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PubMed1987

Age and regional cerebral blood flow at rest and during cognitive activity.

The relationship between age and regional cerebral blood flow (rCBF) activation for cognitive tasks was investigated with the xenon Xe 133 inhalation technique. The sample consisted of 55 healthy subjects, ranging in age from 18 to 72 years, who were studied during rest and during the performance of verbal analogy and spatial orientation tasks. The dependent measures were indexes of gray-matter rCBF and average rCBF (gray and white matter) as well as the percentage of gray-matter tissue. Advanced age was associated with reduced flow, particularly pronounced in anterior regions. However, the extent and pattern of rCBF changes during cognition was unaffected by age. For the percentage of gray matter, there was a specific reduction in anterior regions of the left hemisphere. The findings suggest the utility of this research paradigm for investigating neural underpinnings of the effects of dementia on cognitive functioning, relative to the effects of normal aging.

Adolescent↗

PubMed1998

Immunocytochemical demonstration of locustatachykinin-related peptides in the central complex of the locust brain.

The central complex, a highly ordered neuropil area in the insect brain, plays a role in motor control and spatial orientation. To further elucidate the neurochemical architecture of this brain area, we have investigated the distribution and morphology of neurons containing locustatachykinin I/II-related substances in the central complex of the locust Schistocerca gregaria. The central complex is innervated by at least 66 locustatachykinin I/II-immunoreactive neurons, which belong to two sets of tangential neurons and four sets of columnar neurons. These neurons give rise to immunostaining in the protocerebral bridge, in several layers of the upper division of the central body, and in all layers except layer 5 of the lower division of the central body. Double-label experiments show colocalization of immunoreactivity for both locustatachykinin I/II and octopamine in tangential neurons of the protocerebral bridge. A pair of tangential neurons of the lower division of the central body exhibits both locustatachykinin I/II and gamma-aminobutyric acid (GABA) immunoreactivity. A set of 16 columnar neurons of the lower division of the central body shows colocalized immunoreactivity for locustatachykinin II, leucokinin, and substance P. This study reveals novel features of the anatomical organization of the locust central complex and suggests a prominent role for locustatachykinin-related peptides as neuromediators and cotransmitters within this brain area.

Animals↗

PubMed1999

Afferent and efferent connections of the caudolateral neostriatum in the pigeon (Columba livia): a retro- and anterograde pathway tracing study.

The avian caudolateral neostriatum (NCL) was first identified on the basis of its dense dopaminergic innervation. This fact and data from lesion studies have led to the notion that NCL might be the avian equivalent of prefrontal cortex (PFC). A key feature of the PFC is the ability to integrate information from all modalities needed for the generation of motor plans. By using antero- and retrograde pathway tracing techniques, we investigated the organization of sensory afferents to the NCL and the connections with limbic and somatomotor centers in the basal ganglia and archistriatum. Data from all tracing experiments were compared with the distribution of tyrosine-hydroxylase (TH)-immunoreactive fibers, serving as a marker of dopaminergic innervation. The results show that NCL is reciprocally connected with the secondary sensory areas of all modalities and with at least two parasensory areas. Retrograde tracing also demonstrated further afferents from the deep layers of the Wulst and from the frontolateral neostriatum as well as the sources of thalamic input. Efferents of NCL project onto parts of the avian basal ganglia considered to serve somatomotor or limbic functions. Projections to the archistriatum are mainly directed to the somatomotor part of the intermediate archistriatum. In addition, cells in caudal NCL were found to be connected with the ventral and posterior archistriatum, which are considered avian equivalents of mammalian amygdala. All afferents and projection neurons were confined to the plexus of densest TH innervation. Our results show that the NCL is positioned to amalgamate information from all modalities and to exert control over limbic and somatomotor areas. This organization might comprise the neural basis for such complex behaviours as working memory or spatial orientation.

Afferent Pathways↗

PubMed1999

Morphologic representation of visual and antennal information in the ant brain.

Ants in general are primarily olfactory animals, but many species also express visual behaviors. We analyze in 14 species, which range from purely olfactory to predominantly visually behaving ants, how the brains are equipped to control such behavior. We take the size and manifestation of the eyes as an indicator for the prevalence of vision in a given species, and we correlate it with the size of particular brain regions. Our morphometric data show that the size of the eyes generally correlates well with that of the optic lobes. The antennal lobes and the mushroom bodies have a surprisingly constant relative volume whereas, as expected, the relative size of the optic lobes varies strongly across species. Males of different species are more similar. Compared with workers, they all have large eyes, relatively larger optic lobes, smaller mushroom bodies, and similarly sized antennal lobes. The input regions of the mushroom bodies, the lip and the collar, generally correlate with the size of the optic and antennal lobe, respectively. Accordingly, the composition of the calyx reflects the importance of vision for the animal. We present data supporting the view that the mushroom bodies may participate in spatial orientation, landmark recognition, and visual information storage.

Animals↗

PubMed1998

Combination of digital image analysis and polarization microscopy: theoretical considerations and experimental data.

The potentialities of polarization microscopy has been greatly increased by using specific stains for selective enhancement of the optical anisotropy of a macromolecular constituent of cells and tissues. Such stainings have proved to be especially useful in exploring the spatial orientation pattern of the extracellular matrix components. The retardation value, which characterizes quantitatively the degree of submicroscopic orientation, can be measured traditionally with a compensator plate. This technique, however, is time-consuming and greatly dependent on visual judgment. Several attempts have been made to combine digital image analysis and polarization microscopy to improve the measuring technique in unstained structures. In this paper, we summarize theoretical considerations and experimental data to show the advantages and limitations of this methodological approach when using stained and birefringent specimens. The technique we are suggesting is the measurement of the light intensity using a 12 bit cCCD camera attached to a polarized light microscope and digital image analysis system. The theoretical basis is given by the Fresnel equation describing the relationship between light intensity and retardation value. According to this, there is a sin2 function between the light intensity and the retardation value. The same relationship of these two parameters was observed in our experiments on the birefringent extracellular matrix around chondrocytes grown in agarose gel and interterritorial and territorial matrix of canine articular cartilage stained with picrosirius red. Our results suggest that the retardation values can be calculated directly from the light intensity values if the retardation value is lower than lambda/2.

Animals↗

PubMed2000

DC-ELF characterization of random mixtures of piecewise nonlinear media.

Biological tissues are ensembles of linear and nonlinear, symmetric and asymmetric constituents. As far as their electromagnetic characterization is concerned, they can be modeled as microscopic mixtures of the corresponding material media. Any medium volume can be properly discretized in a finite number of cells which can be modeled as an equivalent three dimensional network of lumped components, in order to characterize its electromagnetic behavior at wavelengths much longer than the relevant average linear size of the constitutive cells. Therefore, any mixture and the corresponding tissue can be characterized in terms of its effective conductance at extremely low frequency, with respect to a reference set of electrodes (ports of the equivalent network). When the above procedure is implemented for evaluating any of the aforesaid conductances, a resulting nonlinear characteristic should be expected. In reality, it may happen that the effect of the constitutive nonlinearities and the related asymmetries are smeared out by the randomness of the interconnections of the lumped components, leading at a macroscopic level to an isotropic constant equivalent conductance, i.e., to an isotropic constant equivalent conductivity of the mixture. The closed form analysis of a random network of nonlinear (piecewise linear) resistors offers a simple but clear cut example of such a property. This result, if extrapolated to biological media, suggests a new hint for explaining why there is no inconsistency between the typical electric characterization of biological tissues as almost linear macroscopic media, by means of their effective conductivity and permittivity, and the nonlinearities of the biochemical processes occurring in the tissue cells. In fact, the nonlinearities may not be observable by means of macroscopic electrical measurements because of the randomized spatial orientation and location of the processes.

Animals↗

PubMed2000

Prospective multiaxial motion correction for fMRI.

Corruption of the image time series due to interimage head motion limits the clinical utility of functional MRI. This paper presents a method for real-time prospective correction of rotation and translation in all six degrees of rigid body motion. By incorporating an orbital navigator (ONAV) echo for each of the sagittal, axial, and coronal planes into the fMRI pulse sequence, rotation and translation can be measured and the spatial orientation of the image acquisition sequence that follows can be corrected prospectively in as little as 160 msec. Testing of the method using a computerized motion phantom capable of performing complex multiaxial motion showed subdegree rotational and submillimeter translational accuracy over a range of +/-8 degrees and +/-8 mm of motion. In vivo images demonstrate correction of simultaneous through-plane and in-plane motion and improved detection of fMRI activation in the presence of head motion.

Artifacts↗

PubMed1981

S-phase fractions of colorectal carcinomas related to pathologic and clinical features.

The S-phase fractions (SPFs) of epithelial cells in 100 resected colorectal carcinomas were measured by in vitro exposure to tritiated thymidine and autoradiography. The frequency distribution of SPFs was gaussian with a median of 17.8 per hundred in 90 unirradiated carcinomas, whereas in ten carcinomas given radiation therapy preoperatively, it was positively skewed with a median of 6.9. Analysis of the unirradiated carcinomas showed no relationship between SPF and various clinical and morphologic features that included age, race, sex, site, size, Dukes' stage, histologic grade of the tumor, number of metastasis-bearing regional lymph nodes, presence of adenomas of the large bowel, survival or relapse-free survival of the patient, or SPF or adjacent normal colorectal crypts. The results show no evidence that colorectal carcinomas can be divided into kinetic subsets. The spatial orientation of labeled cells in autoradiographs indicated presence of a nonproliferative fraction of cells in many tumors that may modulate response to radiation therapy and chemotherapy.

Adenocarcinoma↗

PubMed2000

Conotruncal anomalies in the trisomy 16 mouse: an immunohistochemical analysis with emphasis on the involvement of the neural crest.

The trisomy 16 (Ts16) mouse is generally considered a model for human Down's syndrome (trisomy 21). However, many of the cardiac defects in the Ts16 mouse do not reflect the heart malformations seen in patients suffering from this chromosomal disorder. In this study we describe the conotruncal malformations in mice with trisomy 16. The development of the outflow tract was immunohistochemically studied in serially sectioned hearts from 34 normal and 26 Ts16 mouse embryos ranging from 8.5 to 14.5 embryonic days. Conotruncal malformations observed in the Ts 16 embryos included double outlet right ventricle, persistent truncus arteriosus, Tetralogy of Fallot, and right-sided aortic arch. This spectrum of malformations is remarkably similar to that seen in humans suffering from DiGeorge syndrome (DGS). As perturbation of neural crest development has been proposed in the pathogenesis of DGS we specifically focussed on the fate of neural crest derived cells during outflow tract development of the Ts16 mouse using an antibody that enabled us to trace these cells during development. Severe perturbation of the neural crest-derived cell population was observed in each trisomic specimen. The abnormalities pertained to: 1) the size of the columns of neural crest-derived cells (or prongs); 2) the spatial orientation of these prongs within the mesenchymal tissues of the outflow tract; and 3) the location in which the neural crest cells interact with the myocardium. The latter abnormality appeared to be responsible for ectopic myocardialization found in trisomic embryos. Our observations strongly suggest that abnormal neural crest cell behavior is involved in the pathogenesis of the conotruncal malformations in the Ts16 mouse.

Animals↗

PubMed2001

Wedgelike glycodendrimers as inhibitors of binding of mammalian galectins to glycoproteins, lactose maxiclusters, and cell surface glycoconjugates.

Galectins are mammalian carbohydrate-binding proteins that are involved in cell-cell and cell-matrix adhesion, cell migration, and growth regulation with relevance to inflammation and tumor spread. These important functions account for the interest to design suitable low molecular weight inhibitors that match the distinct modes of presentation of the carbohydrate recognition domains of the different galectin subfamilies. Using 3,5-di-(2-aminoethoxy)benzoic acid as the branching unit, wedgelike glycodendrimers with two, four, and eight lactose moieties (G1-G3) were synthesized. They were tested in solid-phase competition assays with lactose maxiclusters and various N-glycan branching profiles (miniclusters) as the matrix and also in cell assays. Prototype galectins-1 and -7, chimera-type galectin-3, a plant (AB)(2) toxin, and a lactose-binding immunoglobulin G fraction from human serum were the carbohydrate-binding targets. Potent inhibition and remarkable cluster effects were seen for the homodimeric galectin-1, especially in combination with biantennary N-glycans as the matrix. Remarkably, for the tetravalent G2 glycodendrimer, the inhibitory potency of each lactose unit reached a maximum value of 1667 relative to free lactose. In haemagglutination experiments as a model for cell adhesion, galectin-3 was markedly sensitive to increased sugar valency and a relative potency per lactose of 150 was reached. The spatial orientation of the carbohydrate recognition domains of the endogenous lectins and the branching pattern of the carbohydrates of the glycoprotein matrices used are both important factors in the design and synthesis of glycodendrimers with galectin-selective properties.

Animals↗

PubMed2001

Diastereoselective formation of host-guest complexes between a series of phosphate-bridged cavitands and alkyl- and arylammonium ions studied by liquid secondary-ion mass spectrometry.

The reactions occurring between a new class of cavitands that carry up to four dioxaphosphocin binding units and alkyl- and arylammonium ions was investigated by liquid secondary-ion mass spectrometry (LSIMS). As the cavitands existed as distinct diastereomers with different spatial orientation of their binding groups, these geometrical differences proved to have a dramatic influence on their chemical properties, including their ability to form host-guest complexes. In practice, only the cavitands that carry at least three P=O groups oriented toward the inside of the cavity were demonstrated to be strong ligands toward organic ammonium ions, whereas those with only two converging binding groups (either adjacent or opposite in the cavitand structure) still formed host-guest complexes, but they were much weaker. Adjacent binding sites proved to be more effective in interacting with organic ammonium ions than those lying in opposite positions. The isomers with no converging P=O groups did not act as molecular receptors. Even the isomer with one group oriented toward the inside of the cavity did not form host-guest complexes, as the absence of synergistic hydrogen bonding made the interaction from inside the cavity energetically equivalent (or even less favorable) to the outside binding. The presence in the cavitand structure of substituents with an electron-donating character proved to increase the proton affinity of the P=O binding groups and, consequently, their binding energy. The strong proton affinity of the cavitands led to the formation of stable host-guest complexes, as confirmed by the collisionally activated dissociation experiments. Effects of steric hindrance were weak, at least for the cavitands with three converging P=O groups. This confirmed that the cavity has a wide and readily accessible opening. The relative complexation constants were measured for the various guests, yielding scales of relative affinity toward each cavitand. These relative constants may represent thermodynamic values referred to the matrix used in LSIMS experiments, namely 3-nitrobenzyl alcohol (NBA), provided that kinetically controlled selvedge processes are negligible. Absolute complexation constants could not be obtained on account of the unknown pH and the protonation constant in the NBA matrix.

Journal Article↗

PubMed1990

Angular homeostasis: VI. Threshold processes with bivariate liabilities.

The general structure of the threshold model of multifactorial determination is discussed. It is supposed that in place of a single liability (in Falconer's sense) there are two separate liabilities; and whether or not the pathological trait is present depends on a non-additive interaction between the liabilities, so that the region has curved boundaries. The genetics of ontogeny of a process involving spatial orientation (e.g., cardiac ontogeny) is used as a substantive illustration. Genetic analysis of the trait (as contrasted with the liabilities) yields results that on the one hand may seem quite counterintuitive, yet on the other hand they correspond to the kind of bizarre patterns encountered in quasi-empirical genetic counseling for cleft palate or neural tube defect. The impact of refinement of phenotype made possible by non-invasive methods is sketched. This model can be generalized to any number of liabilities, independent or not.

Embryonic and Fetal Development↗

PubMed2004

Interactive web-based programs to teach functional anatomy: the pterygopalatine fossa.

Certain areas of the body contain structures that are difficult to envision in their proper spatial orientations and whose functions are complex and difficult to grasp. This is especially true in the head, where many structures are relatively small and inaccessible. To address this problem, we are designing Web-based programs that consist of high-resolution interactive bitmap illustrations, prepared using Adobe Photoshop, and vector-based animations, prepared via Macromedia Flash. Flash action script language is used for the animations. We have used this approach to prepare a program on the pterygopalatine fossa, an important neurovascular junction in the deep face that is especially difficult to approach by dissection and to depict in static images in an atlas. The program can be viewed online at http://cds.osr.columbia.edu/anatomy/ppfossa/. A table of contents simplifies navigation through the program and a menu enables the user to identify each of the vascular and neuronal components and either to insert or to remove each from its position in the fossa. The functional anatomy of the nerves in the fossa is animated. For example, users can activate and subsequently follow action potentials as they course along axons to their targets. This high degree of interactivity helps promote learning.

Anatomy, Cross-Sectional↗

PubMed2003

Regulation of heart morphology: current molecular and cellular perspectives on the coordinated emergence of cardiac form and function.

BACKGROUND: During early heart development, in addition to cells being induced to differentiate into cardiomyocytes, pathways are activated that lead to cardiac morphogenesis or the development of form. METHODS: Orchestration of organogenesis involves the incremental activation of regulatory pathways that lead to pivotal transition points, such as cardiac compartment delineation and looping. Each embryonic stage sets up the correct patterning of morphoregulatory molecules that will regulate the next process, until an organ is formed from the mesoderm layer after gastrulation. The current review provides an understanding of the morphoregulatory, cell adhesion and extracellular matrix-mediated, processes that coordinate development of heart form with that of function. The period reviewed encompasses the formation of a definitive cardiac compartment from the lateral plate mesoderm to the time-point in which the single, beating heart tube loops directionally to the right. Looping results in the correct spatial orientation for subsequent modeling of the four-chambered heart. Even subtle alterations in looping can form the basis upon which malformations of the inlet or the outlet regions of the heart, or both, are superimposed. RESULTS: In the future, DNA microarray data sets may allow modeling the specific sequence of gene regulatory dynamics leading to these transition points to discover the regulatory "modes" that the cells adopt during heart organogenesis. The regulatory genes, however, can only specify the proteins that will be present. CONCLUSIONS: To fully understand the timing and mechanisms underlying heart development, it is necessary to define the sequential synthesis, patterning, and interaction of the proteins, and of still other receptors, which eventually drive cells to organize into functioning organs.

Animals↗

PubMed2006

Backbone dynamics of human parathyroid hormone (1-34): flexibility of the central region under different environmental conditions.

The presence of a stable tertiary structure in the bioactive N-terminal portion of parathyroid hormone (PTH), a major hormone in the maintenance of extracellular calcium homeostasis, is still debated. In this work, 15N relaxation parameters of the 33 backbone amides of human PTH(1-34) were determined in phosphate-buffered saline solution (PBS) and in the presence of dodecylphosphocholine (DPC) micelles. The relaxation parameters were analyzed using both the model-free formalism (G. Lipari and A. Szabo, Journal of the American Chemical Society, 1982, Vol. 104, pp. 4546-4549) and the reduced spectral density functions approach (J.-F. Lefevre, K. T. Dayie, J. W. Peng, and G. Wagner, Biochemistry, 1996, Vol. 35, pp. 2674-2686). In PBS, the region around Gly12 possesses a high degree of flexibility and the C-terminal helix is less flexible than the N-terminal one. In the presence of DPC micelles, the mobility of the entire molecule is reduced, but the stability of the N-terminal helix increases relative to the C-terminal one. A point of relatively higher mobility at residue Gly12 is still present and a new site of local mobility at residues 16-17 is generated. These results justify the lack of experimental nuclear Overhauser effect (NOE) restraints with lack of tertiary structure and support the hypothesis that, in the absence of the receptor, the relative spatial orientation of the two N- and C-terminal helices is undefined. The flexibility in the midregion of PTH(1-34), maintained in the presence of the membrane-mimetic environment, may enable the correct relative disposition of the two helices, favoring a productive interaction with the receptor.

Amino Acid Sequence↗

PubMed1991

Molecular conformation of a D,L stereoisomeric analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D-Hyi)-].

The crystal structure of a synthetic analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D -Hyi)-] ([L-Val1, L-Val5]meso-valinomycin), C60H102N6O18, has been determined. Crystals grown from petroleum ether are orthorhombic, space group P2(1)2(1)2(1), with cell parameters a = 16.41(1), b = 18.76(1), c = 25.86(1) A, and Z = 4. The atomic coordinates for nonhydrogen atoms, except those of terminal carbons on one side chain, were refined in the anisotropic thermal motion approximation. The coordinate parameters of the H atoms were incorporated into the structure factor calculations at geometrically expected positions. Values of the standard and weighted R factors after refinement are 0.074 and 0.083, respectively. The crystal structure of the molecule is asymmetric and adopts a conformation with four 4----1 type and one 6----1 type intramolecular hydrogen bonds between amide nitrogens and carbonyl oxygens. Valinomycin binds potassium more than 100 times strongly than the D,L stereoisomeric analogue, as a result of a different spatial orientation of potentially interacting carbonyl groups.

Amino Acid Sequence↗

PubMed1993

Characterization of the bioactive form and molecular determinants of recognition of cyclic enkephalin peptides at the delta-opioid receptor.

An extensive and systematic search strategy to determine the conformational profile of 12 cyclic disulfide-bridged opioid peptides with varying affinities at the delta receptor has been carried out to identify the structure that is recognized by the delta receptor for each analogue. The methods and procedures used here for the conformational search have already been validated for [D-Pen2,D-Pen5] enkephalin (DPDPE), one member of this family. Use of these methods led to a low-energy solution conformation of DPDPE in excellent agreement with all the geometric properties deduced from its solution nmr spectra. Each of the analogue was subjected to the same procedure, involving a combination of molecular dynamics simulations at high and low temperature. The study was repeated in two environmental conditions, an apolar environment, simulated by using a distance-dependent dielectric constant, and a polar environment by embedding the peptides in a high constant dielectric (epsilon = 80). An automated comparison of the different conformers based on their backbone rms and average distance between the key aromatic moieties was followed by graphic analysis using maximum structural overlap. The cross-comparison of the conformations for each analogue revealed a unique conformer that may be recognized by the delta receptor for each high-affinity analogue that permitted maintaining the critical elements required for recognition in a simple spatial orientation, while maximizing similarity in other regions.

Amino Acid Sequence↗

PubMed1994

Modified chemotactic peptides: synthesis, crystal conformation, and activity of For-Hse(Me)-Leu-Phe-OMe.

The presence of the sulfur atom of the methionine side chain exerts significant effects at different levels on biochemical behavior of chemotactic N-formylpeptides. In order to acquire more information on this point, the synthesis, the conformation in the crystal, and the activity of For-Hse(Me)-Leu-Phe-OMe (2)--an oxygen analogue of For-Met-Leu-Phe-OMe (fMLP-OMe) containing the O-methyl-L-homoserine in place of the native methionine at position 1--is reported. The new analogue 2 adopts a conformation that is extended at the first two residues and folded at the C-terminal phenylalanine. This conformation is different from that of the parent fMLP-OMe and strikingly similar to that adopted by fMLP-OBu(t). The side-chain spatial orientation of 2 corresponds to that adopted by fMLP-OH when cocrystallized with an immunoglobulin possessing binding properties similar to those of neutrophil receptors. When tested on human neutrophils the formylpeptide 2 is more active than the parent in the stimulation of directed mobility and maintains both the granule enzyme release activity and the superoxide anion production.

Amino Acid Sequence↗