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PubMed2003

Optical single transporter recording: transport kinetics in microarrays of membrane patches.

Optical single transporter recording (OSTR) is an emerging technique for the fluorescence microscopic measurement of transport kinetics in membrane patches. Membranes are attached to transparent microarrays of cylindrical test compartments (TCs) approximately 0.1-100 mum in diameter and approximately 10-100 mum in depth. Transport across membrane patches that may contain single transporters or transporter populations is recorded by confocal microscopy. By these means transport of proteins through single nuclear pore complexes has been recorded at rates of <1 translocation/s. In addition to the high sensitivity in terms of measurable transport rates OSTR features unprecedented spatial selectivity and parallel processing. This article reviews the conceptual basis of OSTR and its realization. Applications to nuclear transport are summarized. The further development of OSTR is discussed and its extension to a diversity of transporters, including translocases and ATP-binding cassette (ABC) pumps, projected.

Active Transport, Cell Nucleus↗
PubMed2002

Sequestration of defensive substances from plants by Lepidoptera.

A number of aposematic butterfly and diurnal moth species sequester unpalatable or toxic substances from their host plants rather than manufacturing their own defensive substances. Despite a great diversity in their life histories, there are some general features in the selective utilization of plant secondary metabolites to achieve effective protection from predators. This review illustrates the biochemical, physiological, and ecological characteristics of phytochemical-based defense systems that can shed light on the evolution of the widely developed sequestering lifestyles among the Lepidoptera.

Animals↗
PubMed2003

The biology of epilepsy genes.

Mutations in over 70 genes now define biological pathways leading to epilepsy, an episodic dysrhythmia of the cerebral cortex marked by abnormal network synchronization. Some of the inherited errors destabilize neuronal signaling by inflicting primary disorders of membrane excitability and synaptic transmission, whereas others do so indirectly by perturbing critical control points that balance the developmental assembly of inhibitory and excitatory circuits. The genetic diversity is now sufficient to discern short- and long-range functional convergence of epileptogenic molecular pathways, reducing the broad spectrum of primary molecular defects to a few common processes regulating cortical synchronization. Synaptic inhibition appears to be the most frequent target; however, each gene mutation retains unique phenotypic features. This review selects exemplary members of several gene families to illustrate principal categories of the disease and trace the biological pathways to epileptogenesis in the developing brain.

Animals↗
PubMed2005

Cortical maps of separable tuning properties predict population responses to complex visual stimuli.

In the earliest cortical stages of visual processing, a scene is represented in different functional domains selective for specific features. Maps of orientation and spatial frequency preference have been described in the primary visual cortex using simple sinusoidal grating stimuli. However, recent imaging experiments suggest that the maps of these two spatial parameters are not sufficient to describe patterns of activity in different orientation domains generated in response to complex, moving stimuli. A model of cortical organization is presented in which cortical temporal frequency tuning is superimposed on the maps of orientation and spatial frequency tuning. The maps of these three tuning properties are sufficient to describe the activity in orientation domains that have been measured in response to drifting complex images. The model also makes specific predictions about how moving images are represented in different spatial frequency domains. These results suggest that the tangential organization of primary visual cortex can be described by a set of maps of separable neuronal receptive field features including maps of orientation, spatial frequency, and temporal frequency tuning properties.

Animals↗
PubMed1993

Response properties of neurons in temporal cortical visual areas of infant monkeys.

1. Inferior temporal cortex (IT) is a "high-order" region of primate temporal visual cortex implicated in visual pattern perception and recognition. To gain some insight into the development of this area, we compared the properties of single neurons in IT in infant monkeys ranging from 5 wk to 7 mo of age with those of neurons in IT in adult animals. Both anesthetized and awake behaving paradigms were used. 2. In immobilized infant monkeys under nitrous oxide anesthesia, the incidence of visually responsive cells was markedly less than in adult monkeys studied under similar conditions. In infants 4-7 mo of age, only half of IT neurons studied were visually responsive, compared with > 80% in adult monkeys. In monkeys < 4 mo old, even fewer (< 10%) could be visually driven. "Habituation" of IT cells to repeated stimulus presentation appeared more pronounced in infant monkeys under nitrous oxide anesthesia than in adult animals. 3. IT cells in the anesthetized infant monkeys that did respond showed receptive field properties similar to those of responsive adult IT neurons studied under similar conditions. Two thirds of the receptive fields plotted in the anesthetized 4 to 7-mo-old group were bilateral, and median field size did not differ between the infants and comparable adult groups, being approximately 20 degrees on a side in each case. 4. In contrast to the results obtained under anesthesia, most IT cells in alert infant monkeys 5 wk-7 mo of age (80%) were responsive to visual stimuli, and this incidence of visually responsive IT neurons did not differ from that obtained in awake adult macaques. However, response magnitude, measured as spikes per second above baseline rate, was significantly lower in the infant alert sample than in the adult control (5.2 vs. 12.6 spikes/s, mean +/- SE, deviation from spontaneous rate, respectively). 5. In addition to having lower magnitudes of visual response, IT cells in the awake infants also tended to have longer and more variable latencies. The overall mean for the infant cells was 196 ms, compared with an overall mean of 140 ms for IT neurons in the alert control adult. 6. Although the magnitude of response of neurons in alert infant IT cortex was lower overall, the incidence and features of stimulus selectivity shown by alert infant IT neurons were strikingly similar to those of IT cells of both anesthetized and unanesthetized adult monkeys.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed2000

Interactions between posture and locomotion: motor patterns in humans walking with bent posture versus erect posture.

Human erect locomotion is unique among living primates. Evolution selected specific biomechanical features that make human locomotion mechanically efficient. These features are matched by the motor patterns generated in the CNS. What happens when humans walk with bent postures? Are normal motor patterns of erect locomotion maintained or completely reorganized? Five healthy volunteers walked straight and forward at different speeds in three different postures (regular, knee-flexed, and knee- and trunk-flexed) while their motion, ground reaction forces, and electromyographic (EMG) activity were recorded. The three postures imply large differences in the position of the center of body mass relative to the body segments. The elevation angles of the trunk, pelvis, and lower limb segments relative to the vertical in the sagittal plane, the ground reaction forces and the rectified EMGs were analyzed over the gait cycle. The waveforms of the elevation angles along the gait cycle remained essentially unchanged irrespective of the adopted postures. The first two harmonics of these kinematic waveforms explain >95% of their variance. The phase shift but not the amplitude ratio between the first harmonic of the elevation angle waveforms of adjacent pairs was affected systematically by changes in posture. Thigh, shank, and foot angles covaried close to a plane in all conditions, but the plane orientation was systematically different in bent versus erect locomotion. This was explained by the changes in the temporal coupling among the three segments. For walking speeds >1 m s(-1), the plane orientation of bent locomotion indicates a much lower mechanical efficiency relative to erect locomotion. Ground reaction forces differed prominently in bent versus erect posture displaying characteristics intermediate between those typical of walking and those of running. Mean EMG activity was greater in bent postures for all recorded muscles independent of the functional role. The waveforms of the muscle activities and muscle synergies also were affected by the adopted posture. We conclude that maintaining bent postures does not interfere either with the generation of segmental kinematic waveforms or with the planar constraint of intersegmental covariation. These characteristics are maintained at the expense of adjustments in kinetic parameters, muscle synergies and the temporal coupling among the oscillating body segments. We argue that an integrated control of gait and posture is made possible because these two motor functions share some common principles of spatial organization.

Adult↗
PubMed1998

Automatic cell segmentation in cyto- and histometry using dominant contour feature points.

Automatic cell segmentation has various application potentials in cytometry and histometry. In this paper, an automatic cluster (touching) cell segmentation approach using the dominant contour feature points has been presented. Dominant feature points are the locations of indentation on the contour of the cluster. First, dominant feature points on the contour of the cluster are detected by distance profile. Next, using shape features of the cells, these feature points are selected for segmentation. We compared the results of the proposed method with manual segmentation and observed that the method has an overall accuracy about to 82%.

Cell Nucleus↗
PubMed1975

Morphologic correlates of technetium-99m stannous pyrophosphate imaging of acute myocardial infarcts in dogs.

To obtain insight into the mechanism(s) responsible for the direct visualization of acute myocardial infarcts by myocardial scintigraphy with technetium-99m stannous pyrophosphate (99mTc-PYP), scintigraphic and morphologic studies were performed in 22 dogs subjected to occlusion of the proximal left anterior descending coronary artery (LAD). Grossly visible myocardial infarcts occurred in ten of 11 dogs with LAD occlusion for one day, five with LAD occlusion for two days, two with LAD occlusion for seven days and two with LAD occlusion for 13 days. Rare, microscopic foci of necrosis were observed in one dog with LAD occlusion for one day, and no lesions were present in two dogs subjected to temporary LAD occlusion for eight minutes and reflow for 24 hours. In the latter three dogs, 99mTc-PYP myocardial scintigrams were negative. In the 19 dogs with gross infarcts, 99mTc-PYP myocardial scintigrams were strongly positive at one and two days after LAD occlusion, much less positive at seven days and faintly positive at 13 days after occlusion. Positive myocardial scintigrams in most showed "doughnut" patterns, with marked peripheral concentration of radioactivity around central zones of much lower activity. On histologic examination, the one and two-day-old infarcts exhibited subendocardially located central zones and surrounding peripheral zones, both of which showed distinctive histopathological and histochemical features, including the selective occurrence in the peripheral zones of calcified muscle cells with ultrastructurally demonstrable apatite-like crystals in mitochondria. Selective occurrence of high tissue levels of 99mTc-PYP radioactivity also was demonstrated in the peripheral zones of four infarcts. Hearts with older infarcts (seven and 13 days) showed progressive replacement of necrotic myocardium by granulation tissue and progressive reduction in calcium deposits in the areas of damage. The data obtained in this study establish a temporal and topographical relationship between calcium accumulation in acute myocardial infarcts and 99mTc-PYP uptake responsible for scintigraphic detection of the lesions with this radionuclide in dogs subjected to proximal LAD occlusion.

Acute Disease↗
PubMed1981

Cardiac infarction injury score: an electrocardiographic coding scheme for ischemic heart disease.

A multivariate decision-theoretic electrocardiogram (ECG) classification scheme called Cardiac Infarction Injury Score (CIIS) was developed using ECGs of 387 patients with myocardial infarction (MI) and 320 subjects without infarction. The most accurate and stable classification was achieved by using a combination of eight binary (single threshold), three ternary (two thresholds), and four ECG features measured on a continuous scale. For practical visual coding of ECGs, the CIIS coding procedure uses a checklist containing 12 items measured from the conventional 12-lead ECG. The CIIS test results indicate that, in comparison with conventional ECG criteria for MI used in clinical trials, the diagnostic accuracy can be considerably improved by optimizing feature and threshold selection and by multivariate analysis. The CIIS detected MI with a sensitivity of 85% and a specificity of 95%. Using a higher severity level, a specificity of 99% was achieved, with a sensitivity of 71%. One of the primary uses of the CIIS is coding of significant worsening of the ECG with new coronary events from annually recorded ECGs in clinical trials and epidemiologic studies.

Adult↗
PubMed1998

Body surface mapping during pacing at multiple sites in the human atrium: P-wave morphology of ectopic right atrial activation.

BACKGROUND: The morphology and polarity of the P wave on 12-lead ECG are of limited clinical value in localizing ectopic atrial rhythms. It was the aim of this study to assess the spatial resolution of body surface P-wave integral mapping in identifying the site of origin of ectopic right atrial (RA) impulse formation in patients without structural atrial disease. METHODS AND RESULTS: Sixty-two-lead ECG recordings were obtained during RA pacing at 86 distinct endocardial sites in nine patients with normal biatrial anatomy. After P-wave integral maps were generated for each paced activation sequence, 17 groups with nearly identical map features were visually selected, and a mean P-wave integral map was computed for each group. Supportive statistical analysis to corroborate qualitative group selection was performed by assessment of (1) intragroup pattern uniformity by use of jackknife correlation coefficient analysis of the integral maps contained in each group and (2) intergroup pattern variability by use of the calculation of cross correlations between the 17 mean integral maps. The spatial resolution of paced P-wave body surface mapping in the right atrium was obtained by estimating the area size of endocardial segments with nearly identical P-wave integral maps by use of a biplane fluoroscopic method to compute the three-dimensional position of each pacing site. The latter approach yielded a mean endocardial segment size of 3.5+/-2.9 cm2 (range, 0.79 to 10.75 cm2). CONCLUSIONS: Use of the P-wave morphology on the 62-lead surface ECG in patients with normal biatrial anatomy allows separation of the origin of ectopic RA impulse formation into one of 17 different endocardial segments with an approximated area size of 3.5 cm2. This database of paced P-wave integral maps provides a versatile clinical tool to perform detailed noninvasive localization of right-sided atrial tachycardia before radiofrequency catheter ablation.

Adult↗
PubMed1998

Effects of parietal lesions in humans on color and location priming.

To determine whether the parietal lobes contribute tot he selection of nonspatial features known to be processed in the ventral stream, the current study examined the effect of chronic unilateral parietal lobe lesions in humans on color and location priming. Patients and normal controls performed a go/no-go color discrimination task in which either the same color and different color pairs of stimuli (prime and probe) were projected sequentially either in the same hemifield or in opposite hemifields. Control subjects and patients both showed independent effects of color and location priming. In the patients, primes in either field produced color priming for target probes in the ipsilesional field but not for probes in the contralesional field. This observation implicates the parietal cortex in processing activated codes of stimulus attributes not only for spatial information but also for visual features processed in the ventral visual pathways.

Aged↗
PubMed2001

Computational design and nonlinear dynamics of a recurrent network model of the primary visual cortex.

Recurrent interactions in the primary visual cortex make its output a complex nonlinear transform of its input. This transform serves preattentive visual segmentation, that is, autonomously processing visual inputs to give outputs that selectively emphasize certain features for segmentation. An analytical understanding of the nonlinear dynamics of the recurrent neural circuit is essential to harness its computational power. We derive requirements on the neural architecture, components, and connection weights of a biologically plausible model of the cortex such that region segmentation, figure-ground segregation, and contour enhancement can be achieved simultaneously. In addition, we analyze the conditions governing neural oscillations, illusory contours, and the absence of visual hallucinations. Many of our analytical techniques can be applied to other recurrent networks with translation-invariant neural and connection structures.

Animals↗
PubMed1986

National Toxicology Program nomenclature for hepatoproliferative lesions of rats.

Diagnostic criteria for hepatoproliferative lesions of Fischer 344 rats are presented to permit more complete categorization of the spectrum of lesions observed in two-year chemical carcinogenicity studies. A nomenclature recently adopted by the National Toxicology Program differs from previous classification schemes in that hepatocellular hyperplasia and hepatocellular adenoma are to be used for lesions which were previously combined under the diagnosis of neoplastic nodule. The term hyperplasia is reserved for proliferative lesions that are perceived to be secondary, nonneoplastic responses to degenerative changes in the liver. Foci of cellular alteration, hepatocellular adenoma, and hepatocellular carcinoma are believed to represent a spectrum of changes that comprise the natural history of neoplasia. This change in nomenclature was made subsequent to a peer review of representative hepatoproliferative lesions from two-year carcinogenicity studies. The revised nomenclature is consistent with traditional pathologic diagnoses for proliferative lesions in other epithelial tissues and should facilitate the interpretation of conventional toxicity and carcinogenicity studies in rats. Morphologic features of other selected rat liver lesions are also presented.

Animals↗
PubMed2005

Two-dimensional MR spectroscopic characterization of breast cancer in vivo.

The major goal of this work was to characterize invasive ductal carcinoma and healthy fatty breast tissues noninvasively using the classification and regression tree analysis (CART) of 2D MR spectral data. 2D L-COSY spectra were acquired in 14 invasive breast carcinoma and 21 healthy fatty breasts using a GE 1.5 Tesla MRI/MRS scanner equipped with a 2-channel phased-array breast MR coil. The 2D spectra were recorded in approximately 10 minutes using a minimum voxel size of 1 ml without any water suppression technique. For healthy breasts, spectra were acquired from at least one fatty region. 2D L-COSY spectra were recorded in a total of 43 voxels. Five diagonal and six cross peak volumes were integrated and at least eighteen ratios were selected as potential features for the statistical method, namely CART. The 2D L-COSY data showed a significant increase for the majority of these ratios in invasive breast carcinomas compared to healthy fatty tissues. Better accuracy of identifying carcinomas and fatty tissues is reported using CART analysis of different combinations of ratios calculated from the relative levels of water, choline, and saturated and unsaturated lipids. This is a first report on the statistical classification of 2D L-COSY in human breast carcinomas in vivo.

Adult↗
PubMed2006

Enhancing access to the Bibliome: the TREC 2004 Genomics Track.

BACKGROUND: The goal of the TREC Genomics Track is to improve information retrieval in the area of genomics by creating test collections that will allow researchers to improve and better understand failures of their systems. The 2004 track included an ad hoc retrieval task, simulating use of a search engine to obtain documents about biomedical topics. This paper describes the Genomics Track of the Text Retrieval Conference (TREC) 2004, a forum for evaluation of IR research systems, where retrieval in the genomics domain has recently begun to be assessed. RESULTS: A total of 27 research groups submitted 47 different runs. The most effective runs, as measured by the primary evaluation measure of mean average precision (MAP), used a combination of domain-specific and general techniques. The best MAP obtained by any run was 0.4075. Techniques that expanded queries with gene name lists as well as words from related articles had the best efficacy. However, many runs performed more poorly than a simple baseline run, indicating that careful selection of system features is essential. CONCLUSION: Various approaches to ad hoc retrieval provide a diversity of efficacy. The TREC Genomics Track and its test collection resources provide tools that allow improvement in information retrieval systems.

Journal Article↗
PubMed2004

Expression of pituitary tumor transforming gene (PTTG) and its binding protein in human astrocytes and astrocytoma cells: function and regulation of PTTG in U87 astrocytoma cells.

Human securin, pituitary tumor transforming gene (PTTG), is a protooncogene. Here we report expressions of PTTG and its interacting protein, PTTG-binding factor in human astrocytic cells. PTTG expression was higher in malignant cells than in primary astrocytes, whereas PTTG-binding factor was not. Using a xenotransplantable, glioma cell line (U87), we observed that knocking down PTTG mRNA by RNA silencing inhibited serum-induced proliferation by approximately 50%. Furthermore, in U87 cells PTTG expression was up-regulated by promalignant ligands epithelial growth factor (EGF) and TGFalpha, both at the protein and mRNA levels. PTTG induction by EGF receptor (EGFR) ligands could be blocked by the specific EGFR inhibitor, AG1478. Hepatocyte growth factor (HGF) also induced PTTG but to a lesser extent than EGF. Although EGF stimulates HGF secretion in U87 cells, the effect of EGF on PTTG mRNA expression is independent of HGF as neutralizing antibody against HGF failed to abolish EGF-induced up-regulation of PTTG mRNA. PTTG mRNA was unchanged by incubating U87 cells with the promalignant growth factor TGFbeta, apoptosis inducing TNFalpha and ligands for nuclear receptors, such as retinoic acid and retinoid X receptors and peroxisome proliferator-activated receptor-gamma, known for their growth-inhibitory and apoptosis-inducing effects on gliomas. In addition, 17beta-estradiol and Ca2+, known to activate PTTG expression, did not change PTTG mRNA levels in U87 cells. In summary, we show higher PTTG expression in astrocytoma than normal astrocytes and secondly, PTTG is involved in glioma cell growth. Finally, regulation of its expression has glioma-specific features and is selectively regulated by promalignant cytokines including EGFR ligands and HGF.

Apoptosis↗
PubMed1999

Clustering of insulin resistance, total and central abdominal fat: same genes or same environment?

Obesity, insulin resistance and disturbed glucose metabolism cluster within the Insulin Resistance Syndrome (IRS). Whether this reflects shared genetic or environmental factors detectable in 'normal' populations (not selected for IRS features) is unknown. This study estimated (i) genetic influences on IRS traits and (ii) shared and specific genetic and environmental factors on the relationships between these traits in healthy female twins. Fasting insulin, glucose, total and central fat were measured in 59 monozygotic (MZ) and 51 dizygotic (DZ) female twin pairs aged (+/- SD) 52 +/- 13 years. Body fat was measured by dual-energy X-ray absorptiometry, insulin resistance and secretion by a modified homeostasis model assessment. Using intraclass correlation coefficients and univariate model-fitting analyses, genetic influences were found in total fat, central fat, insulin resistance, fasting glucose and insulin secretion, with genetic factors explaining 64, 57, 59, 75 and 68% of their variance, respectively, using the latter technique. In matched analysis intra-pair differences in total and central fat related to intra-pair differences in insulin resistance (r2 = 0.19, P < 0.001). Multivariate model-fitting showed a close genetic relationship between total and central fat (r = 0.88). The genetic correlation between IR and central fat (0.41) was significantly greater than that for total fat (0.24), suggesting that central fat is not only a predictor of, but shares considerable genetic influence with, insulin resistance. In Cholesky analysis, these genetic influences were separate from those shared between central and total fat. In conclusion, both shared and specific genetic factors regulate components of the IRS in healthy females. However, there were discrete genetic influences on beta-cell insulin secretion, not shared with other IRS components, suggesting that a separate genetic propensity exists for Type 2 diabetes. These findings suggest we may understand the genetic and environmental influences on IRS from the study of the normal population.

Abdomen↗
PubMed2002

Pulmonary interstitial disease in Ig deficiency.

STUDY OBJECTIVES: To determine the frequency and type of interstitial lung disease (ILD) in consecutive subjects with symptomatic Ig deficiency. PATIENTS: One hundred forty-eight consecutive subjects with repeated respiratory infections and Ig deficiency. MEASUREMENTS: Ig classes and IgG subclasses (IgGSCs), the response to vaccination, pulmonary function tests, chest radiography, CT scan, Ga scan and, when possible, BAL and lung biopsy. RESULTS: Twenty-nine of 148 subjects (19 men and 10 women aged 18 to 72 years) had evidence of ILD. In 20 subjects, no cause of ILD was apparent. The remaining nine cases were ostensibly due to identifiable causes. Twenty subjects had IgGSC deficiency, 8 subjects had common variable immunodeficiency, and 1 subject had combined IgM plus IgGSC deficiency. No isotype deficiency was consistently related to a specific ILD. After administration of IV Ig, eight subjects, all with IgGSC deficiency, improved clinically, physiologically, radiologically, and occasionally histologically, regardless of immunologic or radiologic features. In this selective sample, the prevalence of ILD in consecutive subjects with recurrent respiratory infections and Ig deficiency (29 of 148 subjects; 19.6%) was higher than in the general population (0.8%; p < 0.05). CONCLUSIONS: ILD in Ig deficiency is frequent and usually involves IgGSC deficiency.

Adolescent↗

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