When lymphocytes encounter APCs bearing cognate Ag, they spread across the surface of the APC to scan for additional Ags. This is followed by membrane contraction and the formation of Ag receptor microclusters that initiate the signaling reactions that lead to lymphocyte activation. Breakdown of the submembrane cytoskeleton is likely to be required for the cytoskeleton reorganization that drives cell spreading and for removing physical barriers that limit Ag receptor mobility. In this report, we show that Ag receptor signaling via the Rap GTPases promotes the dephosphorylation and activation of the actin-severing protein cofilin and that this results in increased severing of cellular actin filaments. Moreover, we show that this cofilin-mediated actin severing is critical for the changes in actin dynamics that drive B and T cell spreading, for the formation of BCR microclusters, and for the increased mobility of BCR microclusters within the plasma membrane after BCR engagement. Finally, using a model APC, we show that activation of this Rap–cofilin signaling module controls the amount of Ag that is gathered into BCR microclusters and that this is directly related to the magnitude of the resulting BCR signaling that is initiated during B cell–APC interactions. Thus, Rap-dependent activation of cofilin is critical for the early cytoskeletal changes and BCR reorganization that are involved in APC-dependent lymphocyte activation.

Objective To evaluate the prevalence of seven social factors using physician notes as compared to claims and structured electronic health records (EHRs) data and the resulting association with 30‐day readmissions. Study Setting A multihospital academic health system in southeastern Massachusetts. Study Design An observational study of 49,319 patients with cardiovascular disease admitted from January 1, 2011, to December 31, 2013, using multivariable logistic regression to adjust for patient characteristics. Data Collection/Extraction Methods All‐payer claims, EHR data, and physician notes extracted from a centralized clinical registry. Principal Findings All seven social characteristics were identified at the highest rates in physician notes. For example, we identified 14,872 patient admissions with poor social support in physician notes, increasing the prevalence from 0.4 percent using ICD‐9 codes and structured EHR data to 16.0 percent. Compared to an 18.6 percent baseline readmission rate, risk‐adjusted analysis showed higher readmission risk for patients with housing instability (readmission rate 24.5 percent; p < .001), depression (20.6 percent; p < .001), drug abuse (20.2 percent; p = .01), and poor social support (20.0 percent; p = .01). Conclusions The seven social risk factors studied are substantially more prevalent than represented in administrative data. Automated methods for analyzing physician notes may enable better identification of patients with social needs.

Thrombus formation leading to vaso-occlusive events is a major cause of death, and involves complex interactions between coagulation, fibrinolytic and innate immune systems. Leukocyte recruitment is a key step, mediated partly by chemotactic complement activation factors C3a and C5a. However, mechanisms mediating C3a/C5a generation during thrombosis have not been studied. In a murine venous thrombosis model, levels of thrombin–antithrombin complexes poorly correlated with C3a and C5a, excluding a central role for thrombin in C3a/C5a production. However, clot weight strongly correlated with C5a, suggesting processes triggered during thrombosis promote C5a generation. Since thrombosis elicits fibrinolysis, we hypothesized that plasmin activates C5 during thrombosis. In vitro, the catalytic efficiency of plasmin-mediated C5a generation greatly exceeded that of thrombin or factor Xa, but was similar to the recognized complement C5 convertases. Plasmin-activated C5 yielded a functional membrane attack complex (MAC). In an arterial thrombosis model, plasminogen activator administration increased C5a levels. Overall, these findings suggest plasmin bridges thrombosis and the immune response by liberating C5a and inducing MAC assembly. These new insights may lead to the development of strategies to limit thrombus formation and/or enhance resolution.

B lymphocytes spread and extend membrane processes when searching for antigens and form immune synapses upon contacting cells that display antigens on their surface. Although these dynamic morphological changes facilitate B cell activation, the signaling pathways underlying these processes are not fully understood. We found that activation of the Rap GTPases was essential for these changes in B cell morphology. Rap activation was important for B cell receptor (BCR)- and lymphocyte-function-associated antigen-1 (LFA-1)-induced spreading, for BCR-induced immune-synapse formation, and for particulate BCR ligands to induce localized F-actin assembly and membrane-process extension. Rap activation and F-actin assembly were also required for optimal BCR signaling in response to particulate antigens but not soluble antigens. Thus by controlling B cell morphology and cytoskeletal organization, Rap might play a key role in the activation of B cells by particulate and cell-associated antigens.

Background:The loss of McpC has been shown to reduce chemotaxis to 19 of the 20 amino acids. Results: McpC can directly bind 11 amino acids and indirectly sense four others. Conclusion: McpC can sense a variety of amino acids by using two discrete mechanisms. Significance: We elucidate the mechanisms by which a single receptor can sense a wide variety of ligands.

Key PointsQuestionIs adding preoperative and intraoperative data associated with improved risk stratification of patients undergoing noncardiac surgery for postoperative acute kidney injury?FindingsIn this prognostic study of 42 615 patients who underwent noncardiac surgery, the addition of preoperative to prehospitalization data improved model performance (area under the curve increased from 0.71 to 0.80) as did adding preoperative plus intraoperative data (area under the curve further increased to 0.82).MeaningAlthough electronic health record data may be used to accurately stratify patients at risk of postoperative acute kidney injury, there appears to be only modest improvement in performance when adding intraoperative data to risk stratification models.

Background: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. Methods: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. Findings: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocytespecific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. Interpretation: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Key Points Polyphosphate suppresses complement via the terminal pathway by destabilizing C5b,6, thereby reducing the lytic capacity of the membrane attack complex. Polyphosphate, a novel negative regulator of complement, bridges coagulation and complement and is a potential therapeutic target.