Showing papers by "University of Dundee published in 2006"

Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis

Abstract: Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.

Drug Resistance in Leishmaniasis

Abstract: Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris

Abstract: Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors

Abstract: The three peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. They share a high degree of structural homology with all members of the superfamily, particularly in the DNA-binding domain and ligand- and cofactor-binding domain. Many cellular and systemic roles have been attributed to these receptors, reaching far beyond the stimulation of peroxisome proliferation in rodents after which they were initially named. PPARs exhibit broad, isotype-specific tissue expression patterns. PPARalpha is expressed at high levels in organs with significant catabolism of fatty acids. PPARbeta/delta has the broadest expression pattern, and the levels of expression in certain tissues depend on the extent of cell proliferation and differentiation. PPARgamma is expressed as two isoforms, of which PPARgamma2 is found at high levels in the adipose tissues, whereas PPARgamma1 has a broader expression pattern. Transcriptional regulation by PPARs requires heterodimerization with the retinoid X receptor (RXR). When activated by a ligand, the dimer modulates transcription via binding to a specific DNA sequence element called a peroxisome proliferator response element (PPRE) in the promoter region of target genes. A wide variety of natural or synthetic compounds was identified as PPAR ligands. Among the synthetic ligands, the lipid-lowering drugs, fibrates, and the insulin sensitizers, thiazolidinediones, are PPARalpha and PPARgamma agonists, respectively, which underscores the important role of PPARs as therapeutic targets. Transcriptional control by PPAR/RXR heterodimers also requires interaction with coregulator complexes. Thus, selective action of PPARs in vivo results from the interplay at a given time point between expression levels of each of the three PPAR and RXR isotypes, affinity for a specific promoter PPRE, and ligand and cofactor availabilities.

Study design III: Cross-sectional studies

Abstract: In this series, I previously gave an overview of the main types of study design and the techniques used to minimise biased results. Here, I describe cross-sectional studies, their uses, advantages and limitations.

AMP-activated protein kinase--development of the energy sensor concept.

Abstract: The LKB1→AMPK cascade is switched on by metabolic stresses that either inhibit ATP production (e.g. hypoxia, hypoglycaemia) or that accelerate ATP consumption (e.g. muscle contraction). Any decline in cellular energy status is accompanied by a rise in the cellular AMP: ATP ratio, and this activates AMPK by a complex and sensitive mechanism involving antagonistic binding of the nucleotides to two sites on the regulatory γ subunits of AMPK. Once activated by metabolic stress, AMPK activates catabolic pathways that generate ATP, while inhibiting cell growth and biosynthesis and other processes that consume ATP. While the AMPK system probably evolved in single-celled eukaryotes to maintain energy balance at the cellular level, in multicellular organisms its role has become adapted so that it is also involved in maintaining whole body energy balance. Thus, it is regulated by hormones and cytokines, especially the adipokines leptin and adiponectin, increasing whole body energy expenditure while regulating food intake. Some hormones may activate AMPK by an LKB1-independent mechanism involving Ca2+/calmodulin dependent protein kinase kinases. Low levels of activation of AMPK are likely to play a role in the current global rise in obesity and Type 2 diabetes, and AMPK is the target for the widely used antidiabetic drug metformin.

LKB1-Dependent Signaling Pathways

Abstract: This review focuses on remarkable recent findings concerning the mechanism by which the LKB1 protein kinase that is mutated in Peutz-Jeghers cancer syndrome operates as a tumor suppressor. We discuss evidence that the cellular localization and activity of LKB1 is controlled through its interaction with a catalytically inactive protein resembling a protein kinase, termed STRAD, and an armadillo repeat-containing protein, named mouse protein 25 (MO25). The data suggest that LKB1 functions as a tumor suppressor by not only inhibiting proliferation, but also by exerting profound effects on cell polarity and, most unexpectedly, on the ability of a cell to detect and respond to low cellular energy levels. Genetic and biochemical findings indicate that LKB1 exerts its effects by phosphorylating and activating 14 protein kinases, all related to the AMP-activated protein kinase. The work described in this review shows how a study of an obscure cancer syndrome can uncover new and important regulatory pathways, relevant to the understanding of multiple human diseases.

Identification of multiple distinct Snf2 subfamilies with conserved structural motifs

Abstract: The Snf2 family of helicase-related proteins includes the catalytic subunits of ATP-dependent chromatin remodelling complexes found in all eukaryotes. These act to regulate the structure and dynamic properties of chromatin and so influence a broad range of nuclear processes. We have exploited progress in genome sequencing to assemble a comprehensive catalogue of over 1300 Snf2 family members. Multiple sequence alignment of the helicase-related regions enables 24 distinct subfamilies to be identified, a considerable expansion over earlier surveys. Where information is known, there is a good correlation between biological or biochemical function and these assignments, suggesting Snf2 family motor domains are tuned for specific tasks. Scanning of complete genomes reveals all eukaryotes contain members of multiple subfamilies, whereas they are less common and not ubiquitous in eubacteria or archaea. The large sample of Snf2 proteins enables additional distinguishing conserved sequence blocks within the helicase-like motor to be identified. The establishment of a phylogeny for Snf2 proteins provides an opportunity to make informed assignments of function, and the identification of conserved motifs provides a framework for understanding the mechanisms by which these proteins function.

Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway

Abstract: The diverse cellular and biological functions of the nuclear factor kappa B (NF-κB) pathway, together with the catastrophic consequences of its aberrant regulation, demand specific and highly regulated control of its activity. As described in this review, regulation of the NF-κB pathway is brought about through multiple post-translational modifications that control the activity of the core components of NF-κB signaling: the IκB kinase (IKK) complex, the IκB proteins and the NF-κB subunits themselves. These regulatory modifications, which include phosphorylation, ubiquitination, acetylation, sumoylation and nitrosylation, can vary, depending on the nature of the NF-κB-inducing stimulus. Moreover, they frequently have distinct, sometimes antagonistic, functional consequences and the same modification can have different effects depending on the context. Given the important role of NF-κB in human health and disease, understanding these pathways will not only provide valuable insights into mechanism and function, but could also lead to new drug targets and the development of diagnostic and prognostic biomarkers for many pathological conditions.

ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis

Abstract: We recently identified angiogenin (ANG) as a candidate susceptibility gene for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by adult-onset loss of motor neurons. We now report the finding of seven missense mutations in 15 individuals, of whom four had familial ALS and 11 apparently 'sporadic' ALS. Our findings provide further evidence that variations in hypoxia-inducible genes have an important role in motor neuron degeneration.

The function of immunoglobulin A in immunity

Abstract: The vast surfaces of the gastrointestinal, respiratory, and genitourinary tracts represent major sites of potential attack by invading micro-organisms. Immunoglobulin A (IgA), as the principal antibody class in the secretions that bathe these mucosal surfaces, acts as an important first line of defence. IgA, also an important serum immunoglobulin, mediates a variety of protective functions through interaction with specific receptors and immune mediators. The importance of such protection is underlined by the fact that certain pathogens have evolved mechanisms to compromise IgA-mediated defence, providing an opportunity for more effective invasion. IgA function may also be perturbed in certain disease states, some of which are characterized by deposition of IgA in specific tissues. This review details current understanding of the roles played by IgA in both health and disease.

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations

Abstract: Background Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. Objectives Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. Methods We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. Results Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. Conclusion Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. Clinical implications These findings underline the crucial role of the skin barrier in preventing allergic sensitization.

A randomized controlled trial of Sweet Talk, a text-messaging system to support young people with diabetes.

Abstract: Aims To assess Sweet Talk, a text-messaging support system designed to enhance self-efficacy, facilitate uptake of intensive insulin therapy and improve glycaemic control in paediatric patients with Type 1 diabetes. Methods One hundred and twenty-six patients fulfilled the eligibility criteria; Type 1 diabetes for > 1 year, on conventional insulin therapy, aged 8–18 years. Ninety-two patients were randomized to conventional insulin therapy ( n = 28), conventional therapy and Sweet Talk ( n = 33) or intensive insulin therapy and Sweet Talk ( n = 31). Goal-setting at clinic visits was reinforced by daily text-messages from the Sweet Talk software system, containing personalized goal-specific prompts and messages tailored to patients’ age, sex and insulin regimen. Results HbA 1c did not change in patients on conventional therapy without or with Sweet Talk (10.3 ± 1.7 vs. 10.1 ± 1.7%), but improved in patients randomized to intensive therapy and Sweet Talk (9.2 ± 2.2%, 95% CI − 1.9, − 0.5, P < 0.001). Sweet Talk was associated with improvement in diabetes self-efficacy (conventional therapy 56.0 ± 13.7, conventional therapy plus Sweet Talk 62.1 ± 6.6, 95% CI +2.6, +7.5, P = 0.003) and self-reported adherence (conventional therapy 70.4 ± 20.0, conventional therapy plus Sweet Talk 77.2 ± 16.1, 95% CI +0.4, +17.4, P = 0.042). When surveyed, 82% of patients felt that Sweet Talk had improved their diabetes self-management and 90% wanted to continue receiving messages. Conclusions Sweet Talk was associated with improved self-efficacy and adherence; engaging a classically difficult to reach group of young people. While Sweet Talk alone did not improve glycaemic control, it may have had a role in supporting the introduction of intensive insulin therapy. Scheduled, tailored text messaging offers an innovative means of supporting adolescents with diabetes and could be adapted for other health-care settings and chronic diseases. Diabet. Med. 23, 1332–1338 (2006)

AMPK: A Key Sensor of Fuel and Energy Status in Skeletal Muscle

Abstract: Contraction induces marked metabolic changes in muscle, and the AMP-activated protein kinase (AMPK) is a good candidate to explain these effects. Recent work using a muscle-specific knockout of the upstream kinase, LKB1, has confirmed that the LKB1→AMPK cascade is the signaling pathway responsible for many of these effects.

p53/p63/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress

Abstract: p63, p73 and p53 compose a family of transcription factors involved in cell response to stress and development. p53 is the most frequently mutated gene in cancer (50%) and loss of p53 activity is considered to be ubiquitous to all cancers. Recent publications may have a profound impact on our understanding of p53 tumour suppressor activity. p63, p73 and p53 genes have a dual gene structure conserved in drosophila, zebrafish and man. They encode for multiple p63, p73 or p53 proteins containing different protein domains (isoforms) due to multiple splicing, alternative promoter and alternative initiation of translation. In this review, we describe the different isoforms of p63, p73, p53 and their roles in development and cancer. The changes in the interactions between p53, p63 and p73 isoforms are likely to be fundamental to our understanding in the transition between normal cell cycling and the onset of tumour formation.

Development of a rating system for surgeons' non-technical skills.

Abstract: BACKGROUND Analyses of adverse events in surgery reveal that many underlying causes are behavioural, such as communication failure, rather than technical. Non-technical (i.e. cognitive and interpersonal) skills are not addressed explicitly in surgical training. However, surgeons need to demonstrate these skills, which underpin their technical excellence, to maximise patient safety in the operating theatre. This paper describes the method used to identify surgeons' non-technical skills, and the development of a skills taxonomy and behavioural rating system to structure observation and feedback in surgical training. METHODS Cognitive task analyses (critical incident interviews) were conducted with 27 consultant surgeons in general, cardiac and orthopaedic surgery. The interviews were coded and a multidisciplinary group of surgeons and psychologists used an iterative process to develop a skills taxonomy. This was supported by data gathered from an attitude survey, literature review, analysis of surgical mortality reports and observations in theatre. RESULTS Five categories of non-technical skills were identified, including situation awareness, decision making, task management, leadership and communication and teamwork. This provided a structure for a prototype skill taxonomy (v1.1), which comprised 14 non-technical skill elements. Observable behaviours (markers) indicative of good and poor performance were developed for each element by 16 consultant surgeons to form a prototype behaviour rating system. CONCLUSIONS The prototype skills taxonomy and behaviour rating system are grounded empirically in surgery. The reliability of the system is currently being tested using standardised scenarios. If this evaluation proves successful, the system could be used to structure feedback and guide non-technical skills training.

Monitoring plant and soil water status: established and novel methods revisited and their relevance to studies of drought tolerance

Abstract: In all studies of the effects of water deficits on plant functioning there is a need for an accurate and comprehensive definition of treatments and their effects on plant water status. The various measures of water status used in plant and soil science are reviewed and their appropriateness for different purposes such as for studies of mechanistic effects of water deficits on plants, for breeding of drought-tolerant plants, or for management of irrigation systems are reviewed. An important conclusion is that the frequent emphasis on water potential rather than on cell turgor can be shown to be misleading, as can be measurements in the leaf. The disadvantages of the current trend towards the omission of necessary water-status measurements, especially common in more molecular studies, are outlined, and recommendations made for minimal sets of measurements for specific types of experiments.

Cognitive Empathy and Emotional Empathy in Human Behavior and Evolution

Abstract: This article presents 7 simple models of the relationship between cognitive empathy (mental perspective taking) and emotional empathy (the vicarious sharing of emotion). I consider behavioral outcomes of the models, arguing that, during human evolution, natural selection may have acted on variation in the relationship between cognitive empathy and emotional empathy resulting in two separable, complementary systems. I predict the existence of 4 empathy disorders using a concept of empathic imbalance. I propose hypotheses about the psychology of autism, antisocial personality disorder, schizoid personality disorder, and Williams syndrome. This approach generates new predictions and integrates some previous theoretical work by various authors.

Good cop, bad cop: the different faces of NF-κB

Abstract: Complexes formed from the nuclear factor κB (NF-κB) family of transcription factors are ubiquitously expressed and are induced by a diverse array of stimuli. This results in their becoming activated in a wide variety of different settings. While the functions of NF-κB in many of these contexts have been the subject of intense research and are now well established, it is also clear that there is great diversity in the effects and consequences of NF-κB activation. NF-κB subunits do not necessarily regulate the same genes, in an identical manner, in all of the different circumstances in which they are induced. This review will discuss the different functions of NF-κB, the pathways that modulate NF-κB subunit activity and, in contrast to its more commonly thought of role as a promoter of cancer cell growth and survival, the ability of NF-κB, under some circumstances, to behave as a tumor suppressor.

Yeast kinesin-8 depolymerizes microtubules in a length-dependent manner

Abstract: The microtubule cytoskeleton and the mitotic spindle are highly dynamic structures, yet their sizes are remarkably constant, thus indicating that the growth and shrinkage of their constituent microtubules are finely balanced. This balance is achieved, in part, through kinesin-8 proteins (such as Kip3p in budding yeast and KLP67A in Drosophila) that destabilize microtubules. Here, we directly demonstrate that Kip3p destabilizes microtubules by depolymerizing them--accounting for the effects of kinesin-8 perturbations on microtubule and spindle length observed in fungi and metazoan cells. Furthermore, using single-molecule microscopy assays, we show that Kip3p has several properties that distinguish it from other depolymerizing kinesins, such as the kinesin-13 MCAK. First, Kip3p disassembles microtubules exclusively at the plus end and second, remarkably, Kip3p depolymerizes longer microtubules faster than shorter ones. These properties are consequences of Kip3p being a highly processive, plus-end-directed motor, both in vitro and in vivo. Length-dependent depolymerization provides a new mechanism for controlling the lengths of subcellular structures.

Root responses to soil physical conditions; growth dynamics from field to cell

Abstract: Root growth in the field is often slowed by a combination of soil physical stresses, including mechanical impedance, water stress, and oxygen deficiency. The stresses operating may vary continually, depending on the location of the root in the soil profile, the prevailing soil water conditions, and the degree to which the soil has been compacted. The dynamics of root growth responses are considered in this paper, together with the cellular responses that underlie them. Certain root responses facilitate elongation in hard soil, for example, increased sloughing of border cells and exudation from the root cap decreases friction; and thickening of the root relieves stress in front of the root apex and decreases buckling. Whole root systems may also grow preferentially in loose versus dense soil, but this response depends on genotype and the spatial arrangement of loose and compact soil with respect to the main root axes. Decreased root elongation is often accompanied by a decrease in both cell flux and axial cell extension, and recent computer-based models are increasing our understanding of these processes. In the case of mechanical impedance, large changes in cell shape occur, giving rise to shorter fatter cells. There is still uncertainty about many aspects of this response, including the changes in cell walls that control axial versus radial extension, and the degree to which the epidermis, cortex, and stele control root elongation. Optical flow techniques enable tracking of root surfaces with time to yield estimates of two-dimensional velocity fields. It is demonstrated that these techniques can be applied successfully to time-lapse sequences of confocal microscope images of living roots, in order to determine velocity fields and strain rates of groups of cells. In combination with new molecular approaches this provides a promising way of investigating and modelling the mechanisms controlling growth perturbations in response to environmental stresses.

Corneal Thickness- and Age-Related Biomechanical Properties of the Cornea Measured with the Ocular Response Analyzer

Abstract: PURPOSE. The Ocular Response Analyzer (ORA) is a new instrument that measures the corneal biomechanical response (corneal hysteresis, CH) to rapid indentation by an air jet. CH is the difference in applanation pressures (P1, P2) between the rising and falling phases of the air jet. The investigation had two parts: a characterization study and a validation study. In the characterization study, the purposes were to investigate the intraocular pressure (IOP)– dependence of CH and to characterize the performance of the ORA. In the validation study, the purposes were to investigate the association between CH and both age and central corneal thickness (CCT) and the agreement between ORA and Goldmann applanation tonometer (GAT) IOP measurements. METHODS. For the characterization study, data were collected from 105 untreated subjects (45 ocular hypertensive patients and 60 normal subjects; mean age, 60 years, range, 26 – 82). GAT and ORA measurements were performed before and after IOP lowering of one randomly selected eye with apraclonidine drops. The change in P1 and P2 (arbitrary units) in relation to change in GAT IOP was analyzed to calibrate the instrument. The relation between P1, P2, and CCT was explored and ORA IOP was derived from the analyses. For the validation study, ORA and GAT IOP and CCT were measured in 144 eyes of 144 untreated subjects (mean age, 58 years; range, 19 – 83). The characterization calculations were applied to the dataset and values of CH and ORA IOP were calculated. The relationship between CH and both subject age and CCT was determined. The associations between CH and CCT and between ORA and GAT IOPs, were investigated by linear regression analysis. The agreement between measuring devices was calculated. RESULTS. In the characterization study, P1 changed by 6.41 arbitrary units for every 1-mm Hg change in GAT IOP. CH (P1 P2) changed by 1.60 arbitrary units for every 1-mm Hg change in GAT IOP. For each unit change in P2, P1 changed by 1.27 units. From this association a new IOP-independent corneal factor was derived [P1 (P2/1.27)] and is termed the corneal constant factor (CCF; mm Hg). ORA IOP normalized for CCF was defined as P2 – CCF (mm Hg). The CCF (mm Hg) was associated with CCT (micrometers) and with age: CCF [(0.036 CCT) (0.028 age)] 1.06 (adjusted r 2 0.34; P 0.0001 for CCT, P 0.007 for age). Normalized ORA IOP measurements were not associated with CCT. GAT IOP was associated with CCT and CCF—more strongly with the latter: GAT IOP (0.03 CCT)1.52 (r 2 0.06, P 0.002); GAT IOP (0.65 CCF) 4.5 (r 2 0.13, P 0.0001). The mean difference (95% limits of agreement) between GAT and normalized ORA IOP was 0.1 (6.6 to 6.8) mm Hg. CONCLUSIONS. The CCF describes an IOP-independent biomechanical property of the cornea that increases with thicker CCT and decreases with greater age. It is moderately strongly associated with CCT and yet explains more of the interindividual variation in GAT IOP than does CCT. Normalized ORA IOP measurements are not associated with CCT. (Invest Ophthalmol Vis Sci. 2006;47:5337–5347) DOI:10.1167/iovs.060557

Principles and effects of microRNA-mediated post-transcriptional gene regulation.

Abstract: MicroRNAs (miRNAs) are abundant regulatory RNAs involved in the regulation of many key biological processes. Recent advances in understanding the mechanism of RNA interference and miRNA-mediated mechanisms shed light on major principals of the formation of the regulatory complex and provide models to explain how these small regulatory RNA species interfere with gene expression and how they influence the translational status of the transcriptome.

NGOs, civil society and accountability: making the people accountable to capital

Abstract: Purpose – The purpose of this research is to seek to understand and explain the non‐governmental organisation (NGO) and its location in civil society in order to provide a basis for future research work. The paper aims to explore and develop understandings of accountability specifically in the context of the NGO and then extend these insights to the accountability of all organisations.Design/methodology/approach – The paper is framed within a theoretical conception of accountability and is primarily literature‐based. In addition secondary data relating to the issues of concern are collated and synthesised.Findings – The research finds that the essence of accountability lies in the relationships between the organisation and the society and/or stakeholder groups of interest. The nature of this relationship allows us to infer much about the necessary formality and the channels of accountability. In turn, this casts a light upon taken‐for‐granted assumptions in the corporate accountability and reminds us that...

A nucleoporin is required for induction of Ca2+ spiking in legume nodule development and essential for rhizobial and fungal symbiosis.

Abstract: Nuclear-cytoplasmic partitioning and traffic between cytoplasmic and nuclear compartments are fundamental processes in eukaryotic cells. Nuclear pore complexes mediate transport of proteins, RNAs and ribonucleoprotein particles in and out of the nucleus. Here we present positional cloning of a plant nucleoporin gene, Nup133, essential for a symbiotic signal transduction pathway shared by Rhizobium bacteria and mycorrhizal fungi. Mutation of Nup133 results in a temperature sensitive nodulation deficient phenotype and absence of mycorrhizal colonization. Root nodules developing with reduced frequency at permissive temperatures are ineffective and electron microscopy show that Rhizobium bacteria are not released from infection threads. Measurement of ion fluxes using a calcium-sensitive dye show that Nup133 is required for the Ca2+ spiking normally detectable within minutes after application of purified rhizobial Nod-factor signal molecules to root hairs. Localization of NUP133 in the nuclear envelope of root cells and root hair cells shown with enhanced yellow fluorescent protein fusion proteins suggests a novel role for NUP133 nucleoporins in a rapid nuclear–cytoplasmic communication after host–plant recognition of symbiotic microbes. Our results identify a component of an intriguing signal process requiring interaction at the cell plasma membrane and at intracellular nuclear and plastid organelle-membranes to induce a second messenger.

DExD/H box RNA helicases: multifunctional proteins with important roles in transcriptional regulation.

Abstract: The DExD/H box family of proteins includes a large number of proteins that play important roles in RNA metabolism. Members of this family have been shown to act as RNA helicases or unwindases, using the energy from ATP hydrolysis to unwind RNA structures or dissociate RNA–protein complexes in cellular processes that require modulation of RNA structures. However, it is clear that several members of this family are multifunctional and, in addition to acting as RNA helicases in processes such as pre-mRNA processing, play important roles in transcriptional regulation. In this review I shall concentrate on RNA helicase A (Dhx9), DP103 (Ddx20), p68 (Ddx5) and p72 (Ddx17), proteins for which there is a strong body of evidence showing that they play important roles in transcription, often as coactivators or corepressors through their interaction with key components of the transcriptional machinery, such as CREB-binding protein, p300, RNA polymerase II and histone deacetylases.