Publications by authors named "Fiona Murray"

78 Publications

Sex Differences in Ischemic Stroke Outcomes in Patients With Pulmonary Hypertension.

J Am Heart Assoc 2021 Mar 8;10(6):e019341. Epub 2021 Mar 8.

Keele Cardiovascular Research Group Centre for Prognosis Research Institute for Primary Care and Health Sciences Keele University Stoke-on-Trent UK.

Background The association between systemic hypertension and cerebrovascular disease is well documented. However, the impact of pulmonary hypertension (PH) on acute ischemic stroke outcomes is unknown despite PH being recognized as a risk factor for acute ischemic stroke. We aimed to determine the association between PH and adverse in-hospital outcomes after acute ischemic stroke, as well as whether there are sex differences in this association. Methods and Results Acute ischemic stroke admissions from the US National Inpatient Sample between October 2015 and December 2017 were included. The relationship between PH and outcomes (mortality, prolonged hospitalization >4 days, and routine home discharge) was analyzed using logistic regressions adjusting for demographics, comorbidities, and revascularization therapies. Interaction terms between PH and sex and age groups were also included. A total of 221 249 records representative of 1 106 045 admissions were included; 2.9% of patients had co-morbid PH, and 35.34% of those were male. PH was not associated with in-hospital mortality (odds ratio [OR], 0.96; 95% CI, 0.86-1.09) but was associated with increased odds of prolonged hospitalization (OR, 1.15; 95% CI, 1.09-1.22) and decreased odds of routine discharge (OR, 0.87; 95% CI, 0.81-0.94) for both sexes. Older patients with PH were significantly less likely to be discharged routinely (=0.028) than their younger counterparts. Compared with female patients with PH, men were 31% more likely to die in hospital (=0.024). Conclusions PH was not significantly associated with in-hospital mortality but was associated with prolonged hospitalization and adverse discharge status. Male patients with PH were more likely to die in hospital than female patients.
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http://dx.doi.org/10.1161/JAHA.120.019341DOI Listing
March 2021

Receptor tyrosine kinases activate heterotrimeric G proteins via phosphorylation within the interdomain cleft of Gαi.

Proc Natl Acad Sci U S A 2020 11 2;117(46):28763-28774. Epub 2020 Nov 2.

Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0651;

The molecular mechanisms by which receptor tyrosine kinases (RTKs) and heterotrimeric G proteins, two major signaling hubs in eukaryotes, independently relay signals across the plasma membrane have been extensively characterized. How these hubs cross-talk has been a long-standing question, but answers remain elusive. Using linear ion-trap mass spectrometry in combination with biochemical, cellular, and computational approaches, we unravel a mechanism of activation of heterotrimeric G proteins by RTKs and chart the key steps that mediate such activation. Upon growth factor stimulation, the guanine-nucleotide exchange modulator dissociates Gαi•βγ trimers, scaffolds monomeric Gαi with RTKs, and facilitates the phosphorylation on two tyrosines located within the interdomain cleft of Gαi. Phosphorylation triggers the activation of Gαi and inhibits second messengers (cAMP). Tumor-associated mutants reveal how constitutive activation of this pathway impacts cell's decision to "go" vs. "grow." These insights define a tyrosine-based G protein signaling paradigm and reveal its importance in eukaryotes.
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http://dx.doi.org/10.1073/pnas.2004699117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682395PMC
November 2020

Low-level maternal exposure to cadmium, lead, and mercury and birth outcomes in a Swedish prospective birth-cohort.

Environ Pollut 2020 Oct 9;265(Pt B):114986. Epub 2020 Jun 9.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Observational studies have indicated that low-to-moderate exposure to cadmium (Cd), lead (Pb), and mercury (Hg) adversely affects birth anthropometry, but results are inconclusive. The aim of this study was to elucidate potential impact on birth anthropometry of exposure to Cd, Pb, and Hg in pregnant women, and to identify the main dietary sources. In the NICE (Nutritional impact on Immunological maturation during Childhood in relation to the Environment) birth-cohort in northern Sweden, blood and urine were collected from pregnant women in early third trimester. Cd, Pb and Hg were measured in erythrocytes (n = 584), and Cd also in urine (n = 581), by inductively coupled plasma mass spectrometry. Dietary data were collected through a semi-quantitative food frequency questionnaire administered in mid-third trimester. Birth anthropometry data were extracted from hospital records. In multivariable-adjusted spline regression models, a doubling of maternal erythrocyte Cd (median: 0.29 μg/kg) above the spline knot of 0.50 μg/kg was associated with reduced birth weight (B: -191 g; 95% CI: -315, -68) and length (-0.67 cm; -1.2, -0.14). The association with birth weight remained when the analysis was restricted to never-smokers. Likewise, a doubling of erythrocyte Hg (median 1.5 μg/kg, mainly MeHg) above 1.0 μg/kg, was associated with decreased birth weight (-59 g; -115, -3.0), and length (-0.29 cm; -0.54, -0.047). Maternal Pb (median 11 μg/kg) was unrelated to birth weight and length. Erythrocyte Cd was primarily associated with intake of plant derived foods, Pb with game meat, tea and coffee, and Hg with fish. The results indicated that low-level maternal Cd and Hg exposure were associated with poorer birth anthropometry. Further prospective studies in low-level exposed populations are warranted.
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http://dx.doi.org/10.1016/j.envpol.2020.114986DOI Listing
October 2020

Endogenous IL-33 and Its Autoamplification of IL-33/ST2 Pathway Play an Important Role in Asthma.

J Immunol 2020 03 27;204(6):1592-1597. Epub 2020 Jan 27.

Department of Medicine, University of California San Diego, La Jolla, CA 92093; and

IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33- and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33-induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models.
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http://dx.doi.org/10.4049/jimmunol.1900690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065953PMC
March 2020

Deletion of caveolin scaffolding domain alters cancer cell migration.

Cell Cycle 2019 06 22;18(11):1268-1280. Epub 2019 May 22.

a Veterans Administration San Diego Healthcare System , San Diego , CA , USA.

Caveolin-1 (Cav-1) is an integral membrane protein that plays an important role in proliferative and terminally differentiated cells. As a structural component of Caveolae, Cav-1 interacts with signaling molecules via a caveolin scaffolding domain (CSD) regulating cell signaling. Recent reports have shown that Cav-1 is a negative regulator in tumor metastasis. Therefore, we hypothesize that Cav-1 inhibits cell migration through its CSD. HeLa cells were engineered to overexpress Cav-1 (Cav-1 OE), Cav-1 without a functional CSD (∆CSD), or enhanced green fluorescent protein (EGFP) as a control. HeLa cell migration was suppressed in Cav-1 OE cells while ∆CSD showed increased migration, which corresponded to a decrease in the tight junction protein, zonula occludens (ZO-1). The migration phenotype was confirmed in multiple cancer cell lines. Phosphorylated STAT-3 was decreased in Cav-1 OE cells compared to control and ∆CSD cells; reducing STAT-3 expression alone decreased cell migration. ∆CSD blunted HeLa proliferation by increasing the number of cells in the G2/M phase of the cell cycle. Overexpressing the CSD peptide alone suppressed HeLa cell migration and inhibited pSTAT3. These findings suggest that Cav-1 CSD may be critical in controlling the dynamic phenotype of cancer cells by facilitating the interaction of specific signal transduction pathways, regulating STAT3 and participating in a G2/M checkpoint. Modulating the CSD and targeting specific proteins may offer potential new therapies in the treatment of cancer metastasis.
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http://dx.doi.org/10.1080/15384101.2019.1618118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592257PMC
June 2019

Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE): a prospective birth cohort in northern Sweden.

BMJ Open 2018 10 21;8(10):e022013. Epub 2018 Oct 21.

Sunderby Research Unit, Region Norrbotten, Luleå, Sweden.

Introduction: Prenatal and neonatal environmental factors, such as nutrition, microbes and toxicants, may affect health throughout life. Many diseases, such as allergy and impaired child development, may be programmed already in utero or during early infancy. Birth cohorts are important tools to study associations between early life exposure and disease risk. Here, we describe the study protocol of the prospective birth cohort, 'Nutritional impact on Immunological maturation during Childhood in relation to the Environment' (NICE). The primary aim of the NICE cohort is to clarify the effect of key environmental exposures-diet, microbes and environmental toxicants-during pregnancy and early childhood, on the maturation of the infant's immune system, including initiation of sensitisation and allergy as well as some secondary outcomes: infant growth, obesity, neurological development and oral health.

Methods And Analysis: The NICE cohort will recruit about 650 families during mid-pregnancy. The principal inclusion criterion will be planned birth at the Sunderby Hospital in the north of Sweden, during 2015-2018. Questionnaires data and biological samples will be collected at 10 time-points, from pregnancy until the children reach 4 years of age. Samples will be collected primarily from mothers and children, and from fathers. Biological samples include blood, urine, placenta, breast milk, meconium, faeces, saliva and hair. Information regarding allergic heredity, diet, socioeconomic status, lifestyle including smoking, siblings, pet ownership, etc will be collected using questionnaires. Sensitisation to common allergens will be assessed by skin prick testing and allergic disease will be diagnosed by a paediatrician at 1 and 4 years of age. At 4 years of age, the children will also be examined regarding growth, neurobehavioural and neurophysiological status and oral health.

Ethics And Dissemination: The NICE cohort has been approved by the Regional Ethical Review Board in Umeå, Sweden (2013/18-31M). Results will be disseminated through peer-reviewed journals and communicated on scientific conferences.
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http://dx.doi.org/10.1136/bmjopen-2018-022013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196815PMC
October 2018

GPCRomics: GPCR Expression in Cancer Cells and Tumors Identifies New, Potential Biomarkers and Therapeutic Targets.

Front Pharmacol 2018 22;9:431. Epub 2018 May 22.

Department of Pharmacology, University of California, San Diego, San Diego, CA, United States.

G protein-coupled receptors (GPCRs), the largest family of targets for approved drugs, are rarely targeted for cancer treatment, except for certain endocrine and hormone-responsive tumors. Limited knowledge regarding GPCR expression in cancer cells likely has contributed to this lack of use of GPCR-targeted drugs as cancer therapeutics. We thus undertook GPCRomic studies to define the expression of endoGPCRs (which respond to endogenous molecules such as hormones, neurotransmitters and metabolites) in multiple types of cancer cells. Using TaqMan qPCR arrays to quantify the mRNA expression of ∼340 such GPCRs, we found that human chronic lymphocytic leukemia (CLL) cells/stromal cells associated with CLL, breast cancer cell lines, colon cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, cancer associated fibroblasts (CAFs), and PDAC tumors express 50 to >100 GPCRs, including many orphan GPCRs (which lack known physiologic agonists). Limited prior data exist regarding the expression or function of most of the highly expressed GPCRs in these cancer cells and tumors. Independent results from public cancer gene expression databases confirm the expression of such GPCRs. We propose that highly expressed GPCRs in cancer cells (for example, GPRC5A in PDAC and colon cancer cells and GPR68 in PDAC CAFs) may contribute to the malignant phenotype, serve as biomarkers and/or may be novel therapeutic targets for the treatment of cancer.
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http://dx.doi.org/10.3389/fphar.2018.00431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972277PMC
May 2018

GPCRs in pulmonary arterial hypertension: tipping the balance.

Br J Pharmacol 2018 08 17;175(15):3063-3079. Epub 2018 Apr 17.

College of Life Sciences and Medicine, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

Pulmonary arterial hypertension (PAH) is a progressive, fatal disease characterised by increased pulmonary vascular resistance and excessive proliferation of pulmonary artery smooth muscle cells (PASMC). GPCRs, which are attractive pharmacological targets, are important regulators of pulmonary vascular tone and PASMC phenotype. PAH is associated with the altered expression and function of a number of GPCRs in the pulmonary circulation, which leads to the vasoconstriction and proliferation of PASMC and thereby contributes to the imbalance of pulmonary vascular tone associated with PAH; drugs targeting GPCRs are currently used clinically to treat PAH and extensive preclinical work supports the utility of a number of additional GPCRs. Here we review how GPCR expression and function changes with PAH and discuss why GPCRs continue to be relevant drug targets for the disease.
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http://dx.doi.org/10.1111/bph.14172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031878PMC
August 2018

An exploration of collaborative scientific production at MIT through spatial organization and institutional affiliation.

PLoS One 2017 22;12(6):e0179334. Epub 2017 Jun 22.

Senseable City Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States of America.

Academic research is increasingly cross-disciplinary and collaborative, between and within institutions. In this context, what is the role and relevance of an individual's spatial position on a campus? We examine the collaboration patterns of faculty at the Massachusetts Institute of Technology, through their academic output (papers and patents), and their organizational structures (institutional affiliation and spatial configuration) over a 10-year time span. An initial comparison of output types reveals: 1. diverging trends in the composition of collaborative teams over time (size, faculty versus non-faculty, etc.); and 2. substantively different patterns of cross-building and cross-disciplinary collaboration. We then construct a multi-layered network of authors, and find two significant features of collaboration on campus: 1. a network topology and community structure that reveals spatial versus institutional collaboration bias; and 2. a persistent relationship between proximity and collaboration, well fit with an exponential decay model. This relationship is consistent for both papers and patents, and present also in exclusively cross-disciplinary work. These insights contribute an architectural dimension to the field of scientometrics, and take a first step toward empirical space-planning policy that supports collaboration within institutions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0179334PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480888PMC
September 2017

Functional magnetic resonance imaging for in vivo quantification of pulmonary hypertension in the Sugen 5416/hypoxia mouse.

Exp Physiol 2017 03 14;102(3):347-353. Epub 2017 Feb 14.

Medicine, University of California, San Diego, La Jolla, CA, USA.

New Findings: What is the central question of this study? Non-invasive, quantitative methods to assess right cardiac function in mice with pulmonary hypertension have not been demonstrated. What is the main finding and its importance? This study shows the potential of magnetic resonance imaging to estimate right ventricular ejection fraction and measure spatial, dynamic changes in cardiac structure in the Sugen 5416/hypoxia mouse model of pulmonary hypertension. Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery pressures and right heart failure. Mouse models of PAH are instrumental in understanding the disease pathophysiology. However, few methods are available to evaluate right cardiac function in small animals. In this study, magnetic resonance imaging was used to measure in vivo cardiac dimensions in the Sugen 5416/hypoxia mouse model. Pulmonary hypertension (PH) was induced in C57BL/6 mice by 3 weeks of exposure to 10% oxygen and vascular endothelial growth factor receptor inhibition (20 mg kg SU5416). Control mice were housed in room air and received vehicle (DMSO). Right ventricular pressures were recorded with a pressure-conductance transducer. Short-axis contiguous 1-mm-thick slices were acquired through the heart and great vessels using a fast low-angle shot (FLASH)-cine sequence. Thirteen images were collected throughout each cardiac cycle. Right ventricular systolic pressure was elevated in PH mice (23.6 ± 6 versus 41.0 ± 11 mmHg, control versus PH, respectively; P < 0.001, n = 5-11). Right ventricular wall thickness was greater in PH than in control mice at end diastole (0.30 ± 0.05 versus 0.48 ± 0.06 mm, control versus PH, respectively; P < 0.01, n = 6), but measurements were not different at end systole (control versus PH, 0.59 ± 0.11 versus 0.70 ± 0.11 mm, respectively). Right ventricular ejection fraction was decreased in PH mice (72 ± 3 versus 58 ± 5%, control versus PH, respectively; P < 0.04, n = 6). These data demonstrate that magnetic resonance imaging is a precise method to monitor right ventricular remodelling and cardiac output longitudinally in mouse models of PH.
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http://dx.doi.org/10.1113/EP086067DOI Listing
March 2017

The impact of personal genomics on risk perceptions and medical decision-making.

Nat Biotechnol 2016 09;34(9):912-8

Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Partners HealthCare Personalized Medicine, the Broad Institute and Harvard Medical School, Boston, Massachusetts, USA.

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http://dx.doi.org/10.1038/nbt.3661DOI Listing
September 2016

Should emergency tracheostomy management be a core competency for anaesthetic training?

J Intensive Care Soc 2016 Aug 25;17(3):266. Epub 2016 Jul 25.

Anaesthesia and Intensive Care Medicine, Whipps Cross Hospital, London, UK.

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http://dx.doi.org/10.1177/1751143715618973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606509PMC
August 2016

Relative Pitch Perception and the Detection of Deviant Tone Patterns.

Adv Exp Med Biol 2016 ;894:409-417

Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.

Most people are able to recognise familiar tunes even when played in a different key. It is assumed that this depends on a general capacity for relative pitch perception; the ability to recognise the pattern of inter-note intervals that characterises the tune. However, when healthy adults are required to detect rare deviant melodic patterns in a sequence of randomly transposed standard patterns they perform close to chance. Musically experienced participants perform better than naïve participants, but even they find the task difficult, despite the fact that musical education includes training in interval recognition.To understand the source of this difficulty we designed an experiment to explore the relative influence of the size of within-pattern intervals and between-pattern transpositions on detecting deviant melodic patterns. We found that task difficulty increases when patterns contain large intervals (5-7 semitones) rather than small intervals (1-3 semitones). While task difficulty increases substantially when transpositions are introduced, the effect of transposition size (large vs small) is weaker. Increasing the range of permissible intervals to be used also makes the task more difficult. Furthermore, providing an initial exact repetition followed by subsequent transpositions does not improve performance. Although musical training correlates with task performance, we find no evidence that violations to musical intervals important in Western music (i.e. the perfect fifth or fourth) are more easily detected. In summary, relative pitch perception does not appear to be conducive to simple explanations based exclusively on invariant physical ratios.
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http://dx.doi.org/10.1007/978-3-319-25474-6_43DOI Listing
September 2016

Physiological response of the cold-water coral Desmophyllum dianthus to thermal stress and ocean acidification.

PeerJ 2016 2;4:e1606. Epub 2016 Feb 2.

Centre for Marine Biodiversity and Biotechnology, Heriot-Watt University , Edinburgh, Scotland , United Kingdom.

Rising temperatures and ocean acidification driven by anthropogenic carbon emissions threaten both tropical and temperate corals. However, the synergistic effect of these stressors on coral physiology is still poorly understood, in particular for cold-water corals. This study assessed changes in key physiological parameters (calcification, respiration and ammonium excretion) of the widespread cold-water coral Desmophyllum dianthus maintained for ∼8 months at two temperatures (ambient 12 °C and elevated 15 °C) and two pCO2 conditions (ambient 390 ppm and elevated 750 ppm). At ambient temperatures no change in instantaneous calcification, respiration or ammonium excretion rates was observed at either pCO2 levels. Conversely, elevated temperature (15 °C) significantly reduced calcification rates, and combined elevated temperature and pCO2 significantly reduced respiration rates. Changes in the ratio of respired oxygen to excreted nitrogen (O:N), which provides information on the main sources of energy being metabolized, indicated a shift from mixed use of protein and carbohydrate/lipid as metabolic substrates under control conditions, to less efficient protein-dominated catabolism under both stressors. Overall, this study shows that the physiology of D. dianthus is more sensitive to thermal than pCO2 stress, and that the predicted combination of rising temperatures and ocean acidification in the coming decades may severely impact this cold-water coral species.
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http://dx.doi.org/10.7717/peerj.1606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741066PMC
February 2016

Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling.

Elife 2015 Jun 30;4:e07091. Epub 2015 Jun 30.

Department of Medicine, University of California, San Diego, San Diego, United States.

Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.
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http://dx.doi.org/10.7554/eLife.07091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484057PMC
June 2015

The cAMP-producing agonist beraprost inhibits human vascular smooth muscle cell migration via exchange protein directly activated by cAMP.

Cardiovasc Res 2015 Sep 19;107(4):546-55. Epub 2015 Jun 19.

School of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK

Aims: During restenosis, vascular smooth muscle cells (VSMCs) migrate from the vascular media to the developing neointima. Preventing VSMC migration is therefore a therapeutic target for restenosis. Drugs, such as prostacyclin analogues, that increase the intracellular concentration of cyclic adenosine monophosphate (cAMP) can inhibit VSMC migration, but the mechanisms via which this occurs are unknown. Two main downstream mediators of cAMP are protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). This study has examined the effects of the prostacyclin analogue beraprost on VSMC migration and investigated the intracellular pathways involved.

Methods And Results: In a chemotaxis chamber, human saphenous vein VSMC migrated towards a platelet-derived growth-factor-BB (PDGF) chemogradient. Incubation with therapeutically relevant concentrations of cAMP-producing agonist beraprost significantly decreased PDGF-induced migration. Direct activation of either PKA or Epac inhibited migration whereas inhibition of PKA did not prevent the anti-migratory effect of beraprost. Direct activation of Epac also prevented hyperplasia in ex vivo serum-treated human veins. Using fluorescence resonance energy transfer, we demonstrated that beraprost activated Epac but not PKA. The mechanisms of this Epac-mediated effect involved activation of Rap1 with subsequent inhibition of RhoA. Cytoskeletal rearrangement at the leading edge of the cell was consequently inhibited. Interestingly, Epac1 was localized to the leading edge of migrating VSMC.

Conclusions: These results indicate that therapeutically relevant concentrations of beraprost can inhibit VSMC migration via a previously unknown mechanism involving the cAMP mediator Epac. This may provide a novel target that could blunt neointimal formation.
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http://dx.doi.org/10.1093/cvr/cvv176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540143PMC
September 2015

ENTREPRENEURSHIP. Linking and leveraging.

Science 2015 Jun;348(6240):1203

Massachusetts Institute of Technology, Cambridge, MA 02139, USA. National Bureau of Economic Research, Cambridge, MA 02138, USA.

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http://dx.doi.org/10.1126/science.aac5843DOI Listing
June 2015

G Protein-Coupled Receptor (GPCR) Expression in Native Cells: "Novel" endoGPCRs as Physiologic Regulators and Therapeutic Targets.

Mol Pharmacol 2015 Jul 3;88(1):181-7. Epub 2015 Mar 3.

Departments of Pharmacology (P.A.I., A.W., A.C.Z., A.N.S., N.A., D.S.M., S.Z., T.M., L.Z., K.S., A.M.C., A.V.M., R.M.L., A.C.O., R.C.) and Medicine (P.A.I., F.M.), University of California, San Diego, La Jolla, California.

G protein-coupled receptors (GPCRs), the largest family of signaling receptors in the human genome, are also the largest class of targets of approved drugs. Are the optimal GPCRs (in terms of efficacy and safety) currently targeted therapeutically? Especially given the large number (∼ 120) of orphan GPCRs (which lack known physiologic agonists), it is likely that previously unrecognized GPCRs, especially orphan receptors, regulate cell function and can be therapeutic targets. Knowledge is limited regarding the diversity and identity of GPCRs that are activated by endogenous ligands and that native cells express. Here, we review approaches to define GPCR expression in tissues and cells and results from studies using these approaches. We identify problems with the available data and suggest future ways to identify and validate the physiologic and therapeutic roles of previously unrecognized GPCRs. We propose that a particularly useful approach to identify functionally important GPCRs with therapeutic potential will be to focus on receptors that show selective increases in expression in diseased cells from patients and experimental animals.
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http://dx.doi.org/10.1124/mol.115.098129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4468643PMC
July 2015

Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma.

Proc Natl Acad Sci U S A 2015 Feb 20;112(5):1529-34. Epub 2015 Jan 20.

Departments of Medicine and

The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c(+) cells (Gnas(ΔCD11c) mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas(ΔCD11c) DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.
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http://dx.doi.org/10.1073/pnas.1417972112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321256PMC
February 2015

GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis.

Nat Commun 2014 Jul 21;5:4451. Epub 2014 Jul 21.

Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA.

Progressive liver fibrosis is characterized by the deposition of collagen by activated hepatic stellate cells (HSCs). Activation of HSCs is a multiple receptor-driven process in which profibrotic signals are enhanced and antifibrotic pathways are suppressed. Here we report the discovery of a signalling platform comprising G protein subunit, Gαi and GIV, its guanine exchange factor (GEF), which serves as a central hub within the fibrogenic signalling network initiated by diverse classes of receptors. GIV is expressed in the liver after fibrogenic injury and is required for HSC activation. Once expressed, GIV enhances the profibrotic (PI3K-Akt-FoxO1 and TGFβ-SMAD) and inhibits the antifibrotic (cAMP-PKA-pCREB) pathways to skew the signalling network in favour of fibrosis, all via activation of Gαi. We also provide evidence that GIV may serve as a biomarker for progression of fibrosis after liver injury and a therapeutic target for arresting and/or reversing HSC activation during liver fibrosis.
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http://dx.doi.org/10.1038/ncomms5451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107319PMC
July 2014

Renal phosphate wasting in the absence of adenylyl cyclase 6.

J Am Soc Nephrol 2014 Dec 22;25(12):2822-34. Epub 2014 May 22.

Department of Medicine, University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California; and

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) enhance phosphate excretion by the proximal tubule of the kidney by retrieval of the sodium-dependent phosphate transporters (Npt2a and Npt2c) from the apical plasma membrane. PTH activates adenylyl cyclase (AC) through PTH 1 receptors and stimulates the cAMP/PKA signaling pathway. However, the precise role and isoform(s) of AC in phosphate homeostasis are not known. We report here that mice lacking AC6 (AC6(-/-)) have increased plasma PTH and FGF-23 levels compared with wild-type (WT) mice but comparable plasma phosphate concentrations. Acute activation of the calcium-sensing receptor or feeding a zero phosphate diet almost completely suppressed plasma PTH levels in both AC6(-/-) and WT mice, indicating a secondary cause for hyperparathyroidism. Pharmacologic blockade of FGF receptors resulted in a comparable increase in plasma phosphate between genotypes, whereas urinary phosphate remained significantly higher in AC6(-/-) mice. Compared with WT mice, AC6(-/-) mice had reduced renal Npt2a and Npt2c protein abundance, with approximately 80% of Npt2a residing in lysosomes. WT mice responded to exogenous PTH with redistribution of Npt2a from proximal tubule microvilli to intracellular compartments and lysosomes alongside a PTH-induced dose-response relationship for fractional phosphate excretion and urinary cAMP excretion. These responses were absent in AC6(-/-) mice. In conclusion, AC6 in the proximal tubule modulates cAMP formation, Npt2a trafficking, and urinary phosphate excretion, which are highlighted by renal phosphate wasting in AC6(-/-) mice.
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http://dx.doi.org/10.1681/ASN.2013101102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4243352PMC
December 2014

Naturally occurring human phosphorylcholine antibodies are predominantly products of affinity-matured B cells in the adult.

J Immunol 2014 May 11;192(10):4551-9. Epub 2014 Apr 11.

Unit of Immunology and Chronic Disease, Institute of Environmental Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden;

Phosphorylcholine (PC) is a classic T-independent Ag that is exposed on apoptotic cells, oxidized phospholipids, and bacterial polysaccharides. Experimental as well as epidemiological studies have over the past decade implicated Abs against PC (anti-PC) as anti-inflammatory and a strong protective factor in cardiovascular disease. Although clinically important, little is known about the development of anti-PC in humans. This study was conceived to dissect the human anti-PC repertoire and generate human mAbs. We designed a PC-specific probe to identify, isolate, and characterize PC-reactive B cells from 10 healthy individuals. The donors had all mounted somatically mutated Abs toward PC using a broad variety of Ig genes. PC-reactive B cells were primarily found in the IgM(+) memory subset, although significant numbers also were detected among naive, IgG(+), and CD27(+)CD43(+) B cells. Abs from these subsets were clonally related, suggesting a common origin. mAbs derived from the same donors exhibited equivalent or higher affinity for PC than the well-characterized murine T-15 clone. These results provide novel insights into the cellular and molecular ontogeny of atheroprotective PC Abs, thereby offering new opportunities for Ab-based therapeutic interventions.
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http://dx.doi.org/10.4049/jimmunol.1303035DOI Listing
May 2014

Investors prefer entrepreneurial ventures pitched by attractive men.

Proc Natl Acad Sci U S A 2014 Mar 10;111(12):4427-31. Epub 2014 Mar 10.

Harvard Business School, Harvard University, Boston, MA 02163.

Entrepreneurship is a central path to job creation, economic growth, and prosperity. In the earliest stages of start-up business creation, the matching of entrepreneurial ventures to investors is critically important. The entrepreneur's business proposition and previous experience are regarded as the main criteria for investment decisions. Our research, however, documents other critical criteria that investors use to make these decisions: the gender and physical attractiveness of the entrepreneurs themselves. Across a field setting (three entrepreneurial pitch competitions in the United States) and two experiments, we identify a profound and consistent gender gap in entrepreneur persuasiveness. Investors prefer pitches presented by male entrepreneurs compared with pitches made by female entrepreneurs, even when the content of the pitch is the same. This effect is moderated by male physical attractiveness: attractive males were particularly persuasive, whereas physical attractiveness did not matter among female entrepreneurs.
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http://dx.doi.org/10.1073/pnas.1321202111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970475PMC
March 2014

Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome.

Blood 2013 Oct 4;122(15):2673-82. Epub 2013 Sep 4.

Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland;

Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions.
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http://dx.doi.org/10.1182/blood-2013-03-489518DOI Listing
October 2013

Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome.

Hum Mol Genet 2013 Nov 25;22(22):4502-15. Epub 2013 Jun 25.

Department of Pediatrics, Division of Genetics/Rady Children's Hospital and.

Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS.
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http://dx.doi.org/10.1093/hmg/ddt298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3888132PMC
November 2013

HPRT-deficiency dysregulates cAMP-PKA signaling and phosphodiesterase 10A expression: mechanistic insight and potential target for Lesch-Nyhan Disease?

PLoS One 2013 14;8(5):e63333. Epub 2013 May 14.

Department of Pediatrics, Division of Genetics, University of California San Diego, School of Medicine, La Jolla, California, USA.

Lesch-Nyhan Disease (LND) is the result of mutations in the X-linked gene encoding the purine metabolic enzyme, hypoxanthine guanine phosphoribosyl transferase (HPRT). LND gives rise to severe neurological anomalies including mental retardation, dystonia, chorea, pyramidal signs and a compulsive and aggressive behavior to self injure. The neurological phenotype in LND has been shown to reflect aberrant dopaminergic signaling in the basal ganglia, however there are little data correlating the defect in purine metabolism to the neural-related abnormalities. In the present studies, we find that HPRT-deficient neuronal cell lines have reduced CREB (cAMP response element-binding protein) expression and intracellular cyclic AMP (cAMP), which correlates with attenuated CREB-dependent transcriptional activity and a reduced phosphorylation of protein kinase A (PKA) substrates such as synapsin (p-syn I). Of interest, we found increased expression of phosphodiesterase 10A (PDE10A) in HPRT-deficient cell lines and that the PDE10 inhibitor papaverine and PDE10A siRNA restored cAMP/PKA signaling. Furthermore, reconstitution of HPRT expression in mutant cells partly increased cAMP signaling synapsin phosphorylation. In conclusion, our data show that HPRT-deficiency alters cAMP/PKA signaling pathway, which is in part due to the increased of PDE10A expression and activity. These findings suggest a mechanistic insight into the possible causes of LND and highlight PDE10A as a possible therapeutic target for this intractable neurological disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653951PMC
December 2013

Targeting cAMP in chronic lymphocytic leukemia: a pathway-dependent approach for the treatment of leukemia and lymphoma.

Expert Opin Ther Targets 2013 Aug 7;17(8):937-49. Epub 2013 May 7.

University of California San Diego, Department of Pharmacology, La Jolla, CA 92093, USA.

Introduction: Cyclic AMP (cAMP) promotes growth arrest and/or apoptosis of various types of lymphoma, in particular chronic lymphocytic leukemia (CLL). These responses have spurred the interest in developing agents that increase cAMP to treat such malignancies and to identify mechanisms of the responses.

Areas Covered: The murine T-lymphoma cell line S49, has provided an important, pioneering model to define mechanisms of cAMP-mediated lymphoid cell death. Studies with S49 cells demonstrated that cAMP, acting via protein kinase A (PKA), is pro-apoptotic through a mitochondria-dependent pathway and identified cAMP/PKA-regulated targets involved in apoptosis. Akin to such findings, cAMP promotes apoptosis via PKA of cells from patients with CLL. Analysis of mediators of cAMP accumulation and cAMP-promoted apoptosis in CLL cells has revealed approaches to increase cAMP and engage its pro-apoptotic action.

Expert Opinion: This 'pathway approach' targeted to cAMP has identified GPCR agonists/antagonists, AC activators (e.g., AC7), PDE inhibitors (e.g., PDE7B) and/or activators or inhibitors of downstream mediators (PKA and Epac, respectively), which might be utilized therapeutically in CLL. Therapy directed at such targets may prove to be clinically useful and may also provide a proof-of-principle of the utility of targeting cAMP signaling in other types of cancer.
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http://dx.doi.org/10.1517/14728222.2013.798304DOI Listing
August 2013

Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition.

J Exp Med 2013 Mar 25;210(3):445-55. Epub 2013 Feb 25.

Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-171 76 Solna, Stockholm, Sweden.

Antibodies targeting citrullinated proteins (ACPAs [anticitrullinated protein antibodies]) are commonly found in patients with rheumatoid arthritis (RA), strongly associate with distinct HLA-DR alleles, and predict a more aggressive disease course as compared with seronegative patients. Still, many features of these antibodies, including their site of production and the extent of MHC class II-driven T cell help, remain unclarified. To address these questions, we have used a single B cell-based cloning technology to isolate and express immunoglobulin (Ig) genes from joint-derived B cells of active RA patients. We found ∼25% of synovial IgG-expressing B cells to be specific for citrullinated autoantigens in the investigated ACPA(+) RA patients, whereas such antibodies were not found in ACPA(-) patients. The citrulline-reactive monoclonal antibodies did not react with the unmodified arginine peptides, yet several reacted with more than one citrullinated antigen. A role for active antigen selection of the citrulline-reactive synovial B cells was supported by the strong bias toward amino acid replacement mutations in ACPA(+) antibodies and by their loss of reactivity to citrullinated autoantigens when somatic mutations were reverted to the corresponding germline sequences.
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http://dx.doi.org/10.1084/jem.20121486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3600900PMC
March 2013

Consequences of a simulated rapid ocean acidification event for benthic ecosystem processes and functions.

Mar Pollut Bull 2013 Aug 6;73(2):435-42. Epub 2012 Dec 6.

Oceanlab, University of Aberdeen, Main Street, Newburgh, Aberdeenshire AB41 6AA, UK. Electronic address:

Whilst the biological consequences of long-term, gradual changes in acidity associated with the oceanic uptake of atmospheric carbon dioxide (CO2) are increasingly studied, the potential effects of rapid acidification associated with a failure of sub-seabed carbon storage infrastructure have received less attention. This study investigates the effects of severe short-term (8days) exposure to acidified seawater on infaunal mediation of ecosystem processes (bioirrigation and sediment particle redistribution) and functioning (nutrient concentrations). Following acidification, individuals of Amphiura filiformis exhibited emergent behaviour typical of a stress response, which resulted in altered bioturbation, but limited changes in nutrient cycling. Under acidified conditions, A. filiformis moved to shallower depths within the sediment and the variability in occupancy depth reduced considerably. This study indicated that rapid acidification events may not be lethal to benthic invertebrates, but may result in behavioural changes that could have longer-term implications for species survival, ecosystem structure and functioning.
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http://dx.doi.org/10.1016/j.marpolbul.2012.11.023DOI Listing
August 2013