Servitization through outcome-based contract – a systems perspective from the defence industry

This paper provides a viable systems perspective of an outcome-based service initiative involving major manufacturers in the defence industry. The viable systems perspective allowed a coherent structuration of the complex servitization context involving provider and customer organizations. It also unveiled critical relationship mechanisms that enable synergy and facilitate the achievement of co-capability by the organizations involved. Through a case study approach, the research finds that interventions in the customer system reduce variability in the provider system as well as in the service system as a whole. The systemic interventions are implemented via key provider/customer relationships the study identifies. The relationships deal with the high level of internal variety in outcome-based service systems. A typology for the identified relationships is developed, offering a helpful basis for the purposeful planning and design of interactions aimed at developing co-capability. The paper also offers theoretical propositions defining fundamental features of outcome-based service systems. The unique characteristics of these systems addressed in this paper provide particularly useful insights concerning the implementation of this type of servitization initiative not only in the defence industry, but also in other industrial sectors where servitization initiatives involve complex configurations of provider and customer organizations

Construction and properties of a mutant of herpes simplex virus type 1 with glycoprotein H coding sequences deleted

A mutant of herpes simplex virus type 1 (HSV-1) in which glycoprotein H (gH) coding sequences were deleted and replaced by the Escherichia coli lacZ gene under the control of the human cytomegalovirus IE-1 gene promoter was constructed. The mutant was propagated in Vero cells which contained multiple copies of the HSV-1 gH gene under the control of the HSV-1 gD promoter and which therefore provide gH in trans following HSV-1 infection. Phenotypically gH-negative virions were obtained by a single growth cycle in Vero cells. These virions were noninfectious, as judged by plaque assay and by expression of I-galactosidase following high-multiplicity infection, but partial recovery of infectivity was achieved by using the fusogenic agent polyethylene glycol. Adsorption of gH-negative virions to cells blocked the adsorption of superinfecting wild-type virus, a result in contrast to that obtained with gD-negative virions (D. C. Johnson and M. W. Ligas, J. Virol. 62:4605-4612, 1988). The simplest conclusion is that gH is required for membrane fusion but not for receptor binding, a conclusion consistent with the conservation of gH in all herpesviruses

Lymph node macrophages restrict murine cytomegalovirus dissemination

Cytomegaloviruses (CMVs) establish chronic infections that spread from a primary entry site to secondary vascular sites, such as the spleen, and then to tertiary shedding sites, such as the salivary glands. Human CMV (HCMV) is difficult to analyze, because its spread precedes clinical presentation. Murine CMV (MCMV) offers a tractable model. It is hypothesized to spread from peripheral sites via vascular endothelial cells and associated monocytes. However, viral luciferase imaging showed footpad-inoculated MCMV first reaching the popliteal lymph nodes (PLN). PLN colonization was rapid and further spread was slow, implying that LN infection can be a significant bottleneck. Most acutely infected PLN cells were CD169(+) subcapsular sinus macrophages (SSM). Replication-deficient MCMV also reached them, indicating direct infection. Many SSM expressed viral reporter genes, but few expressed lytic genes. SSM expressed CD11c, and MCMV with a cre-sensitive fluorochrome switch showed switched infected cells in PLN of CD11c-cre mice but yielded little switched virus. SSM depletion with liposomal clodronate or via a CD169-diphtheria toxin receptor transgene shifted infection to ER-TR7(+) stromal cells, increased virus production, and accelerated its spread to the spleen. Therefore, MCMV disseminated via LN, and SSM slowed this spread by shielding permissive fibroblasts and poorly supporting viral lytic replication

Induction of antibody responses to African horse sickness virus (AHSV) in ponies after vaccination with recombinant modified vaccinia Ankara (MVA).

BACKGROUND: African horse sickness virus (AHSV) causes a non-contagious, infectious disease in equids, with mortality rates that can exceed 90% in susceptible horse populations. AHSV vaccines play a crucial role in the control of the disease; however, there are concerns over the use of polyvalent live attenuated vaccines particularly in areas where AHSV is not endemic. Therefore, it is important to consider alternative approaches for AHSV vaccine development. We have carried out a pilot study to investigate the ability of recombinant modified vaccinia Ankara (MVA) vaccines expressing VP2, VP7 or NS3 genes of AHSV to stimulate immune responses against AHSV antigens in the horse. METHODOLOGY/PRINCIPAL FINDINGS: VP2, VP7 and NS3 genes from AHSV-4/Madrid87 were cloned into the vaccinia transfer vector pSC11 and recombinant MVA viruses generated. Antigen expression or transcription of the AHSV genes from cells infected with the recombinant viruses was confirmed. Pairs of ponies were vaccinated with MVAVP2, MVAVP7 or MVANS3 and both MVA vector and AHSV antigen-specific antibody responses were analysed. Vaccination with MVAVP2 induced a strong AHSV neutralising antibody response (VN titre up to a value of 2). MVAVP7 also induced AHSV antigen-specific responses, detected by western blotting. NS3 specific antibody responses were not detected. CONCLUSIONS: This pilot study demonstrates the immunogenicity of recombinant MVA vectored AHSV vaccines, in particular MVAVP2, and indicates that further work to investigate whether these vaccines would confer protection from lethal AHSV challenge in the horse is justifiable

The first poverty line? Davies and Eden’s investigation of rural poverty in late 18th-century England

Two important and well-known surveys of the household budgets of the English rural labouring poor were produced by David Davies and Frederick Eden in the 1790s. We revisit these from the point of view of their original rationale — an investigation of the characteristics and extent of poverty in the countryside. We argue that Davies' standard of ‘tolerable comfort’ can lay claim to being the first poverty line based upon the application of a minimum consumption standard to household income. We find that the majority of households fall below this standard, although those in the south of England were worst off, that family size was the largest coefficient and poverty reduced as the age of the first child increased. The incidence of poverty was not highly correlated with the absence of a woman wage earner

A Point Mutation in a Herpesvirus Polymerase Determines Neuropathogenicity

Infection with equid herpesvirus type 1 (EHV-1) leads to respiratory disease, abortion, and neurologic disorders in horses. Molecular epidemiology studies have demonstrated that a single nucleotide polymorphism resulting in an amino acid variation of the EHV-1 DNA polymerase (N752/D752) is significantly associated with the neuropathogenic potential of naturally occurring strains. To test the hypothesis that this single amino acid exchange by itself influences neuropathogenicity, we generated recombinant viruses with differing polymerase sequences. Here we show that the N752 mutant virus caused no neurologic signs in the natural host, while the D752 virus was able to cause inflammation of the central nervous system and ataxia. Neurologic disease induced by the D752 virus was concomitant with significantly increased levels of viremia (p = 0.01), but the magnitude of virus shedding from the nasal mucosa was similar between the N752 and D752 viruses. Both viruses replicated with similar kinetics in fibroblasts and epithelial cells, but exhibited differences in leukocyte tropism. Last, we observed a significant increase (p < 0.001) in sensitivity of the N752 mutant to aphidicolin, a drug targeting the viral polymerase. Our results demonstrate that a single amino acid variation in a herpesvirus enzyme can influence neuropathogenic potential without having a major effect on virus shedding from infected animals, which is important for horizontal spread in a population. This observation is very interesting from an evolutionary standpoint and is consistent with data indicating that the N752 DNA pol genotype is predominant in the EHV-1 population, suggesting that decreased viral pathogenicity in the natural host might not be at the expense of less efficient inter-individual transmission

Different Evolutionary Stages in the Massive Star Forming Region S255 Complex

To understand evolutionary and environmental effects during the formation of high-mass stars, we observed three regions of massive star formation at different evolutionary stages that reside in the same natal molecular cloud. Methods. The three regions S255IR, S255N and S255S were observed at 1.3 mm with the Submillimeter Array (SMA) and followup short spacing information was obtained with the IRAM 30m telescope. Near infrared (NIR) H + K-band spectra and continuum observations were taken for S255IR with VLT-SINFONI to study the different stellar populations in this region. The combination of millimeter (mm) and near infrared data allow us to characterize different stellar populations within the young forming cluster in detail. While we find multiple mm continuum sources toward all regions, their outflow, disk and chemical properties vary considerably. The most evolved source S255IR exhibits a collimated bipolar outflow visible in CO and H2 emission, the outflows from the youngest region S255S are still small and rather confined in the regions of the mm continuum peaks. Also the chemistry toward S255IR is most evolved exhibiting strong emission from complex molecules, while much fewer molecular lines are detected in S255N, and in S255S we detect only CO isotopologues and SO lines. Also, rotational structures are found toward S255N and S255IR. Furthermore, a comparison of the NIR SINFONI and mm data from S255IR clearly reveal two different (proto) stellar populations with an estimated age difference of approximately 1 Myr. A multi-wavelength spectroscopy and mapping study reveals different evolutionary phases of the star formation regions. We propose the triggered outside-in collapse star formation scenario for the bigger picture and the fragmentation scenario for S255IR.Comment: 23 pages,25 figures, accepted by A&

Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry

Early interactions of herpes simplex virus type-1 (HSV-1) with cells lead to cytoskeletal changes facilitating filopodia formation and membrane fusion. Here, we demonstrate that phosphoinositide 3 kinase (PI3K) signalling may affect multiple steps during HSV-1 entry. An inhibitor of PI3K (LY294002) blocked HSV-1 entry and the blockage was cell-type- and gD receptor-independent. Entry inhibition was also observed with primary cultures of the human corneal fibroblasts and unrelated β- and γ-herpesviruses. Immunofluorescence analysis demonstrated that LY294002 negatively affected HSV-1-induced filopodia formation. Similar effects of the inhibitor were seen on HSV-1 glycoprotein-induced cell-to-cell fusion. Cells expressing HSV-1 glycoproteins (gB, gD, gH and gL) showed significantly less fusion with target cells in the presence of the inhibitor. Expression of a dominant-negative PI3K mutant negatively affected both entry and fusion. We also show that inhibition of PI3K signalling also affected RhoA activation required for HSV-1 entry into certain cell types

Human cytomegalovirus chemokine receptor US28-induced smooth muscle cell migration is mediated by focal adhesion kinase and Src

The human cytomegalovirus-encoded chemokine receptor US28 induces arterial smooth muscle cell (SMC) migration; however, the underlying mechanisms involved in this process are unclear. We have previously shown that US28-mediated SMC migration occurs by a ligand-dependent process that is sensitive to proteintyrosine kinase inhibitors. We demonstrate here that US28 signals through the non-receptor protein-tyrosine kinases Src and focal adhesion kinase (FAK) and that this activity is necessary for US28-mediated SMC migration. In the presence of RANTES (regulated on activation normal T cell expressed and secreted), US28 stimulates the production of a FAK Src kinase complex. Interestingly, Src co-immunoprecipitates with US28 in a ligand-dependent manner. This association occurs earlier than the formation of the FAK Src kinase complex, suggesting that US28 activates Src before FAK. US28 binding to RANTES also promotes the formation of a Grb2 FAK complex, which is sensitive to treatment with the Src inhibitor PP2, further highlighting the critical role of Src in US28 activation of FAK. Human cytomegalovirus US28-mediated SMC migration is inhibited by treatment with PP2 and through the expression of either of two dominant negative inhibitors of FAK (F397Y and NH2-terminal amino acids 1–401). These findings demonstrate that activation of FAK and Src plays a critical role in US28-mediated signaling and SMC migration