32 research outputs found
Differential Requirement for c-Jun N-terminal Kinase 1 in Lung Inflammation and Host Defense
The c-Jun N-terminal kinase (JNK) - 1 pathway has been implicated in the cellular response to stress in many tissues and models. JNK1 is known to play a role in a variety of signaling cascades, including those involved in lung disease pathogenesis. Recently, a role for JNK1 signaling in immune cell function has emerged. The goal of the present study was to determine the role of JNK1 in host defense against both bacterial and viral pneumonia, as well as the impact of JNK1 signaling on IL-17 mediated immunity. Wild type (WT) and JNK1 −/− mice were challenged with Escherichia coli, Staphylococcus aureus, or Influenza A. In addition, WT and JNK1 −/− mice and epithelial cells were stimulated with IL-17A. The impact of JNK1 deletion on pathogen clearance, inflammation, and histopathology was assessed. JNK1 was required for clearance of E. coli, inflammatory cell recruitment, and cytokine production. Interestingly, JNK1 deletion had only a small impact on the host response to S. aureus. JNK1 −/− mice had decreased Influenza A burden in viral pneumonia, yet displayed worsened morbidity. Finally, JNK1 was required for IL-17A mediated induction of inflammatory cytokines and antimicrobial peptides both in epithelial cells and the lung. These data identify JNK1 as an important signaling molecule in host defense and demonstrate a pathogen specific role in disease. Manipulation of the JNK1 pathway may represent a novel therapeutic target in pneumonia
BOREAS – a new MAX-DOAS profile retrieval algorithm for aerosols and trace gases
We present a new MAX-DOAS profiling algorithm for aerosols and trace gases,
BOREAS, which utilizes an iterative solution method including Tikhonov
regularization and the optimal estimation technique. The aerosol profile
retrieval is based on a novel approach in which the absorption depth of
O4 is directly used in order to retrieve extinction coefficient
profiles instead of the commonly used perturbation theory method. The
retrieval of trace gases is done with the frequently used optimal estimation
method but significant improvements are presented on how to deal with wrongly
weighted a priori constraints and for scenarios in which the a priori profile
is inaccurate.
Performance tests are separated into two parts. First, we address the general
sensitivity of the retrieval to the example of synthetic data calculated with
the radiative transfer model SCIATRAN. In the second part of the study, we
demonstrate BOREAS profiling accuracy by validating the results with the help of
ancillary measurements carried out during the CINDI-2 campaign in Cabauw, the
Netherlands, in 2016.
The synthetic sensitivity tests indicate that the regularization between
measurement and a priori constraints is insufficient when knowledge of the
true state of the atmosphere is poor. We demonstrate a priori pre-scaling and
extensive regularization tests as a tool for the optimization of retrieved
profiles. The comparison of retrieval results with in situ, ceilometer,
NO2 lidar, sonde and long-path DOAS measurements during the CINDI-2
campaign always shows high correlations with coefficients greater than 0.75.
The largest differences can be found in the morning hours, when the planetary
boundary layer is not yet fully developed and the concentration of trace
gases and aerosol, as a result of a low night-time boundary layer having
formed, is focused in a shallow, near-surface layer.</p
The protein tyrosine phosphatase PTPN22 negatively regulates presentation of immune complex derived antigens
Design and field test of a robust acoustic disdrometer for distributed rainfall observations
Abstract.Water ManagementCivil Engineering and Geoscience
Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7
Left ventricular noncompaction (LVNC) is a relatively common genetic cardiomyopathy, characterized by prominent trabeculations with deep intertrabecular recesses in mainly the left ventricle. Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD). The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum. Several reports of sporadic as well as familial cases of Ebstein anomaly associated with LVNC have been reported. Recent studies identified mutations in the MYH7 gene, encoding the sarcomeric {beta}-myosin heavy chain protein, in patients harboring this specific phenotype. Here, we will review the association between Ebstein anomaly, LVNC and mutations in MYH7, which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance
NF-kappa B mediated IL-6 production by renal epithelial cells is regulated by C-Jun NH2-terminal kinase
In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling
Antibody-Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated gamma-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of gamma-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors. Cancer Res; 70(8); 3209-17. (C)2010 AACR.Tumourgenetics and immunogenetic
Human renal epithelial cells produce the long pentraxin PTX3
Background. Pentraxin 3 (PTX3) is a prototypic long pentraxin with structural similarities in the C-terminal domain to the classical short pentraxins C-reactive protein (CRP) and serum amyloid P component. PTX3 is suggested to play an important role in the innate resistance against pathogens, regulation of inflammatory reactions, and clearance of apoptotic cells. Unlike the classic pentraxins, PTX3 is mainly expressed extrahepatically. The present study was designed to investigate the expression of PTX3 by human proximal renal tubular epithelial cells (PTECs). Methods. PTECs were cultured in the presence or absence of inflammatory cytokines. PTX3 mRNA expression was measured by reverse transcription-polymerase chain reaction (RT-PCR) in human kidney and PTECs. PTX3 protein levels in PTEC cultures were quantified by enzyme-linked immunosorbent assay (ELISA). Results. PTX3 mRNA was shown to be constitutively expressed in human kidney. Constitutive expression and production of PTX3 was shown in primary mesangial cells, in primary PTECs, and in renal fibroblasts. Further analysis showed that interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha) stimulation strongly enhanced the expression and production of PTX3 in PTECs in a dose- and time-dependent manner. In addition, activation of PTECs with IL-17 and CD40L, respectively, but not with IL-6 or IL-4, resulted in strongly increased production of PTX3, whereas granulocyte macrophage-colony-stimulating factor (GM-CSF) inhibited IL-1-induced PTX3 production. PTX3 produced by PTEC is functionally active in binding C1q. Conclusion. These results indicate that PTX3 is expressed and released by PTECs and that in proinflammatory conditions PTX3 production is up-regulated. Local expression of PTX3 may play a role in the innate immune response and inflammatory reactions in the kidney
A spectrum of mutations in the second gene for autosomal dominant polycystic kidney disease (PKD2).
Recently the second gene for autosomal dominant polycystic kidney disease (ADPKD), located on chromosome 4q21-q22, has been cloned and characterized. The gene encodes an integral membrane protein, polycystin-2, that shows amino acid similarity to the PKD1 gene product and to the family of voltage-activated calcium (and sodium) channels. We have systematically screened the gene for mutations by single-strand conformation-polymorphism analysis in 35 families with the second type of ADPKD and have identified 20 mutations. So far, most mutations found seem to be unique and occur throughout the gene, without any evidence of clustering. In addition to small deletions, insertions, and substitutions leading to premature translation stops, one amino acid substitution and five possible splice-site mutations have been found. These findings suggest that the first step toward cyst formation in PKD2 patients is the loss of one functional copy of polycystin-2