The Naturally Processed CD95L Elicits a c-Yes/Calcium/PI3K-Driven Cell Migration Pathway

Patients affected by chronic inflammatory disorders display high amounts of soluble CD95L. This homotrimeric ligand arises from the cleavage by metalloproteases of its membrane-bound counterpart, a strong apoptotic inducer. In contrast, the naturally processed CD95L is viewed as an apoptotic antagonist competing with its membrane counterpart for binding to CD95. Recent reports pinpointed that activation of CD95 may attract myeloid and tumoral cells, which display resistance to the CD95-mediated apoptotic signal. However, all these studies were performed using chimeric CD95Ls (oligomerized forms), which behave as the membrane-bound ligand and not as the naturally processed CD95L. Herein, we examine the biological effects of the metalloprotease-cleaved CD95L on CD95-sensitive activated T-lymphocytes. We demonstrate that cleaved CD95L (cl-CD95L), found increased in sera of systemic lupus erythematosus (SLE) patients as compared to that of healthy individuals, promotes the formation of migrating pseudopods at the leading edge of which the death receptor CD95 is capped (confocal microscopy). Using different migration assays (wound healing/Boyden Chamber/endothelial transmigration), we uncover that cl-CD95L promotes cell migration through a c-yes/Ca2+/PI3K-driven signaling pathway, which relies on the formation of a CD95-containing complex designated the MISC for Motility-Inducing Signaling Complex. These findings revisit the role of the metalloprotease-cleaved CD95L and emphasize that the increase in cl-CD95L observed in patients affected by chronic inflammatory disorders may fuel the local or systemic tissue damage by promoting tissue-filtration of immune cells

Transcriptome Analysis Describing New Immunity and Defense Genes in Peripheral Blood Mononuclear Cells of Rheumatoid Arthritis Patients

Background: Large-scale gene expression profiling of peripheral blood mononuclear cells from Rheumatoid Arthritis (RA) patients could provide a molecular description that reflects the contribution of diverse cellular responses associated with this disease. The aim of our study was to identify peripheral blood gene expression profiles for RA patients, using Illumina technology, to gain insights into RA molecular mechanisms. Methodology/Principal Findings: The Illumina Human-6v2 Expression BeadChips were used for a complete genome-wide transcript profiling of peripheral blood mononuclear cells (PBMCs) from 18 RA patients and 15 controls. Differential analysis per gene was performed with one-way analysis of variance (ANOVA) and P values were adjusted to control the False Discovery Rate (FDR < 5%). Genes differentially expressed at significant level between patients and controls were analyzed using Gene Ontology (GO) in the PANTHER database to identify biological processes. A differentially expression of 339 Reference Sequence genes (238 down-regulated and 101 up-regulated) between the two groups was observed. We identified a remarkably elevated expression of a spectrum of genes involved in Immunity and Defense in PBMCs of RA patients compared to controls. This result is confirmed by GO analysis, suggesting that these genes could be activated systemically in RA. No significant down-regulated ontology groups were found. Microarray data were validated by real time PCR in a set of nine genes showing a high degree of correlation. Conclusions/Significance: Our study highlighted several new genes that could contribute in the identification of innovative clinical biomarkers for diagnostic procedures and therapeutic interventions

Supplemental Material - Trust in Automated Systems is Influenced Differently by Increasing and Decreasing Automation Reliability

Supplemental Material for Trust in Automated Systems is Influenced Differently by Increasing and Decreasing Automation Reliability by Benjamin S. P. Rittenberg, Christopher W. Holland, Grace E. Barnhart, Sierra M. Gaudreau and Heather F. Neyedli in Human Factors</p

Disease Severity, Pregnancy Outcomes and Maternal Deaths among Pregnant Patients with SARS-CoV-2 Infection in Washington State.

BACKGROUND: Evidence is accumulating that coronavirus disease 2019 (COVID-19) increases the risk for hospitalization and mechanical ventilation in pregnant patients and for preterm delivery. However, the impact on maternal mortality and whether morbidity is differentially affected by disease severity at delivery and trimester of infection is unknown. OBJECTIVES: To describe disease severity and outcomes of SARS-CoV-2 infections in pregnancy across Washington State including pregnancy complications and outcomes, hospitalization, and case fatality. STUDY DESIGN: Pregnant patients with a polymerase chain reaction confirmed SARS-CoV-2 infection between March 1 and June 30, 2020 were identified in a multi-center retrospective cohort study from 35 sites in Washington State. Sites captured 61% of annual state deliveries. Case fatality rates in pregnancy were compared to COVID-19 fatality rates in similarly aged adults in Washington State using rate ratios and rate differences. Maternal and neonatal outcomes were compared by trimester of infection and disease severity at the time of delivery. RESULTS: The principal study findings were: 1) among 240 pregnant patients in Washington State with SARS-CoV-2 infections, 1 in 11 developed severe or critical disease, 1 in 10 were hospitalized for COVID-19, and 1 in 80 died; 2) the COVID-19-associated hospitalization rate was 3.5-fold higher than in similarly-aged adults in Washington State [10.0% vs. 2.8%; rate ratio (RR) 3.5, 95% confidence interval (CI) 2.3-5.3]; 3) pregnant patients hospitalized for a respiratory concern were more likely to have a comorbidity or underlying conditions including asthma, hypertension, type 2 diabetes, autoimmune disease, and Class III obesity; 4) three maternal deaths (1.3%) were attributed to COVID-19 for a maternal mortality rate of 1,250/100,000 pregnancies (95%CI 257-3,653); 5) the COVID-19 case fatality in pregnancy was a significant 13.6-fold (95%CI 2.7-43.6) higher in pregnant patients compared to similarly aged individuals in Washington State with an absolute difference in mortality rate of 1.2% (95%CI -0.3-2.6); and 6) preterm birth was significantly higher among women with severe/critical COVID-19 at delivery than for women who had recovered from COVID-19 (45.4% severe/critical COVID-19 vs. 5.2% mild COVID-19, p\u3c0.001). CONCLUSIONS: COVID-19 hospitalization and case fatality rates in pregnant patients were significantly higher compared to similarly aged adults in Washington State. This data indicates that pregnant patients are at risk for severe or critical disease and mortality compared to non-pregnant adults, as well as preterm birth