Miss Manners: A Specialized Silicon Compiler for Synchronizers

Miss Manners is a synchronizer generator that will produce the layout of a synchronizer given a high-level description. A synchronizer generator is a type of specialized silicon compiler. Synchronizer generators can greatly aid the design of systems that are structured as loosely-coupled networks of autonomous subsystems. Chips that are structured in this way have reduced communication requirements and greater tolerance for transient failures. We describe a language for specifying synchronization requirements and a compiler for translating the language into circuits that enforce the specifications

Surface proteins that promote adherence of Staphylococcus aureus to human desquamated nasal epithelial cells

<p>Abstract</p> <p>Background</p> <p>The natural habitat of <it>Staphylococcus aureus </it>is the moist squamous epithelium in the anterior nares. About 20% of the human population carry <it>S. aureus </it>permanently in their noses and another 60% of individuals are intermittent carriers. The ability of <it>S. aureus </it>to colonize the nasal epithelium is in part due to expression of surface proteins clumping factor B (ClfB) and the iron-regulated surface determinant A (IsdA), which promote adhesion to desquamated epithelial cells present in the anterior part of the nasal vestibule. <it>S. aureus </it>strain Newman defective in IsdA and ClfB exhibited reduced but not completely defective adherence to squamous cells in indicating that other cell surface components might also contribute.</p> <p>Results</p> <p>Surface proteins IsdA, ClfB, and the serine-aspartic acid repeat proteins SdrC, SdrD and SdrE were investigated to determine their contribution to the adherence of <it>S. aureus </it>to desquamated nasal epithelial cells. This was achieved by expression of ClfB, IsdA, SdrC, SdrD and SdrE on the surface of the surrogate Gram-positive host <it>Lactococcus lactis </it>and by isolating mutants of <it>S. aureus </it>Newman defective in one or more factor. The level of adherence of strains to squamous cells isolated from the nares of volunteers was measured. Results consistently showed that ClfB, IsdA, SdrC and SdrD each contributed to the ability of <it>S. aureus </it>to adhere to squamous cells. A mutant lacking all four proteins was completely defective in adherence.</p> <p>Conclusion</p> <p>The ability of <it>S. aureus </it>Newman to adhere to desquamated nasal epithelial cells is multifactorial and involves SdrD and SdrC as well as ClfB and IsdA.</p

Host-Bacteria Interactions in Foreign Body Infections

Persistent staphylococcal infections are a major medical problem, especially when they occur on implanted materials or intravascular catheters. This review describes some of the recently discovered molecular mechanisms of Staphylococcus aureus attachment to host proteins coating biomedical implants. These interactions involve specific surface proteins, called bacterial adhesins, that recognize specific domains of host proteins deposited on indwelling devices, such as fibronectin, fibrinogen, or fibrin. Elucidation of molecular mechanisms of S aureus adhesion to the different host proteins may lead to the development of specific inhibitors blocking attachment of S aureus, which may decrease the risk of bacterial colonization of indwelling device

Improving pumpset selection to support intensification of groundwater irrigation in the Eastern Indo-Gangetic Plains

Intensification of groundwater irrigation is central to goals of improving food security and reducing chronic poverty faced by millions of rural households across the eastern Indo-Gangetic Plains (EIGP) of Nepal and parts of eastern India. At present, levels of groundwater use and access in the EIGP lag far behind other areas of South Asia despite abundant available groundwater resources. A key reason for prevailing access constraints is the dependence on diesel pumpsets for accessing groundwater, which are typically unsubsidised and therefore expensive to purchase and operate. To date, efforts to reduce access costs have focused almost exclusively on how to incentivise adoption of alternative electric or solar-powered pumping technologies, which are viewed as being cheaper to operate and less environmentally damaging due to their lower operational carbon emissions. In contrast, there has been little attention paid to identifying opportunities to make existing diesel pump systems more cost effective for farmers to operate in order to support adaptation to climate change and reduce poverty. In this study, we use evidence from 116 detailed in-situ pump tests along with interviews with pumpset dealers, mechanics and farmers in the Nepal Terai to assess how and why fuel efficiency and operational costs of diesel pump irrigation are affected by farmers’ pumpset selection decisions. We show that costs diesel pumpset irrigation can be reduced significantly by supporting and incentivising farmers (e.g., through equipment advisories, improved supply chains for maintenance services and spare parts) to invest in newer low-cost, portable and smaller horsepower pumpset designs that are more effectively matched to local operating conditions in the EIGP than older Indian manufactured engines that have historically been preferred by farmers in the region. Such interventions can help to unlock potential for intensified irrigation water use in the EIGP, contributing to goals of improving agricultural productivity and resilience to climate extremes while also strengthening farmers capacity to invest in emerging low-carbon pumping technologies.</p

Fibronectin-binding protein B variation in Staphylococcus aureus

BACKGROUND: Fibronectin binding proteins A and B (FnBPA and FnBPB) mediate adhesion of S. aureus to fibrinogen, elastin and fibronectin. We previously identified seven different isotypes of FnBPA based on divergence in the fibrinogen- and elastin-binding A domains. The variation created differences in antigenicity while ligand binding functions were retained. Here, FnBPB variation was examined in both human and bovine isolates and compared to that of FnBPA. RESULTS: Seven different fnbB allelic variants were identified. Some strains that cluster by phylogenetic analysis contain different fnbB variants, whereas more divergent strains contain the same fnbB variant. The phylogeny of fnbB alleles does not match the phylogeny of fnbA alleles. Some FnBPA and FnBPB isotypes that are specified by human S. aureus strains are also found in bovine strains. The seven fnbB allelic variants encode seven distinct isotypes of the FnBPB A domain that are 61 to 85% identical in amino acid sequence. Variant amino acid residues were mapped on a three-dimensional model of the FnBPB A domain and were predicted to be surface-exposed. They are responsible for the antigenic diversity detected with polyclonal antibody and a monoclonal antibody raised against isotype I. Ligand binding by recombinant FnBPB N23 isotypes was compared by ELISA-based solid phase assays and surface plasmon resonance. Each bound to immobilized fibrinogen, elastin and fibronectin dose-dependently and saturably with similar affinities. Binding to fibronectin was surprising because the A domains do not contain any known motifs that mediate binding to fibronectin. This raises the possibility that the A domain of FnBPB contains a novel fibronectin binding motif that binds fibronectin by a novel mechanism. CONCLUSIONS: Seven different isoforms of FnBPB A domain retain ligand-binding functions but are antigenically distinct. The variation in FnBPA and FnBPB occurs in human and bovine S. aureus strains and may act as an immune evasion mechanism. All seven isotypes of FnBPB are capable of binding fibronectin though none contain any known fibronectin-binding motifs. These results have implications for the development of vaccines or immunotherapeutics that target FnBPB

Staphylococcus aureus protein A plays a critical role in mediating bone destruction and bone loss in osteomyelitis.

Staphylococcus aureus is the most frequent causative organism of osteomyelitis. It is characterised by widespread bone loss and bone destruction. Previously we demonstrated that S. aureus protein A (SpA) is capable of binding to tumour necrosis factor receptor-1 expressed on pre-osteoblastic cells, which results in signal generation that leads to cell apoptosis resulting in bone loss. In the current report we demonstrate that upon S. aureus binding to osteoblasts it also inhibits de novo bone formation by preventing expression of key markers of osteoblast growth and division such as alkaline phosphatase, collagen type I, osteocalcin, osteopontin and osteocalcin. In addition, S. aureus induces secretion of soluble RANKL from osteoblasts which in turn recruits and activates the bone resorbing cells, osteoclasts. A strain of S. aureus defective in SpA failed to affect osteoblast growth or proliferation and most importantly failed to recruit or activate osteoclasts. These results suggest that S. aureus SpA binding to osteoblasts provides multiple coordinated signals that accounts for bone loss and bone destruction seen in osteomyelitis cases. A better understanding of the mechanisms through which S. aureus leads to bone infection may improve treatment or lead to the development of better therapeutic agents to treat this notoriously difficult disease

The iron-regulated surface determinant B (IsdB) protein from Staphylococcus aureus acts as a receptor for the host protein vitronectin.

Staphylococcus aureus is an important bacterial pathogen that can cause a wide spectrum of diseases in humans and other animals. S. aureus expresses a variety of virulence factors that promote infection with this pathogen. These include cell-surface proteins that mediate adherence of the bacterial cells to host extracellular matrix components, such as fibronectin and fibrinogen. Here, using immunoblotting, ELISA, and surface plasmon resonance analysis, we report that the iron-regulated surface determinant B (IsdB) protein, besides being involved in heme transport, plays a novel role as a receptor for the plasma and extracellular matrix protein vitronectin (Vn). Vn-binding activity was expressed by staphylococcal strains grown under iron starvation conditions when Isd proteins are expressed. Recombinant IsdB bound Vn dose dependently and specifically. Both near-iron transporter motifs NEAT1 and NEAT2 of IsdB individually bound Vn in a saturable manner, with KD values in the range of 16-18 nm Binding of Vn to IsdB was specifically blocked by heparin and reduced at high ionic strength. Furthermore, IsdB-expressing bacterial cells bound significantly higher amounts of Vn from human plasma than did an isdB mutant. Adherence to and invasion of epithelial and endothelial cells by IsdB-expressing S. aureus cells was promoted by Vn, and an αvβ3 integrin-blocking mAb or cilengitide inhibited adherence and invasion by staphylococci, suggesting that Vn acts as a bridge between IsdB and host αvβ3 integrin