Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases

Formyl peptide receptor 2 (FPR2) is involved in the pathogenesis of chronic inflammatory diseases, being activated either by pro-resolving or proinflammatory ligands. FPR2-associated signal transduction pathways result in phosphorylation of several proteins and in NADPH oxidase activation. We, herein, investigated molecular mechanisms underlying phosphorylation of heat shock protein 27 (HSP27), oxidative stress responsive kinase 1 (OSR1), and myristolated alanine-rich C-kinase substrate (MARCKS) elicited by the pro-resolving FPR2 agonists WKYMVm and annexin A1 (ANXA1)

Intranuclear Signaling Cascades Triggered by Nuclear GPCRs

G protein-couped receptors (GPCRs) play a key role on cellular membranes, where they respond to a broad array of extracellular signals such as lipids, peptides, proteins and sensory agents. Intracellular biological responses triggered by these receptors include hormone secretion, muscle contraction, cellular metabolism a tyrosine kinase receptors transactivation. Recent results indicate that GPCRs localize to and signal also at nuclear level, thus regulating distinct signaling pathways which can also result from the integration of extracellular and intracellular stimuli. Nuclear GPCRs play a central role in many cellular processes, including regulation of gene transcription, cellular proliferation, neovascularization and RNA synthesis. On nuclear membranes and in nucleoplasm are present all the downstream signal transduction components of GPCRs, including G proteins, adenylyl cyclase, and second messengers such as Ca++, ERKs, p38MAPK and other protein kinases. Nuclear GPCRs may be constitutively active or may be activated by ligands internalized from the extracellular space or synthesized within the cell. The translocation of membrane receptors to the nucleus could be attributed to the presence of a Nuclear Localization Signal, which is present in the eighth helix or in the third intracellular loop of a limited number of GPCRs. However, several sequence motifs that do not resemble classical Nuclear Localization Signals can promote import of GPCRs. In this review we discuss the most recent results on nuclear localization and signaling of several GPCRS

Formyl Peptide Receptor 1 Modulates Endothelial Cell Functions by NADPH Oxidase-Dependent VEGFR2 Transactivation

In the vasculature, NADPH oxidase is the main contributor of reactive oxygen species (ROS) which play a key role in endothelial signalling and functions. We demonstrate that ECV304 cells express p47phox, p67phox, and p22phox subunits of NADPH oxidase, as well as formyl peptide receptors 1 and 3 (FPR1/3), which are members of the GPCR family. By RT-PCR, we also detected Flt-1 and Flk-1/KDR in these cells. Stimulation of FPR1 by N-fMLP induces p47phox phosphorylation, which is the crucial event for NADPH oxidase-dependent superoxide production. Transphosphorylation of RTKs by GPCRs is a biological mechanism through which the information exchange is amplified throughout the cell. ROS act as signalling intermediates in the transactivation mechanism. We show that N-fMLP stimulation induces the phosphorylation of cytosolic Y951, Y996, and Y1175 residues of VEGFR2, which constitute the anchoring sites for signalling molecules. These, in turn, activate PI3K/Akt and PLC-γ1/PKC intracellular pathways. FPR1-induced ROS production plays a critical role in this cross-talk mechanism. In fact, inhibition of FPR1 and/or NADPH oxidase functions prevents VEGFR2 transactivation and the triggering of the downstream signalling cascades. N-fMLP stimulation also ameliorates cellular migration and capillary-like network formation ability of ECV304 cells

Gastropods from the Rockshelter Deodoro Roca (Sector B), Ongamira Valley (Cordoba, Argentina): A preliminary analysis

Se presentan los primeros resultados de la caracterización taxonómica y la cuantificación de gasterópodos procedentes de distintas unidades estratigráficas asociadas con las ocupaciones fechadas ca. 3000 AP. del Sector B del sitio ADR. El alero en cuestión había sido excavado en las décadas de 1940 y 1950, oportunidad en la que se obtuvieron gran cantidad de restos faunísticos incluidos camélidos, cérvidos, rheidos y gasterópodos (Menghin y González 1954, Pascual 1954). En 2010 se realizó la excavación de algunos sectores trabajados en la década de 1950 dejando los antiguos perfiles expuestos y la excavación de áreas no trabajadas previamente, lo que permitió identificar la presencia de fogones estructurados, con la particularidad de estar asociados a espesas capas de valvas de gasterópodos donde fueron recuperadas todas las valvas enteras y se realizó un muestreo para su cuantificación en cinco sectores del sitio. El análisis de estas valvas permitió la determinación de seis especies: cinco vivientes y una aparentemente extinta en la región; a partir de lo cual se explora su recurrencia en los sitios arqueológicos de la región, así como su potencial para la subsistencia de los grupos que habitaron el alero en el Holoceno Tardío. La cuantificación permitió interpretar que ca. 3000AP la biomasa disponible de gasterópodos terrestres en el área era muy elevada, por lo cual puede haber resultado de interés para la incorporación a la dieta prehispánica.This paper presents the first results of the taxonomic characterization and the quantification of gastropods from the Sector B of the Deodoro Roca rockshelter, Ongamira (Ischilín, Córdoba), in order to understand their role in pre-Hispanic groups subsistence strategy focusing in occupation ca. 3000bp. The site was firstly excavated in the 1940s and 1950s at which time it was obtained many faunal remains from camelids, deers, rheas and gastropods. In 2010 we proceeded to re-excavate some sectors worked in the 1950´s leaving exposed profiles and excavate other not previously worked; thus we were able to identify the presence of different spaces with structured hearths which had the distinction of being associated with thick layers of gastropods shells. The analysis of these valves allowed the determination of six species, including five that live currently in the region and other that nowadays it is apparently extinct. From this we explore the recurrence of these animals in archaeological sites in the region and its potential for the understanding of the subsistence of the groups that inhabited the rockshelter during the Late Holocene.Fil: Izeta, Andres Dario. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades. Museo de Antropologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Silva Ferreira Da Costa, Thiago. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades. Museo de Antropologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gordillo, Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Ciencias de la Tierra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Cattaneo, Gabriela Roxana. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades. Museo de Antropologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Boretto, Gabriella Margherita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Ciencias de la Tierra; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Robledo, Andrés Ignacio. Universidad Nacional de Cordoba. Facultad de Filosofia y Humanidades. Museo de Antropologia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The effects of painless nerve growth factor on human microglia polarization

Previous studies in the rat suggest that microglial cells represent a potential druggable target for nerve growth factor (NGF) in the brain. The painless human Nerve Growth Factor (hNGFp) is a recombinant mutated form of human nerve growth factor (hNGF) that shows identical neurotrophic and neuroprotective properties of wild-type NGF but displays at least 10-fold lower algogenic activity. From the pharmacological point of view, hNGFp is a biased tropomyosin receptor kinase A (TrkA) agonist and displays a significantly lower affinity for the p75 neurotrophin receptor (p75NTR). This study aimed to evaluate the expression of TrkA and p75NTR NGF receptors in two different human microglia cell lines, and to investigate the effects of hNGFp and wild-type NGF (NGF) on L-arginine metabolism, taken as a marker of microglia polarization. Both NGF receptors are expressed in human microglia cell lines and are effective in transducing signals triggered by NGF and hNGFp. The latter and, to a lesser extent, NGF inhibit cytokine-stimulated inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production in these cells. Conversely NGF but not hNGFp stimulates arginase-mediated urea production

Regulation of inflammation and oxidative stress by formyl peptide receptors in cardiovascular disease progression

G protein-coupled receptors (GPCRs) are the most important regulators of cardiac function and are commonly targeted for medical therapeutics. Formyl-Peptide Receptors (FPRs) are members of the GPCR superfamily and play an emerging role in cardiovascular pathologies. FPRs can modulate oxidative stress through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production whose dysregulation has been observed in different cardiovascular diseases. Therefore, many studies are focused on identifying molecular mechanisms of the regulation of ROS production. FPR1, FPR2 and FPR3 belong to the FPRs family and their stimulation triggers phosphorylation of intracellular signaling molecules and nonsignaling proteins that are required for NADPH oxidase activation. Some FPR agonists trigger inflammatory processes, while other ligands activate proresolving or anti-inflammatory pathways, depending on the nature of the ligands. In general, bacterial and mitochondrial formylated peptides activate a proinflammatory cell response through FPR1, while Annexin A1 and Lipoxin A4 are anti-inflammatory FPR2 ligands. FPR2 can also trigger a proinflammatory pathway and the switch between FPR2-mediated pro- and anti-inflammatory cell responses depends on conformational changes of the receptor upon ligand binding. Here we describe the detrimental or beneficial effects of the main FPR agonists and their potential role as new therapeutic and diagnostic targets in the progression of cardiovascular diseases

Comparison between hospitalized patients affected or not by COVID-19 (RESILIENCY study)

Dear Editor, in the recent report of Munblit and coworkers [1], authors observed that the combination of clinical features was sufficient to diagnose COVID-19 indicating that laboratory testing is not critical in real-life clinical practice. To date, all patients admitted to Emergency Department with acute respiratory failure and/or fever should be considered as a suspected SARS-CoV-2 infection [2-3], and an early recognition of etiology and the prompt therapeutic management are crucial to improve survival [4-5]. From March to July 2020, we performed a prospective, multicenter study (RESILIENCY study). During the study period, all patients hospitalized for suspected or confirmed COVID-19 were prospectively recruited in 3 large hospitals in Rome, Italy. All patients with suspected SARS-CoV-2 infection, admitted to the hospital in case of fever and/or hypoxemic respiratory failure (PaO2 <60 mmHg at rest in ambient air) or of exacerbation of underlying diseases or severe symptoms not manageable outside the hospital, were evaluated according to a predefined protocol (see Figure 1). Overall, 653 patients were included in the study: 309 (47.3%) patients with confirmed COVID-19 and 344 (52.7%) without COVID-19, hospitalized for other causes. Baseline characteristics and outcomes of the study population showed that the main causes of hospitalization among patients without COVID-19 were: acute heart failure (47%), bacterial pneumonia (38.5%), and pulmonary embolism (9.2%). Overall, 67 (21.7%) patients of COVID-19 group and 45 (13.1%) hospitalized for other causes were admitted to intensive care unit; 30-day mortality was observed in 59 (19%) patients of COVID-19 group and 62 (18%) of non-COVID-19 group. The multivariate analysis about risk factors for COVID-19 etiology at time of hospitalization showed that dry cough (OR 3.76, CI 95% 1.98-7.92, P<0.001), duration of fever>3 days (OR 5.21, CI 95% 2.34-9.21, P<0.001), lymphocytopenia (OR 1.98, CI 95% Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1745/5989494 by Sapienza Università di Roma user on 01 December 2020 Accepted Manuscript 3 1.27-4.22, P=0.002) and PaO2/FiO2 ratio<250 (OR 4.98, CI 95% 2.22-9.71, P<0.001) were independently associated with COVID-19 etiology, while procalcitonin value>1 ng/ mL (OR 0.21, CI 95% 0.08-0.82, p<0.001), and lactate>2 mmol/L (OR 0.41, CI 95% 0.15-0.77, p<0.001) were associated with non-COVID-19 etiology. Finally, analysis about predictors of 30-day mortality showed that age (per-year increase OR 1.33; CI 95% 1.11-2.10; p<0.001), cardiovascular disease (OR 4.58; CI 95% 2.07-8.25; p<0.001), and ICU admission (OR 2.1; CI 95% 1.48-4.4; p<0.001) were independently associated with all-cause 30-day mortality, while the use of low-molecularweight heparin (OR 0.22, CI 95% 0.03-0.45, p=0.002) was associated with survival. The findings of the present study can be summarized as follows:1) the prompt identification of specific clinical characteristics (like dry cough or duration of fever>3 days), and laboratory findings (like lymphocytopenia, PaO2/FiO2 ratio<250, procalcitonin value>1 ng/ mL, and lactate>2 mmol/L) can help physicians to distinguish rapidly between COVID19 or other etiologies [6]; 2) the application of a standard approach to management of patients with acute respiratory failure and/or fever associated with the knowledge of clinical and laboratory characteristics of COVID-19 can early drive physicians to therapeutic choices; and 3) age, cardiovascular disease, and ICU admission show an independent association with all-cause 30-day mortality [7], while the use of low-molecular-weight heparin was associated with survival [8]. In conclusion, COVID-19 syndrome is characterized by a heterogeneous clinical, laboratoristic, and radiological presentation, especially at its onset [9]. However, the application of a standard approach to management of patients with acute respiratory failure and/or fever and the knowledge of clinical and laboratory characteristics of COVID-19 can early drive therapeutic choic

Ornamental beads in a hunter-gatherers context from the Córdoba Province: a mineralogical and microstructural analysis of a “Borus” shell

El objetivo de este trabajo es analizar la composicion mineralogica y la microestructura del gasteropodo “Borus” (Megalobulimus lorentzianus) que habita en la provincia de Cordoba y compararla con una cuenta ornamental procedente de un sitio arqueológico de cazadores-recolectores del noroeste de la misma provincia y de esta manera contar con nuevas herramientas para identificar las materias primas utilizadas en su fabricacion. El analisis de difraccion de rayos X en base a un ejemplar actual indico que la concha de “Borus” esta compuesta en su totalidad de aragonita, polimorfo de carbonato de calcio (CaCO3) que cristaliza en el sistema ortorrombico. Ademas, el analisis de su microestructura, a traves de microscopia electronica y laser confocal, mostro una disposicion prismatica de los cristales. Por otro lado, este ultimo análisis realizado en una cuenta proveniente del sitio arqueologico Alero Deodoro Roca (valle de Ongamira, provincia de Cordoba) tambien indico la misma composicion mineralógica y disposicion prismatica, lo que se interpreta como un elemento de afiliacion al taxón mencionado. Con la incorporacion de nuevos materiales este tipo de analisis podra, a futuro, mejorar el conocimiento respecto a la especializacion en la confeccion de cuentas y posibles redes de intercambio en la region central de Argentina.In this article, we analyze the mineralogical composition and microstructure of the “Borus” gastropod (Megalobulimus lorentzianus), which is local to the Cordoba Province. The gastropod was compared against a typical ornamental bead from a hunter-gatherers archaeological site located in the northwest region of the same province, with the aim of producing new tools to identify the raw materials used in bead manufacture. An X-ray diffraction analysis of a modern “Borus” shell specimen indicated that from a mineralogical standpoint it was composed entirely of aragonite, a calcium carbonate polymorph (CaCO3) that crystallizes in the orthorhombic system. In addition, an analysis of its microstructure using laser electron confocal microscope identified a prismatic microstructure. These same analyses, undertaken on a bead from the archaeological site of Alero Deodoro Roca (Ongamira valley, Cordoba Province) revealed the same mineralogical composition and prismatic arrangement, leading to interpret the bead as having a taxonomic affiliation to “Borus” shell. With the addition of new materials, in the future this type of analysis will provide insights regarding specialization in the elaboration of beads and exchange networks in the central region of Argentina.Fil: Boretto, Gabriella Margherita. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Gordillo, Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Izeta, Andres Dario. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; ArgentinaFil: Colombo, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Ciencias de la Tierra. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Centro de Investigaciones en Ciencias de la Tierra; ArgentinaFil: Martinelli, Marisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Cattaneo, Gabriela Roxana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Antropología de Córdoba. Universidad Nacional de Córdoba. Facultad de Filosofía y Humanidades. Instituto de Antropología de Córdoba; Argentin

A semi-analytic model comparison - gas cooling and galaxy mergers

We use stripped-down versions of three semi-analytic galaxy formation models to study the influence of different assumptions about gas cooling and galaxy mergers. By running the three models on identical sets of merger trees extracted from high-resolution cosmological N-body simulations, we are able to perform both statistical analyses and halo-by-halo comparisons. Our study demonstrates that there is a good statistical agreement between the three models used here, when operating on the same merger trees, reflecting a general agreement in the underlying framework for semi-analytic models. We also show, however, that various assumptions that are commonly adopted to treat gas cooling and galaxy mergers can lead to significantly different results, at least in some regimes. In particular, we find that the different models adopted for gas cooling lead to similar results for mass scales comparable to that of our own Galaxy. Significant differences, however, arise at larger mass scales. These are largely (but not entirely) due to different treatments of the `rapid cooling' regime, and different assumptions about the hot gas distribution. At this mass regime, the predicted cooling rates can differ up to about one order of magnitude, with important implications on the relative weight that these models give to AGN feedback in order to counter-act excessive gas condensation in relatively massive haloes at low redshift. Different assumptions in the modelling of galaxy mergers can also result in significant differences in the timings of mergers, with important consequences for the formation and evolution of massive galaxies.Comment: 21 pages, 14 figures. Accepted for publication in MNRAS

Beyond Traditional Morphological Characterization of Lung Neuroendocrine Neoplasms: In Silico Study of Next-Generation Sequencing Mutations Analysis across the Four World Health Organization Defined Groups

Lung neuroendocrine neoplasms (LNENs) classes, as proposed by the World Health Organization 2015, do not provide properly prognostic and therapeutic indications. In fact, high-throughput molecular analysis, based on next-generation sequencing, identified novel molecular subgroups, associated with different genomic signatures, that could pave the way for alternative therapeutic approaches. The present review, coupled with in silico molecular analysis, could show the current genomic alterations state in actual LNENS groups. Interestingly our manuscript suggests that the molecular novelties could improve the LNENs therapeutics efficacy. In more detail, we reported the differences of gene alterations and mutational rate between LNENS, confirming the central pathogenetic role given by a different mutational rate in chromatin remodeling genes and tumor suppressors TP53-RB1. In conclusion, our results underlined that a further molecular layer is needed to improve the efficacy of LNENs medical treatment.Lung neuroendocrine neoplasms (LNENs) represent a rare and heterogeneous population of lung tumors. LNENs incidence rate has increased dramatically over the past 30 years. The current World Health Organization LNENs classification (WHO 2015), distinguished four LNENs prognostic categories, according to their morphology, necrosis amount and mitotic count: typical carcinoid (TC), atypical-carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC). At present, due to their rarity and biological heterogeneity there is still no consensus on the best therapeutic approach. Next-generation-sequencing analysis showed that WHO 2015 LNENs classes, could be characterized also by specific molecular alterations: frequently mutated genes involving chromatin remodeling and generally characterized by low mutational burden (MB) are frequently detected in both TC and AC; otherwise, TP53 and RB1 tumor suppressor genes alterations and high MB are usually detected in LCNEC and SCLC. We provide an overview concerning gene mutations in each WHO 2015 LNENs class in order to report the current LNENs mutational status as potential tool to better understand their clinical outcome and to drive medical treatment