96 research outputs found
Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes
CD38 controls the chemotaxis of leukocytes to some, but not all, chemokines, suggesting that chemokine receptor signaling in leukocytes is more diverse than previously appreciated. To determine the basis for this signaling heterogeneity, we examined the chemokine receptors that signal in a CD38-dependent manner and identified a novel "alternative" chemokine receptor signaling pathway. Similar to the "classical" signaling pathway, the alternative chemokine receptor pathway is activated by G{alpha}i2-containing Gi proteins. However, unlike the classical pathway, the alternative pathway is also dependent on the Gq class of G proteins. We show that G{alpha}q-deficient neutrophils and dendritic cells (DCs) make defective calcium and chemotactic responses upon stimulation with N-formyl methionyl leucyl phenylalanine and CC chemokine ligand (CCL) 3 (neutrophils), or upon stimulation with CCL2, CCL19, CCL21, and CXC chemokine ligand (CXCL) 12 (DCs). In contrast, G{alpha}q-deficient T cell responses to CXCL12 and CCL19 remain intact. Thus, the alternative chemokine receptor pathway controls the migration of only a subset of cells. Regardless, the novel alternative chemokine receptor signaling pathway appears to be critically important for the initiation of inflammatory responses, as G{alpha}q is required for the migration of DCs from the skin to draining lymph nodes after fluorescein isothiocyanate sensitization and the emigration of monocytes from the bone marrow into inflamed skin after contact sensitization
NKG2D regulation of lung pathology and dendritic cell function following respiratory syncytial virus infection
Š The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. Background. Respiratory syncytial virus (RSV) is a common cause of respiratory tract infection in vulnerable populations. Natural killer (NK) cells and dendritic cells (DC) are important for the effector functions of both cell types following infection. Methods. Wild-type and NKG2D-deficient mice were infected with RSV. Lung pathology was assessed by histology. Dendritic cell function and phenotype were evaluated by enzyme-linked immunosorbent assay and flow cytometry. The expression of NKG2D ligands on lung and lymph node DCs was measured by immunostaining and flow cytometry. Adoptive transfer experiments were performed to assess the importance of NKG2D-dependent DC function in RSV infection. Results. NKG2D-deficient mice exhibited greater lung pathology, marked by the accumulation of DCs following RSV infection. Dendritic cells isolated from NKG2D-deficient mice had impaired responses toward Toll-like receptor ligands. Dendritic cells expressed NKG2D ligands on their surface, which was further increased in NKG2D-deficient mice and during RSV infection. Adoptive transfer of DCs isolated from wild-type mice into the airways of NKG2D-deficient mice ameliorated the enhanced inflammation in NKG2D-deficient mice after RSV infection. Conclusion. NKG2D-dependent interactions with DCs control the phenotype and function of DCs and play a critical role in pulmonary host defenses against RSV infection
Methacholine-induced airway hyperresponsiveness is dependent on GÎą\u3csub\u3eq\u3c/sub\u3e signaling
Airway function in health and disease as well as in response to bronchospastic stimuli (i.e., irritants, allergens, and inflammatory mediators) is controlled, in part, by cholinergic muscarinic receptor regulation of smooth muscle. In particular, the dependence of airway smooth muscle contraction/relaxation on heterotrimeric G protein-coupled receptor signaling suggests that these events underlie the responses regulating airway function. GÎąq-containing G proteins are proposed to be a prominent signaling pathway, and the availability of knockout mice deficient of this subunit has allowed for an investigation of its potential role in airway function. Airway responses in GÎąq-deficient mice (activities assessed by both tracheal tension and in vivo lung function measurements) were attenuated relative to wild-type controls. Moreover, ovalbumin sensitization/aerosol challenge of GÎąq-deficient mice also failed to elicit an allergen-induced increase in airway reactivity to methacholine. These findings indicate that cholinergic receptor-mediated responses are dependent on GÎąq-mediated signaling events and identify GÎąq as a potential target of preventative/intervening therapies for lung dysfunction
Ionic Tuning of Cobaltites at the Nanoscale
Control of materials through custom design of ionic distributions represents
a powerful new approach to develop future technologies ranging from spintronic
logic and memory devices to energy storage. Perovskites have shown particular
promise for ionic devices due to their high ion mobility and sensitivity to
chemical stoichiometry. In this work, we demonstrate a solid-state approach to
control of ionic distributions in (La,Sr)CoO thin films. Depositing a Gd
capping layer on the perovskite film, oxygen is controllably extracted from the
structure, up-to 0.5 O/u.c. throughout the entire 36 nm thickness. Commensurate
with the oxygen extraction, the Co valence state and saturation magnetization
show a smooth continuous variation. In contrast, magnetoresistance measurements
show no-change in the magnetic anisotropy and a rapid increase in the
resistivity over the same range of oxygen stoichiometry. These results suggest
significant phase separation, with metallic ferromagnetic regions and
oxygen-deficient, insulating, non-ferromagnetic regions, forming percolated
networks. Indeed, X-ray diffraction identifies oxygen-vacancy ordering,
including transformation to a brownmillerite crystal structure. The unexpected
transformation to the brownmillerite phase at ambient temperature is further
confirmed by high-resolution scanning transmission electron microscopy which
shows significant structural - and correspondingly chemical - phase separation.
This work demonstrates room-temperature ionic control of magnetism, electrical
resistivity, and crystalline structure in a 36 nm thick film, presenting new
opportunities for ionic devices that leverage multiple material
functionalities
A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse
Asthma and mouse models of allergic respiratory inflammation are invariably associated with a pulmonary eosinophilia; however, this association has remained correlative. In this report, a causative relationship between eosinophils and allergen-provoked pathologies was established using eosinophil adoptive transfer. Eosinophils were transferred directly into the lungs of either naive or OVA-treated IL-5-/- mice. This strategy resulted in a pulmonary eosinophilia equivalent to that observed in OVA-treated wild-type animals. A concomitant consequence of this eosinophil transfer was an increase in Th2 bronchoalveolar lavage cytokine levels and the restoration of intracellular epithelial mucus in OVA-treated IL-5-/- mice equivalent to OVA-treated wild-type levels. Moreover, the transfer also resulted in the development of airway hyperresponsiveness. These pulmonary changes did not occur when eosinophils were transferred into naive IL-5-/- mice, eliminating nonspecific consequences of the eosinophil transfer as a possible explanation. Significantly, administration of OVA-treated IL-5-/- mice with GK1.5 (anti-CD4) Abs abolished the increases in mucus accumulation and airway hyperresponsiveness following adoptive transfer of eosinophils. Thus, CD4+ T cell-mediated inflammatory signals as well as signals derived from eosinophils are each necessary, yet alone insufficient, for the development of allergic pulmonary pathology. These data support an expanded view of T cell and eosinophil activities and suggest that eosinophil effector functions impinge directly on lung function
Factors that influence the intra-articular rupture pattern of the ACL graft following single-bundle reconstruction
The number of revision anterior cruciate ligament (ACL) surgeries performed annually continues to rise. The purpose of this study was to determine the most common rupture pattern in ACL revision cases after previous single-bundle reconstruction. The second aim was to determine the relationship between rupture pattern and patient-specific factors (age, gender, time between the initial ACL reconstruction and re-injury, and etiology/mechanism of failure) and surgical factors (graft type, tunnel angle). This was a cohort study of 60 patients that underwent revision ACL surgery after previous single-bundle ACL reconstruction. Three sports medicine-trained orthopedic surgeons reviewed the arthroscopic videos and determined the rupture pattern of the grafts. The rupture pattern was then correlated to the above-mentioned factors. The inter-observer agreement had a kappa of 0.7. The most common rupture pattern after previous single-bundle ACL reconstruction is elongation of the graft. This is different from the native ACL, which displays more proximal ruptures. With the use of autograft tissue and after a longer period of time, the rupture pattern in revision surgery is more similar to that of the native ACL. The most common rupture pattern after previous single-bundle reconstruction was elongation of the graft. Factors that influenced the rupture pattern were months between ACL reconstruction and re-injury and graft type. Cohort study, Level I
Magnetic field-induced non-trivial electronic topology in Fe3âxGeTe2
The anomalous Hall, Nernst and thermal Hall coefficients of
FeGeTe display several features upon cooling, like a reversal in
the Nernst signal below K pointing to a topological transition (TT)
associated to the development of magnetic spin textures. Since the anomalous
transport variables are related to the Berry curvature, a possible TT might
imply deviations from the Wiedemann-Franz (WF) law. However, the anomalous Hall
and thermal Hall coefficients of FeGeTe are found, within our
experimental accuracy, to satisfy the WF law for magnetic-fields
applied along its inter-layer direction. Surprisingly, large anomalous
transport coefficients are also observed for applied along the planar
\emph{a}-axis as well as along the gradient of the chemical potential, a
configuration that should not lead to their observation due to the absence of
Lorentz force. However, as \emph{a}-axis is increased,
magnetization and neutron scattering indicate just the progressive canting of
the magnetic moments towards the planes followed by their saturation. These
anomalous planar quantities are found to not scale with the component of the
planar magnetization (), showing instead a sharp decrease beyond 4 T which is the field required to align the magnetic moments
along . We argue that locally chiral spin structures, such as
skyrmions, and possibly skyrmion tubes, lead to a field dependent
spin-chirality and hence to a novel type of topological anomalous transport.
Locally chiral spin-structures are captured by our Monte-Carlo simulations
incorporating small Dzyaloshinskii-Moriya and biquadratic exchange
interactions.Comment: 34 pages, 10 figures, submitted to Applied Physics Review
Association of toll-interacting protein gene polymorphisms with atopic dermatitis
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disorder, affecting up to 15% of children in industrialized countries. Toll-interacting protein (TOLLIP) is an inhibitory adaptor protein within the toll-like receptor (TLR) pathway, a part of the innate immune system that recognizes structurally conserved molecular patterns of microbial pathogens, leading to an inflammatory immune response. METHODS: In order to detect a possible role of TOLLIP variation in the pathogenesis of AD, we screened the entire coding sequence of the TOLLIP gene by SSCP in 50 AD patients. We identified an amino acid exchange in exon 6 (Ala222Ser) and a synonymous variation in exon 4 (Pro139Pro). Subsequently, these two variations and four additional non-coding polymorphisms (-526 C/G, two polymorphisms in intron 1 and one in the 3'UTR) were genotyped in 317 AD patients and 224 healthy controls. RESULTS: The -526G allele showed borderline association with AD in our cohort (p = 0.012; significance level after correction for multiple testing 0.0102). Haplotype analysis did not yield additional information. Evaluation of mRNA expression by quantitative real-time polymerase chain reaction in six probands with the CC and six with the GG genotype at the -526 C/G locus did not reveal significant differences between genotypes. CONCLUSION: Variation in the TOLLIP gene may play a role in the pathogenesis of AD. Yet, replication studies in other cohorts and populations are warranted to confirm these association results
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