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PubMed1994

Conformational analysis of CCK-B agonists using 1H-NMR and restrained molecular dynamics: comparison of biologically active Boc-Trp-(N-Me) Nle-Asp-Phe-NH2 and inactive Boc-Trp-(N-Me)Phe-Asp-Phe-NH2.

The tetrapeptide Boc-Trp-(N-Me)Nle-Asp-Phe-NH2 is a potent CCK-B agonist. Replacement in this analogue of the norleucine residue by a phenylalanine, to yield Boc-Trp-(N-Me) Phe-Asp-Phe-NH2, led to a 740-fold decrease in affinity whereas the same decrease in affinity was not observed in their nonmethylated counterparts. In order to ascertain the conformational preferences of these two N-methylated tetrapeptides, a study by two-dimensional (2D) nmr spectroscopy and molecular modeling was undertaken. The solution conformation of the two peptides was examined by 1H-nmr in a d6-DMSO/H2O (80:20) mixture. A cis-trans equilibrium, induced by N-methylation, was observed for both analogues, and the proton spectra of the two rotamers were fully characterized in each case. 1H-1H distance constraints, derived from 2D nuclear Overhauser effect spectroscopy and rotating frame nuclear Overhauser effect spectroscopy experiments, were used as inputs for subsequent restrained molecular dynamics simulations. Comparisons of the nmr and molecular modeling data point toward distinct conformational preferences for these two peptides with an opposite spatial orientation of the Trp residue, and could explain the large difference in their biological activities. Furthermore, the tridimensional structure of Boc-Trp-(N-Me)Nle-Asp-Phe-NH2 could serve as a model for the design of nonpeptide CCK-B agonists.

Amino Acid Sequence↗

PubMed2003

A cyclic CCK8 analogue selective for the cholecystokinin type A receptor: design, synthesis, NMR structure and binding measurements.

A cyclic CCK8 analogue, cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 (Dpr=L-2,3-diaminopropionic acid), has been designed on the basis of the NMR structure of the bimolecular complex between the N-terminal fragment of the CCK(A) receptor and its natural ligand CCK8. The conformational features of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 have been determined by NMR spectroscopy in aqueous solution and in water containing DPC-d(38) micelles (DPC=dodecylphosphocholine). The structure of the cyclic peptide in aqueous solution is found to be in a relaxed conformation, with the backbone and Dpr29 side chain atoms making a planar ring and the N-terminal tripeptide extending approximately along the plane of this ring. In DPC/water, the cyclic peptide adopts a "boat-shaped" conformation, which is more compact than that found in aqueous solution. The cyclic constraint between the Dpr29 side chain and the CCK8 carboxyl terminus (Lys34) introduces a restriction in the backbone conformational freedom. However, the interaction of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 with the micelles still plays an important role in the stabilisation of the bioactive conformation. A careful comparison of the NMR structure of the cyclic peptide in a DPC micelle aqueous solution with the structure of the rationally designed model underlines that the turn-like conformation in the Trp30-Met31 region is preserved, such that the Trp30 and Met31 side chains can adopt the proper spatial orientation to interact with the CCK(A) receptor. The binding properties of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 to the N-terminal receptor fragment have been investigated by fluorescence spectroscopy in a micellar environment. Estimates of the apparent dissociation constant, K(d), were in the range of 70-150 nM, with a mean value of 120+/-27 nM. Preliminary nuclear medicine studies on cell lines transfected with the CCK(A) receptor indicate that the sulfated-Tyr derivative of cyclo(29,34)[Dpr(29),Lys(34)]-CCK8 displaces the natural ligand with an IC(50) value of 15 microM.

Cells, Cultured↗

PubMed1983

Cardiogoniometry: a new noninvasive method for detection of ischemic heart disease.

Cardiogoniometry is a new vectorcardiographic method. The vector-loops are constructed from three orthogonal ECG leads and registered on-line by a microprocessor. The angle between the maximal QRS and T vectors, as well as the spatial orientation of these vectors are very constant in healthy individuals. Deviations of these vectors and angles are sensitive indicators for changes in repolarization occurring, for instance, during coronary insufficiency. The changes in these variables were evaluated in 50 patients with suspected coronary artery disease and correlated with angiographic findings. Cardiogoniometry showed a sensitivity of 79% and a specificity of 82%, which is comparable to exercise testing. In contrast to the latter cardiogoniometry can be performed at rest, is free of risk, and therefore also suitable for elderly patients.

Computers↗

PubMed2006

Conformationally constrained CCK8 analogues obtained from a rationally designed peptide library as ligands for cholecystokinin type B receptor.

A library of 14 cyclic peptide analogues derived from the octapeptide C-terminal sequence of the human cholecystokinin hormone (CCK(26-33), or CCK8) was designed, synthesized, and characterized. The 14 peptide analogues were rationally designed to specifically interact with the CCK type B receptor (CCK(B)-R) on the basis of the structure of the bimolecular complex between CCK8 and the third extracellular loop of CCK(B)-R, namely CCK(B)-R(352-379). The rational design of new ligands for CCK(B)-R has relied on stabilization by cyclic constraints of the structural motifs that bring the key residues of the ligand (especially Trp 30, Met 31, and Phe 33) in the proper spatial orientation for optimal interaction with the receptor. The binding affinity of the new ligands for CCK(B)-R was assessed by displacement experiments of (111)In-radiolabeled CCK8 in cells that overexpress the CCK(B) receptor. The new ligands generally showed binding affinities lower than that of parent CCK8, with the best compounds having IC50 values around 10 microM. Structure-activity relationship data show that preservation of the Trp 30-Met 31 motif is essential and that the Phe 33 side chain must be present. NMR conformational studies of the compound with maximal binding affinity (cyclo-B11, IC50=11 microM) in DPC micelles shows that this compound presents a turn-like conformation centered at the Trp 30-Met 31 segment, as planned by rational design. Such a conformation is stabilized by its interaction with the micelle rather than by the cyclic constraint.

Cholecystokinin↗

PubMed2003

Compliance with breast-conservation standards for patients with early-stage breast carcinoma.

BACKGROUND: Multiple treatment guidelines and practice standards have been developed regarding the management of patients with breast carcinoma. Few evaluations of the penetration and utility of these practice standards have been performed. In 1992, the American College of Surgeons (ACOS), the American College of Radiology, the College of American Pathologists, and the Society of Surgical Oncology collaborated in establishing standards for breast-conservation treatment (BCT). The authors sought to determine whether practice patterns for patients with breast carcinoma who underwent BCT were consistent with these standards 2 years after their dissemination and to establish whether compliance varied by the same patient and hospital variables that predicted for the amount of BCT performed. METHODS: A study specific questionnaire was circulated to cancer registrars through the Commission on Cancer of the ACOS asking them to submit reports on patients with Stage I and II breast carcinoma who were diagnosed in 1994. Eight hundred forty-two predominantly community hospitals throughout the United States responded, yielding a total of 16,643 analyzable patients. The frequency of compliance to the 1992 published practice standards for 7097 patients who received BCT was determined. The variation in compliance rates by patient age, race, and insurance status and the treating hospital's geographic locations and cancer programs were evaluated. RESULTS: Of the 22 standards that were evaluated in the areas of preoperative mammography (2 standards), labeling of the surgical specimen (3 standards), pathology report content (10 standards), radiation after lumpectomy (6 standards), and systemic therapy for patients with positive lymph nodes (1 standard), treatment adherence was > or = 80% for 16 standards (73%). Poor compliance was demonstrated for six standards: the documentation of an abnormality's size in the mammogram report, labeling the lumpectomy specimen with the affected quadrant of the breast, spatial orientation of the lumpectomy specimen and inclusion of lymphatic/vascular invasion, ductal carcinoma in situ, and macroscopic margin assessment in the pathology report. Variation in compliance to a standard occurred frequently across the type of hospital cancer program and geographic region (77% for both), and variation occurred less across the patient variables of age (32%), race (41%), and payer (23%). There was not a pattern of more frequent compliance among variables associated with more BCT use. CONCLUSIONS: Large-scale evaluation of the penetration of treatment standards is feasible. For patients who underwent lumpectomy, practice appeared to be consistent (> or = 80% compliance), with 73% of 22 treatment standards evaluated. The standards with poor compliance represent areas for targeted physician education and reevaluation. Significant differences in adherence to a standard were seen frequently based on a hospital's geographic location and type of cancer program. This emphasizes the importance of adequate dissemination of treatment standards to ensure penetration into medical practices of all types.

Adult↗

PubMed1984

Morphometry of spine-free nonpyramidal neurons in rabbit auditory cortex.

A study of the morphometry and laminar distribution of spine-free nonpyramidal neurons in electrophysiologically verified primary auditory cortex was carried out in adult rabbits. By using image-combining computer microscopy, the locations of all impregnated neurons in 300-micrometers Golgi-Cox Nissl sections through the auditory cortex were determined. Spine-free non-pyramidal neurons constitute nearly 72% of the nonpyramidal neurons present. They are distributed in a band extending from 450 to 750 micrometers beneath the pial surface corresponding to laminae III and IV. A combination of dendritic stick, Fourier, and statistical analyses revealed a highly significant spatial orientation of their dendrite systems along a vertical axis parallel to the apical dendrites of pyramidal neurons. A significant tangential orientation of dendrites along a dorsal-ventral axis was also found. A radial analysis of the dendrite systems revealed that the pronounced vertical orientation of spine-free nonpyramidal neurons is due to (1) directed dendritic growth along the vertical axis, (2) decreased branching and rapid termination of tangentially oriented dendrites, and (3) increased branching of vertically growing dendrites. The radial analysis also revealed that the longest branches are those directed toward the white matter.

Animals↗

PubMed1984

Region-specific distribution of catecholamine afferents in primate cerebral cortex: a fluorescence histochemical analysis.

The density, laminar distribution, spatial orientation, and intrahemispheric pathways of norepinephrine (NE)- and dopamine (DA)- containing axons were analyzed in a wide range of cytoarchitectonically distinct areas of cerebral cortex in the adult rhesus monkey by fluorescence histochemistry. Although the boundaries between most areas were rarely sharp, there were marked regional differences in density and distribution of monoamine afferents in different cortical regions. Fibers exhibiting typical DA-like morphology were found only in the temporal and frontal lobes including motor and premotor areas as well as anterior cingulate and prefrontal cortices. In contrast, NE-containing axons were present in all cerebral lobes, with notably high density in the somatosensory area and low numbers in primary visual cortex. Intracerebral distribution was characterized by a network of large preterminal axons coursing both anteroposteriorly and mediolaterally in layer VI and in the subjacent white matter. In most cytoarchitectonic regions examined, catecholamine (CA)-containing axons exhibited a bilaminar distribution into one superficial and one deep fiber band. The location and width of the two dense bands, as well as the orientation and relative density of fibers within them, was region specific. Although fluorescent axons were found at all cortical depths, layers I, and IV usually contained relatively few fluorescent axons while layers II-III and IV-V were often densely innervated. An observation that may reflect a specialization in gyrencephalic brains is the particularly dense CA innervation around sulcal invaginations in all cerebral lobes. The present results confirm previous biochemical evidence of regional heterogeneity in the concentration of DA and NE in the primate neocortex (Brown and Goldman, '77:Brain Res. 124:576-550) an provide the first anatomical demonstration of corresponding differences in the pattern and density of CA innervation in diverse cytoarchitectonic areas in rhesus monkey. These findings raise the possibility of selective targets and functions for CA fibers in different layers and regions of the primate cortex.

Animals↗

PubMed1985

Neurogenesis of the climbing fibers in the human cerebellum: a Golgi study.

The prenatal and early postnatal neurogenesis of the human climbing fibers of the lateral cerebellar hemispheres have been studied, with the rapid Golgi method, and correlated with the developmental stages of Purkinje cells. A transitional phase has been established in the neurogenesis of the human Purkinje cell between the second and third stages of Cajal. This phase coincides with the arrival of the climbing fibers. It is characterized by the reabsorption and subsequent transformation of Purkinje cell's basal dendrites into somatic spines. Following the arrival of the climbing fibers and the establishment of contacts, the Purkinje cell is progressively transformed from an immature stellate and nonoriented cell into a monopolar and spatially oriented one which acquires all of its mature morphological and functional features. The human climbing fibers arrive at the Purkinje cell plate by the 28th week of gestation and establish a transient paraganglionic plexus before contacts with these neurons can be recognized. They start to form pericellular nests by the 29th week, and by the 31st week of gestation all Purkinje cells of the lateral hemispheres have pericellular nests around their bodies. These pericellular nests are progressively and rapidly transformed into supracellular "capuchones" which themselves are also short-lived because the climbing process starts readily in them. Supracellular "capuchones" are recognized by the 34th seek and their fibrils start to climb the dendrites of Purkinje cells (young climbing phase) by the 36th week of gestation. The process of climbing the dendrites of the Purkinje cells will continue through late prenatal and early postnatal life. The human climbing fibers are distributed, in the internal granular layer, within narrow and long vertical territories which are transverse to the long axis of the follium. A single climbing fiber is (1) able to establish contacts with many Purkinje cells located within its narrow territory of distribution; (2) has a tendency to establish contacts with small groups of Purkinje cells rather than with isolate neurons; (3) able to send collaterals to several contiguous cerebellar folia; and (4) able to send collaterals to the internal granular layer and to form pericellular nests in it. The human cerebellum may be considered to be subdivided into a series of parallel, narrow, and transverse structural/functional planes, each one characterized by the distribution of a climbing fiber.(ABSTRACT TRUNCATED AT 400 WORDS)

Axons↗

PubMed1987

The chandelier cell of the human visual cortex: a Golgi study.

The size, location, distribution, and spatial orientation of the chandelier cell of the human visual cortex are described for the first time. The rapid Golgi method has been utilized to study the structural features of these inhibitory interneurons. The human chandelier cell is a small stellate interneuron with prominent idiodendritic and idioaxonic arborizations. These arborizations are distributed within a narrow rectangular tissue slab that measures approximately 300 X 200 X 100 microns. This relatively small and narrow functional territory is oriented perpendicular to the pial surface and to the long axis of the gyrus. The territory of distribution of its axon is larger than and encloses that of its dendrites. The number of specific axonic terminals (candles) per chandelier cell is also relatively small, ranging from 60 to 80 units. These axonic terminals represent the functional units of the neuron and reflect the number of pyramidal cell axons contacted by it. The chandelier cell of the human visual cortex possibly represents the smallest neuron of this kind described to date. The size of its functional territory and the number of its specific axonic terminals are among the smallest of any neuron of this kind thus far described. It is postulated herein that in the course of mammalian phylogeny the chandelier cell shows a tendency toward a progressive reduction in the size of its functional territory and in the number of its functional units (candles), as well as a tendency toward a more "idio" pattern of distribution for its axonic and dendritic arborizations. Perhaps, these progressive evolutionary modifications could reflect a tendency of this type of interneuron toward an increasing specialization. The possible existence of a relationship between the progressive transformation of the chandelier cell and the increasing visual acuity, dexterity, and skillfulness in the course of mammalian phylogeny should be explored.

Female↗

PubMed1989

On the number of Purkinje cells in the human cerebellum: unbiased estimates obtained by using the "fractionator".

Stereological estimates of the numbers of Purkinje cell nucleoli in human cerebellar cortex have been obtained from systematic random samples of tissue by using the fractionator. The estimates are unbiased by fixation, section thickness, or sampling errors and are independent of any assumptions about cell shape, size, or spatial orientation. Twelve brains from aged subjects of both sexes were examined. The average complement of nucleoli in four female brains (age range 71-93 years) amounted to 14.8 millions (with an observed coefficient of variation between subjects of 29%). For three male brains (76-91 years), the corresponding estimates were 15.7 millions (10%). No significant sex differences were found for these small samples. Five brains of unknown sex and age yielded values of 15.8 millions (18%). For the twelve brains examined, the total number of Purkinje cell nucleoli per cerebellum was found to be 15.4 millions (19%). Estimated numbers showed a significant positive correlation with cerebellar weights. The number of nucleoli in an individual cerebellum was obtained with high precision in as short a time as 4 hours.

Aged↗

PubMed1990

Medial forebrain bundle of the rat: III. Cytoarchitecture of the rostral (telencephalic) part of the medial forebrain bundle bed nucleus.

The boundaries of the medial forebrain bundle (MFB) of the rat have been presented in previous work on the structure of this fiber system (Nieuwenhuys et al.: J. Comp. Neurol. 206:49-81, '82). Neuronal cell bodies within these outlines constitute the bed nucleus of the MFB. Many fiber components of the MFB appeared to be spatially arranged within the bundle and featured an orderly topography (Veening et al.: J. Comp. Neurol. 206:82-108, '82). As the fibers of the MFB are thought to be a major source of afferents to the bed nucleus (Millhouse: In P.J. Morgane and J. Panksepp (eds): Anatomy of the Hypothalamus, Vol. 1. New York: Marcel Dekker, pp. 221-265, '79), the latter has been subjected in this and the companion study (Geeraedts et al.: J. Comp. Neurol. 294:537-568, '90) to a detailed cytoarchitectonic analysis. This analysis is based on continuous series sectioned in the three conventional planes. On the basis of cytoarchitectonic characteristics, including size and shape, staining intensity, packing density, and spatial orientation of the cell bodies, it was found that the bed nucleus of the MFB as described in the literature is by no means a cytoarchitectonic unit per se. Rather, the neuronal cell population located within the telencephalic stream of the MFB can be parcellated into a number of cellular groups, which partly or entirely belong to more-or-less known basal telencephalic structures. These structures are designated here as the MFB-related areas. They correspond largely to the subcommissural substantia innominata (SIC), the sublenticular substantia innominata (SIL), the nucleus of the diagonal band of Broca, the olfactory tubercle, the magnocellular preoptic nucleus (POMA), the lateral preoptic area (LPOA), and the interstitial nucleus of the stria medullaris (ISM). The complex of the MFB-related areas is surrounded by the following cellular entities: the nucleus accumbens (ACB), the caudatus-putamen region (CPU), the globus pallidus (GP), the bed nucleus of the stria terminalis (BST), the anterior amygdaloid area (AAA), the amygdaloid nuclear complex (A), the medial preoptic area (MPOA) and the anterior hypothalamic area (AHA). Both MFB-related areas and their surroundings have been identified and delimited in this study. This resulted in a new cytoarchitectonic atlas of the rat's basal telencephalon. Our atlas does not only show the relative positions of the above mentioned cellular groups, but also those of their subdivisions.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Digital image analysis of cytoskeletal F-actin disintegration in renal microvascular endothelium following ischemia/reperfusion.

BACKGROUND: Damaged and/or dysfunctional microvascular endothelium has been implicated in the pathogenesis of ischemic acute renal failure (ARF). Rapidly occurring changes in the endothelial F-actin cytoskeleton as observed in vitro might be responsible, but have been proven difficult to measure accurately in situ. Therefore, the purpose of this study was to examine several methods of digital image analysis in order to quantify the alterations of endothelial F-actin after renal ischemia and reperfusion (I/R), and to relate these to deterioration of renal function. METHODS: Frozen sections of Sham and I/R rat kidneys were fixed in 4% formaldehyde and stained with rhodamine-phalloïdin. Microvascular structures were captured using a 3i Marianastrade mark digital imaging fluorescence microscope workstation. Images were analyzed using 3i SlideBooktrade mark software, employing several masking techniques and line-scans. RESULTS: Digital image analysis demonstrated a decrease in the mean intensity of rhodamine-phalloïdin fluorescence after I/R from 1030 +/- 187 to 735 +/- 121 a.u. (arbitrary units, mean +/- SD, n = 7). The number of F-actin fragments per pixel increased from (15.8 +/- 4.9) x 10(-5) to (20.7 +/- 3.5) x 10(-5) (n = 7), indicating cytoskeletal fragmentation. In addition, line-scan analysis demonstrated a disturbed spatial orientation of the F-actin cytoskeleton after I/R. Finally, the loss of F-actin correlated with a rise in plasma creatinine. CONCLUSIONS: The methods of digital image analysis described in the present study demonstrate that renal I/R induces profound changes in the F-actin cytoskeletal structure of microvascular endothelial cells, implicating an injured and dysfunctional microvascular endothelium, which may contribute to acute renal failure (ARF).

Actins↗

PubMed1993

Interrelationships between densitometric, geometric, and mechanical properties of rat femora: inferences concerning mechanical regulation of bone modeling.

A compensation for differences in bone material quality by bone geometric properties in femora from two different strains of rats was previously shown by us. A feedback mechanism controlling the mechanical properties of the integrated bones was then proposed, in accordance with Frost's mechanostat theory. Evidence of such a system is now offered by the finding of a negative correlation between the modeling-dependent cross-sectional architecture (moment of inertia) and the mineral-dependent stiffness (elastic modulus) of bone material in the femoral diaphyses of 45 normal Wistar rats of different sexes, ages, and sizes. The strength and stiffness of the integrated diaphyses were found to depend on both cross-sectional inertia and body weight, not on bone mineral density. These findings are interpreted as supporting the hypothesis that the architectural efficiency of diaphyseal cross-sectional design resulting from the spatial orientation of bone modeling during growth is optimized as a function of the body weight-dependent bone strain history, within the constraints imposed by bone stiffness. Results suggest a modulating role of biomass, related to the system set point determination, and explain the usually observed lack of a direct correlation between mineral density and strength or stiffness of long bones in studies of geometrically inhomogeneous populations.

Animals↗

PubMed1983

Biosynthesis of the photosynthetic membranes of Rhodopseudomonas sphaeroides.

The steady-state biosynthesis of the photosynthetic membrane (ICM) of Rhodopseudomonas sphaeroides has been reviewed. At moderate light intensities, 500 ft-c, preexisting ICM serves as the insertion matrix for newly synthesized membrane components. Whereas the bulk of the membrane protein, protein-pigment complexes, and pigments are inserted into preexisting ICM throughout the cell cycle, phospholipid is transferred from outside the ICM to the ICM only at the time of cell division. Because the site of cellular phospholipid synthesis is the cytoplasmic membrane, these results infer that despite the physical continuity of cytoplasmic membrane and ICM, there must exist between these membranous domains a "barrier" to the free diffusion of cellular phospholipid. The cyclical alternation in protein to phospholipid ratio of the ICM infers major structural and functional alternations, such as changes in the protein to lipid ratio of the membrane, specific density of the membrane, lipid structure within the membrane, and the rate of cyclic electron flow. When biochemical studies are correlated with detailed electron microscopic investigations we can further conclude that the number of photosynthetic units within the plane of the membrane can vary by nearly a factor of two over the course of the cell cycle. The average physical size of the photosynthetic units is constant for a given light intensity but inversely proportional to light intensity. The distribution of photosynthetic unit size classes within the membrane can be interpreted as suggesting that the "core" of the photosynthetic unit (reaction center plus fixed antenna complex) is inserted into the membrane coordinately as a structural entity. The variable antenna complex is, on the other hand, inserted independent of the "core" and randomly associates with both old and new core complexes. Finally, we conclude that there is substantial substructure to te distribution of photosynthetic units within the ICM, ie, they are highly ordered and exist in a defined spatial orientation to one another.

Bacterial Chromatophores↗

PubMed2004

New approach to quantifying developmental variation in the dentition using serial microtomographic imaging.

Dental morphogenesis and cellular differentiation are expressed in the fully formed tooth by the topography of the dentin-enamel junction and outer enamel surface. These boundaries can be differentiated using a variety of imaging systems. In this study, we used serial microCT imaging to provide accurate 3D reconstructions of developing lower human second deciduous molars. These were used to quantify the volume of enamel and dentin of individual cusps in relation to basal crown height. As growth and differentiation proceed apically, the spatial orientation of cusp tips and their bases were used to estimate their order of initiation and coalescence. We found that the order of coalescence differed from the order of initiation. We also found that dentin cusp height and volume as well as rate and quantity of enamel apposition varied along mesio-distal and bucco-lingual axes, and were independent of order of initiation and duration of growth. These results demonstrate that the potential for variation in crown size and form is maintained throughout development. We propose that the microCT model developed in this study constitutes a new approach for the investigation of developmental variation and its contribution to phylogenetic variation expressed in crown form and size.

Dental Enamel↗

PubMed1993

MHC class I/peptide interactions: binding specificity and kinetics.

Recent developments in the preparation of soluble analogues of the major histocompatibility complex (MHC) class I molecules as well as in the application of real time biosensor technology have permitted the direct analysis of the binding of MHC class I molecules to antigenic peptides. Using synthetic peptide analogues with cysteine substitutions at appropriate positions, peptides can be immobilized on a dextran-modified gold biosensor surface with a specific spatial orientation. A full set of such substituted peptides (known as 'pepsicles', as they are peptides on a stick) representing antigenic or self peptides can be used in the functional mapping of the MHC class I peptide binding site. Scans of sets of peptide analogues reveal that some amino acid side chains of the peptide are critical to stable binding to the MHC molecule, while others are not. This is consistent with functional experiments using substituted peptides and three-dimensional molecular models of MHC/peptide complexes. Detailed analysis of the kinetic dissociation rates (kd) of the MHC molecules from the specifically coupled solid phase peptides reveals that the stability of the complex is a function of the particular peptide, its coupling position, and the MHC molecule. Measured kd values for antigenic peptide/class I interactions at 25 degrees C are in the range of ca 10(-4)-10(-6)/s. Biosensor methodology for the analysis of the binding of MHC class I molecules to solid-phase peptides using real time surface plasmon resonance offers a rational approach to the general analysis of protein/peptide interactions.

Amino Acid Sequence↗

PubMedDate not supplied

Inadequacy of motion correction algorithms in functional MRI: role of susceptibility-induced artifacts.

Functional MR (fMR) has been useful in providing insight into the localization and detection of neural cortical activity. However, patient head motion is inevitable over the course of most fMR experiments. Although methods to align the control and activation fMR images may correct for some of this motional error, they will be incomplete in correcting for those that depend on spatial orientation. MR signal amplitude of structures that lie along air-tissue interfaces, for example, are sensitive to susceptibility errors introduced by their reorientation with respect to the main magnetic field. This analysis, using phantoms, cadaver brain, and volunteers, has shown that this reorientation between control and activation images can create regions of "false activation" that increase in area with rotation. Anatomic regions that are expected to be most affected by these susceptibility-induced magnetic field homogeneity variations are those adjacent to bone or air, such as the mesial and inferior temporal lobes and the inferior and anterior frontal lobes. Interpretation of "activation" in these areas on fMR studies must be performed with careful consideration of this important source of error.

Algorithms↗

PubMed2005

Statistical-overlap theory for elliptical zones of high aspect ratio in comprehensive two-dimensional separations.

The low prediction by statistical-overlap theory of the numbers of singlets and peaks in two-dimensional separations containing zones represented by either circles of small number or eccentric ellipses of any number is shown to result from use of probability expressions for unbound spaces of infinite extent. An exact theory is derived for the probability of singlet formation in a reduced two-dimensional space of unit length, width, and area. The probability is a weighted sum of the probabilities of singlet formation in the interior, edge, and corner regions of the space, which depend only on saturation. The weighting factors are the fractions of area associated with each region and depend on the number of zones, the aspect ratio, the saturation, and the ellipse's spatial orientation. The average numbers of doublets, triplets, and peaks in the space are approximated by combining these results with Roach's equations describing the clustering of circles in an unbound two-dimensional space. Simulations show that theory predicts the number of singlets, doublets, triplets, and peaks, when the number of zones is 25 or more, the aspect ratio is 100 or less, and the saturation is 2 or less. The relationship is derived between the aspect ratios of ellipses in the reduced space and actual separation space. Calculations are presented for comprehensive two-dimensional gas chromatography.

Journal Article↗