Before the use of corticosteroids, the prognosis for polymyositis/dermatomyositis (PM/DM) was extremely poor. To date, although overall prognosis appears to be better, PM and DM are still considered ...to be associated with increased morbidity, primarily related to severe muscle weakness and visceral involvement. Recent series underline that only 20% to 40% of treated patients will achieve PM/DM remission, whereas 60% to 80% will experience a polycyclic or chronic, continuous course of the disease. PM/DM further continues to have a great impact on life in medium- and long-term follow-up, as up to 80% of treated patients are still disabled (using Health Assessment Questionnaire scores). The overall mortality ratio in PM/DM patients also remains threefold higher compared with the general population, with cancer, lung, and cardiac complications and infections being the most common causes of deaths. Predictive factors for a poor prognosis in PM/DM patients are older age, involvement of lung and cardiac systems, dysphagia, cancer, and serum myositis–specific antibodies (including coexistent presence of anti-Ro52 and anti-Jo1 antibodies, anti–signal recognition particle antibody, anti-155/140, and anti–CADM-140 antibodies).
Firms increasingly employ social media for innovation, yet current literature offers little guidance for developing their strategic uses. This study applies a qualitative, theory-building approach to ...derive a conceptual framework of the capabilities that allow companies to benefit by using social media throughout their innovation processes. This framework, designed to support applications of social media for innovation, sheds light on three key capabilities and related resources: social media managers who orchestrate social media activities across the innovation process; top management that cultivates support, team empowerment, and test-and-learn cycles; and agile processes that facilitate rapid decision making and knowledge flows across teams. This article enriches organizational capability theory as it pertains to innovation, and it provides managers with guidance for implementing social media strategies in practice.
Sensing invading pathogens early in infection is critical for establishing host defense. Two cytosolic RIG-like RNA helicases, RIG-I and MDA5, are key to type I interferon (IFN) induction in response ...to viral infection. Mounting evidence suggests that another viral RNA sensor, protein kinase R (PKR), may also be critical for IFN induction during infection, although its exact contribution and mechanism of action are not completely understood. Using PKR-deficient cells, we found that PKR was required for type I IFN induction in response to infection by vaccinia virus lacking the PKR antagonist E3L (VVΔE3L), but not by Sendai virus or influenza A virus lacking the IFN-antagonist NS1 (FluΔNS1). IFN induction required the catalytic activity of PKR, but not the phosphorylation of its principal substrate, eIF2α, or the resulting inhibition of host translation. In the absence of PKR, IRF3 nuclear translocation was impaired in response to MDA5 activators, VVΔE3L and encephalomyocarditis virus, but not during infection with a RIG-I-activating virus. Interestingly, PKR interacted with both RIG-I and MDA5; however, PKR was only required for MDA5-mediated, but not RIG-I-mediated, IFN production. Using an artificially activated form of PKR, we showed that PKR activity alone was sufficient for IFN induction. This effect required MAVS and correlated with IRF3 activation, but no longer required MDA5. Nonetheless, PKR activation during viral infection was enhanced by MDA5, as virus-stimulated catalytic activity was impaired in MDA5-null cells. Taken together, our data describe a critical and non-redundant role for PKR following MDA5, but not RIG-I, activation to mediate MAVS-dependent induction of type I IFN through a kinase-dependent mechanism.
Objective
Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous ...immunoglobulin (IVIG)– and steroid‐resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin‐1 in patients with IVIG‐resistant KD.
Methods
Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient’s body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C‐reactive protein (CRP) levels.
Results
Seventy‐five percent of patients in the intention‐to‐treat group and 87.5% in the per‐protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval 95% CI 68.1–99.8%) of physician evaluations and on 100% (95% CI 73.5–100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% 95% CI 18.7–81.3%) and 6 of 12 patients (50% 95% CI 21.1–78.9%) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred.
Conclusion
Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG‐refractory KD.
A formal 3+2 cyclization mediated by silver(I) oxide and 1,8‐diazabicyclo5.4.0undec‐7‐ene (DBU) is described herein. Through a broad variety of carbonyl compounds, this system can promote cyclization ...reactions with high yield (up to 85 %) and diastereoselectivity (up to 95:5) for a straightforward access to complex and congested dihydrofuran derivatives in one step under mild conditions. Based on DFT studies, the proposed mechanism would involve an allenyl silver intermediate.
An easy way to complex: An unprecedented isomerization/allenyl silver formation/3+2 cyclization promoted by a combination of silver salts and base is presented. The reaction, which is broad in scope, allows the straightforward and diastereoselective (up to 95:5 dr) synthesis of complex dihydrofuran frameworks under mild conditions from easily accessible substrates.
The Lgr5 receptor is a marker of intestinal stem cells (ISCs) that regulates Wnt/b‐catenin signaling. In this study, phenotype analysis of knockin/knockout Lgr5‐eGFP‐IRES‐Cre and Lgr5‐DTReGFP embryos ...reveals that Lgr5 deficiency during Wnt‐mediated cytodifferentiation results in amplification of ISCs and early differentiation into Paneth cells, which can be counteracted by in utero treatment with the Wnt inhibitor LGK974. Conditional ablation of Lgr5 postnatally, but not in adults, alters stem cell fate toward the Paneth lineage. Together, these in vivo studies suggest that Lgr5 is part of a feedback loop to adjust the Wnt tone in ISCs. Moreover, transcriptome analyses reveal that Lgr5 controls fetal ISC maturation associated with acquisition of a definitive stable epithelial phenotype, as well as the capacity of ISCs to generate their own extracellular matrix. Finally, using the ex vivo culture system, evidences are provided that Lgr5 antagonizes the Rspondin 2‐Wnt‐mediated response in ISCs in organoids, revealing a sophisticated regulatory process for Wnt signaling in ISCs.
Synopsis
The stem cell marker Lgr5 is part of a feedback loop allowing fine‐tuning of Wnt signaling in intestinal stem cells during late fetal and postnatal development. Its interaction with the Rspondin 2 ligand modulates epithelial extracellular matrix production.
Lgr5 deficiency during Wnt‐mediated cytodifferentiation results in the amplification of the stem cell pool.
Lgr5 deficiency also increases early Paneth cell differentiation during mouse intestinal development.
Intestinal Lgr5+ stem cell maturation is associated with progressive reduction of matrisome components.
The Rspo2/Lgr5 interaction in intestinal stem cells fine‐tunes Wnt signalling and ECM production in the epithelium.
The stem cell marker Lgr5 is part of a feedback loop allowing fine‐tuning of Wnt signaling in intestinal stem cells during late fetal and postnatal development. Its interaction with the Rspondin 2 ligand modulates epithelial extracellular matrix production.
This paper presents an assessment and comparison of recent mean sea surface (MSS) models. Using a new approach and independent altimeter data sets, we quantify the major improvement of the CNES_CLS15 ...and the DTU15 models. We observe a reduction in the amplitude of omission errors thanks to the use of new geodetic altimeter data sets (i.e., Cryosat‐2 and Jason‐1 geodetic): they are reduced by a factor of 2 compared with previous generations (CNES_CLS11). We also quantify commission errors resulting from the leakage of residual ocean variability and altimeter noise into the MSS models. For wavelengths shorter than 250 km, the error is of the order of 1–2 cm2, i.e., ∼10% to 20% of the sea level anomaly (SLA) variance. The global error of both 2015 models has similar orders of magnitude and spectral power densities, although the commission errors of the CNES_CLS15 model are about half as large as those of the DTU15 model. Its absolute error is also slightly smaller than for the DTU15 model in coastal regions and at high latitudes. Conversely, the DTU15 model produces smaller omission errors, especially in the open ocean over strong bathymetric features. More importantly, the MSS errors still have a substantial impact on altimetry products for wavelengths ranging from 30 to 100 km: the error explains ∼30% of the global SLA variance, and the error can be 2.5 times higher on uncharted ground tracks (e.g., Sentinel‐3) over rugged bathymetry.
Key Points
The use of geodetic measurements in the new MSS (CNES_CLS15, DTU15) contributes to reduce the omission errors by a factor of 2
The commission errors represent between 10% (CNES_CLS15) and 20% (DTU15) of the SLA variance for wavelengths shorter than 250 km
MSS errors on uncharted tracks (e.g., Sentinel‐3A) explain 30% of the SLA variance at short wavelengths (i.e., 30–100 km)
PDF
