After an acute phase of inflammation or injury, restoration of the endothelial barrier is important to regain vascular integrity and to prevent edema formation. However, little is known about ...mediators that control restoration of endothelial barrier function. We show here that oxidized phospholipids that accumulate at sites of inflammation and tissue damage are potent regulators of endothelial barrier function. Oxygenated epoxyisoprostane-containing phospholipids, but not fragmented oxidized phospholipids, exhibited barrier-protective effects mediated by small GTPases Cdc42 and Rac and their cytoskeletal, focal adhesion, and adherens junction effector proteins. Oxidized phospholipid-induced cytoskeletal rearrangements resulted in a unique peripheral actin rim formation, which was mimicked by coexpression of constitutively active Cdc42 and Rac, and abolished by coexpression of dominant-negative Rac and Cdc42. Thus, oxidative modification of phospholipids during inflammation leads to the formation of novel regulators that may be critically involved in restoration of vascular barrier function.
Myelinated fibers are organized into distinct domains that are necessary for saltatory conduction. These domains include the nodes of Ranvier and the flanking paranodal regions where glial cells ...closely appose and form specialized septate-like junctions with axons. These junctions contain a Drosophila Neurexin IV-related protein, Caspr/Paranodin (NCP1). Mice that lack NCP1 exhibit tremor, ataxia, and significant motor paresis. In the absence of NCP1, normal paranodal junctions fail to form, and the organization of the paranodal loops is disrupted. Contactin is undetectable in the paranodes, and K+ channels are displaced from the juxtaparanodal into the paranodal domains. Loss of NCP1 also results in a severe decrease in peripheral nerve conduction velocity. These results show a critical role for NCP1 in the delineation of specific axonal domains and the axon-glia interactions required for normal saltatory conduction.
Stress-induced cardiomyopathy, triggered by acute catecholamine discharge, is a syndrome characterized by transient, apical ballooning linked to acute heart failure and ventricular arrhythmias. Rats ...receiving an acute isoproterenol (ISO) overdose (OV) suffer cardiac apex ischemia-reperfusion damage and arrhythmia, and then undergo cardiac remodeling and dysfunction. Nevertheless, the subcellular mechanisms underlying cardiac dysfunction after acute damage subsides are not thoroughly understood. To address this question, Wistar rats received a single ISO injection (67 mg/kg). We found in vivo moderate systolic and diastolic dysfunction at 2 wk post-ISO-OV; however, systolic dysfunction recovered after 4 wk, while diastolic dysfunction worsened. At 2 wk post-ISO-OV, cardiac function was assessed ex vivo, while mitochondrial oxidative metabolism and stress were assessed in vitro, and Ca(2+) handling in ventricular myocytes. These were complemented with sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA), phospholamban (PLB), and RyR2 expression studies. Ex vivo, basal mechanical performance index (MPI) and oxygen consumption rate (MVO2) were unchanged. Nevertheless, upon increase of metabolic demand, by β-adrenergic stimulation (1-100 nM ISO), the MPI versus MVO2 relation decreased and shifted to the right, suggesting MPI and mitochondrial energy production uncoupling. Mitochondria showed decreased oxidative metabolism, membrane fragility, and enhanced oxidative stress. Myocytes presented systolic and diastolic Ca(2+) mishandling, and blunted response to ISO (100 nM), and all these without apparent changes in SERCA, PLB, or RyR2 expression. We suggest that post-ISO-OV mitochondrial dysfunction may underlie decreased cardiac contractility, mainly by depletion of ATP needed for myofilaments and Ca(2+) transport by SERCA, while exacerbated oxidative stress may enhance diastolic RyR2 activity.
To study the association of different components of physical fitness flexibility, muscle strength and cardiorespiratory fitness (CRF) and a clustered fitness score with health-related quality of life ...(HRQoL) in women with systemic lupus erythematosus (SLE) and to analyze whether participants with high fitness level have better HRQoL.
This cross-sectional study included 70 women with SLE (aged 42.5; SD 13.9 years). The back-scratch test assessed flexibility, the 30-sec chair stand and handgrip strength tests assessed muscle strength, and the 6-min walk test (n = 49) assessed CRF. HRQoL was assessed through the 36-item Short-Form Health Survey (SF-36).
Flexibility was positively associated with the physical function dimension and the physical component summary (PCS) (rpartial between 0.26 and 0.31; p<0.05), and negatively related with social functioning dimension (rpartial = -0.26; p<0.05). Muscle strength was positively associated with the physical function, physical role, bodily pain dimensions and the PCS (rpartial between 0.27 and 0.49; all p<0.05). CRF was positively associated with the physical function and bodily pain dimensions, and PCS (rpartial between 0.39 and 0.65; all p<0.05). The clustered fitness score was associated with the physical function (B = 17.16) and bodily pain (B = 14.35) dimensions, and the PCS (B = 6.02), all p<0.005. Patients with high fitness level had greater scores in the physical function, physical role, and bodily pain dimensions and the PCS, all p≤0.05.
Our study suggests that muscle strength and CRF are positively associated with HRQoL, while flexibility showed contradictory results. These findings highlight the importance of maintaining adequate fitness levels in women with SLE.
The nuclear protein high-mobility group box 1 (HMGB1) can be passively released by necrotic cells or secreted actively by several cell types to regulate immune and inflammatory responses, as well as ...tissue remodeling. We herein aimed to characterize the effect of insulin resistance on HMGB1 in adipose tissue and to examine its potential role as a metabolic regulator in β-pancreatic cells.
Plasma HMGB1 concentration and adipose HMGB1 expression were assessed in relation to obesity and insulin resistance. Cultured adipocytes from lean and obese patients were used to investigate the intracellular distribution and factors regulating HMGB1 release, as well as to test its effects on adipogenesis and lipid metabolism. A regulatory role for HMGB1 in insulin secretion was also investigated.
Circulating HMGB1 was positively associated with body mass index, while adipose HMGB1 mRNA levels correlated with the expression of inflammatory markers. Insulin resistance modified the intracellular distribution of HMGB1 in human adipocytes, with HMGB1 being predominantly nuclear in lean and obese normoglycemic individuals while localized to the cytosol in obese patients with type 2 diabetes. Adipocytes from lean individuals exposed to conditioned media from lipopolysaccharide-stimulated macrophages induced HMGB1 redistribution to the cytoplasm and release. HMGB1 treatment had no effect on differentiation and lipid metabolism in adipocytes. However, HMGB1, whose circulating levels correlated with postload insulin concentration, increased both insulin release and intracellular Ca(2+) concentration in INS-1 cells.
These findings show, for the first time, that HMGB1 expression and release by human adipocytes is altered by inflammatory conditions as those imposed by obesity and insulin resistance. Our data reveal a novel role for HMGB1 as a stimulatory factor of insulin secretion of β-pancreatic cells.
•MnO2-based cathodes for their application in single-chamber MFCs.•CNTs as support materials improve MFC performance compared with black acetylene.•PTFE as binder for MnO2-based cathodes greatly ...affects MFC performance.•Significant COD and heavy metal removal in MFCs using MnO2-based cathodes.•Pressure method as preferable cathode construction technique versus spraying.
Microbial Fuel Cells (MFCs) are a promising technology that offers new opportunities for bioenergy generation with simultaneous wastewater treatment. The search for new and inexpensive catalysts that replace precious metal-based materials for their application in air-cathode single-chamber MFCs is crucial for improving the efficiency of this technology and, thus, for its commercialization and scaling-up in the field of wastewater treatment. In this work, several types of cathodes consisting of a mixture of MnO2 as catalyst material and two different additive conductor supports, carbon nanotubes (CNTs) and acetylene black (AB), respectively, are investigated in single-chamber MFCs, in the presence and in the absence of a polymer binder, polytetrafluoroethylene (PTFE), both in terms of power performance and wastewater treatment (COD and heavy metal removal). Furthermore, the influence of two preparation methods to fix the above mixtures onto carbon cloth electrodes, spraying and mechanical pressure techniques, are compared to optimize cathode construction. Maximum values of current and power densities were observed for the cathode based on MnO2/CNT/PTFE prepared by mechanical pressure, 1.536mAdm−3 and 511.11mWm−3, respectively. This cathode configuration achieved the maximum chemical oxygen demand (COD) removal with a value of 77% after 240h of MFC operation using wastewater as fuel. The analysis of the removal of heavy metals (63Cu, 66Zn, 111Cd, 121Sb, 208Pb, 55Mn and 56Fe) from wastewater in the different MFC types offered removal efficiencies within the interval 60–97% for most of the metals studied.
We study the Maximal Covering Location Problem with Accessibility Indicators and Mobile Units that maximizes the facilities coverage, the accessibility of the zones to the open facilities, and the ...spatial disaggregation. The main characteristic of our problem is that mobile units can be deployed from open facilities to extend the coverage, accessibility, and opportunities for the inhabitants of the different demand zones. We formulate the Maximal Covering Location Problem with Accessibility Indicators and Mobile Units as a mixed-integer linear programming model. To solve larger instances, we propose a matheuristic (combination of exact and heuristic methods) composed of an Estimation of Distribution Algorithm and a parameterized Maximal Covering Location Problem with Accessibility Indicators and Mobile Units integer model. To test our methodology, we consider the Maximal Covering Location Problem with Accessibility Indicators and Mobile Units model to cover the low-income zones with Severe Acute Respiratory Syndrome Coronavirus 2 patients. Using official databases, we made a set of instances where we considered the poverty index, number of population, locations of hospitals, and Severe Acute Respiratory Syndrome Coronavirus 2 patients. The experimental results show the efficiency of our methodologies. Compared to the case without mobile units, we drastically improve the coverage and accessibility for the inhabitants of the demand zones.
•A new version of maximal covering location problem is introduced.•Mobile units related to the facilities optimize the accessibility indicators.•The instances set proposed is based on the COVID-19 situation in Mexico.•A mixed-integer linear programming model solves small and medium size instances.•A matheuristic is proposed to solve large instances.
Breast cancer is one of the most common malignancies worldwide and the most common form of cancer in women. A large proportion of patients begin with localized disease and undergo treatment with ...curative intent, while another large proportion of patients debuts with disseminated metastatic disease. In the last subgroup of patients, the prognosis in recent years has changed radically, given the existence of different targeted therapies thanks to the discovery of different biomarkers. Serological, histological, and genetic biomarkers have demonstrated their usefulness in the initial diagnosis, in the follow-up to detect relapses, to guide targeted treatment, and to stratify the prognosis of the most aggressive tumors in those with breast cancer. Molecular markers are currently the basis for the diagnosis of metastatic disease, given the wide variety of chemotherapy regions and existing therapies. These markers have been a real revolution in the therapeutic arsenal for breast cancer, and their diagnostic validity allows the classification of tumors with higher rates of relapse, aggressiveness, and mortality. In this sense, the existence of therapies targeting different molecular alterations causes a series of changes in tumor biology that can be assessed throughout the course of the disease to provide information on the underlying pathophysiology of metastatic disease, which allows us to broaden our knowledge of the different mechanisms of tissue invasion. Therefore, the aim of the present article is to review the clinical, diagnostic, predictive, prognostic utility and limitations of the main biomarkers available and under development in metastatic breast cancer.
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