Enhancing the Versatility and Performance of Soft Robotic Grippers, Hands, and Crawling Robots Through Three-Dimensional-Printed Multifunctional Buckling Joints.

Soft robotic grippers and hands offer adaptability, lightweight construction, and enhanced safety in human-robot interactions. In this study, we introduce vacuum-actuated soft robotic finger joints to overcome their limitations in stiffness, response, and load-carrying capability. Our design-optimized through parametric design and three-dimensional (3D) printing-achieves high stiffness using vacuum pressure and a buckling mechanism for large bending angles (>90°) and rapid response times (0.24 s). We develop a theoretical model and nonlinear finite-element simulations to validate the experimental results and provide valuable insights into the underlying mechanics and visualization of the deformation and stress field. We showcase versatile applications of the buckling joints: a three-finger gripper with a large lifting ratio (∼96), a five-finger robotic hand capable of replicating human gestures and adeptly grasping objects of various characteristics in static and dynamic scenarios, and a planar-crawling robot carrying loads 30 times its weight at 0.89 body length per second (BL/s). In addition, a jellyfish-inspired robot crawls in circular pipes at 0.47 BL/s. By enhancing soft robotic grippers' functionality and performance, our study expands their applications and paves the way for innovation through 3D-printed multifunctional buckling joints.

Outflanking RANK with a designer antagonist cytokine.

Members of the tumor necrosis factor (TNF) superfamily of cytokines are noncovalently linked trimers that play important roles in regulating the immune system and have emerged as successful therapeutic targets in various rheumatic and autoimmune conditions. Traditionally, antibodies to cytokines or receptor-Fc fusion proteins have been used to block signaling by TNF family cytokines. In this issue of Science Signaling, Warren et al. have taken a new approach to blocking the action of the TNF superfamily member RANKL [receptor activator of nuclear factor κB (RANK) ligand], which plays an important role in regulating bone turnover through stimulation of its receptor RANK on osteoclasts. Beginning with a single-chain fusion protein of three RANKL subunits, the authors used directed mutagenesis to generate a trimer consisting of a nonreceptor binding subunit fused to two "super-agonist" subunits that have increased affinity for RANK. This molecule antagonized the osteoclastogenic activity of wild-type RANKL in vitro and in vivo, thus providing insights into RANK signaling and a paradigm for the development of other antagonists of TNF family cytokines.

The role of LAT-PLCγ1 interaction in γδ T cell development and homeostasis.

LAT is a transmembrane adaptor protein that is vital for integrating TCR-mediated signals to modulate T cell development, activation, and proliferation. Upon T cell activation, LAT is phosphorylated and associates with Grb2, Gads, and PLCγ1 through its four distal tyrosine residues. Mutation of one of these tyrosines, Y136, abolishes LAT binding to PLCγ1. This results in impaired TCR-mediated calcium mobilization and Erk activation. CD4 αß T cells in LATY136F knock-in mice undergo uncontrolled expansion, resulting in a severe autoimmune syndrome. In this study, we investigated the importance of the LAT-PLCγ1 interaction in γδ T cells by crossing LATY136F mice with TCRß(-/-) mice. Our data showed that the LATY136F mutation had no major effect on homeostasis of epithelial γδ T cells, which could be found in the skin and small intestine. Interestingly, a population of CD4(+) γδ T cells in the spleen and lymph nodes underwent continuous expansion and produced elevated amounts of IL-4, resulting in an autoimmune syndrome similar to that caused by αß T cells in LATY136F mice. Development of these hyperproliferative γδ T cells was not dependent on MHC class II expression or CD4, and their proliferation could be suppressed, in part, by regulatory T cells. Our data indicated that a unique subset of CD4 γδ T cells can hyperproliferate in LATY136F mice and suggested that LAT-PLCγ1 signaling may function differently in various subsets of γδ T cells.

The requirement of linker for activation of T cells in the primary and memory responses of CD8 T cells.

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that links TCR engagement to downstream signaling events. Although it is clear that LAT is essential in thymocyte development and initiation of T cell activation, its function during T cell expansion, contraction, and memory formation remains unknown. To study the role of TCR-mediated signaling in CD8 T cells during the course of pathogen infection, we used an inducible mouse model to delete LAT in Ag-specific CD8 T cells at different stages of Listeria infection and analyzed the effect of deletion on T cell responses. Our data showed that LAT is important for maintaining CD8 T cell expansion during the priming phase; however, it is not required for CD8 T cell contraction and memory maintenance. Moreover, LAT deficiency accelerates memory differentiation during the effector-to-memory transition, leading to a higher frequency of KLRG1(low)IL-7R(high)CD62L(high) memory T cells. Nonetheless, these LAT-deficient memory T cells were unable to proliferate or produce cytokines upon secondary infection. Our data demonstrated that, although TCR-mediated signaling is dispensable for contraction and memory maintenance, it regulates CD8 T cell memory differentiation and is essential for the memory response against pathogens.

Computational and bioinformatics frameworks for next-generation whole exome and genome sequencing.

It has become increasingly apparent that one of the major hurdles in the genomic age will be the bioinformatics challenges of next-generation sequencing. We provide an overview of a general framework of bioinformatics analysis. For each of the three stages of (1) alignment, (2) variant calling, and (3) filtering and annotation, we describe the analysis required and survey the different software packages that are used. Furthermore, we discuss possible future developments as data sources grow and highlight opportunities for new bioinformatics tools to be developed.

Regulation of RasGRP1 function in T cell development and activation by its unique tail domain.

The Ras-guanyl nucleotide exchange factor RasGRP1 plays a critical role in T cell receptor-mediated Erk activation. Previous studies have emphasized the importance of RasGRP1 in the positive selection of thymocytes, activation of T cells, and control of autoimmunity. RasGRP1 consists of a number of well-characterized domains, which it shares with its other family members; however, RasGRP1 also contains an ~200 residue-long tail domain, the function of which is unknown. To elucidate the physiological role of this domain, we generated knock-in mice expressing RasGRP1 without the tail domain. Further analysis of these knock-in mice showed that thymocytes lacking the tail domain of RasGRP1 underwent aberrant thymic selection and, following TCR stimulation, were unable to activate Erk. Furthermore, the deletion of the tail domain led to enhanced CD4(+) T cell expansion in aged mice, as well as the production of autoantibodies. Mechanistically, the tail-deleted form of RasGRP1 was not able to traffic to the cell membrane following stimulation, indicating a potential reason for its inability to activate Erk. While the DAG-binding C1 domain of RasGRP1 has long been recognized as an important factor mediating Erk activation, we have revealed the physiological relevance of the tail domain in RasGRP1 function and control of Erk signaling.

Role of LAT in the granule-mediated cytotoxicity of CD8 T cells.

Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is essential to bridge T cell receptor (TCR) engagement to downstream signaling events. The indispensable role of LAT in thymocyte development and T cell activation has been well characterized; however, the function of LAT in cytotoxic-T-lymphocyte (CTL) cytotoxicity remains unknown. We show here that LAT-deficient CTLs failed to upregulate FasL and produce gamma interferon after engagement with target cells and had impaired granule-mediated killing. We further dissected the effect of the LAT deletion on each step of granule exocytosis. LAT deficiency led to altered synapse formation, subsequently causing unstable T cell-antigen-presenting cell (APC) conjugates. Microtubule organizing center polarization and granule reorientation were also impaired by LAT deficiency, leading to reduced granule delivery. Despite these defects, granule release was still observed in LAT-deficient CTLs due to residual calcium flux and phospholipase C (PLC) activity. Our data demonstrated that LAT-mediated signaling intricately regulates CTL cytotoxicity at multiple steps.

Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB.

Linker for activation of B cells (LAB)/non-T cell activation linker is a transmembrane adaptor protein that functions in immunoreceptor-mediated signaling. Published studies have shown that LAB has both positive and negative roles in regulating TCR and high-affinity Fc receptor-mediated signaling and cellular function. In this study, we showed that LAB was also expressed in dendritic cells and that LAB deficiency affected LPS-mediated signaling and cytokine production. LPS-mediated MAPK activation was enhanced in LAB(-/-) bone marrow-derived dendritic cells. These bone marrow-derived dendritic cells also produced more TNF-α, IL-6, and IL-10 than wild-type cells. Moreover, LAB(-/-) mice were hyperresponsive to LPS-induced septic shock. These data indicated that LAB has a negative role in LPS-mediated responses. By using LAB knockin mice, which harbor mutations at five membrane-distal tyrosines, we further showed that, in contrast to its role in immunoreceptor-mediated signaling, LAB function in LPS-mediated signaling pathway did not depend on its tyrosine phosphorylation. Our study suggested a novel mechanism by which LAB functions in the regulation of innate immunity.

Personalizing rare disease research: how genomics is revolutionizing the diagnosis and treatment of rare disease.

A decade after the complete sequencing of the human genome, combined with recent advances in throughput and sequencing costs, the genetics of rare diseases has entered a new era. There has now been an explosion in the identification and mapping of rare diseases, with over 10,000 exomes having been sequenced to date. This article surveys the progress and development of technologies to understand rare disease; it provides a historical overview of traditional techniques such as karyotyping and homozygosity mapping, reviews current methods of whole-exome and -genome sequencing, and provides a future perspective on upcoming developments such as targeted drugs and gene therapy. This article will discuss the implications of these methods for rare disease research, along with a discussion of the success stories that provide great hope and optimism for patients and scientists alike.

A tale of two TRAPs: LAT and LAB in the regulation of lymphocyte development, activation, and autoimmunity.

Transmembrane adaptor proteins (TRAPs) link antigen receptor engagement to downstream cellular processes. Although these proteins typically lack intrinsic enzymatic activity, they are phosphorylated on multiple tyrosine residues following lymphocyte activation, allowing them to function as scaffolds for the assembly of multi-molecular signaling complexes. Among the many TRAPs that have been discovered in recent years, the LAT (linker for activation of T cells) family of adaptor proteins plays an important role in the positive and negative regulation of lymphocyte maturation, activation, and differentiation. Of the two members in this family, LAT is an indispensable component controlling T cell and mast cell activation and function; LAB (linker for activation of B cells), also called NTAL, is necessary to fine-tune lymphocyte activation and may be a key regulator of innate immune responses. Here, we review recent advances on the function of LAT and LAB in the regulation of development and activation of immune cells.