The balance of activating and inhibitory signals from the low affinity Fc gamma receptors modulates immune responses triggered by IgG antibody‐immune complexes. In homeostasis, this leads to antigen ...clearance, while in autoimmune diseases to unwanted immune response. Besides the activating receptors FcɣRIIa, FcɣRIIIa, and the inhibitory FcɣRIIb receptor, a third activating receptor, FcɣRIIc, was shown to be expressed on several immune cell types, however, only in the presence of a functional FCGR2C‐ORF allele. FcɣRIIc expression is associated with autoimmune diseases such as idiopathic thrombocytopenic purpura, systemic lupus erythematosus or systemic sclerosis. Thus, the determination of the functional FCGR2C gene resulting in protein expression on immune cells becomes highly relevant, particularly in the context of unwanted immune responses through inadvertent FcɣRIIc activation by molecules targeting stimulation of the inhibitory receptor FcɣRIIb, currently pursued by several pharmaceutical companies. The high degree of homology within the FCGR2/3 gene cluster complicates development of an accurate method for identification of FcɣRIIc expression. Here we describe a comprehensive approach to characterize genetic status of the FCGR2C gene locus consisting of cDNA sequencing, SNaPshot genotyping and low‐coverage next‐generation sequencing. This might enable Mendelian randomization hypothesis testing across autoimmune diseases to personalize therapies and enhance treatment outcomes.
Highlights • Recombinant FAdV-C capsid proteins were expressed in a baculovirus system. • SPF chickens were vaccinated with purified fiber-1, fiber-2, or hexon loop-1 protein. • Protection induced by ...the individual proteins was assessed in a challenge with virulent FAdV-C. • Clinical signs, mortality, antibody formation, and virus excretion were evaluated. • Recombinant fiber-2 is an effective subunit antigen to protect chickens against HHS.
For autonomous robotics applications, it is crucial that robots are able to accurately measure their potential state and perceive their environment, including other agents within it (e.g., cobots ...interacting with humans). The redundancy of these measurements is important, as it allows for planning and execution of recovery protocols in the event of sensor failure or external disturbances. Visual estimation can provide this redundancy through the use of low-cost sensors and server as a standalone source of proprioception when no encoder-based sensing is available. Therefore, we estimate the configuration of the robot jointly with its pose, which provides a complete spatial understanding of the observed robot. We present GISR - a method for deep configuration and robot-to-camera pose estimation that prioritizes real-time execution. GISR is comprised of two modules: (i) a geometric initialization module, efficiently computing an approximate robot pose and configuration, and (ii) an iterative silhouette-based refinement module that refines the initial solution in only a few iterations. We evaluate our method on a publicly available dataset and show that GISR performs competitively with existing state-of-the-art approaches, while being significantly faster compared to existing methods of the same class. Our code is available at https://github.com/iwhitey/GISR-robot.
Mast cells play crucial roles in a variety of normal and pathophysiological processes and their activation has to be tightly controlled. Here, we demonstrate that the protein tyrosine kinase Tec is a ...crucial regulator of murine mast cell function. Tec was activated upon FcεRI stimulation of BM-derived mast cells (BMMC). The release of histamine in the absence of Tec was normal in vitro and in vivo; however, leukotriene C₄ levels were reduced in Tec⁻ / ⁻ BMMC. Furthermore, the production of IL-4 was severely impaired, and GM-CSF, TNF-α and IL-13 levels were also diminished. Finally, a comparison of WT, Tec⁻ / ⁻, Btk⁻ / ⁻ and Tec⁻ / ⁻Btk⁻ / ⁻ BMMC revealed a negative role for Btk in the regulation of IL-4 production, while for the efficient production of TNF-α, IL-13 and GM-CSF, both Tec and Btk were required. Our results demonstrate a crucial role for Tec in mast cells, which is partially different to the function of the well-characterized family member Btk.
Autonomous manipulation systems operating in domains where human intervention is difficult or impossible (e.g., underwater, extraterrestrial or hazardous environments) require a high degree of ...robustness to sensing and communication failures. Crucially, motion planning and control algorithms require a stream of accurate joint angle data provided by joint encoders, the failure of which may result in an unrecoverable loss of functionality. In this paper, we present a novel method for retrieving the joint angles of a robot manipulator using only a single RGB image of its current configuration, opening up an avenue for recovering system functionality when conventional proprioceptive sensing is unavailable. Our approach, based on a distance-geometric representation of the configuration space, exploits the knowledge of a robot's kinematic model with the goal of training a shallow neural network that performs a 2D-to-3D regression of distances associated with detected structural keypoints. It is shown that the resulting Euclidean distance matrix uniquely corresponds to the observed configuration, where joint angles can be recovered via multidimensional scaling and a simple inverse kinematics procedure. We evaluate the performance of our approach on real RGB images of a Franka Emika Panda manipulator, showing that the proposed method is efficient and exhibits solid generalization ability. Furthermore, we show that our method can be easily combined with a dense refinement technique to obtain superior results.
Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is ...also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).
Pax5 controls the identity and development of B cells by repressing lineage‐inappropriate genes and activating B‐cell‐specific genes. Here, we used genome‐wide approaches to identify Pax5 target ...genes in pro‐B and mature B cells. In these cell types, Pax5 bound to 40% of the cis‐regulatory elements defined by mapping DNase I hypersensitive (DHS) sites, transcription start sites and histone modifications. Although Pax5 bound to 8000 target genes, it regulated only 4% of them in pro‐B and mature B cells by inducing enhancers at activated genes and eliminating DHS sites at repressed genes. Pax5‐regulated genes in pro‐B cells account for 23% of all expression changes occurring between common lymphoid progenitors and committed pro‐B cells, which identifies Pax5 as an important regulator of this developmental transition. Regulated Pax5 target genes minimally overlap in pro‐B and mature B cells, which reflects massive expression changes between these cell types. Hence, Pax5 controls B‐cell identity and function by regulating distinct target genes in early and late B lymphopoiesis.
Genome‐wide sequencing approaches reveal that the transcription factor Pax5 controls the identity and function of B cells by regulating the expression of distinct target genes in pro‐B and mature B cells.
Several developmental stage-, subset-, and lineage-specific Cd8 cis-regulatory regions have been identified. These include the E8(III) enhancer, which directs expression in double-positive (DP) ...thymocytes, and E8(II), which is active in DP cells and CD8(+) T cells. Using a transgenic reporter expression assay, we identified a 285-bp core fragment of the E8(III) enhancer that retains activity in DP thymocytes. In vitro characterization of the core enhancer revealed five regulatory elements that are required for full enhancer activity, suggesting that multiple factors contribute to the developmental stage-specific activity. Furthermore, deletion of E8(III) in the mouse germline showed that this enhancer is required for nonvariegated expression of CD8 in DP thymocytes when E8(II) is also deleted. These results indicate that E8(III) is one of the cis-elements that contribute to the activation of the Cd8a and Cd8b gene complex during T cell development.
The CD4 versus CD8 lineage specification of thymocytes is linked to coreceptor expression. The transcription factor MAZR has been identified as an important regulator of Cd8 expression. Here we show ...that variegated CD8 expression by loss of Cd8 enhancers was reverted in MAZR-deficient mice, which confirms that MAZR negatively regulates the Cd8 loci during the transition to the double-positive (DP) stage. Moreover, loss of MAZR led to partial redirection of major histocompatibility complex (MHC) class I-restricted thymocytes into CD4(+) helper-like T cells, which correlated with derepression of Th-POK, a central transcription factor for helper-lineage development. MAZR bound the silencer of the gene encoding Th-POK, which indicated direct regulation of this locus by MAZR. Thus, MAZR is part of the transcription factor network that regulates the CD8 lineage differentiation of DP thymocytes.
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