Immune regulation of bone loss by Th17 cells

A significant macrophage and T-cell infiltrate commonly occurs in inflammatory joint conditions such as rheumatoid arthritis that have significant bone destruction. Cytokines produced by activated macrophages and T cells are implicated in arthritis pathogenesis and are involved in osteoclast-mediated bone resorption. The scope of the present review is to analyze current knowledge and to provide a better understanding of how macrophage-derived factors promote the differentiation of a novel T-helper subset (Th17) that promotes osteoclast formation and activation

Interleukin-17A upregulates receptor activator of NF-kappaB on osteoclast precursors.

IntroductionThe interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.MethodsHuman CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.ResultsIL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.ConclusionsCollectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases

p-channel thin-film transistors based on spray-coated Cu2O films

Thin films of cuprous oxide (Cu2O) were grown using solution-based spray pyrolysis in ambient air and incorporated into hole-transporting thin-film transistors. The phase of the oxide was confirmed by X-ray diffraction measurements while the optical band gap of the films was determined to be ∼2.57 eV from optical transmission measurements. Electrical characterization of Cu2O films was performed using bottom-gate, bottom-contact transistors based on SiO2 gate dielectric and gold source-drain electrodes. As-prepared devices show clear p-channel operation with field-effect hole mobilities in the range of 10−4–10−3 cm2 V−1 s−1 with some devices exhibiting values close to 1 × 10−2 cm2 V−1 s−1

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations

Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis.

DNAX adaptor protein 12 (DAP12) is a trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells. Absence of functional Dap12 results in osteoclast defects and bone abnormalities. Because DAP12 has no extracelluar binding domains, it must pair with cell surface receptors for signal transduction. There are at least 15 known DAP12-associating cell surface receptors with distinct temporal and cell type-specific expression patterns. Our aim was to determine which receptors may be important in DAP12-associated bone pathologies. Here, we identify myeloid DAP12-associating lectin (MDL)-1 receptor (also known as CLEC5A) as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation. Activation of MDL-1 leads to enhanced recruitment of inflammatory macrophages and neutrophils to the joint and promotes bone erosion. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the clinical signs of autoimmune joint inflammation. These findings suggest that MDL-1 receptor may be a therapeutic target for treatment of immune-mediated skeletal disorders

Interleukin-17A upregulates receptor activator of NF-κB on osteoclast precursors

IntroductionThe interaction between the immune and skeletal systems is evidenced by the bone loss observed in autoimmune diseases such as rheumatoid arthritis. In this paper we describe a new mechanism by which the immune cytokine IL-17A directly affects osteoclastogenesis.MethodsHuman CD14+ cells were isolated from healthy donors, cultured on dentine slices and coverslips and stimulated with IL-17A and/or receptor activator of NF-kappaB ligand (RANKL). Osteoclast differentiation was evaluated by gene expression, flow cytometry, tartrate-resistant acid phosphatase staining, fluorescence and electron microscopy. Physiologic bone remodelling was studied in wild-type (Wt) and IL-17A-/- mice using micro-computer tomography and serum RANKL/osteoprotegerin concentration. Functional osteoclastogenesis assays were performed using bone marrow macrophages isolated from IL-17A-/- and Wt mice.ResultsIL-17A upregulates the receptor activator for NF-kappaB receptor on human osteoclast precursors in vitro, leading to increased sensitivity to RANKL signalling, osteoclast differentiation and bone loss. IL-17A-/- mice have physiological bone homeostasis indistinguishable from Wt mice, and bone marrow macrophages isolated from these mice develop fully functional normal osteoclasts.ConclusionsCollectively our data demonstrate anti-IL-17A treatment as a selective therapeutic target for bone loss associated with autoimmune diseases

Prediction of knot size in uneven-sized Norway spruce stands in Sweden

The size of knots is negatively correlated with bending strength in sawn timber and it is therefore used as a quality grading criterion in national roundwood grading standards. Some standards even use the size of the largest knot as the sole estimate for individual log knottiness. The size of knots is determined by crown horizontal extension, which in turn is dependent on the impact of competing trees. Thus, with knot size models that are competition-dependent, roundwood quality due to knottiness can be simulated for different management alternatives. However, these types of models, calibrated on uneven-sized Norway spruce in Fennoscandia, are currently not available. Therefore, the objective of this study is to develop a competition-dependent model framework for prediction of the largest knot size per stem height section, for application within uneven-sized Norway spruce stands. Data from terrestrial laser scanning of an uneven-sized stand in southern Sweden are used to calibrate a modular prediction framework, consisting of interlinked allometric statistical models. Alternative framework sub-models are presented and the preferred model combination can be selected according to context and available input data. The flexible modular format enables further development of separate sub-components for adaptation to growing conditions not covered by the current calibration range

Early findings from a large-scale user study of CHESTNUT: Validations and implications

Towards a serendipitous recommender system with user-centred understanding, we have built CHESTNUT , an Information Theory-based Movie Recommender System, which introduced a more comprehensive understanding of the concept. Although off-line evaluations have already demonstrated that CHESTNUT has greatly improved serendip-ity performance, feedback on CHESTNUT from real-world users through online services are still unclear now. In order to evaluate how serendip-itous results could be delivered by CHESTNUT , we consequently designed , organized and conducted large-scale user study, which involved 104 participants from 10 campuses in 3 countries. Our preliminary feedback has shown that, compared with mainstream collaborative filtering techniques, though CHESTNUT limited users' feelings of unex-pectedness to some extent, it showed significant improvement in their feelings about certain metrics being both beneficial and interesting, which substantially increased users' experience of serendipity. Based on them, we have summarized three key takeaways, which would be beneficial for further designs and engineering of serendipitous recommender systems, from our perspective. All details of our large-scale user study could be found at https://github.com/unnc-idl-ucc/Early-Lessons-From-CHESTNU

One-dimensional magnetic fluctuations in the spin-2 triangular lattice \alpha-NaMnO2

The S=2 anisotropic triangular lattice alpha-NaMnO2 is studied by neutron inelastic scattering. Antiferromagnetic order occurs at T ~ 45 K with opening of a spin gap. The spectral weight of the magnetic dynamics above the gap (Delta ~ 7.5 meV) has been analysed by the single-mode approximation. Excellent agreement with the experiment is achieved when a dominant exchange interaction (|J|/k_B ~ 73 K), along the monoclinic b-axis and a sizeable easy-axis magnetic anisotropy (|D|/k_B ~ 3 K) are considered. Despite earlier suggestions for two-dimensional spin interactions, the dynamics illustrate strongly coupled antiferromagnetic S=2 chains and cancellation of the interchain exchange due to the lattice topology. alpha-NaMnO2 therefore represents a model system where the geometric frustration is resolved through the lowering of the dimensionality of the spin interactions.Comment: 4 pages, 4 figures, to be published in Physical Review Letter