No creative person is an island : organisational culture, academic project-based creativity, and the mediating role of intraorganisational social ties

This paper examines the relationship between perceptions of organisational culture, academics’ social embeddedness and their creative paper project output. It argues that the extent to which researchers working on paper projects are socially embedded through social ties with colleagues inside and outside their academic department (but within the same university) is a causal step linking organisational values and norms to creative outputs. This study does not, however, find support for the proposed mediating effects. Instead, results indicate that three organisational culture dimensions – i.e. performance orientation, environmental orientation and innovation support – affect employees’ creative project output through their social embeddedness outside the department (but within their own university). As the organisational culture and social embeddedness of employees outside the department are both contextual factors that matter (either indirectly or directly) for the generation of creative project outputs by researchers, this study concludes that “no creative person and no project is an island”.http://www.sajems.org/am2014ai201

Staphylococcal complement evasion by various convertase-blocking molecules

To combat the human immune response, bacteria should be able to divert the effectiveness of the complement system. We identify four potent complement inhibitors in Staphylococcus aureus that are part of a new immune evasion cluster. Two are homologues of the C3 convertase modulator staphylococcal complement inhibitor (SCIN) and function in a similar way as SCIN. Extracellular fibrinogen-binding protein (Efb) and its homologue extracellular complement-binding protein (Ecb) are identified as potent complement evasion molecules, and their inhibitory mechanism was pinpointed to blocking C3b-containing convertases: the alternative pathway C3 convertase C3bBb and the C5 convertases C4b2aC3b and C3b2Bb. The potency of Efb and Ecb to block C5 convertase activity was demonstrated by their ability to block C5a generation and C5a-mediated neutrophil activation in vitro. Further, Ecb blocks C5a-dependent neutrophil recruitment into the peritoneal cavity in a mouse model of immune complex peritonitis. The strong antiinflammatory properties of these novel S. aureus–derived convertase inhibitors make these compounds interesting drug candidates for complement-mediated diseases

Use of Flow Cytometry to Evaluate Phagocytosis of Staphylococcus aureus by Human Neutrophils

Neutrophils play a key role in the human immune response to Staphylococcus aureus infections. These professional phagocytes rapidly migrate to the site of infection to engulf bacteria and destroy them via specialized intracellular killing mechanisms. Here we describe a robust and relatively high-throughput flow cytometry assay to quantify phagocytosis of S. aureus by human neutrophils. We show that effective phagocytic uptake of S. aureus is greatly enhanced by opsonization, i.e. the tagging of microbial surfaces with plasma-derived host proteins like antibodies and complement. Our rapid assay to monitor phagocytosis can be used to study neutrophil deficiencies and bacterial evasion, but also provides a powerful tool to assess the opsonic capacity of antibodies, either in the context of natural immune responses or immune therapies

Natural Human Immunity Against Staphylococcal Protein A Relies on Effector Functions Triggered by IgG3

Staphylococcal protein A (SpA) is a multifunctional, highly conserved virulence factor of Staphylococcus aureus. By binding the Fc portion of all human IgG subclasses apart from IgG3, SpA interferes with antibody and complement deposition on the bacterial surface, impairing staphylococcal clearance by phagocytosis. Because of its anti-opsonic properties, SpA is not investigated as a surface antigen to mediate bacterial phagocytosis. Herein we investigate human sera for the presence of SpA-opsonizing antibodies. The screening revealed that sera containing IgG3 against SpA were able to correctly opsonize the target and drive Fcγ receptor-mediated interactions and phagocytosis. We demonstrated that IgG3 Fc is significantly more efficient in inducing phagocytosis of SpA-expressing S. aureus as compared to IgG1 Fc in an assay resembling physiological conditions. Furthermore, we show that the capacity of SpA antibodies to induce phagocytosis depends on the specific epitope recognized by the IgGs on SpA molecules. Overall, our results suggest that anti-SpA IgG3 antibodies could favor the anti-staphylococcal response in humans, paving the way towards the identification of a correlate of protection against staphylococcal infections

Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.Development and application of statistical models for medical scientific researc

Evaluation of silver bio-functionality in a multicellular in vitro model: towards reduced animal usage in implant-associated infection research

Background: Despite the extensive use of silver ions or nanoparticles in research related to preventing implant-associated infections (IAI), their use in clinical practice has been debated. This is because the strong antibacterial properties of silver are counterbalanced by adverse effects on host cells. One of the reasons for this may be the lack of comprehensive in vitro models that are capable of analyzing host-bacteria and host-host interactions. Methods and results: In this study, we tested silver efficacy through multicellular in vitro models involving macrophages (immune system), mesenchymal stem cells (MSCs, bone cells), and S. aureus (pathogen). Our model showed to be capable of identifying each element of culture as well as tracking the intracellular survival of bacteria. Furthermore, the model enabled to find a therapeutic window for silver ions (AgNO3) and silver nanoparticles (AgNPs) where the viability of host cells was not compromised, and the antibacterial properties of silver were maintained. While AgNO3 between 0.00017 and 0.017 µg/mL retained antibacterial properties, host cell viability was not affected. The multicellular model, however, demonstrated that those concentrations had no effect on the survival of S. aureus, inside or outside host cells. Similarly, treatment with 20 nm AgNPs did not influence the phagocytic and killing capacity of macrophages or prevent S. aureus from invading MSCs. Moreover, exposure to 100 nm AgNPs elicited an inflammatory response by host cells as detected by the increased production of TNF-α and IL-6. This was visible only when macrophages and MSCs were cultured together. Conclusions: Multicellular in vitro models such as the one used here that simulate complex in vivo scenarios can be used to screen other therapeutic compounds or antibacterial biomaterials without the need to use animals

Host–receptor post-translational modifications refine staphylococcal leukocidin cytotoxicity

Staphylococcal bi-component pore-forming toxins, also known as leukocidins, target and lyse human phagocytes in a receptor-dependent manner. S-components of the leukocidins Panton-Valentine leukocidin (PVL), γ-haemolysin AB (HlgAB) and CB (HlgCB), and leukocidin ED (LukED) specifically employ receptors that belong to the class of G-protein coupled receptors (GPCRs). Although these receptors share a common structural architecture, little is known about the conserved characteristics of the interaction between leukocidins and GPCRs. In this study, we investigated host cellular pathways contributing to susceptibility towards S. aureus leukocidin cytotoxicity. We performed a genome-wide CRISPR/Cas9 library screen for toxin-resistance in U937 cells sensitized to leukocidins by ectopic expression of different GPCRs. Our screen identifies posttranslational modification (PTM) pathways involved in the sulfation and sialylation of the leukocidin-receptors. Subsequent validation experiments show differences in the impact of PTM moieties on leukocidin toxicity, highlighting an additional layer of refinement and divergence in the staphylococcal host-pathogen interface. Leukocidin receptors may serve as targets for anti-staphylococcal interventions and understanding toxin-receptor interactions will facilitate the development of innovative therapeutics. Variations in the genes encoding PTM pathways could provide insight into observed differences in susceptibility of humans to infections with S. aureus

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types