Gene expression in fungi

This contribution is based on the four presentations made at the Special Interest Group (SIG) meeting titled Gene Expression in Fungi held during IMC9 in Edinburgh. This overview is independent from other articles published or that will be published by each speaker. In the SIG meeting, basic principles of in vivo animal models for virulence studies were discussed. Infection associated genes of Candida albicans and fungal adaptation to the host was summarized. Azole susceptibility was evaluated as a combined result of several changes in expression of pertinent genes. Gene transfer in fungi, resulting in fungal evolution and gene adaptation to environmental factors, was reported

Trihydrophobin 1 Phosphorylation by c-Src Regulates MAPK/ERK Signaling and Cell Migration

c-Src activates Ras-MAPK/ERK signaling pathway and regulates cell migration, while trihydrophobin 1 (TH1) inhibits MAPK/ERK activation and cell migration through interaction with A-Raf and PAK1 and inhibiting their kinase activities. Here we show that c-Src interacts with TH1 by GST-pull down assay, coimmunoprecipitation and confocal microscopy assay. The interaction leads to phosphorylation of TH1 at Tyr-6 in vivo and in vitro. Phosphorylation of TH1 decreases its association with A-Raf and PAK1. Further study reveals that Tyr-6 phosphorylation of TH1 reduces its inhibition on MAPK/ERK signaling, enhances c-Src mediated cell migration. Moreover, induced tyrosine phosphorylation of TH1 has been found by EGF and estrogen treatments. Taken together, our findings demonstrate a novel mechanism for the comprehensive regulation of Ras/Raf/MEK/ERK signaling and cell migration involving tyrosine phosphorylation of TH1 by c-Src

Reporting Guidelines for Survey Research: An Analysis of Published Guidance and Reporting Practices

Carol Bennett and colleagues review the evidence and find that there is limited guidance and no consensus on the optimal reporting of survey research

Grb2 monomer-dimer equilibrium determines normal versus oncogenic function

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression

The challenges of implementing packaged hospital electronic prescribing and medicine administration systems in UK hospitals: premature purchase of immature solutions?

The UK National Health Service is making major efforts to implement Hospital Electronic Prescribing and Medicine Administration (HEPMA) to improve patient safety and quality of care. Substantial public investments have attracted a wide range of UK and overseas suppliers offering Commercial-Off –The-Shelf (COTS) solutions. A lack of (UK) implementation experience and weak supplier-user relationships are reflected in systems with limited configurability, poorly matched to the needs and practices of English hospitals. This situation echoes the history of comparable corporate information infrastructures - Enterprise Resource Planning systems - in the 1980s/1990s. UK government intervention prompted a similar swarming of immature, often unfinished, products into the market. This resulted, in both cases, in protracted and difficult implementation processes as vendors and adopters struggled to get the systems to work and match the circumstances of the adopting organisations. An analysis of the influence of the Installed Base on Information Infrastructures should explore how the evolution of COTS solutions is conditioned by the structure of adopter and vendor ‘communities’

Supportive care for older people with frailty in hospital: An integrative review

BACKGROUND: Growing numbers of older people living with frailty and chronic health conditions are being referred to hospitals with acute care needs. Supportive care is a potentially highly relevant and clinically important approach which could bridge the practice gap between curative models of care and palliative care. However, future interventions need to be informed and underpinned by existing knowledge of supportive care. AIM: To identify and build upon existing theories and evidence about supportive care, specifically in relation to the hospital care of older people with frailty, to inform future interventions and their evaluation. DESIGN: An integrative review was used to identify and integrate theory and evidence. Electronic databases (Cochrane Medline, EMBASE and CIHAHL) were searched using the key term 'supportive care'. Screening identified studies employing qualitative and/or quantitative methods published between January 1990 and December 2015. Citation searches, reference checking and searches of the grey literature were also undertaken. DATA SOURCES: Literature searches identified 2733 articles. After screening, and applying eligibility criteria based on relevance to the research question, studies were subject to methodological quality appraisal. Findings from included articles (n=52) were integrated using synthesis of themes. RESULTS: Relevant evidence was identified across different research literatures, on clinical conditions and contexts. Seven distinct themes of the synthesis were identified, these were: Ensuring fundamental aspects of care are met, Communicating and connecting with the patient, Carer and family engagement, Building up a picture of the person and their circumstances, Decisions and advice about best care for the person, Enabling self-help and connection to wider support, and Supporting patients through transitions in care. A tentative integrative model of supportive care for frail older people is developed from the findings. CONCLUSION: The findings and model developed here will inform future interventions and can help staff and hospital managers to develop appropriate strategies, staff training and resource allocation models to improve the quality of health care for older people

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

BackgroundHere, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer.MethodsWe examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs.ResultsConcentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC(50) values (IC(50) range: 0.001-11.3 micromol l(-1)). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73-1.11) or paclitaxel (mean CI values, range: 0.76-1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib.ConclusionsThese data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer

Reputation and identity conflict in management consulting

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this record.Based on a case study of a large consulting firm, this paper makes two contributions to the literature on reputation and identity by examining how an organization responds when its identity is substantially misaligned with the experience and perceptions of external stakeholders that form the basis of reputational judgments. First, rather than triggering some form of identity adaptation, it outlines how other forms of identity can come into play to remediate this gap, buffering the organization’s identity from change. This shift to other individual identities is facilitated by a low organizational identity context even when the identity of the firm is coherent and strong. The second contribution concerns the conceptualization of consulting and other professional service firms. We explain how reputation and identity interact in the context of the distinctive organizational features of these firms. Notably, their loosely coupled structure and the central importance of expert knowledge claims enable individual consultants both to reinforce and supplement corporate reputation via individual identity work

Diploids in the Cryptococcus neoformans Serotype A Population Homozygous for the α Mating Type Originate via Unisexual Mating

The ubiquitous environmental human pathogen Cryptococcus neoformans is traditionally considered a haploid fungus with a bipolar mating system. In nature, the α mating type is overwhelmingly predominant over a. How genetic diversity is generated and maintained by this heterothallic fungus in a largely unisexual α population is unclear. Recently it was discovered that C. neoformans can undergo same-sex mating under laboratory conditions generating both diploid intermediates and haploid recombinant progeny. Same-sex mating (α-α) also occurs in nature as evidenced by the existence of natural diploid αADα hybrids that arose by fusion between two α cells of different serotypes (A and D). How significantly this novel sexual style contributes to genetic diversity of the Cryptococcus population was unknown. In this study, ∼500 natural C. neoformans isolates were tested for ploidy and close to 8% were found to be diploid by fluorescence flow cytometry analysis. The majority of these diploids were serotype A isolates with two copies of the α MAT locus allele. Among those, several are intra-varietal allodiploid hybrids produced by fusion of two genetically distinct α cells through same-sex mating. The majority, however, are autodiploids that harbor two seemingly identical copies of the genome and arose via either endoreplication or clonal mating. The diploids identified were isolated from different geographic locations and varied genotypically and phenotypically, indicating independent non-clonal origins. The present study demonstrates that unisexual mating produces diploid isolates of C. neoformans in nature, giving rise to populations of hybrids and mixed ploidy. Our findings underscore the importance of same-sex mating in shaping the current population structure of this important human pathogenic fungus, with implications for mechanisms of selfing and inbreeding in other microbial pathogens