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Biomedical subjects

J M Schmidt

Publications and source records attributed to J M Schmidt.

At least 19 recordsLinked to original sources
PubMed2002

Does a homeopathic ultramolecular dilution of Thyroidinum 30cH affect the rate of body weight reduction in fasting patients? A randomised placebo-controlled double-blind clinical trial.

OBJECTIVE: To test whether an ultramolecular dilution of homeopathic Thyroidinum has an effect over placebo on weight reduction of fasting patients in so-called 'fasting crisis'. DESIGN: Randomised, placebo-controlled, double-blind, parallel group, monocentre study. SETTING/LOCATION: Hospital for internal and complementary medicine in Munich, Germany. SUBJECTS: Two hundred and eight fasting patients encountering a stagnation or increase of weight after a weight reduction of at least 100 g/day in the preceding 3 days. INTERVENTION: One oral dose of Thyroidinum 30cH (preparation of thyroid gland) or placebo. OUTCOME MEASURES: Main outcome measure was reduction of body weight 2 days after treatment. Secondary outcome measures were weight reduction on days 1 and 3, 15 complaints on days 1-3, and 34 laboratory findings on days 1-2 after treatment. RESULTS: Weight reduction on the second day after medication in the Thyroidinum group was less than in the placebo group (mean difference 92 g, 95% confidence interval 7-176 g, P=0.034). Adjustment for baseline differences in body weight and rate of weight reduction before medication, however, weakened the result to a non-significant level (P=0.094). There were no differences between groups in the secondary outcome measures. CONCLUSIONS: Patients receiving Thyroidinum had less weight reduction on day 2 after treatment than those receiving placebo. Yet, since no significant differences were found in other outcomes and since adjustment for baseline differences rendered the difference for the main outcome measure non-significant, this result must be interpreted with caution. Post hoc evaluation of the data, however, suggests that by predefining the primary outcome measure in a different way, an augmented reduction of weight on day 1 after treatment with Thyroidinum may be demonstrated. Both results would be compatible with homeopathic doctrine (primary and secondary effect) as well as with findings from animal research.

Adult↗
PubMed2001

Analysis of two matrix metalloproteinase inhibitors and their metabolites for induction of phospholipidosis in rat and human hepatocytes(1).

ABT-770 [(S)-N-[1-[[4'-trifluoromethoxy-[1,1'-biphenyl]-4-yl]oxy]methyl-2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-N-hydroxyformamide], a matrix metalloproteinase inhibitor (MMPI), produced generalized phospholipidosis in rats. Phospholipid accumulation was accompanied by retention of drug-related material and was associated with increased mortality. Generation of a successful drug candidate depended upon understanding the cause of the phospholipidosis and redesigning the chemical structure accordingly. ABT-770 and other MMPIs, plus several metabolites of each, were assayed for their ability to induce phospholipidosis in primary cultured rat and human hepatocytes. Phospholipid accumulation was detected by following the incorporation of a fluorescent phospholipid analogue into intracytoplasmic inclusion bodies characteristic of phospholipid storage disorders. At 24 and 48 hr, none of the parent compounds induced phospholipidosis in vitro in rat or human hepatocytes. Phospholipidosis was associated primarily with an amine metabolite of ABT-770. The amine metabolite of another MMPI, ABT-518 ([S-(R*,R*)]-N-[1-(2,2-dimethyl-1,3-dioxol-4-yl)-2-[[4-[4-(trifluoromethoxy)-phenoxy]phenyl]sulfonyl]ethyl]-N-hydroxyformamide), produced little phospholipidosis in rat and human hepatocytes even at concentrations up to 100 microM. The presence or absence of phospholipidosis in the in vitro assay correlated well with ultrastructural findings and drug accumulation in rat tissues. ABT-770, which produced phospholipidosis associated with its amine metabolite in vitro and in vivo, also generated a higher tissue to plasma distribution of metabolites particularly in tissues where phospholipidosis was observed. ABT-518 and its amine metabolite, however, produced low tissue to plasma ratios and induced little to no phospholipidosis in vitro or in vivo. These results demonstrate that the phospholipidosis observed for ABT-770 could be attributed to a cationic metabolite, and that altering the properties of such a metabolite, by modification of the parent compound, alleviated the disorder.

Animals↗
PubMed2001

Self-consistent Karplus parametrization of 3J couplings depending on the polypeptide side-chain torsion chi1.

Recently proposed self-consistent 3J coupling analysis (Schmidt, J. M.; Blümel, M.; Löhr, F.; Rüterjans, H. J. Biomol. NMR 1999, 14, 1-12) has been carried out to calibrate Karplus parameters constituting the empirical dependence of 3J coupling constants on the chi1 dihedral angle in amino acid side chains. The procedure involves simultaneous least-squares optimization of six sets of three Karplus coefficients related to all six 3J coupling types accessible in 15N,13C-labeled proteins. A simple concept of fundamental and incremental component couplings is proposed to account for substituent effects, eventually yielding amino acid topology-specific Karplus parameters. The method is exemplified with recombinant Desulfovibrio vulgaris flavodoxin (147 amino acids, 16 kDa) with reference to a total of 749 experimental 3JHalpha,Hbeta, 3JN',Hbeta, 3JC',Hbeta, 3JHalpha,Cgamma, 3JN',Cgamma, and 3JC',Cgamma coupling constants. Unlike other parametrizations, the present method does not make reference to X-ray coordinates, so that the Karplus coefficients obtained are not influenced by differences between solution and crystal states. Cross validation using X-ray torsion angles demonstrates the improvement relative to previous parametrizations. The Karplus coefficients derived are applicable to other proteins, too. Parameter refinement also yields a series of chi1 torsion angles, providing valuable constraints for protein structure determination, as well as optional parameters of local angular mobility in the contexts of Gaussian random fluctuation or a three-site jump model. The procedure permits automatic stereospecific assignments of Hbeta and Cgamma chemical shifts. The majority of the flavodoxin side-chain conformations agrees with high-resolution X-ray structures of the protein. Marked deviations between NMR and X-ray datasets are attributed to different rotameric states due to crystal-packing effects and to conformational equilibria between multiple chi1 rotamers.

Flavodoxin↗
PubMed2001

Flexible alignment of small molecules.

A method is presented for flexibly aligning small molecules. The method accepts a collection of small molecules with 3D coordinates as input and computes a collection of alignments. Each alignment is given a score, which quantifies the quality of the alignment both in terms of internal strain and overlap of molecular features. The results of several computational experiments on pairs of compounds with known binding conformations are used to systematically and objectively tune the parameters for the method. The results indicate the method's utility for the elucidation of pharmacophores and comparative field analysis.

Databases, Factual↗
PubMed2001

Raman spectroscopy of potassium acetate-intercalated kaolinites at liquid nitrogen temperature.

Raman microscopy has been used to study low and high defect kaolinites and their potassium acetate intercalated complexes at 298 and 77 K. Raman spectroscopy shows significant differences in the spectra of the hydroxyl-stretching region of the two types of kaolinites, which is also reflected in the spectroscopy of the hydroxyl-stretching region of the intercalation complexes. Additional bands to the normally observed kaolinite hydroxyl stretching frequencies are observed for the low and high defect kaolinites at 3605 and 3602 cm(-1) at 298 K. Upon cooling to liquid nitrogen temperature, these bands are observed at 3607 and 3604 cm(-1), thus indicating a weakening of the hydrogen bond formed between the inner surface hydroxyls and the acetate ion. Upon cooling to liquid nitrogen temperature, the frequency of the inner hydroxyls shifted to lower frequencies. Collection of Raman spectra at liquid nitrogen temperature did not give better band separation compared to the room temperature spectra as the bands increased in width and shifted closer together.

Kaolin↗
PubMed2001

Improved measurement of (3)J(H(alpha)(i),N(i+1)) coupling constants in H(2)O dissolved proteins.

A modification to the recently proposed alpha/beta-HN(CO)CA-J TROSY pulse sequence (P. Permi et al., J. Magn. Reson. 146, 255-259 (2000)) makes it possible to determine (3)J(H(alpha)(i), N(i+1)) coupling constants from a single E.COSY-type cross-peak pattern rather than from two (1)H(alpha) spin-state-edited subspectra. Advantages are increased (15)N resolution, critical to extracting accurate (1)H(alpha)-(15)N coupling constants, and minimized differential relaxation due to nested (13)C(alpha) and (15)N evolution periods. Application of the improved pulse sequence to Desulfovibrio vulgaris flavodoxin results in (3)J(H(alpha)(i), N(i+1)) values being systematically larger than those obtained with the original scheme. Parametrization of the coupling dependence on the protein backbone torsion angle psi yields the Karplus relation (3)J(H(alpha)(i), N(i+1))=-1.00 cos(2)(psi-120 degrees )+0.65 cos(psi-120 degrees )-0.15 Hz, with a residual root-mean-square difference of 0.13 Hz between measured and back-calculated coupling constants. The curve compares with data derived from ubiquitin (A. C. Wang and A. Bax, J. Am. Chem. Soc. 117, 1810-1813 (1995)), although spanning a slightly larger range of J values in flavodoxin. The orientation of the Ala39/Ser40 peptide link, forming a type-II beta-turn in flavodoxin, is twisted against X-ray-derived torsions by approximately 10 degrees in the NMR structure as evident from the analysis of straight phi- and psi-related (3)J coupling constants. The remaining deviation of some experimental values from the prediction is likely to be due to strong hydrogen bonding, substituent effects, or the additional dependence on the adjacent torsions straight phi.

Flavodoxin↗
PubMed2001

Identifying potential binding modes and explaining partitioning behavior using flexible alignments and multidimensional scaling.

A method is described for the rapid and automatic analysis of flexible molecular alignments using multidimensional scaling and a normalized scoring scheme. A projection scheme was devised to separate orientational and conformational effects. It is shown that the approach can be utilized for the identification of common binding orientations or to the study of differences in partioning behavior. It is suggested that the method can be employed as a novel approach exploring molecular similarity as a dynamic property, so that it includes aspects of motion (by way of mutual orientations), conformations and molecular properties.

Antiviral Agents↗
PubMed2001

Lexical emotional expression across the life span: quantitative and qualitative analyses of word list generation tasks.

The current study examined the effects of age and gender on emotional and nonemotional expression using an experimental word list generation (WLG) task (also referred to in the literature as verbal fluency) from the New York Emotion Battery (Borod, Welkowitz, & Obler, 1992). Subjects were 28 young ( M = 29.6 years), 28 middle-aged (M = 49.8 years), and 28 older (M = 69.9 years) healthy adults. The WLG task consists of 8 emotional (E; 3 positive and 5 negative) and 8 nonemotional (NE) categories. We developed and present here a detailed word error-type analysis that was used to evaluate the lexical output. In this study, both quantitative (amount of output and error-types) and qualitative (accuracy and intensity) analyses were used. While subjects produced more nonemotional than emotional words and more positive than negative words, the amount of error-free output and the number of errors did not change with age. An age group by error-type interaction indicated that older adults, especially men, produced more repetition errors than younger adults. The error-free output was subsequently rated for accuracy and emotional intensity. The rating data revealed that older women's overall lexical output was less accurate than that produced by younger women. Also, negative emotional words were more accurate and intense than positive emotional words. The procedures described here have implications for research assessing word list generation and emotional expression in clinical populations.

Adult↗
PubMed2000

A simple model for the prediction of blood-brain partitioning.

We derived a simple model for the prediction of blood-brain barrier penetration using three descriptors. The model contains the calculated octanol-water partition coefficient, the number of hydrogen-bond acceptors in an aqueous medium and the polar surface area. It was validated using an extensive dataset, comprising 100 diverse drug molecules. The descriptors are easily calculated and the model is suitable for the rapid prediction of the blood-brain barrier partitioning of drugs.

Blood-Brain Barrier↗
PubMed2000

Isolation and structures of schleicherastatins 1-7 and schleicheols 1 and 2 from the teak forest medicinal tree Schleichera oleosa.

Bioassay (P-388 lymphocytic leukemia cell line)-guided separation of an extract prepared from the bark and stem of the Sri Lankan tree Schleichera oleosa led to the isolation of seven cancer cell growth inhibitory hydroxylated sterols designated schleicherastatins 1-7 (1-7) and two related sterols, schleicheols 1 and 2 (8, 9). The structure of schleicherastatin 1 (1) was completely elucidated by X-ray crystal structure determination. Based upon that defined structure, the remaining new sterol structures were deduced by highfield (300 and 500 MHz) NMR and MS interpretations. In this new series of sterols, hydroxylation at C-22 appears to be important for promoting cancer cell growth inhibition.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Heteronuclear relayed E.COSY revisited: determination of 3J(H(alpha),C(gamma)) couplings in Asx and aromatic residues in proteins.

Constant-time 3D heteronuclear relayed E.COSY [Schmidt et al. (1996) J. Biomol. NMR, 7, 142-152], as based on generic 2D small-flip-angle HMQC-COSY [Schmidt et al. (1995) J. Biomol. NMR, 6, 95-105], has been modified to allow for quantitative determination of heteronuclear three-bond 3J(H(alpha),C(gamma)) couplings. The method is applicable to amino acid spin topologies with carbons in the gamma position which lack attached protons, i.e. to asparagine, aspartate, and aromatic residues in uniformly 13C-enriched proteins. The pulse sequence critically exploits heteronuclear triple-quantum coherence (HTQC) of CH2 moieties involving geminal H(beta) proton pairs, taking advantage of improved multiple-quantum relaxation properties, at the same time avoiding scalar couplings between those spins involved in multiple-quantum coherence, thus yielding E.COSY-type multiplets with a splitting structure that is simpler than with the original scheme. Numerical least-squares 2D line-shape simulation is used to extract 3J(H(alpha),C(gamma)) coupling constants which are of relevance to side-chain chi1 dihedral-angle conformations in polypeptides. Methods are demonstrated with recombinant 15N,13C-enriched ribonuclease T1 and Desulfovibrio vulgaris flavodoxin with bound oxidized FMN.

Amino Acids, Cyclic↗
PubMed2000

Hepatitis C virus kinetics.

The balance of virus production and clearance for untreated patients with chronic hepatitis C virus (HCV) results in a decline of viraemia when initiating active antiviral treatment. During the first phase of interferon-alpha therapy, after a delay of about 8-9 h, the kinetics of the viral load is characterized by a rapid dose-dependent decline. This early response can be observed for almost all patients treated with interferon-alpha. After about 24-48 h, the viral decline enters a second phase of relatively slow exponential decay during the following weeks of therapy. Non-responding patients, however, show constant viraemia or even a rebound during this second phase. The rate of the exponential decline of the viral load in responding patients in this second phase is less sensitive to the dose of interferon-alpha and varies considerably among patients. Furthermore, combination therapy with interferon-alpha plus ribavirin does not significantly improve the initial viral decay, although it may prevent more patients from rebounding. Mathematical modelling of viral dynamics reveals high turnover rates of pre-treatment viral production and clearance, and permits the estimation of in vivo half-lives of a few hours for free HCV virions and of 1-70 days for productively infected cells. Infected cell death rate, which determines the second phase decline slope, is predictive of response to treatment. Current models indicate that the early biphasic viral decline is explained if interferon-alpha partially blocks virion production from infected cells, yet they do not rule out additional antiviral or immunological effects. Therapeutic implications are the advisability of use of frequent (daily) and comparatively high initial doses. In conclusion, kinetic analysis of the viral decay during the first weeks of treatment permits the prediction of response at the end-of-therapy and might help to evaluate new drugs and to optimize therapy.

Antiviral Agents↗
PubMed1999

NMR approaches for monitoring domain orientations in calcium-binding proteins in solution using partial replacement of Ca2+ by Tb3+.

This work shows that the partial replacement of diamagnetic Ca2+ by paramagnetic Tb3+ in Ca2+/calmodulin systems in solution allows the measurement of interdomain NMR pseudocontact shifts and leads to magnetic alignment of the molecule such that significant residual dipolar couplings can be measured. Both these parameters can be used to provide structural information. Species in which Tb3+ ions are bound to only one domain of calmodulin (the N-domain) and Ca2+ ions to the other (the C-domain) provide convenient systems for measuring these parameters. The nuclei in the C-domain experience the local magnetic field induced by the paramagnetic Tb3+ ions bound to the other domain at distances of over 40 A from the Tb3+ ion, shifting the resonances for these nuclei. In addition, the Tb3+ ions bound to the N-domain of calmodulin greatly enhance the magnetic susceptibility anisotropy of the molecule so that a certain degree of alignment is produced due to interaction with the external magnetic field. In this way, dipolar couplings between nuclear spins are not averaged to zero due to solution molecular tumbling and yield dipolar coupling contributions to, for example, the one-bond 15N-1H splittings of up to 17 Hz in magnitude. The degree of alignment of the C-domain will also depend on the degree of orientational freedom of this domain with respect to the N-domain containing the Tb3+ ions. Pseudocontact shifts for NH groups and 1H-15N residual dipolar couplings for the directly bonded atoms have been measured for calmodulin itself, where the domains have orientational freedom, and for the complex of calmodulin with a target peptide from skeletal muscle myosin light chain kinase, where the domains have fixed orientations with respect to each other. The simultaneous measurements of these parameters for systems with domains in fixed orientations show great potential for the determination of the relative orientation of the domains.

Amino Acid Sequence↗
PubMed1999

Interaction of talin with actin: sensitive modulation of filament crosslinking activity.

Talin is an adhesion plaque protein believed important in linking actin filaments to the plasma membrane. The nature of a direct talin-actin interaction, however, is complex and has remained unclear. We have systematically characterized the effects of pH, ionic strength, temperature, and protein molar ratio on the interaction between highly purified talin and actin. The ability of talin to increase viscosity of F-actin at 25 degrees C and low ionic strength increased with decreasing pH from 7.3 to 6.4 and increasing molar ratio of talin to actin. At pH 6.4 and low ionic strength, talin could extensively crosslink actin filaments into ordered bundles as shown by negative staining and could cosediment with F-actin at molar ratios as high as one talin to two actin monomers. Talin crosslinked prepolymerized actin filaments to a similar extent as actin filaments polymerized in its presence. The 190-kDa calpain-generated proteolytic fragment of talin bound poorly to actin under conditions favorable for intact talin, but was able to crosslink actin filaments at a lower pH. Increasing the ionic strength within a relatively narrow range significantly decreased ability of talin to bind to actin, regardless of pH. The effects of pH and ionic strength on the talin-actin interaction were rapid and reversible. Low-shear-viscosity studies revealed a strong temperature dependence in the talin-actin interaction with significant crosslinking activity at physiological-like ionic conditions and temperature (37 degrees C). Our results consistently demonstrated that talin crosslinks actin filaments and that this direct interaction is highly sensitive to, and dependent upon, ionic conditions and temperature.

Actins↗
PubMed1999

Regulating plant/insect interactions using CO2 enrichment in model ecosystems.

The greenhouse environment is a challenging artificial ecosystem in which it is possible to study selected plant/insect interaction in a controlled environment. Due to a combination of "direct" and "indirect" effects of CO2 enrichment on plant photosynthesis and plant development, canopy productivity is generally increased. In this paper, we discuss the effects of daytime and nighttime CO2 enrichment protocols on gas exchange of pepper plants (Capsicum annuum L, cv Cubico) grown in controlled environments. In addition, we present the effects of thrips, a common Insect pest, on the photosynthetic and respiratory activity of these plant canopies. Carbon dioxide has diverse effects on the physiology and mortality of insects. However, our data indicate that thrips and whiteflies, at least, are not killed "directly" by CO2 levels used to enhance photosynthesis and plant growth. Together the data suggest that the insect population is affected "indirectly" by CO2 and that the primary effect of CO2 is via its effects on plant metabolism.

Animals↗
PubMed1999

Antineoplastic agents. Part 409: Isolation and structure of montanastatin from a terrestrial actinomycete.

A Montana soil actinomycete, Streptomyces anulatus, produced (1 x 10(-2)% yield) a new cancer cell growth inhibitory cyclooctadepsipeptide named montanastatin (1) accompanied by the potent anticancer antibiotic valinomycin (2) in very high (5.1%) yields. Valinomycin but not montanastatin inhibited growth of a number of pathogenic bacteria and fungi. Interpretation of high-field (500 MHz) NMR and high-resolution FAB mass spectral data allowed assignment of the structure cyclo-(D-Val-L-Lac-L-Val-D-Hiv) to montanastatin. Valinomycin (2) was also isolated from actinomycetes cultured from a tree branch and animal feces collected in Malaysia. Streptomyces exfoliatus, isolated from the tree branch, was found to contain valinomycin in 1.6% yield, while the fecal isolate, S. anulatus, gave valinomycin in 0.9% yield.

Actinomycetales↗