Conformational and functional regulation of the chicken tumor virus number 10 (CT10) regulator of kinase II (CrkII) adaptor protein by cyclophilin A

The Src homology 2 (SH2) and SH3 domain-containing chicken tumor virus number 10 (CT10) regulator of kinase (Crk) adaptor proteins include three cellular members that serve as integral constituents of multiple receptor-linked signal transduction pathways. CrkI and CrkII are products of alternative RNA-splicing which is transcribed from a single gene, while Crk-like (CrkL), which is highly homologous to CrkII, is encoded by a different gene. Thanks to their modular structure, the Crk adaptor proteins can simultaneously interact with activated receptors and a wide range of effector molecules, and orchestrate the assembly of complexes containing enzymes and substrates at the receptor site. They are involved in the regulation of a large number of cellular processes which control cell growth, differentiation, transformation, and apoptosis. Cell activation-dependent tyrosine phosphorylation of CrkII and CrkL serves as a major posttranslational modification mechanism that introduces conformational changes in the proteins by promoting an intramolecular interaction between the phosphotyrosine and the self SH2 domain. The resulting conformational change induces downregulation of CrkII- and CrkL-dependent biological processes. A second type of posttranslational modification mechanism regulates the structure and function of the CrkII adaptor protein by immunophilin-mediated protein isomerization. Two of the most abundant immunophilins in T lymphocytes which function as peptidyl-prolyl cis-trans isomerases (PPIases), namely cyclophilin A (CypA) and FK506-binding proteins (FKBPs), can associate with CrkII and catalyze its reciprocal cis-trans isomerization. This mechanism is of special importance for the regulation of T lymphocyte functions and for T cell-mediated immune responses, since immunophilin inhibitors, such as cyclosporin A (CsA) and FK506, function as immunosuppressive drugs that can prevent allotransplanted graft rejection. The present manuscript focuses on selected functions of Crk adaptor proteins, predominantly in T lymphocytes, and reviews in more detail the current knowledge on the immunophilin-dependent regulation of the structure and function of the CrkII adaptor protein

Dynamics of magnetization at infinite temperature in a Heisenberg spin chain

Understanding universal aspects of quantum dynamics is an unresolved problem in statistical mechanics. In particular, the spin dynamics of the 1D Heisenberg model were conjectured to belong to the Kardar-Parisi-Zhang (KPZ) universality class based on the scaling of the infinite-temperature spin-spin correlation function. In a chain of 46 superconducting qubits, we study the probability distribution, $P(\mathcal{M})$, of the magnetization transferred across the chain's center. The first two moments of $P(\mathcal{M})$ show superdiffusive behavior, a hallmark of KPZ universality. However, the third and fourth moments rule out the KPZ conjecture and allow for evaluating other theories. Our results highlight the importance of studying higher moments in determining dynamic universality classes and provide key insights into universal behavior in quantum systems

Measurement-induced entanglement and teleportation on a noisy quantum processor

Measurement has a special role in quantum theory: by collapsing the wavefunction it can enable phenomena such as teleportation and thereby alter the "arrow of time" that constrains unitary evolution. When integrated in many-body dynamics, measurements can lead to emergent patterns of quantum information in space-time that go beyond established paradigms for characterizing phases, either in or out of equilibrium. On present-day NISQ processors, the experimental realization of this physics is challenging due to noise, hardware limitations, and the stochastic nature of quantum measurement. Here we address each of these experimental challenges and investigate measurement-induced quantum information phases on up to 70 superconducting qubits. By leveraging the interchangeability of space and time, we use a duality mapping, to avoid mid-circuit measurement and access different manifestations of the underlying phases -- from entanglement scaling to measurement-induced teleportation -- in a unified way. We obtain finite-size signatures of a phase transition with a decoding protocol that correlates the experimental measurement record with classical simulation data. The phases display sharply different sensitivity to noise, which we exploit to turn an inherent hardware limitation into a useful diagnostic. Our work demonstrates an approach to realize measurement-induced physics at scales that are at the limits of current NISQ processors

Non-Abelian braiding of graph vertices in a superconducting processor

Indistinguishability of particles is a fundamental principle of quantum mechanics. For all elementary and quasiparticles observed to date - including fermions, bosons, and Abelian anyons - this principle guarantees that the braiding of identical particles leaves the system unchanged. However, in two spatial dimensions, an intriguing possibility exists: braiding of non-Abelian anyons causes rotations in a space of topologically degenerate wavefunctions. Hence, it can change the observables of the system without violating the principle of indistinguishability. Despite the well developed mathematical description of non-Abelian anyons and numerous theoretical proposals, the experimental observation of their exchange statistics has remained elusive for decades. Controllable many-body quantum states generated on quantum processors offer another path for exploring these fundamental phenomena. While efforts on conventional solid-state platforms typically involve Hamiltonian dynamics of quasi-particles, superconducting quantum processors allow for directly manipulating the many-body wavefunction via unitary gates. Building on predictions that stabilizer codes can host projective non-Abelian Ising anyons, we implement a generalized stabilizer code and unitary protocol to create and braid them. This allows us to experimentally verify the fusion rules of the anyons and braid them to realize their statistics. We then study the prospect of employing the anyons for quantum computation and utilize braiding to create an entangled state of anyons encoding three logical qubits. Our work provides new insights about non-Abelian braiding and - through the future inclusion of error correction to achieve topological protection - could open a path toward fault-tolerant quantum computing

Immune checkpoint-targeted therapy: cancer and autoimmune diseases represent two sides of the same coin

International audienc

Histocompatibility and Reproduction: Lessons from the Anglerfish

Reproduction in certain deep-sea anglerfishes involves the permanent attachment of dwarf males to much larger females and fusion of their tissues leading to the establishment of a shared circulatory system. This unusual phenomenon of sexual parasitism enables anglerfishes to maximize reproductive success in the vast and deep oceans, where females and males otherwise rarely meet. An even more surprising phenomenon relates to the observation that joining of genetically disparate male and female anglerfishes does not evoke a strong anti-graft immune rejection response, which occurs in vertebrates following allogeneic parabiosis. Recent studies demonstrated that the evolutionary processes that led to the unique mating strategy of anglerfishes coevolved with genetic changes that resulted in loss of functional genes encoding critical components of the adaptive immune system. These genetic alterations enabled anglerfishes to tolerate the histoincompatible tissue antigens of their mate and prevent the occurrence of reciprocal graft rejection responses. While the exact mechanisms by which anglerfishes defend themselves against pathogens have not yet been deciphered, it is speculated that during evolution, anglerfishes adopted new immune strategies that compensate for the loss of B and T lymphocyte functions and enable them to resist infection by pathogens

Regulation of immune system cell functions by protein kinase C

Members of the protein kinase C (PKC) family of Ser/Thr kinases are encoded by nine distinct but closely related genes, which give rise to more than 12 different protein isoforms via a mechanism of alternative RNA splicing. Most PKC proteins are ubiquitously expressed and participate in a plethora of functions in most cell types. A majority of PKC isoforms is also expressed in cells of the immune system in which they are involved in signal transduction downstream of a range of surface receptors, including the antigen receptors on T and B lymphocytes. PKC proteins are central to signal initiation and propagation, and to the regulation of processes leading to immune cell proliferation, differentiation, homing and survival. As a result, PKC proteins directly impact on the quality and quantity of immune responses and indirectly on the host resistance to pathogens and tendency to develop immune deficiencies and autoimmune diseases. A significant progress was made in recent years in understanding the regulation of PKC enzymes, their mechanism of action and their role in determining immunocyte behavior This volume reviews the most significant contributions made in the field of immune cell regulation by PKC enzymes. Several manuscripts are devoted to the role of distinct PKC isoforms in the regulation of selected immunocyte responses. Additional manuscripts review more general mechanisms of regulation of PKC enzymes, either by post-translational modifications, such as phosphorylation or controlled proteolysis, or by interaction with different binding proteins that may alter the conformation, activity and subcellular location of PKC. Both types of mechanisms can introduce conformational changes in the molecule, which may affect its ability to interact with cofactors, ATP, or substrates. This topic will be followed by a discussion on the positive and negative impact of individual PKC isoforms on cell cycle regulation. A second section of this volume concentrates on selected topics relevant to role of the novel PKC isoform, PKC-theta, in T lymphocyte function. PKC-theta plays important and some non-redundant roles in T cell activation and is a key isoform that recruits to the immunological synapse - the surface membrane area in T cells that comes in direct contact with antigen presenting cells. The immunological synapse is formed in T cells within seconds following the engagement of the TCR by a peptide-bound MHC molecule on the surface of antigen-presenting cells. It serves as a platform for receptors, adaptor proteins, and effector molecules, which assemble into multimolecular activation complexes required for signal transduction. The unique ability of PKC-theta to activate the NF-kB, AP-1 and NF-AT transcription factors is well established, and recent studies contributed essential information on the mechanisms involved in the recruitment of PKC-theta to the center of the immunological synapse and the nature of its substrates and the role of their phosphorylated forms in signal transduction. Additional review manuscripts will describe the unique behavior of PKC-theta in regulatory T cells and its role in the regulation of other cell populations, including those of the innate immune response. This volume brings together leading experts from different disciplines that review the most recent discoveries and offer new perspectives on the contributions of PKC isoforms to biochemical processes and signaling events in different immune cell populations and their impact on the overall host immune response

High rate loading of hybrid joints in a Split Hopkinson Tension Bar

Bonded joints are nowadays seen as one of the preferred joining methods in aerospace applications. However, the difficulty in certifying bond strength and the relatively low energy absorption capability of the joint are barriers to widespread adoption. The use of a hybrid joint, that is, the combination of a mechanical and a bonded joint, allows for a fail-safe design and offers improved performance of the joint. The quasi-static properties of hybrid joints have been investigated by a number of researchers. In contrast, the high rate loading regime has been only sparsely investigated. In this work, hybrid joints are tested in quasi-static and high rate loading in order to analyze their loading rate dependence. The hybrid joint studied is a composite-aluminum double lap shear joint with Sikaforce 7752 adhesive and Hi-Lite-315 countersunk titanium bolts. In order to quantitatively analyze the high rate behavior of the hybrid joints and their respective sub-components, additional tests are carried out on simply bonded and simply bolted specimens. The high rate characterization was performed with a Split Hopkinson Tension Bar. The main challenges for these tests are the relatively large specimen size and complex specimen geometry needed to properly characterize the joint behavior, which both are in contradiction with the assumptions of the classical Split Hopkinson Bar-analysis. In this paper we describe an approach to solve these challenges based on an elastic wave analysis of the system