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PubMed2007

Metabolic engineering of sesquiterpene metabolism in yeast.

Terpenes are structurally diverse compounds that are of interest because of their biological activities and industrial value. These compounds consist of chirally rich hydrocarbon backbones derived from terpene synthases, which are subsequently decorated with hydroxyl substituents catalyzed by terpene hydroxylases. Availability of these compounds is, however, limited by intractable synthetic means and because they are produced in low amounts and as complex mixtures by natural sources. We engineered yeast for sesquiterpene accumulation by introducing genetic modifications that enable the yeast to accumulate high levels of the key intermediate farnesyl diphosphate (FPP). Co-expression of terpene synthase genes diverted the enlarged FPP pool to greater than 80 mg/L of sesquiterpene. Efficient coupling of terpene production with hydroxylation was also demonstrated by coordinate expression of terpene hydroxylase activity, yielding 50 mg/L each of hydrocarbon and hydroxylated products. These yeast now provide a convenient format for investigating catalytic coupling between terpene synthases and hydroxylases, as well as a platform for the industrial production of high value, single-entity and stereochemically unique terpenes.

Alkyl and Aryl Transferases↗

PubMed2006

Protein nanoarray on Prolinker surface constructed by atomic force microscopy dip-pen nanolithography for analysis of protein interaction.

Protein nanoarrays are addressable ensembles of nano-scale protein domain on solid surfaces. This method can serve as a useful platform for ultraminiaturized bioanalysis. In this study, we investigated single molecular nanopatterning and molecular interaction of proteins that were immobilized on Prolinker surface of gold-coated silicon wafer by using dip-pen nanolithography (DPN) method. Contact force and humidity were optimized at 0.01 nN and 80%, respectively. The domain features of protein nanoarrays were developed at the contact time of 5 s. The optimized conditions for the nanoarray process were applied to create protein nanoarray using integrin alpha(v)beta3 and angiogenin. Constructed protein nanoarrays using integrin alpha(v)beta3 have single molecular monolayer with regular domain shape (height 15 +/- 5 nm). The changed height value due to the single molecular interaction between integrin alpha(v)beta3 and vitronectin was approximately 30 +/- 5 nm on Prolinker surface as measured with atomic force microscopy tip. Taken together, these results suggest that protein nanoarray on Prolinker surface fabricated by well-controlled DPN process can be used to analyze single molecular interaction of protein.

Gold↗

PubMed2004

A proposed nomenclature for 15 canine-specific polymorphic STR loci for forensic purposes.

We performed a population study on 15 polymorphic STR loci (FH2010, FH2079, PEZ2, VWF.X, FH2054, FH2087Ub, FH2611, WILMS-TF, PEZ12, PEZ15, PEZ6, FH2087Ua, ZUBECA4, ZUBECA6, FH2132) on 131 randomly selected dogs. Alleles were identified and grouped according to their estimated fragment length using fixed allelic bins encompassing one base-pair. The allele assignment was confirmed by sequence analysis of homozygote and cloned heterozygote alleles. In order to develop a uniform repeat-based nomenclature, extensive sequence analysis was performed on a selection of alleles from each STR locus. The proposed nomenclature refers to the internationally recognised recommendations for human-specific STR loci in forensic applications. The 15 canine-specific STR loci were grouped into 3 classes (simple STRs, compound STRs and complex/hypervariable STRs) according to their complexity and variability within the repeat structure. Finally, we evaluated the precision of fragment size estimation on a capillary electrophoresis platform and demonstrated reproducibility of fragment length estimation for single base-pair intermediate alleles.

Alleles↗

PubMed2026

Hyperprogression Upon Cemiplimab Alone or With Short Course Chemotherapy in PD-L1 ≥ 50% Non-small Cell Lung Cancer: A Biomarker Guided Multicenter International Phase 2 Trial-HYPERBOLIC Study.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS: HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION: to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

CD10↗

PubMed2005

What is the risk of stent thrombosis associated with the use of paclitaxel-eluting stents for percutaneous coronary intervention?: a meta-analysis.

OBJECTIVES: This study investigated the risk of stent thrombosis associated with the use of paclitaxel-eluting stents (PES) compared to bare-metal stents (BMS). BACKGROUND: Clinical experience with coronary drug-eluting stents (DES) is relatively limited. There is concern that DES used for percutaneous coronary intervention may result in subsequent thrombosis. METHODS: We conducted a meta-analysis on eight trials (total of 13 study arms) in 3,817 patients with coronary artery disease who were randomized to either PES or BMS. RESULTS: As compared with BMS, PES do not increase the hazard for thrombosis up to 12 months (risk ratio [RR] = 1.06, 95% confidence interval [CI] 0.55 to 2.04, p = 0.86]). There was no evidence of heterogeneity among the studies (chi-square value for Q-statistic = 5.90 [10 degrees of freedom], p = 0.82). Similar results were obtained when the analysis was restricted to trials with a polymeric stent platform (Treatment of de novo coronary disease using a single pAclitaXel elUting Stent [TAXUS]-I, -II, -IV, and -VI) (RR = 1.01, 95% CI 0.40 to 2.53, p = 0.99), trials with longer lesions (TAXUS-IV and -VI) (RR = 0.62, 95% CI 0.2 to 1.91, p = 0.41), and trials that used a higher dose of paclitaxel (ASian Paclitaxel-Eluting Stent Clinical trial [ASPECT], European evaLUaTion of paclitaxel Eluting Stents [ELUTES], and DELIVER-I) (RR = 1.87, 95% CI 0.52 to 6.81, p = 0.34). CONCLUSIONS: Current evidence suggests that standard dose PES do not increase the hazard of stent thrombosis compared to BMS.

Aged↗

PubMed2002

Voltage-addressable on/off microvalves for high-pressure microchip separations.

We present a microchip-based, voltage-addressable on/off valve architecture that is fundamentally consistent with the pressures and solvents employed for high-pressure liquid chromatography. Laser photopatterning of polymer monoliths inside glass microchannels is used to fabricate mobile fluid control elements, which are opened and closed by electrokinetic pressures. The glass substrates and crosslinked polymer monoliths operate in water-acetonitrile mixtures and have been shown to hold off pressures as high as 350 bar (5000 p.s.i.). Open/closed flow ratios of 10(4) to 10(6) have been demonstrated over the pressure range 1.5-70 bar (20-1000 p.s.i.), and the pressure-leak relationship shows the potential for valving control of flow through packed or monolithic chromatography columns. We expect that this valve platform will enable multiplexing of multiple chromatographic separations on single microchips.

Chromatography, High Pressure Liquid↗

PubMed2006

Measurement and analysis of calcium signaling in heterogeneous cell cultures.

High-content imaging platforms capable of studying kinetic responses at a single-cell level have elevated kinetic recording techniques from labor-intensive low-throughput experiments to potential high-throughput screening assays. We have applied this technology to the investigation of heterogeneous cell cultures derived from primary neural tissue. The neuronal cultures mature into a coupled network and display spontaneous oscillations in intracellular calcium, which can be modified by the addition of pharmacological agents. We have developed algorithms to perform Fourier analysis and quantify both the degree of synchronization and the effects of modulators on the oscillations. Functional and phenotypic experiments can be combined using this approach. We have used post-hoc immunolabeling to identify subpopulations of cells in cocultures and to dissect the calcium responses of these cells from the population response. The combination of these techniques represents a powerful tool for drug discovery.

Algorithms↗

PubMed2000

Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801.

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

Animals↗

PubMed2003

Nanofluidic networks based on surfactant membrane technology.

We explore possibilities to construct nanoscale analytical devices based on lipid membrane technology. As a step toward this goal, we present nanotube-vesicle networks with fluidic control, where the nanotube segments reside at, or very close (<2 microm) to optically transparent surfaces. These nanofluidic systems allow controlled transport as well as LIF detection of single nanoparticles. In the weak-adhesion regime, immobilized vesicles can be approximated as perfect spheres with nanotubes attached at half the height of the vesicle in the axial (z) dimension. In the strong-adhesion regime (relative contact area, Sr* approximately 0.3), nanotubes can be adsorbed to the surface with a distance to the interior of the nanotubes defined by the membrane thickness of approximately 5 nm. Strong surface adsorption restricts nanotube self-organization, enabling networks of nanotubes with arbitrary geometries. We demonstrate LIF detection of single nanoparticles (30-nm-diameter fluorescent beads) inside single nanotubes. Transport of nanoparticles was induced by a surface tension differential applied across nanotubes using a hydrodynamic injection protocol. Controlled transport in nanotubes together with LIF detection enables construction of nanoscale fluidic devices with potential to operate with single molecules. This opens up possibilities to construct analytical platforms with characteristic length scales and volume orders of magnitudes smaller than employed in traditional microfluidic devices.

Liposomes↗

PubMed2004

DNA mutation detection in a polymer microfluidic network using temperature gradient gel electrophoresis.

A miniaturized system for DNA mutation analysis, utilizing temperature gradient gel electrophoresis (TGGE) in a polycarbonate (PC) microfluidic device, is reported. TGGE reveals the presence of sequence heterogeneity in a given heteroduplex sample by introducing a thermal denaturing gradient that results in differences between the average electrophoretic mobilities of DNA sequence variants. Bulk heater assemblies are designed and employed to externally generate temperature gradients in spatial and temporal formats along the separation channels. TGGE analyses of model mutant DNA fragments, each containing a single base substitution, are achieved using both single- and 10-channel parallel measurements in a microfluidic platform. Additionally, a comprehensive polymer microfluidic device containing an integrated microheater and sensor array is developed and demonstrated for performing spatial TGGE for DNA mutation analysis. The device consists of two PC modular substrates mechanically bonded together. One substrate is embossed with microchannels, and the other contains a tapered microheater, lithographically patterned along with an array of temperature sensors. Compared with the external heating approaches, the integrated platform provides significant reduction in power requirement and thermal response time while establishing more accurate and highly effective control of the temperature gradient for achieving improved separation resolution.

DNA Mutational Analysis↗

PubMed2003

Structure of a designed dimeric zinc finger protein bound to DNA.

Proteins that employ dimerization domains to bind cooperatively to DNA have a number of potential advantages over monomers with regards to gene regulation. Using a combination of structure-based design and phage display, a dimeric Cys(2)His(2) zinc finger protein has been created that binds cooperatively to DNA via an attached leucine zipper dimerization domain. This chimera, derived from components of Zif268 and GCN4, displayed excellent DNA-binding specificity, and we now report the 1.5 A resolution cocrystal structure of the Zif268-GCN4 homodimer bound to DNA. This structure shows how phage display has annealed the DNA binding and dimerization domains into a single functional unit. Moreover, this chimera provides a potential platform for the creation heterodimeric zinc finger proteins that can regulate a desired target gene through cooperative DNA recognition.

Amino Acid Sequence↗

PubMed2005

Examination of phosphoryl-mimicking functionalities within a macrocyclic Grb2 SH2 domain-binding platform.

Reported herein are the design, synthesis, and Grb2 SH2 domain-binding affinities of several phosphoryl-mimicking groups displayed within the context of a conformationally constrained macrocyclic platform. With use of surface plasmon resonance techniques, single-digit nanomolar affinities were exhibited by phosphonic acid and malonyl-containing diacidic phosphoryl mimetics (for 4h and 4g, K(D) = 1.47 and 3.62 nM, respectively). Analogues containing monoacidic phosphoryl mimetics provided affinities of K(D) = 16-67 nM. Neutral phosphoryl-mimicking groups did not show appreciable binding.

Adaptor Proteins, Signal Transducing↗

PubMed1999

ORBIT: an integrated environment for user-customized bioinformatics tools.

MOTIVATION: There are a large number of computational programs freely available to bioinformaticians via a client/server, web-based environment. However, the client interface to these tools (typically an html form page) cannot be customized from the client side as it is created by the service provider. The form page is usually generic enough to cater for a wide range of users. However, this implies that a user cannot set as 'default' advanced program parameters on the form or even customize the interface to his/her specific requirements or preferences. Currently, there is a lack of end-user interface environments that can be modified by the user when accessing computer programs available on a remote server running on an intranet or over the Internet. RESULTS: We have implemented a client/server system called ORBIT (Online Researcher's Bioinformatics Interface Tools) where individual clients can have interfaces created and customized to command-line-driven, server-side programs. Thus, Internet-based interfaces can be tailored to a user's specific bioinformatic needs. As interfaces are created on the client machine independent of the server, there can be different interfaces to the same server-side program to cater for different parameter settings. The interface customization is relatively quick (between 10 and 60 min) and all client interfaces are integrated into a single modular environment which will run on any computer platform supporting Java. The system has been developed to allow for a number of future enhancements and features. ORBIT represents an important advance in the way researchers gain access to bioinformatics tools on the Internet.

Computational Biology↗

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

JViz.Rna--a Java tool for RNA secondary structure visualization.

Many tools have been developed for visualization of RNA secondary structures using a variety of techniques and output formats. However, each tool is typically limited to one or two of the visualization models discussed in this paper, supports only a single file format, and is tied to a specific platform. In order for structure prediction researchers to better understand the results of their algorithms and to enable life science researchers to interpret RNA structure easily, it is helpful to provide them with a flexible and powerful tool.jViz.Rna is a multiplatform visualization tool capable of displaying RNA secondary structures encoded in a variety of file formats. The same structure can be viewed using any of the models supported, including linked graph, circle graph, dot plot, and classical structure. Also, the output is dynamic and can easily be further manipulated by the user. In addition, any of the drawings produced can be saved in either the EPS or PNG file formats enabling easy usage in publications and presentations.

Computer Graphics↗

PubMed2002

A micromachine high frequency ultrasound scanner using photolithographic fabrication.

In this paper we describe two new types of transducer assemblies fabricated from polyimide films with photolithography that use a polyimide micromachine (MEMS) actuator to mechanically scan an ultrasound beam. Forward viewing transducers pivoting on cantilever hinges and side scanning transducers tilting on torsion hinges were fabricated on polyimide substrates with tables 1.125 mm and 2.25 mm wide. PZT transducers fabricated on these tables operating at 20 MHz and 30 MHz yielded insertion losses of 20-26 dB and fractional bandwidths of 34-49%. The transducer assemblies driven by MEMS actuators produced sector scans of 45-60 degrees in air at resonant frequencies of 32 to 90 Hz and sector scans in fluid of 6-8 degrees. Real time images of wire phantoms were obtained using a single channel imaging system based on a personal computer platform with LabVIEW (National Instruments Corp., Austin, TX) software.

Equipment Design↗

PubMed2003

Embedded progressive-three-layered fiber long-period gratings for respiratory monitoring.

A long-period grating (LPG) was written into a progressive three-layered single-mode fiber that was embedded into a flexible platform as a curvature sensor. The spectral location and profile of the LPGs were unaltered after implantation in the platform. The curvature sensitivity was 3.747 nm m with a resolution of +/-1.1 x 10(-2) m(-1). The bend sensor is intended to be part of a respiratory monitoring system and was tested on a resuscitation training manikin.

Elasticity↗

PubMed2004

Enrichment of extremely noisy high-throughput screening data using a naïve Bayes classifier.

The noise level of a high-throughput screening (HTS) experiment depends on various factors such as the quality and robustness of the assay itself and the quality of the robotic platform. Screening of compound mixtures is noisier than screening single compounds per well. A classification model based on naïve Bayes (NB) may be used to enrich such data. The authors studied the ability of the NB classifier to prioritize noisy primary HTS data of compound mixtures (5 compounds/well) in 4 campaigns in which the percentage of noise presumed to be inactive compounds ranged between 81% and 91%. The top 10% of the compounds suggested by the classifier captured between 26% and 45% of the active compounds. These results are reasonable and useful, considering the poor quality of the training set and the short computing time that is needed to build and deploy the classifier.

Bayes Theorem↗