Controlled Flavour Changing Neutral Couplings in Two Higgs Doublet Models

We propose a class of Two Higgs Doublet Models where there are Flavour Changing Neutral Currents (FCNC) at tree level, but under control due to the introduction of a discrete symmetry in the full Lagrangian. It is shown that in this class of models, one can have simultaneously FCNC in the up and down sectors, in contrast to the situation encountered in BGL models. The intensity of FCNC is analysed and it is shown that in this class of models one can respect all the strong constraints from experiment without unnatural fine-tuning. It is pointed out that the additional sources of flavour and CP violation are such that they can enhance significantly the generation of the Baryon Asymmetry of the Universe, with respect to the Standard Model.Comment: 29 pages, 3 figure

Symmetry Constrained Two Higgs Doublet Models

We study Two-Higgs-Doublet Models (2HDM) where Abelian symmetries have been introduced, leading to a drastic reduction in the number of free parameters in the 2HDM. Our analysis is inspired in BGL models, where, as the result of a symmetry of the Lagrangian, there are tree-level scalar mediated Flavour-Changing-Neutral-Currents, with the flavour structure depending only on the CKM matrix. A systematic analysis is done on the various possible schemes, which are classified in different classes, depending on the way the extra symmetries constrain the matrices of couplings defining the flavour structure of the scalar mediated neutral currents. All the resulting flavour textures of the Yukawa couplings are stable under renormalisation since they result from symmetries imposed at the Lagrangian level. We also present a brief phenomenological analysis of the most salient features of each class of symmetry constrained 2HDM.Comment: 30 pages, 5 Table

Racotumomab: an anti=idiotype vaccine related to N=glycolyl=containing=gangliosides: Preclinical and clinical data

Neu-glycolyl (NeuGc)-containing gangliosides are attractive targets for immunotherapy with anti-idiotype mAbs, because these glycolipids are not normal components of the cytoplasmic membrane in humans, but their expression has been demonstrated in several human malignant tumors. Racotumomab is an anti-idiotype mAb specific to P3 mAb, an antibody which reacts to NeuGc-containing gangliosides, sulfatides, and other antigens expressed in tumors. Preparations containing racotumomab were able to induce a strong anti-metastatic effect in tumor-bearing mice. Different Phase I clinical trials have been conducted in patients with advanced melanoma, breast cancer, and lung cancer. The results of these clinical trials demonstrated the low toxicity and the high immunogenicity of this vaccine. The induced antibodies recognized and directly killed tumor cells expressing NeuGcGM3. A Phase II/III multicenter, controlled, randomized, double blind clinical trial was conducted to evaluate the effect of aluminum hydroxide-precipitated racotumomab vaccine in overall survival in patients with advanced non-small cell lung cancer. The clinical results of this study showed a significant clinical benefit in the patients who were treated with the anti-idiotype vaccine.Fil: Vazquez, Ana M.. Center of Molecular Immunology; CubaFil: Hernandez, Ana M.. Center of Molecular Immunology; CubaFil: Macias, Amparo. Center of Molecular Immunology; CubaFil: Montero, Enrique. Center of Molecular Immunology; CubaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Gabri, Mariano Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología; ArgentinaFil: Gomez, Roberto E.. Elea Laboratories; Argentin

GH levels and insulin sensitivity are differently associated with biomarkers of cardiovascular disease in active acromegaly

Context: Acromegaly is characterized by GH excess and insulin resistance. It is not known which of these disorders is responsible for the increased atherogenic risk in these patients. Objective: To analyse the associations of GH and homoeostasis model assessment (HOMA) with biomarkers of cardiovascular disease and to compare the above-mentioned variables between patients with active acromegaly and controls. Design and setting: This open cross-sectional study was conducted at a University Hospital. Patients: Twenty-two outpatients were compared with sex- and age-matched control subjects. Main outcomes: Included clinical features, hormonal status, markers of insulin resistance, lipoprotein profile and biomarkers of cardiovascular disease. Results: Patients presented higher triglyceride (median [IQR]) (1·2[1·1-1·6] vs 0·9[0·6-1·1] mm, P < 0·05), low-density lipoprotein-cholesterol (LDL-C) (mean ± SD) (3·5 ± 0·9 vs 3·0 ± 0·7mm, P < 0·05), apoB (0·98 ± 0·23 vs 0·77 ± 0·22 g/l, P < 0·05), free fatty acid (0·69 ± 0·2 vs 0·54 ± 0·2 mM, P < 0·05), oxidized-LDL (120 ± 22 vs 85 ± 19 U/l, P < 0·05) and endothelin-1 (0·90 ± 0·23 vs 0·72 ± 0·17 ng/l, P < 0·05) levels, increased cholesteryl ester transfer protein (CETP) activity (179 ± 27 vs 138 ± 30%/ml/h, P < 0·01) and lower C reactive protein (CRP) (0·25[0·1-0·9] vs 0·85[0·4-1·4] mg/l; P < 0·05) levels than control subjects. Vascular cell adhesion molecule (VCAM-1) concentration was not different. By multiple linear regression analyses, HOMA explained the variability of triglycerides (25%), high-density lipoprotein-cholesterol (HDL-C) (30%) and CETP activity (28%), while GH independently predicted LDL-C (18%), oxidized-LDL (40%) and endothelin-1 levels (19%). Conclusions: In patients with active acromegaly, GH excess contributes to the development of insulin resistance, and the interaction between both disturbances would be responsible for the appearance of atherogenic pro-oxidative and pro-inflammatory factors. Insulin resistance would be preferably associated with an atherogenic lipoprotein profile and to high CETP activity, while high GH levels would independently predict the increase in LDL-C, ox-LDL and endothelin-1

Tissue factor as a novel marker for detection of circulating cancer cells

Tissue factor (TF) is a molecular marker that is up-regulated in cancer cells and aids tumoral dissemination. Our purpose was to develop a nested RT-PCR strategy against TF for detecting blood-borne tumour cells. Our method detected TF expression in a minimum of 1.5 pg total RNA from MCF7 cells. A preliminary study in blood samples from 16 advanced breast carcinoma patients showed that 80% of patients with high TF load progressed and died, while only 18% with low TF load showed the same behaviour. Kaplan-Meier analysis confirmed worse overall survival in patients with high TF load.Fil: Otero, L. L.. Universidad Nacional de Quilmes; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Castro, M.. Universidad de Buenos Aires; ArgentinaFil: Cinat, G.. Universidad de Buenos Aires; ArgentinaFil: Gabri, M. R.. Universidad Nacional de Quilmes; ArgentinaFil: Gomez, Daniel Eduardo. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Effects of diet and/or exercise in enhancing spinal cord sensorimotor learning.

Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA:DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury

Monitoring molecular dynamics of bacterial cellulose composites reinforced with graphene oxide by carboxymethyl cellulose addition

[EN] Broadband Dielectric Relaxation Spectroscopy was performed to study the molecular dynamics of dried Bacterial Cellulose/Carboxymethyl Cellulose-Graphene Oxide (BC/CMC-GO) composites as a function of the concentration of CMC in the culture media. At low temperature the dielectric spectra are dominated by a dipolar process labelled as a beta -relaxation, whereas electrode polarization and the contribution of dc-conductivity dominate the spectra at high temperatures and low frequency. The CMC concentration affects the morphological structure of cellulose and subsequently alters its physical properties. X-ray diffractometry measurements show that increasing the concentration of CMC promotes a decrease of the Ia/Ib ratio. This structural change in BC, that involves a variation in inter- and intramolecular interactions (hydrogen-bonding interactions), affects steeply their molecular dynamics. So, an increase of CMC concentration produces a significantly decrease of the -relaxation strength and an increase of the dc-conductivity.This work was supported by the DGCYT [MAT2015-63955-R]; the Vice-Rectorate for Research of the Pontificia Universidad Catolica del Peril and the National Council of Science, Technology and Technological Innovation of Peru (CONCYTEC/FONDECYT).Sanchis Sánchez, MJ.; Carsí Rosique, M.; Gomez, CM.; Culebras, M.; Gonzales, K.; Gisbert Torres, F. (2017). Monitoring molecular dynamics of bacterial cellulose composites reinforced with graphene oxide by carboxymethyl cellulose addition. Carbohydrate Polymers. 157:353-360. https://doi.org/10.1016/j.carbpol.2016.10.00135336015

Nerve Growth Factor Is Responsible for Exercise-Induced Recovery of Septohippocampal Cholinergic Structure and Function

Exercise has been shown to improve or rescue cognitive functioning in both humans and rodents, and the augmented actions of neurotrophins within the hippocampus and associated regions play a significant role in the improved neural plasticity. The septohippocampal circuit is modified by exercise. Beyond an enhancement of spatial working memory and a rescue of hippocampal activity-dependent acetylcholine (ACh) efflux, the re-emergence of the cholinergic/nestin neuronal phenotype within the medial septum/diagonal band (MS/dB) is observed following exercise (Hall and Savage, 2016). To determine which neurotrophin, brain-derived neurotrophic factor (BDNF) or nerve growth factor (NGF), is critical for exercise-induced cholinergic improvements, control and amnestic rats had either NGF or BDNF sequestered by TrkA-IgG or TrkB-IgG coated microbeads placed within the dorsal hippocampus. Hippocampal ACh release within the hippocampus during spontaneous alternation was measured and MS/dB cholinergic neuronal phenotypes were assessed. Sequestering NGF, but not BDNF, abolished the exercise-induced recovery of spatial working memory and ACh efflux. Furthermore, the re-emergence of the cholinergic/nestin neuronal phenotype within the MS/dB following exercise was also selectively dependent on the actions of NGF. Thus, exercise-induced enhancement of NGF within the septohippocampal pathway represents a key avenue for aiding failing septo-hippocampal functioning and therefore has significant potential for the recovery of memory and cognition in several neurological disorders

Alterations in biomarkers of cardiovascular disease (CVD) in active acromegaly

Objectives: In acromegalic patients, cardiovascular and metabolic comorbidities contribute to enhance mortality. Available data on the lipoprotein profile of these patients are controversial. Our aim was to characterize the lipoprotein profile and emergent biomarkers of cardiovascular disease in active acromegalic patients in comparison with sex- and age-matched healthy controls. Patients: Eighteen patients with active acromegaly and 18 controls were studied. Measurements: Glucose levels, hormonal status, lipoprotein profile and C reactive protein (CRP) were evaluated by standardized methods. Cholesteryl ester transfer protein (CETP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured by radiometric techniques, endothelin-1 and vascular cell adhesion molecule (VCAM)-1 by enzyme-linked immunosorbent assay, and leucocytes CD18, CD49d and CD54 by flow cytometry. Results: After adjusting for body mass index (BMI), acromegalic patients presented a more atherogenic lipoprotein profile, consisting of higher levels of triglycerides and apolipoprotein B and alterations in the ratios which estimate insulin resistance and atherogenic risk. CETP activity was significantly increased in acromegalic patients as compared to controls (168 ± 17 vs. 141 ± 30% per ml h, respectively; P < 0.05). Endothelin-1 levels evidenced an increase in the patients' group (0.9 ± 0.2 vs. 0.7 ± 0.2 ng/l, respectively; P < 0.01) and showed positive and significant correlations with GH, IGF-1 and IGFBP-3 (r = 0.45, 0.42 and 0.44, respectively; P < 0.01 for all of them; with BMI as a fixed variable). Lymphocytes from acromegalic patients showed increased CD49d content (282 ± 59 vs. 246 ± 48 arbitrary units, respectively; P < 0.05). Conclusions: Taken together, the alterations described seem to contribute to constituting a state of higher propensity for the development of atherosclerotic cardiovascular disease, which adds to the presence of specific cardiomyopathy.Fil: Boero, Laura Estela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Manavela, M.. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Gomez Rosso, Leonardo Adrián. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; ArgentinaFil: Insua, C.. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños Pedro Elizalde (ex Casa Cuna); ArgentinaFil: Berardi, V.. No especifíca;Fil: Fornari, M.C.. No especifíca;Fil: Brites, Fernando Daniel. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentin

HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes

Background and aims: Metabolic syndrome (MS) and type 2 diabetes are highly associated with an abnormal lipoprotein profile, which may be generated and accentuated by high cholesteryl ester transfer protein (CETP) activity. Given the difficulty in measuring CETP activity, the aim was to identify simple biochemical predictors of high CETP activity. Design and methods: Eighty five subjects at risk for type 2 diabetes were classified according to the presence of MS. Lipoprotein profile, HOMA-IR and endogenous CETP activity were evaluated. Results: As expected, MS patients presented higher concentration of glucose, insulin, triglycerides and non-HDL-C and lower HDL-C levels. Moreover, MS patients exhibited increased HOMA-IR and CETP activity. Employing a ROC curve for MS, high CETP activity was defined as >250%ml⁻¹ h⁻¹. The predictive variables of high CETP were non-HDL-C≥160mg/dl (OR=11.1;95%IC=3.3-38.2;p2.1 (OR=4.4;95%IC=1.3-14.8;p<0.05). Conclusions: High non-HDL-C and insulin resistance were predictors for increased CETP activity which measurement is not accessible for clinical laboratories