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PubMed2002

Modular design of a novel chimeric protein with combined thrombin inhibitory activity and plasminogen-activating potential.

In order to design plasminogen activators with improved thrombolytic properties we sought to construct the bifunctional protein HLS-2 which combines both a plasminogen-activating and an anticoagulative activity. The chimeric protein comprises four elements: a derivative of thrombin inhibitor hirudin, a 6-amino acid spacer, the sequence of plasminogen-activator staphylokinase (Sak), and a 13-amino acid expression tag at the C-terminus. The gene of the fusion protein was obtained by SOE-PCR, cloned into pCANTAB5E, and expressed in E. coli BL21. HLS-2 was purified from periplasmatic extracts and characterized by Western blotting. Plasminogen-activation of HLS-2 and of Sak in equimolar mixtures with plasminogen showed near equivalence as measured by plasmin-mediated cleavage of chromogenic substrate S-2403. For catalytic amounts of plasminogen-activator, however, HLS-2 was less effective by a factor of 1.7. HLS-2 also inhibited both the amidolytic and the fibrinolytic activities of thrombin. Similar concentrations of either commercial HV1 (42 pmol/L) or HLS-2 (250 pmol/L) were required to halve the initial rate of thrombin reaction with fluorogenic substrate Tos-Gly-Pro-Arg-AMC, suggesting the retention of high-affinity inhibition of thrombin by the fusion protein sufficiently strong to substitute anticoagulative comedication during fibrinolytic treatment. The results provide a rationale for further testing the efficacy of HLS-2 for the lysis of platelet-rich arterial blood clots and for the prevention of reocclusion after thrombolysis.

Amides↗
PubMed1999

Tn4371: A modular structure encoding a phage-like integrase, a Pseudomonas-like catabolic pathway, and RP4/Ti-like transfer functions.

Tn4371 is a 55-kb catabolic transposon originally isolated from Ralstonia eutropha A5 that encodes enzymes catalyzing the complete degradation of biphenyl. Unlike previously described transposons encoding similar genes for aromatic compound degradation. Tn4371 carries a phage-like degradation, Tn4371 integrase gene and RP4/Ti-like transfer genes. Tn4371 transposition involves an excision/integration process and, consistent with this site-specific recombination mechanism, the ends of the element are transiently covalently bound. Transposition is targeted to a limited number of sites on the CH34 chromosome and pMOL30 plasmid as well as on RP4. One of these sites consists of a 5'-TTTTTCAT-3' sequence which is also present between the covalently joined ends of the transposon. Conjugative transfer of Tn4371 could not yet be demonstrated although the functionality of its transfer machinery could be established through the identification of a second transposable element, Tn-bph, which contains the right half of Tn4371, including the bph catabolic gene cluster and the identified transfer genes. Tn-bph transfers by conjugation and integrates in a new host genome independently of the larger element. Tn4371 thus appears as composite transposon combining an enteric phage-like integration system, RP4/Ti-like conjugation genes, and Pseudomonas-like catabolic genes.

Amino Acid Sequence↗
PubMed1999

Biochemical analysis of the modular enzyme inosine 5'-monophosphate dehydrogenase.

Two prominent domains have been identified in the X-ray crystal structure of inosine-5'-monophosphate dehydrogenase (IMPDH), a core domain consisting of an alpha/beta barrel which contains the active site and an inserted subdomain whose structure is less well defined. The core domain encompassing amino acids 1-108 and 244-514 of wild-type human IMPDH (II) connected by the tetrapeptide linker Ile-Arg-Thr-Gly was expressed. The subdomain including amino acids 99-244 of human wild-type IMPDH (II) was expressed as a His-tagged fusion protein, where the His-tag was removable by enterokinase cleavage. These two proteins as well as wild-type human IMPDH (II), all proteins expressed in Escherichia coli, have been purified to apparent homogeneity. Both the wild-type and core domain proteins are tetrameric and have very similar enzymatic activities. In contrast, the subdomain migrates as a monomer or dimer on a gel filtration column and lacks enzymatic activity. Circular dichroism spectropolarimetry indicates that the core domain retains secondary structure very similar to full-length IMPDH, with 30% alpha-helix and 30% beta-sheet vs 33% alpha-helix and 29% beta-sheet for wild-type protein. Again, the subdomain protein is distinguished from both wild-type and core domain proteins by its content of secondary structure, with only 15% each of alpha-helix and beta-sheet. These studies demonstrate that the core domain of IMPDH expressed separately is both structurally intact and enzymatically active. The availability of the modules of IMPDH will aid in dissecting the architecture of this enzyme of the de novo purine nucleotide biosynthetic pathway, which is an important target for immunosuppressive and antiviral drugs.

Animals↗
PubMed1995

A modular artificial neural net for controlling a six-legged walking system.

A system that controls the leg movement of an animal or a robot walking over irregular ground has to ensure stable support for the body and at the same time propel it forward. To do so, it has to react adaptively to unpredictable features of the environment. As part of our study of the underlying mechanisms, we present here a model for the control of the leg movement of a 6-legged walking system. The model is based on biological data obtained from the stick insect. It represents a combined treatment of realistic kinematics and biologically motivated, adaptive gait generation. The model extends a previous algorithmic model by substituting simple networks of artificial neurons for the algorithms previously used to control leg state and interleg coordination. Each system controlling an individual leg consists of three subnets. A hierarchically superior net contains two sensory and two 'premotor' units; it rhythmically suppresses the output of one or the other of the two subordinate nets. These are continuously active. They might be called the 'swing module' and the 'stance module' because they are responsible for controlling the swing (return stroke) and the stance (power stroke) movements, respectively. The swing module consists of three motor units and seven sensory units. It can produce appropriate return stroke movements for a broad range of initial and final positions, can cope with mechanical disturbances of the leg movement, and is able to react to an obstacle which hinders the normal performance of the swing movement. The complete model is able to walk at different speeds over irregular surfaces. The control system rapidly reestablishes a stable gait when the movement of the legs is disturbed.

Gait↗
PubMed1991

Intrastriatal grafts derived from fetal striatal primordia. III. Induction of modular patterns of fos-like immunoreactivity by cocaine.

Cocaine, a catecholamine agonist, has been shown to produce a transient induction of the immediate-early gene c-fos and its protein product Fos in the striatum of normal rats. In the present study we report that the expression of Fos can be induced by cocaine challenge in intrastriatal grafts derived from cell suspensions of embryonic striatal primordia. Fos-like immunoreactivity in the nuclei of grafted neurons was detected 2 hr after the injection of 50 mg/kg cocaine into the host rats. Neurons with Fos-immunoreactive nuclei tended to form clusters in the striatal grafts. The Fos-rich clusters were aligned with acetylcholinesterase (AChE)-rich and tyrosine hydroxylase (TH)-rich patches demonstrated in adjoining sections. Previous studies have shown that presynaptic and postsynaptic cellular markers of the dopaminergic system in the striatum, including immunostaining for TH and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), and binding for high affinity dopamine uptake sites and for dopamine D1 and D2 receptor sites, are all concentrated in the AChE-rich patch regions (P regions) of such embryonic striatal grafts. The preferential expression of Fos in neurons of the P regions of the grafts thus implies that the induction of Fos was cell-type specific in being concentrated in the parts of the grafts that express striatal phenotype and that are innervated by catecholamine-containing fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1988

A modular analog neuron-model for research and teaching.

An analog electronic neuron for modeling neuronal networks and for teaching purposes is presented. The circuitry represents a new approach, since ionic channels are all modeled by fast relay switches in combination with resistors. Thus, the synapse design includes nonlinear PSP superposition and reversal potentials. The spike is modeled with Na+ and K+ currents. Detailed circuit diagrams and examples of performance are given. Besides its use in network research, the model has been successfully used over 3 years of teaching practice.

Action Potentials↗
PubMed1996

A modular questionnaire for the assessment of longterm quality of life in leukaemia patients: the MRC/EORTC QLQ-LEU.

We describe the psychometric analysis of a supplementary quality of life measure (MRC/EORTC QLQ-LEU) for evaluating long term sequelae of leukaemia treatments. The questionnaire under development was administered to 388 patients entered into the EORTC-GIMEMA AML 8A and the MRC AML10 clinical trials who were in complete remission for at least one year after completion of treatment on these trials. Results indicated a measure which is useful in evaluating the long-term effects of treatment in relation to chronic graft-vs-host disease and infection susceptibility. The performance of this measure in terms of its sensitivity and specificity between treatment arms was established by comparisons between the three treatment modalities in the above-mentioned trials and is the subject of further investigation. The new Leukaemia Module can be recommended for use alongside generic QOL instruments as a measure of long-term quality of life in leukaemia trials.

Acute Disease↗
PubMed1996

Marmor modular knee plateau positioning and prosthesis survival in 55 knees with rheumatoid arthritis.

In a long-term follow-up of 55 Marmor knee arthroplasties in patients with rheumatoid arthritis operated on between 1975 and 1977, the radiologically visible indicator wire was used to identify the position of the tibial components. The survival rate of the prostheses at 15 years was 0.71, and the revisions were evenly distributed over the observation period of 16 years. No significant relationship was found between the slope of the tibial components postoperatively and the survival of the prostheses. However, a postoperative valgus angle of the leg of 3 deg or more tended to increase the risk of revision (RH = 2.7, 95% CL = 0.8-8.9). The patient's sex, affected side or weight did not influence prosthesis survival.

Adult↗
PubMed1993

Control involving metabolism and gene expression: the square-matrix method for modular decomposition.

Control of DNA supercoiling by the free-energy of hydrolysis of ATP that involves gene expression is analyzed in terms of three levels of unconnected metabolic pathways. These are synthesis and breakdown of topoisomerase mRNAs, synthesis and breakdown of topoisomerase proteins and supercoiling and relaxation of DNA. The so-called square-matrix method previously developed for the control of metabolic pathways, is extended to deal with this hierarchical control system. It turns out that also in this case, the matrix of control coefficients is equal to the inverse of the so-called elasticity matrix, which contains all relevant elasticity coefficients as well as information about the structure and connectedness of the pathways involved. For a simpler case of a hierarchy of two systems, we demonstrate that the explicit matrix inversion method may be replaced by an implicit in which the regulatory effects that run through the other level are described by an additional elasticity coefficient which may then be treated as if local.

Adenosine Triphosphate↗
PubMed1987

Software for health care analysts: a modular approach.

The many concerns about the cost and quality of health care suggest the need to facilitate planners' using existing data bases for utilization review, program evaluation, and technology assessment. Despite both the availability of relevant data and widespread improvements in computing power, integrated computer software to permit analyses by nonspecialists has not previously been developed. This paper discusses the features of a health policy information system which aids working with hospital discharge abstracts, medical claims, cancer registries, and vital statistics files. Analyses of small area utilization, length of stay, in-hospital mortality, and readmissions are facilitated by this package. This information system, named the Health Applications System, includes an analysis module, three information management modules, and a set of record linkage modules. The modules were developed using the macroprocessor in the fourth-generation SAS system. Features of the software and their implications for data analysis are discussed.

Data Interpretation, Statistical↗
PubMed1990

Modularity of osteoclast behaviour and "mode-specific" inhibition of osteoclast function.

This study is part of an attempt to understand the role of specific cellular activities in the bone resorptive process. Experiments were performed whereby known pharmacological agents were used to inhibit individual modes of osteoclastic activity, such as motility and secretion. The effects of such treatments on bone resorption were assessed by quantitative scanning electron microscopy. The compounds included colchicine, which was used to inhibit osteoclast motility; molybdate ions which were used to selectively inhibit the catalytic activity of secreted acid phosphatase, and omeprazole which was employed to inhibit the secretion of hydrogen ions. All compounds inhibited osteoclastic bone resorption, but singularly affected defined modes of activity. These findings suggest that each mode of osteoclastic activity is essential for the bone resorptive process, and that "mode-specific" inhibition may provide a means whereby excessive activity of the osteoclast can be regulated in disease.

Acid Phosphatase↗