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At least 1,153 records · Page 64Linked to original sources
PubMed2004

Capsule induction technique in a rat model for bladder wall replacement: an overview.

The search for a reliable technique for functional genitourinary tissue replacement remains a challenging task. The most recent advances in cell biology and tissue engineering have utilized various avascular and acellular collagen scaffolds with or without seeded cells. These techniques, however, are frequently complicated by tissue necrosis, contracture and resorption due to limited vascularization. We employed a new three-stage, evolving animal model with stage I optimizing the culture delivery vehicle, stage II employing a seeded vascularized capsule flap, and stage III adding a contractile matrix in the form of pedicled gracilis muscle prelaminated with autologous, in vitro-expanded urothelial cells to reconstruct an entire supratrigonal bladder-wall defect in rats.Specimens stained with hematoxylin and eosin (H&E), alpha(1)-actin staining, and a specific immunohistochemical staining (AE(1)&AE(3)-anticytoceratin monoclonal antibody stain) showed a continuous, multilayered, functioning urothelial lining along the transposed prelaminated gracilis flap in the animals of the final-stage experiment. Successful urinary reconstruction requires a contractile neoreservoir resistant to resorption over time and a stable, protective urothelial lining. We demonstrated that a gracilis muscle flap can be seeded with autologous cultured urothelial cells suspended in fibrin glue. This prelaminated flap can be safely transposed onto its pedicle and become successfully integrated into the remaining bladder wall, demonstrating urothelial lining and the potential to contract. Further studies in larger animals with urodynamic assessment is warranted to determine if this type of bladder-wall replacement technique is suitable for urinary reconstruction in humans.

Animals↗
PubMed2005

Statistical signals in bioinformatics.

The Arthur M. Sackler Colloquium of the National Academy of Sciences, "Frontiers in Bioinformatics: Unsolved Problems and Challenges," organized by David Eisenberg, Russ Altman, and myself, was held October 15-17, 2004, to provide a forum for discussing concepts and methods in bioinformatics serving the biological and medical sciences. The deluge of genomic and proteomic data in the last two decades has driven the creation of tools that search and analyze biomolecular sequences and structures. Bioinformatics is highly interdisciplinary, using knowledge from mathematics, statistics, computer science, biology, medicine, physics, chemistry, and engineering.

Animals↗
PubMed2002

Inhibitors of the subtilase-like pro-protein convertases (SPCs).

Following protein biosynthesis, some of the most important cellular mechanisms that generate biological diversity are the enzymatically driven post-translational modifications that ultimately lead to the formation of bioactive molecules. Within the secretory pathway, a multitude of precursor proteins are thus modified resulting in hormones, neuropeptides, growth factors, receptors and even enzymes. These modifications include cleavage at specific sites through endo- or exo-peptidase action, amidation, glycosylation and sulfation. In recent years, an important family of these processing enzymes was discovered and characterized. The so-called proprotein convertases are the products of seven distinct genes and function as endopeptidases that cleave protein precursors C-terminal to basic residue sites. They are structurally related to the bacterial subtilisin family of enzymes and are thus referred to as the subtilisin-like proprotein convertases (SPCs). Many studies have examined the inhibition of this family of enzymes, through the search of endogenous inhibitors or through the development of peptidyl, non-peptidyl or protein inhibitors. Some potent inhibitors have been discovered or engineered. While it is certain that potent inhibitors could serve as important tools to further elucidate the specific functions of each SPC, it has also been suggested that such inhibitors may be developed into lead compounds that could have important therapeutic applications. This review examines the progress made in regards to endogenous and engineered inhibitors and evidence for possible uses as molecular tools or in therapeutic applications. It is noted that although important inhibitory potencies have often been reported, there is generally insufficient evidence to demonstrate high levels of specificity. It is thus suggested that an important short-term challenge before the field will be a better understanding of the catalytic specificity of each SPC.

Drug Design↗
PubMed1993

An animal model to predict the immunogenicity of murine V regions in humans.

Clinical trials with genetically engineered chimeric mouse/human monoclonal antibodies have demonstrated that mouse variable regions differ dramatically in their degree of immunogenicity. These observations led us to search for an animal model that could predict mouse variable region (V region) immunogenicity prior to human clinical trials. We selected monoclonal antibodies 17-1A and B72.3 for study because human trials have demonstrated the very low immunogenicity of the mouse 17-1A V region and the high immunogenicity of the mouse B72.3 V region. Random-bred New Zealand white rabbits were injected intravenously with mouse 17-1A, B72.3, or both using a dose and schedule comparable to human trials. After initial injection only two of ten rabbits developed an antibody response to mouse 17-1A, while all five animals receiving a second injection developed antibody that was entirely mouse constant region-specific. On the other hand, nine of ten rabbits demonstrated an antibody response to initial infusion of mouse B72.3 that was greater than 90% specific for the complementarity-determining region components of the V regions. Competitive inhibition with isolated heavy and light chains demonstrated specificity for heavy or light chains (approximately 60%) or a requirement for both (40%). Thus, as in humans, the V region of 17-1A elicited little or no immune response in rabbits, while the V region of B72.3 was highly immunogenic.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Gene therapy for HIV infection.

HIV-1 is the causative agent of acquired immune deficiency syndrome (AIDS) and is a major international health concern. The limited effectiveness of current antiviral therapies has led to the search for alternative treatments. One emerging field of medical treatment is termed human gene therapy. In principle, human gene therapy calls for the engineering of the cells from a medical patient with an agent that can potentially result in a therapeutic benefit to the patient. It has been suggested that gene therapy technology may be applied as an anti-HIV-1 agent. The term 'intracellular immunization' was suggested for strategies that work within a potential HIV-1 target cell to inhibit the productive infection of that cell by HIV-1. Various strategies based on this intracellular approach have been proposed and include the use of antisense, and transdominant HIV proteins. Both of these approaches can inhibit HIV-1 in vitro and a clinical trial has been proposed to test their effectiveness in vivo.

CD4-Positive T-Lymphocytes↗
PubMed2005

Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets.

Identification of genes that affect the product accumulation phenotype of recombinant strains is an important problem in industrial strain construction and a central tenet of metabolic engineering. We have used systematic (model-based) and combinatorial (transposon-based) methods to identify gene knockout targets that increase lycopene biosynthesis in strains of Escherichia coli. We show that these two search strategies yield two distinct gene sets, which affect product synthesis either through an increase in precursor availability or through (largely unknown) kinetic or regulatory mechanisms, respectively. Exhaustive exploration of all possible combinations of the above gene sets yielded a unique set of 64 knockout strains spanning the metabolic landscape of systematic and combinatorial gene knockout targets. This included a global maximum strain exhibiting an 8.5-fold product increase over recombinant K12 wild type and a twofold increase over the engineered parental strain. These results were further validated in controlled culture conditions.

Carotenoids↗
PubMed2003

Optimising enzyme function by directed evolution.

The past decade has seen a revolution in our ability to engineer designer enzymes using genetic tools that mimic evolution on a laboratory timescale. Many excellent examples of directed evolution applied to a wide range of enzymes have clearly demonstrated its future role in adapting enzymes for use in the chemical industry. Recent advances in 'smart' library design and computational screening are now permitting much deeper searches of sequence space, which potentially increases the extent to which enzyme function can be modified.

Animals↗
PubMedDate not supplied

Resorbable extracellular matrix grafts in urologic reconstruction.

PURPOSE: There is an increasingly large body of literature concerning tissue-engineering products that may be used in urology. Some of these are quite complex (such as multilayer patient-specific cell-seeded implants) yet the most simple and successful products to date are also the most uncomplicated: resorbable acellular extra-cellular matrices (ECMs) harvested from animals. ECMs have been used in a variety of difficult urologic reconstruction problems, and this review is intended to summarize this complex literature for the practicing urologist. METHODS: Medline search of related terms such as "SIS, small intestinal submucosa, ECM, extracellular matrix, acellular matrix and urologic reconstruction". Manuscripts missed in the initial search were taken from the bibliographies of the primary references. RESULTS: Full review of potential clinical uses of resorbable extra-cellular matrices in urologic reconstruction. CONCLUSIONS: Currently, the "state of the art" in tissue engineering solutions for urologic reconstruction means resorbable acellular xenograft matrices. They show promise when used as a pubovaginal sling or extra bolstering layers in ureteral or urethral repairs, although recent problems with inflammation following 8-ply pubovaginal sling use and failures after 1- and 4-ply SIS repair of Peyronie's disease underscore the need for research before wide adoption. Preliminary data is mixed concerning the potential for ECM urethral patch graft, and more data is needed before extended uses such as bladder augmentation and ureteral replacement are contemplated. The distant future of ECMs in urology likely will include cell-seeded grafts with the eventual hope of producing "off the shelf" replacement materials. Until that day arrives, ECMs only fulfill some of the requirements for the reconstructive urologist.

Animals↗
PubMed2004

The KNOTTIN website and database: a new information system dedicated to the knottin scaffold.

The KNOTTIN website and database organize information about knottins or inhibitor cystine knots, small disulfide-rich proteins with a knotted topology. Thanks to their small size and high stability, knottins provide appealing scaffolds for protein engineering and drug design. Static pages present the main historical and recent results about knottin discoveries, sequences, structures, folding, functions, applications and bibliography. Database searches provide dynamically generated tabular reports or sequence alignments for knottin three-dimensional structures or sequences. BLAST/HMM searches are also available. A simple nomenclature, based on loop lengths between cysteines, is proposed and is complemented by a uniform numbering scheme. This standardization is applied to all knottin structures in the database, facilitating comparisons. Renumbered and structurally fitted knottin PDB files are available for download. The standardized numbering is used for automatic drawing of two-dimensional Colliers de Perles. The KNOTTIN website and database are available at http://knottin.cbs.cnrs.fr and http://knottin.com.

Amino Acid Motifs↗
PubMed2003

Pathogenic mechanisms of diseases caused by Rickettsia.

The specter of bioterrorism employing genetically engineered Rickettsia resistant to all antibiotics should reawaken the world's desire to elucidate the pathogenesis of typhus and spotted fever rickettsioses in a search for mechanisms vulnerable to interdiction. The pathogenetic sequence includes rickettsial entry into the dermis, hematogenous dissemination to vascular endothelial cells (most critically in brain and lungs), increased vascular permeability, edema, and immunity mediated by NK cells, IFN-gamma, TNF-alpha, RANTES, antibodies, and cytotoxic T lymphocytes. Silverman has demonstrated the role of reactive oxygen species (ROS) produced by R. rickettsii-infected endothelial cells in peroxidative damage to cell membranes in vitro, and Heinzen has described actin-based rickettsial intracellular mobility and intercellular spread. At this point the availability of sequences of rickettsial genomes and excellent animal models of rickettsioses have yielded insufficient progress towards the identification of rickettsial virulence factors and knowledge of the importance of injury mediated by ROS, phospholipase A(2), protease(s) or other mechanisms in vivo. Attention to the rickettsiosis-associated procoagulant state led to determination that hemostatic mechanisms largely prevent major hemorrhage without disseminated intravascular coagulation or thrombosis-mediated ischemia. Particularly lacking is knowledge of early events in vivo at the portal of entry in skin (or lung), of the effects of the inoculum medium (arthropod saliva or feces), mediators produced by infected endothelium under conditions of flow and of the contributions in vivo of immune effectors to pathology, of the role of apoptosis in rickettsial infection, and of the endothelial cell alterations that account for increased vascular permeability. The host cell receptor for the Rickettsia ligand and the mechanism of rickettsial escape from the phagosome need to be elucidated.

Chronic Disease↗
PubMed2005

Grp78, Grp94, and Grp170 interact with alpha1-antitrypsin mutants that are retained in the endoplasmic reticulum.

In alpha1-antitrypsin (alpha1-AT) deficiency, a mutant form of alpha1-AT polymerizes in the endoplasmic reticulum (ER) of liver cells resulting in chronic hepatitis and hepatocellular carcinoma by a gain of toxic function mechanism. Although some aspects of the cellular response to mutant alpha1-AT Z have been partially characterized, including the involvement of several proteasomal and nonproteasomal mechanisms for disposal, other parts of the cellular response pathways, particularly the chaperones with which it interacts and the signal transduction pathways that are activated, are still not completely elucidated. The alpha1-AT Z molecule is known to interact with calnexin, but, according to one study, it does not interact with Grp78. To carry out a systematic search for the chaperones with which alpha1-AT Z interacts in the ER, we used chemical cross-linking of several different genetically engineered cell systems. Mutant alpha1-AT Z was cross-linked with Grp78, Grp94, calnexin, Grp170, UDP-glucose glycoprotein:glucosyltransferase, and two unknown proteins of approximately 110-130 kDa. Sequential immunoprecipitation/immunoblot analysis and coimmunoprecipitation techniques demonstrated each of these interactions without chemical cross-linking. The same chaperones were found to interact with two nonpolymerogenic alpha1-AT mutants that are retained in the ER, indicating that these interactions are not specific for the alpha1-AT Z mutant. Moreover, sucrose density gradient centrifugation studies suggest that approximately 85% of alpha1-AT Z exists in heterogeneous soluble complexes with multiple chaperones and approximately 15% in extremely large polymers/aggregates devoid of chaperones. Agents that perturb the synthesis and/or activity of ER chaperones such as tunicamycin and calcium ionophore A23187, have different effects on the solubility and degradation of alpha1-AT Z as well as on its residual secretion.

Cell Culture Techniques↗
PubMed2002

Cognitive engineering in interface design.

Today, many medical information systems are not satisfactory to their users. To ensure ultimate acceptance of health care information systems asks for systems that map on health care workers' tasks and on their cognitive processes in performing these tasks. The development of human-oriented computer interfaces requires insight in users' information needs and information processing in view of the tasks that will be computer-supported. Cognitive engineering aims at understanding the fundamental principles behind human activities that are relevant in designing a system that supports these activities. The application of cognitive engineering methods may therefore contribute to computer systems that fit better in health care working practices. We used cognitive engineering methods in designing a user interface for a physicians' workstation to support them in preparing their patient screening. The information needs and information search strategies of 4 physicians were revealed by systematic analyses of verbal protocols and video's while they successively worked through 10 paper-based patient records in preparing their patient visits. The results of these analyses were used as input for the design of a conceptual higher-order model that represents both the information needs and information search strategy of these physicians. Based on this higher-order conceptual model, we developed paper-mock ups and a first prototype of the user interface. The physicians will evaluate this prototype in the next phase of the project.

Cognition↗
PubMed1989

Patent literature as a source of information for research and development: an investigation on calcium phosphate-containing biomaterials, Part I.

The usefulness of patent literature for research and development is mostly unknown. Therefore a specific patent retrieval has been carried out concerning calcium phosphate-containing biomaterials. This research field includes chemical, medical, and engineering problems and is of importance to the development of bioactive materials for bone replacement. The preliminary work includes information on the characteristics and the availability of patent literature as well as about patent classification systems according to which the documents are filed in patent collections. By reading the non-patent literature searching questions can be formulated. The proper patent retrieval starts with the study of secondary literature especially that in Chemical Abstracts, which report on patents since 1907. The structure of Chemical Abstracts, their indexes and sections help to find relevant patents of chemical or chemical engineering contents fast and inspire to read patents of bordering areas. This retrieval from Chemical Abstracts led to 171 patents disclosed 1975-1985 and to 95 patents disclosed in 1986; the latter are listed in a table. The contents of the abstracts inform on the research activity and help to reduce time and effort for a continuation of the retrieval in a patent collections or database.

Bibliographies as Topic↗
PubMedDate not supplied

[Genomics and gene engineering: rationale to the development of new means of tuberculosis control].

The review contains information on modern approaches to the development of antituberculosis vaccines and remedies. Data on the comparative effectiveness of different subunit and DNA vaccines against tuberculosis are presented. The use of comparative and structural genomics for the search and characterization of new Mycobacterium tuberculosis genes, whose products may prove to be important antigens for the development of vaccines or target proteins for remedies against tuberculosis, is considered.

Adjuvants, Immunologic↗
PubMed2006

Tissue engineering of blood vessels.

BACKGROUND: Tissue engineering techniques have been employed successfully in the management of wounds, burns and cartilage repair. Current prosthetic alternatives to autologous vascular bypass grafts remain poor in terms of patency and infection risk. Growing biological blood vessels has been proposed as an alternative. METHODS: This review is based on a literature search using Medline, PubMed, ISIS and CAS of original articles and reviews, and unpublished material and abstracts. RESULTS AND CONCLUSIONS: Complete incorporation into host tissues and the maintenance of a viable and self-renewing endothelial layer are the fundamental goals to be achieved when developing a tissue-engineered blood vessel. Sourcing of cells and modulating their interaction with extracellular matrix and supporting scaffold have been the focus of intense research. Although the use of tissue-engineered blood vessels in humans is so far limited, advances in our knowledge of stem cell precursors and the development of new biomaterials should enable this technology to reach routine clinical practice within a decade.

Biotechnology↗
PubMed2007

Spintronics: a challenge for materials science and solid-state chemistry.

Spintronics is a multidisciplinary field involving physics, chemistry, and engineering, and is a new research area for solid-state scientists. A variety of new materials must be found to satisfy different demands. The search for ferromagnetic semiconductors and stable half-metallic ferromagnets with Curie temperatures higher than room temperature remains a priority for solid-state chemistry. A general understanding of structure-property relationships is a necessary prerequisite for the design of new materials. In this Review, the most important developments in the field of spintronics are described from the point of view of materials science.

Journal Article↗
PubMed2003

Insights into alpha1 adrenoceptor function in health and disease from transgenic animal studies.

Alpha(1)-adrenoceptors (ARs) mediate some of the main actions of the natural catecholamines, epinephrine and norepinephrine, and have a crucial role in the regulation of arterial blood pressure. Since alpha(1)-AR was subdivided into three subtypes (alpha(1A)-AR, alpha(1B)-AR and alpha(1D)-AR), the search has been on to discover subtype-specific physiological roles and to develop subtype-selective agonists and antagonists. Recently, several strains of genetically engineered mice have become available. Studies with these mice have provided several clues to help elucidate subtype-specific physiological functions; for instance, alpha(1A)-AR and alpha(1D)-AR subtypes play an important role in the regulation of blood pressure, suggesting that subtype-selective antagonists might be desirable antihypertensive agents. The ability to study subtype-specific functions in different mouse strains by altering the same alpha(1)-AR in different ways strengthens the conclusions drawn from pharmacological studies. Although these genetic approaches have limitations, they have significantly increased our understanding of the functions of alpha(1)-AR subtypes.

Animals↗