and adolescents: effects on the prevalence of obesity

BACKGROUND AND AIMS: There is little information regarding the effect of different definitions of obesity on nutritional epidemiology. The aim was thus to assess: (a) the values of percentage of body fat (%BF) by gender and age; (b) the prevalence of obesity according to different %BF cut-offs; and (c) the sensitivity and specificity of BMI according to different %BF cut-offs used to define obesity. METHODS: Cross-sectional study on 2494 boys and 2519 girls aged 10­18 years from the Lisbon area. %BF was measured using a hand-held device. In a sub sample of 211 boys and 724 girls %BF was assessed using skin folds. RESULTS: %BF levels were higher in girls and decreased with age in both genders. Prevalence of obesity varied considerably according to the %BF cut-off used: in boys, it ranged from 4.7% (age-specific 95th percentile) to 26.5% (fixed 25% cut-off), whereas by BMI it was 5.3%. In girls, prevalence of obesity ranged from 0.4% (age-specific BMI-derived %BF values) to 25.4% (fixed 30% cut-off), whereas by BMI it was 4.7%. The specificity of BMI criteria was over 95% irrespective of the %BF cut-off used; conversely, most sensitivities were below 40%. Sensitivities over 50% were obtained for the age-specific BMI-derived %BF values in boys and the age-specific 95th %BF percentile in both genders. Using %BF derived from the skin fold measurements leads to similar results. CONCLUSIONS: Prevalence of obesity varies considerably according to the %BF cut-off used. BMI cut-offs have a low sensitivity but a high specificity. Age- and gender-specific cut-offs for %BF should be used to define pediatric obesity.

Tracheostomy in children.

We reviewed the records of 108 patients who had a tracheostomy performed over a 10-year period from July 1979 to April 1989. Median age at tracheostomy was 6 months (1 week-15 years). Indications for surgery were acquired subglottic stenosis (31.4%), bilateral vocal cord paralysis (22.2%), congenital airway malformations (22.2%) and tumours (11.1%). No epiglottis and no emergency situation had to be managed by tracheostomy. Operation was uneventful in all, but 8 patients (7.4%) developed a pneumothorax in the postoperative period. Twenty-one (19.5%) had severe complications during the cannulation period (tube obstruction in 11 patients with cardiorespiratory arrest in 4; dislocation of the tube in 6 patients). Fifteen patients (13.8%) had severe complications after decannulation (2 had a cardiorespiratory arrest); all 15 had to be recannulated. At the end of the study period 85 patients (78.7%) were successfully decannulated with a median period of tracheostomy of 486 days (8 days-6.6 years). The median hospital stay was 159 days (13 days-2.7 years). All patients could be discharged. Eight patients (7.4%) died but no death was related to tracheostomy. In summary the mortality rate is lower than reported in previous reviews and tracheostomy is a safe operation even in small children but cannula-related complications may lead to life-threatening events. The management of tracheostomized small children and infants in a highly staffed and monitored intensive care unit has allowed better handling of complications and has resulted in a reduction in cannula-related deaths.

Aminoterminal amphipathic α-helix AH1 of hepatitis C virus nonstructural protein 4B possesses a dual role in RNA replication and virus production.

Nonstructural protein 4B (NS4B) is a key organizer of hepatitis C virus (HCV) replication complex formation. In concert with other nonstructural proteins, it induces a specific membrane rearrangement, designated as membranous web, which serves as a scaffold for the HCV replicase. The N-terminal part of NS4B comprises a predicted and a structurally resolved amphipathic α-helix, designated as AH1 and AH2, respectively. Here, we report a detailed structure-function analysis of NS4B AH1. Circular dichroism and nuclear magnetic resonance structural analyses revealed that AH1 folds into an amphipathic α-helix extending from NS4B amino acid 4 to 32, with positively charged residues flanking the helix. These residues are conserved among hepaciviruses. Mutagenesis and selection of pseudorevertants revealed an important role of these residues in RNA replication by affecting the biogenesis of double-membrane vesicles making up the membranous web. Moreover, alanine substitution of conserved acidic residues on the hydrophilic side of the helix reduced infectivity without significantly affecting RNA replication, indicating that AH1 is also involved in virus production. Selective membrane permeabilization and immunofluorescence microscopy analyses of a functional replicon harboring an epitope tag between NS4B AH1 and AH2 revealed a dual membrane topology of the N-terminal part of NS4B during HCV RNA replication. Luminal translocation was unaffected by the mutations introduced into AH1, but was abrogated by mutations introduced into AH2. In conclusion, our study reports the three-dimensional structure of AH1 from HCV NS4B, and highlights the importance of positively charged amino acid residues flanking this amphipathic α-helix in membranous web formation and RNA replication. In addition, we demonstrate that AH1 possesses a dual role in RNA replication and virus production, potentially governed by different topologies of the N-terminal part of NS4B.

Cancer chronotherapeutics: experimental, theoretical, and clinical aspects.

The circadian timing system controls cell cycle, apoptosis, drug bioactivation, and transport and detoxification mechanisms in healthy tissues. As a consequence, the tolerability of cancer chemotherapy varies up to several folds as a function of circadian timing of drug administration in experimental models. Best antitumor efficacy of single-agent or combination chemotherapy usually corresponds to the delivery of anticancer drugs near their respective times of best tolerability. Mathematical models reveal that such coincidence between chronotolerance and chronoefficacy is best explained by differences in the circadian and cell cycle dynamics of host and cancer cells, especially with regard circadian entrainment and cell cycle variability. In the clinic, a large improvement in tolerability was shown in international randomized trials where cancer patients received the same sinusoidal chronotherapy schedule over 24h as compared to constant-rate infusion or wrongly timed chronotherapy. However, sex, genetic background, and lifestyle were found to influence optimal chronotherapy scheduling. These findings support systems biology approaches to cancer chronotherapeutics. They involve the systematic experimental mapping and modeling of chronopharmacology pathways in synchronized cell cultures and their adjustment to mouse models of both sexes and distinct genetic background, as recently shown for irinotecan. Model-based personalized circadian drug delivery aims at jointly improving tolerability and efficacy of anticancer drugs based on the circadian timing system of individual patients, using dedicated circadian biomarker and drug delivery technologies.