Analysis of western lowland gorilla (Gorilla gorilla gorilla) specific Alu repeats

Abstract Background Research into great ape genomes has revealed widely divergent activity levels over time for Alu elements. However, the diversity of this mobile element family in the genome of the western lowland gorilla has previously been uncharacterized. Alu elements are primate-specific short interspersed elements that have been used as phylogenetic and population genetic markers for more than two decades. Alu elements are present at high copy number in the genomes of all primates surveyed thus far. The AluY subfamily and its derivatives have been recognized as the evolutionarily youngest Alu subfamily in the Old World primate lineage. Results Here we use a combination of computational and wet-bench laboratory methods to assess and catalog AluY subfamily activity level and composition in the western lowland gorilla genome (gorGor3.1). A total of 1,075 independent AluY insertions were identified and computationally divided into 10 subfamilies, with the largest number of gorilla-specific elements assigned to the canonical AluY subfamily. Conclusions The retrotransposition activity level appears to be significantly lower than that seen in the human and chimpanzee lineages, while higher than that seen in orangutan genomes, indicative of differential Alu amplification in the western lowland gorilla lineage as compared to other Homininae.http://deepblue.lib.umich.edu/bitstream/2027.42/112762/1/13100_2013_Article_86.pd

Analysis of western lowland gorilla (Gorilla gorilla gorilla) specific Alu repeats

Background: Research into great ape genomes has revealed widely divergent activity levels over time for Alu elements. However, the diversity of this mobile element family in the genome of the western lowland gorilla has previously been uncharacterized. Alu elements are primate-specific short interspersed elements that have been used as phylogenetic and population genetic markers for more than two decades. Alu elements are present at high copy number in the genomes of all primates surveyed thus far. The AluY subfamily and its derivatives have been recognized as the evolutionarily youngest Alu subfamily in the Old World primate lineage. Results: Here we use a combination of computational and wet-bench laboratory methods to assess and catalog AluY subfamily activity level and composition in the western lowland gorilla genome (gorGor3.1). A total of 1,075 independent AluY insertions were identified and computationally divided into 10 subfamilies, with the largest number of gorilla-specific elements assigned to the canonical AluY subfamily. Conclusions: The retrotransposition activity level appears to be significantly lower than that seen in the human and chimpanzee lineages, while higher than that seen in orangutan genomes, indicative of differential Alu amplification in the western lowland gorilla lineage as compared to other Homininae. © 2013 McLain et al.; licensee BioMed Central Ltd

An alu-based phylogeny of gibbons (hylobatidae)

Gibbons (Hylobatidae) are small, arboreal apes indigenous to Southeast Asia that diverged from other apes ∼15-18 Ma. Extant lineages radiated rapidly 6-10 Ma and are organized into four genera (Hylobates, Hoolock, Symphalangus, and Nomascus) consisting of 12-19 species. The use of short interspersed elements (SINEs) as phylogenetic markers has seen recent popularity due to several desirable characteristics: the ancestral state of a locus is known to be the absence of an element, rare potentially homoplasious events are relatively easy to resolve, and samples can be quickly and inexpensively genotyped. During radiation of primates, one particular family of SINEs, the Alu family, has proliferated in primate genomes. Nomascus leucogenys (northern white-cheeked gibbon) sequences were analyzed for repetitive content with RepeatMasker using a custom library. The sequences containing Alu elements identified as members of a gibbon-specific subfamily were then compared with orthologous positions in other primate genomes. A primate phylogenetic panel consisting of 18 primate species, including 13 gibbon species representing all four extant genera, was assayed for all loci, and a total of 125 gibbon-specific Alu insertions were identified. The resulting amplification patterns were used to generate a phylogenetic tree. We demonstrate significant support for Symphalangus as the most basal lineage within the family. Our findings also place Nomascus as a derived lineage, sister to Hoolock, with the Nomascus-Hoolock clade sister to Hylobates. Further, our analysis groups N. leucogenys and Nomascus siki as sister taxa to the exclusion of the other Nomascus species assayed. This study represents the first use of SINEs to determine the genus level phylogenetic relationships within the family Hylobatidae. These relationships have been resolved with robust support at most internal nodes, demonstrating the utility of SINE-based phylogenetic analysis. We postulate that hybridization and rapid radiation may have contributed to the complex and contradictory findings of the previous studies. Our findings will aid in the conservation of these threatened primates and inform future studies of the biogeographical history and distribution of modern gibbon species. © 2012 The Author

Endovascular strategy or open repair for ruptured abdominal aortic aneurysm: one-year outcomes from the IMPROVE randomized trial.

AIMS: To report the longer term outcomes following either a strategy of endovascular repair first or open repair of ruptured abdominal aortic aneurysm, which are necessary for both patient and clinical decision-making. METHODS AND RESULTS: This pragmatic multicentre (29 UK and 1 Canada) trial randomized 613 patients with a clinical diagnosis of ruptured aneurysm; 316 to an endovascular first strategy (if aortic morphology is suitable, open repair if not) and 297 to open repair. The principal 1-year outcome was mortality; secondary outcomes were re-interventions, hospital discharge, health-related quality-of-life (QoL) (EQ-5D), costs, Quality-Adjusted-Life-Years (QALYs), and cost-effectiveness [incremental net benefit (INB)]. At 1 year, all-cause mortality was 41.1% for the endovascular strategy group and 45.1% for the open repair group, odds ratio 0.85 [95% confidence interval (CI) 0.62, 1.17], P = 0.325, with similar re-intervention rates in each group. The endovascular strategy group and open repair groups had average total hospital stays of 17 and 26 days, respectively, P < 0.001. Patients surviving rupture had higher average EQ-5D utility scores in the endovascular strategy vs. open repair groups, mean differences 0.087 (95% CI 0.017, 0.158), 0.068 (95% CI -0.004, 0.140) at 3 and 12 months, respectively. There were indications that QALYs were higher and costs lower for the endovascular first strategy, combining to give an INB of £3877 (95% CI £253, £7408) or €4356 (95% CI €284, €8323). CONCLUSION: An endovascular first strategy for management of ruptured aneurysms does not offer a survival benefit over 1 year but offers patients faster discharge with better QoL and is cost-effective. CLINICAL TRIAL REGISTRATION: ISRCTN 48334791

The effect of aortic morphology on peri-operative mortality of ruptured abdominal aortic aneurysm

Aims To investigate whether aneurysm shape and extent, which indicate whether a patient with ruptured abdominal aortic aneurysm (rAAA) is eligible for endovascular repair (EVAR), influence the outcome of both EVAR and open surgical repair. Methods and results The influence of six morphological parameters (maximum aortic diameter, aneurysm neck diameter, length and conicality, proximal neck angle, and maximum common iliac diameter) on mortality and reinterventions within 30 days was investigated in rAAA patients randomized before morphological assessment in the Immediate Management of the Patient with Rupture: Open Versus Endovascular strategies (IMPROVE) trial. Patients with a proven diagnosis of rAAA, who underwent repair and had their admission computerized tomography scan submitted to the core laboratory, were included. Among 458 patients (364 men, mean age 76 years), who had either EVAR (n = 177) or open repair (n = 281) started, there were 155 deaths and 88 re-interventions within 30 days of randomization analysed according to a pre-specified plan. The mean maximum aortic diameter was 8.6 cm. There were no substantial correlations between the six morphological variables. Aneurysm neck length was shorter in those undergoing open repair (vs. EVAR). Aneurysm neck length (mean 23.3, SD 16.1 mm) was inversely associated with mortality for open repair and overall: adjusted OR 0.72 (95% CI 0.57, 0.92) for each 16 mm (SD) increase in length. There were no convincing associations of morphological parameters with reinterventions. Conclusion Short aneurysm necks adversely influence mortality after open repair of rAAA and preclude conventional EVAR. This may help explain why observational studies, but not randomized trials, have shown an early survival benefit for EVAR. Clinical trial registration: ISRCTN 48334791

The α-ketoglutarate dehydrogenase complex in cancer metabolic plasticity

Deregulated metabolism is a well-established hallmark of cancer. At the hub of various metabolic pathways deeply integrated within mitochondrial functions, the α-ketoglutarate dehydrogenase complex represents a major modulator of electron transport chain activity and tricarboxylic acid cycle (TCA) flux, and is a pivotal enzyme in the metabolic reprogramming following a cancer cell’s change in bioenergetic requirements. By contributing to the control of α-ketoglutarate levels, dynamics, and oxidation state, the α-ketoglutarate dehydrogenase is also essential in modulating the epigenetic landscape of cancer cells. In this review, we will discuss the manifold roles that this TCA enzyme and its substrate play in cancer

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Analysis of western lowland gorilla (Gorilla gorilla gorilla) specific Alu repeats

BACKGROUND: Research into great ape genomes has revealed widely divergent activity levels over time for Alu elements. However, the diversity of this mobile element family in the genome of the western lowland gorilla has previously been uncharacterized. Alu elements are primate-specific short interspersed elements that have been used as phylogenetic and population genetic markers for more than two decades. Alu elements are present at high copy number in the genomes of all primates surveyed thus far. The AluY subfamily and its derivatives have been recognized as the evolutionarily youngest Alu subfamily in the Old World primate lineage. RESULTS: Here we use a combination of computational and wet-bench laboratory methods to assess and catalog AluY subfamily activity level and composition in the western lowland gorilla genome (gorGor3.1). A total of 1,075 independent AluY insertions were identified and computationally divided into 10 subfamilies, with the largest number of gorilla-specific elements assigned to the canonical AluY subfamily. CONCLUSIONS: The retrotransposition activity level appears to be significantly lower than that seen in the human and chimpanzee lineages, while higher than that seen in orangutan genomes, indicative of differential Alu amplification in the western lowland gorilla lineage as compared to other Homininae