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S H Koenig

Publications and source records attributed to S H Koenig.

At least 37 records · Page 2Linked to original sources
PubMed1994

Variation of the magnetic relaxation rate 1/T1 of water protons with magnetic field strength (NMRD profile) of untreated, non-calcified, human astrocytomas: correlation with histology and solids content.

The magnetic relaxation rate 1/T1 of tissue water protons was measured over a wide range of magnetic field strengths (NMRD profile) for 92 fresh surgical specimens of astrocytomas to search for correlations of 1/T1 with tumor histology, as determined by light microscopy, and to assess the diagnostic potential of NMRD profiles for grading astrocytomas. A third goal was to elucidate the molecular determinants of 1/T1. Each specimen was histologically graded and inspected for evidence of mineral deposits (Ca, Fe); its dry weight was determined and expressed in % of original wet weight. To minimize variability not directly related to tumor grade, this initial report is limited to NMRD profiles of 47 non-calcified, non-hemorrhagic, untreated astrocytomas. For these, the mean value of 1/T1 at very low magnetic field strengths was found to increase with increasing grade of malignancy; no clear correlation could be demonstrated at high fields where most imaging is done. The spread of 1/T1 for different grades of malignancy is large, however, and the overlap significant, even at the lowest field, so that astrocytomas can not be graded by NMRD profiles alone. Average 1/T1 and average dry weight increase with grade of malignancy; but the variability of 1/T1 among specimens of the same dry weight is large, indicating that at least one other cellular parameter, not variable in normal tissue, influences 1/T1 strongly. We hypothesize that this parameter reflects changes at the molecular level in size distribution, mobility, or intermolecular interaction of cytoplasmic proteins. Which specific changes are induced by malignant transformation in astrocytomas remains to be investigated.

Adolescent↗
PubMed1993

A unified view of relaxation in protein solutions and tissue, including hydration and magnetization transfer.

Protein in water solution increases magnetic relaxation rates of solvent nuclei to an extent that depends on magnetic field strength and molecular weight. Koenig and Schillinger (J. Biol. Chem. 244, 3283 (1969)) showed that a small fraction of the water molecules in the first hydration shell, bound irrotationally with a residence lifetime in the range 0.1 to 10 microseconds, would account for the phenomena. No experiments, as yet, have proven the existence of such long-lived waters, nor yielded a value for their lifetime. Analogous measurements on solutions of both denatured and cross-linked protein give data different from that of native protein, but much like results for tissue. By comparing proton and deuteron relaxation rates in solutions of native and cross-linked protein, it is possible to demonstrate the existence of these relatively long-lived waters; the data indicate that 1% of a monolayer of the waters of hydration of protein have lifetimes that cluster near 1 microsecond and, it is argued, are held in place by multiple hydrogen bonds. Assigning shorter lifetimes for waters held by fewer bonds, it is possible to develop a unified view of relaxation of water nuclei in protein solutions and in tissue, and to relate it to recent crystallographic data on hydrated protein.

Humans↗
PubMed1993

Magnetization transfer in cross-linked bovine serum albumin solutions at 200 MHz: a model for tissue.

We report results for proton 1/T1, 1/T2, and K, the rate of magnetization transfer from solvent to solute, for 5 and 10 wt. % solutions of bovine serum albumin, both native and chemically cross-linked, in undeuterated and approximately 50% deuterated water, at 4.7 T (200.1 MHz) and 19 degrees C. At this field, although K > 1/T1 for the cross-linked samples, magnetization transfer contributes little to 1/T1 directly. Therefore K was measured using off-resonance irradiation of the protein protons. The data for all the samples can be fit using a theoretical model for magnetization transfer, with three parameters: the intrinsic longitudinal relaxation rates of solute and solvent protons, and K. The magnitude of K is so large that the newly-identified, long-lived (approximately 1 microseconds) hydration sites (S.H. Koenig, R.D. Brown III, and R. Ugolini, Magn. Reson. Med., 29, 77 (1993)) must be invoked to account for K, as is necessary to explain the differential effects of cross linking on the magnetic field dependence of 1/T1 of protons and deuterons and the large 1/T1 and 1/T2 values below approximately 20 MHz in immobilized systems. Although these sites are few in number, their long resident lifetime becomes the correlation time for magnetization transfer when protein is immobilized, accounting for the large value of K. Recent data from several laboratories have shown that cross-linked protein, as used here, is a good model for 1/T1 and 1/T2 of tissue, as a function of temperature and magnetic field.

Cross-Linking Reagents↗
PubMed1993

A molecular theory of relaxation and magnetization transfer: application to cross-linked BSA, a model for tissue.

Homogeneous soft tissue, as regards its magnetic relaxation properties, is well-modeled by solutions of cross-linked protein (see Koenig and Brown, Prog. NMR Spectr. 22, 487 (1991)). Interactions at the solute-solvent interface alter the hydrodynamics of solvent water, and also couple the solute and solvent proton Zeeman energy reservoirs, giving hydrodynamic and cross-relaxation contributions to water proton relaxation that respond differently to deuteration of solvent. We report measurements of the magnetic field dependence of 1/T1 of water protons in cross-linked bovine serum albumin (BSA), for partially deuterated solvent and, in order to separate these two contributions, of 1/T1 of deuterons. The major experimental finding is that, in addition to recently identified water-binding sites on protein (covering approximately 0.2% of the surface) with water lifetimes of about 1 microsecond, there is another group of sites with lifetimes of about 23 ns, covering approximately 2% of the surface, which are evident in both proton and deuteron data. In addition, we have formulated a theory of interfacial proton-proton magnetic interactions which--with these four parameters, plus two that quantify the protein-water coupling at each site--can account for all the proton and deuteron data, in both native and cross-linked BSA.

Cross-Linking Reagents↗
PubMed1993

Intermolecular protein interactions in solutions of bovine lens beta L-crystallin. Results from 1/T1 nuclear magnetic relaxation dispersion profiles.

We report the magnetic field dependence of 1/T1 of solvent water protons and deuterons (nuclear magnetic relaxation dispersion, or NMRD, profiles) for solutions of steer lens beta L-crystallin. Such data allow the study of intermolecular protein interactions over a wide concentration range, here 1-34% vol/vol, by providing a measure of the rotational relaxation time of solute macromolecules. We conclude that, for approximately less than 5% protein, the solute particles are noncompact, with a rotationally averaged volume approximately three times that of a compact 60-kD sphere. (Earlier results for alpha-crystallin, approximately 1,000 kD, from optical and osmotic measurements (Vérétout and Tardieu, 1989. J. Mol. Biol. 205:713-728), show a similar, approximately twofold, effect). At intermediate concentrations, to approximately 20% protein, there is evidence for limited association or oligomerization, as found for the structurally related gamma II-crystallin (Koenig et al. 1990. Biophys. J. 57:461-469), to a limiting size about two-thirds that of alpha-crystallin. The difference in NMRD behavior of the three classes of crystallins is consonant with their differing osmotic properties (Vérétout and Tardieu. J. Mol. Biol. 1989, 205:713-728; Kenworthy, McIntosh, and Magid. Biophys. J. 1992. 61:A477; Tardieu et al. 1992. Eur. Biophys. J. 21:1-12). We indicate how the unusual structures and interactions of these three classes of proteins can be combined to optimize transparency and minimize colloid osmotic difficulties in eye lens.

Animals↗
PubMed1992

Nuclear magnetic relaxation dispersion and 31P-NMR studies of the effect of covalent modification of membrane surfaces with poly(ethylene glycol).

Covalent attachment of methoxypoly(ethylene glycol) (MPEG) 5000 to the surface of unilamellar liposomes composed of egg phosphatidylcholine and dioleoylphosphatidylethanolamine (DOPE) (8:2) containing paramagnetic chelates, either entrapped within the interior volume of the liposomes, or associated with the membrane surface, had no effect upon the measured spin-lattice relaxation rates (1/T1) for water in these systems. 31P-NMR studies indicate no destabilization of dioleoylphosphatidylcholine (DOPC)/(DOPE) (1:1) vesicles following attachment of MPEG. However, in DOPC/DOPE (1:3) mixtures, covalent modification with MPEG results in a destabilization of multilamellar vesicles into smaller vesicular structures. These results indicate that covalent attachment of poly(ethylene glycol) to liposomal magnetic resonance agents may prove a useful method for increasing their utility as vascular MR agents by extending their lifetime in the circulation, without decreasing the relaxivity of paramagnetic species associated with the liposome, but that the presence of PEG covalently attached to the membrane surface may modify the polymorphic phase behavior of the lipid system to which it is covalently linked.

Lipid Bilayers↗
PubMed1992

Permeability of liposomal membranes to water: results from the magnetic field dependence of T1 of solvent protons in suspensions of vesicles with entrapped paramagnetic ions.

The diffusive permeability to water molecules, Pd, of lipid vesicles with entrapped paramagnetic solute ions can be determined rapidly from analysis of the magnetic field dependence (nuclear magnetic relaxation dispersion, or NMRD profile) of T1 of exterior solvent water protons. Such data yield tau, the mean lifetime of solvent molecules inside the vesicles, from tau = (fT1Para) - T1Ves, where f is the volume fraction of entrapped water, T1Para is the observed T1 corrected for buffer background, and T1Ves is the relaxation time of water protons in the entrapped solution. For small spherical unilamellar vesicles of inner radius R, Pd = R/3 tau, f can be obtained accurately from knowledge of both the concentration of Gd(DTPA)2- in the solution in which the vesicles were formed and the average concentration of ions in the final sample. At low temperatures, in the limit of slow exchange, T1Para becomes independent of field and tau = fT1Para; the observation of a field-independent profile is a control that confirms that no paramagnetic material is external to the vesicles. We have measured T1Para, using a field-cycling relaxometer, for suspensions of POPC (1-palmitoyl-2-oleoyl-lecithin) vesicles with 100-500 mM entrapped Gd(DTPA)2- and membrane concentrations of cholesterol ranging from 0 to 40 mol %. These profiles, which span the field range 0.01-50 MHz proton Larmor frequency, were taken at 5, 15, 25, and 35 degrees C. Concentrations of Gd(DTPA)2- were determined independently by both ICP analyses and NMRD methods. Values for Pd for vesicles with 100 mM Gd(DTPA)2- and outer diameters 100 nm +/- 20%, as determined by quasielastic light scattering, are 63, 47, 24, 16, and 8.7 x 10(-4) cm s-1, at 25 degrees C, for cholesterol concentrations of 0, 10, 20, 30, and 40%, respectively. The corresponding activation enthalpies are 14, 14, 14, 17, and 17 kcal/M. Comparison with 2H NMR studies of deuterated POPC vesicles with no cholesterol at 20 degrees C, and with 10% at 40 degrees C, which yielded the same order parameter for the palmitoyl acyl chains, gives no indication of a correlation between order parameter and permeability.

Contrast Media↗
PubMed1992

The design of liposomal paramagnetic MR agents: effect of vesicle size upon the relaxivity of surface-incorporated lipophilic chelates.

The 1/T1 NMRD profiles of lipid vesicles with the paramagnetic ion Gd attached via a chelate covalently linked to the membrane surface show a peak at approximately 20 MHz indicating that fluctuations of approximately 10(-8) s contribute to the form of the dispersion profile. If the correlation time for fluctuations of the paramagnetic chelate on the membrane surface is much less than the correlation time for rotation of the lipid vesicle, it would be expected that the measured 1/T1 relaxation rate for solvent protons should be invariant with vesicle size above a certain minimum vesicle diameter. We show that this is indeed the case for vesicles in the size range 50 to 400 nm average diameter and discuss general design considerations for the preparation of vesicle-associated MR contrast agents based upon paramagnetic chelates either trapped within the vesicle interior or attached to the membrane surface.

Chelating Agents↗
PubMed1992

Nuclear magnetic relaxation dispersion profiles of aqueous solutions of a series of Gd(NOTA) analogs.

Nuclear magnetic relaxation dispersion (NMRD) profiles and ESR linewidths have been measured for a series of neutral Gd(3+)-triazamacrocyclic complexes and compared with previous data for the simplest member of the macrocyclic triaza series, Gd(NOTA), and for the widely studied linear triaza complex, Gd(DTPA)2-. Water proton relaxivities and their temperature dependence were found to vary widely with the size of the triaza macrocycle and the identity of the side-chain chelating groups. The number of rapidly exchanging water molecules directly coordinated to the Gd3+ ion (q) was found to vary from 2 to 4 for eight of the ten complexes examined and a linear relationship between the 50-MHz relaxivity value and integral values of q is presented for this series of complexes. tau s values derived from ESR linewidths for some of the complexes are in reasonable agreement with those derived from their NMRD profiles; however, those complexes which either tended to form aggregates in solution or gave evidence for multiple averaged solution structures showed broad, near Lorentzian linewidths which were clearly not dominated by the electron spin relaxation time (tau s).

Aza Compounds↗
PubMed1992

1/T1 rho and low-field 1/T1 of tissue water protons arise from magnetization transfer to macromolecular solid-state broadened lines.

We argue that, for solutions of immobilized protein and for tissue, the dependence of 1/T1 of solvent protons on B(0) at low fields and 1/T1 rho on B1 for all B(0) are both manifestations of the same underlying phenomena: magnetization transfer between mobile water protons and solid-state broadened protein proton levels. Broadening causes rapid mixing of spin orientation within the transverse plane, at all B(0), unless B1 is greater than the protein internal field; this affects 1/T1 rho of solvent protons by magnetization transfer. Similarly, decreasing B(0) below the internal field mixes all orientations of magnetization, which affects the solvent proton low-field 1/T1 and high-field 1/T2.

Animals↗
PubMed1992

Intermolecular protein interactions in solutions of calf lens alpha-crystallin. Results from 1/T1 nuclear magnetic relaxation dispersion profiles.

From analyses of the magnetic field dependence of 1/T1 (NMRD profiles) of water protons in solutions of calf lens alpha-crystallin at several concentrations, we find two regimes of solute behavior in both cortical and nuclear preparations. Below approximately 15% vol/vol protein concentration, the solute molecules appear as compact globular proteins of approximately 1,350 (cortical) and approximately 1,700 (nuclear) kD. At higher concentrations, the effective solute particle size increases, reversibly, as evidenced by the appearance of spectra-like 14N peaks in the NMRD profiles and a change in the field and temperature dependence of 1/T1. At these higher concentrations, the profiles are very similar to those of calf gamma II-crystallin, a crystallin that undergoes an analogous transition near approximately 15% protein (Koenig, S. H., C.F. Beaulieu, R. D. Brown III, and M. Spiller, 1990. Biophys. J. 57:461-469). By comparison with recent analyses of NMRD results for solutions of immobilized proteins as models for the transition from protein solutions to tissue (Koenig, S. H., and R. D. Brown III. 1991. Prog. NMR Spectr. 22:487-567), we argue that alpha-crystallin solute behaves as aggregates approximately greater than 50,000 kD as protein concentration is progressively increased above 15%. Finally, the concentration dependence of the NMRD profiles of alpha- and gamma II-crystallin can readily explain recent osmotic pressure data, in particular the intersection of the respective pressure curves at approximately 23% vol/vol (Vérétout, F., and A. Tardieu. 1989. Eur. Biophys. J. 17:61-68).

Animals↗
PubMed1991

Interactions of asparagine-linked carbohydrates with concanavalin A. Nuclear magnetic relaxation dispersion and circular dichroism studies.

By using near-UV circular dichroism (CD) and solvent proton nuclear magnetic relaxation dispersion measurements, three different conformational states have been detected in Ca(2+)-Mn(2+)-concanavalin A upon binding a variety of asparagine-linked carbohydrates. Two of these transitions have been described previously, one for the binding of monosaccharides such as methyl alpha-D-mannopyranoside and oligosaccharides with terminal alpha-Glc or alpha-Man residues, and the second for the binding of oligomannose and complex type carbohydrates (Brewer, C. F., and Bhattacharyya, L. (1986) J. Biol. Chem. 261, 7306-7310). The third transition occurs upon binding a bisected biantennary complex type carbohydrate with terminal GlcNAc residues. Temperature-dependent nuclear magnetic relaxation dispersion and CD measurements have identified regions of the protein near the two metal ion binding sites that are associated with the conformation changes, and Tyr-12, which is part of the monosaccharide binding site, as responsible for the CD changes. The results support our previous conclusions that the rotamer conformation of the (alpha 1,6) arm of bisected complex type oligosaccharides binds to concanavalin A with dihedral angle omega = -60 degrees whereas nonbisected complex type oligosaccharides bind with omega = 180 degrees (Bhattacharyya, L., Haraldsson, M., and Brewer, C. F. (1987) J. Biol. Chem. 262, 1294-1299). The present findings also explain the effects of increasing chain length of bisected complex type carbohydrates on their interactions with the lectin.

Asparagine↗
PubMed1991

Cholesterol of myelin is the determinant of gray-white contrast in MRI of brain.

The relative brightness of adult white matter in T1-weighted MRI arises from myelin, but the mechanisms responsible remain to be clarified. Koenig et al. [Magn. Reson. Med. 14, 482 (1990)] conjectured that the cholesterol of myelin (approximately 30% of its lipid) was responsible. We present 1/T1 and magnetization transfer contrast imaging data [Wolff and Balaban, Magn. Reson. Med. 10, 135 (1989)] on a model system--50% lipid--50% water by weight, with the lipid one-half phosphatidyl choline (PC) and one-half cholesterol--and a control in which the lipid is all PC. The differences between the model and control samples mimic the myelin contribution to white matter in both experiments.

Brain↗
PubMed1991

From the relaxivity of Gd(DTPA)2- to everything else.

We resolve the observed magnetic field-dependent relaxivity of Gd(DTPA)2- into inner and outer sphere contributions by comparison with theory. After noting that the outer sphere part, which contributes comparable to both 1/T1 and 1/T2, is identical to the "susceptibility" effect, we demonstrate the transition from the outer sphere relaxivity of small complexes, e.g., Gd(DTPA)2-, to that of large magnetic particulates, e.g., magnetite, used as T2 agents. This transition is expressed as a shift from a quantum to a classical mechanical description of relaxivity. We next show how to extrapolate the inner sphere contribution of Gd(DTPA)2- to similar small agents with greater structural symmetry, e.g., Gd(NOTA)-, by lengthening the electronic relaxation time and to ternary macromolecular complexes of small agents with protein by lengthening the rotational relaxation time. Finally, we indicate how relatively large lipid vesicles containing either small paramagnetic complexes or magnetized particulates may be considered analogs of Gd(DTPA)2-, with analogous inner and outer sphere contributions.

Contrast Media↗
PubMed1990

Interactions of nitroxides with plasma and blood: effect on 1/T1 of water protons.

Nitroxide stable free radicals (nitroxides) have potential utility as MRI contrast-enhancing agents with the additional capability of reflecting redox metabolism. In order to gain a better understanding of their potential interactions in vivo, we have studied the longitudinal NMRD profiles (1/T1 as a function of field strength) and ESR spectra for lipophilic and aqueous-soluble nitroxides in blood, plasma, and plasma components. Typical water-soluble nitroxides do not interact appreciably with blood, plasma, or plasma proteins. Fatty acid nitroxides do interact physically with blood, predominantly by intercalation within red blood cell membranes and binding to albumin. The latter interaction results in significantly enhanced relaxivity for the nitroxide/HSA complex. Relaxation of water protons in this case is dominated by inner sphere processes, ostensibly due to water molecules hydrogen bonded to nitroxide moieties. The rotational reorientation time for the complex, the electronic relaxation time, and the exchange time for the water molecule reversably bound to the nitroxide, all appear significantly to influence the correlation time (approximately 16 ns) for this inner sphere contribution.

Blood Proteins↗
PubMed1990

Relaxometry of brain: why white matter appears bright in MRI.

The remarkable success of magnetic resonance imaging of adult brain relates to the unusually large ratio of the longitudinal relaxation rates 1/T1 of white and gray matter, approximately 2:1 at physiological temperature and traditional imaging fields. Several investigators have conjectured that myelin is the source of the greater 1/T1 of white matter without, however, suggesting details of the molecular mechanisms responsible. From measurements of the magnetic field dependence of 1/T1 (NMRD profiles) of adult and neonatal gray and white matter at 5 and 35 degrees C, we find a thermally activated contribution to the NMRD profile of adult white matter that is not present in the profiles of either adult gray or neonatal gray and white matter. We attribute this contribution to myelin and develop a quantitative model that accounts for the unique relaxation behavior of myelinated white matter. We find that myelin water, 15% of the total, has a relatively short T1 that arises from an unexpectedly large interaction with myelin lipid; when cast in terms of an interaction over the entire myelin bilipid-water interface, it is sevenfold greater than the analogous protein-water interfacial interaction. Its magnitude remains to be accounted for, but cholesterol, known to alter the relaxation rates of lipid protons, may play an important role. The contribution of myelin to 1/T1 at physiological temperatures is attributed to thermally activated transmembrane diffusion of water and, hence, more rapid mixing of axonal and the rapidly relaxing myelin water molecules.

Adult↗