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At least 469 records · Page 26Linked to original sources
PubMed1999

Prediction of protein tertiary structure to low resolution: performance for a large and structurally diverse test set.

We report the tertiary structure predictions for 95 proteins ranging in size from 17 to 160 residues starting from known secondary structure. Predictions are obtained from global minimization of an empirical potential function followed by the application of a refined atomic overlap potential. The minimization strategy employed represents a variant of the Monte Carlo plus minimization scheme of Li and Scheraga applied to a reduced model of the protein chain. For all of the cases except beta-proteins larger than 75 residues, a native-like structure, usually 4-6 A root-mean-square deviation from the native, is located. For beta-proteins larger than 75 residues, the energy gap between native-like structures and the lowest energy structures produced in the simulation is large, so that low RMSD structures are not generated starting from an unfolded state. This is attributed to the lack of an explicit hydrogen bond term in the potential function, which we hypothesize is necessary to stabilize large assemblies of beta-strands.

Algorithms↗
PubMed2001

Muc-1, integrin, and osteopontin expression during the implantation cascade in sheep.

The extracellular matrix protein osteopontin (OPN) is a component of histotroph that increases in uterine flushings from pregnant ewes during the peri-implantation period and is localized on the apical surfaces of the uterine luminal epithelium (LE) and conceptus trophectoderm (Tr). The potential involvement of OPN in the implantation adhesion cascade in sheep was investigated by examining temporal, spatial, and potential functional relationships between OPN, Muc-1, and integrin subunits during the estrous cycle and early pregnancy. Immunoreactive Muc-1 was highly expressed at the apical surfaces of uterine luminal (LE) and glandular epithelium (GE) in both cycling and pregnant ewes but was decreased dramatically on LE by Day 9 and was nearly undetectable by Day 17 of pregnancy when intimate contact between LE and Tr begins. In contrast, integrin subunits alpha(v), alpha(4), alpha(5), beta(1), beta(3), and beta(5) were constitutively expressed on conceptus Tr and at the apical surface of uterine LE and GE in both cyclic and early pregnant ewes. The apical expression of these subunits could contribute to the apical assembly of several OPN receptors including the alpha(v)beta(3), alpha(v)beta(1), alpha(v)beta(5), alpha(4)beta(1), and alpha(5)beta(1) heterodimers on endometrial LE and GE, and conceptus Tr in sheep. Functional analysis of potential OPN interactions with conceptus and endometrial integrins was performed on LE and Tr cells in vitro using beads coated with OPN, poly-L-lysine, or recombinant OPN in which the Arg-Gly-Asp sequence was replaced with RGE or RAD. Transmembrane accumulation of talin or alpha-actinin at the apical surface of uterine LE and conceptus Tr cells in contact with OPN-coated beads revealed functional integrin activation and cytoskeletal reorganization in response to OPN binding. These results provide a physiological framework for the role of OPN, a potential mediator of implantation in sheep, as a bridge between integrin heterodimers expressed by Tr and uterine LE responsible for adhesion for initial conceptus attachment.

Actinin↗
PubMed1987

[Changes in the duration of action potentials of functionally different Helix neurons in response to serotonin].

Bath application of serotonin was studied for its effect on the duration of action potentials in sensory neurons, interneurons and motoneurons participating in avoidance behaviour of snail. Serotonin application increased the action potential duration in sensory neurons, while in interneurons and motoneurons such changes were absent. An increase of the action potential duration in sensory neurons can be the mechanism of the EPSP amplitude increase recorded in interneurons during application of serotonin. Functional consequences of selective reactions in neurons with different functional role are discussed.

Action Potentials↗
PubMed2000

Identifying sequence-structure pairs undetected by sequence alignments.

We examine how effectively simple potential functions previously developed can identify compatibilities between sequences and structures of proteins for database searches. The potential function consists of pairwise contact energies, repulsive packing potentials of residues for overly dense arrangement and short-range potentials for secondary structures, all of which were estimated from statistical preferences observed in known protein structures. Each potential energy term was modified to represent compatibilities between sequences and structures for globular proteins. Pairwise contact interactions in a sequence-structure alignment are evaluated in a mean field approximation on the basis of probabilities of site pairs to be aligned. Gap penalties are assumed to be proportional to the number of contacts at each residue position, and as a result gaps will be more frequently placed on protein surfaces than in cores. In addition to minimum energy alignments, we use probability alignments made by successively aligning site pairs in order by pairwise alignment probabilities. The results show that the present energy function and alignment method can detect well both folds compatible with a given sequence and, inversely, sequences compatible with a given fold, and yield mostly similar alignments for these two types of sequence and structure pairs. Probability alignments consisting of most reliable site pairs only can yield extremely small root mean square deviations, and including less reliable pairs increases the deviations. Also, it is observed that secondary structure potentials are usefully complementary to yield improved alignments with this method. Remarkably, by this method some individual sequence-structure pairs are detected having only 5-20% sequence identity.

Algorithms↗
PubMed1995

An automated method for dynamic ligand design.

An automated method for the dynamic ligand design (DLD) for a binding site of known structure is described. The method can be used for the creation of de novo ligands and for the modification of existing ligands. The binding site is saturated with atoms (sp3 carbon atoms in the present implementation) that form molecules under the influence of a potential function that joins atoms to each other with the correct stereochemistry. The resulting molecules are linked to precomputed functional group minimum energy positions in the binding site. The generalized potential function allows atoms to sample a continuous parameter space that includes the Cartesian coordinates and their occupancy and type, e.g., the method allows change of an sp3 carbon into an sp2 carbon or oxygen. A parameter space formulated in this way can then be sampled and optimized by a variety of methods. In this work, molecules are generated by use of a Monte Carlo simulated annealing algorithm. The DLD method is illustrated by its application to the binding site of FK506 binding protein (FKBP), an immunophilin. De novo ligands are designed and modification of the immunosuppressant drug FK506 are suggested. The results demonstrate that the dynamic ligand design approach can automatically construct ligands which complement both the shape and charge distribution of the binding site.

Algorithms↗
PubMed1994

Modeling large RNAs and ribonucleoprotein particles using molecular mechanics techniques.

There is a growing body of low-resolution structural data that can be utilized to devise structural models for large RNAs and ribonucleoproteins. These models are routinely built manually. We introduce an automated refinement protocol to utilize such data for building low-resolution three-dimensional models using the tools of molecular mechanics. In addition to specifying the positions of each nucleotide, the protocol provides quantitative estimates of the uncertainties in those positions, i.e., the resolution of the model. In typical applications, the resolution of the models is about 10-20 A. Our method uses reduced representations and allows us to refine three-dimensional structures of systems as big as the 16S and 23S ribosomal RNAs, which are about one to two orders of magnitude larger than nucleic acids that can be examined by traditional all-atom modeling methods. Nonatomic resolution structural data--secondary structure, chemical cross-links, chemical and enzymatic footprinting patterns, protein positions, solvent accessibility, and so on--are combined with known motifs in RNA structure to predict low-resolution models of large RNAs. These structural constraints are imposed on the RNA chain using molecular mechanics-type potential functions with parameters based on the quality of experimental data. Surface potential functions are used to incorporate shape and positional data from electron microscopy image reconstruction experiments into our models. The structures are optimized using techniques of energy refinement to get RNA folding patterns. In addition to providing a consensus model, the method finds the range of models consistent with the data, which allows quantitative evaluation of the resolution of the model. The method also identifies conflicts in the experimental data. Although our protocol is aimed at much larger RNAs, we illustrate these techniques using the tRNA structure as an example and test-bed.

Anticodon↗
PubMed2003

Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine.

One explanation for the weak relationship between neuropsychological deficits and conventional measures of disease burden in multiple sclerosis is that brain 'plasticity' allows adaptive reorganization of cognitive functions to limit impairment, despite injury. We have tested this hypothesis. Ten patients with multiple sclerosis and 11 healthy controls were studied using a functional MRI (fMRI) counting Stroop task. The two subject groups had comparable performances, but a predominantly left medial prefrontal region [Brodmann area (BA) 8/9/10] was more active during the task in patients than in controls (corrected P < 0.001), while a right frontal region (including BA 45 and the basal ganglia) was more active in controls than in patients (corrected P = 0.004). The magnitude of the differences correlated with the normalized brain parenchymal volume, a measure of disease burden (r = -0.72, P = 0.02). We then tested the effects of acute administration of rivastigmine, a central cholinesterase inhibitor, on patterns of brain activation. In five out of five multiple sclerosis patients there was a relative normalization of the abnormal Stroop-associated brain activation, although no change in the patterns of brain activation was found in any of four healthy controls given the drug and tested in the same way. We suggest that recruitment of medial prefrontal cortex is a form of adaptive brain plasticity that compensates, in part, for relative deficits in processing related to the reduced right prefrontal cortex activity with multiple sclerosis. This functional plasticity is modulated by cholinergic agonism and must arise from potentially highly dynamic mechanisms such as the 'unmasking' of latent pathways.

Adult↗
PubMed2006

Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons.

5-Hydroxytryptamine (5-HT) is one of the major chemical mediators released in injured and inflamed tissue and is capable of inducing hyperalgesia in vivo. However, the cellular mechanisms of 5-HT-induced hyperalgesia remain unclear. Transient receptor potential V1 (TRPV1) plays a pivotal role in nociceptive receptors. In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca(2+) imaging and whole-cell patch-clamp techniques. In more than 70% of DRG neurons, 5-HT potentiated the increases of [Ca(2+)](i) induced by capsaicin, protons and noxious heat. Capsaicin-induced current and depolarizing responses, and proton-induced currents were also augmented by 5-HT. RT-PCR analysis revealed the expression of 5-HT(2A) and 5-HT(7) receptors in rat DRG neurons. Agonists for 5-HT(2A) and 5-HT(7) receptors mimicked the potentiating effect of 5-HT, and their antagonists decreased it. In DRG ipsilateral to the complete Freund's adjuvant-injected inflammation side, expression levels of 5-HT(2A) and 5-HT(7) mRNAs increased, and the potentiating effect of 5-HT was more prominent than in the contralateral control side. These results suggest that the PKC- and PKA-mediated signalling pathways are involved in the potentiating effect of 5-HT on TRPV1 functions through the activation of 5-HT(2A) and 5-HT(7) receptors, respectively. Under inflammatory conditions, the increases of the biosynthesis of these 5-HT receptors may lead to further potentiation of TRPV1 functions, resulting in the generation of inflammatory hyperalgesia in vivo.

Analgesics, Non-Narcotic↗
PubMed1988

[New aspects of nuclear medicine diagnosis of kidney function: improved potential by pharmacologic intervention and quantitative analytic procedures].

In nuclear medicine new trends in the diagnosis of renal function are based on the introduction of new radiopharmaceuticals, improvements in the methodological part of the procedure and precise pharmacological intervention in response to given indications. Tc99m mercaptoacetyltriglycine (Tc99m MAG3) was tested as replacement for I123 orthoiodohippuric acid (I123 oIH) both in the form of a HPLC purified substance and as an impure kit preparation. HPLC purified Tc99m MAG3 clearance determinations in anuric patients showed a low extrarenal excretion amounting to only about 5% of the total clearance in normal patients. Kit preparations yielded about 90% of the labelled product; impurities were pertechnetate, reduced hydrolyzed Tc99m and chemically unidentified labelled products which showed a significantly lower renal, but increased hepatobiliary excretion in comparison with Tc99m MAG3. The renal clearance with kit preparations of Tc99m MAG3 was 55% of the clearance with oIH at a comparable urinary excretion. Significantly higher protein binding and therefore, a decrease in the distribution volume of Tc99m was found in comparison with I123 oIH. No difference was recorded between the two substances with respect to the renogram curves in normal subjects, apart from a modest delay in the elimination of Tc99m MAG3. For clinical purposes kit preparations of Tc99m MAG3 proved equal to I123 oIH. The influence of angiotensin converting enzyme (ACE) inhibitors (captopril) leads to characteristic changes in the renograms of patients with Goldblatt hypertension. Quantitative criteria for the evidence of haemodynamically significant renal artery stenosis were derived from investigations without and with captopril (25 mg) (I123 oIH and Tc99m DTPA) in 21 patients with essential hypertension. The criteria were defined as follows: a delay in peak activity (Tmax) in the I123 oIH captopril renogram exceeding 2 minutes as compared with the baseline value and/or a lower uptake of Tc99m DTPA in comparison with the uptake of I123 oIH (uptake quotient I123 oIH/Tc99m DTPA greater than 1.2). The diagnostic and prognostic potential of the captopril renogram was compared with that of the captopril test by investigating 34 patients with renal artery stenosis (23 uni-, 11 bilateral) (atherosclerosis: 23, fibromuscular hyperplasia: 11). The captopril renogram was positive more often (n = 12) than the captopril test (n = 4) in patients without renal functional impairment of the stenosed kidney. Similar results were obtained with both methods in patients with atrophic kidneys: captopril renography was positive in all cases with a positive captopril test.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

Ab initio investigation of interactions between models of membrane-active compounds and polar groups of membranes: complexes involving amine, ether, amide, phosphate, and carboxylate.

Ab initio (MINI-1) molecular orbital calculations were performed on model systems to investigate the hydrogen bonds and proton transfer between antiarrhythmics and polar groups of the cell membrane. Methylamine cation, dimethyl ether, and N-methylacetamide served as models of associative sites for the antiarrhythmics mexiletine and tocainide. Formate and phosphate anions, the methylamine cation, and formamide were chosen as models for the membrane polar groups. Protonated methylamine forms a very strong complex with the formate and phosphate anions. However, the formate COO- group is a better proton acceptor than the phosphate PO4- group. The effect of specific hydration on the proton potential functions was investigated in the HCOO- ... +HNH2CH3 and H2PO4- ... +HNH2CH3 systems. The proton potential functions, calculated at the equilibrium distances RO ... N, with a single minimum were found. The ab initio calculations at the longer RO ... N = 0.275 nm distance indicate double-minimum potentials. The increasing hydration stabilizes a second minimum corresponding to the charged O- ... +HN structures. The complexes involving the amide and ether groups of tocainide and mexiletine and the protonated primary amine group of the membrane are considerably weaker. The weakest hydrogen bonds are formed by the amine group of the drug (in its neutral and ionized state) with the peptide group.

Amides↗
PubMed1984

Testicular function in potential sperm donors: normal ranges and the effects of smoking and varicocele.

Testicular exocrine (semen analysis) and endocrine (plasma LH, FSH, prolactin and testosterone) function was assessed in 119 consecutive healthy men presenting for screening as potential sperm donors. Since these volunteers were unbiased with respect to their fertility status, this sample of the general male population was suitable to determine normal ranges and the influence of a variety of physical (height, weight, standardized body weight, varicocele) and demographic (age, marital and fertility status, tobacco and alcohol consumption) factors on normal human testicular endocrine and exocrine function, without the confounding effects of bias in selection of subjects. The statistical distribution of all seminal parameters was non-gaussian, but cube-root transformation of the data normalized the distribution, allowing for parametric statistical analysis. The median (and 95% confidence limits) for the various semen parameters was 73.0 (10.6-235.3) million sperm per ml; 189.0 (12.6-868) million sperm per ejaculate; 50.4 (5.9-181.9) million motile sperm per ml; 133.0 (6.9-661.7) million motile sperm per ejaculate; 54.0 (7.0-172.9) million morphologically normal sperm per ml and 138.5 (7.5-672) million morphologically normal sperm per ejaculate. Testicular volume was correlated positively with measures of physique such as standardized body weight (r = 0.25, P less than 0.01) and body surface area (r = 0.30, P less than 0.002), and negatively with plasma levels of FSH (r = -0.31), P less than 0.002) but not LH. Sperm output was positively correlated with testicular volume (r = 0.28, P less than 0.005) and negatively correlated with plasma FSH (r = -0.31, P less than 0.002) and plasma LH (r = -0.31, P less than 0.002). Smoking was associated with a highly significant reduction in sperm output and motility. Men with varicocele (25%) were significantly taller, had slightly lower haemoglobin levels and moderate left (but not right) testicular atrophy, but neither seminal nor hormonal parameters were different from men without varicocele. There was no difference in any markers of human testicular function between men according to marital or fertility status, grades of moderate alcohol consumption or the presence of low titres of sperm antibodies.

Adult↗
PubMed2001

Telomerase: biological function and potential role in cancer management.

Telomeres are the specialized ends of eukaryotic chromosomes, thought to have many functions, most importantly serving as a clock signaling entry into cellular senescence. These structures are maintained by the reverse transcriptase telomerase, a peculiar enzyme in both structure, since it contains its own template RNA and function, since it is inactivated in most normal tissues but activated in the vast majority of malignant tumors. These features have made telomerase a subject of intense investigation, both to understand its cellular role and regulation and to exploit its activation in cancer to develop drugs or diagnostic methods based on telomerase. This work gathers all the information currently available in the biological and clinical fields of telomerase research.

Humans↗
PubMed2003

Algorithm for normal mode analysis with general internal coordinates.

A technique for performing normal vibrational analysis for biological macromolecules using general internal coordinates is proposed. The technique is based on the conventional algorithm for calculating the second derivatives of potential and kinetic energies using intramolecular dihedral angles, intermolecular translation, and rotation as variables [Braun, W. et al., J Phys Soc Jpn 1984, 53, 3269]. We extend the algorithm to include more general internal coordinates, bond stretching, angle bending, and so forth, without assuming two-body interactions. The essential point is the separation of the variables for potential functions and vibrational analysis. With our technique, we can arbitrarily choose any combination of internal coordinates as variables, free from the functional form of potential energy. We can analyze complex systems such as a multiple molecular system including solvents or a transition state of chemical reactions. In addition, mixed use of the potentials of molecular mechanics and quantum chemistry is possible.

Journal Article↗
PubMed2002

Geminate rebinding in trehalose-glass embedded myoglobins reveals residue-specific control of intramolecular trajectories.

It is becoming increasingly apparent that hydrophobic cavities (also referred to as xenon cavities) within proteins have significant functional implications. The potential functional role of these cavities in modulating the internal dynamics of carbon monoxide in myoglobin (Mb) is explored in the present study by using glassy matrices derived from trehalose to limit protein dynamics and to eliminate ligand exchange between the solvent and the protein. By varying the temperature (-15 to 65 degrees C) and humidity for samples of carbonmonoxy myoglobin embedded in trehalose-glass, it is possible to observe a hierarchy of distinct geminate recombination phases that extend from nanosecond to almost seconds that can be directly associated with rebinding from specific hydrophobic cavities. The use of mutant forms of Mb reveals the role of key residues in modulating ligand access between these cavities and the distal hemepocket.

Animals↗
PubMed1988

Short latency visual evoked potentials in functional amblyopia shown using moving topography.

The conduction from the eye to the visual cortex through the brainstem was investigated in 43 cases of functional amblyopia by means of moving topography of short latency visual evoked potential (SVEP). Anomaly of the SVEP such as a defect of the main component and remarkable reduction of amplitude was found in cases with severe amblyopia whose visual acuity was less than 0.5. The incidence of abnormal SVEP was recognized in 44% of anisometropic amblyopia (18 cases), 52% of strabismic amblyopia (15 cases), and 50% of deprivation amblyopia (10 cases). The results suggested a reduction of electric activity in the subcortical visual pathway including transmitting nuclei.

Adolescent↗
PubMed1995

Return of the H-word (heterochromatin).

Recent advances in studies of yeast, Drosophila and humans have renewed interest in heterochromatin. These recent studies have demonstrated the interspersion and rapid spread of transposable elements into Drosophila heterochromatin; documented the requirement of heterochromatic genes for heterochromatin; identified heterochromatin-like regions in yeast chromosomes; confirmed an important role for satellite DNA in human centromere function; and suggested potential functions for heterochromatin-associated proteins.

Animals↗
PubMed1999

Anatomical model matching with fuzzy implicit surfaces for segmentation of thoracic volume scans.

Many segmentation methods for thoracic volume data require manual input in the form of a seed point, initial contour, volume of interest etc. The aim of the work presented here is to further automate this segmentation initialization step. In this paper an anatomical modeling and matching method is proposed to coarsely segment thoracic volume data into anatomically labeled regions. An anatomical model of the thorax is constructed in two steps: 1) individual organs are modeled with blended fuzzy implicit surfaces and 2) the single organ models are grouped into a tree structure with a solid modeling technique named constructive solid geometry (CSG). The combination of CSG with fuzzy implicit surfaces allows a hierarchical scene description by means of a boundary model, which characterizes the scene volume as a boundary potential function. From this boundary potential, an energy function is defined which is minimal when the model is registered to the tissue-air transitions in thoracic magnetic resonance imaging (MRI) data. This allows automatic registration in three steps: feature detection, initial positioning and energy minimization. The model matching has been validated in phantom simulations and on 15 clinical thoracic volume scans from different subjects. In 13 of these sets the matching method accurately partitioned the image volumes into a set of volumes of interest for the heart, lungs, cardiac ventricles, and thorax outlines. The method is applicable to segmentation of various types of thoracic MR-images, provided that a large part of the thorax is contained in the image volume.

Heart↗