Role of the LPA1 receptor in mood and emotional regulation

Depression is a debilitating psychiatric condition characterized by anhedonia and behavioural despair among others symptoms. Despite the high prevalence and devastating impact of depression, underlying neurobiological mechanisms of mood disorders are still not well known. Regardless its complexity, central features of this disease can be modelled in rodents in order to better understand the potential mechanisms underlying. On the other hand, the lack of LPA1 receptor compromises the morphological and functional integrity of the limbic circuit and the neurogenesis in hippocampus, induces cognitive alterations on hippocampal-dependent tasks and dysfunctional coping of chronic stress, provokes exaggerated endocrine responses to emotional stimuli and impairs adaptation of the hypothalamic-pituitary-adrenal axis after chronic stress. Factors, which all have been related with depression. Here, we sought to establish the involvement of the LPA1 receptor in regulation of mood and emotion. To this end, in wild-type and maLPA1-null mice active coping responses to stress were examined using the forced swimming test (FST). To assess hedonic behaviour saccharine preference test and female urine sniffing test were used. Our data indicated that the absence of the LPA1 receptor significantly affected to coping strategies. Thus, while null mice displayed less immobility than wt in FST, exhibited more climbing and less swimming behaviour, responses that could be interpreted as an emotional over-reaction (i.e., a panic-like response) to stress situations. Concerning hedonic behaviour, the lack of the LPA1 receptor diminished saccharin preference and female urine sniffing time. Overall, these data supports the role of LPA1 receptor in mood and emotional regulation. Specially, the lack of this receptor induced emotional dysregulation and anhedonic behaviour, a core symptom of depression.Universidad de Málaga, Campus de Excelencia Andalucía Tech. Andalusian Regional Ministries of Economy, Innovation, Science and Employment (SEJ-1863; CTS643) and of Health (PI-0234-2013; Nicolas Monardes Programme), MINECO (PSI2013-44901-P) and National Institute of Health Carlos III (Sara Borrel)

NOA36 Protein Contains a Highly Conserved Nucleolar Localization Signal Capable of Directing Functional Proteins to the Nucleolus, in Mammalian Cells

NOA36/ZNF330 is an evolutionarily well-preserved protein present in the nucleolus and mitochondria of mammalian cells. We have previously reported that the pro-apoptotic activity of this protein is mediated by a characteristic cysteine-rich domain. We now demonstrate that the nucleolar localization of NOA36 is due to a highly-conserved nucleolar localization signal (NoLS) present in residues 1–33. This NoLS is a sequence containing three clusters of two or three basic amino acids. We fused the amino terminal of NOA36 to eGFP in order to characterize this putative NoLS. We show that a cluster of three lysine residues at positions 3 to 5 within this sequence is critical for the nucleolar localization. We also demonstrate that the sequence as found in human is capable of directing eGFP to the nucleolus in several mammal, fish and insect cells. Moreover, this NoLS is capable of specifically directing the cytosolic yeast enzyme polyphosphatase to the target of the nucleolus of HeLa cells, wherein its enzymatic activity was detected. This NoLS could therefore serve as a very useful tool as a nucleolar marker and for directing particular proteins to the nucleolus in distant animal species

The absence of LPA1 receptor results in lipidome dysregulation and Neuropeptide-Y underexpression

LPA1 receptor is one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts as an intercellular signaling molecule. It has been shown that the LPA1 receptor is involved in emotional regulation and, when depleted, has a key role in vulnerability to stress. In this sense, maLPA1-null mice, a knockout model for LPA1 receptor has been recently proposed as a model of anxious depression. Here, we sought to elucidate the effect of the genetic depletion of this receptor of LPA1 receptor in both lipidome and Neuropeptide-Y (NPY) signaling, two factors associated with adaptive stress regulation. For that purpose, we measured the lipidomic profile of wild-type mice and maLPA1-null mice in both hippocampus and serum. In addition, through immunohistochemical procedures we quantified NPY+ cells in hippocampus, basolateral amygdala (BLA) and central amygdala (CeA). Interestingly, the comparative lipidomics analysis revealed differences in certain subspecies which are related to LPA1 receptor functionality. Regarding NPY, we found a reduction in BLA, but not in hippocampus. Overall, both lipid abnormalities and amygdalar dysfunction of NPY can be related to lower resources in stress coping and, in turn, higher vulnerability to the noxious effect of stress that might lead to anxiety and depressive-like states.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Factorization of absolutely continuous polynomials

In this paper we study the ideal of dominated (p,s)-continuous polynomials, that extend the nowadays well known ideal of p-dominated polynomials to the more general setting of the interpolated ideals of polynomials. We give the polynomial version of Pietsch s factorization Theorem for this new ideal. Our factorization theorem requires new techniques inspired in the theory of Banach lattices.The authors thank the referee for his/her suggestions. D. Achour acknowledges with thanks the support of the Ministere de l'Enseignament Superieur et de la Recherche Scientifique (Algeria) under project PNR 8-U28-181. E. Dahia acknowledges with thanks the support of the Ministere de l'Enseignament Superieur et de la Recherche Scientifique (Algeria) under grant 170/PGRS/C.U.K.M(2012) for short term stage. P. Rueda acknowledges with thanks the support of the Ministerio de Economia y Competitividad (Spain) MTM2011-22417. E.A. Sanchez Perez acknowledges with thanks the support of the Ministerio de Economia y Competitividad (Spain) MTM2012-36740-C02-02.Achour, D.; Dahia, E.; Rueda, P.; Sánchez Pérez, EA. (2013). Factorization of absolutely continuous polynomials. Journal of Mathematical Analysis and Applications. 405:259-270. https://doi.org/10.1016/j.jmaa.2013.03.063S25927040

Absence of LPA1 receptor results in altered pattern of limbic activation after tail suspension test

Stress serves as an adaptive mechanism and helps organisms to cope with life-threatening situations. However, individual vulnerability to stress and dysregulation of this system may precipitate stress-related disorders such as depression. The neurobiological circuitry in charge of dealing with stressors has been widely studied in animal models. Recently our group has demonstrated a role for lysophosphatidic acid (LPA) through the LPA1 receptor in vulnerability to stress, in particular the lack of this receptor relates to robust decrease of adult hippocampal neurogenesis and induction of anxious and depressive states. Nevertheless, the specific abnormalities in the limbic circuit in reaction to stress remains unclear. The aim of this study is to examine the differences in the brain activation pattern in the presence or absence of LPA1 receptor after acute stress. For this purpose, we have studied the response of maLPA1-null male mice and normal wild type mice to an intense stressor: Tail Suspension Test. Activation induced by behaviour of brain regions involved in mood regulation was analysed by stereological quantification of c-Fos immunoreactive positive cells. We also conducted multidimensional scaling analysis in order to unravel coativation between structures. Our results revealed hyperactivity of stress-related structures such as amygdala and paraventricular nucleus of the hypothalamus in the knockout model and different patterns of coactivation in both genotypes using a multidimensional map. This data provides further evidence to the engagement of the LPA1 receptors in stress regulation and sheds light on different neural pathways under normal and vulnerability conditions that can lead to mood disorders.Universidad de Malaga, Campus de Excelencia internacional Andalucía Tech. Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863); Postdoctoral Fellowship ‘Sara Borrell’ of the National Institute of Health Carlos III E. C.; Grant of the Andalusian Ministry of Economy, Innovation , Science and Employment C. R. (FPDI 2010). Grant of the Spanish Ministry of Education, Culture and Sport s (FPU14/01610)

The limbic brain under stress: a role for the LPA1 receptor

Adverse events can impact brain structure and function and are considered primary sources of risk for depression, anxiety, and other psychiatric disorders. In this sense, the neurobiological circuitry in charge of dealing with stressors has been widely studied in animal models. Our group has demonstrated a role for lysophosphatidic acid (LPA) through the LPA1-receptor in controlling anxious and depressive states, owing to aggravation of the detrimental consequences of stress in the brain. Indeed, our group has recently proposed the variant maLPA1-null mice, i.e. mice lacking the LPA1 receptor, as an endophenotype for anxious depression. In addition, we have previously reported hyperactivation of key stress-related brain areas after stress, such as basolateral amygdala. Here, we seek to further examine the engagement of the LPA1 receptor in the regulation of the limbic circuit following an acute stressor, tail suspension test, in wildtype and knockout animals. To that end, c-Fos expression was evaluated as a measure of functional activity in both basal and stress conditions, followed by interregional correlation matrices to establish the brain map of functional activation. Additionally, we observed whether one single dose of the antidepressant treatment with desipramine is able to normalize the functional brain map. Results revealed that the absence of the LPA1 receptor induce an anomalous pattern of brain functional activity after TST, which was reverted by desipramine administration.These results provide further insight to the involvement of the LPA1 receptor in stress regulation and shed light on divergent brain pathways under normal and vulnerability conditions that can be implicated in depressive symptoms. Finally, how this pattern might be reverted by antidepressant treatment can be useful for developing new pharmaceutical targets regarding the LPA1 receptor.Funding: Andalusian Ministry of Economy, Innovation, Science and Employment (SEJ1863 to C.P) and of Health (Nicolas Monardes programme, to G.E-T); the Spanish Ministry of Economy and Competitiveness (PSI2013-44901-P to L.J.S. and C.P.). Author R.D. M-F holds a Grant of the Spanish Ministry of Education, Culture and Sports (FPU14/01610). Author S.T. holds a Grant of the Andalusian Ministry of Economy, Innovation, Science and Employment (FPDI 2014). I Plan Propio de Investigación y Transferencia, Universidad de Málaga. Campus de Excelencia. Andalucía Tech

Autophagy modulates endothelial junctions to restrain neutrophil diapedesis during inflammation

The migration of neutrophils from the blood circulation to sites of infection or injury is a key immune response and requires the breaching of endothelial cells (ECs) that line the inner aspect of blood vessels. Unregulated neutrophil transendothelial cell migration (TEM) is pathogenic, but the molecular basis of its physiological termination remains unknown. Here, we demonstrated that ECs of venules in inflamed tissues exhibited a robust autophagic response that was aligned temporally with the peak of neutrophil trafficking and was strictly localized to EC contacts. Genetic ablation of EC autophagy led to excessive neutrophil TEM and uncontrolled leukocyte migration in murine inflammatory models, while pharmacological induction of autophagy suppressed neutrophil infiltration into tissues. Mechanistically, autophagy regulated the remodeling of EC junctions and expression of key EC adhesion molecules, facilitating their intracellular trafficking and degradation. Collectively, we have identified autophagy as a modulator of EC leukocyte trafficking machinery aimed at terminating physiological inflammation

Fortalecimiento de gestiones a través del Centro de Información de Actividades Porcinas (CIAP) para el desarrollo sustentable de pequeños y medianos productores porcinos familiares de la zona de influencia de la Facultad de Ciencias Agrarias de la Universidad Nacional de Rosario

Fortalecimiento de gestiones a través del Centro de Información de Actividades Porcinas (CIAP) para el desarrollo sustentable de pequeños y medianos productores porcinos familiares de la zona de influencia de la Facultad de Ciencias Agrarias de la Universidad Nacional de RosarioFil: Silva, Patricia. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias; Argentin

NEXT-CRAB-0: A High Pressure Gaseous Xenon Time Projection Chamber with a Direct VUV Camera Based Readout

The search for neutrinoless double beta decay ($0\nu\beta\beta$) remains one of the most compelling experimental avenues for the discovery in the neutrino sector. Electroluminescent gas-phase time projection chambers are well suited to $0\nu\beta\beta$ searches due to their intrinsically precise energy resolution and topological event identification capabilities. Scalability to ton- and multi-ton masses requires readout of large-area electroluminescent regions with fine spatial resolution, low radiogenic backgrounds, and a scalable data acquisition system. This paper presents a detector prototype that records event topology in an electroluminescent xenon gas TPC via VUV image-intensified cameras. This enables an extendable readout of large tracking planes with commercial devices that reside almost entirely outside of the active medium.Following further development in intermediate scale demonstrators, this technique may represent a novel and enlargeable method for topological event imaging in $0\nu\beta\beta$.Comment: 32 Pages, 22 figure

Design, characterization and installation of the NEXT-100 cathode and electroluminescence regions

NEXT-100 is currently being constructed at the Laboratorio Subterr\'aneo de Canfranc in the Spanish Pyrenees and will search for neutrinoless double beta decay using a high-pressure gaseous time projection chamber (TPC) with 100 kg of xenon. Charge amplification is carried out via electroluminescence (EL) which is the process of accelerating electrons in a high electric field region causing secondary scintillation of the medium proportional to the initial charge. The NEXT-100 EL and cathode regions are made from tensioned hexagonal meshes of 1 m diameter. This paper describes the design, characterization, and installation of these parts for NEXT-100. Simulations of the electric field are performed to model the drift and amplification of ionization electrons produced in the detector under various EL region alignments and rotations. Measurements of the electrostatic breakdown voltage in air characterize performance under high voltage conditions and identify breakdown points. The electrostatic deflection of the mesh is quantified and fit to a first-principles mechanical model. Measurements were performed with both a standalone test EL region and with the NEXT-100 EL region before its installation in the detector. Finally, we describe the parts as installed in NEXT-100, following their deployment in Summer 2023.Comment: 35 pages, 25 Figures, update includes accepted version in JINS