The distribution of basal motion beneath a High Arctic polythermal glacier

Peer reviewed

The distribution of basal motion beneath a High Arctic polythermal glacier

Peer reviewed

Body composition and basal metabolic rate in pre-school children : no sex difference

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A tumoral and invasive phenotype independent of c-Met mutation

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Caractérisation du carcinome mammaire de phénotype basal

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Hydrogen sulphide rescues preeclampsia-like phenotype aggravated by high sFlt-1 in placenta growth factor (PlGF) deficiency

Placenta growth factor (PlGF) deficient mice are fertile at a Mendelian ratio. Interestingly, low maternal plasma levels of PlGF are strongly associated with early onset of preeclampsia, a pregnancy hypertensive disorder characterised by high blood pressure, proteinuria and fetal growth restriction. PlGF is increasingly being recognised as an early diagnostic biomarker, but the physiological importance of PlGF in the pathogenesis of preeclampsia is unknown. We investigated whether the decreased levels of PlGF in pregnancy exacerbate the fetal growth restriction associated with preeclampsia in the presence of high sFlt-1 and the potential of hydrogen sulphide to ameliorate these effects. Pregnant PlGF−/− mice were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) at 1 × 109 pfu/ml at E10.5 and mean arterial blood pressure (MAP), biochemical and histological analysis of maternal kidney, placenta and embryos were assessed at the end of pregnancy. Ad-sFlt-1 significantly increased MAP and induced severe glomerular endotheliosis in PlGF−/− mice compared to wild-type animals. Soluble Flt-1 also significantly elevated albumin–creatinine ratio and increased levels of urinary kidney injury molecule-1, a marker for proximal tubule injury. Furthermore, sFlt-1 over expression increased fetal resorption rate in the PlGF−/− mice and promoted abnormal placental vascularisation. To determine whether placental PlGF is critical for preventing fetal growth restriction associated with preeclampsia, we generated haploinsufficient PlGF+/− placentas and embryos in dams and exposed to high sFlt-1 environment. These mothers showed reduced fetal resorption, gestational hypertension and proteinuria when compared to pregnant PlGF−/− mice. Furthermore, treatment with hydrogen sulphide-releasing agent, GYY4137, significantly reduced resorption, hypertension and proteinuria observed in Ad-sFlt-1 treated pregnant PlGF−/− mice. Our study shows that placental PlGF is a critical protective factor against the damaging effects of high sFlt-1 associated with preeclampsia and activation of the hydrogen sulphide pathway may rescue preeclampsia phenotypes even under low PlGF environment.

The effect of the senescence-associated secretory phenotype (SASP) on glucose homeostasis in metabolic cells

Aim: Dysregulated glucose homeostasis is a hallmark of Type 2diabetes. A distinctive feature of ageing is the accumulation ofsenescent cells, defined as cells that have undergone irreversible lossof proliferative capacity. Characteristic of senescent cells is thesenescence-associated secretory phenotype (SASP) involving theproduction of factors which reinforce senescence arrest in neigh-bouring tissue environments. We hypothesise that SASP inducesmetabolic dysfunction in non-senescent cells, impairing glucosemetabolism and propagating insulin resistance. We sought todetermine the effect of SASP on glucose homeostasis in hepatic,adipose and skeletal muscle cell lines. Methods: Human dermal fibroblasts were subjected to a geno-toxic dose of doxorubicin to induce senescence, confirmed using ab-galactosidase assay. Conditioned media containing SASP werecollected post 24h and 48h of inducing senescence and used at20% and 40% concentrations to treat AML-12 hepatocytes, 3T3-L1 adipocytes and C2C12 myocytes for 24h and 48h. Cells andmedia were collected and glucose and lipid concentrations weremeasured before and after the respective incubation periods. Results: Cell media obtained from C2C12 myocytes exposed to40% SASP for 24h and 48h and AML-12 hepatocytes after 48hexhibited significantly higher concentrations of glucose in com-parison to control media (p < 0.0001, p < 0.05) suggesting areduced glucose uptake. Glucose utilisation remained unchanged in3T3-L1 cells. Conclusion: Our data suggest an important role for SASP inaltering glucose homeostasis and identify SASP as a potentialmediator between ageing and the increase in age-related insulinresistance.

Hydrogen sulphide rescues preeclampsia-like phenotype aggravated by high sFlt-1 in Placenta Growth Factor (PlGF) deficiency

INTRODUCTION: Low circulating levels of placenta growth factor (PlGF) is strongly associated with the onset of preeclampsia, a maternal hypertensive disorder characterized by high blood pressure and proteinuria after 20 weeks of gestation. Although, PlGF-deficient mice are born healthy and fertile at a Mendelian ratio, the physiological importance of PlGF in the pathogenesis of preeclampsia is unclear. We hypothesised that decreased levels of PlGF in pregnancy exacerbates the fetal growth restriction associated with preeclampsia in the presence of high sFlt-1. METHODS: Pregnant PlGF-/- mice were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) at high (i) 1.5x109 pfu/ml and low (ii) 0.5x109 pfu/ml doses. Mean arterial blood pressure (MBP), biochemical and histological assessments of maternal kidney, placenta and embryos were performed. RESULTS: Ad-sFlt-1 significantly increased MBP and induced severe glomerular endotheliosis in PlGF-/- mice at E10.5 gestation compared to wild-type animals. High sFlt-1 also significantly elevated albumincreatinine ratio and increased levels of urinary kidney injury molecule-1, a marker for proximal tubule injury.At a high dose of sFlt-1, there was complete fetal resorption in the pregnant PlGF-/- mice, and even the lower dose of sFlt-1 induced severe fetal resorption and abnormal placental vascularization. Hydrogen sulphide-releasing agent, GYY4137, significantly reduced resorption, hypertension and proteinuria in Ad-sFlt-1 treated pregnant PlGF-/- mice. To determine if placental PlGF is critical for preventing fetal growth restriction associated with preeclampsia, we generated haploinsufficient PlGF+/- placentas and embryos were generated in wild-time dams and exposed to high sFlt-1 environment. This resulted in reduced fetal resorption, gestational hypertension and proteinuria when compared to pregnant PlGF-/- mice. CONCLUSIONS: Placental PlGF is a critical protective factor against the damaging effects of high sFlt-1 in preeclampsia and the hydrogen sulphide pathway may rescue preeclampsia phenotypes.

A Framework to Support the Sharing and Reuse of Computable Phenotype Definitions Across Health Care Delivery and Clinical Research Applications.

INTRODUCTION: The ability to reproducibly identify clinically equivalent patient populations is critical to the vision of learning health care systems that implement and evaluate evidence-based treatments. The use of common or semantically equivalent phenotype definitions across research and health care use cases will support this aim. Currently, there is no single consolidated repository for computable phenotype definitions, making it difficult to find all definitions that already exist, and also hindering the sharing of definitions between user groups. METHOD: Drawing from our experience in an academic medical center that supports a number of multisite research projects and quality improvement studies, we articulate a framework that will support the sharing of phenotype definitions across research and health care use cases, and highlight gaps and areas that need attention and collaborative solutions. FRAMEWORK: An infrastructure for re-using computable phenotype definitions and sharing experience across health care delivery and clinical research applications includes: access to a collection of existing phenotype definitions, information to evaluate their appropriateness for particular applications, a knowledge base of implementation guidance, supporting tools that are user-friendly and intuitive, and a willingness to use them. NEXT STEPS: We encourage prospective researchers and health administrators to re-use existing EHR-based condition definitions where appropriate and share their results with others to support a national culture of learning health care. There are a number of federally funded resources to support these activities, and research sponsors should encourage their use.

Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans.

Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote β-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or β-cell function and neither augments nor antagonizes the effects of AG.

Assessing the immune phenotype of cardiac syndrome x: a prospective study of biomarkers

Cardiac Syndrome X (CSX), the presence of angina pectoris with objective signs of myocardial ischaemia despite angiographically normal epicardial coronary arteries, appears to be due to coronary microvascular dysfunction and is known to be associated with an elevation of several inflammatory biomarkers, suggesting a possible role for inflammation in its pathogenesis. We aimed to further characterise this relationship by prospectively analysing a wide variety of molecular biomarkers in a cohort of CSX patients thereby charting the changes in biomarkers throughout the natural history of CSX from its initial diagnosis to eventual disease quiescence. We found that CSX patients, when compared to healthy controls, have a persistent low-grade systemic inflammatory response characterised by an elevation of Tumour Necrosis Factor and Interferon-gamma, regardless of the presence of contemporaneous signs or symptoms of disease activity. Interleukin-6 and C-reactive Protein (CRP) are only elevated when patients have clinical evidence of disease activity and may be state markers in CSX. Moreover, CRP levels appear to correlate with signals of disease severity such as the time taken to develop symptoms during exercise stress testing. We have also demonstrated that the enzyme Indoleamine-2,3- dioxygenase is upregulated in active disease thus providing a possible explanation for the increased burden of psychological disease encountered in CSX. Analysis of the microRNA transcriptome showed that miR-143 is significantly under-expressed in CSX patients. This could allow phenotype switching in vascular smooth muscle cells with the resultant vascular remodelling causing reduced vessel responsiveness to local rheological stimuli and reduced luminal diameter with consequent increased microvascular resistance during times of increased myocardial oxygen demand, thereby limiting maximal hyperaemia during exercise. Our findings corroborate many previous hypotheses regarding the role of inflammation in CSX, generate new insights into possible pathogenic mechanisms and offer new therapeutic targets for the future management of this important cardiological condition.

A tumoral and invasive phenotype independent of c-Met mutation

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Caractérisation du carcinome mammaire de phénotype basal

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Environmental carbonate chemistry selects for phenotype of recently isolated strains of Emiliania huxleyi

Coccolithophorid algae, particularly Emiliania huxleyi, are prolific biomineralisers that, under many conditions, dominate communities of marine eukaryotic plankton. Their ability to photosynthesise and form calcified scales (coccoliths) has placed them in a unique position in the global carbon cycle. Contrasting reports have been made with regards to the response of E. huxleyi to ocean acidification. Therefore, there is a pressing need to further determine the fate of this key organism in a rising CO2 world. In this paper, we investigate the phenotype of newly isolated, genetically diverse, strains of E. huxleyi from UK Ocean Acidification Research Programme (UKOA) cruises around the British Isles, the Arctic, and the Southern Ocean. We find a continuum of diversity amongst the physiological and photosynthetic parameters of different strains of E. huxleyi morphotype A under uniform, ambient conditions imposed in the laboratory. This physiology is best explained by adaptation to carbonate chemistry in the former habitat rather than being prescribed by genetic fingerprints such as the coccolithophore morphology motif (CMM). To a first order, the photosynthetic capacity of each strain is a function of both aqueous CO2 availability, and calcification rate, suggestive of a link between carbon concentrating ability and calcification. The calcification rate of each strain is related linearly to the natural environmental [CO32−] at the site of isolation, but a few exceptional strains display low calcification rates at the highest [CO32−] when calcification is limited by low CO2 availability and/or a lack of a carbon concentrating mechanism. We present O2-electrode measurements alongside coccolith oxygen isotopic composition and the uronic acid content (UAC) of the coccolith associated polysaccharide (CAP), that act as indirect tools to show the differing carbon concentrating ability of the strains. The environmental selection revealed amongst our recently isolated strain collection points to the future outcompetition of the slow growing morphotypes B/C and R (which also lack a carbon concentrating mechanism) by more rapidly photosynthesising, and lightly calcified strains of morphotype A but with their rate of calcification highly dependent on the surface ocean saturation state. The mechanism of E. huxleyi response to carbonate chemistry in the modern ocean appears to be selection from a continuum of phenotype.