747 research outputs found
GCN2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection
The reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is a well-characterized mechanism of translational control in response to a wide variety of cellular stresses, including viral infection. Beside PKR, the eIF2alpha kinase GCN2 participates in the cellular response against viral infection by RNA viruses with central nervous system tropism. PKR has also been involved in the antiviral response against HIV-1, although this antiviral effect is very limited due to the distinct mechanisms evolved by the virus to counteract PKR action. Here we report that infection of human cells with HIV-1 conveys the proteolytic cleavage of GCN2 and that purified HIV-1 and HIV-2 proteases produce direct proteolysis of GCN2 in vitro, abrogating the activation of GCN2 by HIV-1 RNA. Transfection of distinct cell lines with a plasmid encoding an HIV-1 cDNA clone competent for a single round of replication resulted in the activation of GCN2 and the subsequent eIF2alpha phosphorylation. Moreover, transfection of GCN2 knockout cells or cells with low levels of phosphorylated eIF2alpha with the same HIV-1 cDNA clone resulted in a marked increase of HIV-1 protein synthesis. Also, the over-expression of GCN2 in cells led to a diminished viral protein synthesis. These findings suggest that viral RNA produced during HIV-1 infection activates GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleaves GCN2 to overcome its antiviral effect
Generation of a novel three-dimensional scaffold-based model of the bovine endometrium
Bovine in vitro endometrial models that resemble tissue function in vivo are needed to study infertility, long-term uterine alterations induced by pathogens and impact of endocrine disruptor chemicals on reproductive function and other reproductive system complications that cause high economic losses in livestock species. The present study aimed to generate an innovative, reproducible, and functional 3D scaffold-based model of the bovine endometrium structurally robust for long term-culture. We developed a multicellular model containing both endometrial epithelial and stromal cells. Epithelial cells organized to form a luminal-like epithelial layer on the surface of the scaffold. Stromal cells produced their own extracellular matrix forming a stable subepithelial compartment that physiologically resembles the normal endometrium. Both cell types released prostaglandin E2 and prostaglandin F2α following a treatment with oxytocin and arachidonic acid. Additionally signal pathways mediating oxytocin and arachidonic acid stimulation of prostaglandin synthesis were analyzed by real time PCR (RT-PCR). Oxytocin receptor (OXTR), prostaglandin E2 receptor 2 (EP2), prostaglandin E2 receptor 4 (EP4), prostaglandin F receptor (PTGFR), prostaglandin E synthase (PTGES), PGF-synthase (PGFS) and prostaglandin-endoperoxide synthase 2 (COX-2) expression was detected in both control and treatment groups, however, only significant changes in abundance of OXTR mRNA transcripts were found. The results obtained by this study are a step forward in bovine in vitro culture technology. This 3D scaffold-based model provides a platform to study regulatory mechanisms involved in endometrial physiology and can set the basis for a broader tool for designing and testing novel therapeutic strategies for recurrent uterine pathologies
Thermogalvanic effects on the corrosion of copper in heavy brine LiBr solutions
Thermogalvanic corrosion of copper in heavy brine LiBr solutions has been investigated using a zero-resistance ammeter (ZRA). The temperature gradients between copper electrodes immersed in the same LiBr solution result in the formation of thermogalvanic cells with hot anodes, leading to high and sustained thermogalvanic currents. Copper loss rates, calculated using Faraday's law, substantially exceed 0.025 mm year−1, a value regarded as the threshold of low corrosion rates. The effects of thermogalvanic coupling on the surface properties of the anode and the cathode have been analysed by means of electrochemical impedance spectroscopy (EIS). The results obtained in this analysis have been related to the process of copper electrodissolution in bromide media
The Ground State of Graphene and Graphene Disordered by Vacancies
Graphene clusters consisting of 24 to 150 carbon atoms and hydrogen
termination at the zigzag boundary edges have been studied, as well as clusters
disordered by vacancy(s). Density Function Theory and Gaussian03 software were
used to calculate graphene relative stability, desorption energy, band gap,
density of states, surface shape, dipole momentum and electrical polarization
of all clusters by applying the hybrid exchange-correlation functional
Beke-Lee-Yang-Parr. Furthermore, infrared frequencies were calculated for two
of them. Different basis sets, 6-31g**, 6-31g* and 6-31g, depending on the
sizes of clusters are considered to compromise the effect of this selection on
the calculated results. We found that relative stability and the gap decreases
according to the size increase of the graphene cluster. Mulliken charge
variation increase with the size. For about 500 carbon atoms, a zero HOMO-LUMO
gap amount is predicted. Vacancy generally reduces the stability and having
vacancy affects the stability differently according to the location of
vacancies. Surface geometry of each cluster depends on the number of vacancies
and their locations. The energy gap changes as with the location of vacancies
in each cluster. The dipole momentum is dependent on the location of vacancies
with respect to one another. The carbon-carbon length changes according to each
covalence band distance from the boundary and vacancies. Two basis sets, 6-31g*
and 6-31g**, predict equal amount for energy, gap and surface structure, but
charge distribution results are completely different.Comment: 21 pages, 14 figures, 2 table
Updating known distribution models for forecasting climate change impact on endangered species
To plan endangered species conservation and to design adequate management programmes, it is necessary to predict their
distributional response to climate change, especially under the current situation of rapid change. However, these
predictions are customarily done by relating de novo the distribution of the species with climatic conditions with no regard
of previously available knowledge about the factors affecting the species distribution. We propose to take advantage of
known species distribution models, but proceeding to update them with the variables yielded by climatic models before
projecting them to the future. To exemplify our proposal, the availability of suitable habitat across Spain for the endangered
Bonelli’s Eagle (Aquila fasciata) was modelled by updating a pre-existing model based on current climate and topography to
a combination of different general circulation models and Special Report on Emissions Scenarios. Our results suggested that
the main threat for this endangered species would not be climate change, since all forecasting models show that its
distribution will be maintained and increased in mainland Spain for all the XXI century. We remark on the importance of
linking conservation biology with distribution modelling by updating existing models, frequently available for endangered
species, considering all the known factors conditioning the species’ distribution, instead of building new models that are
based on climate change variables only.Ministerio de Ciencia e Innovación and FEDER (project CGL2009-11316/BOS
Effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to nelfinavir in children
BACKGROUND: Antiretroviral treatment (ART) in children has special features and consequently, results obtained from clinical trials with antiretroviral drugs in adults may not be representative of children. Nelfinavir (NFV) is an HIV-1 Protease Inhibitor (PI) which has become as one of the first choices of PI for ART in children. We studied during a 3-year follow-up period the effects of highly active antiretroviral therapy with nelfinavir in vertically HIV-1 infected children. METHODS: Forty-two vertically HIV-infected children on HAART with NFV were involved in a multicentre prospective study. The children were monitored at least every 3 months with physical examinations, and blood sample collection to measure viral load (VL) and CD4+ cell count. We performed a logistic regression analysis to determinate the odds ratio of baseline characteristics on therapeutic failure. RESULTS: Very important increase in CD4+ was observed and VL decreased quickly and it remained low during the follow-up study. Children with CD4+ <25% at baseline achieved CD4+ >25% at 9 months of follow-up. HIV-infected children who achieved undetectable viral load (uVL) were less than 40% in each visit during follow-up. Nevertheless, HIV-infected children with VL >5000 copies/ml were less than 50% during the follow-up study. Only baseline VL was an important factor to predict VL control during follow-up. Virological failure at defined end-point was confirmed in 30/42 patients. Along the whole of follow-up, 16/42 children stopped HAART with NFV. Baseline characteristics were not associated with therapeutic change. CONCLUSION: NFV is a safe drug with a good profile and able to achieve an adequate response in children
Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties
Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaolhuprine hybrids, purported to hit several key targets involved in Alzheimer"s disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS.+, DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Aβ42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Aβ42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaolhuprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads
Identification and Quantification of Urinary Microbial Phenolic Metabolites by HPLC-ESI-LTQ-Orbitrap-HRMS and Their Relationship with Dietary Polyphenols in Adolescents
This study aimed to develop and validate a liquid chromatography/electrospray ionization-linear ion trap quadrupole-Orbitrap-high-resolution mass spectrometry (HPLC/ESI-LTQ-Orbitrap-HRMS) method to identify and quantify urinary microbial phenolic metabolites (MPM), as well as to explore the relationship between MPM and dietary (poly)phenols in Spanish adolescents. A total of 601 spot urine samples of adolescents aged 12.02 ± 0.41 years were analyzed. The quantitative method was validated for linearity, limit of detection, limit of quantification, recovery, intra-and inter-day accuracy and precision, as well as postpreparative stability according to the criteria established by the Association of Official Agricultural Chemists International. A total of 17 aglycones and 37 phase II MPM were identified and quantified in 601 spot urine samples. Phenolic acids were the most abundant urinary MPM, whereas stilbenes, hydroxytyrosol, and enterodiol were the least abundant. Urinary hydroxycoumarin acids (urolithins) were positively correlated with flavonoid and total (poly)phenol intake. An HPLC-ESI-LTQ-Orbitrap-HRMS method was developed and fully validated to quantify MPM. The new method was performed accurately and is suitable for MPM quantification in large epidemiological studies. Urinary lignans and urolithins are proposed as potential biomarkers of grain and nut intake in an adolescent population
Efficacy and safety of a booster dose of influenza vaccination in solid organ transplant recipients, TRANSGRIPE 1-2: study protocol for a multicenter, randomized, controlled clinical trial
BACKGROUND: Despite administration of annual influenza
vaccination, influenza-associated complications in transplant
recipients continue to be an important cause of hospitalization
and death. Although influenza vaccination has been proven to be
the most effective measure to reduce influenza infection after
transplantation, transplant recipients are still vulnerable to
influenza infections, with lower serological responses to
vaccination compared to the general population. In order to
assess the efficacy and safety of an alternative immunization
scheme for solid organ transplant recipients, the TRANSGRIPE1-2
Study Group aimed to test a booster dose administration 5 weeks
after the standard vaccination. The primary objective of this
trial was to compare short-term and long-term neutralizing
antibody immunogenicity of a booster dose of influenza
vaccination to the standard single-dose immunization scheme.
Secondary objectives included the evaluation of the efficacy
and/or safety, cellular immune response, incidence of influenza
infection, graft rejection, retransplant and mortality rates.
METHODS/DESIGN: This phase III, randomized, controlled,
open-label clinical trial was conducted between October 2012 and
December 2013 in 12 Spanish public referral hospitals. Solid
organ transplant recipients (liver, kidney, heart or lung),
older than 16 years of age more than 30 days after
transplantation were eligible to participate. Patients (N = 514)
were stratified 1:1 by center, type of organ and time after
transplantation and who either received the standard single dose
(n = 257) or were treated according to a novel influenza
vaccination schedule comprising the administration of a booster
dose 5 weeks after standard vaccination (n = 254).
Seroconversion rates were measured as a determinant of
protection against influenza (main outcome). Efficacy and safety
outcomes were followed until 1 year after influenza vaccination
with assessment of short-term (0, 5, 10 and 15 weeks) and
long-term (12 months) results. Intention-to-treat, per-protocol
and safety analyses will be performed. DISCUSSION: This trial
will increase knowledge about the safety and efficacy of a
booster dose of influenza vaccine in solid organ transplant
recipients. At the time the manuscript was submitted for
publication, trial recruitment was closed with a total of 499
participants included during a 2-month period (within the
seasonal influenza vaccination campaign). TRIAL REGISTRATION:
ClinicalTrials.gov Identifier: NCT01761435 (registered 13
December 2012). EudraCT Identifier: 2011-003243-21 (registered 4
July 2011)
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