The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid ...arthritis, psoriasis, and inflammatory bowel disease. Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals. Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases. The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity. Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases. Many other Jakinibs are in preclinical development or in various phases of clinical trials. This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling. The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs. Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.
Detecting single–photon level signals—carriers of both classical and quantum information—is particularly challenging for low-energy microwave frequency excitations. Here we introduce a ...superconducting amplifier based on a Josephson junction transmission line. Unlike current standing-wave parametric amplifiers, this traveling wave architecture robustly achieves high gain over a bandwidth of several gigahertz with sufficient dynamic range to read out 20 superconducting qubits. To achieve this performance, we introduce a subwavelength resonant phase-matching technique that enables the creation of nonlinear microwave devices with unique dispersion relations. We benchmark the amplifier with weak measurements, obtaining a high quantum efficiency of 75% (70% including noise added by amplifiers following the Josephson amplifier). With a flexible design based on compact lumped elements, this Josephson amplifier has broad applicability to microwave metrology and quantum optics.
Harnessing the full power of nascent quantum processors requires the efficient management of a limited number of quantum bits with finite coherent lifetimes. Hybrid algorithms, such as the ...variational quantum eigensolver (VQE), leverage classical resources to reduce the required number of quantum gates. Experimental demonstrations of VQE have resulted in calculation of Hamiltonian ground states, and a new theoretical approach based on a quantum subspace expansion (QSE) has outlined a procedure for determining excited states that are central to dynamical processes. We use a superconducting-qubit-based processor to apply the QSE approach to theH2molecule, extracting both ground and excited states without the need for auxiliary qubits or additional minimization. Further, we show that this extended protocol can mitigate the effects of incoherent errors, potentially enabling larger-scale quantum simulations without the need for complex error-correction techniques.
The discovery of cytokines as key drivers of immune-mediated diseases has spurred efforts to target their associated signalling pathways. Janus kinases (JAKs) are essential signalling mediators ...downstream of many pro-inflammatory cytokines, and small-molecule inhibitors of JAKs (jakinibs) have gained traction as safe and efficacious options for the treatment of inflammation-driven pathologies such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. Building on the clinical success of first-generation jakinibs, second-generation compounds that claim to be more selective are currently undergoing development and proceeding to clinical trials. However, important questions remain about the advantages and limitations of improved JAK selectivity, optimal routes and dosing regimens and how best to identify patients who will benefit from jakinibs. This Review discusses the biology of jakinibs from a translational perspective, focusing on recent insights from clinical trials, the development of novel agents and the use of jakinibs in a spectrum of immune and inflammatory diseases.
Word of mouth (WOM) affects diffusion and sales, but why are certain products talked about more than others, both right after consumers first experience them and in the months that follow? This ...article examines psychological drivers of immediate and ongoing WOM. The authors analyze a unique data set of everyday conversations for more than 300 products and conduct both a large field experiment across various cities and a controlled laboratory experiment with real conversations. The results indicate that more interesting products get more immediate WOM but, contrary to intuition, do not receive more ongoing WOM over multiple months or overall. In contrast, products that are cued more by the environment or are more publicly visible receive more WOM both right away and over time. Additional analyses demonstrate which promotional giveaways in WOM marketing campaigns are associated with increased WOM. Overall, the findings shed light on psychological drivers of WOM and provide insight into designing more effective WOM campaigns.
As the incidence of primary total joint arthroplasty rises in the United States, it is important to investigate how this will impact rates of revision arthroplasty. The purpose of this study was to ...analyze the incidence and future projections of revision total hip arthroplasty (rTHA) and revision total knee arthroplasty (rTKA) to 2030. Anticipating surgical volume will aid surgeons in designing protocols to efficiently and effectively perform rTHA/rTKA.
The national inpatient sample was queried from 2002 to 2014 for all rTHA/rTKA. Using previously validated measures, Poisson and linear regression analyses were performed to project annual incidence of rTHA/rTKA to 2030, with subgroup analyses on modes of failure and age.
In 2014, there were 50,220 rTHAs and 72,100 rTKAs. From 2014 to 2030, rTHA incidence is projected to increase by between 43% and 70%, whereas rTKA incidence is projected to increase by between 78% and 182%. The 55-64 and 65-74 age groups increased in revision incidence during the study period, whereas 75-84 age group decreased in incidence. For rTKA, infection and aseptic loosening are the 2 most common modes of failure, whereas periprosthetic fracture and infection are most common for rTHA.
The incidence of rTHA/rTKA is projected to increase, particularly in young patients and for infection. Given the known risk factor profiles and advanced costs associated with revision arthroplasty, our projections should encourage institutions to generate revision-specific protocols to promote safe pathways for cost-effective care that is commensurate with current value-based health care trends.
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The creation of a quantum network requires the distribution of coherent information across macroscopic distances. We demonstrate the entanglement of two superconducting qubits, separated by more than ...a meter of coaxial cable, by designing a joint measurement that probabilistically projects onto an entangled state. By using a continuous measurement scheme, we are further able to observe single quantum trajectories of the joint two-qubit state, confirming the validity of the quantum Bayesian formalism for a cascaded system. Our results allow us to resolve the dynamics of continuous projection onto the entangled manifold, in quantitative agreement with theory.
Warming experiments are increasingly relied on to estimate plant responses to global climate change. For experiments to provide meaningful predictions of future responses, they should reflect the ...empirical record of responses to temperature variability and recent warming, including advances in the timing of flowering and leafing. We compared phenology (the timing of recurring life history events) in observational studies and warming experiments spanning four continents and 1,634 plant species using a common measure of temperature sensitivity (change in days per degree Celsius). We show that warming experiments underpredict advances in the timing of flowering and leafing by 8.5-fold and 4.0-fold, respectively, compared with long-term observations. For species that were common to both study types, the experimental results did not match the observational data in sign or magnitude. The observational data also showed that species that flower earliest in the spring have the highest temperature sensitivities, but this trend was not reflected in the experimental data. These significant mismatches seem to be unrelated to the study length or to the degree of manipulated warming in experiments. The discrepancy between experiments and observations, however, could arise from complex interactions among multiple drivers in the observational data, or it could arise from remediable artefacts in the experiments that result in lower irradiance and drier soils, thus dampening the phenological responses to manipulated warming. Our results introduce uncertainty into ecosystem models that are informed solely by experiments and suggest that responses to climate change that are predicted using such models should be re-evaluated.
Summary Objectives Joint degeneration in osteoarthritis (OA) is characterised by damage and loss of articular cartilage. The pattern of loss is consistent with damage occurring only where the ...mechanical loading is high. We have investigated using RNA-sequencing (RNA-seq) and systems analyses the changes that occur in damaged OA cartilage by comparing it with intact cartilage from the same joint. Methods Cartilage was obtained from eight OA patients undergoing total knee replacement. RNA was extracted from cartilage on the damaged distal medial condyle (DMC) and the intact posterior lateral condyle (PLC). RNA-seq was performed to identify differentially expressed genes (DEGs) and systems analyses applied to identify dysregulated pathways. Results In the damaged OA cartilage, there was decreased expression of chondrogenic genes SOX9, SOX6, COL11A2, COL9A1/2/3, ACAN and HAPLN1; increases in non-chondrogenic genes COL1A1, COMP and FN1; an altered pattern of secreted proteinase expression; but no expression of major inflammatory cytokines. Systems analyses by PhenomeExpress revealed significant sub-networks of DEGs including mitotic cell cycle, Wnt signalling, apoptosis and matrix organisation that were influenced by a core of altered transcription factors (TFs), FOSL1, AHR, E2F1 and FOXM1. Conclusions Gene expression changes in damaged cartilage suggested a signature non-chondrogenic response of altered matrix protein and secreted proteinase expression. There was evidence of a damage response in this late OA cartilage, which surprisingly showed features detected experimentally in the early response of cartilage to mechanical overload. PhenomeExpress analysis identified a hub of DEGs linked by a core of four differentially regulated TFs.
Skeletal muscles are the largest cells in the body and are one of the few syncytial ones. There is a longstanding belief that a given nucleus controls a defined volume of cytoplasm, so when a muscle ...grows (hypertrophy) or shrinks (atrophy), the number of myonuclei change accordingly. This phenomenon is known as the "myonuclear domain hypothesis." There is a general agreement that hypertrophy is accompanied by the addition of new nuclei from stem cells to help the muscles meet the enhanced synthetic demands of a larger cell. However, there is a considerable controversy regarding the fate of pre-existing nuclei during atrophy. Many researchers have reported that atrophy is accompanied by the dramatic loss of myonuclei
apoptosis. However, since there are many different non-muscle cell populations that reside within the tissue, these experiments cannot easily distinguish true myonuclei from those of neighboring mononuclear cells. Recently, two independent models, one from rodents and the other from insects, have demonstrated that nuclei are not lost from skeletal muscle fibers when they undergo either atrophy or programmed cell death. These and other data argue against the current interpretation of the myonuclear domain hypothesis and suggest that once a nucleus has been acquired by a muscle fiber it persists.
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