Global down-regulation of HOX gene expression in PML-RAR alpha(+) acute promyelocytic leukemia identified by small-array real-time PCR

Acute promyelocytic leukemia (APL) is associated with a reciprocal and balanced translocation involving the retinoic acid receptor-alpha (RARalpha). All-trans retinoic acid (ATRA) is used to treat APL and is a potent morphogen that regulates HOX gene expression in embryogenesis and organogenesis. HOX genes are also involved in hematopoiesis and leukemogenesis. Thirty-nine mammalian HOX genes have been identified and classified into 13 paralogous groups clustered on 4 chromosomes. They encode a complex net-Work of transcription regulatory proteins whose precise targets remain poorly understood. The overall function of the network appears to be dictated by gene dosage. To investigate the mechanisms involved in HOX gene regulation in hematopoiesis and leukemogenesis by precise measurement of individual HOX genes, a small-array real-time HOX (SMART-HOX) quantitative polymerase chain reaction (PCR) platform was designed and validated. Application of SMART-HOX to 16 APL bone marrow samples revealed a global down-regulation of 26 HOX genes compared with normal controls. HOX gene expression was also altered during differentiation induced by ATRA in the PML-RARalpha(+) NB4 cell line. PML-RARalpha, fusion proteins have been reported to act as part of a repressor complex during myelold cell differentiation, and a model linking HOX gene expression to this PML-RARalpha repressor complex is now proposed.

Correlation Between the Electrical and Optical Properties of an Atmospheric Pressure Plasma During Siloxane Coating Deposition

The effect of varying process parameters on atmospheric plasma characteristics and properties of nanometre thick siloxane coatings is investigated in a reel-to-reel deposition process. Varying plasma operation modes were observed with increasing applied power for helium and helium/oxygen plasmas. The electrical and optical behaviour of the dielectric barrier discharge were determined from current/voltage, emission spectroscopy and time resolved light emission measurements. As applied power increased, multiple discharge events occurred, producing a uniform multi-peak pseudoglow discharge, resulting in an increase in the discharge gas temperature. The effects of different operating modes on coating oxidation and growth rates were examined by injecting hexamethyldisiloxane liquid precursor into the chamber under varying operating conditions. A quenching effect on the plasma was observed, causing a decrease in plasma input power and emission intensity. Siloxane coatings deposited in helium plasmas had a higher organic component and higher growth rates than those deposited in helium/oxygen plasmas.

Music, rhythm, rise time perception and developmental dyslexia: Perception of musical meter predicts reading and phonology

Introduction: Rhythm organises musical events into patterns and forms, and rhythm perception in music is usually studied by using metrical tasks. Metrical structure also plays an organisational function in the phonology of language, via speech prosody, and there is evidence for rhythmic perceptual difficulties in developmental dyslexia. Here we investigate the hypothesis that the accurate perception of musical metrical structure is related to basic auditory perception of rise time, and also to phonological and literacy development in children. Methods: A battery of behavioural tasks was devised to explore relations between musical metrical perception, auditory perception of amplitude envelope structure, phonological awareness (PA) and reading in a sample of 64 typically-developing children and children with developmental dyslexia. Results: We show that individual differences in the perception of amplitude envelope rise time are linked to musical metrical sensitivity, and that musical metrical sensitivity predicts PA and reading development, accounting for over 60% of variance in reading along with age and I.Q. Even the simplest metrical task, based on a duple metrical structure, was performed significantly more poorly by the children with dyslexia. Conclusions: The accurate perception of metrical structure may be critical for phonological development and consequently for the development of literacy. Difficulties in metrical processing are associated with basic auditory rise time processing difficulties, suggesting a primary sensory impairment in developmental dyslexia in tracking the lower-frequency modulations in the speech envelope. © 2010 Elsevier.

GPVI levels in platelets: relationship to platelet function at high shear

We have investigated the density of the collagen receptors glycoprotein VI (GPVI) and alpha(2)beta(1) on human platelets and their relationship to polymorphisms within the GPVI gene. GPVI levels varied 1.5-fold and showed a weak correlation (r = 0.35) with the levels of alpha(2)beta(1), which varied 3-fold. GPVI genotype had a significant effect on receptor levels with carriers of the proline 219 allele (approximately 22% of the population) having 10% lower GPVI levels than the more common serine homozygotes. GPVI and alpha(2)beta(1) levels were found to be significantly decreased on platelets from patients with myeloproliferative disorders (MPDs). In both the MPD and the control group, GPVI levels were found not to affect platelet function under high shear in whole blood. Similarly murine platelets that express up to 5-fold lower levels of GPVI showed no significant difference than controls in thrombus formation on a high-density collagen-coated surface. However platelets lacking the GPVI/Fc receptor gamma-chain (FcR gamma-chain) complex or a functional FcR gamma-chain (immunoreceptor tyrosine-based activation motif [ITAM] point mutant) exhibited severely abrogated thrombus formation at 800 s(-1) and 1500 s(-1). These results demonstrate that GPVI levels are tightly controlled and play a critical role in thrombus formation on collagen; nevertheless, a range of receptor densities can support platelet function under high shear. (C) 2003 by The American Society of Hematology.

Nonlinear time series prediction based on a power-law noise model

In this paper we investigate the influence of a power-law noise model, also called noise, on the performance of a feed-forward neural network used to predict time series. We introduce an optimization procedure that optimizes the parameters the neural networks by maximizing the likelihood function based on the power-law model. We show that our optimization procedure minimizes the mean squared leading to an optimal prediction. Further, we present numerical results applying method to time series from the logistic map and the annual number of sunspots demonstrate that a power-law noise model gives better results than a Gaussian model.

Effect of accelerated rehabilitation on function after ankle sprain: randomised controlled trial

Objective: To compare an accelerated intervention incorporating early therapeutic exercise after acute ankle sprains with a standard protection, rest, ice, compression, and elevation intervention.

Design: Randomised controlled trial with blinded outcome assessor.

Setting: Accident and emergency department and university based sports injury clinic.

Participants: 101 patients with an acute grade 1 or 2 ankle sprain.

Interventions: Participants were randomised to an accelerated intervention with early therapeutic exercise (exercise group) or a standard protection, rest, ice, compression, and elevation intervention (standard group).

Main outcome measures: The primary outcome was subjective ankle function (lower extremity functional scale). Secondary outcomes were pain at rest and on activity, swelling, and physical activity at baseline and at one, two, three, and four weeks after injury. Ankle function and rate of reinjury were assessed at 16 weeks.

Results: An overall treatment effect was in favour of the exercise group (P=0.0077); this was significant at both week 1 (baseline adjusted difference in treatment 5.28, 98.75% confidence interval 0.31 to 10.26; P=0.008) and week 2 (4.92, 0.27 to 9.57; P=0.0083). Activity level was significantly higher in the exercise group as measured by time spent walking (1.2 hours, 95% confidence interval 0.9 to 1.4 v 1.6, 1.3 to 1.9), step count (5621 steps, 95% confidence interval 4399 to 6843 v 7886, 6357 to 9416), and time spent in light intensity activity (53 minutes, 95% confidence interval 44 to 60 v 76, 58 to 95). The groups did not differ at any other time point for pain at rest, pain on activity, or swelling. The reinjury rate was 4% (two in each group).

Conclusion: An accelerated exercise protocol during the first week after ankle sprain improved ankle function; the group receiving this intervention was more active during that week than the group receiving standard care.

Restoration of adipose function in obese, glucose-tolerant men following pioglitazone treatment is associated with CCAAT enhancer-binding protein β upregulation

Obese AT (adipose tissue) exhibits increased macrophage number. Pro-inflammatory CD16+ peripheral monocyte numbers are also reported to increase with obesity. The present study was undertaken to simultaneously investigate obesity-associated changes in CD16+ monocytes and ATMs (AT macrophages). In addition, a pilot randomized placebo controlled trial using the PPAR (peroxisome-proliferator-activated receptor) agonists, pioglitazone and fenofibrate was performed to determine their effects on CD14+/CD16+ monocytes, ATM and cardiometabolic and adipose dysfunction indices. Obese glucose-tolerant men (n=28) were randomized to placebo, pioglitazone (30 mg/day) and fenofibrate (160 mg/day) for 12 weeks. A blood sample was taken to assess levels of serum inflammatory markers and circulating CD14+/CD16+ monocyte levels via flow cytometry. A subcutaneous AT biopsy was performed to determine adipocyte cell surface and ATM number, the latter was determined via assessment of CD68 expression by IHC (immunohistochemistry) and real-time PCR. Subcutaneous AT mRNA expression of CEBPß (CCAAT enhancer-binding protein ß), SREBP1c (sterol-regulatory-element-binding protein 1c), PPAR?2, IRS-1 (insulin receptor substrate-1), GLUT4 (glucose transporter type 4) and TNFa (tumour necrosis factor a) were also assessed. Comparisons were made between obese and lean controls (n=16) at baseline, and pre- and post-PPAR agonist treatment. Obese individuals had significantly increased adipocyte cell surface, percentage CD14+/CD16+ monocyte numbers and ATM number (all P=0.0001). Additionally, serum TNF-a levels were significantly elevated (P=0.017) and adiponectin levels reduced (total: P=0.0001; high: P=0.022) with obesity. ATM number and percentage of CD14+/CD16+ monocytes correlated significantly (P=0.05). Pioglitazone improved adiponectin levels significantly (P=0.0001), and resulted in the further significant enlargement of adipocytes (P=0.05), without effect on the percentage CD14+/CD16+ or ATM number. Pioglitazone treatment also significantly increased subcutaneous AT expression of CEBPß mRNA. The finding that improvements in obesity-associated insulin resistance following pioglitazone were associated with increased adipocyte cell surface and systemic adiponectin levels, supports the centrality of AT to the cardiometabolic derangement underlying the development of T2D (Type 2 diabetes) and CVD (cardiovascular disease).

Fetal brain function in response to maternal alcohol consumption: Early evidence of damage

Background: Studies of the adverse neurobehavioral effects of maternal alcohol consumption on the fetus have been largely confined to the postnatal period, after exposure to alcohol has finished. This study explored the brain function of the fetus, at the time of exposure to alcohol, to examine its effect on information processing and stability of performance. Methods: Five groups of fetuses, defined by maternal alcohol consumption patterns, were examined: control (no alcohol); moderate (5 to 10 units/wk either drunk evenly across the week or as a binge, in 2 to 3 days); heavy (20+ units/wk drunk evenly or as a binge). Fetal habituation performance was examined on 3 occasions, separated by 7 days, beginning at 35 weeks of gestation. The number of trials required to habituate on each test session and the difference in performance across test sessions were recorded. Results: Fetuses exposed to heavy binge drinking required significantly more trials to habituate and exhibited a greater variability in performance across all test sessions than the other groups. Maternal drinking, either heavily but evenly or moderately as a binge, resulted in poorer habituation, and moderate binge drinking resulted in greater variability compared with no, or even, drinking. Conclusions: Decreased information processing, reflected by poorer habituation, and increased variability in performance may reflect the initial manifestations of structural damage caused by alcohol to the brain. These results will lead to a greater understanding of the effects of alcohol on the fetus's brain, enable the antenatal identification of fetal alcohol spectrum disorders, and lead to the early implementation of better management strategies. © 2012 by the Research Society on Alcoholism.


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Temporal extension of Laplacian Eigenmaps for unsupervised dimensionality reduction of time series

A novel non-linear dimensionality reduction method, called Temporal Laplacian Eigenmaps, is introduced to process efficiently time series data. In this embedded-based approach, temporal information is intrinsic to the objective function, which produces description of low dimensional spaces with time coherence between data points. Since the proposed scheme also includes bidirectional mapping between data and embedded spaces and automatic tuning of key parameters, it offers the same benefits as mapping-based approaches. Experiments on a couple of computer vision applications demonstrate the superiority of the new approach to other dimensionality reduction method in term of accuracy. Moreover, its lower computational cost and generalisation abilities suggest it is scalable to larger datasets. © 2010 IEEE.

Visual function and dysfunction in early and late age-related maculopathy

Late age-related maculopathy (ARM) is responsible for the majority of blind registrations in the Western world among persons over 50 years of age. It has devastating effects on quality of life and independence and is becoming a major public health concern. Current treatment options are limited and most aim to slow progression rather than restore vision; therefore, early detection to identify those patients most suitable for these interventions is essential. In this work, we review the literature encompassing the investigation of visual function in ARM in order to highlight those visual function parameters which are affected very early in the disease process. We pay particular attention to measures of acuity, contrast sensitivity (CS), cone function, electrophysiology, visual adaptation, central visual field sensitivity and metamorphopsia. We also consider the impact of bilateral late ARM on visual function as well as the relationship between measures of vision function and self-reported visual functioning. Much interest has centred on the identification of functional changes which may predict progression to neovascular disease; therefore, we outline the longitudinal studies, which to date have reported dark-adaptation time, short-wavelength cone sensitivity, colour-match area effect, dark-adapted foveal sensitivity, foveal flicker sensitivity, slow recovery from glare and slower foveal electroretinogram implicit time as functional risk factors for the development of neovascular disease. Despite progress in this area, we emphasise the need for longitudinal studies designed in light of developments in disease classification and retinal imaging, which would ensure the correct classification of cases and controls, and provide increased understanding of the natural course and progression of the disease and further elucidate the structure-function relationships in this devastating disorder.

Detecting sequence dependent transcriptional pauses from RNA and protein number time series

Background: Evidence suggests that in prokaryotes sequence-dependent transcriptional pauses a?ect the dynamics of transcription and translation, as well as of small genetic circuits. So far, a few pause-prone sequences have been identi?ed from in vitro measurements of transcription elongation kinetics.

Results: Using a stochastic model of gene expression at the nucleotide and codon levels with realistic parameter values, we investigate three di?erent but related questions and present statistical methods for their analysis. First, we show that information from in vivo RNA and protein temporal numbers is su?cient to discriminate between models with and without a pause site in their coding sequence. Second, we demonstrate that it is possible to separate a large variety of models from each other with pauses of various durations and locations in the template by means of a hierarchical clustering and a random forest classi?er. Third, we introduce an approximate likelihood function that allows to estimate the location of a pause site.

Conclusions: This method can aid in detecting unknown pause-prone sequences from temporal measurements of RNA and protein numbers at a genome-wide scale and thus elucidate possible roles that these sequences play in the dynamics of genetic networks and phenotype.

THE MARINE RADIOCARBON BOMB PULSE ACROSS THE TEMPERATE NORTH ATLANTIC: A COMPILATION OF Delta C-14 TIME HISTORIES FROM ARCTICA ISLANDICA GROWTH INCREMENTS

Marine radiocarbon bomb-pulse time histories of annually resolved archives from temperate regions have been underexploited. We present here series of Delta C-14 excess from known-age annual increments of the long-lived bivalve mollusk Arctica islandica from 4 sites across the coastal North Atlantic (German Bight, North Sea; Tromso, north Norway; Siglufjordur, north Icelandic shelf; Grimsey, north Icelandic shelf) combined with published series from Georges Bank and Sable Bank (NW Atlantic) and the Oyster Ground (North Sea). The atmospheric bomb pulse is shown to be a step-function whose response in the marine environment is immediate but of smaller amplitude and which has a longer decay time as a result of the much larger marine carbon reservoir. Attenuation is determined by the regional hydrographic setting of the sites, vertical mixing, processes controlling the isotopic exchange of C-14 at the air-sea boundary, C-14 content of the freshwater flux, primary productivity, and the residence time of organic matter in the sediment mixed layer. The inventories form a sequence from high magnitude-early peak (German Bight) to low magnitude-late peak (Grimsey). All series show a rapid response to the increase in atmospheric Delta C-14 excess but a slow response to the subsequent decline resulting from the succession of rapid isotopic air-sea exchange followed by the more gradual isotopic equilibration in the mixed layer due to the variable marine carbon reservoir and incorporation of organic carbon from the sediment mixed layer. The data constitute calibration series for the use of the bomb pulse as a high-resolution dating tool in the marine environment and as a tracer of coastal ocean water masses.

A 64-point fourier transform chip for video motion compensation using phase correlation

Details of a new low power fast Fourier transform (FFT) processor for use in digital television applications are presented. This has been fabricated using a 0.6-µm CMOS technology and can perform a 64 point complex forward or inverse FFT on real-time video at up to 18 Megasamples per second. It comprises 0.5 million transistors in a die area of 7.8 × 8 mm and dissipates 1 W. The chip design is based on a novel VLSI architecture which has been derived from a first principles factorization of the discrete Fourier transform (DFT) matrix and tailored to a direct silicon implementation.

Corpus callosum size and inter-hemispheric function in schizophrenia

We studied the relationship between corpus callosum area and both inter-hemispheric facilitation and interference in schizophrenics and controls. Mid-sagittal sections through the corpus callosum were measured using structural magnetic resonance imaging on 42 patients and 43 normal controls, along with symptom profiles. In a sub-sample, a modified version of the Stroop Test was also performed (27 patients and 29 controls) to assess inter-hemispheric facilitation and interference of colour naming. In the larger sample (total subjects, n=85), there were no significant differences between patients and controls in CC area but a trend towards smaller values in patients in all but the posterior segment. In the sub-sample, bilateral facilitation was greater, and interference, less in schizophrenics compared with controls. There was a positive correlation between facilitation and posterior CC area, parallelled by a negative correlation between interference and posterior CC area, in both patients and controls, which only reached statistical significance when both groups were combined. These findings suggest that the link, between CC size and neuropsychological processes involving inter-hemispheric transfer of information, is common to both schizophrenics and normal controls. There were significant negative correlations between anterior CC area and psychomotor poverty (avolition, anhedonia and affective flattening), and a suggestion that the negative correlation between age and CC size in controls was not present in patients.

Time-dependent density functional theory study of charge transfer in collisions

We study the charge transfer between colliding ions, atoms, or molecules, within time-dependent density functional theory. Two particular cases are presented, the collision between a proton and a Helium atom, and between a gold atom and a butane molecule. In the first case, proton kinetic energies between 16 keV and 1.2 MeV are considered, with impact parameters between 0.31 and 1.9 angstrom. The partial transfer of charge is monitored with time. The total cross-section is obtained as a function of the proton kinetic energy. In the second case, we analyze one trajectory and discuss spin-dependent charge transfer between the different fragments.