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1.
J Endocrinol Invest ; 2021 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-33586025

RESUMEN

PURPOSE: Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. METHODS: Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson's trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. RESULTS: Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. CONCLUSIONS: Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

2.
J Endocrinol Invest ; 2020 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-32772323

RESUMEN

PURPOSE: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.

6.
Animal ; 13(7): 1350-1357, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30501681

RESUMEN

Longevity is one of the most important traits determining dairy cow profitability. In the last decades dairy cows suffered a lowering in the age at culling. With the aim to identify the genes involved in longevity, dates of birth, yields, dates of calving during lifespan and culling dates were collected for 946 culled cows which had been genotyped with the Bovine High Density panel. Using the GenABEL package in R, genome-wide association analysis was performed on three potential traits of longevity: (1) 'days in production,' (2) 'days in herd,' (3) number of calvings over lifespan.' Five genome-wide significant single nucleotide polymorphisms (SNPs) associated with all three longevity traits were detected. Several consecutive SNPs identified on chromosomes 16 and 30 indicated the presence of two suggestive quantitative trait loci (QTL). The genes comprised in the QTL regions had biological functions related to fertility, reproductive disorders, heat stress and welfare of cows. These findings might contribute to improving breeding strategies to improve longevity.


Asunto(s)
Bovinos/genética , Bovinos/fisiología , Estudio de Asociación del Genoma Completo/veterinaria , Longevidad/genética , Animales , Femenino , Genotipo , Polimorfismo de Nucleótido Simple , Embarazo , Sitios de Carácter Cuantitativo
7.
Sci Rep ; 8(1): 10318, 2018 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-29985450

RESUMEN

Principal research on energy from thermonuclear fusion uses Deuterium-Tritium plasmas magnetically trapped in toroidal devices. As major scientific problem for an economic (i.e., really feasible) reactor, we must understand how to lead strongly heated plasmas to sustain a high fusion gain while large fraction of current is self-produced via the presence of strong pressure gradient. To suppress turbulent eddies that impair thermal insulation and pressure tight of the plasma, current drive (CD) is necessary. However, tools envisaged so far in ITER (International Thermonuclear Experiment Rector) are unable accomplishing this task that requires efficiently and flexibly matching the natural current profiles of plasma. Consequently, viability of a thermonuclear reactor should be problematic. Multi-megawatt radio-frequency (RF) power coupled to plasma would produce the necessary CD, but modelling results based on previous understanding found difficult the extrapolation of this CD concept to reactor conditions of high temperature plasma, and greater flexibility of method would also be required. Here we present new model results based on standard quasilinear (QL) theory that allow establish conditions to drive efficiently and flexibly the RF-driven current at large radii of the plasma column, as necessary for the goal of a reactor.

8.
Mol Psychiatry ; 22(12): 1673-1679, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-28894302

RESUMEN

The dopamine transporter (DAT) is an important regulator of brain dopamine (DA) homeostasis, controlling the intensity and duration of DA signaling. DAT is the target for psychostimulants-like cocaine and amphetamine-and plays an important role in neuropsychiatric disorders, including attention-deficit hyperactivity disorder and drug addiction. Thus, a thorough understanding of the mechanisms that regulate DAT function is necessary for the development of clinical interventions to treat DA-related brain disorders. Previous studies have revealed a plethora of protein-protein interactions influencing DAT cellular localization and activity, suggesting that the fine-tuning of DA homeostasis involves multiple mechanisms. We recently reported that G-protein beta-gamma (Gßγ) subunits bind directly to DAT and decrease DA clearance. Here we show that Gßγ induces the release of DA through DAT. Specifically, a Gßγ-binding/activating peptide, mSIRK, increases DA efflux through DAT in heterologous cells and primary dopaminergic neurons in culture. Addition of the Gßγ inhibitor gallein or DAT inhibitors prevents this effect. Residues 582 to 596 in the DAT carboxy terminus were identified as the primary binding site of Gßγ. A TAT peptide containing the Gßγ-interacting domain of DAT blocked the ability of mSIRK to induce DA efflux, consistent with a direct interaction of Gßγ with the transporter. Finally, activation of a G-protein-coupled receptor, the muscarinic M5R, results in DAT-mediated DA efflux through a Gßγ-dependent mechanism. Collectively, our data show that Gßγ interacts with DAT to promote DA efflux. This novel mechanism may have important implications in the regulation of brain DA homeostasis.


Asunto(s)
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Dopamina/metabolismo , Subunidades beta de la Proteína de Unión al GTP/metabolismo , Subunidades gamma de la Proteína de Unión al GTP/metabolismo , Animales , Unión Competitiva , Encéfalo/metabolismo , Células Cultivadas , Cricetulus , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Neuronas Dopaminérgicas/metabolismo , Femenino , Humanos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Ratas Sprague-Dawley , Receptor Muscarínico M5/metabolismo
9.
Oxid Med Cell Longev ; 2017: 9085947, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28852434

RESUMEN

Exposure to ionizing radiation during diagnostic procedures increases systemic oxidative stress and predisposes to higher risk of cancer and cardiovascular disease development. Many studies indicated that antioxidants protect against radiation-induced damage and have high efficacy and lack of toxicity in preventing radiation exposure damages. The purpose of this study was to investigate the in vitro protective effect of a new antioxidant mixture, named RiduROS, on oxidative stress generation and DNA double-strand breaks (DSBs) induced by low doses of X-rays in endothelial cells. Human umbilical vein endothelial cells (HUVEC) were treated with RiduROS mixture 24 h before a single exposure to X-rays at an absorbed dose of 0.25 Gy. The production of reactive oxygen species (ROS) was evaluated by fluorescent dye staining and nitric oxide (NO) by the Griess reaction, and DSBs were evaluated as number of γ-H2AX foci. We demonstrated that antioxidant mixture reduced oxidative stress induced by low dose of X-ray irradiation and that RiduROS pretreatment is more effective in protecting against radiation-induced oxidative stress than single antioxidants. Moreover, RiduROS mixture is able to reduce γ-H2AX foci formation after low-dose X-ray exposure. The texted mixture of antioxidants significantly reduced oxidative stress and γ-H2AX foci formation in endothelial cells exposed to low-dose irradiation. These results suggest that RiduROS could have a role as an effective radioprotectant against low-dose damaging effects.


Asunto(s)
Antioxidantes/farmacología , Citoprotección , Daño del ADN , Células Endoteliales de la Vena Umbilical Humana/patología , Células Endoteliales de la Vena Umbilical Humana/efectos de la radiación , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/efectos de la radiación , Sustancias Protectoras/farmacología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Citoprotección/efectos de los fármacos , Relación Dosis-Respuesta en la Radiación , Histonas/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rayos X
10.
J Appl Microbiol ; 123(2): 414-428, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28609559

RESUMEN

AIMS: Adeno-associated virus type 2 (AAV) is a nonpathogenic parvovirus that is a promising tool for gene therapy. We aimed to construct plasmids for optimal expression and assembly of capsid proteins and evaluate adenovirus (Ad) protein effect on AAV single-stranded DNA (ssDNA) formation in Saccharomyces cerevisiae. METHODS AND RESULTS: Yeast expression plasmids have been developed in which the transcription of AAV capsid proteins (VP1,2,3) is driven by the constitutive ADH1 promoter or galactose-inducible promoters. Optimal VP1,2,3 expression was obtained from GAL1/10 bidirectional promoter. Moreover, we demonstrated that AAP is expressed in yeast and virus-like particles (VLPs) assembled inside the cell. Finally, the expression of two Ad proteins, E4orf6 and E1b55k, had no effect on AAV ssDNA formation. CONCLUSIONS: This study confirms that yeast is able to form AAV VLPs; however, capsid assembly and ssDNA formation are less efficient in yeast than in human cells. Moreover, the expression of Ad proteins did not affect AAV ssDNA formation. SIGNIFICANCE AND IMPACT OF THE STUDY: New manufacturing strategies for AAV-based gene therapy vectors (rAAV) are needed to reduce costs and time of production. Our study explores the feasibility of yeast as alternative system for rAAV production.


Asunto(s)
Proteínas de la Cápside/genética , ADN de Cadena Simple/genética , Dependovirus/genética , Saccharomyces cerevisiae/genética , Cápside , Proteínas de la Cápside/metabolismo , ADN de Cadena Simple/metabolismo , Expresión Génica , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Humanos , Plásmidos/genética , Plásmidos/metabolismo , Saccharomyces cerevisiae/metabolismo
11.
Hernia ; 21(3): 383-389, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-27878458

RESUMEN

PURPOSE: Laparoendoscopic single site totally extraperitoneal (TEP) hernia repair showed to be a feasible alternative to conventional laparoscopic hernia repair; nevertheless single site surgery, with the loss of instruments triangulation can be a demanding procedure. To overcome those hurdles, the Single Site® (SS) platform of the da Vinci (DV) Si robotic system enables to perform surgical procedures through a 25-mm skin incision, with a stable 3D vision and restoring an adequate triangulation of the surgical instruments. We present in details the technique and the preliminary results of DV-SS TEP, to our knowledge the first cases reported in literature. METHODS: In March 2016, three consecutive male patients (mean age 46.6 years-mean BMI 25.3) with bilateral symptomatic inguinal hernia were submitted to DV-SS TEP in our institutions. Feasibility, codification of the technique, operative time and perioperative outcomes were recorded. RESULTS: All the procedures were completed as scheduled, with no conversion to other techniques. Mean operative time was 98.6 min, ranging between 155 and 55 min, reflecting the learning curve of the operating room team on this new procedure. No intraoperative or postoperative complications were experienced and all the patients were discharged within 24 h after surgery. Patients reported satisfactory postoperative course, with no recurrence of inguinal hernia and satisfaction in cosmetic result at 6-month follow-up. CONCLUSIONS: DV-SS TEP inguinal hernia repair showed to be feasible and effective surgical option for bilateral groin hernia repair. Patients' outcome was uneventful, with optimal cosmetic results. Further studies comparing this innovative technique to TEP or LESS TEP should be promoted.


Asunto(s)
Hernia Inguinal/cirugía , Herniorrafia/métodos , Procedimientos Quirúrgicos Robotizados , Adulto , Humanos , Masculino , Persona de Mediana Edad
12.
Acta Otorhinolaryngol Ital ; 36(4): 259-264, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27734977

RESUMEN

The purpose of the present study was to evaluate the advantages of a video-assisted, minimally invasive transcervical approach to benign and malignant parapharyngeal space (PPS) tumours. Ten patients affected by benign and malignant PPS neoplasms underwent a combined transcervical and video-assisted minimally invasive approach, using Hopkins telescopes. We describe the operative technique and perform a review of the literature. Definitive histology revealed 3 pleomorphic adenomas, 2 schwannomas, 2 metastatic papillary thyroid carcinomas, one carcinoma ex pleomorphic adenoma, one cavernous haemangioma and one basal cell adenoma. Mean tumour size was 37.2 mm (range: 19-60). Operation time ranged from 75 min to 185 min (mean: 146.7). One case was converted to transcervical-transparotid approach. Patients were discharged on postoperative day 2-5. One patients presented hypoglossal nerve paresis. The minimally invasive video-assisted transcervical approach is safe and feasible for selected benign and malignant PPS tumours. Furthermore, it offers harmless dissection in a deep and narrow space, accurate haemostasis and continuous control of critical anatomic structures.


Asunto(s)
Neoplasias Faríngeas/cirugía , Cirugía Asistida por Video , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cuello , Cirugía Asistida por Video/métodos
13.
Reprod Domest Anim ; 51(5): 840-3, 2016 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-27550832

RESUMEN

Because the priority of AI industry is to identify subfertile bulls, a predictive model that allowed for the prediction of 91% bulls of low fertility was implemented based on seminological (motility) parameters and DNA status assessed both as DNA fragmentation index (DFI) and by TUNEL assay using sperm of 105 Holstein-Friesian bulls (four batches per bull) selected based on in vivo estimated relative conception rates (ERCR). Thereafter, sperm quality and male fertility traits of bulls were explored by GWAS using a high-density (777K) Illumina chip. After data editing, 85 bulls and 591,988 SNPs were retained for GWAS. Of 12 SNPs with false discovery rate <0.2, four SNPs located on BTA28 and BTA18 were significantly associated (LD-adjusted Bonferroni <0.05) with the non-compensatory sperm parameters DFI and TUNEL. Other SNPs of interest for potential association with TUNEL were found on BTA3, in the same chromosome where associations with non-compensatory in vivo bull fertility were already reported. Further suggestive SNPs for sperm membrane integrity were located on BTA28, the chromosome where QTL studies previously reported associations with sperm quality traits. Suggestive SNPs for ERCR were found on BTA18 in the vicinity of a site already associated with in vivo bull fertility. Additional SNPs associated with ERCR and sperm kinetic parameters were also identified. In contrast to other, but very few GWAS on fertility traits in bovine spermatozoa, which reported significant SNPs located on BTX, we have not identified SNPs of interest in this sexual chromosome.


Asunto(s)
Bovinos/genética , Bovinos/fisiología , Fertilidad , Estudio de Asociación del Genoma Completo , Genoma , Análisis de Semen/veterinaria , Animales , Masculino , Motilidad Espermática , Espermatozoides/fisiología
14.
Acta Otorhinolaryngol Ital ; 36(3): 167-73, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-27214828

RESUMEN

Several therapeutic options are used for treatment of early stage glottic carcinoma (Tis/T1/T2): open partial laryngectomy (OPL), radiotherapy and CO2 laser-assisted endoscopic surgery. Laser surgery has gradually gained approval in the management of laryngeal cancer. We present our experience in endoscopic laser surgery for early stage glottic carcinomas. This was a retrospective analysis of 72 patients with T1-T2 glottic cancer treated with laser cordectomy between 2006 and 2012. All patients had at least a 36-month follow-up period. Percentages for disease-specific survival, disease-free survival (DFS) and laryngeal preservation rates were 98.6%, 84.7% and 97.2% respectively. Considering neoplastic features that could predict long-term oncological outcome, tumoural involvement of anterior commissure and pathological staging (pT) significantly correlate with local recurrence (p = 0.021 and p = 0.035) and with a lowered DFS (p = 0.017 and p = 0.023). Other variables such as clinical staging, type of cordectomy, involvement of other structures and surgical margin status showed no significant impact on oncological endpoints. CO2 laser surgery is a reliable technique for T1-T2 glottic cancer considering oncological outcomes. The recurrence rate seems to be affected by involvement of anterior commissure and pT stage.


Asunto(s)
Endoscopía/métodos , Glotis , Neoplasias Laríngeas/cirugía , Terapia por Láser/efectos adversos , Láseres de Gas/efectos adversos , Complicaciones Posoperatorias/etiología , Anciano , Femenino , Humanos , Neoplasias Laríngeas/patología , Masculino , Estadificación de Neoplasias , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento
15.
Transl Psychiatry ; 6: e809, 2016 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-27187231

RESUMEN

Agonism of the glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) has been effective at treating aspects of addictive behavior for a number of abused substances, including cocaine. However, the molecular mechanisms and brain circuits underlying the therapeutic effects of GLP-1R signaling on cocaine actions remain elusive. Recent evidence has revealed that endogenous signaling at the GLP-1R within the forebrain lateral septum (LS) acts to reduce cocaine-induced locomotion and cocaine conditioned place preference, both considered dopamine (DA)-associated behaviors. DA terminals project from the ventral tegmental area to the LS and express the DA transporter (DAT). Cocaine acts by altering DA bioavailability by targeting the DAT. Therefore, GLP-1R signaling might exert effects on DAT to account for its regulation of cocaine-induced behaviors. We show that the GLP-1R is highly expressed within the LS. GLP-1, in LS slices, significantly enhances DAT surface expression and DAT function. Exenatide (Ex-4), a long-lasting synthetic analog of GLP-1 abolished cocaine-induced elevation of DA. Interestingly, acute administration of Ex-4 reduces septal expression of the retrograde messenger 2-arachidonylglycerol (2-AG), as well as a product of its presynaptic degradation, arachidonic acid (AA). Notably, AA reduces septal DAT function pointing to AA as a novel regulator of central DA homeostasis. We further show that AA oxidation product γ-ketoaldehyde (γ-KA) forms adducts with the DAT and reduces DAT plasma membrane expression and function. These results support a mechanism in which postsynaptic septal GLP-1R activation regulates 2-AG levels to alter presynaptic DA homeostasis and cocaine actions through AA.


Asunto(s)
Ácido Araquidónico/metabolismo , Dopamina/metabolismo , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Núcleos Septales/metabolismo , Animales , Ácidos Araquidónicos/metabolismo , Cocaína/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Endocannabinoides/metabolismo , Exenatida , Receptor del Péptido 1 Similar al Glucagón/agonistas , Glicéridos/metabolismo , Homeostasis , Incretinas/farmacología , Ratones , Microdiálisis , Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Núcleos Septales/efectos de los fármacos , Ponzoñas/farmacología
16.
J Antimicrob Chemother ; 71(6): 1627-31, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26888911

RESUMEN

BACKGROUND: After the advent of ART, non-AIDS-related comorbidities are the main causes of death in HIV patients. Multiple biomarkers have been studied as markers of disease. We wanted to test soluble endothelial protein C receptor (sEPCR) in an HIV setting. OBJECTIVES: The primary objective was to determine whether sEPCR decreases after 48 weeks of ART in naive HIV patients. Secondary objectives were to compare sEPCR levels between patients with chronic HIV infection (CHI) and primary HIV infection (PHI) and to analyse if there is a correlation between sEPCR and both immunovirological parameters and different markers of inflammation. PATIENTS AND METHODS: We analysed sEPCR in 33 patients with CHI and 19 patients with PHI naive to ART. sEPCR was compared together with immunovirological parameters (HIV RNA and CD4 cell count) and IL-6 or D-dimer (DD). RESULTS AND CONCLUSIONS: After 48 weeks of ART, in CHI, the sEPCR decrease was significant (P = 0.0006) and sEPCR at baseline was correlated with both CD4 cell increase (r = +0.463, P = 0.007) and HIV RNA decrease (r = -0.363, P = 0.038). In PHI, sEPCR was stable (P = 0.35); there was a correlation between 48 week DD change and IL-6 change (r = +0.696, P = 0.0009) and also between 48 week DD change and sEPCR change (r = +0.553, P = 0.014). Despite the small sample size, we hypothesize that sEPCR levels reflect coagulant pathway activation caused by the endothelial damage during chronic infection more than a marker of the cytokine storm that occurs during PHI. Alternatively, in PHI, the link found between sEPCR and DD secondary to IL-6 suggests sEPCR is an indirect marker of inflammation.


Asunto(s)
Antirretrovirales/uso terapéutico , Antígenos CD/sangre , Terapia Antirretroviral Altamente Activa , Biomarcadores/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Inflamación/patología , Receptores de Superficie Celular/sangre , Adulto , Recuento de Linfocito CD4 , Receptor de Proteína C Endotelial , Femenino , Humanos , Masculino , Estudios Prospectivos , Carga Viral
17.
Clin Microbiol Infect ; 22(4): 386.e1-386.e3, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26706617

RESUMEN

Naturally occurring resistance-associated variants (RAVs) within the protease domain of hepatitis C virus (HCV) genotype (G) 1a separated into clades 1 and 2, and G1b were investigated in 59 HIV/HCV coinfected patients. RAVs were detected in 10/23 G1a/clade 1 and 1/19 G1b (p 0.0059). A similar frequency of RAVs was found when comparing G1a/clade 2 and G1b (p 0.1672). A cross-resistance to the macrocyclic compounds simeprevir and paritaprevir was detected in two G1a/clade 2 and 1 G1b sequences and none of G1a/clade 1 sequences. The simultaneous characterization of subtype and natural RAVs by population analysis of the NS3 domain by may add important information for anti-HCV treatment strategies including protease inhibitors.


Asunto(s)
Antivirales/farmacología , Farmacorresistencia Viral , Genotipo , Infecciones por VIH/complicaciones , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/virología , Inhibidores de Proteasas/farmacología , Adulto , Femenino , Hepacivirus/enzimología , Hepacivirus/genética , Humanos , Compuestos Macrocíclicos/farmacología , Masculino , Mutación Missense , ARN Viral/genética , Análisis de Secuencia de ADN , Simeprevir/farmacología , Proteínas no Estructurales Virales/genética
18.
Rev Sci Instrum ; 86(8): 083310, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26329184

RESUMEN

High-energy e(-) and π(-) were measured by the multichannel plate (MCP) detector at the PiM1 beam line of the High Intensity Proton Accelerator Facilities located at the Paul Scherrer Institute, Villigen, Switzerland. The measurements provide the absolute detection efficiencies for these particles: 5.8% ± 0.5% for electrons in the beam momenta range 17.5-300 MeV/c and 6.0% ± 1.3% for pions in the beam momenta range 172-345 MeV/c. The pulse height distribution determined from the measurements is close to an exponential function with negative exponent, indicating that the particles penetrated the MCP material before producing the signal somewhere inside the channel. Low charge extraction and nominal gains of the MCP detector observed in this study are consistent with the proposed mechanism of the signal formation by penetrating radiation. A very similar MCP ion detector will be used in the Neutral Ion Mass (NIM) spectrometer designed for the JUICE mission of European Space Agency (ESA) to the Jupiter system, to perform measurements of the chemical composition of the Galilean moon exospheres. The detection efficiency for penetrating radiation determined in the present studies is important for the optimisation of the radiation shielding of the NIM detector against the high-rate and high-energy electrons trapped in Jupiter's magnetic field. Furthermore, the current studies indicate that MCP detectors can be useful to measure high-energy particle beams at high temporal resolution.

19.
Theriogenology ; 83(2): 199-205, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25442389

RESUMEN

The objectives of the present work were to compare the primary sex ratio in sperm with the secondary sex ratio recorded in the offspring produced by artificial insemination (AI) with the same sperm and assess whether the primary sex ratio is influenced by sperm survival and motility after thawing. Calving data of 98 Holstein Friesian bulls used in AI were collected during 4 years, and commercial semen of the same bulls was analyzed immediately after thawing and after swim-up using a real-time polymerase chain reaction method developed and validated in our laboratory. Calving data relative to single bulls did not reveal any significant deviation between genders from the theoretical 1:1 for none of the bulls, being the mean values of male and female calves born 52.1 ± 2.80% and 47.9 ± 2.71%, respectively. Thereafter, calving events of bulls were classified and analyzed according to four classes of years: 2009 (n = 13,261), 2010 (n = 21,551), 2011 (n = 24,218), and 2012 (n = 41,726), and seasons categorized as winter, spring, summer, and fall. When data aggregated per years were analyzed, the difference between the two sexes was significant (P < 0.005) in favor of the male gender, whereas no influence of the season was evidenced. Real-time polymerase chain reaction did not evidence any difference between the mean values of frequency of Y chromosome-bearing sperm detected in three sperm batches of the same bulls analyzed immediately after thawing (51.1 ± 2.1), nor a difference with respect to the theoretical 1:1 ratio was reported after sperm analysis of one batch of sperm of the bulls analyzed after swim-up and immediately after thawing (50.1 ± 2.1 and 49.8 ± 1.8, respectively). The results are consistent with the observation of the farmers who often report a skewed sex ratio of the calves being born with AI in favor of the male gender. However, we have not evidenced differences in the primary sex ratio with respect to the theoretical 1:1 ratio both at thawing and after swim-up, thus demonstrating that the freezing procedure itself does not impact selectively on the survival of the X or Y chromosome-bearing sperm. Therefore, we hypothesize that the difference between genders observed after AI is more likely due to the events occurring after fertilization, which can comprise an impaired function of the X- or Y-bearing sperm with consequences on embryo development or a maternal influence.


Asunto(s)
Bovinos , Razón de Masculinidad , Espermatozoides , Animales , Bencenosulfonatos/análisis , Supervivencia Celular , Criopreservación/veterinaria , Femenino , Inseminación Artificial/veterinaria , Masculino , Embarazo , Reacción en Cadena en Tiempo Real de la Polimerasa , Estaciones del Año , Preservación de Semen/métodos , Preservación de Semen/veterinaria , Análisis para Determinación del Sexo , Motilidad Espermática , Espermatozoides/química , Espermatozoides/fisiología
20.
Chem Commun (Camb) ; 51(3): 584-7, 2015 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-25415509

RESUMEN

An integrated approach which combines in-cell NMR spectroscopy with optical and X-ray fluorescence microscopy was developed to describe the intracellular maturation state of human Cu,Zn-SOD1. Microscopy data show a correlation between the intracellular levels of SOD1 and the content of zinc, corresponding to zinc binding to SOD1 observed by in-cell NMR.


Asunto(s)
Fluorescencia , Espectroscopía de Resonancia Magnética , Superóxido Dismutasa/química , Cobre/química , Humanos , Espacio Intracelular , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa/ultraestructura , Superóxido Dismutasa-1 , Rayos X , Zinc/química
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