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PubMedDate not supplied

Generating biological models through gene transfer to domestic animals.

Transgenic domestic animals remain infrequently used as models for biochemical, biomedical or pharmaceutical studies. The difficulty in obtaining these animals and the cost of their maintenance explains this situation. This review briefly summarizes the different techniques of gene transfer, targeted or not, and also the techniques for constructing vectors for transgene expression. A few examples of domestic animal models are also reported.

Animals↗
PubMed1999

A method for distinguishing 1-acyl from 2-acyl lysophosphatidylcholines generated in biological systems.

Phospholipases A(1) and A(2) frequently coexist in biological systems. Generation of lysophosphatidylcholine (LPC) in such systems cannot be assigned to any of these types of enzymes unless the position of the fatty acid in the lysocompound can be unambiguously determined. We here present a simple method to achieve this purpose. It is based on the initial chemical acylation of the isolated LPC with a labeled fatty acid, followed by the enzymatic analysis of the resulting phosphatidylcholine (PC), using snake or bee venom phospholipase A(2). Thus, if treatment of the PC with this enzyme releases a labeled free fatty acid, it is demonstrated that the initial LPC was acylated at position sn-1, whereas if the product of hydrolysis yields labeled LPC, then the initial LPC was acylated at position sn-2. This is the first method devised to determine the source of LPC in the presence of mixtures of phospholipases A(1) and A(2) in complex biological systems.

Acylation↗
PubMed2006

Preparative singlet oxygenation of linoleate provides doubly allylic dihydroperoxides: putative intermediates in the generation of biologically active aldehydes in vivo.

Photoinduced oxygenation generates biologically active, oxidatively truncated lipids in the retina. Previously, doubly allylic dihydroperoxides, 9,12-dihydroperoxyoctadeca-10,13-dienoic acid (9,12-diHPODE) and 10,13-dihydroperoxyoctadeca-8,11-dienoic acid (10,13-diHPODE), were postulated as key intermediates in the free radical-promoted oxidative fragmentation of linoleate that generates aldehydes, such as the cytotoxic gamma-hydroxyalkenal 4-hydroxy-2-nonenal (HNE), in vivo. We now report an efficient preparation of regioisomerically pure 9,12- and 10,13-diHPODE, devised to enable studies of their fragmentation reactions. Free radical-induced oxygenation of linoleate initially generates conjugated monohydroperoxy octadecadienoates (HPODEs) that are then converted into diHPODEs. In contrast, we found that singlet oxygenation of conjugated HPODEs does not produce diHPODEs. Unconjugated HPODEs are unique products of singlet oxygenation of linoleate that are coproduced with conjugated HPODEs. Preparative separation of the mixture of regioisomeric mono and diHPODEs generated by singlet oxygenation of linloeate is impractical. However, a simple tactic circumvented the problem. Thus, selective conversion of the undesired conjugated HPODEs into Diels-Alder adducts could be accomplished under mild conditions by reaction with N-phenyltriazolinedione. These adducts were readily removed, and the two remaining unconjugated HPODEs could then be easily isolated regioisomerically pure. Each of these was subsequently converted into a different, regioisomerically pure, diHPODE through further singlet oxygenation.

Aldehydes↗
PubMed1983

Generation of biologically active, complement-(C5) derived peptides by cathepsin H.

The thiol proteinase cathepsin H, isolated and purified from rat liver lysosomes, provokes acute inflammation characterized by the accumulation of polymorphonuclear leukocytes (PMN) when injected intracutaneously into newborn rats. We have examined the possibility that the accumulation of PMN at skin sites injected with cathepsin H is due, in part, to generation locally of C-derived chemotactic factors. We have found that cathepsin H acts in a concentration- and time-dependent fashion in whole human (and rat) EDTA-plasma to generate C5-derived peptides with chemotactic activity for PMN. Chemotactic activity was not generated in EDTA-plasma by either heat-inactivated cathepsin H or by a combination of active enzyme and a thiol proteinase inhibitor isolated from rat epidermis. Cathepsin H also acted in a concentration- and time-dependent fashion on isolated (functionally pure) human C5 to yield chemotactic activity for PMN as well as PMN lysosomal enzyme-releasing activity. Whereas 10 ng/ml cathepsin H generated significant chemotactic activity from isolated C5 (1000 CH50 U/ml), 7 to 10 micrograms/ml were required to generate chemotactic activity in whole EDTA-plasma. Cathepsin H not only was capable of generating biologically active, C5-derived peptides, but also was capable of degrading these peptides. Incubation of either whole EDTA-plasma or isolated C5 with high concentrations of cathepsin H (e.g., 25 micrograms/ml and 100 ng/ml, respectively) caused the rapid appearance of chemotactic activity followed by an equally rapid disappearance. PMN accumulated more rapidly in the skin of newborn rats injected with cathepsin H-treated C5 than in the skin of animals injected with cathepsin H alone. These data suggest that generation by cathepsin H of C-derived chemotactic activity contributes to the ability of this enzyme to induce dermal inflammation.

Animals↗
PubMed2005

Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases.

Endostatin, a potent inhibitor of endothelial cell proliferation, migration, angiogenesis and tumor growth, is proteolytically cleaved from the C-terminal noncollagenous NC1 domain of type XVIII collagen. We investigated the endostatin formation from human collagen XVIII by several MMPs in vitro. The generation of endostatin fragments differing in molecular size (24-30 kDa) and in N-terminal sequences was identified in the cases of MMP-3, -7, -9, -13 and -20. The cleavage sites were located in the protease-sensitive hinge region between the trimerization and endostatin domains of NC1. MMP-1, -2, -8 and -12 did not show any significant activity against the C-terminus of collagen XVIII. The anti-proliferative effect of the 20-kDa endostatin, three longer endostatin-containing fragments generated in vitro by distinct MMPs and the entire NC1 domain, on bFGF-stimulated human umbilical vein endothelial cells was established. The anti-migratory potential of some of these fragments was also studied. In addition, production of endostatin fragments between 24-30 kDa by human hepatoblastoma cells was shown to be due to MMP action on type XVIII collagen. Our results indicate that certain, especially cancer-related, MMP family members can generate biologically active endostatin-containing polypeptides from collagen XVIII and thus, by releasing endostatin fragments, may participate in the inhibition of endothelial cell proliferation, migration and angiogenesis.

Amino Acid Sequence↗
PubMed1988

Generation of biologically active interleukin-1 beta by proteolytic cleavage of the inactive precursor.

Interleukin-1 beta (IL-1 beta) is derived from an inactive precursor by proteolytic cleavage. To study IL-1 beta processing, we expressed the precursor in Escherichia coli, partially purified it, and used it as a substrate for various potentially relevant protease preparations. The precursor alone was virtually inactive, but incubation with membranes from human monocytes or myeloid cell lines yielded a 500-fold increase in IL-1 bioactivity. Western blot analysis of the incubated material showed that the 31,000-Da precursor is broken down to three major products, ranging from 17,400 to about 19,000 Da. The most active of these products is the smallest one, and it co-migrates during electrophoresis with mature IL-1 beta. Four purified known proteases were also tested for their effect on precursor IL-1 beta, and none of these products co-migrated with the mature protein. Chymotrypsin and Staphylococcus aureus protease yielded slightly larger products, which were highly active. Elastase and trypsin yielded substantially larger products, and these had little IL-1 activity. The products of three of the known proteases were identified by NH2-terminal sequencing. These results show conclusively that proteolysis of precursor IL-1 beta generates biological activity and that the cleavage must occur close to the mature NH2 terminus.

Base Sequence↗
PubMed2000

Prenatal epidemiology of pediatric tumors.

With the exception of a small percentage of cases attributable to hereditary cancer syndromes (eg, familial retinoblastoma) or genetic syndromes (Down syndrome), the etiology of most childhood cancers is unknown. Recent epidemiologic studies have focused on the prenatal period and have investigated potential associations with parental age, cigarette smoking, birth weight of the child, parental occupational exposures, and specific environmental exposures. The following challenges lie ahead for future epidemiologic studies of childhood cancer: 1) improvement of diagnostic classification; 2) improved methods for exposure assessment; 3) evaluation of data from molecular biology to generate biologically derived hypotheses; and 4) incorporation of markers of genetic susceptibility when feasible.

Adolescent↗
PubMed1994

A sensitive spectrophotometry-based method for the determination of the rate of hydrogen peroxide generation in biological systems.

A new sensitive spectrophotometric method for the determination of the rate of hydrogen peroxide generation in biological systems has been developed. This method is based on the measurement of the oxidation rate of reduced cytochrome c by H2O2 in the presence of a mediator and permits the detection of H2O2 generation rates as low as 60 nM min-1. The solution of the differential equations of the kinetic process permitted the calculation of the kinetic rate constants and assessment of the conditions required to measure the hydrogen peroxide generation rate.

Amine Oxidase (Copper-Containing)↗
PubMed2000

Multiple oscillators provide metastability in rhythm generation.

Biological rhythms such as cardiac and circadian rhythms arise from activity of multiple oscillators with dispersed intrinsic frequencies. It has been proposed that a stable population rhythm, fundamental to normal physiological processes, can be achieved in these systems by synchronization, through mutual entrainment, of individual oscillators. Mutual entrainment, however, is unlikely to be the mechanism underlying the generation of a stable rhythm in a population of multiple weakly coupled or uncoupled oscillators. We have recently identified such a population that is involved in the sympathetic regulation of vascular tone in a thermoregulatory circulation. In this paper, we investigate the stability of the output rhythm of these sympathetic oscillators by subjecting the system to a periodic driving force (the lung inflation cycle-related activity). We show that a population rhythm coupled to the drive can remain stable over a much wider driving frequency range compared with that of any one of its constituent oscillators. This population rhythmicity still exists despite the fact that the dominant frequencies of individual oscillators are not necessarily 1:1 frequency-locked to the drive. We provide evidence to show that this population metastability is achieved through linear and nonlinear dynamic interactions between the driving force and single sympathetic oscillators. Our study suggests that the generation of a stable population rhythm can exist even in the absence of mutual entrainment of its constituents, and this allows the population to generate a stable and flexible patterned response.

Activity Cycles↗
PubMed2001

Detection of hydroxyl radicals by D-phenylalanine hydroxylation: a specific assay for hydroxyl radical generation in biological systems.

Hydroxylation of l-phenylalanine (Phe) by hydroxyl radical (*OH) yields 4-, 3-, and 2-hydroxyl-Phe (para-, meta-, and ortho-tyrosine, respectively). Phe derivative measurements have been employed to detect *OH formation in cells and tissues, however, the specificity of this assay is limited since Phe derivatives also arise from intracellular Phe hydroxylase. d-Phe, the d-type enantiomer, is not hydroxylated by Phe hydroxylase. We evaluate whether d-Phe reacts with *OH as well as l-Phe, providing a more reliable probe for *OH generation in biological systems. With *OH generated by a Fenton reaction or xanthine oxidase, d- and l-Phe equally gave rise to p, m, o-tyr and this could be prevented by *OH scavengers. Resting human neutrophils (PMNs) markedly converted l-Phe to p-tyr, through non-oxidant-mediated reactions, whereas d-Phe was unaffected. In contrast, when PMNs were stimulated in the presence of redox cycling iron the *OH formed resulted in more significant rise of p-tyr from d-Phe (9.4-fold) than l-Phe (3.6-fold) due to the significant background formation of p-tyr from l-Phe. Together, these data indicated that d- and l-Phe were equally hydroxylated by *OH. Using d-Phe instead of l-Phe can eliminate the formation of Phe derivatives from Phe hydroxylase and achieve more specific, sensitive measurement of *OH in biological systems.

Cell Survival↗
PubMed2005

Generation of biologically active interleukin-1beta by meprin B.

Interleukin-1beta (IL-1beta) is a proinflammatory cytokine that is synthesized as an inactive precursor molecule that must be proteolytically processed to generate the biologically active form. Maturation of the precursor is primarily performed by caspase-1, an intracellular cysteine protease; however, processing by other proteases has been described. Meprins are cell surface and secreted metalloproteases expressed by renal and intestinal brush-border membranes, leukocytes, and cancer cells. In this study we show that purified recombinant meprin B can process the interleukin-1beta precursor to a biologically active form. Amino-terminal sequencing and mass spectrometry analysis of the product of digestion by activated meprin B determined that proteolytic cleavage resulted in an additional six amino acids relative to the site utilized by caspase-1. The biological activity of the meprin B-cleaved cytokine was confirmed by measuring the proliferative response of helper T-cells. These results suggest that meprin may play an important role in activation of this proinflammatory cytokine in various pathophysiological conditions.

Amino Acid Sequence↗
PubMed2004

Pattern generation of biological ligands on a biodegradable poly(glycolic acid) film.

The micropatterns of biological ligands (biotin and RGD peptides) were generated on a flat surface of biodegradable polymer, poly(glycolic acid) (PGA). The immobilization of biological ligands onto the surface of biodegradable polymers (especially aliphatic polyesters) is usually hampered by the absence of functionalizable groups on the polymer backbone. We demonstrate herein that PGA polymer films were modified by surface hydrolysis to introduce carboxylic acid groups on the film surfaces, which were subsequently used for patterning amine-terminated ligands by microcontact printing. Fluorescence microscopy was used to verify the pattern of biotin on the surface of the PGA films after complexation with fluorescein-conjugated streptavidin. In addition, the cellular micropatterns were obtained from micropatterns of RGD peptides on the surface-hydrolyzed PGA films.

Biodegradation, Environmental↗
PubMed1994

Determination of the rate of superoxide generation from biological systems by spin trapping: use of rapid oxygen depletion to measure the decay rate of spin adducts.

A method was developed to measure the superoxide generation rate from biological systems using the spin trapping method. Kinetic treatment of the decay rate of the superoxide adduct of 5,5-dimethylpyrroline N-oxide (DMPO) revealed that the EPR signal intensity of the system is proportional to the superoxide generation rate. Rapid depletion of oxygen in the sample was utilized to terminate superoxide generation so that the decay rate of the DMPO superoxide adduct (DMPO-OOH) could be determined. For this decay measurement, a controlled atmosphere EPR cavity was developed and was used with an open-air sample cell. Superoxide generation rates determined with this method for stimulated neutrophils and for the hypoxanthine-xanthine oxidase system were comparable to those obtained with the cytochrome c reduction method. This method is specifically applicable to the system in which dissolved oxygen supplied from the gas phase is utilized as a source of superoxide.

Cyclic N-Oxides↗
PubMed2000

Defining sameness: historical, biological, and generative homology.

Current debate concerning homology arises from three different research interests-phylogenetics, character evolution, and generative pathways. Phylogenetic homology focuses on descent of the character from a common ancestor. Biological homology addresses character evolution and diversification. Exceptions to the general case complicate these two approaches: historically and biologically homologous characters may be produced by different generative pathways, and minutely similar characters produced by the same generative pathways may have a sporadic phylogenetic distribution. We suggest that for studies of comparative developmental biology, new descriptive terms are needed to distinguish similar structures that result from the same generative pathways from those that result from different generative pathways. The terms syngeny, meaning "same genesis", and allogeny, meaning "different genesis", allow the acknowledgement of sameness at the generative level and can be used in combination with the terminology of historical homology and biological homology to describe any given character.

Animals↗
PubMed2006

Cell electrospinning: a unique biotechnique for encapsulating living organisms for generating active biological microthreads/scaffolds.

Jet-based technologies are increasingly being explored as potential high-throughput and high-resolution methods for the manipulation of biological materials. Previously shown to be of use in generating scaffolds from biocompatible materials, we were interested to explore the possibility of using electrospinning technology for the generation of scaffolds comprised of living cells. For this, it was necessary to identify appropriate parameters under which viable threads containing living cells could be produced. Here, we describe a method of electrospinning that can be used to deposit active biological threads and scaffolds. This has been achieved by use of a coaxial needle arrangement where a concentrated living biosuspension flows through the inner needle and a medical-grade poly(dimethylsiloxane) (PDMS) medium with high viscosity (12,500 mPa s) and low electrical conductivity (10-15 S m-1) flows through the outer needle. Using this technique, we have identified the operational conditions under which the finest cell-bearing composite microthreads are formed. Collected cells that have been cultured, postelectrospinning, have been viable and show no evidence of having incurred any cellular damage during the bionanofabrication process. This study demonstrates the feasibility of using coaxial electrospinning technology for biological and biomedical applications requiring the deposition of living cells as composite microthreads for forming active biological scaffolds.

Animals↗
PubMed1994

The role of metabolic transformations in generation of biological order.

Transformations of metabolic organization are considered as a ground of structure generation during ontogenesis and evolution. The emergence of non-linearity in metabolic pathways which leads to the formation of biochemical cycles is caused by the separation between the direct and reverse enzymatic reactions, one of them being coupled with the pool of macroergs, whereas the other--non-coupled. The absence of couplings in one of the halves of such primary cycle can lead to the increase of metabolic flow and to the generation of bifurcations resulting in the formation of new metabolic pathway. For their internalization the genetic reconstructions are necessary. Deposition of compounds from the cycles leads to the generation of internal rhythms and to morphogenetic processes. Morphology is formed by stable trajectories of the formation and deposition of certain compounds according to the principles of curvilinear symmetry.

Animals↗
PubMed2006

A novel TAT fusion protein with osteoinductive activity.

Osteoblasts are thought to be differentiated from pluripotent mesenchymal stem cells. Several intracellular and extracellular osteoinductive proteins are involved in this process. Such proteins include the bone morphogenetic proteins (BMPs) and the LIM mineralization proteins (LMPs) etc. LMP-1 is a novel LIM domain protein promoting the differentiation of osteoblasts during bone formation. It contains three LIM domains/motifs, one PDZ domain and a unique sequence. Through analysis of the amino acid sequence and the function of the LMPs, it has been found that the PDZ domain (1-93 aa) and a unique region (94-133 aa) appear to be critical for bone formation. The TAT protein of human immunodeficiency virus can be fused with other macromolecules, peptides or proteins and transport them into cells successfully. Once being transduced into cells, the fusion protein can recover its biological activity through being rapidly refolded. We supposed that TAT could be fused with LMP-1 (1-133 aa) and LMP-1 (94-133 aa) and the fusion proteins could be easily transduced through biological membranes and generate biological activity. The clinical application of BMPs has been limited for their relatively high cost and the unstable osteoinductivity. If the hypothesis proved to be practical, we would have a more effective new way to promote bone repair and regeneration.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Generation of biologically active angiostatin kringle 1-3 by activated human neutrophils.

The contribution of polymorphonuclear neutrophils (PMN) to host defense and natural immunity extends well beyond their traditional role as professional phagocytes. In this study, we demonstrate that upon stimulation with proinflammatory stimuli, human PMN release enzymatic activities that, in vitro, generate bioactive angiostatin fragments from purified plasminogen. We also provide evidence that these angiostatin-like fragments, comprising kringle domain 1 to kringle domain 3 (kringle 1-3) of plasminogen, are generated as a byproduct of the selective proteolytic activity of neutrophil-secreted elastase. Remarkably, affinity-purified angiostatin kringle 1-3 fragments generated by neutrophils inhibited basic fibroblast growth factor plus vascular endothelial growth factor-induced endothelial cell proliferation in vitro, and both vascular endothelial growth factor-induced angiogenesis in the matrigel plug assay and fibroblast growth factor-induced angiogenesis in the chick embryo chorioallantoic membrane assay, in vivo. These results represent the first demonstration that biologically active angiostatin-like fragments can be generated by inflammatory human neutrophils. Because angiostatin is a potent inhibitor of angiogenesis, tumor growth, and metastasis, the data suggest that activated PMN not only act as potent effectors of inflammation, but might also play a critical role in the inhibition of angiogenesis in inflammatory diseases and tumors, by generation of a potent anti-angiogenic molecule.

Angiostatins↗