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Showing papers by "University of Glasgow published in 2002"


Journal ArticleDOI
27 Jun 2002-Nature
TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Abstract: Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

9,785 citations


Journal ArticleDOI
TL;DR: Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals and was extended to elderly individuals the treatment strategy currently used in middle aged people.

3,162 citations


Journal ArticleDOI
TL;DR: This work reveals that levels of inbreeding depression vary across taxa, populations and environments, but are usually substantial enough to affect both individual and population performance.
Abstract: Whether inbreeding affects the demography and persistence of natural populations has been questioned. However, new pedigree data from field populations and molecular and analytical tools for tracing patterns of relationship and inbreeding have now enhanced our ability to detect inbreeding depression within and among wild populations. This work reveals that levels of inbreeding depression vary across taxa, populations and environments, but are usually substantial enough to affect both individual and population performance. Data from bird and mammal populations suggest that inbreeding depression often significantly affects birth weight, survival, reproduction and resistance to disease, predation and environmental stress. Plant studies, based mostly on comparing populations that differ in size or levels of genetic variation, also reveal significant inbreeding effects on seed set, germination, survival and resistance to stress. Data from butterflies, birds and plants demonstrate that populations with reduced genetic diversity often experience reduced growth and increased extinction rates. Crosses between such populations often result in heterosis. Such a genetic rescue effect might reflect the masking of fixed deleterious mutations. Thus, it might be necessary to retain gene flow among increasingly fragmented habitat patches to sustain populations that are sensitive to inbreeding.

2,945 citations


Journal ArticleDOI
TL;DR: The first evidence for collective memory is presented in such animal groups (where the previous history of group structure influences the collective behaviour exhibited as individual interactions change) during the transition of a group from one type of collective behaviour to another.

1,906 citations


Journal ArticleDOI
TL;DR: In this article, the effect of atrial fibrillation on long-term morbidity and mortality was described, and Cox proportional hazards models were used to adjust for age and cardiovascular conditions.

1,407 citations


Journal ArticleDOI
TL;DR: In this paper, the authors examine some popular choice modelling approaches to environmental valuation, which can be considered as alternatives to more familiar valuation techniques based on stated preferences such as the contingent valuation method.
Abstract: In this paper, we examine some popular ‘choice modelling’ approaches to environmental valuation, which can be considered as alternatives to more familiar valuation techniques based on stated preferences such as the contingent valuation method. A number of choice modelling methods are consistent with consumer theory, and its focus on an attribute-based theory of value permits a superior representation of many environmental management contexts. However, choice modelling surveys can place a severe cognitive burden upon respondents and induce satisficing rather than maximising behavioural patterns. In this framework, we seek to identify the best available choice modelling alternative and investigate its potential to ‘solve’ some of the major biases associated with standard contingent valuation. We then discuss its use in the light of policy appraisal needs within the EU. An application to the demand for rock climbing in Scotland is provided as an illustration.

1,139 citations


Journal ArticleDOI
TL;DR: In this article, interviews were conducted with seven large multinational companies in the chemical and pharmaceutical sectors of the UK and Germany in order to identify any internal contextual factors influencing the nature and extent of reporting.
Abstract: Prior empirical research into factors which are influential in determining the extent and nature of corporate social reporting has primarily been concerned with the impact of corporate characteristics (such as size and industry grouping) or general contextual factors (such as the social, political and economic context). Relatively little prior work has examined the internal contextual factors and their impact on reporting despite increasing emphasis in the field of practice on reporting processes and governance structures. In this study interviews were conducted with seven large multinational companies in the chemical and pharmaceutical sectors of the UK and Germany in order to identify any internal contextual factors influencing the nature and extent of reporting. The work highlights the lack of explanatory power of the existing social reporting theories. A more inclusive model of corporate social reporting is presented.

1,095 citations


Journal ArticleDOI
TL;DR: It is shown that siRNAs produced in plants from a green fluorescent protein (GFP) transgene are in short and long size classes, whereas those from endogenous retroelements are only in the long class, revealing an unexpected level of complexity in the RNA silencing pathway in plants that may also apply in animals.
Abstract: RNA silencing is a eukaryotic genome defence system that involves processing of double-stranded RNA (dsRNA) into 21-26 nt, short interfering RNA (siRNA). The siRNA mediates suppression of genes corresponding to the dsRNA through targeted RNA degradation. In some plant systems there are additional silencing processes, involving systemic spread of silencing and RNA-directed methylation/transcriptional suppression of homologous genomic DNA. We show here that siRNAs produced in plants from a green fluorescent protein (GFP) transgene are in short (21-22 nt) and long (24-26 nt) size classes, whereas those from endogenous retroelements are only in the long class. Viral suppressors of RNA silencing and mutations in Arabidopsis indicate that these classes of siRNA have different roles. The long siRNA is dispensable for sequence-specific mRNA degradation, but correlates with systemic silencing and methylation of homologous DNA. Conversely, the short siRNA class correlates with mRNA degradation but not with systemic signalling or methylation. These findings reveal an unexpected level of complexity in the RNA silencing pathway in plants that may also apply in animals.

1,084 citations


Journal ArticleDOI
TL;DR: This work demonstrates its viability by sorting four different orbital angular momentum states, and is thus able to encode two bits of information on a single photon, having implications for entanglement experiments, quantum cryptography and high density information transfer.
Abstract: We propose an interferometric method for measuring the orbital angular momentum of single photons. We demonstrate its viability by sorting four different orbital angular momentum states, and are thus able to encode two bits of information on a single photon. This new approach has implications for entanglement experiments, quantum cryptography and high density information transfer.

1,013 citations


Journal ArticleDOI
TL;DR: Numerical calculations of both spin and orbital angular momentum are confirmed by means of experiments with particles trapped off axis in optical tweezers, where the size of the particle means it interacts with only a fraction of the beam profile.
Abstract: We explain that, unlike the spin angular momentum of a light beam which is always intrinsic, the orbital angular momentum may be either extrinsic or intrinsic. Numerical calculations of both spin and orbital angular momentum are confirmed by means of experiments with particles trapped off axis in optical tweezers, where the size of the particle means it interacts with only a fraction of the beam profile. Orbital angular momentum is intrinsic only when the interaction with matter is about an axis where there is no net transverse momentum.

915 citations


Journal ArticleDOI
TL;DR: A framework for deriving probabilistic models of Information Retrieval using term-weighting models obtained in the language model approach by measuring the divergence of the actual term distribution from that obtained under a random process is introduced.
Abstract: We introduce and create a framework for deriving probabilistic models of Information Retrieval. The models are nonparametric models of IR obtained in the language model approach. We derive term-weighting models by measuring the divergence of the actual term distribution from that obtained under a random process. Among the random processes we study the binomial distribution and Bose--Einstein statistics. We define two types of term frequency normalization for tuning term weights in the document--query matching process. The first normalization assumes that documents have the same length and measures the information gain with the observed term once it has been accepted as a good descriptor of the observed document. The second normalization is related to the document length and to other statistics. These two normalization methods are applied to the basic models in succession to obtain weighting formulae. Results show that our framework produces different nonparametric models forming baseline alternatives to the standard tf-idf model.

Journal ArticleDOI
Rob Gray1
TL;DR: A review of the social accounting literature of the last 25 years or so with particular attention to the role played by Accounting, Organizations and Society (AOS) in its development can be found in this article.
Abstract: This paper provides one review of the social accounting literature of the last 25 years or so with particular attention to the role played by Accounting, Organizations and Society (AOS) in its development. The principal theme of the essay is that social accounting, at its best, is designed to open up a space for new accountings between the ‘conventional' accounting literature and practice and the ‘alternative' critiques and theorising. It seeks to do this, as the title suggests, through privileging — even demanding — engagement and imaginings of new accountings that — it seems inevitable — owe at least as much to pragmatism as to critique. Despite many poor beginnings and a heavy weight of substantive critique, the social accounting project(s) are advancing and are increasingly informed by the alternative/critical projects. The way forward proposed is for social accounting to both draw more from the wealth of theorising and, simultaneously, to take more confidence in itself and learn how to write up — and publish — the extensive experience of engagement which is so central to social accounting.

Journal ArticleDOI
TL;DR: For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.
Abstract: Stilbenes, in particular trans-resveratrol and its glucoside, are widely reported to be beneficial to health, having been shown to possess antioxidative, anticarcinogenic, and antitumor properties. Major dietary sources include grapes, wine, peanuts, and soy; however, they can also be introduced into the diet through Itadori tea, which has long been used in Japan and China as a traditional herbal remedy for heart disease and strokes. Analysis of grapes, peanuts, and Itadori tea shows that they contain mainly trans-resveratrol glucoside. In contrast, red wines are primarily a source of the aglycones cis- and trans-resveratrol. While peanuts and grapes contain low levels of the stilbenes, Itadori tea and red wine both supply relatively high concentrations of resveratrol. For people who do not consume alcohol, Itadori tea may be a suitable substitute for red wine. However, further study on the potential biological effects of other endogenous compounds in Itadori tea is required and there is also a need for more information on the absorption and in vivo biomedical actions of free and conjugated resveratrol.

Journal ArticleDOI
TL;DR: The soluble glutathione transferases (GSTs) represent an excellent example of how protein families can diversify to fulfill multiple functions while conserving form and structure.
Abstract: The soluble glutathione transferases (GSTs, EC 2.5.1.18) are encoded by a large and diverse gene family in plants, which can be divided on the basis of sequence identity into the phi, tau, theta, zeta and lambda classes. The theta and zeta GSTs have counterparts in animals but the other classes are plant-specific and form the focus of this article. The genome of Arabidopsis thaliana contains 48 GST genes, with the tau and phi classes being the most numerous. The GST proteins have evolved by gene duplication to perform a range of functional roles using the tripeptide glutathione (GSH) as a cosubstrate or coenzyme. GSTs are predominantly expressed in the cytosol, where their GSH-dependent catalytic functions include the conjugation and resulting detoxification of herbicides, the reduction of organic hydroperoxides formed during oxidative stress and the isomerization of maleylacetoacetate to fumarylacetoacetate, a key step in the catabolism of tyrosine. GSTs also have non-catalytic roles, binding flavonoid natural products in the cytosol prior to their deposition in the vacuole. Recent studies have also implicated GSTs as components of ultraviolet-inducible cell signaling pathways and as potential regulators of apoptosis. Although sequence diversification has produced GSTs with multiple functions, the structure of these proteins has been highly conserved. The GSTs thus represent an excellent example of how protein families can diversify to fulfill multiple functions while conserving form and structure.

Journal ArticleDOI
01 May 2002-Diabetes
TL;DR: Observations about C-reactive protein add to the notion that low-grade inflammation is important in the pathogenesis of type 2 diabetes, and have clinical potential in helping to better predict individuals destined to develop type 1 diabetes.
Abstract: Accumulating evidence implicates inflammation as a potential pathway in the pathogenesis of type 2 diabetes. The objective of the present study was to assess the ability of C-reactive protein (CRP) to predict the development of diabetes in middle-aged men in the West of Scotland Coronary Prevention Study. Baseline plasma samples for CRP measurement were available for 5,245 men of whom 127 were classified as having a transition from normal glucose control to overt diabetes during the study, based on American Diabetes Association criteria. Baseline CRP was an important predictor of the development of diabetes in univariate analysis (hazard ratio [HR] for an increase of 1 SD = 1.55; 95% CI 1.32–1.82; P 4.18 mg/l) was associated with a greater than threefold risk of developing diabetes (HR 3.07; 95% CI 1.33–7.10) in a multivariate analysis at 5 years. Thus, CRP predicts the development of type 2 diabetes in middle-aged men independently of established risk factors. Because CRP, the most commonly used acute-phase protein in clinical practice, is very stable in serum, our observations have clinical potential in helping to better predict individuals destined to develop type 2 diabetes. They also add to the notion that low-grade inflammation is important in the pathogenesis of type 2 diabetes.

Journal ArticleDOI
TL;DR: There is optimism that drugs which inhibit Src's kinase activity, or the activity of its downstream effectors, might have profound effects on cancer cell behaviour and be useful therapeutic agents.

Journal ArticleDOI
TL;DR: The kynurenine pathway is the main pathway for tryptophan metabolism and generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites.
Abstract: At-a-glance The kynurenine pathway is the main pathway for tryptophan metabolism. It generates compounds that can modulate activity at glutamate receptors and possibly nicotinic receptors, in addition to some as-yet-unidentified sites. The pathway is in a unique position to regulate other aspects of the metabolism of tryptophan to neuroactive compounds, and also seems to be a key factor in the communication between the nervous and immune systems. It also has potentially important roles in the regulation of cell proliferation and tissue function in the periphery. As a result, the pathway presents a multitude of potential sites for drug discovery in neuroscience, oncology and visceral pathology.

Journal ArticleDOI
30 May 2002-Nature
TL;DR: In this article, a feedback-optimized coherent control over the energy-flow pathways in the light-harvesting antenna complex LH2 from Rhodopseudomonas acidophila, a photosynthetic purple bacterium, is presented.
Abstract: Coherent light sources have been widely used in control schemes that exploit quantum interference effects to direct the outcome of photochemical processes. The adaptive shaping of laser pulses is a particularly powerful tool in this context: experimental output as feedback in an iterative learning loop refines the applied laser field to render it best suited to constraints set by the experimenter. This approach has been experimentally implemented to control a variety of processes, but the extent to which coherent excitation can also be used to direct the dynamics of complex molecular systems in a condensed-phase environment remains unclear. Here we report feedback-optimized coherent control over the energy-flow pathways in the light-harvesting antenna complex LH2 from Rhodopseudomonas acidophila, a photosynthetic purple bacterium. We show that phases imprinted by the light field mediate the branching ratio of energy transfer between intra- and intermolecular channels in the complex's donor acceptor system. This result illustrates that molecular complexity need not prevent coherent control, which can thus be extended to probe and affect biological functions.

Journal Article
TL;DR: Empathy is a complex multi-dimensional concept that has moral cognitive emotive and behavioural components and studies in mental health and in nursing suggest it plays a key role.
Abstract: Empathy is a complex multi-dimensional concept that has moral cognitive emotive and behavioural components Clinical empathy involves an ability to: (a) understand the patient's situation, perspective, and feelings (and their attached meanings); (b) to communicate that understanding and check its accuracy; and (c) to act on that understanding with the patient in a helpful (therapeutic) way. Research on the effect of empathy on health outcomes in primary care is lacking, but studies in mental health and in nursing suggest it plays a key role. Empathy can be improved and successfully taught at medical school especially if it is embedded in the students actual experiences with patients. A variety of assessment and feedback techniques have also been used in general medicine psychiatry and nursing. Further work is required to determine if clinical empathy needs to be, and can be, improved in the primary care setting.

Journal ArticleDOI
TL;DR: The results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.
Abstract: NK cell cytotoxicity, IFN-γ expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-γ expression, whereas IFN-αβ/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-αβ/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.

Journal ArticleDOI
TL;DR: The singular value decomposition and its interpretation as a linear biplot have proved to be a powerful tool for analysing many forms of multivariate data as discussed by the authors, including compositional data consisting of positive vectors.
Abstract: Summary. The singular value decomposition and its interpretation as a linear biplot have proved to be a powerful tool for analysing many forms of multivariate data. Here we adapt biplot methodology to the specific case of compositional data consisting of positive vectors each of which is constrained to have unit sum. These relative variation biplots have properties relating to the special features of compositional data: the study of ratios, subcompositions and models of compositional relationships. The methodology is applied to a data set consisting of six-part colour compositions in 22 abstract paintings, showing how the singular value decomposition can achieve an accurate biplot of the colour ratios and how possible models interrelating the colours can be diagnosed.

Journal ArticleDOI
TL;DR: Using well‐validated sets of data, these findings re‐confirm the importance of heart failure as a major public health problem in the UK.
Abstract: We have recently shown that heart failure admission rates continue to increase in the UK -- particularly in older age groups. As hospital activity represents the major cost component of health care expenditure related to heart failure, this study evaluated the current cost of this syndrome to the National Health Service (NHS) in the UK. We applied contemporary estimates of health care activity associated with heart failure to the whole UK population on an age and sex-specific basis to calculate its cost to the NHS for the year 1995. Direct components of health care included in these estimates were hospital admissions associated with a principal diagnosis of heart failure, associated outpatient consultations, general practice consultations and prescribed drug therapy. We also calculated the cost of nursing-home care following a primary heart failure admission and the cost of hospitalisations associated with a secondary diagnosis of heart failure. Adjusting for probable increases in hospital activity and the progressive ageing of the UK population, we have also projected the cost of heart failure to the NHS for the year 2000. We estimated that there were 988000 individuals requiring treatment for heart failure in the UK during 1995. The 'direct' cost of health care for these patients was estimated to be pound 716 million, or 1.83% of total NHS expenditure. Hospitalisations and drug prescriptions accounted for 69 and 18% of this expenditure, respectively. The additional costs associated with long-term nursing home care and secondary heart failure admissions accounted for a further pound 751 million (2.0% of total NHS expenditure). By the year 2000, we estimated that the combined total direct cost of heart failure would have risen to pound 905 million -- equivalent to 1.91% of total NHS expenditure. Using well-validated sets of data, these findings re-confirm the importance of heart failure as a major public health problem in the UK. The annual direct cost of heart failure to the NHS in 2000 is likely to be of the order of 1.9% of total expenditure -- the predominant cost component being hospitalisation.

Journal ArticleDOI
TL;DR: Differences in diet‐tissue discrimination factors before and after the diet switch may mean that toward the end of the experiment, some of the nutrients for blood synthesis had been coming from stores, and repeated measures mixed models provided evidence that increases in metabolic rate might accelerate fractional turnover rates in blood.
Abstract: By switching great skuas Catharacta skua from one isotopically distinct diet to another, we measured diet-tissue discrimination factors and tested the assumption that dietary nitrogen and carbon isotope signatures are incorporated into blood and feathers at similar rates. We also examined the effects of metabolic rate and looked for evidence of isotopic routing. We found that blood delta(15)N and delta(13)C signatures altered after the diet switch at similar rates (14.4 d and 15.7 d, respectively). Qualitative analyses imply that the same was true with feathers. Mass balance calculations suggest that only a small amount of lipid is likely to be involved in the synthesis of blood and feathers. Differences in diet-tissue discrimination factors before and after the diet switch may mean that toward the end of the experiment, some of the nutrients for blood synthesis had been coming from stores. Repeated measures mixed models provided evidence that increases in metabolic rate might accelerate fractional turnover rates in blood. There is a need for more laboratory-based experimental isotope studies in order to address further questions that this study has raised.

Proceedings ArticleDOI
07 Nov 2002
TL;DR: An overview on developments and a summary of the state-of-the-art of inverter technology in Europe for single-phase grid-connected photovoltaic (PV) systems for power levels up to 5 kW is provided.
Abstract: An overview on developments and a summary of the state-of-the-art of inverter technology in Europe for single-phase grid-connected photovoltaic (PV) systems for power levels up to 5 kW is provided in this paper. The information includes details not only on the topologies commercially available but also on the switching devices employed and the associated switching frequencies, efficiency, price trends and market share. Finally, the paper outlines issues associated with the development of relevant international industry standards affecting PV inverter technology.

Journal ArticleDOI
TL;DR: A resurgence of interest in the region as a scale of economic organization has been apparent within economic geography over the past decade or so as mentioned in this paper, in view of the apparent shift towards a knowledge-based approach.
Abstract: A resurgence of interest in the region as a scale of economic organization has been apparent within economic geography over the past decade or so. In view of the apparent shift towards a ‘knowledge...

Journal ArticleDOI
TL;DR: In this article, an integrated psychobiological inhibition model of insomnia is developed that accounts for the research data, and it is proposed that sleep homeostatic and circadian factors are compromised by impairment of the automaticity and plasticity associated with good sleep.
Abstract: This paper critically reviews the evidence base for previously reported conceptual models of the development and persistence of insomnia. Although a number of perspectives have some empirical support, no one approach emerges as preeminent. Importantly, the efficacy of any particular psychological intervention cannot be taken as confirmation of presumed, underlying mechanisms. An integrated psychobiological inhibition model of insomnia is developed that accounts for the research data. The model views insomnia as arising from inhibition of de-arousal processes associated with normal sleep. It is proposed that sleep homeostatic and circadian factors are compromised by impairment of the automaticity and plasticity associated with good sleep, and that cognitive/affective processes activate the clinical complaint of insomnia. Common pathways for the action of cognitive-behavioral interventions are identified, and a research agenda is set for further conceptual and clinical study.

Journal ArticleDOI
TL;DR: The course and outcome of pregnancy, growth, and development during childhood and the extent of worker productivity are diminished during hookworm disease, and cost-effective measures based on highly efficacious anthelminthic drugs are now available to reduce and control disease caused by these infections.
Abstract: Poor people in developing countries endure the burden of disease caused by four common species of soil-transmitted nematode that inhabit the gastrointestinal tract. Disease accompanying these infections is manifested mainly as nutritional disturbance, with the differing infections having their deleterious effects at different phases during the human life cycle. Reduced food intake, impaired digestion, malabsorption, and poor growth rate are frequently observed in children suffering from ascariasis and trichuriasis. Poor iron status and iron deficiency anemia are the hallmarks of hookworm disease. The course and outcome of pregnancy, growth, and development during childhood and the extent of worker productivity are diminished during hookworm disease. Less is known about the impact of these infections in children under 2 years of age. The severity of disease caused by soil-transmitted nematodes has consistently been found to depend on the number of worms present per person. Cost-effective measures based on highly efficacious anthelminthic drugs are now available to reduce and control disease caused by these infections.

Journal ArticleDOI
TL;DR: Analysis of data from two large phase III trials demonstrates that efficacy is not compromised in patients requiring a dose reduction for adverse events, indicating that capecitabine provides a better-tolerated alternative to i.v. 5-FU/leucovorin as treatment for patients with metastatic colorectal cancer.

Journal ArticleDOI
25 Oct 2002-Science
TL;DR: It is shown that β-arrestins coordinate both processes by recruiting PDEs to activated β2-adrenergic receptors in the plasma membrane of mammalian cells by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rates of its degradation at the membrane.
Abstract: Catecholamines signal through the β 2 -adrenergic receptor by promoting production of the second messenger adenosine 3′,5′-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to β-arrestins and by cAMP degradation by phosphodiesterase (PDE) enzymes. We show that β-arrestins coordinate both processes by recruiting PDEs to activated β 2 -adrenergic receptors in the plasma membrane of mammalian cells. In doing so, the β-arrestins limit activation of membrane-associated cAMP-activated protein kinase by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rate of its degradation at the membrane.

Journal ArticleDOI
TL;DR: Evidence is provided that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane‐cleaving protease SPP that promotes the release of core protein from the ER membrane, then free for subsequent trafficking to lipid droplets.
Abstract: Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.