Mutations in the cystic fibrosis gene in patients with congenital absence of the vas deferens

Background: Congenital bilateral absence of the vas deferens (CBAVD) is a form of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. The molecular basis of CBAVD is not completely understood. Although patients with cystic fibrosis have mutations in both copies of the CFTR gene, most patients with CBAVD have mutations in only one copy of the gene. Methods: To investigate CBAVD at the molecular level, we have characterized the mutations in the CFTR gene in 102 patients with this condition. None had clinical manifestations of cystic fibrosis. We also analyzed a DNA variant (the 5T allele) in a noncoding region of CFTR that causes reduced levels of the normal CFTR protein. Parents of patients with cystic fibrosis, patients with types of infertility other than CBAVD, and normal subjects were studied as controls. Results: Nineteen of the 102 patients with CBAVD had mutations in both copies of the CFTR gene, and none of them had the 5T allele. Fifty-four patients had a mutation in one copy of CFTR, and 34 of them (63 percent) had the 5T allele in the other CFTR gene. In 29 patients no CFTR mutations were found, but 7 of them (24 percent) had the 5T allele. In contrast, the frequency of this allele in the general population was about 5 percent. Conclusions: Most patients with CBAVD have mutations in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene with a cystic fibrosis mutation in the other copy is the most common cause of CBAVD. The 5T allele mutation has a wide range of clinical presentations, occurring in patients with CBAVD or moderate forms of cystic fibrosis and in fertile men.

Asymmetric stochastic switching driven by intrinsic molecular noise

Low-copy-number molecules are involved in many functions in cells. The intrinsic fluctuations of these numbers can enable stochastic switching between multiple steady states, inducing phenotypic variability. Herein we present a theoretical and computational study based on Master Equations and Fokker-Planck and Langevin descriptions of stochastic switching for a genetic circuit of autoactivation. We show that in this circuit the intrinsic fluctuations arising from low-copy numbers, which are inherently state-dependent, drive asymmetric switching. These theoretical results are consistent with experimental data that have been reported for the bistable system of the gallactose signaling network in yeast. Our study unravels that intrinsic fluctuations, while not required to describe bistability, are fundamental to understand stochastic switching and the dynamical relative stability of multiple states.

Molecular dating of caprines using ancient DNA sequences of Myotragus balearicus, an extinct endemic Balearic mammal

Background: Myotragus balearicus was an endemic bovid from the Balearic Islands (Western Mediterranean) that became extinct around 6,000-4,000 years ago. The Myotragus evolutionary lineage became isolated in the islands most probably at the end of the Messinian crisis, when the desiccation of the Mediterranean ended, in a geological date established at 5.35 Mya. Thus, the sequences of Myotragus could be very valuable for calibrating the mammalian mitochondrial DNA clock and, in particular, the tree of the Caprinae subfamily, to which Myotragus belongs. Results: We have retrieved the complete mitochondrial cytochrome b gene (1,143 base pairs), plus fragments of the mitochondrial 12S gene and the nuclear 28S rDNA multi-copy gene from a well preserved Myotragus subfossil bone. The best resolved phylogenetic trees, obtained with the cytochrome b gene, placed Myotragus in a position basal to the Ovis group. Using the calibration provided by the isolation of Balearic Islands, we calculated that the initial radiation of caprines can be dated at 6.2 ± 0.4 Mya. In addition, alpine and southern chamois, considered until recently the same species, split around 1.6 ± 0.3 Mya, indicating that the two chamois species have been separated much longer than previously thought. Conclusion: Since there are almost no extant endemic mammals in Mediterranean islands, the sequence of the extinct Balearic endemic Myotragus has been crucial for allowing us to use the Messinian crisis calibration point for dating the caprines phylogenetic tree.

A chromosomal insertion toolbox for promoter probing, mutant complementation and pathogenicity studies in Ralstonia solanacearum

We describe here the construction of a delivery system for stable and directed insertion of gene constructs in a permissive chromosomal site of the bacterial wilt pathogen Ralstonia solanacearum. The system consists of a collection of suicide vectors the Ralstonia chromosome (pRC) series that carry an integration element flanked by transcription terminators and two sequences of homology to the chromosome of strain GMI1000, where the integration element is inserted through a double recombination event. Unique restriction enzyme sites and a GATEWAY cassette enable cloning of any promoter::gene combination in the integration element. Variants endowed with different selectable antibiotic resistance genes and promoter::gene combinations are described. We show that the system can be readily used in GMI1000 and adapted to other R. solanacearum strains using an accessory plasmid. We prove that the pRC system can be employed to complement a deletion mutation with a single copy of the native gene, and to measure transcription of selected promoters in monocopy both in vitro and in planta. Finally, the system has been used to purify and study secretion type III effectors. These novel genetic tools will be particularly useful for the construction of recombinant bacteria that maintain inserted genes or reporter fusions in competitive situations (i.e., during plant infection).

High Prevalence of Signs of Renal Damage Despite Normal Renal Function in a Cohort of HIV-Infected Patients: Evaluation of Associated Factors

Renal disorders are an emerging problem in HIV-infected patients. We performed a cross-sectional study of the first 1000 HIV-infected patients attended at our HIV unit who agreed to participate. We determined the frequency of renal alterations and its related risk factors. Summary statistics and logistic regression were applied. The study sample comprised 970 patients with complete data. Most were white (94%) and men (76%). Median (IQR) age was 48 (42–53) years. Hypertension was diagnosed in 19%, dyslipidemia in 27%, and diabetes mellitus in 3%. According to the Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation, 29 patients (3%) had an eGFR < 60 ml/min/1.73m2; 18 of them (62%) presented altered albumin/creatinine and protein/creatinine (UPC or UAC) ratios. Of the patients with eGFR> 60mL/min, it was present in 293 (30%), 38 of whom (7.1%) had UPC> 300mg/g. Increased risk of renal abnormalities was correlated with hypertension (OR, 1.821 [95%CI, 1.292;2.564]; p = 0.001), age (OR, 1.015 [95%CI, 1.001;1.030], per one year; p = 0.040), and use of tenofovir disoproxil fumarate (TDF) plus protease inhibitor (PI), (OR, 1.401 [95%CI, 1.078;1.821]; p = 0.012). Current CD4 cell count was a protective factor (OR, 0.9995 [95%CI, 0.9991;0.9999], per one cell; p = 0.035). A considerable proportion of patients presented altered UPC or UAC ratios, despite having an eGFR > 60mL/min. CD4 cell count was a protective factor; age, hypertension, and use of TDF plus PIs were risk factors for renal abnormalities. Based on our results, screen of renal abnormalities should be considered in all HIV-infected patients to detect these alterations early.

Privacy-Aware Peer-to- Peer Content Distribution Using Automatically Recombined Fingerprints

Peer-reviewed

Simulació del comportament d'uns individus en un entorn i desenvolupament d'un videojoc educatiu de programació

Aquest projecte tracta la implementació d’una aplicació capaç de simular el comportament d’uns individus que segueixen el seu propi algorisme en un entorn que planteja certes dificultat per a la supervivència: hi ha obstacles i fonts que proveeixen energia que els individus necessiten per existir. S’han desenvolupat les eines necessàries perquè l’usuari pugui visualitzar, recollir dades i interactuar amb l’entorn d’una forma còmoda i intuïtiva. Sobre aquesta base, s’ha implementat un videojoc que planteja reptes a l’usuari que es poden resoldre a través de l’edició dels algorismes d’un o més individus, és a dir, a través de la programació. D’aquesta manera s’introdueix a l’usuari en els principis de l’algorismia d’una forma lúdica i molt visual.

Diseño de una aplicación web para la gestión de una revista científica

Este proyecto tiene como finalidad el análisis, diseño y desarrollo de una aplicación web en base a una revista científica. La mecánica de la revista consiste en la propia revisión y edición de los artículos por parte de los usuarios dados de alta en el aplicativo. Los usuarios que componen la web, puede tener diferentes perfiles: autor, editor, revisor, técnico editor y administrador. Cada usuario tiene unas tareas específicas en el flujo de revisión y edición. El proyecto se ha desarrollado sobre la plataforma ASP.NET y SQL para el diseño de la base de datos.

Edició de llibres infantils i juvenils: la poesia

Una visió panoràmica de l'edició de llibres infantils i juvenils de poesia en llengua catalana durant el darrer bienni en permet fer una valoració globalment esperançadora. Quant als creadors, s'hi han incorporat noves veus, algunes de les quals han contribuït a la renovació temàtica i a la qualitat tant del llenguatge literari com del visual, han augmentat els llibres on flueix la paraula sense encarcaraments ni rimes forçades i s'han publicat obres en què la interrelació íntima aconseguida entre paraula i imatge va més enllà de la funció ornamental de bona part d'il·lustracions dels llibres de poesia. En l'àmbit editorial, els fenòmens més interessants del bienni són l'aparició de tres col·leccions de poesia i l'augment d'edicions en la nostra llengua i de versions de poesia d'altres cultures, algunes en edicions molt acurades. Pel que fa a la difusió i divulgació, s'han atorgat premis a obres de creació i a estudis sobre el gènere i s'han organitzat diverses exposicions.

Estudi i implantació de programari lliure

Actualment la majoria de nosaltres sabem de l’existència de molts programes lliures, però hem tenir clar que lliure no vol dir sempre programa gratuït. Tot i que a vegades sí que pot ser-ho, es té en compte molt més que això: és una manera de pensar i entendre el programari i al llarg dels anys ha generat tot un moviment social. Considerem que un programa lliure és aquell que garanteix als usuaris la llibertat per executar, copiar, distribuir, estudiar, canviar i millorar el codi programat, com molt bé defineixen les seves llibertats bàsiques. El programari lliure el podem trobar funcionant en ordinadors personals, escoles, empreses diverses, administracions, etc. ja que la majoria de programes que utilitzenactualment, com hem vist, tenen el seu equivalent en lliure. El fet de si és viable que una empresa es passi a programari lliure, depèn ben bé del seu entorn, ja que en funció d’aquest li serà més o menys fàcil la migració. La finalitat d’aquest projecte és, primer de tot, fer un ampli estudi del món del programari lliure i del seu moviment social. S’ha fet una recerca de diferents aspectes dins del programari lliure per conèixer-lo a fons i després s’ha proposat una possible implantació d’aquest en un usuari domèstic i en una administració pública, tenint en compte tots els aspectes vistos en l’estudi, valorant si totes les idees que defensa i els beneficis que aporta són aplicables i viables en qualsevol persona i àmbit i el perquè. Com a conclusió principal en destacaria que tot i que el programa lliure disposa d’una ideologia que agrada i té uns programes tècnicament perfectes (sense que això sigui el seu objectiu principal), penso que encara hi ha molt camí per recórrer quant a una migració en grans entorns, ja que per exemple en un ajuntament una migració total és encara difícil (tot i que no impossible perquè n’hi ha que s’hi han migrat). A l’apartat d’annexos s’hi inclou un glossari amb un seguit de terminologies amb paraules que no tothom pot saber i s’ha cregut oportú incloure-les en aquest apartat. La primera vegada que apareix alguna d’aquestes paraules la podem trobar senyalitzada amb un *.

Progressive Purkinje Cell Degeneration in tambaleante Mutant Mice Is a Consequence of a Missense Mutation in HERC1 E3 Ubiquitin Ligase

The HERC gene family encodes proteins with two characteristic domains: HECT and RCC1-like. Proteins with HECT domain shave been described to function as ubiquitin ligases, and those that contain RCC1-like domains have been reported to function as GTPases regulators. These two activities are essential in a number of important cellular processes such as cell cycle, cell signaling, and membrane trafficking. Mutations affecting these domains have been found associated with retinitis pigmentosa, amyotrophic lateral sclerosis, and cancer. In humans, six HERC genes have been reported which encode two subgroups of HERC proteins: large (HERC1-2) and small (HERC3-6). The giant HERC1 protein was the first to be identified. It has been involved in membrane trafficking and cell proliferation/growth through its interactions with clathrin, M2-pyruvate kinase, and TSC2 proteins. Mutations affecting other members of the HERC family have been found to be associated with sterility and growth retardation. Here, we report the characterization of a recessive mutation named tambaleante, which causes progressive Purkinje cell degeneration leading to severe ataxia with reduced growth and lifespan in homozygous mice aged over two months. We mapped this mutation in mouse chromosome 9 and then performed positional cloning. We found a GuA transition at position 1448, causing a Gly to Glu substitution (Gly483Glu) in the highly conserved N- terminal RCC1-like domain of the HERC1 protein. Successful transgenic rescue, with either a mouse BAC containing the normal copy of Herc1 or with the human HERC1 cDNA, validated our findings. Histological and biochemical studies revealed extensive autophagy associated with an increase of the mutant protein level and a decrease of mTOR activity. Our observations concerning this first mutation in the Herc1 gene contribute to the functional annotation of the encoded E3 ubiquitin ligase and underline the crucial and unexpected role of this protein in Purkinje cell physiology.