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PubMedDate not supplied

Dual role of calmodulin in excitable cells.

Consideration of the enzymatic reactions governing calcium channel phosphorylation and dephosphorylation leads one to deduce that there exist separate groups of enzymes, membrane-bound and cytoplasmic that are activated by a common mediator, calmodulin (CaM), whose time-dependent appearance (via diffusion) at both locales is controlled by both intracellular calcium levels and electrostatic interaction with the membrane. In brief, the change in the sign and extent of the electrical charge borne by the modulator in the presence of calcium (Ca) brings about the electrostatic attraction that enables the transport of [Ca-CaM] to the membrane. This translocation of Ca-CaM makes possible a sequential activation of cellular enzymes whose locations differ. The sequence, both spatial and temporal, of the activation of various cellular enzymes by Ca-CaM appears to be a control network shared in common by excitable cells containing a stimulus-response pathway mediated by second messengers.

Adenylyl Cyclases↗
PubMed2000

A neural mechanism of hierarchical discrimination of odors in the olfactory cortex based on spatiotemporal encoding of odor information.

We propose a neural mechanism for discrimination of different complex odors in the olfactory cortex based on the dynamical encoding scheme. Both constituent molecules of the odor and their mixing ratios are encoded simultaneously into a spatiotemporal activity pattern (limit cycle attractor) in the olfactory bulb [Hoshino O, Kashimori Y, Kambara T (1998) Biol Cybern 79:109-120]. We present a functional model of the olfactory cortex consisting of some dynamical mapping modules. Each dynamical map is represented by itinerancy among the limit cycle attractors. When a temporal sequence of spatial activity patterns corresponding to a complex odor is injected from the bulb to the network of the olfactory cortex, the neural activity state of each mapping module is fixed to a relevant spatial pattern injected. Recognition of an odor is accomplished by a combination of firing patterns fixed in all the mapping modules. The stronger the response strength of the component, the earlier the component is recognized. The hierarchical discrimination of an odor is made by recognizing the components in order of decreasing response strengths.

Discrimination Learning↗
PubMed1990

Topographic segmentation of waking EEG in medication-free schizophrenic patients.

Lehmann has demonstrated that EEG topography can be used to segment EEG map series into a sequence of spatially stationary segments characterized by location of potential maxima and minima. We employed topographic segmentation techniques to study 9 channel EEGs recorded from 11 medication-free schizophrenic patients and 10 normal controls during resting and active task conditions, retesting 8 patients after neuroleptic treatment. To define EEG segments, average reference potential maps corresponding to global field power peaks in theta, alpha, and low beta activity were classified according to locations of extreme minimum and maximum values. Normals and schizophrenics did not differ in the number or types of switches between segments, or the frequency of hemisphere crossing of potential extrema. However, EEGs of normal subjects were characterized by significantly more (P less than 0.003) unused theta segment types (of a theoretically possible 36). Moreover, medication significantly (P less than 0.02) increased the number of unused theta segment types in EEGs of schizophrenics. We interpret these findings as evidence of increased spatial variability of brain electrical activity in schizophrenics and discuss their functional implications.

Adult↗
PubMed1993

MR imaging of fat-containing tissues: valuation of two quantitative imaging techniques in comparison with localized proton spectroscopy.

Since lipid protons, consisting mainly of triacylglycerols (TAG), are rather mobile, magnetic resonance imaging (MRI) is ideally suited for the examination of fat-containing tissues such as bone marrow. In contrast to water protons, however, lipid protons are chemically distinct and give rise to at least eight resonance peaks with different T1 and T2 relaxation times in the 1H spectrum. This is why the characterization of fat-containing tissues by quantitative MRI is much more difficult than that of most other tissues. In our study we wanted to examine the accuracy and the potential of a 1H chemical shift imaging (CSI) technique and a multiple spin-echo imaging (MSEI) technique. A stimulated-echo (STEAM) sequence for spatially localized proton spectroscopy was used as the reference method. In the first part of this paper, we describe quantitative imaging experiments which were performed to assess the accuracy of the fat-water separation according to the Dixon method and the bi-exponential decomposition of the MSEI data. For that purpose, we used a two-compartment phantom filled with either an aqueous Gd-DTPA solution and vegetable oil or with two different aqueous Gd-DTPA solutions, respectively. The analysis of the 1H CSI data revealed that the presence of non-methylen protons in neutral fats leads to a slight under-estimation (of about 15%) of the relative fat fraction. The error is described theoretically and verified quantitatively by STEAM measurements. The bi-exponential analysis of the transverse relaxation data, on the other hand, yields reliable T2 values if the relative proton density of both components is higher than 15%. IN the second part of our investigation, the same techniques were applied to acquire data from the subcutaneous fatty tissue, the femoral head, and the lumbar vertebrae of three healthy volunteers. In the bone marrow spectra, only two broad resonances could be resolved; they were superpositions of diverse molecular groups with different T1 and T2 relaxation times. In these cases, localized proton spectroscopy does not provide additional information with respect to 1H CSI. The MSEI data of the three examined fat containing tissue regions were adequately fitted by a bi-exponential function despite the fact that there were much more chemically distinct protons present in fatty tissues.

Adipose Tissue↗
PubMed2002

Altered GABAergic function accompanies hippocampal degeneration in mice lacking ClC-3 voltage-gated chloride channels.

Mice lacking ClC-3 chloride channels, encoded by the Clcn3 gene, undergo neurodegeneration of the hippocampal formation and retina [Neuron, 29 (2001) 185-196; Genes Cells, 7 (2002) 597-605]. We independently created a mouse lacking the Clcn3 gene which demonstrated similar central nervous system abnormalities, including early postnatal degeneration of retinal photoreceptors. However, we observed a characteristic spatial-temporal sequence of hippocampal neurodegeneration that differs from the pattern previously reported. Anterior-to-posterior degeneration and astrogliosis of the dentate gyrus and hippocampus progressed over months. Sequential loss of hippocampal neuronal subpopulations began in the dentate gyrus and progressed to CA3, followed by CA1 neurons. Projection neurons of the entorhinal cortex degenerated, secondary to the loss of their synaptic targets within the hippocampal formation. Other characteristics of the Clcn3(-/-) mice included an abnormal gait, kyphosis, and absence of hindlimb escape extension upon tail elevation. Spontaneous seizures were observed in four adult Clcn3(-/-) mice, and one mouse died during the event. We hypothesized that neuronal injury may be related to recurrent seizures. Clcn3(-/-) mice had normal serum electrolytes and pH, and exhibited neither hyperglycemia nor rebound hypoglycemia following a glucose load. They displayed a greatly reduced susceptibility to pentylenetetrazole-induced seizures and an abnormally prolonged sedation to benzodiazepines. There was no change in vulnerability to kainic acid-induced seizures. Immunostaining revealed a progressive loss of GABA synthesizing cells in the dentate gyrus. The death of these cells was preceded by increased GABA(A) receptor immunoreactivity. These data suggest that GABA(A) inhibitory neurotransmission is altered in Clcn3(-/-) mice. The increase in GABA(A) receptor density may represent a compensatory response either to chronic excessive excitatory stimuli or reduced inhibitory input from local GABAergic interneurons within the dentate gyrus.

Animals↗
PubMed1996

Visualizing the spatial relationships between defined DNA sequences and the axial region of extracted metaphase chromosomes.

Using fluorescence in situ hybridization to extracted metaphase chromosomes, we present visual evidence that specific human DNA sequences occupy distinctive positions with respect to the axial region of chromosomes and that the DNA is organized into loops emanating from this region. In a stretch of unique DNA on chromosome 11, large loops of DNA can be traced and one specific region associated with the axial region of the chromosome. Within rDNA, nontranscribed spacer sequences are more closely apposed to the chromosome axis than are rRNA genes. Heterochromatic and euchromatic DNAs appear to be organized into loops of similar size. We could not detect loops at centromeres; most alphoid DNA appears to remain close to the axial region.

Centromere↗
PubMedDate not supplied

Phosphorylation of tau, Abeta-formation, and apoptosis after in vivo inhibition of PP-1 and PP-2A.

Chronic inhibition of protein phosphatases 1 and 2A in vivo was induced by infusion of okadaic acid into lateral ventricles of rat brain for up to 4 months. Cytoskeletal pathology, alterations of the amyloid precursor protein, and apoptotic cell death induced by this treatment followed a certain sequence and spatial distribution. Changes in the expression, phosphorylation, and subcellular distribution of neurofilament proteins and tau, as well as first signs of apoptotic cell death, occurred already after about 2 weeks. The distribution of apoptotic cells, however, was different from those revealing a high accumulation of hyperphosphorylated tau, indicating that those cytoskeletal pathology had no obvious sequelae for the viability of these neurones. A continuation of treatment for longer than 2 weeks induced diffuse deposits of both hyperphosphorylated tau and A beta-amyloid-immunoreactive material in white matter areas that increased in size and number over time. Because tau-phosphorylation is a regulator of the dynamic stability of microtubules, the pathology observed in the present experimental paradigm in the white matter might be viewed as an indication of a disturbed axonal transport. It is hypothesized that perturbations of the axonal transport might also be critically involved in the formation of paired helical filaments and amyloid deposits in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1998

The latest in ultrasound: three-dimensional imaging. Part II.

INTRODUCTION: The three-dimensional (3D) reconstruction of ultrasound images has become a widespread option in ultrasound equipment. Specific softwares have become available and 3D reconstruction feasible since the early 1990s, particularly since 1994. POSSIBLE CLINICAL APPLICATIONS: Several clinical applications are feasible in all parenchymatous organs (mainly the liver and prostate), hollow viscera (e.g. the bladder and gallbladder), peripheral vessels (supra-aortic trunks and limb vessels) and central (the aorta and iliac arteries) or cerebral vessels. Moreover, tumoral vessels in parenchymatous organs can be reconstructed, and even the fetus in the uterine cavity, with excellent detailing. The recent introduction of echocontrast agents and second harmonic imaging has permitted to study normal and abnormal peripheral, central and parenchymatous vessels, with similar patterns to those obtained with digital angiography. The spatial relationships between the vascular structures of the liver, kidney and placenta were studied with 3D ultrasound angiograms. The applications of this new technique include the analysis of vascular anatomy and the potential assessment of organ perfusion. THE LATEST APPLICATIONS--INTRAVASCULAR STUDIES: Some catheters with an ultrasound transducer in the tip have been tested for intravascular studies. Just like conventional transducers, they provide two-dimensional (2D) images which are then postprocessed into longitudinal 3D or volume reconstructions. The former resemble angiographic images and can be viewed 3D rotating the image along its longitudinal axis. Volume images, which are more complex and slower to obtain, can be rotated on any spatial plane and provide rich detailing of the internal vascular lumen. The clinical importance of intravascular ultrasound with 3D volume reconstructions lies in the diagnosis of vascular conditions and the assessment and monitoring of intravascular interventional procedures--e.g. to detect inaccurate deployment of intravascular stents and endoluminal grafts during the maneuver. Three-dimensional reconstructions involve geometric data assembly and volumetric interpolation of a spatially related sequence of tomographic cross sections generated by an ultrasound catheter withdrawn at a constant rate through a vascular segment of interest, resulting in the display of a straight segment. Therefore particular care is needed and there are some useful hints to avoid mistakes. CONCLUSIONS: Three dimensional reconstructions of B-mode and color Doppler images are no longer a work in progress and their clinical importance and possible applications are both established and ever-increasing. On the other hand, independent of the different types of energy used, also computed tomography and magnetic resonance 3D reconstructions are very useful from a clinical viewpoint and they have become an established routine technique for both these methods. It is very likely that 3D volume reconstructions in ultrasound will find numerous applications in the near future. They may help to increase the diagnostic confidence and to facilitate diagnosis, intraprocedure monitoring in interventional radiology and follow-up and also to reduce the number of invasive examinations with iodinated contrast agents. This could result in cutting the cost and duration of the most expensive examinations. New, although invasive, applications can be hypothesized for intravascular or intraluminal catheters with an ultrasound transducer inside.

Blood Vessels↗
PubMed2000

Dynamic brain topography of somatosensory evoked potentials and equivalent dipoles in response to graded painful skin and muscle stimulation.

The differential effects of painful stimulation of skin vs. muscle on the cerebral electrophysiology have been poorly described. This study examined the somatosensory evoked potentials (SEPs) and the associated dipole models of non-painful and graded painful electrical stimulation applied to the skin and muscle in 20 healthy subjects. With the psychophysical stimulus-response functions determined, the skin stimulation showed a steeper slope than muscle stimulation. For both types of stimulation, the SEPs indicated a similar temporo-spatial activation sequence: F4/N90-P4/P95, Fc2/N135, Cz/P250, Cz/P300, and Cz/N460. The SEP amplitudes increased significantly with the stimulus intensities in these components. The peak SEP latencies of skin stimulation were in general shorter than that of muscle stimulation. The SEP amplitudes to skin stimulation were significantly larger than those caused by muscle stimulation at every stimulus intensity level, except the early mid-latency component. In this case, muscle stimulation caused higher amplitudes over the contralateral parietal-frontal sites. For both types of stimulation, the topographic maps were quite similar. Equivalent dipole modeling revealed identical site parameters (<1.0 cm) between skin and muscle stimulation. However, the electrical skin stimulation did not correlate with the pain intensity. Pain intensity, in contrast, was uniquely associated with the Cz/P250 amplitudes for the muscle stimulation. It is concluded that non-nociceptive and nociceptive electrical stimuli applied to skin and muscle are processed in the common cerebral areas, but exhibit differential SEP effects.

Adult↗
PubMed1996

Correct Hox gene expression established independently of position in Caenorhabditis elegans.

The Hox genes are expressed in a conserved sequence of spatial domains along the anteroposterior (A/P) body axes of many organisms. In Drosophila, position-specific signals located along the A/P axis establish the pattern of Hox gene expression. In the nematode Caenorhabditis elegans, it is not known how the pattern of Hox gene expression is established. C. elegans uses lineal control mechanisms and local cell interactions to specify early blastomere identities. However, many cells expressing the same Hox gene are unrelated by lineage, suggesting that, as in Drosophila, domains of Hox gene expression may be defined by cell-extrinsic A/P positional signals. To test this, we have investigated whether posterior mesodermal and ectodermal cells will express their normal posterior Hox gene when they are mispositioned in the anterior. Surprisingly, we find that correct Hox gene expression does not depend on cell position, but is highly correlated with cell lineage. Thus, although the most striking feature of Hox gene expression is its positional specificity, in C. elegans the pattern is achieved, at least in part, by a lineage-specific control system that operates without regard to A/P position.

Animals↗
PubMed2026

Spatiotemporal single-cell profiling reveals T cell clonal dynamics and phenotypic plasticity in human graft-versus-host disease.

Allogeneic hematopoietic cell transplantation cures hematologic diseases but is limited by acute graft&#x2011;versus&#x2011;host disease. How human T cell clones drive epithelial injury remains poorly mapped. We studied 31 transplant recipients, integrating longitudinal T cell antigen receptor (TCR) profiling with single-cell RNA sequencing/TCR sequencing and spatial transcriptomics to track T cell clonal dynamics. We developed DecompTCR to resolve temporal dynamics and adapted computational tools to map clone phenotypes and niches in tissue. Our analyses revealed that cyclophosphamide selectively depletes alloreactive clones, although insufficient early expansion leads to incomplete depletion and severe disease. Severe graft&#x2011;versus&#x2011;host disease is marked by persistent expansion of alloreactive clones, rewiring of homeostatic cell types and diversification of donor-derived CD8+ clonotypes that acquire Hobit (ZNF683)+ tissue&#x2011;resident memory T (TRM) cell programs during migration to epithelium. Spatial deconvolution identified CD8+ effector/Hobit+ TRM hubs near intestinal stem&#x2011;cell-rich crypt bases and crypt&#x2011;loss regions. This clonotype&#x2011;resolved framework links tissue&#x2011;instructed TRM cell remodeling to localized epithelial injury, nominating early-repertoire dynamics and spatial hub burden as biomarkers.

Journal Article↗
PubMed1990

Cellular sources of noncollagenous matrix proteins: role of fat-storing cells in fibrogenesis.

The main types of noncollagenous ECM proteins in liver are FN, laminin, PGs and elastin. Also present is a pure carbohydrate polymer, hyaluronic acid. Their concentrations increase during fibrogenesis in a specific sequence and spatial distribution. FN is among the first to appear. The accumulation of matrix proteins in the space of Disse (perisinusoidal fibrosis) is most important for some clinical consequences of fibrosis. Perisinusoidal FSC are the cell type responsible for exaggerated ECM formation at sites of tissue injury, since these cells synthesize at a high rate in vitro all the noncollagenous matrix components occurring in fibrotic liver matrix (FN, laminin, dermatan sulfate, chondroitin sulfate, hyaluronic acid) and since FSC proliferate and transform into myofibroblast-like cells with an enhanced matrix protein synthesis rate. Recent experimental data suggest strong cellular cooperation of these cells with activated liver macrophages or Kupffer cells, platelets, and regenerating hepatocytes, which leads via a paracrine mechanism involving TGF beta, TGF alpha/EGF, PDGF, and probably other cytokines to stimulated proteoglycan synthesis, proliferation, and transformation into myofibroblast-like cells. The latter cell type has the potential of auto-stimulation (by an autocrine process) involving secretion of TGF beta and TGF alpha/EGF. Based on these findings, a model of FSC activation is proposed (Fig. 10).

Animals↗
PubMed1998

Memory performances in young, elderly, and very old healthy individuals versus patients with Alzheimer's disease: evidence for discontinuity between normal and pathological aging.

In this study we compared memory performances of 29 probable patients with AD (17 mildly and 12 moderately demented) with those of 39 healthy young subjects, 36 elderly subjects (matched with the AD group for age and years of schooling), and 19 healthy very old subjects. In most of the memory tasks used in the present study, a progressive decline in performance was observed passing from the Young to the Elderly to the Very Old to the AD group. However, patients with AD were selectively impaired in the backward reproduction of verbal and spatial span sequences and in the semantic encoding of verbal material. These data are consistent with the hypothesis of not only quantitative but also a qualitative discontinuity between the process of normal aging and the dementia syndrome.

Adult↗
PubMed1988

Non-invasive measurement of pulmonary arterial pressure: II. A radionuclide method.

Pulmonary artery pulse pressure (PP) and diastolic pressure (Pd) may be obtained by applying a haemodynamic model of blood flow kinetics and wall mechanics to the pulmonary artery: Pp = rho(ws/(Ss/Sd-1))2log(Ss/Sd)-1/2 rho w2s Pd = (Sd/Ss)1/2Pp where rho is blood density, ws is peak ejection velocity, and Ss and Sd are peak maximal and end diastolic cross-sectional areas of the main pulmonary artery. The different parameters of the equations were measured from radionuclide first pass and equilibrium studies. Radionuclide first pass studies were performed in 24 patients with intravenous injection of 20 mCi of 99Tcm red blood cells with a gamma camera in a 20 degrees right anterior oblique position: data were collected in list mode, i.e. a continuous sequence of spatial and temporal coordinates of each photon. Pulmonary arterial pressure was recorded simultaneously with a microtip catheter during the first pass study. Gated first pass images of the right side of the heart were reconstructed, regions of interest drawn over the right ventricle and the main pulmonary artery (MPA) and time-activity curves generated. Peak systolic (Cs) and end diastolic (Cd) counts obtained from the MPA curve were proportional to the cross sections Ss and Sd of the MPA and Ss/Sd = Cs/Cd. The diameter (D) of the pulmonary artery was calculated as the distance between the two zeros of the second derivative of a cross-sectional profile. The averaged cross-sectional area was S = pi D2/4. ECG gated blood pool studies were performed in a LAO 40 degrees position when the tracer was at equilibrium; they were processed automatically and the right ventricular end diastolic counts (EDC) converted into volume (EDV) using an aortic volume/count ratio. Right ventricular peak ejection rate (PER) was obtained from the RV time-activity curve and the instantaneous peak ejection velocity was calculated, ws = PER X EDV/S X EDC. PP and Pd were calculated in mmHg and the radionuclide method yielded pressure values that correlated reasonably with catheterisation values: PP(rad) = 0.99 PP(cath)-0.55, r = 0.84 and Pd(rad) = 0.67 Pd(cath) + 4.91, r = 0.74. We conclude that radionuclide techniques can provide a non-invasive method based on a haemodynamic model for measuring pulmonary arterial pressure.

Adult↗
PubMed1998

The functional neuroanatomy of simple and complex sequential finger movements: a PET study.

The brain regions activated by simple repetitive and sequential finger movements of different length were localized by measuring regional cerebral blood flow (rCBF) with PET. The experimental design consisted of finger movements cued by auditory pacing at 0.5 Hz. In all conditions of different sequence length the contralateral primary sensorimotor and premotor cortex, supplementary motor area and ipsilateral cerebellar cortex were activated. These areas showed a large increase in activation from rest to simple repetitive movement, and a further increase with the shortest sequence, suggesting an executive role in running sequences. The ipsilateral premotor area (Brodmann area 6), bilateral posterior parietal areas (Brodmann area 7) and precuneus showed an increase in rCBF related only to the length of the sequences, without any change from rest to simple repetitive movement. These areas are more selectively related to sequence performance. This finding is consistent with the hypothesis that these areas function in the storage of motor sequences in spatial working memory. Our results suggest that sequential finger movements recruit discrete sets of brain areas with different functions.

Adult↗
PubMed1995

Compartmentalization of specific pre-mRNA metabolism: an emerging view.

It is increasingly recognized that the mammalian interphase nucleus contains a number of non-membranous compartments in which macromolecules associated with different nuclear functions concentrate. This review focuses on the function of a major compartment consisting of domains highly enriched in pre-mRNA splicing components and poly (A) RNA, commonly identified by the splicing factor, SC-35. RNA synthesis, as judged interdomain space. However, uridine labels several types of nuclear RNA, only a fraction of which is pre-mRNA, and such studies cannot address the question of whether specific genes are transcribed in specific places. Similarly, interpretations of transcriptional inhibition studies are compromised by the global impact that inhibition has on nuclear structure and function, and by conflicting results. Localization of specific protein coding genes or RNAs circumvents these limitations. For several sequences studied thus far, a non-random relationship to SC-35 domains has been observed, with most, but not all, active genes encoding intron-containing pre-mRNAs showing a very high degree of association. In some cases this was directly demonstrated to be the site of transcription and processing. Consistent with earlier uridine incorporation studies, we have found that transcription occurs at the outer edge of the SC-35 domain, likely corresponding to the border of ultrastructures termed interchromatin granule clusters. These preliminary glimpses into gene localization strongly argue for a sequence-specific spatial association of some transcriptionally active genes with SC-35 domains, and suggest an integrated functional organization of the genome with these nuclear compartments enriched in splicing factors and poly (A) RNA.

Animals↗