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Search Results: 1 - 10 of 32622 matches for " John Macleod "
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Regulation of Villin by Wnt5a/Ror2 Signaling in Human Intestinal Cells
Rebecca Cheung,Jacqueline Kelly,R. John Macleod
Frontiers in Physiology , 2011, DOI: 10.3389/fphys.2011.00058
Abstract: Regulation of expression of the intestinal epithelial actin-binding protein, villin, is poorly understood. The aim of this study was to determine whether Wnt5a stimulates Ror2 in intestinal epithelia caused transient increases in phospho-ERK1/2 (pERK1/2) and subsequently increased expression of villin transcript and protein. To demonstrate Wnt5a–Ror2 regulation of villin expression, we overexpressed wild-type, truncated, or mutant Ror2 constructs in HT29 adenocarcinoma cells and non-transformed fetally derived human intestinal epithelial cells, added conditioned media containing Wnt5a and measured changes in ERK1/2 phosphorylation, villin amplicons, and protein expression by RT-PCR and Western blot techniques. Wnt5a addition caused a transient increase in pERK1/2, which was maximal at 10 min but extinguished by 30 min. Transient transfection with a siRNA duplex against Ror2 diminished Ror2 amplicons and protein and reduced the extent of pERK1/2 activation. Structure–function analysis revealed that the deletion of the cysteine-rich, kringle, or tyrosine kinase domain or substitution mutations of tyrosine residues in the intracellular Ser/Thr-1 region of Ror2 prevented the Wnt5a stimulation of pERK1/2. Deletion of the intracellular proline and serine/threonine-rich regions of Ror2 had no effect on Wnt5a stimulation of pERK1/2. The increase in villin expression was blocked by pharmacological inhibition of MEK-1 and casein kinase 1, but not by PKC and p38 inhibitors. Neither Wnt3a nor epidermal growth factor addition caused increases in villin protein. Our findings suggest that Wnt5a/Ror2 signaling can regulate villin expression in the intestine.
Extracellular Calcium-Sensing Receptor Inhibition of Intestinal EpithelialTNF Signaling Requires CaSR-Mediated Wnt5a/Ror2 Interaction
Jacqueline C. Kelly,R. John MacLeod
Frontiers in Physiology , 2011, DOI: 10.3389/fphys.2011.00017
Abstract: Tumor necrosis factor alpha (TNFα) and its receptor TNFR1 play a central role in the development of colitis-associated colon cancer. To understand a role for the extracellular calcium-sensing receptor (CaSR) and its non-canonical Wnt mediators, Wnt5a/Ror2, we used reductionistic systems. We added lipopolysaccharide (LPS) to mouse peritoneal macrophages, RAW264.7 cells, a murine macrophage cell line, and 18Co colonic myofibroblasts, to stimulate TNFα secretion and then activated endogenous CaSR. CaSR activation inhibited TNFα secretion, which in RAW264.7 cells knockdown of CaSR by short-interfering RNA (siRNA) duplex reversed. LPS-stimulated NFκB promoter activity in RAW264.7 cells was inhibited by CaSR activation with Ca2+ or other polyvalent CaSR agonists. Reducing CaSR expression with siRNA duplex prevented this inhibition. Following LPS addition to CaSR–HEK cells or RAW264.7 macrophages, CaSR stimulation deneddylated Cullin1. Wnt5a added to HT-29 cells which overexpressed Ror2 or T84 monolayers treated with 3 mM Ca2+ reduced TNFR1 protein expression ~70%. TNFα/INFγ addition to high resistance T84 monolayers reduced transepithelial resistance 50% within 4 h. CaSR activation (3 mM Ca2+) together with rhWnt5a (200 ng/ml) prevented this reduction while Wnt3a addition had no effect. LPS-stimulated TNFα secretion from RAW264.7 cells was not effected by rhWnt5a but increased 10-fold by Wnt3a. Together our results suggest that following LPS challenge, CaSR activation will inhibit NFκB activity and reduce TNFα secretion from macrophages and stroma while Wnt5a/Ror2 engagement on intestinal epithelia reduces TNFR1 expression, allowing TNFα signaling to be titrated. Our results also suggest that canonical Wnt signaling may enhance TLR4 stimulation of TNFα secretion from murine macrophages.
Variation in NHS utilisation of vault smear tests in women post-hysterectomy: A study, using routinely collected datasets
Helen J Stokes-Lampard, John Macleod, Sue Wilson
BMC Women's Health , 2008, DOI: 10.1186/1472-6874-8-6
Abstract: All women resident in the West Midlands region, of the United Kingdom, who had a hysterectomy operation between 1st April 2002 and 30th March 2003 will be identified from the Hospital Episodes Statistics database which also contains proxy data on deprivation status, derived from postcode and self declared ethnicity. These data will be linked to regional cervical screening records for each woman and histopathology laboratory records from the relevant hospitals. Study objectives are to describe: Indications for the hysterectomy operation, histology at hysterectomy, subsequent follow-up by use or non-use of vaginal vault cytology tests and variation between histological groups. Additionally the data will be categorised according to a woman's cytology screening history prior to surgery (i.e. always normal, borderline, resolved abnormalities, CIN etc) and these different groups compared. Variations in these outcomes according to age, deprivation and ethnic group will also be examined. Analysis will be undertaken using SPSS.This study will clarify patterns of current practice in one large English region and determine whether this practice reflects existing guidelines. The study will also strengthen the evidence base for future guidelines.National Research Register N0138173331Surgical removal of the uterus (womb) is a 'hysterectomy' operation; over 98% women who have their uterus removed also have the cervix uteri or 'neck' of the uterus removed at the same time, a total hysterectomy[1]. This leaves the vagina as a pouch with a blind end at the site of amputation of the cervix. There were around 39,000 hysterectomy procedures undertaken in the UK in 2005 [2], a cumulative lifetime incidence of 20% [3,4], making it one of the most frequently performed major surgical procedures [5].The most common indication for a hysterectomy is menorrhagia which accounts for 46% of all hysterectomies. Prolapse accounts for a further 20%, and fibroids (or leiomyoma) another 18%–21% [6]; 90%
The Edinburgh Addiction Cohort: recruitment and follow-up of a primary care based sample of injection drug users and non drug-injecting controls
John Macleod, Lorraine Copeland, Matthew Hickman, James McKenzie, Jo Kimber, Daniela De Angelis, James R Robertson
BMC Public Health , 2010, DOI: 10.1186/1471-2458-10-101
Abstract: Individuals thought to be drug injectors were identified through a single primary medical care facility in Edinburgh between 1980 and 2006 and flagged with the General Registry Office. From October 2005 - October 2007, these cases were traced and invited to undergo interview assessment covering early life experience, substance use, health and social histories. Age and sex matched controls for confirmed cases (alive and dead) were later recruited through the same health facility. Controls for living cases completed the same structured interview schedule. Data were also collected on cases and controls through linkage to routine primary care records, death registrations, hospital contact statistics and police and prison records. All interviews were conducted with the knowledge and permission of the current GP.The initial cohort size was 814. At start of follow up 227 had died. Of the remaining 587: 20 had no contact details and 5 had embarked from the UK; 40 declined participation; 38 did not respond to invitations; 14 were excluded by their GP on health or social grounds and 22 had their contact details withheld by administrative authorities. 448 were interviewed of whom 16 denied injection and were excluded. Of 191 dead cases with medical records 4 were excluded as their records contained no evidence of injection. 5 interviewed cases died before follow up was concluded though these individuals were counted as "live" cases. 1 control per case (dead and alive) was recruited. Linkage to Scottish Morbidity Records data (available from 1981 onwards) on general acute inpatient and day cases, mental health inpatient and day cases and cancer was provided by Information Services, NHS Scotland, for all cases interviewed and all dead cases. The Scottish Prison Service provided records for 198 (46%) of cases interviewed, 48 cases not interviewed and 34 (18%) of dead cases. For a sub-sample of 100 interviewees a search of the Lothian and Borders police database was made for offic
Immune mechanisms of protection: can adjuvants rise to the challenge?
Amy S McKee, Megan KL MacLeod, John W Kappler, Philippa Marrack
BMC Biology , 2010, DOI: 10.1186/1741-7007-8-37
Abstract: The immune system is functionally diverse, able to make a refined response to hundreds of different types of infectious organisms. The initiation of an immune response to an infection requires collaboration between innate immune cells, which recognize general distinguishing features of pathogens, and the T lymphocytes of the adaptive immune system, whose highly variable antigen receptors are specific for a given pathogen. The activation of T lymphocytes depends on interactions with professional antigen-presenting cells (APCs), specialized cells of the innate immune system that are directly activated by the pathogens they engulf and regurgitate for presentation to, and activation of, T cells. The T cells then proliferate and are mobilized to protect the body by activating other immune cells or by killing infected cells. Among the immune cells activated by T lymphocytes, most importantly, are the B lymphocytes that produce antibodies. T lymphocytes direct the types of antibodies that B cells produce and the activity of other immune cells, thereby directing the immune response to optimally provide protection against different types of infections.At the end of an immune response, the majority of activated B and T cells will undergo apoptosis, but a small number remain as memory cells, primed ready in case the host is exposed to the same infection [1,2]. Vaccines must work in a similar way, priming antigen-specific T and B cells, some of which convert to the memory cells that will control subsequent infections by the invader targeted by the vaccine. Moreover, like the infection itself, the vaccine must generate the optimal type of immune response to protect against a particular pathogen.The different ways in which the immune system can respond to antigen are schematically summarized in Figure 1, which shows the two major classes of T lymphocyte, cytotoxic (or CD8) cells and helper (or CD4) cells, and their principal actions. For example, virus infections can be cleared b
SDSSJ14584479+3720215: A Benchmark JHK Blazar Light Curve from the 2MASS Calibration Scans
James R. A. Davenport,John J. Ruan,Andrew C. Becker,Chelsea L. Macleod,Roc M. Cutri
Physics , 2015, DOI: 10.1088/0004-637X/803/1/2
Abstract: Active galactic nuclei (AGNs) are well-known to exhibit flux variability across a wide range of wavelength regimes, but the precise origin of the variability at different wavelengths remains unclear. To investigate the relatively unexplored near-IR variability of the most luminous AGNs, we conduct a search for variability using well sampled JHKs-band light curves from the 2MASS survey calibration fields. Our sample includes 27 known quasars with an average of 924 epochs of observation over three years, as well as one spectroscopically confirmed blazar (SDSSJ14584479+3720215) with 1972 epochs of data. This is the best-sampled NIR photometric blazar light curve to date, and it exhibits correlated, stochastic variability that we characterize with continuous auto-regressive moving average (CARMA) models. None of the other 26 known quasars had detectable variability in the 2MASS bands above the photometric uncertainty. A blind search of the 2MASS calibration field light curves for AGN candidates based on fitting CARMA(1,0) models (damped-random walk) uncovered only 7 candidates. All 7 were young stellar objects within the {\rho} Ophiuchus star forming region, five with previous X-ray detections. A significant {\gamma}-ray detection (5{\sigma}) for the known blazar using 4.5 years of Fermi photon data is also found. We suggest that strong NIR variability of blazars, such as seen for SDSSJ14584479+3720215, can be used as an efficient method of identifying previously-unidentified {\gamma}-ray blazars, with low contamination from other AGN.
Hadronic interactions, precocious unification, and cosmic ray showers at Auger energies
Luis Anchordoqui,Haim Goldberg,Jared MacLeod,Tom McCauley,Tom Paul,Steve Reucroft,John Swain
Physics , 2001, DOI: 10.1142/S0217732301003930
Abstract: At Auger energies only model predictions enable us to extract primary cosmic ray features. The simulation of the shower evolution depends sensitively on the first few interactions, necessarily related to the quality of our understanding of high energy hadronic collisions. Distortions of the standard ``soft semi-hard'' scenario include novel large compact dimensions and a string or quantum gravity scale not far above the electroweak scale. Na\"{\i}vely, the additional degrees of freedom yield unification of all forces in the TeV range. In this article we study the influence of such precocious unification during atmospheric cascade developments by analyzing the most relevant observables in proton induced showers.
Hopes, challenges, barriers and enabling factors: the complexities of being an impoverished young father
Catriona Macleod
Psychology in Society , 2011,
Abstract:
The management of terminal delirium
Macleod A
Indian Journal of Palliative Care , 2006,
Abstract: Delirium is a distressing and disturbing clinical event. Palliation of the symptoms by multi-component interventions can be effective. The goal of interventions is to raise the deliriant threshold by combined symptom relief, environmental, psychological and pharmacological interventions. Haloperidol remains the drug of choice for delirium. For intractable delirious symptoms at the end of life terminal sedation may be indicated.
Eyelid closure at death
Macleod A
Indian Journal of Palliative Care , 2009,
Abstract: Aim: To observe the incidence of full or partial eyelid closure at death. Materials and Methods: The presence of ptosis was recorded in 100 consecutive hospice patient deaths. Results: Majority (63%) of the patients died with their eyes fully closed, however, 37% had bilateral ptosis at death, with incomplete eye closure. In this study, central nervous system tumor involvement and/or acute hepatic encephalopathy appeared to be pre-mortem risk factors of bilateral ptosis at death. Conclusion: Organicity and not psychogenicity is, therefore, the likely etiology of failure of full eyelid closure at death.
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