The Heat Shock Protein 90 Inhibitor, AT13387, Protects the Alveolo-Capillary Barrier and Prevents HCI-Induced Chronic Lung Injury and Pulmonary Fibrosis

Hydrochloric acid (HCl) exposure causes asthma-like conditions, reactive airways dysfunction syndrome, and pulmonary fibrosis. Heat Shock Protein 90 (HSP90) is a molecular chaperone that regulates multiple cellular processes. HSP90 inhibitors are undergoing clinical trials for cancer and are also being studied in various pre-clinical settings for their anti-inflammatory and anti-fibrotic effects. Here we investigated the ability of the heat shock protein 90 (HSP90) inhibitor AT13387 to prevent chronic lung injury induced by exposure to HCl in vivo and its protective role in the endothelial barrier in vitro. We instilled C57Bl/6J mice with 0.1N HCl (2 µL/g body weight, intratracheally) and after 24 h began treatment with vehicle or AT13387 (10 or 15 mg/kg, SC), administered 3×/week; we analyzed histological, functional, and molecular markers 30 days after HCl. In addition, we monitored transendothelial electrical resistance (TER) and protein expression in a monolayer of human lung microvascular endothelial cells (HLMVEC) exposed to HCl (0.02 N) and treated with vehicle or AT13387 (2 µM). HCl provoked persistent alveolar inflammation; activation of profibrotic pathways (MAPK/ERK, HSP90); increased deposition of collagen, fibronectin and elastin; histological evidence of fibrosis; and a decline in lung function reflected in a downward shift in pressure–volume curves, increased respiratory system resistance (Rrs), elastance (Ers), tissue damping (G), and hyperresponsiveness to methacholine. Treatment with 15 mg/kg AT13387 reduced alveolar inflammation, fibrosis, and NLRP3 staining; blocked activation of ERK and HSP90; and attenuated the deposition of collagen and the development of chronic lung injury and airway hyperreactivity. In vitro, AT13387 prevented HCl-induced loss of barrier function and AKT, ERK, and ROCK1 activation, and restored HSP70 and cofilin expression. The HSP90 inhibitor, AT13387, represents a promising drug candidate for chronic lung injury that can be administered subcutaneously in the field, and at low, non-toxic doses

Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancie

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Magnetic trapping of a cold Rb-Cs atomic mixture

We present an apparatus for the study of an ultracold gaseous atomic mixture of 133Cs and 87Rb. The mixture is prepared using a double magneto-optical trap (MOT) system in which a two-species pyramid MOT acts as a source of cold atoms for a `science' MOT. Measurements of the interspecies trap loss rate coe±cients ¯RbCs and ¯CsRb in the science MOT are reported. After the initial MOT phase, atoms in the mixture are optically pumped into the magnetically trappable jF = 3;mF = ¡3i and jF =1;mF =¡1i states of Cs and Rb (respectively) and loaded into an Io®e-Pritchard magnetic trap. We demonstrate a novel technique for limiting the interspecies loss rate in the science MOT by spatially separating the two trapped atom clouds, which greatly enhances the number of atoms which can be loaded into the magnetic trap

Implementation of the Water Framework Directive: Investigations for establishing a lake typology using littoral macroinvertebrates in the Republic of Ireland

The EU Water Framework Directive requires ecological status to be defined based on the deviation of biological communities away from low impacted reference status. The first step in developing an ecological assessment system is therefore to establish and define type-specific reference communities. Sixty-nine candidate reference lakes were sampled in the Republic of Ireland. Four groups were identified by cluster analysis and a CCA ordination revealed alkalinity, lake area and altitude to be significant determinants of the species data.JRC.H.5-Rural, water and ecosystem resource

Constraining Clouds and Convective Parameterizations in a Climate Model Using Paleoclimate Data

Cloud and convective parameterizations strongly influence uncertainties in equilibrium climate sensitivity. We provide a proof-of-concept study to constrain these parameterizations in a perturbed parameter ensemble of the atmosphere-only version of the Goddard Institute for Space Studies Model E2.1 simulations by evaluating model biases in the present-day runs using multiple satellite climatologies and by comparing simulated δ18O of precipitation (δ18Op), known to be sensitive to parameterization schemes, with a global database of speleothem δ18O records covering the Last Glacial Maximum (LGM), mid-Holocene (MH) and pre-industrial (PI) periods. Relative to modern interannual variability, paleoclimate simulations show greater sensitivity to parameter changes, allowing for an evaluation of model uncertainties over a broader range of climate forcing and the identification of parts of the world that are parameter sensitive. Certain simulations reproduced absolute δ18Op values across all time periods, along with LGM and MH δ18Op anomalies relative to the PI, better than the default parameterization. No single set of parameterizations worked well in all climate states, likely due to the non-stationarity of cloud feedbacks under varying boundary conditions. Future work that involves varying multiple parameter sets simultaneously with coupled ocean feedbacks will likely provide improved constraints on cloud and convective parameterizations. © 2022 The Authors. Journal of Advances in Modeling Earth Systems published by Wiley Periodicals LLC on behalf of American Geophysical Union.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

The Identification of Lake Types using Macrophyte Community Composition in Ireland

The Water Framework Directive requires that lakes be separated into types using physical and chemical factors such as altitude, lake area, depth and alkalinity. The objective of establishing a typology is to minimise variation in biological communities in ‘reference’ condition. Rather than imposing arbitrary physical and chemical boundaries to types (as in system A of the WFD) an alternative approach is to examine lakes of potential reference condition to determine the different types of macrophyte communities expected under natural conditions. Sixty-three lakes of potential reference condition were sampled in 2002 in the Republic of Ireland. Alkalinity was found to be the main factor determining differences in macrophyte composition in the lakes.JRC.H.5-Rural, water and ecosystem resource