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Biomedical subjects

M Q Zhang

Publications and source records attributed to M Q Zhang.

At least 55 records · Page 3Linked to original sources

Alignment of molecular sequences seen as random path analysis.

We propose a generating functional method--random path analysis (RPA)--that generalizes the classical dynamic programming (DP) method widely used in sequence alignments. For a given cost function, DP is a deterministic method that finds an optimal alignment by minimizing the total cost function for all possible alignments. By allowing uncertainty, RPA is a statistical method that weights fluctuating alignments by probabilities. Therefore, DP maybe thought of as the deterministic limit of RPA when the fluctuations approach zero. DP is the method of choice if one is only interested in optimal alignment. But we argue that, when information beyond the optimal alignment is desired, RPA gives a natural extension of DP for biological applications. As an algebraic approach, RPA is computationally intensive for long sequences, but it can provide better parametric control for developing analytical or perturbational results and it is more informative and biologically relevant. The idea of RPA opens up new opportunities for simulational approaches and more importantly it suggests a novel hardware implementation that has the potential of improving the way a sequence alignment is done. Here we focus on deriving a mathematically rigorous solution to RPA both in its combinatorial form and in its graphical representation; this puts DP in logical perspective under a more general conceptual framework.

Animals↗

A sequence compilation and comparison of exons that are alternatively spliced in neurons.

Alternative splicing is an important regulatory mechanism to create protein diversity. In order to elucidate possible regulatory elements common to neuron specific exons, we created and statistically analysed a database of exons that are alternatively spliced in neurons. The splice site comparison of alternatively and constitutively spliced exons reveals that some, but not all alternatively spliced exons have splice sites deviating from the consensus sequence, implying diverse patterns of regulation. The deviation from the consensus is most evident at the -3 position of the 3' splice site and the +4 and -3 position of the 5' splice site. The nucleotide composition of alternatively and constitutively spliced exons is different, with alternatively spliced exons being more AU rich. We performed overlapping k-tuple analysis to identify common motifs. We found that alternatively and constitutively spliced exons differ in the frequency of several trinucleotides that cannot be explained by the amino acid composition and may be important for splicing regulation.

Alternative Splicing↗

Fission yeast gene structure and recognition.

A database of 210 Schizosaccharomyces pombe DNA sequences (524,794 bp) was extracted from GenBank (release number 81.0) and examined by a number of methods in order to characterize statistical features of these sequences that might serve as signals or constraints for messenger RNA splicing. The statistical information compiled includes splicing signal (donor, acceptor and branch site) profiles, translational initiation start profile, exon/intron length distributions, ORF distribution, CDS size distribution, codon usage table, and 6-tuple distribution. The information content of the various signals are also presented. A rule-based interactive computer program for finding introns called INTRON.PLOT has been developed and was used to successfully analyze 7 newly sequenced genes.

Base Sequence↗

Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity.

A series of optically active analogues of the H1-antihistamine ebastine, with chiral center(s) at the benzhydryl and/or phenylbutyl part of the molecule, have been synthesized. Their in vitro antihistaminic and antimuscarinic activities were investigated, along with a molecular modelling study. It was found that introduction of the benzhydryl chiral center yielded significant stereoselectivity for both antihistaminic and antimuscarinic activities. The steric preferences of the benzhydryl chiral center for antihistaminic and antimuscarinic actions were mirror images of each other. The (-)-isomer of 4-methylebastine (6d) showed more than 10-fold higher in vitro antihistaminic potency than ebastine. Meanwhile the selectivity of 6d for histamine H1-receptors was also increased by more than 20 times in comparison with ebastine. The chirality at the phenylbutyl part of the molecule does not significantly alter the antihistaminic or antimuscarinic activity of the compounds although the (S)-isomers showed slightly but unanimously higher antihistaminic activity than the (R)-isomers. These results have been discussed with existing stereoselectivity data of antihistamines and an asymmetric pharmacophore model for H1-antagonists has been described.

Animals↗

Chiral manipulation of drug selectivity: studies on a series of terfenadine-derived dual antagonists on H1-receptors and calcium channels.

A series of terfenadine derivatives were evaluated for enantioselectivity on histamine H1-receptors and calcium channels. Whereas H1-receptors are only sterically discriminative against the benzhydryl part of the molecules, calcium channels showed enantioselectivity to either the phenylbutyl part or the benzhydryl part provided that an appropriate lipophilicity is preserved at the chiral site. It is speculated that the hydrophilicity of the butanol moiety is responsible for the lack of stereoselectivity of terfenadine enantiomers since it drives the side chain out of the stereoselective site of calcium channels, which are lipophilic. In four different test systems, (guinea-pig ileum, guinea-pig lung membranes, rat aorta and rat cortex membranes), this series of compounds generally showed about 10 times higher activity on H1-receptors than on calcium channels. By introducing a chiral center in the different parts of the molecule we were able to increase the selectivity of an enantiomer VUF4648 to calcium channels.

Animals↗

Terfenadine: a mixture of equipotent antihistamine enantiomers without a clear 'isomeric ballast'.

Terfenadine was the first non-sedating histamine H1 receptor antagonist and one of the most frequently prescribed H1 antihistamines. Terfenadine has one asymmetric centre in the molecule and is currently used as a racemate. Different methods and approaches for obtaining pure enantiomers of terfenadine are summarized and discussed in the present paper. Studies on antihistamine activity of the enantiomers, their side-effects on the central nervous system, calcium channel affinity and metabolism are also reviewed and analysed.

Animals↗

Genome mapping by nonrandom anchoring: a discrete theoretical analysis.

As part of our effort to construct a physical map of the genome of the fission yeast Schizosaccharomyces pombe, we have made theoretical predictions for the progress expected, as measured by the expected length fraction of island coverage and by the expected properties of the anchored islands such as the number and the size of islands. Our experimental strategy is to construct a random clone library and screen the library for clones having unique sequence at both ends. This scheme is essentially the same as the clone-limited double sequence-tagged-site selection scheme which was used in a computer simulation by Palazzolo et al. [Palazzolo, M. J., Sawyer, S. A., Martin, C. H., Smoller, D. A. & Hartl, D. L. (1991) Proc. Natl. Acad. Sci. USA 88, 8034-8038]. Both simulation and ongoing experiments in our laboratory have shown that the nonrandom anchoring method is far superior to random anchoring. In this paper, we propose a theoretical model to explain the simulated data and the experimental data.

Chromosome Mapping↗

Hypertrophy of rat sensory ganglion neurons following intestinal obstruction.

BACKGROUND: Neuroplastic changes following ileum hypertrophy have been reported in intrinsic enteric neurons. The hypothesis in the present study was that intestinal hypertrophy induces neuronal changes in dorsal root ganglia (DRG). METHODS: Under sodium pentobarbital anesthesia, partial obstruction was produced in the rat by tying a plastic ring around the terminal loop of ileum. Fast Blue (FB) (Sigma, St. Louis, MO) was injected into the obstructed ileum wall, and the rat was perfused after 8 days. DRG were immunostained and examined to identify and measure sizes of perikarya containing FB and/or calcitonin gene-related peptide (CGRP) or FB and/or substance P (SP). RESULTS: Of the DRG neurons that projected to the ileum in control or obstructed animals, approximately 50% were CGRP-immunoreactive (IR) and 30% were SP-IR (colchicine pretreatment was not used). Neurons that projected to the obstructed ileum were increased in size compared with neurons in nonobstructed controls. Some of these neurons were CGRP-IR or SP-IR; some were large FB-labeled neurons that were not SP-IR or CGRP-IR. CONCLUSIONS: The morphology of sensory autonomic neurons in adult animals is influenced by dynamic interactions with the targets they innervate, whether directly or transneuronally.

Animals↗

A weight array method for splicing signal analysis.

A new method of sequence analysis, using a weight array method (WAM), which generalizes the traditional Staden weight matrix method (WMM), is proposed. With the help of a statistical mechanical model, the discriminant function is identified with the energy function describing macromolecular interactions. The method is applied to the study of 5'-splice signals in Schizosaccharomyces pombe pre-mRNA sequences. The results show that there may exist weak pairwise correlations within the signals and that our method can help to better discriminate these signals. Experiments are proposed to test the predictions of the theory.

Animals↗

Calcium antagonism and structure-affinity relationships of terfenadine, a histamine H1 antagonist, and some related compounds.

Calcium channel affinity of terfenadine and its optical isomers was determined by the displacement of [3H]nitrendipine on rat cerebral cortex membranes. Terfenadine showed a pKd of 6.36 +/- 0.03 whereas its R(+)-isomer (VUF4567) had a pKd value of 6.39 +/- 0.03 and the S(-)-isomer (VUF4568) had a pKd of 6.40 +/- 0.04. The same affinity between the enantiomers suggests that the binding domain on the membrane is not sterically restricted towards the part of the molecule in which the chiral centre is present. The characteristics of terfenadine in regulating [3H]nitrendipine binding were similar to those of some other diphenyl-alkylamine type calcium antagonists. It allosterically altered the binding affinity for nitrendipine and acted at the same site linked to the calcium channel as gallopamil. A structure-affinity relationship among a group of terfenadine analogues is discussed.

Animals↗

[In vitro measurement of antibacterial activities of topical antibacterial creams].

A new method of in vitro measurement of antibacterial activity of different antimicrobial creams is introduced in this paper. The tested cream in known quantity is uniformed suspended in a solid medium, and bacteria of known quantity are inoculated. The result is expressed in MIC. In this observation, four creams were tested against 3 bacteria. It is the authors impression that the new method is better than the traditional disc method, as it reflects better the actual antibacterial activity of the drug in a cream base. It is helpful in selecting an effective drug or to evaluate the effectiveness of certain drugs in clinical practice.

Escherichia coli↗

Quinolone antimicrobial agents: structure-activity relationships.

The rapid growth in the quinolone research changed the whole face of the previous SAR concepts. So far structural modifications at all positions of the quinolone nucleus except the 4-oxo group have successfully lead to the discovery of potent antimicrobial agents. At position 1, ethyl and its bioisosteres such as fluoroethyl, methylamino, methoxy, etc, are optimal substituents while some groups with a tert.-carbon atom directly connected with N-1 position such as tert.-butyl, phenyl, etc. are also promising for the activity of the quinolone compounds. Steric bulk is no longer considered as the only factor which influences the activity of the compounds. However, it could only be answered by further research how big such steric bulk tolerance at position 1 would be and what is the precise role that the N-1 substituents play in the mechanism of action of the quinolones. Fluorination has been extensively employed as a modifying technique to almost all possible positions of the quinolone nucleus. While being maintained at C-6, a fluorine atom was also introduced to C-5 and C-8 to produce potent analogues. Fluorination of N-1 substituents, e.g., fluoroethyl, fluorophenyl, etc., and C-7 substituents, e.g. 2-((fluoromethyl)piperazinyl and fluorohomopiperazinyl, etc., yielded also a handful of potent quinolones. Amino-and chloro groups are found to be beneficial for positions 5 and 8, respectively. The "medium size" concept concerning the 7-substituents is no longer valid. Numerous potent quinolones with a "large" group substituted on position 7 have been discovered. A certain amount of free rotation in the 7-substituents appears to emerge as an important factor which influences the activity of the compounds. Some radical modifications in 7-substituents, e.g. C--C linkage between the nucleus and 7-substituents, afforded new insight into the SAR of quinolones. A planarity between the 4-oxo group and 3-carboxylic group may be important for binding to the DNA gyrase as demonstrated by a group of enolized isothiazoloquinolone derivatives. Further research will surely lead to the better understanding on the mechanism of action of quinolones as well as the discovery of analogues with better activity features, lower adverse effects and more favourable pharmacokinetic properties.

4-Quinolones↗

[Ranitidine in the prevention of upper gastrointestinal tract hemorrhage following thermal injury].

This paper reports the use of Ranitidine in preventing upper gastrointestinal tract hemorrhage following thermal injury. In 12 hours after intravenous injection of Ranitidine, gastric pH was elevated from 3.25 +/- 0.26 to 5.16 +/- 0.47 (P less than 0.01) in twenty-one burn patients, with mean TBSA 62.6% +/- 17.2% (31%-87.5%), mean third degree BSA 41.4% +/- 18.3% (0-68%). The volume of gastric secretion was decreased from 15.81 +/- 4.4 ml to 2.85 +/- 0.9 ml. The free acid of gastric secretion was decreased from 25.74 +/- 4.42 mmol/L to 5.98 +/- 3.68 mmol/L (P less than 0.01). The total titratable acidity of gastric secretion was decreased from 44.76 +/- 5.76 mmol/L to 13.85 +/- 0.02 mmol/L (P less than 0.01). Three patients had occult blood in their gastric contents on admission, and it turned negative after Ranitidine therapy. However, during 1987-1988, the incidence of upper gastrointestinal tract hemorrhage of fifty-one patients with similar TBSA and third degree BSA burned was 21.6%. Changes in gastric secretion and lowered incidence of upper gastrointestinal hemorrhage after Ranitidine therapy suggest that Ranitidine may be effective in preventing upper gastrointestinal tract hemorrhage following thermal injury.

Adolescent↗

Influence of N substitution on antimycobacterial activity of ciprofloxacin.

Ciprofloxacin analogs with various substitutions on the piperazine nitrogen were tested against several mycobacteria. In contrast to what has been found with other gram-positive and gram-negative bacteria, alkyl analogs such as N-isopropylciprofloxacin were shown to be significantly more active than ciprofloxacin. MICs of 0.125 microgram/ml against Mycobacterium tuberculosis were found.

Ciprofloxacin↗

The intestine as a model for neuronal plasticity.

This study focuses on establishing the nature and extent of the changes that occur in gastroenteric innervation, specifically the myenteric plexus of the rat ileum, following an injury generated by experimental obstruction. A partial obstruction was accomplished by placing a cuff around the terminal portion of the ileum of the rat. Substantial hypertrophy of the enteric muscle wall occurred after 3-5 weeks. Light microscopic examination of the myenteric plexus revealed changes in the numbers of neuronal perikarya, ganglia and perikarya per ganglia; sizes and shapes of perikarya; and thicknesses of nerve fiber bundles. Using vasoactive intestinal polypeptide (VIP) and substance P light microscopic immunohistochemistry, we observed indications of transmitter accumulation in cell bodies and nerve fibers and reactive, degenerative and regenerative changes in axonal endings. Electron microscopic studies provided evidence for neuroplastic changes, as demonstrated by the appearance of reactive and regenerative, or growth, cones in the myenteric plexus.

Animals↗

Experiences in the treatment of electrical burns covering deep wounds with various tissue flaps.

From 1979 to 1986, 121 patients with electrical burns were admitted to our, unit (6% of all the burned patients admitted during that period). Of these cases 64 were regarded as having deep burns (e.g. burns which injured muscles, tendons, nerves, bones and capsules of the joints etc.). Thirty-five flaps of various types of tissues (including one free muscle flap, two island fascial flaps, four island skin flaps, three arterial skin flaps, two musculocutaneous flaps and twenty-three random skin flaps) were used for the coverage of deep burns in twenty-seven patients. Thirty three flaps survived completely while two were partially lost; three flaps developed severe sub-flap infections but the tissue of the flaps survived totally. Three typical cases are reported in this paper. The advantages of early extensive exploration and thorough debridement of the deep electrical wounds are discussed. It also introduces the practical usage of various flaps for wound coverage in these typical cases. When flaps were needed for deep electrical burns, we chose local flaps first, and used axial pattern flaps, island flaps, etc. as much as possible; if only a random flap was available in the site, we elevated it with some deep fascia to enhance its ability to prevent infection. We considered the free tissue transfer and the transfer of fascial flaps to be important alternatives. Debridement followed by immediate wound coverage should be done as soon after resuscitation as possible. Generally the operations were performed within the third to fifth days after the electrical burn. This is the best period for active treatment in order to salvage the remaining functions of the burned extremities. Operations performed after six days must be done only under the careful control of anti-infective measures. From our experience we have found that muscle flaps and musculocutaneous flaps were the most suitable approaches for the coverage of deeply infected wounds especially when bones were involved. Careful attention was taken to excise the necrotic muscle tissues, especially those that were "sandwiched" between necrotic muscle bundles. This was done primarily by gross evaluation according to the judgement of the surgeon intraoperatively. The swollen and hardened regions of the skin of involved extremities generally corresponded to the areas of necrotic muscle tissue at about three days after the injuries or later. This was used as a reference to indicate where to place or extend the exploratory incisions. We frequently preserved denatured peripheral nerves and tendons, because these injured structures often later regain their functions partially or completely with a reliable coverage.(ABSTRACT TRUNCATED AT 400 WORDS)

Accidents, Occupational↗