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PubMed2002

Calcitonin decreases the adherence and survival of HEK-293 cells by a caspase-independent mechanism.

We recently reported that calcitonin (CT) can profoundly inhibit the growth of HEK-293 cells transfected with the human calcitonin receptor (hCTR). We also obtained preliminary evidence that suggested a role for CT in cell survival, and in the present study we have investigated the pro-apoptotic action of CT, which we observe in conditions of low serum concentration. Under these conditions, we have found that CT treatment of HEK-293 cells stably transfected with the insert-negative form of the human CTR (HR12 cells) caused a time-dependent decrease in cell number associated with loss of cellular attachment. Loss of cellular adherence in CT-treated cultures caused programmed cell death, as shown by Annexin V staining of cells, failure of cells to exclude Trypan Blue dye, condensation and cleavage of nuclear DNA, and appearance of hypodiploid cells in fluorescence-activated cell sorting (FACS) analysis. The accumulation of non-adherent cells and cell death was concomitant with increased intracellular activity of caspase-3. However, inhibition of caspase activation in HR12 cells did not prevent CT-mediated loss of attachment and did not maintain the viability of non-adherent cells, indicating that caspase activation accompanied, but was probably not the cause of, the loss of cell viability. Neither the effects of CT on cell survival nor the activation of caspase-3 were observed in serum-replete conditions, suggesting that serum-derived factors provide protection of cells from CT-induced apoptosis. The inhibitory effects of CT on cell growth were found previously to be related to activation of Erk1/2 MAP kinase. In the present experiments, it was found that the Erk1/2 inhibitor, PD 98059, inhibited the CT-induced loss of cellular adherence and the consequent reduction in cell numbers. These results demonstrate that CT can negatively affect cell survival and they identify roles for cell adherence and MAP kinase activation in this process.

Apoptosis↗
PubMed1998

Lateralized ultradian rhythms: evidence from tactile discrimination of either hand.

Endogenous ultradian rhythms with periods of one or a few hours affect not only on physiological and behavioural functions but also perception and cognition. In particular, lateralized ultradian rhythms which seem to operate separately in the right and left hemispheres of the brain can be monitored by testing the tactile discrimination of the contralateral hand. The present paper is based on two subsequent studies: First, ultradian rhythms in tactile discrimination of either hand were examined in German subjects under laboratory conditions. Considerably different ultradian periods of right and left-handed tactile error rate were found in men but not in women. In a second study, a group of Kenyan Masai shepherds were tested while the subjects were leading herds on daily feeding routes through a savanna habitat. They showed ultradian periods of about 2 hours in tactile discrimination of either hand. Since the right hemisphere is specialized for visuospatial, the left for verbal processing lateralized ultradian rhythms may serve for a long-scale timing of neural processes underlying spatial and semantic mapping of the environment. Sex difference in German subjects and lateral differences found in left-handed (right-hemispheric) ultradian rhythms of German and Masai subjects are discussed from this point of view.

Activity Cycles↗
PubMedDate not supplied

A manager's guide to organizational change.

With the increasing use of consultants to facilitate organizational change, managers need to be better informed about the range of available consulting services. In an effort to help managers better understand the various consulting approaches, Kleiner describes five techniques: "socio-technical systems;" "contingency;" "MAPS;" "Michigan survey feedback," and "process consultation." The author compares these techniques along nine dimensions: assumptions about technology and people; targets; objectives and directions of change; and the data and data collection methods used. While conceding the complexity of these considerations, Kleiner concludes that the benefits of meticulousness and care in consultant selection justify the effort.

Administrative Personnel↗
PubMed2000

Brain-derived neurotrophic factor causes cAMP response element-binding protein phosphorylation in absence of calcium increases in slices and cultured neurons from rat visual cortex.

Neurotrophins play a crucial role in the developmental plasticity of the visual cortex, but very little is known about the cellular mechanisms involved in their action. In many models of synaptic plasticity, increases in cytosolic calcium concentration and activation of the transcription factor cAMP response element-binding protein (CREB) are crucial factors for the induction and maintenance of long-lasting changes of synaptic efficacy. Whether BDNF modulates intracellular calcium levels in visual cortical neurons and the significance of this action for BDNF signal transduction is still controversial. We investigated whether CREB phosphorylation and calcium changes are elicited by acute BDNF presentation in postnatal visual cortical slices and cultures. We found that BDNF did not cause any calcium increase, but it induced robust CREB phosphorylation in neurons from both preparations. We further analyzed signal transduction and its dependency on calcium changes in cultured neurons. CREB phosphorylation required trkB activation because treatment with the trk inhibitor k252a completely blocked CREB phosphorylation. In agreement with the imaging experiments, we verified that calcium changes were not necessary for CREB activation because preincubation with BAPTA-AM did not diminish the level of CREB phosphorylation induced by BDNF stimulation. CREB phosphorylation was accompanied by gene expression, because we observed the upregulation of c-fos expression, which was also not affected by preincubation with BAPTA-AM. Finally, BDNF caused phosphorylation of mitogen-activated protein kinase (MAPK), and because the treatment with the MAPK inhibitor U0126 completely abolished CREB activation and c-fos upregulation, it is likely that both processes depend mainly on the MAP kinase pathway. These results indicate that MAPK and CREB, but not intracellular calcium, are important mediators of neurotrophin actions in the visual cortex.

Activating Transcription Factor 2↗
PubMed2001

Peptide loading of nascent MHC class I molecules.

A critical molecular interaction during assembly of the major histocompatibility complex (MHC) class I molecules takes place between the heavy chain and the transporter-associated with antigen-processing (TAP) complex. The recent mapping of regions of the heavy chain involved in the binding to TAP suggests a complex molecular interaction essential for the cell surface expression of the MHC class I. The advances made in understanding the TAP-MHC class I interaction are reviewed and discussed here.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

[Digital subtraction angiography for the assessment of myocardial perfusion].

Coronary angiography does not only permit to evaluate the severity of coronary disease but also to assess coronary flow reserve in various myocardial perfusion areas by digital processing. Use of colour flow mapping allows the assessment of both, density as well as distribution velocity of contrast-medium (= parametric imaging). The advantage of this technique is given by the possibility to assess coronary flow reserve not only at rest but also under physiologic situations such as bicycle ergometry. Clinical investigations have shown that coronary flow reserve determined after papaverine administration does not correlate with physiologic conditions such as physical exercise.

Angiography, Digital Subtraction↗
PubMed2003

Groundwater-surface water interaction in inland New South Wales: a scoping study.

Groundwater and surface water have traditionally been managed separately in New South Wales (NSW). However, where rivers and aquifers are hydraulically connected, groundwater pumping has the potential to deplete streamflow. To highlight the major areas of connection in inland NSW, major streams were overlaid with groundwater depth data and the locations of irrigation bores. A consistent pattern was revealed related to basin geomorphology. The main areas of connection are the mid-sections of the major rivers where alluvial systems are well developed yet still narrow and constricted and groundwater depths are shallow. The mapping was validated and the processes explored by calculating water balances for a connected and disconnected reach in the Murrumbidgee River. These showed that, in highly connected reaches, river losses and/or gains are closely related to groundwater levels.

Agriculture↗
PubMed2003

Sleep, vigilance and cognition in postmenopausal women: placebo-controlled studies with 2 mg estradiol valerate, with and without 3 mg dienogest.

OBJECTIVE: To determine the effects in postmenopausal women with insomnia of hormone replacement therapy (HRT) with 2 mg estradiol valerate (E2V) alone, or in combination with 3 mg dienogest (DNG), in the context of the introduction of the novel preparation Climodien (2 mg E2V/2 mg DNG) (Schering AG, Berlin, Germany). METHODS: Parallel groups of women with insomnia related to the postmenopausal syndrome were randomized to 2 months' treatment with 2 mg E2V, 2 mg E2V/3 mg DNG or placebo (respectively, n = 17, 16, 16). Patients were then studied with techniques for assessing sleep quality, vigilance and cognition. Sleep quality was determined subjectively by means of the questionnaire-based sleep and awakening quality scale (SSA), and objectively with polysomnography. Sleep-related breathing disorders were evaluated by means of the apnea/hypopnea index. Vigilance was measured using quantitative electroencephalography with statistical probability mapping. Cognition (speed of information processing, cognition processing capacity and perceptual processing resources) was studied using the techniques of auditory event-related potentials (P300 latency and amplitude). RESULTS AND CONCLUSIONS: Treatment with 2 mg E2V and 2 mg E2V/3 mg DNG significantly improved subjective sleep quality and showed trends towards improvements in objective sleep quality. The combination of 2 mg E2V/3 mg DNG also improved the apnea/hypopnea index. Vigilance was slightly improved by treatment with 2 mg E2V and markedly with 2 mg E2V/3 mg DNG. Speed of information processing was improved with 2 mg EV2 and 2 mg E2V/3 mg DNG, whilst the latter also improved cognitive processing capacity and perceptual processing resources. The study provides evidence that HRT can improve sleep quality and mental functioning in postmenopausal women and that E2V/DNG combinations, such as 2 mg E2V/2 mg DNG, should be considered for this indication and also for the treatment of sleep-related breathing disorders in the menopause. The addition of dienogest to estradiol valerate did not antagonize the benefits of estradiol valerate in terms of sleep quality but rather potentiated estradiol valerate-related improvements in vigilance and some aspects of cognition.

Aged↗
PubMedDate not supplied

[Medical and ecological assessment of climate effects on urolithiasis morbidity in population of Primorsky territory].

The article presents medicoecological estimation of quantitative relations between monsoon climate and urolithiasis primary morbidity in the Primorsky Territory. Quantitative estimation of the climate was performed by V. I. Rusanov (1973) who calculated daily meteorological data for 1 p.m. throughout 1991-1999. Primary urolithiasis morbidity for this period of time was provided by regional health department. The data were processed by methods of medical mapping and paired correlation analysis. In the Territory, mapping revealed the same location of the zones with high frequency of discomfortable weather of class V and VI causing chilblain in positive air temperatures and zones with elevated primary urolithiasis morbidity in children and adults. Correlation analysis confirmed mapping results and determined significant negative correlations between frequency of relatively comfortable moment weather classes II-IV and morbidity of children and adults, positive correlation between frequency of discomfortable class VI and adult morbidity. Thus, high frequency of days per year with discomfortable classes of moment weather in low positive air temperatures may be one of the factors of urolithiasis risk in population of the Primorsky Territory. Climatic factors should be taken into consideration in planning primary prophylaxis of this disease in the Primorsky Territory.

Adult↗
PubMed2005

Laterality of brain areas associated with arithmetic calculations revealed by functional magnetic resonance imaging.

BACKGROUND: Asymmetry of bilateral cerebral function, i.e. laterality, is an important phenomenon in many brain actions: arithmetic calculation may be one of these phenomena. In this study, first, laterality of brain areas associated with arithmetic calculations was revealed by functional magnetic resonance imaging (fMRI). Second, the relationship among laterality, handedness, and types of arithmetic task was assessed. Third, we postulate possible reasons for laterality. METHODS: Using a block-designed experiment, twenty-five right-handed and seven left-handed healthy volunteers carried out simple calculations, complex calculations and proximity judgments. T1WI and GRE-EPI fMRI were performed with a GE 1.5T whole body MRI scanner. Statistical parametric mapping (SPM99) was used to process data and localize functional areas. Numbers of activated voxels were recorded to calculate laterality index for evaluating the laterality of functional brain areas. RESULTS: For both groups, the activation of functional areas in the frontal lobe showed a tendency towards the nonpredominant hand side, but the functional areas in the inferior parietal lobule had left laterality. During simple and complex calculations, the laterality indices of the prefrontal cortex and premotor area were higher in the right-handed group than that in the left-handed group, whereas the laterality of the inferior parietal lobule had no such significant difference. In both groups, when the difficulty of the task increased, the laterality of the prefrontal cortex, premotor area, and inferior parietal lobule decreased, but the laterality of posterior part of the inferior frontal gyrus increased. CONCLUSIONS: The laterality of the functional brain areas associated with arithmetic calculations can be detected with fMRI. The laterality of the functional areas was related to handedness and task difficulty.

Brain↗
PubMed1986

Development of ultrastructural specializations during the formation of acetylcholine receptor aggregates on cultured myotubes.

The ultrastructure of cultured rat myotubes was examined at stages in the initial assembly of acetylcholine receptor (AChR) aggregates in order to elucidate the role of cell-surface specializations in aggregate formation. Within 4-6 hr, embryonic brain extract (EBX) induces the formation of sites of AChR density elevated 5-9 X above that of surrounding regions, and the appearance of these aggregates is preceded by the formation of clouds of punctate microaggregates (Olek et al., 1983). A video image-intensification system was used to monitor this redistribution of fluorescently labeled AChR, and sites of aggregation were mapped on identified myotubes. After processing the cultures for electron microscopy, thin sections were taken through identified aggregate sites at various stages in assembly. Specializations, including a basal lamina, mound-shaped plasma membrane contours with occasional deep infoldings, and a subjacent dense cytoskeletal specialization, which tended to exclude other cytoplasmic organelles, were associated with newly formed aggregates found 4-6 hr after adding EBX to the cultures. Analysis of random thin sections through EBX-treated and untreated myotubes showed that the extent of specializations of the basal lamina and cytoplasm was approximately threefold greater in cells exposed to EBX for 4 hr, suggesting a concurrent, and possibly interdependent, organization of such specializations with AChR aggregate assembly. Examination of sections through clouds of microaggregates, which formed within 90 min, revealed mound-shaped plasma membrane contours and underlying cytoplasm depleted of organelles but relatively little basal lamina and submembrane cytoskeletal density. These results suggest that the initial stage of AChR aggregate assembly involves relatively subtle changes in the structure of the cell cortex and that the evolution of microaggregates to aggregates may require the formation of additional cytoskeletal and extracellular matrix structures.

Animals↗
PubMed1998

Involvement of p62 nucleoporin in angiotensin II-induced nuclear translocation of STAT3 in brain neurons.

Chronic stimulation of brain neurons by angiotensin II (Ang II) results in a increase in norepinephrine (NE) uptake. This involves stimulation of transcription of NE transporter and tyrosine hydroxylase genes and is associated with translocation of signaling molecules and transcription factors from the cytoplasmic compartment into the neuronal nucleus (). We report here that the phosphorylation of p62, a glycoprotein nucleoporin of the nuclear pore complex (NPC), by MAP kinase is involved in this process. Ang II caused a time-dependent translocation of signal transducers and activators of transcription (STAT3) from the cytoplasmic compartment into the nucleus. This translocation was attenuated by pretreatment with antisense oligonucleotide (AON) to MAP kinase. Ang II also stimulated phosphorylation of p62, and a maximal phosphorylation of 12-fold was observed with 100 nM Ang II. This stimulation was blocked by losartan, an AT1 receptor subtype-specific antagonist. The conclusion that MAP kinase is involved in Ang II-induced phosphorylation of p62 and nuclear translocation of STAT3 is supported by the following. (1) p62 phosphorylation was blocked by a peptide that competes with p62 as a MAP kinase substrate both in vitro and in vivo; (2) AON to MAP kinase attenuated Ang II stimulation of p62 phosphorylation; and (3) in addition, it also blocked nuclear translocation of STAT3. Intracellular loading of the peptide containing MAP kinase substrate consensus of the p62 reduced Ang II stimulation of p62 phosphorylation and nuclear translocation of STAT3 in both in vivo and in vitro experiments. These observations suggest that Ang II-induced phosphorylation of p62 may accelerate the activity of the NPC, which would result in an increase in the nuclear transport of transcription factors and signaling molecules. This will stimulate transcriptional processes associated with Ang II regulation of NE neuromodulation.

Angiotensin II↗
PubMed2004

Towards a new mapping of brain cortex function.

The aim of imaging neuroscience is to describe the functional organization of human brain at the level of large neuronal groupings, networks and systems. The systems level of description addresses how integrated brain functions are embodied in the physical structure of the brain. Magnetic resonance imaging is currently the technique of choice for the study of cerebral structure-function relationships and the analysis of structural and functional brain images can now be carried out automatically using statistical parametric mapping. The resultant ability to perform clinical-functional-anatomical correlative studies with complete objectivity and unparalleled sensitivity is providing powerful new opportunities for studying the relationship between structure and function, and how these parameters interact with pathology. One of the most exciting and dramatic observations to come from human brain mapping has been the dynamic plasticity of function in both normal brains and the brains of patients with neurological and neuropsychiatric disorders. Recent activation studies have provided interesting information about the brain's capacity to reorganize after injury and in association with practice and learning. The emerging studies of brain plasticity and its modulation by drugs and other therapies indicate potentially useful approaches to the rehabilitation of adults with brain damage, including damage resulting from cerebral ischaemia. Brain maps must therefore be viewed as dynamic, changing with development, disease progression, normal learning and in parallel with the recovery of function after acute injury. The dynamic plasticity of functional brain maps provides an exciting opportunity to study these processes.

Brain Mapping↗
PubMed2000

The JNK and P38 MAP kinase signaling pathways in T cell-mediated immune responses.

The mitogen-activated protein (MAP) kinase family members, which include the extracellular response kinases (ERK), p38, and c-Jun amino terminal kinases (JNK), play a role in mediating signals triggered by cytokines, growth factors, and environmental stress. JNK and p38 MAP kinases have been involved in inflammatory processes induced by a variety of stimuli, such as oxidative stress. Here, we describe the role of the JNK and p38 MAP kinase signaling pathways in the development of T cells in the thymus, and activation and differentiation of T cells in the peripheral immune system.

Animals↗
PubMed2003

Statistical density modification using local pattern matching.

A method for improving crystallographic phases is presented that is based on the preferential occurrence of certain local patterns of electron density in macromolecular electron-density maps. The method focuses on the relationship between the value of electron density at a point in the map and the pattern of density surrounding this point. Patterns of density that can be superimposed by rotation about the central point are considered equivalent. Standard templates are created from experimental or model electron-density maps by clustering and averaging local patterns of electron density. The clustering is based on correlation coefficients after rotation to maximize the correlation. Experimental or model maps are also used to create histograms relating the value of electron density at the central point to the correlation coefficient of the density surrounding this point with each member of the set of standard patterns. These histograms are then used to estimate the electron density at each point in a new experimental electron-density map using the pattern of electron density at points surrounding that point and the correlation coefficient of this density to each of the set of standard templates, again after rotation to maximize the correlation. The method is strengthened by excluding any information from the point in question from both the templates and the local pattern of density in the calculation. A function based on the origin of the Patterson function is used to remove information about the electron density at the point in question from nearby electron density. This allows an estimation of the electron density at each point in a map, using only information from other points in the process. The resulting estimates of electron density are shown to have errors that are nearly independent of the errors in the original map using model data and templates calculated at a resolution of 2.6 A. Owing to this independence of errors, information from the new map can be combined in a simple fashion with information from the original map to create an improved map. An iterative phase-improvement process using this approach and other applications of the image-reconstruction method are described and applied to experimental data at resolutions ranging from 2.4 to 2.8 A.

Crystallography, X-Ray↗
PubMed2000

The corticofugal system for hearing: recent progress.

Peripheral auditory neurons are tuned to single frequencies of sound. In the central auditory system, excitatory (or facilitatory) and inhibitory neural interactions take place at multiple levels and produce neurons with sharp level-tolerant frequency-tuning curves, neurons tuned to parameters other than frequency, cochleotopic (frequency) maps, which are different from the peripheral cochleotopic map, and computational maps. The mechanisms to create the response properties of these neurons have been considered to be solely caused by divergent and convergent projections of neurons in the ascending auditory system. The recent research on the corticofugal (descending) auditory system, however, indicates that the corticofugal system adjusts and improves auditory signal processing by modulating neural responses and maps. The corticofugal function consists of at least the following subfunctions. (i) Egocentric selection for short-term modulation of auditory signal processing according to auditory experience. Egocentric selection, based on focused positive feedback associated with widespread lateral inhibition, is mediated by the cortical neural net working together with the corticofugal system. (ii) Reorganization for long-term modulation of the processing of behaviorally relevant auditory signals. Reorganization is based on egocentric selection working together with nonauditory systems. (iii) Gain control based on overall excitatory, facilitatory, or inhibitory corticofugal modulation. Egocentric selection can be viewed as selective gain control. (iv) Shaping (or even creation) of response properties of neurons. Filter properties of neurons in the frequency, amplitude, time, and spatial domains can be sharpened by the corticofugal system. Sharpening of tuning is one of the functions of egocentric selection.

Animals↗
PubMed2004

Automatic beam angle selection in IMRT planning using genetic algorithm.

The selection of suitable beam angles in external beam radiotherapy is at present generally based upon the experience of the human planner. The requirement to automatically select beam angles is particularly highlighted in intensity-modulated radiation therapy (IMRT), in which a smaller number of modulated beams is hoped to be used, in comparison with conformal radiotherapy. It has been proved by many researchers that the selection of suitable beam angles is most valuable for a plan with a small number of beams (< or = 5). In this paper an efficient method is presented to investigate how to improve the dose distributions by selecting suitable coplanar beam angles. In our automatic beam angle selection (ABAS) algorithm, the optimal coplanar beam angles correspond to the lowest objective function value of the dose distributions calculated using the intensity-modulated maps of this group of candidate beams. Due to the complexity of the problem and the large search space involved, the selection of beam angles and the optimization of intensity maps are treated as two separate processes and implemented iteratively. A genetic algorithm (GA) incorporated with an immunity operation is used to select suitable beam angles, and a conjugate gradient (CG) method is used to quickly optimize intensity maps for each selected beam combination based on a dose-based objective function. A pencil-beam-based three-dimensional (3D) full scatter convolution (FSC) algorithm is employed for the dose calculation. Two simulated cases with obvious optimal beam angles are used to verify the validity of the presented technique, and a more complicated case simulating a prostate tumour and two clinical cases are employed to test the efficiency of ABAS. The results show that ABAS is valid and efficient and can improve the dose distributions within a clinically acceptable computation time.

Algorithms↗
PubMed2006

A literature-based similarity metric for biological processes.

BACKGROUND: Recent analyses in systems biology pursue the discovery of functional modules within the cell. Recognition of such modules requires the integrative analysis of genome-wide experimental data together with available functional schemes. In this line, methods to bridge the gap between the abstract definitions of cellular processes in current schemes and the interlinked nature of biological networks are required. RESULTS: This work explores the use of the scientific literature to establish potential relationships among cellular processes. To this end we have used a document based similarity method to compute pair-wise similarities of the biological processes described in the Gene Ontology (GO). The method has been applied to the biological processes annotated for the Saccharomyces cerevisiae genome. We compared our results with similarities obtained with two ontology-based metrics, as well as with gene product annotation relationships. We show that the literature-based metric conserves most direct ontological relationships, while reveals biologically sounded similarities that are not obtained using ontology-based metrics and/or genome annotation. CONCLUSION: The scientific literature is a valuable source of information from which to compute similarities among biological processes. The associations discovered by literature analysis are a valuable complement to those encoded in existing functional schemes, and those that arise by genome annotation. These similarities can be used to conveniently map the interlinked structure of cellular processes in a particular organism.

Databases, Bibliographic↗