Gene deficiency in activating Fcγ receptors influences the macrophage phenotypic balance and reduces atherosclerosis in mice

Immunity contributes to arterial inflammation during atherosclerosis. Oxidized low-density lipoproteins induce an autoimmune response characterized by specific antibodies and immune complexes in atherosclerotic patients. We hypothesize that specific Fcγ receptors for IgG constant region participate in atherogenesis by regulating the inflammatory state of lesional macrophages. In vivo we examined the role of activating Fcγ receptors in atherosclerosis progression using bone marrow transplantation from mice deficient in γ-chain (the common signaling subunit of activating Fcγ receptors) to hyperlipidemic mice. Hematopoietic deficiency of Fcγ receptors significantly reduced atherosclerotic lesion size, which was associated with decreased number of macrophages and T lymphocytes, and increased T regulatory cell function. Lesions of Fcγ receptor deficient mice exhibited increased plaque stability, as evidenced by higher collagen and smooth muscle cell content and decreased apoptosis. These effects were independent of changes in serum lipids and antibody response to oxidized low-density lipoproteins. Activating Fcγ receptor deficiency reduced pro-inflammatory gene expression, nuclear factor-κB activity, and M1 macrophages at the lesion site, while increasing anti-inflammatory genes and M2 macrophages. The decreased inflammation in the lesions was mirrored by a reduced number of classical inflammatory monocytes in blood. In vitro, lack of activating Fcγ receptors attenuated foam cell formation, oxidative stress and pro-inflammatory gene expression, and increased M2-associated genes in murine macrophages. Our study demonstrates that activating Fcγ receptors influence the macrophage phenotypic balance in the artery wall of atherosclerotic mice and suggests that modulation of Fcγ receptor-mediated inflammatory responses could effectively suppress atherosclerosis

Pensamiento crítico para el Pensamiento gráfico

PASSMORE (1967) define el Pensamiento Crítico como un proceso que es a la vez reflexivo e imaginativo, cualidades imprescindibles en todo proceso de diseño. En este artículo nos centramos en la utilización del Pensamiento Crítico para mejorar lo que se ha dado en llamar Pensamiento Gráfico. El trabajo se divide en dos partes complementarias. En la primera, se formula un marco teórico en torno a los conceptos de Pensamiento Crítico y Pensamiento Gráfico, para proponer una metodología de enseñanza de la ingeniería que relacione ambos conceptos. En la segunda, se aplican dichos aspectos al estudio de una herramienta esencial dentro del proceso de diseño, el diagrama, y a la manera de proyectar en la contemporaneidad. - Critical thinking is defined by PASSMORE (1967) as a process that is both reflexive and imaginative, essencial aspects of the design process. This paper focuses on the use of Critical Thinking to improve what we call Graphic Thinking. The content is two fold. The first part establishes a theoretical framework around the concepts of Critical Thinking and Graphic Thinking, in order to propose a methodology for engineering education through the combination of both concepts. The second one deals with those concepts, which are applied to one of the basic tools within the design process, the diagram, analysing through it the contemporary way of designing

Evaluación ambiental estratégica de la explotación petrolera costa afuera en la Región Caribe Colombiana

La propuesta de investigación doctoral consiste en la realización de una Evaluación Ambiental Estratégica a la explotación petrolera costa afuera en la región del caribe colombiano, guiado por la necesidad de los planes gubernamentales de realizar estas actividades y la oposición generada por los accidentes ambientales ocurridos en Colombia y alrededor del mundo; la investigación buscara generar una guía que permita fortalecer el plan de desarrollo desde los marco institucionales y políticos. Empresas vinculadas al sector petrolero y gasífero, tales como la Agencia Nacional de Hidrocarburos (ANH), Comisión de Regulación de Energía y Gas (CREG), la Unidad de Planeación Minero-Energética (UPME), empresas operadoras de campos costa afuera, además del Ministerio de Minas y Energía. En términos generales, las entidades encargadas de la regulación, planeación y control del mercado del gas y el petróleo. Los eventuales resultados de esta tesis doctoral implicarían un cambio en los esquemas para la exploración y explotación de los campos petroleros costa afuera en la región caribe de Colombia. La Evaluación Ambiental Estratégica permitirá tener un modelo de evaluación para generar propuestas y recomendaciones para la formulación de una política petrolera adaptada a la problemática ambiental y social del país

Estado del arte del proyecto

La propuesta de investigación doctoral consiste en la realización de una Evaluación Ambiental Estratégica a la explotación petrolera costa afuera en la región del caribe colombiano, guiado por la necesidad de los planes gubernamentales de realizar estas actividades y la oposición generada por los accidentes ambientales ocurridos en Colombia y alrededor del mundo; la investigación buscara generar una guía que permita fortalecer el plan de desarrollo desde los marco institucionales y políticos. Empresas vinculadas al sector petrolero y gasífero, tales como la Agencia Nacional de Hidrocarburos (ANH), Comisión de Regulación de Energía y Gas (CREG), la Unidad de Planeación Minero-Energética (UPME), empresas operadoras de campos costa afuera, además del Ministerio de Minas y Energía. En términos generales, las entidades encargadas de la regulación, planeación y control del mercado del gas y el petróleo. Los eventuales resultados de esta tesis doctoral implicarían un cambio en los esquemas para la exploración y explotación de los campos petroleros costa afuera en la región caribe de Colombia. La Evaluación Ambiental Estratégica permitirá tener un modelo de evaluación para generar propuestas y recomendaciones para la formulación de una política petrolera adaptada a la problemática ambiental y social del país

Effects of coffee with different roasting degrees on obesity and related metabolic disorders

This study aimed to assess the effect of unroasted, dark and very dark roasted coffee on obesity and metabolic disorders in obese rats. All coffee samples significantly reduced weight gain (∼17%) compared to obese control. Coffee reduced glucose levels (∼17%) upon a glucose tolerance test in all cases compared to the control, while fasting glucose only decreased (∼26%) with very dark coffee. Insulin levels and insulin resistance significantly decreased (∼77% and 65% respectively) with all coffee samples compared to the control. Unroasted and dark roasted coffee decreased triglycerides (∼21% and ∼ 11%, respectively), and unroasted coffee also reduced free fatty acids (∼43%) and adipocyte size. Coffee decreased liver steatosis (∼55%) and Caspase-3 levels (∼27%), regardless of the roasting degree. Overall, coffee plays a positive role in restraining obesity and related metabolic disorders but, depending on the metabolic pathway and relevant marker, an effect of roasting could be either found or not

Disruption of ER-mitochondria tethering and signalling in C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia

Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The mechanisms by which the expansions cause disease are not properly understood but a favoured route involves its translation into dipeptide repeat (DPR) polypeptides, some of which are neurotoxic. However, the precise targets for mutant C9orf72 and DPR toxicity are not fully clear, and damage to several neuronal functions has been described. Many of these functions are regulated by signalling between the endoplasmic reticulum (ER) and mitochondria. ER-mitochondria signalling requires close physical contacts between the two organelles that are mediated by the VAPB-PTPIP51 ‘tethering’ proteins. Here, we show that ER-mitochondria signalling and the VAPB-PTPIP51 tethers are disrupted in neurons derived from induced pluripotent stem (iPS) cells from patients carrying ALS/FTD pathogenic C9orf72 expansions and in affected neurons in mutant C9orf72 transgenic mice. In these mice, disruption of the VAPB-PTPIP51 tethers occurs prior to disease onset suggesting that it contributes to the pathogenic process. We also show that neurotoxic DPRs disrupt the VAPB-PTPIP51 interaction and ER-mitochondria contacts and that this may involve activation of glycogen synthase kinases-3β (GSK3β), a known negative regulator of VAPB-PTPIP51 binding. Finally, we show that these DPRs disrupt delivery of Ca2+ from ER stores to mitochondria, which is a primary function of the VAPB-PTPIP51 tethers. This delivery regulates a number of key neuronal functions that are damaged in ALS/FTD including bioenergetics, autophagy and synaptic function. Our findings reveal a new molecular target for mutant C9orf72-mediated toxicity

Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while re-expression of NKX6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis

Present Status and Future Programs of the n_TOF Experiment

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 3.0, which permits unrestricted use, distribution, and reproduction in any noncommercial medium, provided the original work is properly citedThe neutron time-of-flight facility n_TOF at CERN, Switzerland, operational since 2001, delivers neutrons using the Proton Synchrotron (PS) 20 GeV/c proton beam impinging on a lead spallation target. The facility combines a very high instantaneous neutron flux, an excellent time of flight resolution due to the distance between the experimental area and the production target (185 meters), a low intrinsic background and a wide range of neutron energies, from thermal to GeV neutrons. These characteristics provide a unique possibility to perform neutron-induced capture and fission cross-section measurements for applications in nuclear astrophysics and in nuclear reactor technology.The most relevant measurements performed up to now and foreseen for the future will be presented in this contribution. The overall efficiency of the experimental program and the range of possible measurements achievable with the construction of a second experimental area (EAR-2), vertically located 20 m on top of the n_TOF spallation target, might offer a substantial improvement in measurement sensitivities. A feasibility study of the possible realisation of the installation extension will be also presented

Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - N-TOF

The 238U fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The 238U fission cross section has been measured relative to the 235U fission cross section at CERN - n-TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards