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.
The transcription factor E2A controls the initiation of B lymphopoiesis, which is arrested at the pre-pro-B cell stage in E2A-deficient mice. Here, we demonstrate by conditional mutagenesis that E2A ...is essential for the development of pro-B, pre-B, and immature B cells in the bone marrow. E2A is, however, dispensable for the generation of mature B cells and plasma cells in peripheral lymphoid organs. In contrast, germinal center B cell development is impaired in the absence of E2A despite normal AID expression and class-switch recombination. Molecular analysis revealed that E2A is required not only for initiating but also for maintaining the expression of
Ebf1,
Pax5, and the B cell gene program in pro-B cells. Notably, precocious
Pax5 transcription from the
Ikzf1 locus promotes pro-B cell development in E2A-deficient mice, demonstrating that ectopic
Pax5 expression is sufficient to activate the B lymphoid transcription program in vivo in the absence of E2A.
The use of epidermal growth factor receptor inhibitors (EGFRI) for the treatment of solid tumors is increasing due to elevated expression of epidermal growth factor receptors (EGFR) in the ...stimulation of tumor development. EGFR inhibitors have shown to be effective in the treatment of neoplasms of the head, neck, colon, and lung. Inhibition of EGFR may cause cutaneous reactions in more than 50% of patients. The most common skin manifestations are papulopustular lesions in the seborrhoeic areas (upper torso, face, neck, and scalp). Other cutaneous side effects include xerosis and hair and nail changes. The onset of eruption is usually within one to three weeks after starting therapy, although in some cases it may occur much later. All dermatologic side effects are reversible and generally resolve after adequate therapy. However, for a minority of patients side effects are severe and intolerable, demanding dose reduction or even interruption of therapy. A positive correlation has been demonstrated between the degree of cutaneous toxicity and the antitumor response. For dermatologists the goal is to provide treatment of symptoms, so that the patient may continue to benefit from the EGFRI therapy. However, frequent cutaneous manifestations, even though related to a better antitumor response, may limit use of the therapy considering the interference with patient quality of life. Early management of cutaneous side effects of EGFRI may prevent severe, extensive symptoms, the need for dose reduction, or antitumor therapy interruption. This indicates a dermatologist should play a role in early stages of treatment.
Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients ...from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11
CTLA-4
vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.
The transcription factor EBF1 is essential for lineage specification in early B cell development. In this study, we demonstrate by conditional mutagenesis that EBF1 is required for B cell commitment, ...pro-B cell development, and subsequent transition to the pre-B cell stage. Later in B cell development, EBF1 was essential for the generation and maintenance of several mature B cell types. Marginal zone and B-1 B cells were lost, whereas follicular (FO) and germinal center (GC) B cells were reduced in the absence of EBF1. Activation of the B cell receptor resulted in impaired intracellular signaling, proliferation and survival of EBF1-deficient FO B cells. Immune responses were severely reduced upon Ebf1 inactivation, as GCs were formed but not maintained. ChIP- and RNA-sequencing of FO B cells identified EBF1-activated genes that encode receptors, signal transducers, and transcriptional regulators implicated in B cell signaling. Notably, ectopic expression of EBF1 efficiently induced the development of B-1 cells at the expense of conventional B cells. These gain- and loss-of-function analyses uncovered novel important functions of EBF1 in controlling B cell immunity.
B-cell lymphoma 11A (BCL11A) downregulation in human primary adult erythroid progenitors results in elevated expression of fetal γ-globin. Recent reports showed that BCL11A expression is activated by ...KLF1, leading to γ-globin repression. To study regulation of erythropoiesis and globin expression by KLF1 and BCL11A in an in vivo model, we used mice carrying a human β-globin locus transgene with combinations of Klf1 knockout, Bcl11a floxed, and EpoRCre knockin alleles. We found a higher percentage of reticulocytes in adult Klf1wt/ko mice and a mild compensated anemia in Bcl11acko/cko mice. These phenotypes were more pronounced in compound Klf1wt/ko::Bcl11acko/cko mice. Analysis of Klf1wt/ko, Bcl11acko/cko, and Klf1wt/ko::Bcl11acko/cko mutant embryos demonstrated increased expression of mouse embryonic globins during fetal development. Expression of human γ-globin remained high in Bcl11acko/cko embryos during fetal development, and this was further augmented in Klf1wt/ko::Bcl11acko/cko embryos. After birth, expression of human γ-globin and mouse embryonic globins decreased in Bcl11acko/cko and Klf1wt/ko::Bcl11acko/cko mice, but the levels remained much higher than those observed in control animals. Collectively, our data support an important role for the KLF1-BCL11A axis in erythroid maturation and developmental regulation of globin expression.
•Our data support an important role for the KLF1-BCL11A axis in erythroid maturation and hemoglobin switching.•In adults, gamma-globin levels decline in Bcl11a and Klf1::Bcl11a mutants, suggesting an additional layer of gamma-globin silencing.
Coreceptor expression is tightly regulated during thymocyte development. Deletion of specific Cd8 enhancers leads to variegated expression of CD8alphabeta heterodimers in double-positive thymocytes. ...Here we show CD8 variegation is correlated with an epigenetic 'off' state, linking Cd8 enhancer function with chromatin remodeling of the adjacent genes Cd8a and Cd8b1 (Cd8). The zinc finger protein MAZR bound the Cd8 enhancer and interacted with the nuclear receptor corepressor N-CoR complex in double-negative thymocytes. MAZR was downregulated in double-positive and CD8 single-positive thymocytes. 'Enforced' expression of MAZR led to impaired Cd8 activation and variegated CD8 expression. Our results demonstrate epigenetic control of the Cd8 loci and identify MAZR as an important regulator of Cd8 expression.
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