HAM-5 functions as a MAP kinase scaffold during cell fusion in Neurospora crassa.

Cell fusion in genetically identical Neurospora crassa germlings and in hyphae is a highly regulated process involving the activation of a conserved MAP kinase cascade that includes NRC-1, MEK-2 and MAK-2. During chemotrophic growth in germlings, the MAP kinase cascade members localize to conidial anastomosis tube (CAT) tips every ∼8 minutes, perfectly out of phase with another protein that is recruited to the tip: SOFT, a recently identified scaffold for the MAK-1 MAP kinase pathway in Sordaria macrospora. How the MAK-2 oscillation process is initiated, maintained and what proteins regulate the MAP kinase cascade is currently unclear. A global phosphoproteomics approach using an allele of mak-2 (mak-2Q100G) that can be specifically inhibited by the ATP analog 1NM-PP1 was utilized to identify MAK-2 kinase targets in germlings that were potentially involved in this process. One such putative target was HAM-5, a protein of unknown biochemical function. Previously, Δham-5 mutants were shown to be deficient for hyphal fusion. Here we show that HAM-5-GFP co-localized with NRC-1, MEK-2 and MAK-2 and oscillated with identical dynamics from the cytoplasm to CAT tips during chemotropic interactions. In the Δmak-2 strain, HAM-5-GFP localized to punctate complexes that did not oscillate, but still localized to the germling tip, suggesting that MAK-2 activity influences HAM-5 function/localization. However, MAK-2-GFP showed cytoplasmic and nuclear localization in a Δham-5 strain and did not localize to puncta. Via co-immunoprecipitation experiments, HAM-5 was shown to physically interact with NRC-1, MEK-2 and MAK-2, suggesting that it functions as a scaffold/transport hub for the MAP kinase cascade members for oscillation and chemotropic interactions during germling and hyphal fusion in N. crassa. The identification of HAM-5 as a scaffold-like protein will help to link the activation of MAK-2 cascade to upstream factors and proteins involved in this intriguing process of fungal communication

Effect of smoking on physical and cognitive capability in later life: a multicohort study using observational and genetic approaches

Objectives: The observed associations between smoking and functional measures at older ages are vulnerable to bias and confounding. Mendelian randomisation (MR) uses genotype as an instrumental variable to estimate unconfounded causal associations. We conducted a meta-analysis of the observational associations and implemented an MR approach using the smoking-related single nucleotide polymorphism rs16969968 to explore their causal nature. Setting: 9 British cohorts belonging to the HALCyon collaboration. Participants: Individual participant data on N=26 692 individuals of European ancestry (N from earliest phase analysed per study) of mean ages 50-79 years were available for inclusion in observational meta-analyses of the primary outcomes. Primary outcomes: Physical capability, cognitive capability and cognitive decline. The smoking exposures were cigarettes per day, current versus ex-smoker, current versus never smoker and ever versus never smoker. Results: In observational analyses current and ever smoking were generally associated with poorer physical and cognitive capability. For example, current smokers had a general fluid cognition score which was 0.17 z-score units (95% CI -0.221 to -0.124) lower than ex-smokers in cross-sectional analyses. Current smokers had a walk speed which was 0.25 z-score units lower than never smokers (95% CI -0.338 to -0.170). An MR instrumental variable approach for current versus ex-smoker and number of cigarettes smoked per day produced CIs which neither confirmed nor refuted the observational estimates. The number of genetic associations stratified by smoking status were consistent with type I error. Conclusions: Our observational analysis supports the hypothesis that smoking is detrimental to physical and cognitive capability. Further studies are needed for a suitably powered MR approach

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

<b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p> <b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p> <b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts

How do MNC R&D laboratory roles affect employee international assignments?

Research and development (R&D) employees are important human resources for multinational corporations (MNCs) as they are the driving force behind the advancement of innovative ideas and products. International assignments of these employees can be a unique way to upgrade their expertise; allowing them to effectively recombine their unique human resources to progress existing knowledge and advance new ones. This study aims to investigate the effect of the roles of R&D laboratories in which these employees work on the international assignments they undertake. We categorise R&D laboratory roles into those of the support laboratory, the locally integrated laboratory and the internationally interdependent laboratory. Based on the theory of resource recombinations, we hypothesise that R&D employees in support laboratories are not likely to assume international assignments, whereas those in locally integrated and internationally interdependent laboratories are likely to assume international assignments. The empirical evidence, which draws from research conducted on 559 professionals in 66 MNC subsidiaries based in Greece, provides support to our hypotheses. The resource recombinations theory that extends the resource based view can effectively illuminate the international assignment field. Also, research may provide more emphasis on the close work context of R&D scientists rather than analyse their demographic characteristics, the latter being the focus of scholarly practice hitherto

Psychosocial aspects of feeding children with neurodisability

The psychosocial support needs of parents considering a gastrostomy feeding tube for their disabled child are often overlooked, yet there is a growing body of evidence that attests to the decisional conflicts parents, often mothers, experience. This may be in addition to the stress associated with feeding a disabled child. The support needs of families and caregivers should be assessed, including the values parents attach to oral and tube feeding. Structured support should be embedded within the care pathway and both professionals, and service users, with appropriate training should be identified to ensure parental information needs, and any emotional, practical and financial issues are addressed

Loss of Adenomatous polyposis coli function renders intestinal epithelial cells resistant to the cytokine IL-22

Interleukin-22 (IL-22) is a critical immune defence cytokine that maintains intestinal homeostasis and promotes wound healing and tissue regeneration, which can support the growth of colorectal tumours. Mutations in the adenomatous polyposis coli gene (Apc) are a major driver of familial colorectal cancers (CRCs). How IL-22 contributes to APC-mediated tumorigenesis is poorly understood. To investigate IL-22 signalling in wild-type (WT) and APC-mutant cells, we performed RNA sequencing (RNAseq) of IL-22-treated murine small intestinal epithelial organoids. In WT epithelia, antimicrobial defence and cellular stress response pathways were most strongly induced by IL-22. Surprisingly, although IL-22 activates signal transducer and activator of transcription 3 (STAT3) in APC-mutant cells, STAT3 target genes were not induced. Our analyses revealed that ApcMin/Min cells are resistant to IL-22 due to reduced expression of the IL-22 receptor, and increased expression of inhibitors of STAT3, particularly histone deacetylases (HDACs). We further show that IL-22 increases DNA damage and genomic instability, which can accelerate cellular transition from heterozygosity (ApcMin/+) to homozygosity (ApcMin/Min) to drive tumour formation. Our data reveal an unexpected role for IL-22 in promoting early tumorigenesis while excluding a function for IL-22 in transformed epithelial cells

Insula-specific responses induced by dental pain: a proton magnetic resonance spectroscopy study

OBJECTIVES: To evaluate whether induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex after stimulation of the right maxillary canine and to examine whether these metabolic changes and the subjective pain intensity perception correlate. METHODS: Ten male volunteers were included in the pain group and compared with a control group of 10 other healthy volunteers. The pain group received a total of 87-92 electrically induced pain stimuli over 15 min to the right maxillary canine tooth. Contemporaneously, they evaluated the subjective pain intensity of every stimulus using an analogue scale. Neurotransmitter changes within the left insular cortex were evaluated by MR spectroscopy. RESULTS: Significant metabolic changes in glutamine (+55.1%), glutamine/glutamate (+16.4%) and myo-inositol (-9.7%) were documented during pain stimulation. Furthermore, there was a significant negative correlation between the subjective pain intensity perception and the metabolic levels of Glx, Gln, glutamate and N-acetyl aspartate. CONCLUSION: The insular cortex is a metabolically active region in the processing of acute dental pain. Induced dental pain leads to quantitative changes in brain metabolites within the left insular cortex resulting in significant alterations in metabolites. Negative correlation between subjective pain intensity rating and specific metabolites could be observed

Developing international business relationships in a Russian context

The collapse of the former Soviet Union has opened up a wealth of business opportunities for companies seeking new markets in the Russian Federation. Despite this, firms intending to do business in Russia have found themselves hampered by cultural differences in business practices and expectations. As Russia integrates into the global economy, understanding such practices and the managerial mindset of business people is crucial for managers who hope to navigate Russia's complex markets. This study draws on the trust literature and adopts quantitative tools to deconstruct the Russian 'Sviazi' system of social capital business networking. We develop a model isolating three dimensions of Sviazi: one an affective or emotional component; the second, a conative component; and the third, a cognitive component. The model provides a useful guide for helping foreign firms to succeed in Russia, while also serving as a basis for further research in the field. Keywords

Organic pollutants in sea-surface microlayer and aerosol in thecoastal environment of Leghorn—(Tyrrhenian Sea)

The levels of dissolved and particle-associated n-alkanes, alkylbenzenes, phthalates, PAHs, anionic surfactants and surfactant fluorescent organic matter ŽSFOM. were measured in sea-surface microlayer ŽSML. and sub-surface water ŽSSL. samples collected in the Leghorn marine environment in September and October 1999. Nine stations, located in the Leghorn harbour and at increasing distances from the Port, were sampled three times on the same day. At all the stations, SML concentrations of the selected organic compounds were significantly higher than SSL values and the enrichment factors ŽEFsSML concentrationrSSL concentration. were greater in the particulate phase than in the dissolved phase. SML concentrations varied greatly among the sampling sites, the highest levels Žn-alkanes 3674 mgrl, phthalates 177 mgrl, total PAHs 226 mgrl. being found in the particulate phase in the Leghorn harbour. To improve the knowledge on pollutant exchanges between sea-surface waters and atmosphere, the validity of spray drop adsorption model ŽSDAM. was verified for SFOM, surface-active agents, such as phthalates, and compounds which can interact with SFOM, such as n-alkanes and PAHs. q2001 Elsevier Science B.V. All rights reserved