CXCL13 in Sjögrenˈs syndrome increases with disease progression in mice and is elevated in human sera and saliva; blockade of CXCL13 ameliorates disease in an SS murine model.
SS is an autoimmune ...disease. pSS affects exocrine glands predominantly, whereas sSS occurs with other autoimmune connective tissue disorders. Currently, care for patients with SS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms remain uncertain. B‐cell abnormalities have been identified in SS. CXCL13 directs B‐cell chemotaxis and is elevated in several autoimmune diseases. In this study, we tested the hypothesis that CXCL13 is elevated in SS in mice and humans and that neutralization of the chemokine ameliorates disease in a murine model. We assayed CXCL13 in mouse models and human subjects with SS to determine whether CXCL13 is elevated both locally and systemically during SS progression and whether CXCL13 may play a role in and be a biomarker for the disease. Cxcl13 expression in salivary tissue increases with disease progression, and its blockade resulted in a modest reduction in glandular inflammation in an SS model. We demonstrate that in humans CXCL13 is elevated in serum and saliva, and an elevated salivary CXCL13 level distinguishes patients with xerostomia. These data suggest a role for CXCL13 as a valuable biomarker in SS, as 74% of patients with SS displayed elevated CXCL13 in sera, saliva, or both. Thus, CXCL13 may be pathogenically involved in SS and may serve as a new marker and a potential therapeutic target.
Scholarly interest in the study of trust and distrust in organizations has grown dramatically over the past five years. This interest has been fueled, at least in part, by accumulating evidence that ...trust has a number of important benefits for organizations and their members. A primary aim of this review is to assess the state of this rapidly growing literature. The review examines recent progress in conceptualizing trust and distrust in organizational theory, and also summarizes evidence regarding the myriad benefits of trust within organizational systems. The review also describes different forms of trust found in organizations, and the antecedent conditions that produce them. Although the benefits of trust are well-documented, creating and sustaining trust is often difficult. Accordingly, the chapter concludes by examining some of the psychological, social, and institutional barriers to the production of trust.
Multiple K ⁺ transporters and channels and the corresponding mutants have been described and studied in the plasma membrane and organelle membranes of plant cells. However, knowledge about the ...molecular identity of chloroplast K ⁺ transporters is limited. Potassium transport and a well-balanced K ⁺ homeostasis were suggested to play important roles in chloroplast function. Because no loss-of-function mutants have been identified, the importance of K ⁺ transporters for chloroplast function and photosynthesis remains to be determined. Here, we report single and higher-order loss-of-function mutants in members of the cation/proton antiporters-2 antiporter superfamily KEA1 , KEA2 , and KEA3 . KEA1 and KEA2 proteins are targeted to the inner envelope membrane of chloroplasts, whereas KEA3 is targeted to the thylakoid membrane. Higher-order but not single mutants showed increasingly impaired photosynthesis along with pale green leaves and severely stunted growth. The pH component of the proton motive force across the thylakoid membrane was significantly decreased in the kea1kea2 mutants, but increased in the kea3 mutant, indicating an altered chloroplast pH homeostasis. Electron microscopy of kea1kea2 leaf cells revealed dramatically swollen chloroplasts with disrupted envelope membranes and reduced thylakoid membrane density. Unexpectedly, exogenous NaCl application reversed the observed phenotypes. Furthermore, the kea1kea2 background enables genetic analyses of the functional significance of other chloroplast transporters as exemplified here in kea1kea2Na ⁺/H ⁺ antiporter1 (nhd1) triple mutants. Taken together, the presented data demonstrate a fundamental role of inner envelope KEA1 and KEA2 and thylakoid KEA3 transporters in chloroplast osmoregulation, integrity, and ion and pH homeostasis.
Objectives The objective of this study was to perform a systematic review and meta-analysis of the predictive value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for future ...cardiovascular events and death in hypertrophic cardiomyopathy (HCM). Background The utility of LGE for detecting myocardial fibrosis is well established. The prognostic value of LGE in HCM has been described in several studies, but controversy exists given the limited power of these studies to predict future events. Methods We searched multiple databases including PubMed for studies of LGE in HCM that reported selected clinical outcomes (cardiovascular mortality, sudden cardiac death SCD, aborted SCD, and heart failure death). We performed a systematic review of the literature and meta-analysis to determine pooled odds ratios for these clinical events. Results Four studies evaluated 1,063 patients over an average follow-up of 3.1 years. The pooled prevalence of LGE was 60%. The pooled odds ratios (OR) demonstrate that LGE by CMR correlated with cardiac death (pooled OR: 2.92, 95% confidence interval CI: 1.01 to 8.42; p = 0.047), heart failure death (pooled OR: 5.68, 95% CI: 1.04 to 31.07; p = 0.045), and all-cause mortality (pooled OR: 4.46, 95% CI: 1.53 to 13.01; p = 0.006), and showed a trend toward significance for predicting sudden death/aborted sudden death (pooled OR: 2.39, 95% CI: 0.87 to 6.58; p = 0.091). Conclusions Late gadolinium enhancement by CMR has prognostic value in predicting adverse cardiovascular events among HCM patients. There are significant relationships between LGE and cardiovascular mortality, heart failure death, and all-cause mortality in HCM. Additionally, LGE and SCD/aborted SCD displayed a trend toward significance. The assessment of LGE by CMR has the potential to provide important information to improve risk stratification in HCM in clinical practice.
Cardiac MR imaging has made major inroads in the new millennium in the diagnosis and assessment of prognosis for patients with cardiomyopathies. Imaging of left and right ventricular structure and ...function and tissue characterization with late gadolinium enhancement (LGE) as well as T1 and T2 mapping enable accurate diagnosis of the underlying etiology. In the setting of coronary artery disease, either transmurality of LGE or contractile reserve in response to dobutamine can assess the likelihood of recovery of function after revascularization. The presence of scar reduces the likelihood of a response to medical therapy and to cardiac resynchronization therapy in heart failure. The presence and extent of LGE relate to overall cardiovascular outcome in cardiomyopathies. A major role for cardiac MR imaging in cardiomyopathies is to identify myocardial scar for diagnostic and prognostic purposes.
Abstract
The repeating fast radio burst source FRB 121102 has been shown to have an exceptionally high and variable Faraday rotation measure (RM), which must be imparted within its host galaxy, ...likely by or within its local environment. In the redshifted (
z
= 0.193) source reference frame, the RM decreased from 1.46 × 10
5
rad m
−2
to 1.33 × 10
5
rad m
−2
between 2017 January and August, showing day-timescale variations of ∼200 rad m
−2
. Here we present 16 FRB 121102 RMs from burst detections with the Arecibo 305 m radio telescope, the Effelsberg 100 m, and the Karl G. Jansky Very Large Array, providing a record of FRB 121102’s RM over a 2.5 yr time span. Our observations show a decreasing trend in RM, although the trend is not linear, dropping by an average of 15% year
−1
and is ∼ 9.7 × 10
4
rad m
−2
at the most recent epoch of 2019 August. Erratic, short-term RM variations of ∼10
3
rad m
−2
week
−1
were also observed between MJDs 58215–58247. A decades-old neutron star embedded within a still-compact supernova remnant or a neutron star near a massive black hole and its accretion torus have been proposed to explain the high RMs. We compare the observed RMs to theoretical models describing the RM evolution for FRBs originating within a supernova remnant. FRB 121102’s age is unknown, and we find that the models agree for source ages of ∼6–17 yr at the time of the first available RM measurements in 2017. We also draw comparisons to the decreasing RM of the Galactic center magnetar, PSR J1745−2900.
Abstract
Gas–liquid flows occur in many natural environments such as breaking waves, river rapids and human-made systems, including nuclear reactors and water treatment or conveyance infrastructure. ...Such two-phase flows are commonly investigated using phase-detection intrusive probes, yielding velocities that are considered to be directly representative of bubble velocities. Using different state-of-the-art instruments and analysis algorithms, we show that bubble–probe interactions lead to an underestimation of the real bubble velocity due to surface tension. To overcome this velocity bias, a correction method is formulated based on a force balance on the bubble. The proposed methodology allows to assess the bubble–probe interaction bias for various types of gas-liquid flows and to recover the undisturbed real bubble velocity. We show that the velocity bias is strong in laboratory scale investigations and therefore may affect the extrapolation of results to full scale. The correction method increases the accuracy of bubble velocity estimations, thereby enabling a deeper understanding of fundamental gas-liquid flow processes.
Abstract
We report the discovery of PSR J1757−1854, a 21.5-ms pulsar in a highly-eccentric, 4.4-h orbit with a neutron star (NS) companion. PSR J1757−1854 exhibits some of the most extreme ...relativistic parameters of any known pulsar, including the strongest relativistic effects due to gravitational-wave damping, with a merger time of 76 Myr. Following a 1.6-yr timing campaign, we have measured five post-Keplerian parameters, yielding the two component masses (mp = 1.3384(9) M⊙ and mc = 1.3946(9) M⊙) plus three tests of general relativity, which the theory passes. The larger mass of the NS companion provides important clues regarding the binary formation of PSR J1757−1854. With simulations suggesting 3-σ measurements of both the contribution of Lense–Thirring precession to the rate of change of the semimajor axis and the relativistic deformation of the orbit within ∼7–9 yr, PSR J1757−1854 stands out as a unique laboratory for new tests of gravitational theories.
Background Induction chemotherapy before surgical resection increases survival compared with surgical resection alone in patients with stage IIIA-N2 non–small-cell lung cancer (NSCLC). We ...hypothesized that, following a response to induction chemotherapy, surgical resection would be superior to thoracic radiotherapy as locoregional therapy. Methods Selected patients with histologic or cytologic proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy. Responding patients were subsequently randomly assigned to surgical resection or radiotherapy. Survival curves were estimated using Kaplan–Meier analyses from time of randomization. Results Induction chemotherapy resulted in a response rate of 61% (95% confidence interval CI = 57% to 65%) among the 579 eligible patients. A total of 167 patients were allocated to resection and 165 to radiotherapy. Of the 154 (92%) patients who underwent surgery, 14% had an exploratory thoracotomy, 50% a radical resection, 42% a pathologic downstaging, and 5% a pathologic complete response; 4% died after surgery. Postoperative radiotherapy was administered to 62 (40%) of patients in the surgery arm. Among the 154 (93%) irradiated patients, overall compliance to the radiotherapy prescription was 55%, and grade 3/4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7%; one patient died of radiation pneumonitis. Median and 5-year overall survival for patients randomly assigned to resection versus radiotherapy were 16.4 versus 17.5 months and 15.7% versus 14%, respectively (hazard ratio = 1.06, 95% CI = 0.84 to 1.35). Rates of progression-free survival were also similar in both groups. Conclusion In selected patients with pathologically proven stage IIIA-N2 NSCLC and a response to induction chemotherapy, surgical resection did not improve overall or progression-free survival compared with radiotherapy. In view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these patients.
We sought to compare the diagnostic performance of coronary computed tomography angiography (CCTA), computed tomography perfusion (CTP), and computed tomography (CT)-fractional flow reserve (FFR) for ...assessing the functional significance of coronary stenosis as defined by invasive FFR in patients with known or suspected coronary artery disease (CAD). CCTA has proved clinically useful for excluding obstructive CAD because of its high sensitivity and negative predictive value (NPV); however, the ability of CTA to identify functionally significant CAD has remained challenging. We searched PubMed/Medline for studies evaluating CCTA, CTP, or CT-FFR for the noninvasive detection of obstructive CAD compared with catheter-derived FFR as the reference standard. Pooled sensitivity, specificity, PPV, NPV, likelihood ratios, and odds ratio of all diagnostic tests were assessed. Eighteen studies involving a total of 1,535 patients were included. CTA demonstrated a pooled sensitivity of 0.92, specificity 0.43, PPV of 0.56, and NPV of 0.87 on a per-patient level. CT-FFR and CTP increased the specificity to 0.72 and 0.77, respectively (p = 0.004 and p = 0.0009) resulting in higher point estimates for PPV 0.70 and 0.83, respectively. There was no improvement in the sensitivity. The CTP protocol involved more radiation (3.5 mSv CCTA vs 9.6 mSv CTP) and a higher volume of iodinated contrast (145 ml). In conclusion, CTP and CT-FFR improve the specificity of CCTA for detecting functionally significant stenosis as defined by invasive FFR on a per-patient level; both techniques could advance the ability to noninvasively detect the functional significance of coronary lesions.
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