Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sjogren's Syndrome Patients at Diagnosis

Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sjogren's syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton's tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS

Can cognitive psychological research on reasoning enhance the discussion around moral judgments?

In this article we will demonstrate how cognitive psychological research on reasoning and decision making could enhance discussions and theories of moral judgments. In the first part, we will present recent dual-process models of moral judgments and describe selected studies which support these approaches. However, we will also present data that contradict the model predictions, suggesting that approaches to moral judgment might be more complex. In the second part, we will show how cognitive psychological research on reasoning might be helpful in understanding moral judgments. Specifically, we will highlight approaches addressing the interaction between intuition and reflection. Our data suggest that a sequential model of engaging in deliberation might have to be revised. Therefore, we will present an approach based on Signal Detection Theory and on intuitive conflict detection. We predict that individuals arrive at the moral decisions by comparing potential action outcomes (e.g., harm caused and utilitarian gain) simultaneously. The response criterion can be influenced by intuitive processes, such as heuristic moral value processing, or considerations of harm caused

Enhanced Bruton's tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis

Rationale Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. Methods B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. Results More IgA(+) memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = - 0.50). Bruton's tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA(+) germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). Conclusion Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.</p

Effect of response format on cognitive reflection: Validating a two- and four-option multiple choice question version of the Cognitive Reflection Test

The Cognitive Reflection Test, measuring intuition inhibition and cognitive reflection, has become extremely popular since it reliably predicts reasoning performance, decision-making and beliefs. Across studies, the response format of CRT items sometimes differs, assuming construct equivalence of the tests with open-ended vs. multiple choice items (the equivalence hypothesis). Evidence and theoretical reasons, however, suggest that the cognitive processes measured by these response formats and their associated performances might differ (the non-equivalence hypothesis). We tested the two hypotheses experimentally by assessing the performance in tests with different response formats and by comparing their predictive and construct validity. In a between-subjects experiment (n = 452), participants answered an open-ended, a two- or a four-option response format of stem-equivalent CRT items and completed tasks on belief bias, denominator neglect and paranormal beliefs (benchmark indicators of predictive validity) as well as actively open-minded thinking and numeracy (benchmark indicators of construct validity). We found no significant differences between the three response formats in the number of correct responses, the number of intuitive responses (with the exception of the two-option version being higher than the other tests) and in the correlational patterns with the indicators of predictive and construct validity. All three test versions were similarly reliable but the multiple-choice formats were completed more quickly. We speculate that the specific nature of the CRT items helps to build construct equivalence among the different response formats. We recommend using the validated multiple-choice version of the CRT presented here, particularly the four-option CRT, for practical and methodological reasons

When fast logic meets slow belief: Evidence for a parallel-processing model of belief bias.

Two experiments pitted the default-interventionist account of belief bias against a parallel-processing model. According to the former, belief bias occurs because a fast, belief-based evaluation of the conclusion pre-empts a working-memory demanding logical analysis. In contrast, according to the latter both belief-based and logic-based responding occur in parallel. Participants were given deductive reasoning problems of variable complexity and instructed to decide whether the conclusion was valid on half the trials or to decide whether the conclusion was believable on the other half. When belief and logic conflict, the default-interventionist view predicts that it should take less time to respond on the basis of belief than logic, and that the believability of a conclusion should interfere with judgments of validity, but not the reverse. The parallel-processing view predicts that beliefs should interfere with logic judgments only if the processing required to evaluate the logical structure exceeds that required to evaluate the knowledge necessary to make a belief-based judgment, and vice versa otherwise. Consistent with this latter view, for the simplest reasoning problems (modus ponens), judgments of belief resulted in lower accuracy than judgments of validity, and believability interfered more with judgments of validity than the converse. For problems of moderate complexity (modus tollens and single-model syllogisms), the interference was symmetrical, in that validity interfered with belief judgments to the same degree that believability interfered with validity judgments. For the most complex (three-term multiple-model syllogisms), conclusion believability interfered more with judgments of validity than vice versa, in spite of the significant interference from conclusion validity on judgments of belief

Slower is not always better: Response-time evidence clarifies the limited role of miserly information processing in the Cognitive Reflection Test

We report a study examining the role of `cognitive miserliness' as a determinant of poor performance on the standard three-item Cognitive Reflection Test (CRT). The cognitive miserliness hypothesis proposes that people often respond incorrectly on CRT items because of an unwillingness to go beyond default, heuristic processing and invest time and effort in analytic, reflective processing. Our analysis (N = 391) focused on people's response times to CRT items to determine whether predicted associations are evident between miserly thinking and the generation of incorrect, intuitive answers. Evidence indicated only a weak correlation between CRT response times and accuracy. Item-level analyses also failed to demonstrate predicted response time differences between correct analytic and incorrect intuitive answers for two of the three CRT items. We question whether participants who give incorrect intuitive answers on the CRT can legitimately be termed cognitive misers and whether the three CRT items measure the same general construct

Elucidating the mechanism of Danicamtiv on force, kinetics, and myosin structure and function

Myosin modulators are a novel class of small molecules that alter cardiac contractility. Omecamtiv mecarbil, the first identified myosin activator, showed only modest clinical benefits in systolic heart failure patients. Thus, there is an urgency to develop alternative myosin activators. Danicamtiv (Dani) has emerged as a potential candidate; however, a detailed mechanism is not known. Here, we aim to elucidate the mechanism of Dani on contractile function in pig cardiac muscle. Demembranated ventricular tissues show a significant 0.1 pCa unit increase in calcium sensitivity and 10% increase in maximal force after incubation in 1 µM Dani. The most potent effects occur in submaximal calcium concentrations, leading to a flattening of the force-calcium relationship, suggesting decreased cooperativity. Maximal rates of tension redevelopment are decreased by approximately 60% with Dani. Isolated cardiac myofibrils provide details about contractile kinetics. Experiments with 1 µM Dani show a 49% decrease in fast-phase relaxation kinetics. Slow-phase isometric relaxation exhibits 47% slower crossbridge detachment rate and 34% longer thin filament deactivation. Next, we assess ATP utilization in the crossbridge cycle. Filament sliding velocity slows 55% on addition of 0.5 µM Dani, similar to the effect of ADP on velocity. The effects of Dani and ADP are not additive suggesting a similar mode of action. ATP binding is unaltered up to 10 µM Dani using stopped flow spectroscopy. Results of X-ray diffraction studies of porcine myocardium at rest show an increase in equatorial intensity ratio (I1,1/I1,0) in response to 50 µM Dani, reflecting an increased proximity of myosin heads to the thin filament. In conclusion, we hypothesize that Dani primes the thick filament for activation and alters relaxation through inhibited ATP hydrolysis product release. Future studies will test these hypotheses