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Hybrid grammar-based approach to nonlinear dynamical system identification from biological time series.

We introduce a grammar-based hybrid approach to reverse engineering nonlinear ordinary differential equation models from observed time series. This hybrid approach combines a genetic algorithm to search the space of model architectures with a Kalman filter to estimate the model parameters. Domain-specific knowledge is used in a context-free grammar to restrict the search space for the functional form of the target model. We find that the hybrid approach outperforms a pure evolutionary algorithm method, and we observe features in the evolution of the dynamical models that correspond with the emergence of favorable model components. We apply the hybrid method to both artificially generated time series and experimentally observed protein levels from subjects who received the smallpox vaccine. From the observed data, we infer a cytokine protein interaction network for an individual's response to the smallpox vaccine.

Algorithms↗

ASHRAE Standard 62: tobacco industry's influence over national ventilation standards.

OBJECTIVE: To describe the role of the tobacco industry in the development of ventilation standards for indoor air quality by influencing the American Society of Heating, Refrigeration, and Air Conditioning Engineers (ASHRAE). METHODS: Review of tobacco industry documents available on the internet between January 2001 and March 2002. Search terms included "ASHRAE", "ventilation", "minutes", "memo", and the names of key players and organisations as identified in the initial searches. Analysis of ASHRAE and other relevant documents publicly available and the personal files of a Standard 62 committee member; interviews of a selected number of ASHRAE players; observation of an ASHRAE meeting. RESULTS: The tobacco industry has been involved in the development of ventilation standards for over 20 years. It has successfully influenced the standard and continues to attempt to change the standard from a smoke-free framework into an "accommodation" framework. The industry acts directly and through consultants and allies. The major health groups have been largely absent and the health interests have been poorly represented in standard development. While concentrated in the USA, ASHRAE standards are adopted worldwide. CONCLUSION: The tobacco industry determined that allowing smoking in ventilation standards for indoor air quality was a high priority and dedicated significant human and financial resources to ensure that its interests were represented. The health groups, until recently, have largely ignored the policy implications for tobacco control of standard development. This situation is changing, but unless health groups maintain high visibility within ASHRAE, the tobacco industry may succeed in creating a standard that ignores the dangers of secondhand smoke.

Air Conditioning↗

Processing and release of human proinsulin-cleavage products into culture media by different engineered non-endocrine cells: a specific assessment by capillary electrophoresis.

The aim of this study was to compare the metabolic pathway to mature insulin through the intermediate forms (32-33 split, 65-66 split, des31,32 and des64,65) in human or murine cells engineered for the release of wild-type human proinsulin and in a genetically mutated one, in the search for a new approach for an insulin-dependent diabetes mellitus cure by gene therapy. Primary human fibroblasts, myoblasts and stabilized cell lines (HepG2 and NIH3T3) were transduced either with a retroviral vector coding for wild-type proinsulin or for a genetically mutated one, carrying cleavage sites sensitive to furin. The pattern of all the proinsulin cleavage products released into the cell culture supernatants was analyzed by capillary electrophoresis. All the cells transduced with the wild-type gene released intact proinsulin. HepG2 released a considerable amount of 65-66 split and des64,65, while primary myoblasts released all the intermediate forms and a limited amount of mature insulin. All the cells transduced with a furin-sensitive proinsulin gene released a higher amount of mature insulin (23-59% conversion yield) than the cells expressing wild-type proinsulin, whereas the total insulin was nearly constant. Only primary cells released all the cleavage products. Screening a wide variety of non-endocrine cells has revealed a large difference in the processing and release of immature and mature insulin forms, pointing to human hepatic cells as the most efficacious. Capillary electrophoresis provided on-line and in a single run a complete overview of the proinsulin metabolic pathway in different cells.

3T3 Cells↗

The history of the neurosurgical engine.

The opening of the skull of a living human being dates back to early civilization. The procedure may have been performed as early as the Neolithic period. Surgeons have continued to search for a better, easier, quicker, and safer method to open the skull. Today, most neurosurgeons are well acquainted with the surgical drill; however, few are familiar with the development of this instrument from its beginnings in dentistry to its use in modern neurosurgery. As cerebral localization advanced in the late 19th century, so, too, did the demands for better techniques for entering the cranial cavity and exposing more extensive areas of the brain. Mechanical devices began to appear in operating theaters throughout the world. Despite the enthusiasm of its inventors, the surgical engine was used by but a few pioneer cranial surgeons. The use of a surgical engine in the operating room has become commonplace. Its presence continues to demand respect. There is no doubt that this instrument has helped advance neurosurgery. Its development and refinement are rich in history and closely parallel the development of modern neurosurgery.

History, 18th Century↗

Tissue engineering for periodontal regeneration.

As a result of periodontal regeneration research, a series of clinical techniques have emerged that permit tissue engineering to be performed for more efficient regeneration and repair of periodontal defects and improved implant site development. Historically, periodontal regeneration research has focused on a quest for "magic filler" material. This search has led to the development of techniques utilizing autologous bone and bone marrow, allografts, xenografts, and various man-made bone substitutes. Though these techniques have had limited success, the desire for a more effective regenerative approach has resulted in the development of tissue engineering techniques. Tissue engineering is a relatively new field of reconstructive biology which utilizes mechanical, cellular, or biologic mediators to facilitate reconstruction/regeneration of a particular tissue. In periodontology, the concept of tissue engineering had its beginnings with guided tissue regeneration, a mechanical approach utilizing nonresorbable membranes to obtain regeneration in defects. In dental implantology, guided bone regeneration membranes +/- mechanical support are used for bone augmentation of proposed implant placement sites. With the availability of partially purified protein mixture from developing teeth and growth factors from recombinant technology, a new era of tissue engineering whereby biologic mediators can be used for periodontal regeneration. The advantage of recombinant growth factors is this tissue engineering device is consistent in its regenerative capacity, and variations in regenerative response are due to individual healing response and/or poor surgical techniques. In this article, the authors review how tissue engineering has advanced and discuss its impact on the clinical management of both periodontal and osseous defects in preparation for implant placement. An understanding of these new tissue engineering techniques is essential for comprehending today's ever-expanding oral plastic surgery procedures.

Algorithms↗

Genetic selection of short peptides that support protein oligomerization in vivo.

An important goal in protein engineering is to control associations between designed proteins. This is most often done by fusing known, naturally occurring oligomerization modules, such as leucine zippers [1] [2] [3], to the proteins of interest [4] [5] [6]. It is of considerable interest to design or discover new oligomerization domains that have novel binding specificities [7] [8] [9] [10] [11] in order to expand the 'toolbox' of the protein engineer and also to eliminate associations of the designed proteins with endogenous factors. We report here a simple genetic selection scheme through which to search libraries for peptides that are able to mediate homodimerization or higher-order self-oligomerization of a protein in vivo. We found several peptides that support oligomerization of the lambda repressor DNA-binding domain in Escherichia coli cells, some of them as efficiently as the endogenous dimerization domain or the GCN4 leucine zipper. Many are very small, comprising as few as six residues. This study strongly supports the notion that peptide sequence space is rich in small peptides, which might be useful in protein engineering and other applications.

Amino Acid Sequence↗

[Scientometrics and bibliometrics of biomedical engineering periodicals and papers].

This investigation was made to reveal the current status, research trend and research level of biomedical engineering in Chinese mainland by means of scientometrics and to assess the quality of the four domestic publications by bibliometrics. We identified all articles of four related publications by searching Chinese and foreign databases from 1997 to 2001. All articles collected or cited by these databases were searched and statistically analyzed for finding out the relevant distributions, including databases, years, authors, institutions, subject headings and subheadings. The source of sustentation funds and the related articles were analyzed too. The results showed that two journals were cited by two foreign databases and five Chinese databases simultaneously. The output of Journal of Biomedical Engineering was the highest. Its quantity of original papers cited by EI, CA and the totality of papers sponsored by funds were higher than those of the others, but the quantity and percentage per year of biomedical articles cited by EI were decreased in all. Inland core authors and institutions had come into being in the field of biomedical engineering. Their research topics were mainly concentrated on ten subject headings which included biocompatible materials, computer-assisted signal processing, electrocardiography, computer-assisted image processing, biomechanics, algorithms, electroencephalography, automatic data processing, mechanical stress, hemodynamics, mathematical computing, microcomputers, theoretical models, etc. The main subheadings were concentrated on instrumentation, physiopathology, diagnosis, therapy, ultrasonography, physiology, analysis, surgery, pathology, method, etc.

Authorship↗

Macrotetrolide biosynthesis: a novel type II polyketide synthase.

Polyketide biosynthesis is catalyzed by polyketide synthase (PKS) and three types of bacterial PKS are known to date. Feeding experiments with isotope-labeled precursors established the polyketide origin of the macrotetrolides, but the labeling pattern cannot be rationalized according to the established PKS paradigm. Genetic analysis of the macrotetrolide biosynthesis unveiled an unprecedented organization for a polyketide gene cluster that features five genes encoding discrete ketoacyl synthase (KS) and four genes encoding discrete ketoreductase (KR) but lacking an acyl carrier protein (ACP). Macrotetrolide biosynthesis is proposed to involve a novel type II PKS that acts directly on acyl CoA substrates, functions noniteratively, and catalyzes both C-C and C-O bond formation. These findings demonstrate once again Nature's versatility in making complex molecules and suggests new strategies for PKS engineering to further expand the scope and diversity of polyketide library. They also should serve as an inspiration in searching for PKS with novel chemistry for combinatorial biosynthesis.

Acyl Coenzyme A↗

Effectiveness of roll-over protective structures in reducing farm tractor fatalities.

OBJECTIVE: The purpose of this systematic review was to evaluate the effectiveness of roll-over protection structures (ROPS) as an engineering control for prevention of fatalities from farm tractor roll-overs. METHODS: Using a systematic approach to literature searching, relevant studies from peer-reviewed journals, technical and government reports, and unpublished reports were retrieved. Studies meeting initial criteria for possible inclusion were screened to determine whether they addressed the review topic (ROPS), included comparison data and included outcomes data such as injury or fatality. Articles that evaluated the use and impact of ROPS on operators of agricultural tractors were reviewed. Outcomes included two primary categories: implementation of ROPS and fatalities. MAIN RESULTS: Of a total 207 citations reviewed, 53 met initial screening criteria and 21 studies were included in this review. Farm tractor roll-overs result in approximately 200 fatalities per year in the United States. ROPS or crush-proof cabs, which are designed to protect the farmer during a roll-over incident, are currently used on only about 50% of the estimated 4.8 million tractors in the United States. A significant proportion of tractors built after 1985 (when manufacturers began implementing a voluntary ROPS standard) have had ROPS removed. Evidence from Sweden and other Northern European countries clearly demonstrates that ROPS can essentially eliminate roll-over fatalities. In the United States, the only fatalities associated with roll-overs of ROPS-equipped tractors occurred when farmers did not use a seatbelt to hold them within the protective envelope of the ROPS. Estimates of costs of programs to retrofit older tractors with ROPS range from approximately $500,000 to $900,000 per life saved, which is comparable to other accepted life-saving interventions. CONCLUSIONS: Future research efforts should include the development of collapsible and telescoping ROPS that can be used in low clearance areas such as dairy barns and fruit orchards. ROPS retrofits also need to be developed for many older tractor models. Effective educational and incentive programs need to be developed to increase the acceptance and use of ROPS among U.S. farmers. A national policy should be implemented to ensure that all tractors operated in the United States are equipped with ROPS or crush-proof cabs.

Accidents, Occupational↗

Brain-derived neurotrophic factor induces phosphorylation of fibroblast growth factor receptor substrate 2.

Brain-derived neurotrophic factor (BDNF) promotes neuronal survival. Gaining an understanding of how BDNF, via the tropomyosin-related kinase B (TRKB) receptor, elicits specific cellular responses is of contemporary interest. Expression of mutant TrkB in fibroblasts, where tyrosine 484 was changed to phenylalanine, abrogated Shc association with TrkB, but only attenuated and did not block BDNF-induced phosphorylation of mitogen-activated protein kinase (MAPK). This suggests there is another BDNF-induced signaling mechanism for activating MAPK, which compelled a search for other TrkB substrates. BDNF induces phosphorylation of fibroblast growth factor receptor substrate 2 (FRS2) in both fibroblasts engineered to express TrkB and human neuroblastoma (NB) cells that naturally express TrkB. Additionally, BDNF induces phosphorylation of FRS2 in primary cultures of cortical neurons, thus showing that FRS2 is a physiologically relevant substrate of TrkB. Data are presented demonstrating that BDNF induces association of FRS2 with growth factor receptor-binding protein 2 (GRB2) in cortical neurons, fibroblasts, and NB cells, which in turn could activate the RAS/MAPK pathway. This is not dependent on Shc, since BDNF does not induce association of Shc and FRS2. Finally, the experiments suggest that FRS2 and suc-associated neurotrophic factor-induced tyrosine-phosphorylated target are the same protein.

Adaptor Proteins, Signal Transducing↗

Amino acid substitutions preserve protein folding by conserving steric and hydrophobicity properties.

We present a comprehensive analysis of amino acid substitution patterns (sets of residues in a position of a multiple alignment) and conservation of physicochemical properties in alignments of protein sequences. Of the one million possible substitution patterns, only a few hundred account for the majority of aligned positions. Very similar distributions of substitution patterns are observed in all but one of the diverse databases of multiple alignments. In these substitution patterns we analyzed the conservation of 511 physicochemical and steric amino acid properties. Highest conservation was observed in those steric and transfer free energy-related properties that are crucial for folding. The best conserved steric properties include the minimal width of the side chains and their interactions with other residues. Among the hydrophobicity-related properties, charge and those properties that provide information on propensities to form secondary structures or side chain conformation, appear to be better conserved than pure hydrophobicity measures. Physicochemical sequence analysis based on the most conserved properties is expected to aid searching a protein sequence query against a database of multiple alignments, prediction of secondary and tertiary structures and protein engineering.

Amino Acids↗

Activation of Sirt1 decreases adipocyte formation during osteoblast differentiation of mesenchymal stem cells.

UNLABELLED: In vitro, mesenchymal stem cells differentiate to osteoblasts when exposed to bone-inducing medium. However, adipocytes are also formed. We showed that activation of the nuclear protein deacetylase Sirt1 reduces adipocyte formation and promotes osteoblast differentiation. INTRODUCTION: Mesenchymal stem cells (MSCs) can differentiate into osteoblasts, adipocytes, chondrocytes, and myoblasts. It has been suggested that a reciprocal relationship exists between the differentiation of MSCs into osteoblasts and adipocytes. Peroxisome proliferator-activated receptor gamma2 (PPARgamma2) is a key element for the differentiation into adipocytes. Activation of Sirt1 has recently been shown to decrease adipocyte development from preadipocytes through inhibition of PPARgamma2. MATERIALS AND METHODS: We used the mouse mesenchymal cell line C3H10T1/2 and primary rat bone marrow cells cultured in osteoblast differentiation medium with or without reagents affecting Sirt1 activity. Adipocyte levels were analyzed by light microscopy and flow cytometry (FACS) after staining with Oil red O and Nile red, respectively. Osteoblast and adipocyte markers were studied with quantitative real-time PCR. Mineralization in cultures of primary rat bone marrow stromal cells was studied by von Kossa and alizarin red staining. RESULTS: We found that Sirt1 is expressed in the mesenchymal cell line C3H10T1/2. Treatment with the plant polyphenol resveratrol as well as isonicotinamide, both of which activate Sirt1, blocked adipocyte development and increased the expression of osteoblast markers. Nicotinamide, which inhibits Sirt1, increased adipocyte number and increased expression of adipocyte markers. Furthermore, activation of Sirt1 prevented the increase in adipocytes caused by the PPARgamma-agonist troglitazone. Finally, activation of Sirt1 in rat primary bone marrow stromal cells increased expression of osteoblast markers and also mineralization. CONCLUSIONS: In this study, we targeted Sirt1 to control adipocyte development during differentiation of MSCs into osteoblasts. The finding that resveratrol and isonicotinamide markedly inhibited adipocyte and promoted osteoblast differentiation may be relevant in the search for new treatment regimens of osteoporosis but also important for the evolving field of cell-based tissue engineering.

Adipocytes↗

NIH Consensus statement. Bioelectrical impedance analysis in body composition measurement. National Institutes of Health Technology Assessment Conference Statement. December 12-14, 1994.

OBJECTIVE: To provide physicians with a responsible assessment of bioelectrical impedance analysis (BIA) technology for body composition measurement. PARTICIPANTS: A non-Federal, nonadvocate, 13-member panel representing the fields of nutrition, pediatrics, surgery, public health, biomedical engineering, epidemiology, and biostatistics. In addition, 20 experts in nutrition, pediatrics, metabolism, biomedical engineering, physiology, and epidemiology presented data to the panel and a conference audience of 220. EVIDENCE: The literature was searched through Medline and an extensive bibliography of reference was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. ASSESSMENT PROCESS: The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after conference. CONCLUSIONS: BIA provides a reliable estimate of total body water under most conditions. It can be a useful technique for body composition analysis in healthy individuals and in those with a number of chronic conditions such as mild-to-moderate obesity, diabetes mellitus, and other medical conditions in which major disturbances of water distribution are not prominent. BIA values are affected by numerous variables including body position, hydration status, consumption of food and beverages, ambient air and skin temperature, recent physical activity, and conductance of the examining table. Reliable BIA requires standardization and control of these variables. A specific, well-defined procedure for performing routine BIA measurements is not practiced. Therefore, the panel recommends that a committee of appropriate scientific experts and instruments manufacturers be formed with the goal of setting instruments standards and procedural methods.

Adipose Tissue↗

The use of live biocatalysts for pesticide detoxification.

During the past decade, numerous microorganisms capable of degrading pesticides have been isolated, and detoxification processes based on these live biocatalysts have been developed. Recently, novel detoxification strategies using genetically engineered microorganisms with extended degradative capabilities have been investigated and, in some cases, shown to be more effective. One promising approach for the detoxification of organophosphate pesticides uses genetically engineered Escherichia coli with surface-expressed organophosphorus hydrolase. Continuous efforts in this direction are required, in conjunction with a search for microorganisms capable of degrading pesticides rapidly, to establish efficient and cost-effective large-scale processes for pesticide detoxification.

Bacteria↗

The thermo-expandable metallic stent for managing benign prostatic hyperplasia: a systematic review.

OBJECTIVES: To systematically review published reports of the safety, effectiveness and durability of a self-expanding metallic prostatic stent (Memokath, Engineers & Doctors A/S Ltd., Denmark) in patients with benign prostatic hyperplasia (BPH) who are unfit for surgery. METHODS: We systematically searched the Medline and Embase databases from 1992. The reference lists of included studies and the bibliographies of review articles were also searched. We contacted the manufacturer of Memokath for additional information. The primary outcomes were treatment failure (stent removal, replacement or repositioning) and urological symptom scores. Secondary outcomes were urodynamic indices and minor complications. Two reviewers independently assessed the methodological quality of the studies and extracted data. Data were synthesized using narrative techniques. RESULTS: In all, 14 case series described the use of the Memokath stent in 839 men with BPH. All patients were at high operative risk. Most studies were of poor quality with an inadequate follow-up. Treatment failure rates were 0-48% but the duration of follow-up was often unclear. Five studies reported International Prostate Symptom Scores and found reductions of 11-19 points after stent insertion. All seven studies that reported on maximum urinary flow rates found that these increased, and the four that described residual urine volumes found that these decreased. Minor complications were inconsistently reported. CONCLUSIONS: The Memokath stent can provide an effective treatment for BPH in men at high operative risk; it also appears to be safe, but inadequate follow-up does not allow firm conclusions on stent durability.

Aged↗

Linear fuzzy gene network models obtained from microarray data by exhaustive search.

BACKGROUND: Recent technological advances in high-throughput data collection allow for experimental study of increasingly complex systems on the scale of the whole cellular genome and proteome. Gene network models are needed to interpret the resulting large and complex data sets. Rationally designed perturbations (e.g., gene knock-outs) can be used to iteratively refine hypothetical models, suggesting an approach for high-throughput biological system analysis. We introduce an approach to gene network modeling based on a scalable linear variant of fuzzy logic: a framework with greater resolution than Boolean logic models, but which, while still semi-quantitative, does not require the precise parameter measurement needed for chemical kinetics-based modeling. RESULTS: We demonstrated our approach with exhaustive search for fuzzy gene interaction models that best fit transcription measurements by microarray of twelve selected genes regulating the yeast cell cycle. Applying an efficient, universally applicable data normalization and fuzzification scheme, the search converged to a small number of models that individually predict experimental data within an error tolerance. Because only gene transcription levels are used to develop the models, they include both direct and indirect regulation of genes. CONCLUSION: Biological relationships in the best-fitting fuzzy gene network models successfully recover direct and indirect interactions predicted from previous knowledge to result in transcriptional correlation. Fuzzy models fit on one yeast cell cycle data set robustly predict another experimental data set for the same system. Linear fuzzy gene networks and exhaustive rule search are the first steps towards a framework for an integrated modeling and experiment approach to high-throughput "reverse engineering" of complex biological systems.

Artificial Intelligence↗

Problems of postgraduate medical training in Nigeria.

BACKGROUND: Postgraduate medical training in Nigeria has been in dire straits for about two decades now. That it has continued to survive, is a tribute to the average resident doctor who has become immunized, and who has grown a thick skin of armour, as well the spirit of altruism of the medical teachers--consultants (young and old), who despite odds, have kept their focus clear, above the murky waters of national distraction and daunting socio economic challenges. METHOD: A review of relevant literature on medical education in Nigeria was undertaken by manual library search. RESULTS: This paper x-rays the strong points that have still prevailed to hold the rudiments and ideals of postgraduate medical training in a viable position up to date. It discusses the weaknesses and threats--potential and real--to the training programme. CONCLUSION: This paper attempts to search, and actually hopes, for silver lining in the Nigerian sky as possible solution lifelines that may yet re-engineer the programme.

Education, Medical, Graduate↗

Engineering precursor flow for increased erythromycin production in Aeromicrobium erythreum.

Metabolic engineering technology for industrial microorganisms is under development to create rational, more reliable, and more cost-effective approaches to strain improvement. Strain improvement is a critical component of the drug development process, yet the genetic basis for high production by industrial microorganisms is still a mystery. In this study, a search was begun for genetic modifications critical for high-level antibiotic production. The model system used was erythromycin production studied in the unicellular actinomycete, Aeromicrobium erythreum. A tagged-mutagenesis approach allowed reverse engineering of improved strains, revealing two genes, mutB and cobA, in the primary metabolic branch for methylmalonyl-CoA utilization. Knockouts in these genes created a permanent metabolic switch in the flow of methylmalonyl-CoA, from the primary branch into a secondary metabolic branch, driving erythromycin overproduction. The model provides insights into the regulation and evolution of secondary metabolism.

Actinobacteria↗