Statins and metabolism of high density lipoprotein

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis. Statins are widely and successfully used for lowering plasma cholesterol levels causing up to 45% reduction of plasma cholesterol and considerable reduction in risk of cardiovascular diseases. The main atheroprotective action of statins is reduction of plasma low density lipoprotein levels due to improved clearance of this lipoprotein by the liver. In addition, statins cause mild elevation of high density lipoprotein (HDL) concentration, but the mechanism responsible for this effect of statins on HDL metabolism is not well understood. It has been hypothesized that statins affect the HDL level through inhibition of cholesteryl ester transfer protein activity or by stimulating apolipoprotein A-I synthesis. Increased cholesterol efflux from liver due to raised expression of the ABCA1 transporter may also elevate HDL levels. Whereas raising the plasma HDL-C concentration may contribute to the atheroprotective effect of statins, its magnitude is uncertain and additional mechanisms that improve the functionality of HDL may be equally or more important. In this review we analyze what is currently known about effect of statins on HDL metabolism and on reverse cholesterol transport in particular.     

18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values (<1 ng/mL) after radical prostatectomy

OBJECTIVES: To assess the value of positron emission tomography (PET)/computed tomography (CT) with either (18)F-choline and/or (11)C-acetate, of residual or recurrent tumour after radical prostatectomy (RP) in patients with a prostate-specific antigen (PSA) level of <1 ng/mL and referred for adjuvant or salvage radiotherapy. PATIENTS AND METHODS: In all, 22 PET/CT studies were performed, 11 with (18)F-choline (group A) and 11 with (11)C-acetate (group B), in 20 consecutive patients (two undergoing PET/CT scans with both tracers). The median (range) PSA level before PET/CT was 0.33 (0.08-0.76) ng/mL. Endorectal-coil magnetic resonance imaging (MRI) was used in 18 patients. Nineteen patients were eligible for evaluation of biochemical response after salvage radiotherapy. RESULTS: There was abnormal local tracer uptake in five and six patients in group A and B, respectively. Except for a single positive obturator lymph node, there was no other site of metastasis. In the two patients evaluated with both tracers there was no pathological uptake. Endorectal MRI was locally positive in 15 of 18 patients; 12 of 19 responded with a marked decrease in PSA level (half or more from baseline) 6 months after salvage radiotherapy. CONCLUSIONS: Although (18)F-choline and (11)C-acetate PET/CT studies succeeded in detecting local residual or recurrent disease in about half the patients with PSA levels of <1 ng/mL after RP, these studies cannot yet be recommended as a standard diagnostic tool for early relapse or suspicion of subclinical minimally persistent disease after surgery. Endorectal MRI might be more helpful, especially in patients with a low likelihood of distant metastases. Nevertheless, further research with (18)F-choline and/or (11)C-acetate PET with optimal spatial resolution might be needed for patients with a high risk of distant relapse after RP even at low PSA values.     

RING domain-mediated interaction is a requirement for MDM2's E3 ligase activity

The RING domain of MDM2 that is essential for its E3 ligase activity mediates binding to itself and its structural homologue MDMX. Whereas it has been reported that RING domain interactions are critical, it is not well understood how they affect the E3 ligase activity of MDM2. We report that the E3 ligase activity requires the RING domain-dependent complex formation. In vivo, MDM2 and MDMX hetero-RING complexes are the predominant form versus the MDM2 homo-RING complex. Importantly, the MDM2/MDMX hetero-RING complexes exhibit a greater E3 ligase activity than the MDM2 homo-RING complexes. Disruption of the binding between MDM2 and MDMX resulted in a marked increase in both abundance and activity of p53, emphasizing the functional importance of this heterocomplex in p53 control.     

Non-blinking and photostable upconverted luminescence from single lanthanide-doped nanocrystals

The development of probes for single-molecule imaging has dramatically facilitated the study of individual molecules in cells and other complex environments. Single-molecule probes ideally exhibit good brightness, uninterrupted emission, resistance to photobleaching, and minimal spectral overlap with cellular autofluorescence. However, most single-molecule probes are imperfect in several of these aspects, and none have been shown to possess all of these characteristics. Here we show that individual lanthanide-doped upconverting nanoparticles (UCNPs)—specifically, hexagonal phase NaYF₄ (β-NaYF₄) nanocrystals with multiple Yb³⁺ and Er³⁺ dopants—emit bright anti-Stokes visible upconverted luminescence with exceptional photostability when excited by a 980-nm continuous wave laser. Individual UCNPs exhibit no on/off emission behavior, or “blinking,” down to the millisecond timescale, and no loss of intensity following an hour of continuous excitation. Amphiphilic polymer coatings permit the transfer of hydrophobic UCNPs into water, resulting in individual water-soluble nanoparticles with undiminished photophysical characteristics. These UCNPs are endocytosed by cells and show strong upconverted luminescence, with no measurable anti-Stokes background autofluorescence, suggesting that UCNPs are ideally suited for single-molecule imaging experiments.     

Neuropsychologic assessment of frontal lobe dysfunction.

Given the pervasive nature of executive deficit, assessment of executive functions is of crucial importance in neuropsychiatry, child and adolescent psychiatry, geriatric psychiatry, and other related areas. A number of neuropsychologic tests of executive function commonly are used in assessing several clinical disorders, including but not limited to traumatic brain injury, schizophrenia, depression, attention deficit disorder/attention deficit hyperactivity disorder, and dementia. Because the concept of executive control in its current form constitutes an over arching construct, a construct that is based on the cognitive symptoms of the frontal lobe disorder caused by many disparate underlying conditions, no single measure of executive function can adequately tap the construct in its entirety.Therefore, it is necessary to administer several tests of executive function,each assessing a particular aspect of the executive function. An appropriate combination of such neuropsychologic tests and batteries, including the Wisconsin Card Sorting Test, Tower test, Stroop test, the D-KEFS, and the ECB, provides an adequate but relatively crude mechanism for assessing executive systems dysfunction. Neuroscientists continue to refine their understanding of the nature of executive control, and additional innovative procedures that reflect state-of-the-art insights of cognitive neuroscience have been introduced recently. Among a few first steps in that direction are nonveridical, actor-centered procedures such as the CBT and the Iowa Gambling Test.     

The mode and tempo of genome size evolution in eukaryotes

Eukaryotic genome size varies over five orders of magnitude; however, the distribution is strongly skewed toward small values. Genome size is highly correlated to a number of phenotypic traits, suggesting that the relative lack of large genomes in eukaryotes is due to selective removal. Using phylogenetic contrasts, we show that the rate of genome size evolution is proportional to genome size, with the fastest rates occurring in the largest genomes. This trend is evident across the 20 major eukaryotic clades analyzed, indicating that over long time scales, proportional change is the dominant and universal mode of genome-size evolution in eukaryotes. Our results reveal that the evolution of eukaryotic genome size can be described by a simple proportional model of evolution. This model explains the skewed distribution of eukaryotic genome sizes without invoking strong selection against large genomes.     

Magnetic resonance imaging and spectroscopy of transgenic models of cancer

The complexity of cancer, where a single genetic alteration can have multiple functional effects, makes it a fascinating but humbling disease to study, and the necessity of investigating it in its entirety is more imperative than ever before. Advances in transgene technology have made it possible to create cancer cells, or mice with specific genetic alterations, and the application of an array of both functional and molecular non-invasive MR methods to these transgenic cancer cells and mice to characterize their phenotypic traits is revolutionizing our understanding of cancer. With the establishment of multi-modality molecular imaging centers within barrier or pathogen-free facilities, multi-parametric and multi-modality imaging of transgenic mouse models of human cancer are becoming increasingly prevalent. In this review, we outline some of the methods currently available for generating transgenic mice and cancer cell lines. We also present examples of the application of MR methods to transgenic models that are providing novel insights into the molecular and functional characteristics of cancer and are leading to an era of "non-invasive phenotyping" of the effects of specific molecular alterations in cancer.     

BORIS,a novel male germ-line-specific protein associated with epigenetic reprogramming events,shares the same 11-zinc-finger domain with CTCF,the insulator protein involved in reading imprinting marks in the soma

CTCF, a conserved, ubiquitous, and highly versatile 11-zinc-finger factor involved in various aspects of gene regulation, forms methylation-sensitive insulators that regulate X chromosome inactivation and expression of imprinted genes. We document here the existence of a paralogous gene with the same exons encoding the 11-zinc-finger domain as mammalian CTCF genes and thus the same DNA-binding potential, but with distinct amino and carboxy termini. We named this gene BORIS for Brother of the Regulator of Imprinted Sites. BORIS is present only in the testis, and expressed in a mutually exclusive manner with CTCF during male germ cell development. We show here that erasure of methylation marks during male germ-line development is associated with dramatic up-regulation of BORIS and down-regulation of CTCF expression. Because BORIS bears the same DNA-binding domain that CTCF employs for recognition of methylation marks in soma, BORIS is a candidate protein for the elusive epigenetic reprogramming factor acting in the male germ line.     

A SAMHD1 mutation associated with Aicardi–Goutières syndrome uncouples the ability of SAMHD1 to restrict HIV‐1 from its ability to downmodulate type I interferon in humans

Mutations in the human SAMHD1 gene are known to correlate with the development of the Aicardi–Goutières syndrome (AGS), which is an inflammatory encephalopathy that exhibits neurological dysfunction characterized by increased production of type I interferon (IFN); this evidence has led to the concept that the SAMHD1 protein negatively regulates the type I IFN response. Additionally, the SAMHD1 protein has been shown to prevent efficient HIV‐1 infection of macrophages, dendritic cells, and resting CD4+ T cells. To gain insights on the SAMHD1 molecular determinants that are responsible for the deregulated production of type I IFN, we explored the biochemical, cellular, and antiviral properties of human SAMHD1 mutants known to correlate with the development of AGS. Most of the studied SAMHD1 AGS mutants exhibit defects in the ability to oligomerize, decrease the levels of cellular deoxynucleotide triphosphates in human cells, localize exclusively to the nucleus, and restrict HIV‐1 infection. At least half of the tested variants preserved the ability to be degraded by the lentiviral protein Vpx, and all of them interacted with RNA. Our investigations revealed that the SAMHD1 AGS variant p.G209S preserve all tested biochemical, cellular, and antiviral properties, suggesting that this residue is a determinant for the ability of SAMHD1 to negatively regulate the type I IFN response in human patients with AGS. Overall, our work genetically separated the ability of SAMHD1 to negatively regulate the type I IFN response from its ability to restrict HIV‐1.