Emission of neutron–proton and proton–proton pairs in neutrino scattering

We use a recently developed model of relativistic meson-exchange currents to compute the neutron–proton and proton–proton yields in (νμ,μ−) scattering from 12C in the 2p–2h channel. We compute the response functions and cross sections with the relativistic Fermi gas model for different kinematics from intermediate to high momentum transfers. We find a large contribution of neutron–proton configurations in the initial state, as compared to proton–proton pairs. In the case of charge-changing neutrino scattering the 2p–2h cross section of proton–proton emission (i.e., np in the initial state) is much larger than for neutron–proton emission (i.e., two neutrons in the initial state) by a (ω,q)-dependent factor. The different emission probabilities of distinct species of nucleon pairs are produced in our model only by meson-exchange currents, mainly by the Δ isobar current. We also analyze other effects including exchange contributions and the effect of the axial and vector currents.Dirección General de Investigación Científica y Técnica FIS2014-59386-P y FIS2014-53448-C2-1Agencia de Innovación y Desarrollo de Andalucía FQM225 y FQM160Ministerio de Economía y Competitividad IJCI-2014-20038Instituto Nazionale di Fisica Nucleare IS-MANYBODYU.S. Department of Energy DE-FC02-94ER4081

Gene therapy for liver diseases: recent strategies for treatment of viral hepatitis and liver malignancies

Gene therapy has emerged as a powerful and very plastic tool to regulate biological functions in diseased tissues with application in virtually all medical fields. An increasing number of experimental and clinical studies underline the importance of genes as curative agents in the future. However, intense research is needed to evaluate the potential of gene therapy to improve efficacy and minimise the toxicity of the procedure

Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas

Stimulation of the antitumor immune response by dendritic cells (DC) is critically dependent on their tightly regulated ability to produce interleukin-12 (IL-12). To enhance this effect artificially, bone marrow (BM)-derived DC were genetically engineered to produce high levels of functional IL-12 by ex vivo infection with a recombinant defective adenovirus (AdCMVIL-12). DC-expressing IL-12 injected into the malignant tissue eradicated 50-100% well established malignant nodules derived from the injection of two murine colon adenocarcinoma cell lines. Successful therapy was dependent on IL-12 transfection and was mediated only by syngeneic, but not allogeneic BM-derived DC, indicating that compatible antigen-presenting molecules were required. The antitumor effect was inhibited by in vivo depletion of CD8+ T cells and completely abrogated by simultaneous depletion with anti-CD4 and anti-CD8 mAbs. Mice which had undergone tumor regression remained immune to a rechallenge with tumor cells, showing the achievement of long-lasting systemic immunity that also was able to reject simultaneously induced concomitant untreated tumors. Tumor regression was associated with a detectable CTL response directed against tumor-specific antigens probably captured by DC artificially released inside tumor nodules. Our results open the possibility of similarly treating the corresponding human malignancies

Genetic heterogeneity in the toxicity to systemic adenoviral gene transfer of interleukin-12

Despite the efficacy of IL-12 in cancer experimental models, clinical trials with systemic recombinant IL-12 showed unacceptable toxicity related to endogenous IFNgamma production. We report that systemic administration of a recombinant adenovirus encoding IL-12 (AdCMVmIL-12) has a dramatically different survival outcome in a number of mouse pure strains over a wide range of doses. For instance at 2.5 x 10(9) p.f.u., systemic AdCMVmIL-12 killed all C57BL/6 mice but spared all BALB/c mice. Much higher IFNgamma concentrations in serum samples of C57BL/6 than in those from identically treated BALB/c were found. Causes for heterogeneous toxicity can be traced to differences among murine strains in the levels of gene transduction achieved in the liver, as assessed with adenovirus coding for reporter genes. In accordance, IL-12 serum concentrations are higher in susceptible mice. In addition, sera from C57BL/6 mice treated with AdCMVmIL-12 showed higher levels of IL-18, a well-known IFNgamma inducer. Interestingly, lethal toxicity in C57BL/6 mice was abolished by administration of blocking anti-IFNgamma mAbs and also by simultaneous depletion of T cells, NK cells, and macrophages. These observations together with the great dispersion of IFNgamma produced by human PBMCs upon in vitro stimulation with IL-12, or infection with recombinant adenovirus encoding IL-12, suggest that patients might also show heterogeneous degrees of toxicity in response to IL-12 gene transfer

Topical application of a peptide inhibitor of transforming growth factor-beta1 ameliorates bleomycin-induced skin fibrosis

Transforming growth factor-beta (TGF-beta) plays a crucial role in the pathogenesis of skin fibrotic diseases. Systemic TGF-beta inhibitors effectively inhibit fibrosis in different animal models; however, systemic inhibition of TGF-beta raises important safety issues because of the pleiotropic physiological effects of this factor. In this study, we have investigated whether topical application of P144 (a peptide inhibitor of TGF-beta1) ameliorates skin fibrosis in a well-characterized model of human scleroderma. C3H mice received daily subcutaneous injections of bleomycin for 4 wk, and were treated daily with either a lipogel containing P144 or control vehicle. Topical application of P144 significantly reduced skin fibrosis and soluble collagen content. Most importantly, in mice with established fibrosis, topical treatment with P144 lipogel for 2 wk significantly decreased skin fibrosis and soluble collagen content. Immunohistochemical studies in P144-treated mice revealed a remarkable suppression of connective tissue growth factor expression, fibroblast SMAD2/3 phosphorylation, and alpha-smooth muscle actin positive myofibroblast development, whereas mast cell and mononuclear cell infiltration was not modified. These data suggest that topical application of P144, a peptide inhibitor of TGF-beta1, is a feasible strategy to treat pathological skin scarring and skin fibrotic diseases for which there is no specific therapy

Chemical abundances of Seyfert 2 AGNs, I: comparing oxygen abundances from distinct methods using SDSS

We compare the oxygen abundance (O/H) of the narrow-line regions (NLRs) of Seyfert 2 AGNs obtained through strong-line methods and from direct measurements of the electron temperature (Te-method). The aim of this study is to explore the effects of the use of distinct methods on the range of metallicity and on the mass-metallicity relation of active galactic nuclei (AGNs) at low redshifts (z<~0.4). We used the Sloan Digital Sky Survey (SDSS) and NASA/IPACExtragalactic Database (NED) to selected optical (3000Fil: Dors, Oli L.. Universidade Do Vale Do Paraiba; BrasilFil: de Freitas Rosa, Morsyleide. Universidade Do Vale Do Paraiba; BrasilFil: Amores, E. B.. Universidade Estadual de Feira de Santana; BrasilFil: Almarcha Pérez, Martha Ayelén. Instituto de Astrofísica de Andalucía - Csic; EspañaFil: Cardaci, Monica Viviana. Instituto de Astrofísica de la Plata (conicet- Universidad Nacional de la Plata); Argentina. Universidad Nacional de La Plata; ArgentinaFil: Hägele, Guillermo Federico. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Armah, M.. Universidade Do Vale Do Paraiba; BrasilFil: Krabbe, A. C.. Universidade Do Vale Do Paraiba; BrasilFil: Ruiz Faúndez, Giovanni Patricio. Laboratorio Nacional de Astrofisica, Itajuba; Brasi

Epidemiological studies on dengue virus type 3 in Playa municipality, Havana, Cuba, 2001–2002

SummaryObjectivesRecognizing the uniqueness of secondary dengue virus (DENV)-1/3 dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) cases at an interval of 24 years, we sought to estimate DENV infections as well as the ratios between mild disease and DHF/DSS by DENV infection sequence in Playa District (Havana, Cuba) during the 2001–2002 outbreak of dengue virus type 3 (DENV-3).MethodsA retrospective seroepidemiological study was conducted in 2003 in Playa District. Blood samples were collected from a 1% random sample of residents and were studied for the prevalence of dengue neutralizing antibodies.ResultsDENV-3 was found to have infected 7.2% (95% confidence interval (95% CI) 6.0–8.4%) of susceptible individuals (the entire cohort), the majority of whom experienced silent infections. Virtually every individual who had a secondary infection in the sequence DENV-1 then DENV-3 became ill, with a ratio of severe to mild cases of 1:35 (95% CI 1:67–1:23). Secondary infections in the sequence DENV-2/3 were less pathogenic than DENV-1/3. Mild disease accompanying secondary DENV2/3 occurred at a ratio of 1:4.49 infections (95% CI 1:5.77–1:3.42) secondary infections.ConclusionsThe results obtained highlight the role of the infecting serotype and also the sequence of the viral infection in the clinical outcome of a dengue infection

Long-Term Carbon Sequestration in Pine Forests under Different Silvicultural and Climatic Regimes in Spain

Proactive silviculture treatments (e.g., thinning) may increase C sequestration contributing to climate change mitigation, although, there are still questions about this effect in Mediterranean pine forests. The aim of this research was to quantify the storage of biomass and soil organic carbon in Pinus forests along a climatic gradient from North to South of the Iberian Peninsula. Nine experimental Pinus spp trials were selected along a latitudinal gradient from the pre-Pyrenees to southern Spain. At each location, a homogeneous area was used as the operational scale, and three thinning intensity treatments: unthinned or control (C), intermediate thinning (LT, removal of 30–40% of the initial basal area) and heavy thinning (HT, removal of 50–60%) were conducted. Growth per unit area (e.g., expressed as basal area increment-BAI), biomass, and Soil Organic Carbon (SOC) were measured as well as three sets of environmental variables (climate, soil water availability and soil chemical and physical characteristics). One-way ANOVA and Structural Equation Modelling (SEM) were used to study the effect of thinning and environmental variables on C sequestration. Biomass and growth per unit area were higher in the control than in the thinning treatments, although differences were only significant for P. halepensis. Radial growth recovered after thinning in all species, but it was faster in the HT treatments. Soil organic carbon (SOC10, 0–10 cm depth) was higher in the HT treatments for P. halepensis and P. sylvestris, but not for P. nigra. SEM showed that Pinus stands of the studied species were beneficed by HT thinning, recovering their growth quickly. The resulting model explained 72% of the variation in SOC10 content, and 89% of the variation in silvicultural condition (basal area and density) after thinning. SOC10 was better related to climate than to silvicultural treatments. On the other hand, soil chemical and physical characteristics did not show significant influence over SOC10- Soil water availability was the latent variable with the highest influence over SOC10. This work is a new contribution that shows the need for forest managers to integrate silviculture and C sequestration in Mediterranean pine plantations

Dendritic cells delivered inside human carcinomas are sequestered by interleukin-8

In the course of a clinical trial consisting of intratumoral injections of dendritic cells (DCs) transfected to produce interleukin-12, the use of (111)In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. In search for factors that could explain this retention, it was found that tumors from patients suffering hepatocellular carcinoma, colorectal or pancreatic cancer were producing IL-8 and that this chemokine attracted monocyte-derived dendritic cells that uniformly express both IL-8 receptors CXCR1 and CXCR2. Accordingly, neutralizing antihuman IL-8 monoclonal antibodies blocked the chemotactic attraction of DCs by recombinant IL-8, as well as by the serum of the patients or culture supernatants of human colorectal carcinomas. In addition, tissue culture supernatants of colon carcinoma cells inhibited DC migration induced by MIP-3beta in an IL-8-dependent fashion. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion

Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress

AIMS: Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.This work was supported by the Ministerio de Ciencia e Innovación and Fondo Europeo de Desarrollo Regional (FEDER)/FSE (SAF2016-80305P; SAF2017-88089-R; SAF2016-79151-R; RTI2018-099246-B-I00), Ministerio de Innovación, Cultura y Deportes (PGC2018-097019-B-I00), Instituto de Salud Carlos III (ISCIII; FIS PI18/0919); Comunidad de Madrid (CM) (AORTASANA B2017/BMD-3676) FEDER-a way to build Europe, Bayer AG (2019-09-2433), CM-Universidad Autónoma de Madrid (SI1-PJI-2019-00321), and British Heart Foundation (CH/12/4/29762; RE//18/6/34217). M.G.-A. was supported by an FPI-UAM fellowship, R.R.-D. by a Juan de la Cierva contract (IJCI-2017-31399), and A.C.M. by a Walton Fellowship, University of Glasgow. The CNIC is supported by ISCIII, the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505)