Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma.

BACKGROUND & AIMS Subtle inter-patient genetic variation and environmental factors combine to determine disease progression in non-alcoholic fatty liver disease (NAFLD). Carriage of the PNPLA3 rs738409 c.444C >G minor allele (encoding the I148M variant) has been robustly associated with advanced NAFLD. Although most hepatocellular carcinoma (HCC) is related to chronic viral hepatitis or alcoholic liver disease, the incidence of NAFLD-related HCC is increasing. We examined whether rs738409 C >G was associated with HCC-risk in patients with NAFLD. METHODS PNPLA3 rs738409 genotype was determined by allelic discrimination in 100 European Caucasians with NAFLD-related HCC and 275 controls with histologically characterised NAFLD. RESULTS Genotype frequencies were significantly different between NAFLD-HCC cases (CC=28, CG=43, GG=29) and NAFLD-controls (CC=125, CG=117, GG=33) (p=0.0001). In multivariate analysis adjusted for age, gender, diabetes, BMI, and presence of cirrhosis, carriage of each copy of the rs738409 minor (G) allele conferred an additive risk for HCC (adjusted OR 2.26 [95% CI 1.23-4.14], p=0.0082), with GG homozygotes exhibiting a 5-fold [1.47-17.29], p=0.01 increased risk over CC. When compared to the UK general population (1958 British Birth Cohort, n=1476), the risk-effect was more pronounced (GC vs. CC: unadjusted OR 2.52 [1.55-4.10], p=0.0002; GG vs. CC: OR 12.19 [6.89-21.58], p<0.0001). CONCLUSIONS Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis but also of HCC. If validated, these findings suggest that PNPLA3 genotyping has the potential to contribute to multi-factorial patient-risk stratification, identifying those to whom HCC surveillance may be targeted.

The identification and characterization of the Staphylococcus aureus microbial immunomodulatory molecules (MIMS) Map and Efb

Staphylococcus aureus is an opportunistic pathogen that is a major health threat in the clinical and community settings. An interesting hallmark of patients infected with S. aureus is that they do not usually develop a protective immune response and are susceptible to reinfection, in part because of the ability of S. aureus to modulate host immunity. The ability to evade host immune responses is a key contributor to the infection process and is critical in S. aureus survival and pathogenesis. This study investigates the immunomodulatory effects of two secreted proteins produced by S. aureus, the MHC class II analog protein (Map) and the extracellular fibrinogen-binding protein (Efb). Map has been demonstrated to modulate host immunity by interfering with T cell function. Map has been shown to significantly reduce T cell proliferative responses and significantly reduce delayed-type hypersensitivity responses to challenge antigen. In addition, the effects of Map on the infection process were tested in a mouse model of infection. Mice infected with Map− S. aureus (Map deficient strain) presented with significantly reduced levels of arthritis, osteomyelitis and abscess formation compared to mice infected with the wild-type Map+S. aureus strain suggesting that Map−S. aureus is much less virulent than Map+S. aureus. Furthermore, Map−S. aureus-infected nude mice developed arthritis and osteomyelitis to a severity similar to Map +S. aureus-infected controls, suggesting that T cells can affect disease outcome following S. aureus infection and Map may attenuate cellular immunity against S. aureus. The extracellular fibrinogen-binding protein (Efb) was identified when cultured S. aureus supernatants were probed with the complement component C3. The binding of C3 to Efb resulted in studies investigating the effects of Efb on complement activation. We have demonstrated that Efb can inhibit both the classical and alternative complement pathways. Moreover, we have shown that Efb can inhibit complement mediated opsonophagocytosis. Further studies have characterized the Efb-C3 binding interaction and localized the C3-binding domain to the C-terminal region of Efb. In addition, we demonstrate that Efb binds specifically to a region within the C3d fragment of C3. This study demonstrates that Map and Efb can interfere with both the acquired and innate host immune pathways and that these proteins contribute to the success of S. aureus in evading host immunity and in establishing disease. ^

Temperaturas óptimas para resembrar especies mesotérmicas sobre céspedes de Cynodon dactylon en el centro-sur de la provincia de Córdoba, Argentina

Los objetivos fueron determinar temperaturas medias de suelo (TMS) y mínimas de aire (TMA) adecuadas para realizar resiembras otoñales; evaluar la tasa de crecimiento (TCC) de Cynodon dactylon (Bermuda) que minimice la competencia con la especie resembrada y el comportamiento de distintas especies mesotérmicas en el centro-sur de la provincia de Córdoba. Se resembró durante 2010 y 2011, en un diseño de parcelas divididas con cinco fechas de siembra (FS) quincenalmente desde principios de marzo, con tres genotipos: Lolium multiflorum cv Axcella, L. perenne y L. perenne cv Excel I. Las temperaturas se midieron entre principios de marzo y hasta que la bermuda entró en dormición, calculando TMA y TMS. En las subparcelas resembradas se registraron calidad visual y cobertura total; además, en la bermuda se calculó la TCC. Las resiembras que lograron valores más altos de calidad visual, cobertura y bajas TCC de la Bermuda, se dieron con TMS entre 18 - 21°C y TMA entre 11,5 - 15,5°C. De acuerdo con los valores medios normales de la región centro-sur de Córdoba, las temperaturas óptimas se observan entre la segunda década de marzo y primera de abril. Los tres genotipos tuvieron comportamientos similares independientemente de la FS utilizada.

Discriminación del estado de la carretera mediante procesado acústico en vehículo

La rápida adopción de dispositivos electrónicos en el automóvil, ha contribuido a mejorar en gran medida la seguridad y el confort. Desde principios del siglo 20, la investigación en sistemas de seguridad activa ha originado el desarrollo de tecnologías como ABS (Antilock Brake System), TCS (Traction Control System) y ESP (Electronic Stability Program). El coste de despliegue de estos sistemas es crítico: históricamente, sólo han sido ampliamente adoptados cuando el precio de los sensores y la electrónica necesarios para su construcción ha caído hasta un valor marginal. Hoy en día, los vehículos a motor incluyen un amplio rango de sensores para implementar las funciones de seguridad. La incorporación de sistemas que detecten la presencia de agua, hielo o nieve en la vía es un factor adicional que podría ayudar a evitar situaciones de riesgo. Existen algunas implementaciones prácticas capaces de detectar carreteras mojadas, heladas y nevadas, aunque con limitaciones importantes. En esta tesis doctoral, se propone una aproximación novedosa al problema, basada en el análisis del ruido de rodadura generado durante la conducción. El ruido de rodadura es capturado y preprocesado. Después es analizado utilizando un clasificador basado en máquinas de vectores soporte (SVM), con el fin de generar una estimación del estado del firme. Todas estas operaciones se realizan en el propio vehículo. El sistema propuesto se ha desarrollado y evaluado utilizando Matlabr, mostrando tasas de aciertos de más del 90%. Se ha realizado una implementación en tiempo real, utilizando un prototipo basado en DSP. Después se han introducido varias optimizaciones para permitir que el sistema sea realizable usando un microcontrolador de propósito general. Finalmente se ha realizado una implementación hardware basada en un microcontrolador, integrándola estrechamente con las ECU del vehículo, pudiendo obtener datos capturados por los sensores del mismo y enviar las estimaciones del estado del firme. El sistema resultante ha sido patentado, y destaca por su elevada tasa de aciertos con un tamaño, consumo y coste reducidos. ABSTRACT Proliferation of automotive electronics, has greatly improved driving safety and comfort. Since the beginning of the 20th century, investigation in active safety systems has resulted in the development of technologies such as ABS (Antilock Brake System), TCS (Traction Control System) and ESP (Electronic Stability Program). Deployment cost of these systems is critical: historically, they have been widely adopted only when the price of the sensors and electronics needed to build them has been cut to a marginal value. Nowadays, motor vehicles include a wide range of sensors to implement the safety functions. Incorporation of systems capable of detecting water, ice or snow on the road is an additional factor that could help avoiding risky situations. There are some implementations capable of detecting wet, icy and snowy roads, although with important limitations. In this PhD Thesis, a novel approach is proposed, based on the analysis of the tyre/road noise radiated during driving. Tyre/road noise is captured and pre-processed. Then it is analysed using a Support Vector Machine (SVM) based classifier, to output an estimation of the road status. All these operations are performed on-board. Proposed system is developed and evaluated using Matlabr, showing success rates greater than 90%. A real time implementation is carried out using a DSP based prototype. Several optimizations are introduced enabling the system to work using a low-cost general purpose microcontroller. Finally a microcontroller based hardware implementation is developed. This implementation is tightly integrated with the vehicle ECUs, allowing it to obtain data captured by its sensors, and to send the road status estimations. Resulting system has been patented, and is notable because of its high hit rate, small size, low power consumption and low cost.

Opera Dionysii [Texto impreso]

Contiene : Veteris translationis ; Noue translationis ; Nouissime translatôis Marsilii

Léon Jaussely: de la tradicion Beaux-Arts al urbanismo moderno

El trabajo del arquitecto francés Léon Jaussely (1875-1932) apenas es conocido en España excepto por su propuesta para el Plan de Enlaces de Barcelona. Por otra parte, incluso en Francia, su labor de urbanista continua siendo relativamente desconocida, respecto a la de otros contemporáneos, como Tony Garnier o Alfred Agache, de la que se ha denominado Escuela Francesa de Urbanismo. Este olvido puede estar vinculado a la dispersión de su obra y a que algunos de los documentos más significativos de sus planes (memorias y planos de ordenación) no hayan llegado hasta nosotros. Sin embargo, la documentación conservada y su obra escrita (artículos y los cursos de Art urbain que impartió en l?École des Hautes Études Urbaines y l?École des Beaux-Arts), permiten reconstruir el pensamiento de Jaussely y también la evolución de su modo de intervenir en la ciudad, ambos estrechamente vinculados a las transformaciones disciplinares de las primeras décadas del siglo XX.

Keeping Mars warm with new super greenhouse gases

Our selection of new super greenhouse gases to fill a putative “window” in a future Martian atmosphere relies on quantum-mechanical calculations. Our study indicates that if Mars could somehow acquire an Earth-like atmospheric composition and surface pressure, then an Earth-like temperature could be sustained by a mixture of five to seven fluorine compounds. Martian mining requirements for replenishing the fluorine could be comparable to current terrestrial extraction.

Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma.

Recombinant adenoviral mediated delivery of suicide and cytokine genes has been investigated as a treatment for hepatic metastases of colon carcinoma in mice. Liver tumors were established by intrahepatic implantation of a poorly immunogenic colon carcinoma cell line (MCA-26), which is syngeneic in BALB/c mice. Intratumoral transfer of the herpes simplex virus type 1 thymidine kinase (HSV-tk) and the murine interleukin (mIL)-2 genes resulted in substantial hepatic tumor regression, induced an effective systemic antitumoral immunity in the host and prolonged the median survival time of the treated animals from 22 to 35 days. The antitumoral immunity declined gradually, which led to tumor recurrence over time. A recombinant adenovirus expressing the mIL-12 gene was constructed and tested in the MCA-26 tumor model. Intratumoral administration of this cytokine vector alone increased significantly survival time of the animals with 25% of the treated animals still living over 70 days. These data indicate that local expression of IL-12 may also be an attractive treatment strategy for metastatic colon carcinoma.

CP-154,526: a potent and selective nonpeptide antagonist of corticotropin releasing factor receptors.

Here we describe the properties of CP-154,526, a potent and selective nonpeptide antagonist of corticotropin (ACTH) releasing factor (CRF) receptors. CP-154,526 binds with high affinity to CRF receptors (Ki < 10 nM) and blocks CRF-stimulated adenylate cyclase activity in membranes prepared from rat cortex and pituitary. Systemically administered CP-154,526 antagonizes the stimulatory effects of exogenous CRF on plasma ACTH, locus coeruleus neuronal firing and startle response amplitude. Potential anxiolytic activity of CP-154,526 was revealed in a fearpotentiated startle paradigm. These data are presented in the context of clinical findings, which suggest that CRF is hypersecreted in certain pathological states. We propose that a CRF antagonist such as CP-154,526 could affirm the role of CRF in certain psychiatric diseases and may be of significant value in the treatment of these disorders.

Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions.

The ability of neurotrophins to modulate the survival and differentiation of neuronal populations involves the Trk/MAP (mitogen-activated protein kinase) kinase signaling pathway. More recently, neurotrophins have also been shown to regulate synaptic transmission. The synapsins are a family of neuron-specific phosphoproteins that play a role in regulation of neurotransmitter release, in axonal elongation, and in formation and maintenance of synaptic contacts. We report here that synapsin I is a downstream effector for the neurotrophin/Trk/MAP kinase cascade. Using purified components, we show that MAP kinase stoichiometrically phosphorylated synapsin I at three sites (Ser-62, Ser-67, and Ser-549). Phosphorylation of these sites was detected in rat brain homogenates, in cultured cerebrocortical neurons, and in isolated presynaptic terminals. Brain-derived neurotrophic factor and nerve growth factor upregulated phosphorylation of synapsin I at MAP kinase-dependent sites in intact cerebrocortical neurons and PC12 cells, respectively, while KCl- induced depolarization of cultured neurons decreased the phosphorylation state at these sites. MAP kinase-dependent phosphorylation of synapsin I significantly reduced its ability to promote G-actin polymerization and to bundle actin filaments. The results suggest that MAP kinase-dependent phosphorylation of synapsin I may contribute to the modulation of synaptic plasticity by neurotrophins and by other signaling pathways that converge at the level of MAP kinase activation.

Re-expression of the alpha 2 beta 1 integrin abrogates the malignant phenotype of breast carcinoma cells.

To assess the role of altered alpha 2 beta 1 integrin expression in breast cancer, we expressed the alpha 2 beta 1 integrin de novo in a poorly differentiated mammary carcinoma that expressed no detectable alpha 2-integrin subunit. Expression of the alpha 2 beta 1 integrin resulted in a dramatic phenotypic alteration from a fibroblastoid, spindle-shaped, non-contact-inhibited, motile, and invasive cell to an epithelioid, polygonal-shaped, contact-inhibited, less motile, and less invasive cell. Although expression of the alpha 2 subunit did not alter adhesion to collagen, it profoundly altered cell spreading. Re-expression of the alpha 2 beta 1 integrin restored the ability to differentiate into gland-like structures in three-dimensional matrices and markedly reduced the in vivo tumorigenicity of the cells. These results indicate that the consequences of diminished alpha 2 beta 1-integrin expression in the development of breast cancer and, presumably, of other epithelial malignancies are increased tumorigenicity and loss of the differentiated epithelial phenotype.

The GA5 locus of Arabidopsis thaliana encodes a multifunctional gibberellin 20-oxidase: molecular cloning and functional expression.

The biosynthesis of gibberellins (GAs) after GA12-aldehyde involves a series of oxidative steps that lead to the formation of bioactive GAs. Previously, a cDNA clone encoding a GA 20-oxidase [gibberellin, 2-oxoglutarate:oxygen oxidoreductase (20-hydroxylating, oxidizing), EC 1.14.11.-] was isolated by immunoscreening a cDNA library from liquid endosperm of pumpkin (Cucurbita maxima L.) with antibodies against partially purified GA 20-oxidase. Here, we report isolation of a genomic clone for GA 20-oxidase from a genomic library of the long-day species Arabidopsis thaliana Heynh., strain Columbia, by using the pumpkin cDNA clone as a heterologous probe. This genomic clone contains a GA 20-oxidase gene that consists of three exons and two introns. The three exons are 1131-bp long and encode 377 amino acid residues. A cDNA clone corresponding to the putative GA 20-oxidase genomic sequence was constructed with the reverse transcription-PCR method, and the identity of the cDNA clone was confirmed by analyzing the capability of the fusion protein expressed in Escherichia coli to convert GA53 to GA44 and GA19 to GA20. The Arabidopsis GA 20-oxidase shares 55% identity and > 80% similarity with the pumpkin GA 20-oxidase at the derived amino acid level. Both GA 20-oxidases share high homology with other 2-oxoglutarate-dependent dioxygenases (2-ODDs), but the highest homology was found between the two GA 20-oxidases. Mapping results indicated tight linkage between the cloned GA 20-oxidase and the GA5 locus of Arabidopsis. The ga5 semidwarf mutant contains a G-->A point mutation that inserts a translational stop codon in the protein-coding sequence, thus confirming that the GA5 locus encodes GA 20-oxidase. Expression of the GA5 gene in Ara-bidopsis leaves was enhanced after plants were transferred from short to long days; it was reduced by GA4 treatment, suggesting end-product repression in the GA biosynthetic pathway.

Pamphlets about Australia.

Vol. 1 consists of reprints of various journal articles from 1900-1907; vol. 2 of pamphlets mostly aimed at potential emigrants.

Dem Rambam's tsaṿoʼoh : ... di lebens-geshikhṭe fun ... Rabenu Moysheh ben Maimen ... oykh di ... tsaṿoʼoh ṿos er hoṭ gishribin fir zayne ḳinder.

Mode of access: Internet.