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Sphingosine-1 Phosphate (S1P) helps mediate lymphocyte egress from lymph nodes, yet significant mechanistic questions remain. Here we show that B lymphocyte egress sites exist close to lymph node follicles. Recent B cell emigrants localize towards follicle centers, while longer-term residents tend towards cortical sinusoids. Exiting B lymphocytes squeeze through apparent portals in the lymphatic endothelium. Treatment with the S1P receptor agonist FTY720 empties the cortical sinusoids of lymphocytes, blocks lymphatic endothelial penetration, and displaces B lymphocytes into the T cell zone. S1P3−/− B cells, which lack chemoattractant responses to S1P, transit lymph nodes normally, while Gnai2−/− B cells, which have impaired responses to chemokines and S1P, transit more rapidly than do wild type cells. This study identifies a major site of B lymphocyte lymph node egress, shows that FTY720 treatment blocks passage through the cortical lymphatic endothelium, and argues against a functional role for S1P chemotaxis in B lymphocyte egress.

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Cell adhesion is dependent on many factors, including the repertoire of extracellular matrix (ECM) proteins and their receptors, e.g. integrins, synthesized by the cell, the composition of the ECM adsorbed to the surface, and the intrinsic chemistry of the surface. Factors that govern bone cell, i.e. osteoblast, adhesion and ECM elaboration significantly influence its re-modeling into mature bone, and ultimately its ability to integrate with biomaterials used for orthopedic prostheses. In this study, we have investigated how treatment with bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor-beta (TGF-beta) superfamily that promotes ectopic bone formation, modulates the organization and expression of osteoblastic cell proteins. Specifically, we analyzed how BMP-2 treatment affects cytoskeletal components, ECM, and alpha 5 and beta 1 integrin receptor subunits in osteoblastic cells plated on Ti6A14V, a titanium alloy widely used for orthopedic implants that interacts with bone cells in vitro and in vivo. Osteoblastic cells were pre-treated with BMP-2 for 12 h prior to plating; BMP-2 treatment stimulated adhesion and proliferation of osteoblastic cells and this adhesive advantage was reflected in enhanced long-term matrix mineralization in the BMP-2 pretreated cultures. Confocal laser scanning microscopic analysis of BMP-2 treated cells showed that enhanced cytoskeletal organization and focal contact formation occurred. These changes were accompanied by a concomitant increase in the spatial organization of fibronectin, whereas vitronectin, collagen type I, osteopontin, and osteocalcin showed little change. The changes in ECM organization correlated with increased fibronectin, alpha 5 and beta 1 integrin subunit, and focal adhesion kinase (p125FAK) expression, as well as increased p125FAK phosphorylation. By confocal microscopy, the alpha 5 integrin subunit was more concentrated in lamellipodia after BMP-2 treatment. These results demonstrate that BMP-2 significantly altered osteoblastic cytoskeletal and ECM organization and enhanced expression of fibronectin and of specific integrin receptor subunits, with concomitant changes in the levels and phosphorylation of p125FAK. These effects may contribute to downstream cellular responses important for bone cell function, and growth.

Optimal treatment for a chronic infected prosthesis is the removal of infected and necrotic tissue and all the components of the prosthesis with staged revision in conjunction with systemic antibiotics. If this is not possible because of the poor general condition of the patient, because of unacceptable functional results secondary to removal of the prosthesis, or because the patient refuses surgery in an attempt to salvage the infected prosthesis, a reasonable alternative is long-term oral suppressive antibiotic therapy for maintenance of a functioning prosthesis. Prompt recognition with rapid debridement and initiation of antibiotic therapy seems crucial. Our study confirms a favorable outcome of maintenance of functioning prostheses in 86.2% of patients after a mean followup of 5 years. All patients had initial debridement with 4 to 6 weeks of systemic antibiotic therapy. Advanced age did not seem to predict poor outcome. Joint location, duration of symptoms, and the time of onset of infection did not predict success or failure. The overall success rate for Staphylococcus aureus prosthetic joint infection was 69% after a mean followup of 5 years. The ideal regimen and optimal duration of oral suppressive therapy for a favorable outcome is not well-established and needs additional data with prospective multicenter studies.

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Recent proposals for trusted hardware platforms, such as Intel SGX and the MIT Sanctum processor, offer compelling security features but lack formal guarantees. We introduce a verification methodology based on a trusted abstract platform (TAP), a formalization of idealized enclave platforms along with a parameterized adversary. We also formalize the notion of secure remote execution and present machine-checked proofs showing that the TAP satisfies the three key security properties that entail secure remote execution: integrity, confidentiality and secure measurement. We then present machine-checked proofs showing that SGX and Sanctum are refinements of the TAP under certain parameterizations of the adversary, demonstrating that these systems implement secure enclaves for the stated adversary models. CCS CONCEPTS• Security and privacy → Formal methods and theory of security; Security in hardware; Trusted computing; Information flow control;

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