Faculty Bibliography

Alterations in the metabolic control of lipid and glucose homeostasis predispose an individual to develop cardiometabolic diseases, such as type 2-diabetes mellitus and atherosclerosis. Work over the last years has suggested that microRNAs (miRNAs) play an important role in regulating these physiological processes. The contribution of miRNAs in regulating metabolism is exemplified by miR-33, an intronic miRNA encoded in the Srebp genes. miR-33 controls cellular cholesterol export and fatty acid degradation, whereas its host genes stimulate cholesterol and fatty acid synthesis. Other miRNAs, such as miR-122, also play a critical role in regulating lipid homeostasis by controlling cholesterol synthesis and lipoprotein secretion in the liver. This review article summarizes the recent findings in the field, highlighting the contribution of miRNAs in regulating lipid and glucose metabolism. We will also discuss how the modulation of specific miRNAs may be a promising strategy to treat metabolic diseases.

Introduction: Increasing evidence suggests that the ratio of number of nodes harboring metastatic cancer to the total number of lymph node examined (lymph node ratio, LNR) affects survival after pancreatic resection for adenocarcinoma. We reviewed impact of lymph node status and LNR in our population of patients undergoing pancreatic resection for adenocarcinomMa.e thods: From our institutional pancreatic adenocarcinoma database, we identified 273 patients who underwent pancreatectomy during the period 1990-2011. of those, 51 had no nodes harvested in the specimen (No LN) and 86 had negative nodes (N0). Among those with positive nodes LNR wa<=s 0.1 in 27, <= 0.2 in 30, <= 0.3 in 21, <= 0.4 in 18 and > 0.4 in 40. Overall median survival was the study end point. Results: The 7 groups were similar in terms of gender, age, ECOG, primary procedure, and status of resection margins (see Table 1). T stage was higher in patients with elevated LNR (p=0.02). Survival was lower for patients with positive nodes (p < 0.01). This difference remained significant when excluding from analysis patients without harvested nodes (p = 0.005). Patient with LNR <= 0.1 had survival similar to N0 patients (20.1 vs. 20.0, p = 0.09). We observed a trend toward a worse survival in patients with higher LNR, which did not reach statistical significanCcoen. clusions: In our experience patients with LNR < 0.1 appeared to have survival similar to those with negative nodes. However LNR did not improve survival prognostication across patients with positive nodes. (Table Presented)

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates organismal growth in response to many environmental cues, including nutrients and growth factors. Cell-based studies showed that mTORC1 senses amino acids through the RagA-D family of GTPases (also known as RRAGA, B, C and D), but their importance in mammalian physiology is unknown. Here we generate knock-in mice that express a constitutively active form of RagA (RagA(GTP)) from its endogenous promoter. RagA(GTP/GTP) mice develop normally, but fail to survive postnatal day 1. When delivered by Caesarean section, fasted RagA(GTP/GTP) neonates die almost twice as rapidly as wild-type littermates. Within an hour of birth, wild-type neonates strongly inhibit mTORC1, which coincides with profound hypoglycaemia and a decrease in plasma amino-acid concentrations. In contrast, mTORC1 inhibition does not occur in RagA(GTP/GTP) neonates, despite identical reductions in blood nutrient amounts. With prolonged fasting, wild-type neonates recover their plasma glucose concentrations, but RagA(GTP/GTP) mice remain hypoglycaemic until death, despite using glycogen at a faster rate. The glucose homeostasis defect correlates with the inability of fasted RagA(GTP/GTP) neonates to trigger autophagy and produce amino acids for de novo glucose production. Because profound hypoglycaemia does not inhibit mTORC1 in RagA(GTP/GTP) neonates, we considered the possibility that the Rag pathway signals glucose as well as amino-acid sufficiency to mTORC1. Indeed, mTORC1 is resistant to glucose deprivation in RagA(GTP/GTP) fibroblasts, and glucose, like amino acids, controls its recruitment to the lysosomal surface, the site of mTORC1 activation. Thus, the Rag GTPases signal glucose and amino-acid concentrations to mTORC1, and have an unexpectedly key role in neonates in autophagy induction and thus nutrient homeostasis and viability.

BACKGROUND: Seventy-five million people are estimated to be hypertensive in sub-Saharan Africa. This translates in high morbidity and mortality, as hypertension is now considered to be the number one single risk factor for death worldwide. Accurate data from countries lacking national disease surveillance is needed to guide future evidence-driven health policies. The authors aimed to estimate the prevalence, awareness, management and control of hypertension and associated factors in an adult population of Angola. METHODS: A community-based survey of 1,464 adults, following the World Health Organization's Stepwise Approach to Chronic Disease Risk Factor Surveillance, was conducted to estimate the prevalence of hypertension, awareness, treatment and control in Dande, Northern Angola. Using a demographic surveillance system database, a representative sample of subjects, stratified by sex and age (18-40 and 41-64 years old), was selected. RESULTS: Prevalence of hypertension (systolic blood pressure >/=140 mmHg and/or diastolic blood pressure >/=90 mmHg and/or hypertensive therapy) was of 23% (95% CI: 21% to 25.2%). A follow-up consultation confirmed the hypertensive status in 82% of the subjects who had a second measurement on average 23 days after the first. Amongst hypertensive individuals, 21.6% (95% CI: 17.0% to 26.9%) were aware of their status. Only 13.9% (95% CI: 5.9% to 29.1%) of the subjects aware of their condition were under pharmacological treatment, of which approximately one-third were controlled. Older age, lower level of education, higher body mass index and abdominal obesity were found to be significantly (p<0.01) associated with hypertension. CONCLUSIONS: Our survey is the first to provide insightful data on hypertension prevalence in Angola. There is an urgent need for strategies to improve prevention, diagnosis and access to adequate treatment in this country, where a massive economic growth and consequent potential impact on lifestyle risk factors could lead to an increase in the prevalence of hypertension and cardiovascular disease.

Sphingosine-1-phosphate (S1P) binds G-protein coupled S1pr1-5 receptors to regulate a multitude of physiological effects, especially those in the vascular and immune systems. S1P receptors in the vascular system have been characterized primarily in mammals. Here we report that the S1P receptors and metabolic enzymes are conserved in the genome of zebrafish Danio rerio. Bioinformatic analysis identified seven S1P receptor-like sequences in the zebrafish genome, including duplicated orthologs of receptors 3 and 5. Sphingolipidomic analysis detected erythrocyte and plasma S1P as well as high plasma ceramides and sphingosine. Morpholino-mediated knockdown of s1pr1 causes global and pericardial edema, loss of blood circulation, and vascular defects characterized by both reduced vascularization in intersegmental vessels, decreased proliferation of intersegmental and axial vessels, and hypersprouting in the caudal vein plexus. The s1pr2 gene was previously characterized as a regulator of cell migration and heart development but its role in angiogenesis is not known. However, when expression of both s1pr1 and s1pr2 is suppressed, severely reduced vascular development of the intersegmental vessels was observed with doses of the s1pr1 morpholino that alone did not cause any discernible vascular defects, suggesting that s1pr1 and s1pr2 function cooperatively to regulate vascular development in zebrafish. Similarly, the S1P transporter, spns2, also cooperated with s1pr1. We propose that extracellular S1P acts through vascular S1P receptors to regulate vascular development.

Benjamin Franklin, mostly known for his participation in writing The Declaration of Independence and work on electricity, was also one of the first scientists to seek to understand the properties of oil monolayers on water surfaces. During one of his many voyages across the Atlantic Ocean, Franklin observed that oil had a calming effect on waves when poured into rough ocean waters. Though at first taking a backseat to many of his other scientific and political endeavors, Franklin went on to experiment with oil, spreading monomolecular films on various bodies of water, and ultimately devised a concept of particle repulsion that is indirectly related to the hydrophobic effect. His early observations inspired others to measure the dimensions of oil monolayers, which eventually led to the formulation of the contemporary lipid bilayer model of the cell membrane.

PURPOSE: Muller glia respond to retinal injury by a reactive gliosis, but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the nonmammalian retina, however, Muller glia act as stem/progenitor cells. Here, we tested the function of Wnt signaling in the postinjury retina, focusing on its ability to influence mammalian Muller cell dedifferentiation, proliferation, and neurogenesis. METHODS: A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (ND:YAG) laser was used to create light burns on the retina of Axin2(LacZ/+) Wnt reporter mice. At various time points after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries also were created in Axin2(LacZ/LacZ) mice, and the effect of potentiated Wnt signaling on retinal repair was assessed. RESULTS: A subpopulation of mammalian Muller cells are Wnt responsive and, when Wnt signaling is increased, these cells showed enhanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of the Wnt negative regulator Axin2, Muller cells proliferated after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Muller cells also exhibited long-term survival and, in some cases, expressed the rod photoreceptor marker, rhodopsin. CONCLUSIONS: The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Muller cells to proliferate and dedifferentiate into RPCs. These data raised the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.