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PubMed2026

Modular synthetic cross-kingdom promoters enable coordinated expression in Escherichia coli and Saccharomyces cerevisiae.

Synthetic biology and metabolic engineering increasingly demand predictable and interoperable gene expression across phylogenetically distant organisms, as the need for portable genetic systems and transferable metabolic pathways continues to grow. However, fundamental differences in promoter architecture and transcriptional logic across kingdoms remain a key bottleneck in developing universal expression platforms. Here, we designed a set of modular hybrid promoters that enable tunable and quantitatively consistent gene expression in both Escherichia coli and Saccharomyces cerevisiae. These promoters integrate bacterial -10/-35 motifs and Shine-Dalgarno sequences with minimal yeast TATA boxes and Kozak sequences to ensure transcriptional and translational compatibility. The promoter set supported weak, moderate, and strong expression with high relative consistency across species. Applied to the biosynthetic pathway for the valuable pigment prodeoxyviolacein, the hybrid promoters enabled coordinated production in both hosts. This work establishes a broadly compatible promoter architecture and provides a foundational toolkit for cross-kingdom, multi-host synthetic biology.

Promoter Regions, Genetic↗

PubMed2006

The effect of 6 weeks of custom-molded foot orthosis intervention on postural stability in participants with >or=7 degrees of forefoot varus.

OBJECTIVE: Postural stability (PS) was assessed in a group of participants with >or=7 degrees of forefoot varus (FV) after 6 weeks of custom-molded functional foot orthosis (FO) intervention to investigate the effect of FO intervention in a population that may have decreased PS due to their foot structure. DESIGN: A force platform was used to assess right and left single-limb stance position and eyes open and eyes closed condition PS. SETTING: PS was assessed in a biomechanics research laboratory. PARTICIPANTS: Twelve participants with >or=7 degrees of FV (MFV) and 5 participants with <7 degrees of FV (LFV) participated in the study. INTERVENTIONS: PS of the MFV group was assessed initially when FOs were received and after 6 weeks of FO intervention. The LFV group PS was assessed during initial and 6-week testing sessions. MAIN OUTCOME MEASURES: The root mean square of the center of pressure velocity was used to quantify single-limb stance PS during no FO and FO conditions. RESULTS: LFV group PS did not change significantly (P=0.829) over the 6-week time period. Significant improvement was, however, reported in the MFV group anteroposterior (P=0.003) and mediolateral (P=0.032) PS at the 6-week assessment versus the initial assessment during both the noFO and FO conditions. CONCLUSIONS: Six weeks of FO intervention may significantly improve PS in participants with >or=7 degrees of FV both when wearing FOs and when not wearing FOs.

Adult↗

PubMed2005

Robust half-metallic character and large oxygen magnetism in a perovskite cuprate.

The new perovskite cuprate material Sr8CaRe3Cu4O24, which behaves ferrimagnetically and shows an unusually high Curie temperature (T(C) approximately 440 K), is found from density-functional theory calculation to display several surprising properties after hole doping or chemical substitution: (1) Half metal (HM) is realized by replacing Re with W or Mo while T(C) remains high; (2) hole-doped Sr8CaRe3Cu4O24 is also HM with high T(C). Moreover, we find that the O atoms will carry a large magnetic moment after hole doping, which is in sharp contrast to the generally accepted concept that magnetism in solids requires partially filled shells of d or f electrons in cations. The material Sr8CaRe3Cu4O24 is therefore expected to provide a very useful platform for material design and development.

Journal Article↗

PubMed2004

Pure shear horizontal SAW biosensor on langasite.

The undetected introduction of pathogens into food or water supplies can produce grave consequences in terms of economic loss and human suffering. Sensitive and selective sensors capable of quickly detecting microbial pathogens are urgently needed to limit the effects of bioterrorist incidents, accidents, or pollution. Shear horizontal surface acoustic wave (SH SAW) devices provide an attractive platform for the design of microbial biosensors that function in liquid media, where Rayleigh-type modes are rapidly attenuated. This paper reports on an exploratory SH SAW delay line designed and fabricated on langasite, La3Ga5SiO14 (LGS), along the novel Euler propagation direction (0 degrees, 22 degrees, 90 degrees). A liquid chamber was fabricated and attached to the top surface, and the device was submitted to liquid and biochemical tests. Moderate (6 dB) additional attenuation of the transmission coefficient, /S21/, was consistently observed when the SH SAW delay line was assembled in the test fixture and submitted to the liquid tests, indicating that LGS is an attractive candidate for liquid sensing. Sensor selectivity can be achieved by integrating the LGS SH SAW delay line with a biochemical recognition layer. A test setup was implemented for the characterization of LGS SH SAW-based biosensors. The delay line response to biomolecule binding was shown by detection of sequential binding of proteins to the SH SAW device delay path. The biotinylated sensor was exposed sequentially to biotin-binding deglycosylated avidin, biotin-modified rabbit IgG, and goat anti-rabbit IgG antibody. As each protein was bound to the sensing surface, marked changes in the delay-line phase were recorded. The reported results demonstrate the capability of these devices to act as biochemical detectors in aqueous solutions, and this work represents the first effort using the novel material LGS in SAW-based biosensor technology.

Acoustics↗

PubMed1996

Bronchoalveolar lavage in asthma research.

A great deal of information about the pathophysiology of asthma and its treatment have been obtained through the use of bronchoalveolar lavage (BAL), especially in combination with airway biopsies. The introduction of highly sophisticated methods for examining BAL aspirate, including fluorocein activated cell scanning (FACS) analysis and molecular biology techniques has emphasized the potential power of this method of airway investigation. For those contemplating the use of BAL in asthma research programmes, we hope that this review will provide a useful insight into the current state of knowledge about the technique and its application, and that it will provide a solid platform for study design.

Asthma↗

PubMed2002

A new geometric and mechanical verification device for medical LINACs.

The goal of quality assurance (QA) for a radiation oncology medical LINAC is to maintain an acceptable level of equipment performance and reliability. The increasing complexity of Radiation Oncology equipment and treatment techniques have led to increased demands on the work load of the medical physicist. Regular testing needs to be as efficient as possible. Generally, the QA tests, as recommended by the AAPM Task Group 40 for medical LINACs, can be grouped into two categories: dosimetry and mechanical checks. A new QA device has been developed that facilitates many of the daily and monthly mechanical QA checks. Its efficiency and speed is achieved through a set of QA tools that are mounted on a single platform, which is designed to fit into the accessory mount of the medical LINAC. Named Mini-GARD (MG), it verifies the accuracy of the digital readouts for gantry angles, collimator angles, and field sizes. It also tests crosshair position, the optical distance indicator (ODI), and patient setup laser alignment. It uses two calibrated digital levels for the gantry and collimator angle verification, an electronic tape measure for ODI verification, and a calibrated transparent projection scale for the remaining tests. This paper evaluates the stability and accuracy of the device in clinical tests over a period of a year. Results show that the MG is reliable and capable of measuring gantry and collimator angle constancy to +/-0.3 degrees, ODI constancy to +/-0.05 cm, and field size accuracies to +/-0.05 cm.

Algorithms↗

PubMed1995

Analog neural network-based helicopter gearbox health monitoring system.

The development of a reliable helicopter gearbox health monitoring system (HMS) has been the subject of considerable research over the past 15 years. The deployment of such a system could lead to a significant saving in lives and vehicles as well as dramatically reduce the cost of helicopter maintenance. Recent research results indicate that a neural network-based system could provide a viable solution to the problem. This paper presents two neural network-based realizations of an HMS system. A hybrid (digital/analog) neural system is proposed as an extremely accurate off-line monitoring tool used to reduce helicopter gearbox maintenance costs. In addition, an all analog neural network is proposed as a real-time helicopter gearbox fault monitor that can exploit the ability of an analog neural network to directly compute the discrete Fourier transform (DFT) as a sum of weighted samples. Hardware performance results are obtained using the Integrated Neural Computing Architecture (INCA/1) analog neural network platform that was designed and developed at The Charles Stark Draper Laboratory. The results indicate that it is possible to achieve a 100% fault detection rate with 0% false alarm rate by performing a DFT directly on the first layer of INCA/1 followed by a small-size two-layer feed-forward neural network and a simple post-processing majority voting stage.

Aircraft↗

PubMed2006

Interactions of VEGF isoforms with VEGFR-1, VEGFR-2, and neuropilin in vivo: a computational model of human skeletal muscle.

The vascular endothelial growth factor (VEGF) family of cytokines is involved in the maintenance of existing adult blood vessels as well as in angiogenesis, the sprouting of new vessels. To study the proangiogenic activation of VEGF receptors (VEGFRs) by VEGF family members in skeletal muscle, we develop a computational model of VEGF isoforms (VEGF(121), VEGF(165)), their cell surface receptors, and the extracellular matrix in in vivo tissue. We build upon our validated model of the biochemical interactions between VEGF isoforms and receptor tyrosine kinases (VEGFR-1 and VEGFR-2) and nonsignaling neuropilin-1 coreceptors in vitro. The model is general and could be applied to any tissue; here we apply the model to simulate the transport of VEGF isoforms in human vastus lateralis muscle, which is extensively studied in physiological experiments. The simulations predict the distribution of VEGF isoforms in resting (nonexercising) muscle and the activation of VEGFR signaling. Little of the VEGF protein in muscle is present as free, unbound extracellular cytokine; the majority is bound to the cell surface receptors or to the extracellular matrix. However, interstitial sequestration of VEGF(165) does not affect steady-state receptor binding. In the absence of neuropilin, VEGF(121) and VEGF(165) behave similarly, but neuropilin enhances the binding of VEGF(165) to VEGFR-2. This model is the first to study VEGF tissue distribution and receptor activation in human muscle, and it provides a platform for the design and evaluation of therapeutic approaches.

Computer Simulation↗

PubMed2006

Intensity-based hierarchical Bayes method improves testing for differentially expressed genes in microarray experiments.

BACKGROUND: The small sample sizes often used for microarray experiments result in poor estimates of variance if each gene is considered independently. Yet accurately estimating variability of gene expression measurements in microarray experiments is essential for correctly identifying differentially expressed genes. Several recently developed methods for testing differential expression of genes utilize hierarchical Bayesian models to "pool" information from multiple genes. We have developed a statistical testing procedure that further improves upon current methods by incorporating the well-documented relationship between the absolute gene expression level and the variance of gene expression measurements into the general empirical Bayes framework. RESULTS: We present a novel Bayesian moderated-T, which we show to perform favorably in simulations, with two real, dual-channel microarray experiments and in two controlled single-channel experiments. In simulations, the new method achieved greater power while correctly estimating the true proportion of false positives, and in the analysis of two publicly-available "spike-in" experiments, the new method performed favorably compared to all tested alternatives. We also applied our method to two experimental datasets and discuss the additional biological insights as revealed by our method in contrast to the others. The R-source code for implementing our algorithm is freely available at http://eh3.uc.edu/ibmt. CONCLUSION: We use a Bayesian hierarchical normal model to define a novel Intensity-Based Moderated T-statistic (IBMT). The method is completely data-dependent using empirical Bayes philosophy to estimate hyperparameters, and thus does not require specification of any free parameters. IBMT has the strength of balancing two important factors in the analysis of microarray data: the degree of independence of variances relative to the degree of identity (i.e. t-tests vs. equal variance assumption), and the relationship between variance and signal intensity. When this variance-intensity relationship is weak or does not exist, IBMT reduces to a previously described moderated t-statistic. Furthermore, our method may be directly applied to any array platform and experimental design. Together, these properties show IBMT to be a valuable option in the analysis of virtually any microarray experiment.

Animals↗

PubMed2006

Computational model of vascular endothelial growth factor spatial distribution in muscle and pro-angiogenic cell therapy.

Members of the vascular endothelial growth factor (VEGF) family of proteins are critical regulators of angiogenesis. VEGF concentration gradients are important for activation and chemotactic guidance of capillary sprouting, but measurement of these gradients in vivo is not currently possible. We have constructed a biophysically and molecularly detailed computational model to study microenvironmental transport of two isoforms of VEGF in rat extensor digitorum longus skeletal muscle under in vivo conditions. Using parameters based on experimental measurements, the model includes: VEGF secretion from muscle fibers; binding to the extracellular matrix; binding to and activation of endothelial cell surface VEGF receptors; and internalization. For 2-D cross sections of tissue, we analyzed predicted VEGF distributions, gradients, and receptor binding. Significant VEGF gradients (up to 12% change in VEGF concentration over 10 mum) were predicted in resting skeletal muscle with uniform VEGF secretion, due to non-uniform capillary distribution. These relative VEGF gradients were not sensitive to extracellular matrix composition, or to the overall VEGF expression level, but were dependent on VEGF receptor density and affinity, and internalization rate parameters. VEGF upregulation in a subset of fibers increased VEGF gradients, simulating transplantation of pro-angiogenic myoblasts, a possible therapy for ischemic diseases. The number and relative position of overexpressing fibers determined the VEGF gradients and distribution of VEGF receptor activation. With total VEGF expression level in the tissue unchanged, concentrating overexpression into a small number of adjacent fibers can increase the number of capillaries activated. The VEGF concentration gradients predicted for resting muscle (average 3% VEGF/10 mum) is sufficient for cellular sensing; the tip cell of a vessel sprout is approximately 50 mum long. The VEGF gradients also result in heterogeneity in the activation of blood vessel VEGF receptors. This first model of VEGF tissue transport and heterogeneity provides a platform for the design and evaluation of therapeutic approaches.

Cell- and Tissue-Based Therapy↗

PubMed2026

Rab9 depletion enhances human adenovirus type 26 transduction efficiency through increased internalization and reduced late endosomal/lysosomal retention.

Understanding intracellular trafficking is central to decoding viral pathogenesis and engineering optimized viral vectors. How a virus or vector is routed through the endocytic pathway directly dictates its genome release, immune sensing, and overall transduction efficiency. Human adenovirus type 26 (HAdV-D26) presents a promising platform for vector design due to its low preexisting immunity, potent immune stimulation, scalable production, and versatile genetic engineering capacity. Although increasingly significant, the fundamental mechanisms governing HAdV-D26 intracellular trafficking are still not fully understood. Our study demonstrates that compared to well-described human adenovirus type 5 (HAdV-C5), HAdV-D26 undergoes prolonged intracellular trafficking, transiently localizing to early endosomes before residing in late endosomes/lysosomes for up to four hours post-infection. Inhibition of lysosomal acidification modestly enhances HAdV-D26 transduction efficiency, whereas blocking transport from early to late endosomes/lysosomes does not. Strikingly, Rab9 knockdown reduces HAdV-D26 late endosomal/lysosomal localization while increasing both virus internalization and genome delivery to the host cell nucleus. These findings indicate that late endosomal sorting pathways actively influence HAdV-D26 infection outcomes. By identifying a previously unappreciated role for Rab9 in adenovirus transduction, our results provide new mechanistic insight into HAdV-D26 intracellular trafficking, highlight serotype-specific differences in adenovirus entry pathways, and identify endosomal trafficking steps that may be targeted to improve adenoviral vector performance.

Humans↗

PubMed2004

Beta-thalassemia microelectronic chip: a fast and accurate method for mutation detection.

BACKGROUND: beta-Thalassemia is one of the most common genetic diseases in humans. We developed an automated electronic microchip for fast and reliable detection of the nine most frequent mutations accounting for >95% of the beta-thalassemia alleles in the Mediterranean area. METHODS: We developed a microchip-based assay to identify the nine most frequent mutations (cd39C>T, IVS1-110G>A, IVS1-1G>A, IVS1-6T>C, IVS2-745C>G, cd6delA, -87C>G, IVS2-1G>A, and cd8delAA) by use of the Nanogen Workstation. The biotinylated amplicon was electronically addressed on the chip to selected pads, where it remained embedded through interaction with streptavidin in the permeation layer. The DNA at each test site was then hybridized to a mixture of fluorescently labeled wild-type or mutant probes. RESULTS: Assays conditions were established based on the analysis of 700 DNA samples from compound heterozygotes or homozygotes for the nine mutations. The assays were blindly validated on 250 DNA samples previously genotyped by other methods, with complete concordance of results. Alternative multiplexed formats were explored: the combination of multiplex PCR with multiple addressing and/or hybridization allowed analysis of all nine mutations in the same sample on one test site of the chip. CONCLUSIONS: The open flexible platform can be designed by the user according to the local prevalence of mutations in each geographic area and can be rapidly extended to include the remaining mutations causing beta-thalassemia in other regions of the world.

Fluorometry↗

PubMed2000

PepTool and GeneTool: platform-independent tools for biological sequence analysis.

Although we are unable to discuss all of the functionality available in PepTool and GeneTool, it should be evident from this brief review that both packages offer a great deal in terms of functionality and ease-of-use. Furthermore, a number of useful innovations including platform-independent GUI design, networked parallelism, direct internet connectivity, database compression, and a variety of enhanced or improved algorithms should make these two programs particularly useful in the rapidly changing world of biological sequence analysis. More complete descriptions of the programs, algorithms and operation of PepTool and GeneTool are available on the BioTools web site (www.biotools.com), in the associated program user manuals and in the on-line Help pages.

Amino Acid Sequence↗

PubMed2005

Dendritic cell fusion vaccines for cancer immunotherapy.

The use of tumour vaccines is being explored as a means of generating effective antitumour immune responses in patients with cancer. Dendritic cells (DCs) are the most potent antigen-presenting cells that are essential for initiating primary immune responses. As such, DCs are being studied as a platform for the design of cancer vaccines. DCs loaded with tumour antigens or whole tumour cell derivatives stimulate tumour-specific immunity. A promising vaccine strategy involves the fusion of DCs with whole tumour cells. DC/tumour fusions express a broad array of tumour antigens, including those yet to be identified, in the context of DC-mediated costimulation. Animal models have demonstrated that vaccination with fusion cells is protective against tumour challenge and results in the regression of established metastatic disease. In vitro human studies have demonstrated that DC/tumour fusions potently stimulate antitumour immunity and lysis of autologous tumour cells. Vaccination of cancer patients with DC/tumour fusions is being studied in Phase I/II clinical trials. Preliminary results demonstrate that generation of a vaccine is feasible and that vaccination is associated with minimal toxicity. Immunological and clinical responses have been found in a subset of patients.

Animals↗

PubMed2006

Can leukemia-derived dendritic cells generate antileukemia immunity?

Tumor vaccines are being explored as a means of generating antitumor immune responses in patients with cancer. Based on the efficacy of allogeneic transplantation, acute myelogenous leukemia appears to be susceptible to cellular immune-based therapy. Dendritic cells (DCs) are the most potent antigen-presenting cells and, as such, are being studied as a platform for the design of cancer vaccines. In acute leukemia, a promising approach involves the generation of DCs from leukemic blasts via cytokine exposure ex vivo. Leukemia-derived DCs potentially retain the tumor-associated antigens of the leukemic clone, which are presented in the context of the immune stimulating machinery of the mature DC. However, the efficacy of this approach may be limited by intrinsic abnormalities in the malignant clone that prevent differentiation towards a normal DC phenotype.

Dendritic Cells↗

PubMed2005

Bioplex technology: novel synthetic gene delivery pharmaceutical based on peptides anchored to nucleic acids.

Non-viral gene delivery is an important approach in order to establish safe in vivo gene therapy in the clinic. Although viral vectors currently exhibit superior gene transfer efficacy, the safety aspect of viral gene delivery is a concern. In order to improve non-viral in vivo gene delivery we have designed a pharmaceutical platform called Bioplex (biological complex). The concept of Bioplex is to link functional entities via hybridising anchors, such as Peptide Nucleic Acids (PNA), directly to naked DNA. In order to promote delivery functional entities consisting of biologically active peptides or carbohydrates, are linked to the PNA anchor. The PNA acts as genetic glue and hybridises with DNA in a sequence specific manner. By using functional entities, which elicit receptor-mediated endocytosis, improved endosomal escape and enhance nuclear entry we wish to improve the transfer of genetic material into the cell. An important aspect is that the functional entities should also have tissue-targeting properties in vivo. Examples of functional entities investigated to date are the Simian virus 40 nuclear localisation signal to improve nuclear uptake and different carbohydrate ligands in order to achieve receptor specific uptake. The delivery system is also endowed with regulatory capability, since the release of functional entities can be controlled. The aim is to create a safe, pharmaceutically defined and stable delivery system for nucleic acids with enhanced transfection properties that can be used in the clinic.

Animals↗

PubMed2005

Hyaluronan and sulphated hyaluronan micropatterns: effect of chemical and topographic cues on lymphatic endothelial cell alignment and proliferation.

While tissue engineered blood vessels have entered surgical practice, the construction of artificial lymphatic vessels has never been attempted due to the small dimensions and fragility of lymphatic vessels. A possible alternative would be to obtain a new growth of interrupted lymphatic vessels. We have previously reported that lymphatic endothelial cells align when cultured on striped micropatterns of hyaluronan (Hyal) and aminosilanized glass. We here report a comparative study in which lymphatic endothelial cells have been plated on micropatterns with stripes of different width and height obtained by the photoimmobilization of Hyal and its sulphated derivative (HyalS) on aminosilanized glass to verify whether their response correlated with surface-chemistry andlor topography. On Hyal micropatterns, cells adhered to aminosilanized glass, avoiding Hyal stripes and molding their shape in accordance to the micropattern topography. Stress fibers, integrins and focal adhesion kinase organized accordingly. HyalS micropatterns with the same topography were unable to guide cell response, cells randomly adhered to HyalS and glass stripes, and polarization was attained only by increasing stripe height. These data indicate that surface chemistry is the main cue responsible for lymphatic endothelial cell guidance. When surface chemistry of stripes promotes cell adhesion as well as that of the substrate, topographical parameters become prevalent. Micropatterns with defined chemical and topographical properties may contribute to the design of new platforms for controlled cell growth in tissue engineering of lymphatic vessels.

Actins↗

PubMed2005

The Burden of Obstructive Lung Disease Initiative (BOLD): rationale and design.

Quantifying COPD prevalence worldwide is needed to document COPD's effect on disability, health care costs, and impaired quality of life and to inform governments and health planners. As an adjunct to data obtained from population-based studies, and for countries where a fully powered prevalence survey cannot be done, modeling of COPD prevalence and its economic burdens can help estimate potential health care needs and costs. For comparability, standardized methods for prevalence surveys are needed that can be used in countries at all levels of economic development. The Burden of Obstructive Lung Disease (BOLD) Initiative has developed a set of methods for estimating COPD prevalence and a model for assessing its economic impact, and piloted these methods in China and Turkey. The methods were revised to reflect the findings in the pilot studies, and BOLD is now making the standardized methods available worldwide. The BOLD Operations Center provides training, materials, quality control, and data analysis. BOLD emphasizes data quality control at every stage of the process. Data from paper forms completed in the field are entered electronically to a specially designed secure Web platform. Pre- and post-bronchodilator spirometry testing is done on all participants, and all spirometry data are reviewed for quality. Questionnaires are used to obtain information about respiratory symptoms, health status, exposure to risk factors, and economic data about the burden of COPD. BOLD's standardized methods will provide a uniform way to compare COPD burden within and between countries, and where differences are found, to explore explanations for these differences.

Cost of Illness↗