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Due to the implications of poly- and perfluoroalkyl substances (PFAS) on the environment and public health, great attention has been recently made to finding innovative materials and methods for PFAS removal. In this work, PFAS is considered universal contamination which can be found in many wastewater streams. Conventional materials and processes used to remove and degrade PFAS do not have enough competence to address the issue particularly when it comes to eliminating short-chain PFAS. This is mainly due to the large number of complex parameters that are involved in both material and process designs. Here, we took the advantage of artificial intelligence to introduce a model (XGBoost) in which material and process factors are considered simultaneously. This research applies a machine learning approach using data collected from reported articles to predict the PFAS removal factors. The XGBoost modeling provided accurate adsorption capacity, equilibrium, and removal estimates with the ability to predict the adsorption mechanisms. The performance comparison of adsorbents and the role of AI in one dominant are studied and reviewed for the first time, even though many studies have been carried out to develop PFAS removal through various adsorption methods such as ion exchange, nanofiltration, and activated carbon (AC). The model showed that pH is the most effective parameter to predict PFAS removal. The proposed model in this work can be extended for other micropollutants and can be used as a basic framework for future adsorbent design and process optimization.

Given that not all points on the efficient portfolio frontier in the mean-variance space have constant returns to scale, and investments are determined according to the investor’s preferences, as i...

There is abundant evidence that infectious sepsis both in humans and mice with polymicrobial sepsis results in robust activation of complement. Major complement activation products involved in sepsis include C5a anaphylatoxin and its receptors (C5aR1 and C5aR2) and, perhaps, the terminal complement activation product, C5b-9. These products (and others) also cause dysfunction of the innate immune system, with exaggerated early proinflammatory responses, followed by decline of the innate immune system, leading to immunosuppression and multiorgan dysfunction. Generation of C5a during sepsis also leads to activation of neutrophils and macrophages and ultimate appearance of extracellular histones, which have powerful proinflammatory and prothrombotic activities. The distal complement activation product, C5b-9, triggers intracellular Ca(2+) fluxes in epithelial and endothelial cells. Histones activate the NLRP3 inflammasome, products of which can damage cells. C5a also activates MAPKs and Akt signaling pathways in cardiomyocytes, causing buildup of [Ca(2+)]i, defective action potentials and substantial cell dysfunction, resulting in cardiac and other organ dysfunction. Cardiac dysfunction can be quantitated by ECHO-Doppler parameters. In vivo interventions that block these complement-dependent products responsible for organ dysfunction in sepsis reduce the intensity of sepsis. The obvious targets in sepsis are C5a and its receptors, histones, and perhaps the MAPK pathways. Blockade of C5 has been considered in sepsis, but the FDA-approved antibody (eculizumab) is known to compromise defenses against neisseria and pneumonococcal bacteria, and requires immunization before the mAb to C5 can be used clinically. Small molecular blocking agents for C5aRs are currently in development and may be therapeutically effective for treatment of sepsis.

Melia azedarach L. is an economically and medicinally important woody tree that is traditionally used for management of malaria, diabetes and skin diseases. This study was performed to survey the effects of different cytokinin combinations on direct in vitro regeneration of M. azedarach L. The explants were grown on semisolid Murashige and Skoog (MS) medium supplemented with a combination of BAP and TDZ (0, 0.5, 1 and 1.5 mg l−1) with IBA (0.1 mg l−1) and GA3 (0.5 mg l−1). The highest regenerated shoot number (6.5) was obtained on MS medium fortified with 0.1 mg l−1 TDZ plus 2 mg l−1 BAP in 4 weeks after culture. Also highest shoot length (8 cm) was obtained in 0.5 mg l−1 BAP plus TDZ (0.1, 0.25 and 0.5). In addition, the best rate of root induction (80%) and a number of roots per rooted shoot (2.3) were observed on 1/2 MS containing the 0.25 mg l−1 IBA. Regenerated plantlets were successfully acclimatized and hardened to culture room and then transferred to greenhouse; the plantlets survival rate was 90%. The present optimized regeneration protocol will serve as alternative approaches for Persian lilac conservation and large-scale propagation.

The aim of this thesis was to describe, investigate and compare the effects of smoking and atopy in asthma and COPD. A part of the research focused on asthmatic patients with ageing and smoking COPD phenotype, resulting in difficulties to discriminate between these two disorders. The following conclusions can be drawn: • Pathologists are able to differentiate between asthma and COPD, on condition they use a number of pathological criteria, and take the clinical setting into account, particularly the use of inhaled corticosteroids (ICS). • Prevalence of atopy is significantly higher in COPD patients who are males, have overweight and lower age. Atopy significantly associates with higher prevalence of respiratory symptoms and higher likelihood to lose cough upon treatment with busedonide.• Absence of atopy and non-ICS use contribute independently to higher numbers of IL-17 expressing cells. IL17-positive cells were found to be predominantly neutrophils. • CCL20 levels are higher in sputum of asthmatics who use ICS, whereas glucocorticoids increase the release of CCL20 by primary bronchial epithelial cells in vitro.• Smoking associates with higher epithelial HDAC-2 expression in airway biopsies from asthmatics, independent of ICS-use. • Increased Eosinophil Peroxidase (EPX) immunopositivity in airway biopsies from asthmatic subjects associates significantly with lower intact epithelium, particularly in uncontrolled asthma.In summary: heterogeneous populations of asthma and COPD patients determine the broad spectrum of obstructive airway diseases. Smoking and atopy may modulate the underlying inflammatory and clinical phenotype, and affect corticosteroid responsiveness. This heterogeneity should be taken into account when designing clinical studies.

The RNA-binding protein HuR (elavl1) positively regulates the expression of its targets by increasing mRNA stability and translation. Th2 and Th17 related genes play critical roles in airway inflammation in both mouse and human. Using in vitro and in vivo studies, we have previously shown that these proinflammatory genes are regulated by HuR. Here, we generated a conditional ablation of HuR in T cells (distal Lck-cre HuRfl/fl). We found significant decreases in Th2 differentiation, cytokine production, and lung inflammation in an alum-emulsified ovalbumin (ova-alum) model of allergic airway inflammation using this novel mouse model. We hypothesized that HuR might similarly regulate lung inflammation in human asthma. Using peripheral CD4+ T cells from 45 asthmatic patients, we found the inhibitory effect of the HuR-specific inhibitor CMLD-2, as well as an AMPK activator (acadesine aka AICAR), on both Th2/Th17 signature cytokines in both protein and mRNA levels. Our asthmatics were classified into type 2 high or non-type 2 high based on their blood eosinophil and FeNO levels. Interestingly, there were significant positive correlations between Th2 cytokine levels in CD4+ cells with levels of eosinophils and FeNO from asthmatics. Surprisingly, IFNγ (protein and mRNA) were also markedly decreased by HuR inhibition. Our bioinformatic studies also revealed proteins with high interaction with HuR including MAPK14/p38α and PTEN, common in the pathways with IFNγ, are affected by HuR inhibitor. Taken together, our mouse and human data suggest that HuR plays a crucial permissive role in both allergen- and nonallergen-driven airway inflammation by regulating key genes and that interfering with its function may be a novel way to treat asthma. Supported by R01: AI080870, R21: AI079341

The RNA-binding protein HuR (Elavl1) plays a critical role in T cell activation and function by regulating the stability and transport of its mRNA targets. To study the role of HuR in regulatory T cell (Treg) development and function, we generated the Foxp3YFP-Cre HuRfl/fl mouse in which HuR is selectively deleted in CD4+Foxp3+ cells, a lineage with crucial roles in self-tolerance and immune homeostasis. Foxp3+ Treg-specific HuR deletion results in abnormal phenotypic features (scurfy-like mice, hair loss, stippled/banded tails, significant failure to thrive, splenomegaly and multi-organ inflammation, including lung and lymphoid organs), likely the result of reduced Treg function, a phenotype similar to human IPEX syndrome (an autoimmune disorder). Unexpectedly, our RNAseq data showed reduced levels of TLR4, IL-1β, IL-18 and NLRP3 mRNA expression in HuR deficient Tregs (Foxp3YFP-Cre HuRfl/fl). In control WT mice, in vitro LPS treatment of Tregs induced increased expression of TLR4 and IL-1β production, associated with increased nucleocytoplasmic shuttling of HuR. In contrast, the expression of TLR4 and IL-1β was significantly decreased in Tregs from Foxp3YFP-Cre HuRfl/fl mice. Homozygous Foxp3YFP-Cre HuRfl/fl mice had statistically significant reductions in Treg numbers and increased frequency of activated effector T cells. We were also able to detect IL-1β secretion from WT Tregs in vitro following LPS treatment, which was amplified by the addition of DAMP agonists (e.g., ATP or Nigericin). In contrast, HuR KO Tregs had decreases in IL-1β secretion. Together, our data show that HuR is critical for normal CD4+Foxp3+ regulatory T cell function. Supported by grants from NIH (R01 AI080870 and R21 AI079341).

Polymicrobial sepsis (after cecal ligation and puncture, CLP) causes robust complement activation with release of C5a. Many adverse events develop thereafter and will be discussed in this review article. Activation of complement system results in generation of C5a which interacts with its receptors (C5aR1, C5aR2). This leads to a series of harmful events, some of which are connected to the cardiomyopathy of sepsis, resulting in defective action potentials in cardiomyocytes (CMs), activation of the NLRP3 inflammasome in CMs and the appearance of extracellular histones, likely arising from activated neutrophils which form neutrophil extracellular traps (NETs). These events are associated with activation of mitogen-activated protein kinases (MAPKs) in CMs. The ensuing release of histones results in defective action potentials in CMs and reduced levels of [Ca(2+)]i-regulatory enzymes including sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2) and Na(+)/Ca(2+) exchanger (NCX) as well as Na(+)/K(+)-ATPase in CMs. There is also evidence that CLP causes release of IL-1β via activation of the NLRP3 inflammasome in CMs of septic hearts or in CMs incubated in vitro with C5a. Many of these events occur after in vivo or in vitro contact of CMs with histones. Together, these data emphasize the role of complement (C5a) and C5a receptors (C5aR1, C5aR2), as well as extracellular histones in events that lead to cardiac dysfunction of sepsis (septic cardiomyopathy).

We determined the roles of TLR3 and TLR9 in adverse events of polymicrobial sepsis, with a focus on development of septic cardiomyopathy, progression of which we have recently shown to be complement- and histones-dependent. So Wt, TLR3-knocked out (K.O.), and TLR9-K.O. mice were subjected to polymicrobial sepsis following cecal ligation and puncture (CLP). In the absence of either TLR3 or TLR9, the intensity of echocardiogram (Echo)-Doppler dysfunction during development of cardiomyopathy was substantially reduced in the K.O. mice. Based on our prior studies emphasizing the adverse effects of plasma C5a and histones in the cardiomyopathy of sepsis, in TLR3- and TLR9-K.O. mice, there were striking reductions in plasma levels of C5a and histones as well as reduced levels of cytokines in plasma and heart tissue after CLP. Since we know that histones cause cardiac dysfunction, rat cardiomyocytes (CMs) were exposed in vitro to the histones (purified from calf thymus), which caused bleb formation on the surfaces of CMs, suggesting histones may perturb the cell membrane of CMs. In vitro, exposure of CMs to the histones for 3 hours caused lactate dehydrogenase release from CMs. These data indicate that sepsis-induced cardiac dysfunction requires presence of TLR3 and TLR9 and may be linked to histone-induced damage of CMs.

Drug-target protein interaction (DTI) prediction is considered as a fundamental step in the process of drug discovery. The experimental methods in this domain, despite having accurate and beneficial results, are time-consuming. In the last few years, not only have these computational methods been overcome to these problems, but the results of them have been extremely efficient. One type of these techniques is based on network prediction on biomedical networks. Today, different network-based approaches have been suggested for identifying relations between drugs and targets which work on homogeneous networks well. But these approaches do not consider edge semantics in the network. In this paper, we employ the edge2vec algorithm for node embedding on the heterogeneous network and then by the use of the support vector machine method to predict drug-target interactions. Our method has obtained a significant accuracy than the existing methods.

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defect in one of the components of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme. The enzyme is at least composed of membrane-bound subunits gp91-phox and p22-phox (also named cytochrome b558 ), and cytosolic ones p40-phox, p47-phox and p67-phox. A defect in the enzyme activity leads to impaired intracellular killing of phagocytic cells. The CYBA gene encoding p22-phox is located on chromosome 16q24. In this study, new genetic changes of CYBA gene in 22 Iranian patients with autosomal recessive-CGD (AR-CGD) were identified. Twenty-two patients with CGD were referred to Immunology, Asthma and Allergy Research Institute (IAARI) and enrolled in this study based on defect in NADPH oxidase activity, demographic data and clinical histories. All patients had p22-phox deficiency based on Western blotting. Genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs), and PCR followed by direct sequencing was performed to find p22-phox mutations. Mutation analysis of CYBA revealed 12 different mutations, including three novel mutations: one was deletion of exon 1, and two were point mutations in exon 3 (c.136G>A (p.Gly46Ser)), and exon 6 (c.388C>T (p.Gln130X)). Three new mutations of CYBA gene in four of 22 Iranian patients with AR-CGD were found. These three novel mutations can partly complete the database of Human Gene Mutation Database (HGMD) and other related ones. It can also be helpful for further prenatal diagnosis in the affected families. Given that currently bone marrow transplantation is considered to be the curative treatment for patients with CGD, finding mutations will also be useful for timely decision-making in bone marrow transplantation.

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo. In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.—Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

Histones invoke strong proinflammatory responses in many different organs and cells. We assessed biological responses to purified or recombinant histones, using human and murine phagocytes and mouse lungs. H1 had the strongest ability in vitro to induce cell swelling independent of requirements for toll-like receptors (TLRs) 2 or 4. These responses were also associated with lactate dehydrogenase release. H3 and H2B were the strongest inducers of [Ca2+]i elevations in phagocytes. Cytokine and chemokine release from mouse and human phagocytes was predominately a function of H2A and H2B. Double TLR2 and TLR4 knockout (KO) mice had dramatically reduced cytokine release induced in macrophages exposed to individual histones. In contrast, macrophages from single TLR-KO mice showed few inhibitory effects on cytokine production. Using the NLRP3 inflammasome protocol, release of mature IL-1β was predominantly a feature of H1. Acute lung injury following the airway delivery of histones suggested that H1, H2A, and H2B were linked to alveolar leak of albumin and the buildup of polymorphonuclear neutrophils as well as the release of chemokines and cytokines into bronchoalveolar fluids. These results demonstrate distinct biological roles for individual histones in the context of inflammation biology and the requirement of both TLR2 and TLR4.

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6−/− mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6−/− mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6−/− mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.

There is abundant evidence in sepsis that systemic activation of the complement system is robust and often is associated with multiorgan damage, septic shock, death, and a variety of other harmful complications, including progressive immunosuppression and impairment of the inflammatory system. Sepsis, whether in animals or humans, has been associated with activation of the classical, alternative, and lectin pathways of complement. Studies in mice with polymicrobial sepsis (after cecal ligation and puncture) have been especially informative because of availability of mice with knockout of complement proteins and receptors for complement activation products (such as C5a and C3a) and availability of many reagents (antibodies) that can provide important information. Strong evidence has been obtained that C5a interacting with its receptors (C5aR1 and 2) induces a series of events that interfere with cell, tissue, and organ function. In particular, this has led to much information on how complement can be linked to cardiac dysfunction of sepsis, which may be lethal.

RNA-binding protein human antigen R (HuR) is a master regulator of gene expression in human pathophysiology. Our animal studies in the past showed multiple critical roles for HuR in regulating proinflammatory markers in CD4+ T cells. We hypothesized HuR plays an important role in expression of GATA3 and Th2 cytokines in type 2 high asthma and its inhibition impairs these Th2 inflammatory responses. Peripheral CD4+ T cells were isolated from 26 healthy controls and 32 type 2 high asthmatics (blood eosinophil ≥300 cells/μl or FeNO levels ≥25ppb) and stimulated with anti-CD3/CD28 for 4 days, followed by determination of GATA3 and cytokines expression by flow cytometry and LEGENDplex. HuR levels were quantitated by Western blot, flow cytometry, and qPCR. Inhibition of inflammatory responses was evaluated using a cumarin-derived small molecule named CMLD-2 (a HuR-specific inhibitor). Actinomycin D treatment was used to measure mRNA decay rates of targeted HuR mRNAs. HuR protein levels in CD4+ T cells was significantly higher in type 2 high asthmatics compared to healthy controls. The expression and secretion of Th2 cytokines were significantly higher in asthmatics compared to controls. Our further mRNA and protein studies in type 2 high asthmatics showed reduced expression of GATA3 and Th2 cytokines after CMLD-2 treatment. There was also a significant reduction in gata3 mRNA stability with CMLD-2 treatment, compared with vehicle in the asthmatics. Our study is the first to demonstrate the role of RNA-binding protein HuR in type 2 high asthmatics and that interfering with HuR action using CMLD-2 ameliorates GATA3 and Th2 cytokines production. This data suggests HuR may serve as a novel and powerful therapeutic target to treat type 2 high asthmatics.

The RNA binding protein HuR (elavl1) stabilizes target mRNAs and aids in their transport to the heavy polysomes, ultimately resulting in increased protein expression. We have previously shown that HuR plays a critical role in T helper cell fate decisions, with HuR deficient mice having significant impairment in Th2 differentiation. Interestingly, HuR deficiency also leads to large increases in IL-2 production. We hypothesized that HuR is important for normal T cell activation and expansion. To investigate this, we used mouse models in which HuR was conditionally ablated during T cell development either early at the double positive stage (CD4-Cre ROSA HuRfl/fl) or late (distal Lck-Cre ROSA HuRfl/fl). Upon activation in vitro, HuR KO T cells had significant reductions in CD25 (IL-2Ra) protein and RNA. An in vivo OVA challenge model was used to determine ascertain the effects of HuR KO on airway inflammation. Despite only half of CD4+ T cells in dLck-Cre HuR KO mice lacking HuR, there was a significant decrease in total inflammation, with essentially no T cell infiltrate. These mice also had significantly reduced BAL IL-13. Furthermore, mice were immunized with either OVA or KLH, boosted 10 days later, and antigen specific proliferative responses measured in vitro. T cells lacking HuR had profound proliferation defects compared to control cells, regardless of the antigen system employed. Interestingly, non-specific CD3/CD28 stimulation only partially restored these proliferative defects. RNA-Seq analysis of activated HuR deficient T cells indicated altered expression in multiple genes associated with T cell activation and function. We conclude HuR function is vital for normal antigen-specific activation and proliferation in CD4+ T cells.

There is accumulating evidence during sepsis that cardiomyocyte (CM) homeostasis is compromised, resulting in cardiac dysfunction. An important role for complement in these outcomes is now demonstrated. Addition of C5a to electrically paced CMs caused prolonged elevations of intracellular Ca2+ concentrations during diastole, together with the appearance of spontaneous Ca2+ transients. In polymicrobial sepsis in mice, we found that three key homeostasis-regulating proteins in CMs were reduced: Na+/K+-ATPase, which is vital for effective action potentials in CMs, and two intracellular Ca2+ concentration regulatory proteins, that is, sarcoplasmic/endoplasmic reticulum calcium ATPase 2 and the Na+/Ca2+ exchanger. Sepsis caused reduced mRNA levels and reductions in protein concentrations in CMs for all three proteins. The absence of either C5a receptor mitigated sepsis-induced reductions in the three regulatory proteins. Absence of either C5a receptor (C5aR1 or C5aR2) diminished development of defective systolic and diastolic echocardiographic/Doppler parameters developing in the heart (cardiac output, left ventricular stroke volume, isovolumic relaxation, E′ septal annulus, E/E′ septal annulus, left ventricular diastolic volume). We also found in CMs from septic mice the presence of defective current densities for Ik1, l-type calcium channel, and Na+/Ca2+ exchanger. These defects were accentuated in the copresence of C5a. These data suggest complement-related mechanisms responsible for development of cardiac dysfunction during sepsis.

Following a severe primary infection or trauma, the risk of developing pneumonia increases due to acquired immune defects collectively known as sepsis-induced immunosuppression. In this issue of Immunity, Roquilly et al. (2017) show that dendritic cells and macrophages developing in the lung after the resolution of a severe infection acquire tolerogenic properties that contribute to persistent immunosuppression and susceptibility to secondary infections.

In this mini review, we describe the molecular mechanisms in polymicrobial sepsis that lead to a series of adverse events including activation of inflammatory and prothrombotic pathways, a faulty innate immune system, and multiorgan dysfunction. Complement activation is a well-established feature of sepsis, especially involving generation of C5a and C5b-9, along with engagement of relevant receptors for C5a. Activation of neutrophils by C5a leads to extrusion of DNA, forming neutrophil extracellular traps that contain myeloperoxidase and oxidases, along with extracellular histones. Generation of the distal complement activation product, C5b-9 (known as the membrane attack complex, MAC), also occurs in sepsis. C5b-9 activates the NLRP3 inflammasome, which damages mitochondria, together with appearance in plasma of IL-1β and IL-18. Histones are strongly proinflammatory as well as being prothrombotic, leading to activation of platelets and development of venous thrombosis. Multiorgan dysfunction is also a feature of sepsis. It is well known that septic cardiomyopathy, which if severe, can lead to death. This complication in sepsis is linked to reduced levels in cardiomyocytes of three critical proteins (SERCA2, NCX, Na+/K+-ATPase). The reductions in these three key proteins are complement- and histone-dependent. Dysfunction of these ATPases is linked to the cardiomyopathy of sepsis. These data suggest novel targets in the setting of sepsis in humans.

Sepsis is the leading cause of death in the intensive care unit with an overall mortality rate of 20%. Individuals who are obese and have type 2 diabetes have increased recurrent, chronic, nosocomial infections that worsen the long-term morbidity and mortality from sepsis. Additionally, animal models of sepsis have shown that obese, diabetic mice have lower survival rates compared with nondiabetic mice. Neutrophils are essential for eradication of bacteria, prevention of infectious complications, and sepsis survival. In diabetic states, there is a reduction in neutrophil chemotaxis, phagocytosis, and reactive oxygen species (ROS) generation; however, few studies have investigated the extent to which these deficits compromise infection eradication and mortality. Using a cecal ligation and puncture model of sepsis in lean and in diet-induced obese mice, we demonstrate that obese diabetic mice have decreased “emergency hematopoiesis” after an acute infection. Additionally, both neutrophils and monocytes in obese, diabetic mice have functional defects, with decreased phagocytic ability and a decreased capacity to generate ROS. Neutrophils isolated from obese diabetic mice have decreased transcripts of Axl and Mertk, which partially explains the phagocytic dysfunction. Furthermore, we found that exogenous GM-CSF administration improves sepsis survival through enhanced neutrophil and monocytes phagocytosis and ROS generation abilities in obese, diabetic mice with sepsis.

Older asthmatic patients may develop fixed airway obstruction and clinical signs of chronic obstructive pulmonary disease (COPD). We investigated the added value of pathological evaluation of bronchial biopsies to help differentiate asthma from COPD, taking into account smoking, age, and inhaled corticosteroid (ICS) use. Asthma and COPD patients (24 of each category) were matched for ICS use, age, FEV1, and smoking habits. Five pulmonary and five general pathologists examined bronchial biopsies using an interactive website, without knowing patient information. They were asked to diagnose asthma or COPD on biopsy findings in both a pairwise and randomly mixed order of cases during four different phases, with intervals of 4–6 weeks, covering a maximal period of 36 weeks. Clinically concordant diagnoses of asthma or COPD varied between 63 %-73 %, without important differences between pairwise vs randomly mixed examination or between general vs pulmonary pathologists. The highest percentage of concordant diagnoses was in young asthmatic patients without ICS use and in COPD patients with ICS use. In non ICS users with fixed airway obstruction, a COPD diagnosis was favored if abnormal presence of glands, squamous metaplasia, and submucosal infiltrate was present and an asthma diagnosis in case of abnormal presence of goblet cells. In ICS users with fixed airway obstruction, abnormal presence of submucosal infiltrates, basement membrane thickening, eosinophils, and glands was associated with asthma. Histological characteristics in bronchial biopsies are reproducibly recognized by pathologists, yet the differentiation by histopathology between asthma and COPD is difficult without information about ICS use. Electronic supplementary material The online version of this article (doi:10.1007/s00428-015-1824-6) contains supplementary material, which is available to authorized users.

Discussion of how humans with sepsis develop increased levels of PD-1 and PD-L1 on their blood leukocytes, which can be neutralized with antibodies and reversing leukocyte dysfunctions.

Sepsis develops when an infection surpasses local tissue containment. A series of dysregulated physiologic responses are generated, leading to organ dysfunction and a 10% mortality risk. When patients with sepsis demonstrate elevated serum lactates and require vasopressor therapy to maintain adequate blood pressure in the absence of hypovolemia, they are in septic shock with an in-hospital mortality rate greater than 40%. With improvements in intensive care treatment strategies, overall sepsis mortality has diminished to approximately 20% at 30 days; however, mortality continues to steadily climb after recovery from the acute event. Traditionally, it was thought that the complex interplay between inflammatory and anti-inflammatory responses led to sepsis-induced organ dysfunction and mortality. However, a closer examination of those who die long after sepsis subsides reveals that many initial survivors succumb to recurrent, nosocomial, and secondary infections. The co-morbidly challenged, physiologically frail diabetic individuals suffer the highest infection rates. Recent reports suggest that even after clinical “recovery” from sepsis, persistent alterations in innate and adaptive immune responses exists resulting in chronic inflammation, immune suppression, and bacterial persistence. As sepsis-associated immune defects are associated with increased mortality long-term, a potential exists for immune modulatory therapy to improve patient outcomes. We propose that diabetes causes a functional immune deficiency that directly reduces immune cell function. As a result, patients display diminished bactericidal clearance, increased infectious complications, and protracted sepsis mortality. Considering the substantial expansion of the elderly and obese population, global adoption of a Western diet and lifestyle, and multidrug resistant bacterial emergence and persistence, diabetic mortality from sepsis is predicted to rise dramatically over the next two decades. A better understanding of the underlying diabetic-induced immune cell defects that persist following sepsis are crucial to identify potential therapeutic targets to bolster innate and adaptive immune function, prevent infectious complications, and provide more durable diabetic survival.

Th17-mediated neutrophilic airway inflammation has been implicated in decreased response to glucocorticoids in asthma. We aimed to investigate the effect of glucocorticoids on the airway epithelial release of the neutrophilic and Th17-cell chemoattractant CCL20.We studied CCL20 and CXCL8 sputum levels in asthmatic subjects using inhaled glucocorticoids or not, and the effect of budesonide on CCL20 and CXCL8 production in primary bronchial epithelial cells. The mechanism behind the effect of budesonide-induced CCL20 production was studied in 16HBE14o- cells using inhibitors for the glucocorticoid receptor, intracellular pathways and metalloproteases.We observed higher levels of CCL20, but not CXCL8, in the sputum of asthmatics who used inhaled glucocorticoids. CCL20 levels correlated with inhaled glucocorticoid dose and sputum neutrophils. Budesonide increased tumour necrosis factor (TNE)-alpha-induced CCL20 by primary bronchial epithelium, while CXCL8 was suppressed. In 16HBE14o- cells, similar effects were observed at the CCL20 protein and mRNA levels, indicating transcriptional regulation. Although TNF-alpha-induced CCL20 release was dependent on the ERK, p38 and STAT3 pathways, the increase by budesonide was not. Inhibition of glucocorticoid receptor or ADAM17 abrogated the budesonide-induced increase in CCL20 levels.We show that glucocorticoids enhance CCL20 production by bronchial epithelium, which may constitute a novel mechanism in Th17-mediated glucocorticoid-insensitive inflammation in asthma.

At the present paper, the new concepts of fuzzy quasi norm, fuzzy Banach space, fuzzy quasi continuity and fuzzy quasi boundedness is introduced. Furthermore, we define the fuzzy quasi operator norm and also it is shown that the set all of fuzzy quasi bounded operator from X to Y is fuzzy quasi Banach space. Finally, we have introduced and investigated some notions and some results on *-algebra theory.

It is well known that cardiac dysfunction develops during sepsis in both humans and in rodents (rats, mice). These defects appear to be reversible, since after "recovery" from sepsis, cardiac dysfunction disappears and the heart returns to its function that was present before the onset of sepsis. Our studies, using in vivo and in vitro models, have demonstrated that C5a and its receptors (C5aR1 and C5aR2) play key roles in cardiac dysfunction developing during sepsis. Use of a neutralizing antibody to C5a largely attenuates cardiac dysfunction and other adverse events developing during sepsis. The molecular basis for cardiac dysfunctions is linked to generation of C5a and its interaction with C5a receptors present on surfaces of cardiomyocytes (CMs). It is established that C5a interactions with C5a receptors leads to significant reductions involving faulty contractility and relaxation in CMs. In addition, C5a interactions with C5a receptors on CMs results in reductions in Na+/K+-ATPase in CMs. This ATPase is essential for intact action potentials in CMs. The enzymatic activity and protein for this ATPase were strikingly reduced in CMs during sepsis by unknown mechanisms. In addition, C5a interactions with C5aRs also caused reductions in CM homeostatic proteins that regulate cytosolic [Ca2+]i in CMs: sarco/endoplasmic reticulum Ca2+-ATPase2 (SERCA2) and Na+/Ca2+ exchanger (NCX). In the absence of C5a receptors, defects in SERCA2 and NCX in CMs after sepsis are strikingly attenuated. These observations suggest new strategies to protect the heart from dysfunction developing during sepsis.

While the phlogistic activities of IgM or IgG immune complexes (IC) have been well established as complement-activating agents and seem likely to play important roles in humans with vasculitis, certain types of glomerulonephritis as well as in a variety of autoimmune diseases, the predominant clinical strategies have involved the use of immunosuppressive or antiinflammatory drugs. Over the past decade, new insights into molecular events developing during IC models in rodents have identified new phlogistic products that may be candidates for therapeutic blockade. Extracellular histones, located in the web-like structures of neutrophil extracellular traps (NETs), are released from complement-activated polymorphonuclear neutrophils (PMNs) downstream of IC deposition. Extracellular histones appear to be a new class of highly tissue-damaging products derived from complement-activated PMNs. Histones have also been discovered in cell-free broncho-alveolar lavage fluids (BALFs) from humans with acute respiratory distress syndrome (ARDS). Recent studies emphasize that, in the setting of ARDS-like reactions in rodents, extracellular histones are released and are exceedingly proinflammatory, tissue damaging and prothrombotic. Such studies suggest that in humans with ARDS, extracellular histones may represent therapeutic targets for blockade.

C5a is an inflammatory mediator generated by complement activation that positively regulates various arms of immune defense, including Toll-like receptor 4 (TLR4) signaling. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is activated by pathogen products and cellular/tissue damage products and is a major contributor of IL-1β. In this study, we investigate whether C5a modulates lipopolysaccharide- (LPS-) induced NLRP3 inflammasome activation in myeloid cells. Appearance of plasma IL-1βduring endotoxemia was reduced inC5aR1-/-mice when compared to wild-type mice. In vitro, C5a significantly enhanced LPS-induced production of IL-1βin bone marrow Ly6C-high inflammatory monocytes, accompanied by augmented intracellular pro-IL-1βexpression. This effect was abolished during p38 blockade by SB 203580 and in the absence of C5aR1. Conversely, C5a suppressed LPS-induced macrophage production of IL-1β, which was accompanied by attenuated levels of pro-IL-1β, NLRP3, and caspase-1 expression. C5a’s suppressive effects were negated during phosphoinositide 3-kinase (PI3K) inhibition by wortmannin but were largely preserved in the absence of C5aR1. Thus, C5a bidirectionally amplifies TLR4-mediated NLRP3 inflammasome activation in monocytes while suppressing this pathway in macrophages. However, as C5aR1 deficiency attenuates the IL-1βresponse to LPS challenge in vivo, our results suggest overall that C5a augments physiologic inflammasome responses.

Chronic granulomatous disease (CGD) is a rare immunodeficiency disorder in which phagocytic leukocytes fail to generate superoxide (O-2(-)) and antimicrobial oxidants. The therapeutic validity of interferon-gamma (IFN-gamma) has been well established in CGD patients but its underlying mechanisms remain poorly understood. One probable mechanism has been suggested to be modulation of nitric oxide (NO) release from phagocytic cells. Herein, we investigated NO production from neutrophil cells in CGD patients on treatment with IFN-gamma in vivo and in vitro.We measured NO levels in sera from 19 CGD patients (group I: 7 patients treated with TMP-SMX, group II: 12 patients treated with TMP-SMX and IFN-gamma simultaneously) and healthy control individuals (8 cases). We also measured NO production from neutrophils in both patients groups as well as in control group after adding 100 U IFN-gamma in vitro.Our results showed that there was a significant difference between the groups in the NO levels of serum; patients who received IFN-gamma had significantly higher amount of NO than the other groups. Besides, NO levels increased significantly after adding 100 U IFN-gamma in vitro in three studied groups, considerably in the patients on treatment with IFN-gamma.As a brief conclusion, the effect of IFN-gamma in increasing NO production is obvious. This could be an explanation for the therapeutic effect of IFN-gamma in patients with CGD as NO acts as a bactericidal agent and plays a role in host defense mechanism instead of O-2(-). (C) 2012 Elsevier B.V. All rights reserved.