Current systems used to perform sample preparations that integrate with digital microfluidics use liquid valves, rotary valves, or small volume injection loops that are expensive and often require a large apparatus to operate. Other digital microfluidic systems require operators to directly pipette sample reagents into the platform which can incorporate human error and the potential exposure to hazardous chemicals. In order for automated and consistent benchtop chemical synthesis using digital microfluidics to exist, a compact and inexpensive system must be able to interface with the external environment to allow efficient chemical delivery and retrieval. (more...)

Stapled peptide technology utilizes chemical bonds to constrain peptides into α-helical conformations and results in an extension of potency due to increased resistance to proteases as well as greater cell permeability and bioactivity by the protein. Thus, stapled peptides have emerged as promising therapeutic candidates for treating a variety of human diseases.  Numerous studies have been carried out to develop bioactive-stapled peptides. Among them, there are ring closing metathesis (RCM), azide-alkyne Huisgen cycloaddition (CuAAC), alkylation of cysteine, and lactam bridge formation. However, the RCM and CuAAC methods are very expensive and the latter two methods are generally low efficiency reactions. To address these problems, UCLA researchers have developed an alternative approach to producing stapled peptides that of very low cost and high efficiency. (more...)

New catalytic processes for the synthesis of enantiomerically pure heterocyclic compounds. (more...)

Researchers at the University of California, Irvine have developed a microfluidic peristaltic pump that does not require off-chip controllers for actuation, but rather is driven by on-chip pneumatic circuitry. (more...)

Using pulsed laser radiation, University of California, Irvine researchers have developed a novel methodology to provide a mechanical agonist to single or multiple cells and stimulate cellular mechanotransduction. These researchers have also shown this laser methodology can be used in a high-throughput assay format in 3D and 2D cell cultures. The UCI researchers have shown that this technology is highly effective in eliciting a mechanotransduction response that can be modulated by inhibitors or activators of mechanotransduction signaling axes. (more...)

   For in vitro measurements of ion channels, the ion channels typically are situated in lipid bilayers which are suspended at the interface between two chambers; ionic currents are measured when a bias voltage is applied between two chambers. In vivo studies of ion channels are typically performed with patch-clamp excision of membranes using micro-pipettes, a laborious, time-consuming process with low yield. In spite of this, these studies have yielded important information between structure and function of ion channels in biology. Although these naturally occurring biological nanopores are relatively weak in their structural durability and have a limited life-time, they are still intriguing candidates for sensing technology due to their sensitivity and specificity.    Researchers at the University of California, Irvine have developed a novel sensor device that allows for the interrogation of a single ion channel nanopore. The device integrates lipid bilayers on semiconducting carbon nanotube networks with ion channel nanopores    This new sensor device measures the current when a ligand binds to the ion channel nanopore. This technology is easier to implement than the patch clamp excision of membranes. In addition, the fabrication of these devices is in principle compatible with printed circuit technology. (more...)

UCR researchers have developed a simple microfluidic device that is free from any type of valve or pump.  The chip has been demonstrated to extract RNA fragments from cell lysates within 15 minutes. Droplets containing silica magnetic particles worked as the transportation vehicle, and were isolated from each other and contained in microwells. The enclosure of droplets in microwells diminished cross contamination between droplets, and also permitted the usage of multiple channels for parallel analysis of numerous samples. This multiwell/multi-channel (M&M) chip offers very high simplicity in automatic operation and parallel sample handling with low fabrication cost, improving both the speed and specificity of small RNAs detection.  (more...)

Nitrogen-rich tetrazines, have broad applications in biochemistry including small-molecule imaging, genetically targeted protein tagging, post-synthetic DNA labeling, nanoparticle-based clinical diagnostics, in-vivo imaging, as well as significant use in materials science, coordination chemistry, and the production of high energy materials such as those used in specialty explosives research. Among other uses, tetrazines can serve as coupling agents for molecular imaging compounds such as fluorophores or magnetic contrast agents, or even as ligands for metal catalysts or inorganic materials such as metal-organic frameworks. Tetrazines are also valuable synthetic intermediates, and have been elegantly deployed on route to several natural product syntheses. Despite the promise of tetrazines, the lack of convenient synthetic methods is a significant roadblock to their broader use and study. (more...)

A polymer that exhibits antifouling properties, including antimicrobial and antialgal properties. (more...)

A protocol that provides both the benefits of using a reactive and selective cuprate for 1,4-additions and the advantages of metal enolates other than copper  toward alkylation or 1,2-addition. (more...)

UC San Diego bioengineers have developed smart, self-healing hydrogels with far-reaching applications including medial sutures, targeted drug delivery, industrial sealants and self-healing plastics.  Photo Credit: Joshua Knoff, UC San Diego Jacobs School of Engineering. The gels, when damaged and then healed, have excellent mechanical properties including stretching, weight support, heat resistance and recovery from deformation. A recent paper in PNAS provides details of the development of these materials and discussion regarding some of  their possible applications can be found below under "Related Materials". (more...)

Congestive heart failure (CHF) is defined as abnormal heart function resulting in inadequate cardiac output for metabolic needs. It has been reported that 3-4 million adults in the United States have CHF and the incidence is increasing. Annually in US hospitals, CHF is the most frequent non-elective admission and the discharge diagnosis for 500,000 patients. Once symptoms of heart failure are moderately severe, the prognosis is worse than most cancers in that 50% of such patients are dead within 4 years. Present treatments for CHF include pharmacological therapies, coronary revascularization procedures (e.g. coronary artery bypass surgery and angioplasty), and implantable cardiac defibrillators and biventricular pacemakers. However, even with optimal therapy, approximately half of the patients with severe CHF die within 4 years. Cardiac transplantation provides a better solution, but is available for only 1 patient per 1000 with CHF. Adenylyl cyclase has long been recognized as a pivotal effector molecule in cardiac myocytes and other cells. It has been demonstrated that the amount of adenylyl cyclase type VI (AC VI ) sets a limit on the ability of cardiac myocytes to generate cAMP and that cardiac-directed expression of AC VI increases cardiac contractile function in transgenic mice. When AC VI is expressed in the background of G q -associated cardiomyopathy, cardiac function and survival are improved. It has also been shown that global left ventricular ( LV ) function and responsiveness can be changed by gene transfer of AC VI in a manner that can be applied clinically through intracoronary delivery. (more...)

A University of California scientist has invented a method for measuring femtomolar amounts of GTP and GDP, and has used this method to determine absolute amounts of Ras -bound GTP and GDP in mammalian cells. Other researchers have previously associated tumors with Ras mutations that block the reaction converting bound GTP to GDP. Initial studies using the UC invention confirm that certain tumor cells have elevated levels of bound GTP (in the case of leukemic cell line, 45 times as much as the non-leukemic counterpart) due to the blockage of phosphate cleavage. Given the importance of G-proteins in regulating cell proliferation and cell function, direct quantitative assays of bound GTP and GDP permit detection and detailed characterization of a variety of cancers and genetic disorders linked to G-protein dysfunction. Consequently, the UC quantitation method is potentially significant both as a research and a diagnostic tool. In clinical use, the invention might be adapted to a kit format for detecting tumor cells in tissue samples. It is expected that such diagnostic applications for the invention would provide more accurate and precise results than current antibody-based methods. (more...)

Acyl-COA: cholesterol acyl transferases or ACAT is an enzyme that catalyzes the esterification of cholesterol to form cholesteryl ester. Minimally, ACAT-mediated formation of cholesteryl ester from cholesterol prevents the toxic accumulation of excess cholesterol in a cell and maintains a free diffusion gradient across the cell membrane, particularly in the small intestine. In addition, the assembly and secretion of Apolipoprotein-B containing lipoproteins in the liver and intestines is thought to be dependent on the ACAT-mediated formation of cholesteryl esters from cholesterol. In steroidogenic tissue such as the adrenal glands, ACAT activity produces cytosolic droplets loaded with cholesteryl esters from which they can be mobilized as cholesterol substrates for the generations of steroids. Furthermore, macrophages that accumulate cholesteryl ester in cytosolic lipid droplets as a result of ACAT activity appear foamy and are a characteristic early indicator of atherosclerotic lesions. Animal models that completely lack ACAT protein are viable, albeit with tissue-specific reductions in cholesteryl ester, suggesting that another ACAT enzyme is present in these animals. (more...)

Liposomal carriers are hollow spherical structures that have been widely used to improve the delivery, extend the circulation time and decrease the toxicity of a number of drugs in development and approved for human use. However, many drug chemotypes are inefficiently loaded. One such chemotype includes drugs that cannot be readily dissolved in water. These 'hydrophobic' compounds require suspension in detergents for ultimate incorporation into the wall of the liposome, which greatly limits the loading capacity. In order to gain access to the vastly superior capacity of the hollow internal cavity of the liposome, UC researchers have developed a counter-intuitive and highly efficient method for encapsulating challenging drug chemotypes. (more...)

High-throughput, automated, large-scale mircoarry format assay in a short time frame and at low cost. (more...)

Researchers at the University of California, Irvine have developed a novel high resolution imaging technique, referred to as Photo-Magnetic Imaging (PMI), that combines the abilities of optical and magnetic resonance (MR) imaging systems. Images are created with PMI by heating tissue with a light (e.g. laser) and measuring the resulting temperature change with MR Thermometry. This change in temperature can then be related to a tissue’s absorption, scattering, and metabolic properties. PMI addresses the limitations of current optical imaging techniques by providing a repeatable, non-contact, high resolution optical image with increased quantitative accuracy. This technique can be used for a wide-range of applications including but not limited to imaging of small animals for research purposes. This technique may also be used in imaging the tissue and organs of a patient. (more...)

Surfaces are frequently micropatterned with proteins in order to capture and culture cells in distinct gerometric configurations. Researchers at UC Davice have developed a novel method for micropatterning surfaces with photoliabile protein to capture and release of cells, triggered by UV light. (more...)

Optical microscopy methods have tremendous application in the study of cells and other biological structures.Current imaging methods, such as STED and PALM, have allowed scientists to capture super-resolution images that have been difficult in the past.However, these current imaging methods are inadequate to detect the dynamic movements of live cell structures which are continually changing shape and position in the millisecond to second time scale.In addition, current scanning techniques, which utilize laser scanning in a predetermined pattern, are inefficient when the features to be imaged are at the nanometer scale.A method that is effective at capturing super-resolution images of dynamic, nanoscale biological samples will be an important scientific tool. Researchers at the University of California, Irvine have developed an optical imaging method that can produce 3D images of small, moving cellular structures with fluorescent surfaces.The method is based on a feedback principle according to the shape of the objects present in the sample, instead of having a predetermined path.The feedback approach produces high quality 3D images in seconds and does not require sample fixation.This method works with live cells and is compatible with correlation techniques like FCS and RICS. (more...)

Genotoxic (DNA damage-inducing) chemicals often increase the risk of cancer. Genotoxicity testing is mandatory for approval of new drugs as an indicator of potential carcingenicity and is therefore genotoxicity is generally undesired. However, genotoxic activity can also in some cases be deliberately screened for to help identify DNA-targeting compounds, as leads for the development of antimicrobial, immunosuppressive, or antitumor agents. The most popular genotoxicity assay is the Ames’ test. This test uses Salmonella and E. coli as model organisms because of the exquisite conservation of DNA damage and repair mechanisms across kingdoms. The Ames’ test detects point mutations and frameshifts based on the reversion of inactivating mutations in the biosynthesis operon of a given amino acid. Because this assay detects mutations rather than more indirect effects of genotoxicity such as changes in gene expression, it has a high degree of specificity (77% compared to ~50% for other genotoxicity tests). However, the classic Ames’ test presents a number of technical limitations, notably the large amount of test sample required. The Ames’ test is not easily amenable to high throughput screening. Some high-throughput versions of the Ames’ test have been developed, and are based on fluctuation analysis in liquid culture. In this case the readout is binary (i.e. growth vs. no growth) in individual wells of a 96-well plate. UCSC researchers’ newly developed technology generates a quantitative signal that is proportional to the number of random mutations present in the culture. Thus, the information provided in a 96-well plate for the liquid Ames’ test could be obtained in one well, dramatically reducing the amount of test sample required. (more...)

A novel health monitoring system (HMS) to use data from continuous glucose monitoring systems to calculate the risk of a hypoglycemic attack. (more...)

Coherent anti-Stokes Raman scattering (CARS) microscopy, a form of nonlinear optical microscopy, has gained enormous attention in the biomedical community for its potential to provide high resolution images at fast imaging acquisition rates. Typical applications of CARS include skin and superficial tissue imaging, often in an in vitro setting. Up to this point, a suitable device that enables the CARS imaging of tissues in vivo has not been available. However, researchers at the University of California, Irvine have developed a novel, fiber-based imaging probe that is optimized for CARS to enable the label-free,in vivo probing of tissues. (more...)

Dual-beam optical traps, used in conjunction with microfluidic channels, are used for manipulating µm-scale dielectric objects such as biological cells or polystyrene beads. This type of manipulation is helpful for studying the mechanical properties of soft particles and the dynamics of particles suspended in microfluidic flows, and for holding and observing living cells over extended periods of time. However, optical traps/microfluidic systems suitable for practical applications have been quite complicated and expensive to make, primarily due to the difficulties of holding optical fibers in place mechanically on the chip or of using in situ optical wave guides or lasers as substitutes for optical fibers. Of particular concern is the need to incorporate complex microfabricated components into a system’s design to make it compact enough for use with microscopes. (more...)

The Notch pathway is a highly conserved cellular signaling pathway that plays a role in numerous developmental processes by controlling cell fate decisions. The Notch protein is a transmembrane receptor comprised of a large extracellular domain, a short transmembrane segment, and a smaller intracellular domain. When the Notch extracellular domain is activated by ligands, the intracellular domain is proteolytically cleaved, allowing it to translocate to the nucleus to alter gene expression. UCLA researchers have developed novel polyclonal antibodies against either the extracellular ligand-binding domain or the cleaved, "activated" Notch intracellular domain. These antibodies do not cross-react and can be used for a variety of applications, including immunoblot, immunoprecipitation, and immunohistochemistry. (more...)

Diacylglycerol acyltransferase-1 (DGAT-1) is an enzyme involved in triglyceride synthesis.  Inhibitors of DGAT-1 are currently in clinical trials as treatments for diabetes and obesity. (more...)

Researchers at the University of California, Irvine have developed a process and method to increase microwell density by as much as twofold in a 2D imaging plane using 3-D arrangements of micro-well reactor plates. (more...)

The recent identification of rare cell populations within tissues that are associated with specific biological behaviors, for example, progenitor cells, has illuminated a limitation of current technologies to study such adherent cells directly from primary tissues. The micropallet array is a recently developed technology designed to address this limitation by virtue of its capacity to isolate and recover single adherent cells on individual micropallets. The capacity to apply this technology to primary tissues and cells with restricted growth characteristics, particularly adhesion requirements, is critically dependent on the capacity to generate functional extracellular matrix (ECM) coatings. The discontinuous nature of the micropallet array surface provides specific constraints on the processes for generating the desired ECM coatings that are necessary to achieve the full functional capacity of the micropallet array. We have developed strategies, reported herein, to generate functional coatings with various ECM protein components: fibronectin, EHS tumor basement membrane extract, collagen, and laminin-5; confirmed by evaluation for rapid cellular adherence of four dissimilar cell types: fibroblast, breast epithelial, pancreatic epithelial, and myeloma. These findings are important for the dissemination and expanded use of micropallet arrays and similar microtechnologies requiring the integrated use of ECM protein coatings to promote cellular adherence. (GunnN.M., MS; Bachman M., Li G.P., Nelson E.L.Fabrication and biological evaluation of uniform extracellular matrix coatings on discontinuous photolithography generated micropallet arrays. J Biomed Mater Res A. 2010 Nov;95(2):401-12.) (more...)

The field of the invention generally relates to methods of constructing high surface area structures using photoresist patterning in combination with electrochemical polymer deposition.The methods described herein can be used to create structures for a wide variety of applications including, but not limited to, micro-reactors, electrodes, and sensors (e.g., biosensors). (more...)

Microfluidic systems have broad applications in diagnostic testing industry., and microfluidic technology advancement desires increasing the detection sensitivity of the systems. The detection sensitivity has been improved by directly modifying the sensor or amplifying either the testing sample or results. However, the currently used amplification systems are complex and contribute to energy consumption. For systems utilize microfluidic channels, a major challenge exists in how to drive test samples into the diagnostic chip.In most cases, external energy sources such as mechanical pumps, electronic power generators or high pressured gas driving forces are necessary.This also greatly limits the application of microfluidic systems, especially for the cost effective or portable diagnostic assay chips. (more...)

Researchers at the University of California, Irvine have developed a new controllable method to fabricate functionalized carbon nanowires that can then be covalently bound to antibodies, proteins, mRNA, DNA or other reagents. These antibodies and reagents may then bind with analytes of interest in solution causing a measurable change in the electrical current. Additionally, interdigitated electrode arrays may also be fabricated by using nanowires made from this method. (more...)

A novel method for the production of emulsions and dispersions, directed to methods for the formation of colloidal suspensions. These suspensions are formed with or without mechanical action and without surfactants, polymers, or stabilizing agents. (more...)

Researchers at the University of California, Irvine have developed a simple method for the rapid self-assembly of predictable high density droplet-reactor arrays for high throughput microfluidic applications in biology and chemistry. By controlling the ratio of the chamber height to droplet diameter, the resulting self-assembled 3D colloidal, lattice droplet pattern formations can be selectively tuned for optimal real-time and/or long-term 2D visualization and image capture of reactions occuring in the droplet micro-reactors. (more...)

Mode-locked lasers are widely used to produce ultrashort light pulses (in the femtosecond range), for use in science and industry. Poor dispersion compensation, also called chirp, is a limiting factor in reducing the pulse length in many of these systems. While linear chirp can be eliminated with simple and mature technology—grating pairs, chirped mirrors, dispersion-compensating fibers, etc.—higher-order chirp is more difficult to eliminate. One approach to eliminating higher-order chirp is to use a programmable spatial light modulator—for example, a liquid-crystal or acousto-optic modulator—in the Fourier plane of a grating pair. These modulators, however, are very expensive, easily damaged, and absorb some of the light. Deformable mirrors can perform a similar role, but are also very expensive. Other approaches to tunably compensate higher-order chirp require extra optical components that make them difficult to align and adjust. Still other approaches are not tunable, or else tunable over only one degree of freedom. The present invention is an optical component that compensates higher-order chirp. It is very inexpensive and simple to manufacture, has low light loss, and has enormous damage threshold. Most importantly, it has three independent degrees of freedom, which adjust linear chirp, quadratic chirp, and cubic chirp. Each of these adjustments requires no realignment: Only the component itself needs to be adjusted. Therefore the invention could have widespread use, both as an OEM component of commercial lasers, and also as an easily-implemented upgrade to legacy systems. (more...)

Researchers at the University of California, Irvine have developed a Laplace pressure trap that can fuse droplets from different inlets and fuse droplets generated at different frequencies. The device traps and fuses droplets passively by balancing the driving hydrostatic pressure with increasing Laplace pressure imposed by the device’s design geometry. Above are video frames showing the Laplace pressure trap and of a single droplet fusion event at the Laplace trap. Frame A - Reference droplet can be seen waiting for its fusion partner. Excess partner droplets can be seen exiting towards the outlet. Frames B and C show the reference droplet and its fusion partner fuse and move toward the outlet. Frame D shows the next reference droplet approaching the trap. (more...)

The Overman laboratory at the University of California, Irvine has generated a library of ~1,200 unusually diverse small drug-like molecules. (more...)

Diagnostic device for detecting malaria infection by blood sample testing. (more...)

Researchers at UC Berkeley have developed a synthetic polymer interface for the long-term self-renewal of human embryonic stem cells (hESCs) in defined media. Current culture systems for hESCs require the use of isolated animal derived extracellular matrix proteins or mouse embryonic feeder cells. The proposed use of a completely synthetic cell culture substrate avoids the problems associated with the variability of and the exposure to animal products. The hydrogel network coating is comprised of aminopropylmethacrylamide (APMAAm) monomer and N,N-methylenebis(acrylamide) (bis) crosslinker that was grafted to standard tissue culture polystyrene (TCPS) dishes via photoinitiated addition polymerization. Results for hESC proliferation and pluripotency markers were both qualitatively and quantitatively similar to cells cultured on MatrigelÔ -coated substrates.   (more...)

Novel polymeric micro- and nanoparticles with non-spherical shapes and methods of making such particles. The particles have an average diameter of about 10 nm to about 100 µm and can have a wide variety of non-spherical shapes. (more...)

Patent rights to a group of novel rice beta-glucanase genes and the corresponding beta-glucanase enzymes are available for non-exclusive licensing.  The genes, and the gene promoters, are useful in a variety of transgenic monocot plants for achieving increased plant resistance to fungal infection, improved growth characteristics, biomass conversion and high levels of expression of heterologous protein in various tissues obtained from the plants. (more...)

Researchers at the University of California, Davis have developed an effective local therapeutic strategy with substantially reduced side effects using a combined treatment with increased and stable loading of doxorubicin (Dox) using a complex of Dox and copper (II). Cu-liposomes were loaded with Dox up to a maximum concentration of 0.6mg-drug/mg-lipid with 100% loading. UC Davis researchers have studied the efficacy of Cu-Dox liposomes and optimized the treatment strategy using the highly invasive and metastatic Met-1 tumor, a syngeneic model of human breast carcinoma. All animals receiving the combined therapy survived throughout the 28 day course treatment and did not show any side effects throughout the 28 day of treatment. A significant tumor regression was accomplished on combining Cu-Dox liposomes with another drug and tumor insonation. (more...)

High-throughput and low-cost techniques for fabrication at sub-50nm scale on wide area substrates are currently a very active and competitive field of cross-disciplinary R&D. Of the recent crop of nanofabrication technologies, dip-pen nanolithography (DPN) is notable for its success in serving the nanofabrication needs of biotechnology, advanced materials, and nano-scale devices. In DPN, molecules in an “ink” are transferred from a coated atomic force microscopy tip to a substrate, forming a pattern as the tip is scanned. DPN however has the disadvantages of slow processing and patterning of small areas and limited parallelization capabilities. (more...)

The most common way to make micro and nano scale particles of custom shapes is by lithography and etching, which requires expensive lithography masks, systems, and additional steps. Nanoimprintation, where a patterned form is pressed into a polymer to stamp out features, is an alternative for making customized particles. There are disadvantages to nanoimprintation, however, such as the form becoming clogged with polymer material, the enormous forces necessary to create enough pressure to stamp out very small objects, and often there is a residual layer of polymer that remains in areas outside the depressions where the form and flat substrate should make hard contact. Another popular option is step-and-flash nanoimprintation, where the form is used to stamp features into a photoresist, which is then exposed to light (flashed) to crosslink. Less force is required in step-and-flash because photoresist is generally less viscous than molten polymer, but step-and-flash still carries the other disadvantages associated with conventional nanoimprintation. (more...)

Biotin (vitamin H) is an essential coenzyme that is also used to tag proteins for detection, labeling, and purification purposes. The process of adding biotin to proteins is called biotinylation. Biotin labeling has also been applied to drug targeting and viral gene therapy vector-targeting strategies. Traditionally, biotin labeling has been performed in vitro by chemical methods. The problem with these chemical methods is that the random and heterogeneous modifications can lead to the inactivation of biological function after mixing with streptavidin or avidin. Antibody biotinylation especially leads to heterogeneous conjugates. Therefore, there is a need for a method that will uniformly biotinylated proteins without altering binding properties and resulting in loss of affinity. (more...)

BACKGROUND:  There is a general need for dynamically regulatable protein binding domains to control functional protein interactions in a variety of experimental and commercial applications. The majority of such systems that have been developed are based on the administration of chemical dimerizers which require the slow, irreversible diffusion into the cell of small molecules that target the dimer-interface site. An alternative method is the control of protein interaction in any suitable host cell or organisms by light. This invention relates to a light-regulatable protein-protein interaction system based upon phytochromes, a family of photoreceptors that enable plants to adapt to their prevailing light environment. TECHNOLOGY:   UCSF inventors have developed the first genetically encoded system for the fine spatial and temporal control of the localization and activity of proteins on sub-micrometer and sub-second scales. The system has further been optimized to be modular and easily switched to future arbitrary signaling pairs and localization tags. (more...)

The present invention relates to a method for determining cancer susceptibility by quantifying DNA damage-induced mRNA in whole blood. (more...)

Inflammatory bowel disease (IBD) consists of a group of chronic gastrointestinal inflammatory disorders with unknown etiology, including ulcerative colitis (UC) and Crohn’s disease (CD). Immunosuppressive and anti-inflammatory agents in high maintenance doses are the principal drugs used in the therapy of IBD. However, about 20-25 percent of patients with UC fail to respond to this intensive therapy and are therefore referred to surgery. In general, patients with CD are even less responsive to medical therapy and usually do not respond to surgical treatment. These unresponsive patients are in need of effective treatments. (more...)

Researchers at the University of California, Irvine have developed a novel micron-sized hybrid particle complex, consisting of an AAL linked to SPIO particles, that can be used as a multimodal imaging agent, as well as a drug delivery vehicle. (more...)

The present invention is related generally to a method for screening subjects to determine those subjects more likely to develop diabetes by quantization of insulin producing cells. The present invention is also related to the diagnosis of diabetes to monitor disease progression or treatment efficacy of candidate drugs. (more...)

Similarity search methods are important for data mining in many fields, such as biology, finance, and artificial intelligence. In molecular biology, for example, computer-assisted sequence comparison is widely recognized as an essential analytical tool. The quality of an alignment is usually characterized by an alignment score. Statistical significance (e.g., a p-or E- value) needs to be assigned to the alignment score in order to interpret the result. This statistics assessment is however a difficult and time-consuming task for the existing Smith-Waterman-type or HMM-based algorithms, whenever gaps are involved. A novel hybrid algorithm has recently been devised so that the alignments it generates obey universal statistics, without sacrificing the sensitivity and computational cost compared to the best of the existing methods. The alignment scores of the hybrid algorithm have been shown to satisfy the so-called Gumbel distribution, with the few Gumbel parameters readily computable, for a large class of scoring functions and for a wide range of sequence lengths and amino acid frequencies. These allow one to rapidly characterize the results of sequence comparison, without the need for extensive simulation for each scoring functions as it is currently done. The hybrid algorithm has been successfully tested on known classes of protein sequences. For more information, see: Y.-K. Yu and T. Hwa, Statistical Significance of Probabilistic Sequence Alignment and Related Local Hidden Markov Models, J. Comp. Biol., submitted for publication. (more...)

Protecting groups can be used to mask compounds, or portions of compounds, from interacting in chemical or biological systems. For example, a protecting group can prevent a compound from undergoing a chemical reaction by changing the chemical nature of a functionality. Photolabile protecting groups, sometimes called caging groups, have become a mainstay of organic synthesis, biotechnology, and cell biology because cleavage by light is a very mild deprotection step that is usually not encountered in typical experimental manipulations. Before photolysis, these caged compounds are biologically or chemically inactive because at least one of the key functionalities is blocked. Triggered by a pulse of light, the protecting group is released and the molecule may be activated. In this way, photolabile protecting groups can be removed from a protected compound by irradiation to control release of the compound both spatially and temporally. In this manner, compounds of biologically active products can be used to probe biological effects of the compounds. (more...)

UCSF scientists have developed a method to engineer a synthetic, feedback-regulated MAPK signaling pathway using scaffold-mediated feedback loops. This method can be used to systematically re-program MAPK signaling responses, allowing one to engineer and modify the MAPK signaling pathway to optimally control dynamic and complex behaviors in living cells. Many potential applications exist, including engineering of metabolic processes for optimal biofuel production. (more...)

The most common method for manufacturing polyolefins and their derivatives is by polymerization of olefin monomers with Ziegler-Natta catalysts or by the use of free radical, nucleophilic, or electrophilic initiators. Although one can achieve high molecular weights with these methods, the resulting products are often polydisperse. Many types of polymers are very difficult, if not impossible to manufacture by olefin polymerization. (more...)

Her2/neu is over-expressed in various types of tumor cells, including 20-30% of breast cancers, adenocarcinomas of the ovary, salivary gland, stomach and kidney, colon cancer, and non-small cell lung cancer. Passive immunotherapeutics like Herceptin control and prevent further tumor cell growth. Unlike active immunotherapeutics, Herceptin does not mediate the immunological cellular destruction. Active immunotherapeutics such as vaccines elicit T helper-1 (Th1) and Cytotoxic T lymphocytes (CTL) biased immune responses and are generally observed for proteins expressed in the intracellular compartment, and less prominently with extracellular or secreted proteins. Rapid degradation of a protein containing polyepitopes can contribute to establishing a bias in the immune response, facilitate antigen presentation and, perhaps assist in establishing specificity of the immune response. This type of immunological response should result in immunological cellular destruction. (more...)

Preservation of posttranslational modifications during purification is crucial for successful mass spectrometric analyses of protein modifications. Current tandem-affinity purification strategies require native conditions and are therefore susceptible to loss of posttranslational modifications during cell lysis and purification because modifying as well as de-modifying enzymes remain active under these conditions. (more...)

Light-Independent Phytochrome Signaling (more...)

While ease of genetic manipulation has traditionally favored the use of bacteria for commercial-scale production of recombinant proteins, differences between prokaryotes and eukaryotes in their post-translational protein processing and the difficulties of recovering and purifying proteins from bacteria has spurred interest in using plants as an alternative. However, the high cost and low yield of recombinant proteins produced in plants, and, in some systems, the further difficulties with post-translational protein processing, contamination, and/or purification have slowed the progress of producing therapeutic and other beneficial proteins in plants. Researchers working at the University of California have developed a family of inventions that offer commercially-viable plant systems for the expression, secretion, and recovery of recombinant proteins. In contrast to previously-used plant systems, the UC systems employ alpha amylase promoters and signal peptide sequences that allow for more precise control of expression and much higher ultimate yields. These UC inventions include: Rice DNA sequences that can be used for metabolically-regulated or hormonally-regulated recombinant protein expression and secretion from germinating seeds; Additional rice DNA sequences that allow for regulated recombinant protein expression in plant cells in response to sugar depletion or deprivation; Rice signal peptide DNA sequences that can be used for secretion of recombinant proteins from monocotyledonous plants and cell cultures; and Sugar-beet DNA sequences that can be used for expression of recombinant proteins in dicotyledonous plants and cell cultures. Additional Patented Technologies from this Inventor UC Case No. 1998-287, "DNA Sequences Capable of Expressing Foreign Proteins and Metabolites in Dicotyledonous Plants and Cell Culture" U.S. Patent 7,045,681 issued on 16 May, 2006 UC Case No. 1997-229, "Sugar-Regulatory Sequences in Alpha-Amylase Genes" U.S. Patent 6,919,493 issued on 19 Jul, 2005 U.S. Patent 6,680,425 issued on 20 Jan, 2004 U.S. Patent 6,048,973 issued on 11 Apr, 2000 UC Case No. 2002-416, "Production of Mature Proteins in Plants" U.S. Patent 6,066,781 issued on 23 May, 2000 (more...)

Efficient Production of 14C-Vitamin B12 for Human Microdosing and Other Applications (more...)

University of California researchers have developed a new recombinant viral insecticide that kills host insects 50% more quickly than the wild type virus. Baculoviruses are a class of pathogens selective for insects. The viruses have recently been proven to be efficient vectors for the expression of foreign genes as well. This has led to the development of recombinant viruses which selectively kill their hosts by expressing the foreign gene. Previous attempts using inserted insect diuretic hormone and juvenile hormone esterase genes have met with some success, but showed little increase in potency over control viruses. Scientists at the University of California have now developed a new recombinant virus which expresses a neurotoxin that selectively targets and blocks the insect's sodium channels. This mode of action is similar to that of many widely used chemical insecticides. This new virus shows 25% greater efficacy over previously engineered viruses. These results suggest that such a recombinant insect-specific virus could be used as a safe and effective insecticide, and be of great commercial value to agriculture. (more...)

In 2007, diabetes accounted for $174 billion in health-care costs, with 20.8 million Americans diagnosed with this disease. Type I diabetes comprises up to 10% of diabetes mellitus cases in North America. Intensive insulin therapy can help reduce the risks of developing complications like neuropathy, nephropathy and ketoacidosis, but it requires three or more insulin injections or use of an external insulin infusion pump. We currently have excellent insulin infusion pumps, and continuous glucose sensors are now sufficiently accurate to be used to regulate insulin delivery. What is missing is a program (algorithm) to regulate insulin delivery based on the signal from a continuous glucose sensor. In addition, the risk of nocturnal hypoglycemia is still high. (more...)

In 2007, diabetes accounted for $174 billion in health-care costs, with 20.8 million Americans diagnosed with this disease. Type I diabetes comprises up to 10% of diabetes mellitus cases in North America. Intensive insulin therapy can help reduce the risks of developing complications like neuropathy, nephropathy and ketoacidosis, but it requires three or more insulin injections or use of an external insulin infusion pump. We currently have excellent insulin infusion pumps, and continuous glucose sensors are now sufficiently accurate to be used to regulate insulin delivery. What is missing is a program (algorithm) to regulate insulin delivery based on the signal from a continuous glucose sensor. In addition, the risk of nocturnal hypoglycemia is still high. (more...)

The rising incidence of infectious bacterial strains that are resistant to multiple broad-spectrum antibiotics poses serious complications to the treatment of infectious diseases. Absent knowledge of a given infectious agent's susceptibility to various antibiotics, physicians face the dilemma of prescribing an antibiotic that may prove to be ineffective, or prescribing an antibiotic capable of treating the most resistant strains but, if used unnecessarily, may accelerate the breeding of even more resistant strains. In these circumstances, selection of the optimal antibiotic requires rapid profiling of a bacteria's susceptibility to various antibiotics. However, current methods for assaying susceptibility of a purified bacterial culture, involving observations of the strain's visibile growth in antibiotic media, can take up to a full day. Thus, there is an urgent need for more rapid methods for assaying susceptibility that are suitable for use in clinical settings. (more...)

 Recent research focuses on the study on higher harmonics of the response of an atomic force microscope in tapping mode, which change characteristically with respect to the Youngs Modulus of the sample. Higher harmonics are excited more with harder materials. These higher harmonics can be mechanically preamplified with an appropriate construction or excitation of the system and be read out with the usual optical measurement units. (more...)

 While many assays exist for the detection of DNA, RNA, proteins and other molecular targets, most sensors require sample purity and rigorous controls available only under ideal laboratory settings. These constraints significantly dampen the effectiveness of most reported sensing technologies for real world applications. Rapid, accurate and cost-effective sensors that can quickly identify and quantify targets within contaminated samples would provide a critical tool for diagnostics, forensics, food safety, water/soil testing, civil defense, and other applications. (more...)

Scientists at the University of California and the University of Wisconsin working on cell cycle and development research have created a suite of antibodies to important transcriptional regulators.  These antibodies target the following: Histone 2B Phosphorylated Histone 2B TAF1 (Tata Box Binding Protein Associated Factor 1) Ash1 (histone methyl-transferase that methylates Histones 3 and 4) MLL (a DNA-binding protein that methylates histone H3) MDU (Drosophila Set/MBD protein) The following table provides more deatail: Antigen Species Type Reactivity H2B Drosophila Monoclonal (rat) universal H2B-S33P (phospho-group on serine 33) Drosophila Monoclonal (rat) Polyclonal (rabbit) Drosophila Ash1 (epigenetic activator) COOH term Drosophila Monoclonal (rat) Polyclonal (rabbit) Drosophila Ash1 (epigenetic activator) COOH term Drosophila Polyclonal Drosophila TAF1 (coactivator) Drosophila Mono (rat) and polyclonal (rabbit) Drosophila MLL (mammalian epigenetic activator) Mouse Polyclonal (rabbit) Mouse, Human Mdu (Drosophila Set/MBD protein Drosophila Monoclonal (rat) Drosophila (more...)

 While many assays exist for the detection of DNA, RNA, proteins and other molecular targets, most sensors require sample purity and rigorous controls available only under ideal laboratory settings. These constraints significantly dampen the effectiveness of most reported sensing technologies for real world applications. Rapid, accurate and cost-effective sensors that can quickly identify and quantify targets within contaminated samples would provide a critical tool for diagnostics, forensics, food safety, water/soil testing, civil defense, and other applications. (more...)

The human epidermal growth factor (EGF) receptor homologs, HER2 and HER3, are cell surface receptor kinases that are involved in the control of cell proliferation and differentiation. Overexpression of these kinases is found in several solid tumor malignancies, such as breast and ovarian cancers. Inhibiting signaling through these kinases is therefore an important clinical intervention, as is evidenced by the success of Herceptin, a humanized antibody against HER2. However, antibodies have some disadvantages as therapeutics, such as relatively large production costs and difficulty of selection. Furthermore, a significant portion of patients with HER2 overexpression does not respond to Herceptin. Thus, there is a need to develop novel small molecule therapeutics that inhibit HER2 and/or HER3. These new small molecule drugs could provide new diagnostics tools as well as treatment options for patients that fail to respond to Herceptin. (more...)

University of California researchers have developed a family of antibody fusion proteins with a potential for various therapeutic applications. These inventions represent both novel technologies and products with novel applications. These UC fusion proteins combine an antibody with various cytokines. While these cytokines have been used previously as direct antitumor agents, these antibody-cytokine fusion proteins can be employed in a novel therapeutic strategy. In this role, the fusion proteins enhance the immune response to a particular tumor marker. Studies in an animal model have demonstrated that these fusion proteins lead to significant anti-proliferative activity against a murine tumor expressing a breast cancer antigen; the results suggest that both humoral and cell-mediate responses contribute to the observed anti-tumoral activity. It is expected that these fusion proteins will lend themselves to both prophylactic and therapeutic vaccinations; they may be used separately or in combination to achieve an additive or synergistic anti-proliferative effect. (more...)

The HER2 receptor is overexpressed in ovarian and breast cancer cells and this overexpression has been correlated with increased morbidity and mortality. HER2 forms a heterodimer complex with the related receptor HER3, and this complex has a growth stimulatory response when activated by the ligand heregulin. Therefore, it has been suggested that binding of heregulin to the HER2/HER3 heterodimer may be important in the pathogenesis of breast and ovarian cancer. However, the domains of HER3 involved in ligand binding and heterodimerization have not been identified. (more...)

Novel silicone materials that further extend the range of beneficial properties that are controllable. In particular, the novel UC method of vulcanizing/curing silicones introduces cross-linking agents that efficiently disperse fracture energy in response to stress and that are capable of self-healing after yielding to rupture or deformation. (more...)

Glioblastoma multiforme is the most common primary neoplasm of the central nervous system and remains among the most deadly of human cancers. It has previously been shown that accumulation of multiple genetic lesions underlies the malignant progression of this cancer. Although some of these genetic abnormalities have been well-documented, recent insight into the extent of gene expression differences underlying malignancy reveals that hundreds of gene transcripts may be expressed at significantly different levels between normal and neoplastic cells. Identification of these genes has direct clinical relevance if combined with the development of innovative rational therapies that specifically target these differentially expressed gene products. (more...)

Programmed cell death or apoptosis is a critical event in normal cellular differentiation and development as well as in degenerative diseases, cancer and aging. Currently, the most widely used assay for detecting apoptosis is DNA fragmentation. However, since DNA fragmentation can occur in a variety of situations without apoptosis, is a late stage nuclear event in apoptosis, and increases with postmortem time, it is not a reliable indicator of apoptosis. (more...)

One method of studying tumors in mice is by using the CRE recombination system to delete or overexpress cancer-control genes in particular tissues at particular times. However, a hurdle in studying tumorogenesis is the difficulty in monitoring the progress of tumors in vivo. Current techniques require sacrifice of the animal followed by in situ work. These methods require the use of large numbers of animals and preclude the possibility of following the progress of a particular tumor over time. (more...)

Stroke and CNS injuries together cost Americans an estimated $75 billion a year in medical and rehabilitation expenses and lost productivity. Currently, there are no effective, clinically approved methods that promote nerve regeneration and subsequent restoration of CNS function. New research from the University of California has identified a potential therapeutic target for modulating neuron outgrowth. An antigen, present on most cells but long thought to be absent from neuronal cells, has been detected on nerve cells during embryonic brain development. This observation raised the question as to what role this antigen might play in neuronal guidance and axon growth. (more...)

Current non-surgical cancer therapies rely on the use of compounds or radiation doses that are non-specific for the tumor cells and are highly toxic to humans. Although these treatments are particularly effective against tumor cells, they are also destructive to the surrounding normal cells, which leads to severe side effects. In addition, the non-specificity of these therapies limits their efficacy. Efforts to develop more specific treatments have focused on targeting the defective processes in the tumor cells, such as those involving mutations in oncogenes and tumor suppressor genes. One of the most desirable molecular targets for clinical intervention in cancer is the p53 tumor suppressor gene, since it is the most frequently mutated gene in human cancers. However, scientists have encountered difficulty in studying the anti-tumor function of p53 due to limited simple situations in which to study the gene. In particular, it has not been possible to take advantage of classical genetic methods to identify genes that act with p53 to suppress tumor formation. (more...)

The use of lung surfactant dispersions, based on lipid and protein components extracted from animal lung tissue, has significantly reduced mortality and morbidity from respiratory distress syndrome (RDS) in premature infants in the past decade. However, existing lung surfactants are not potent enough or cost effective enough to treat adult RDS and acute asthma, both of which represent far larger indications than neonatal RDS. Growing concerns of possible viral and prion contamination from animal sources (e.g. mad-cow disease), as well as overcoming the expense in isolation and formulation of native surfactant components, make the synthetic 'mimetic' approach an attractive alternative to traditional therapies. (more...)

Scientists at the University of California have shown that a specific enzyme is an essential regulator of Salmonella virulence. This enzyme is prevalent in many organisms including most enterobacteria, certain gram negative and gram positive bacteria, as well as archaebacteria. It is expected that this enzyme will be a major virulence factor for many types of infection, including cholera (Vibrio cholerae), the plague (Yersinia), brain infections (Haemophilus influenzae), typhoid fever (Salmonella typhi), and kidney disease (E. Coli O157:H7). Salmonella typhimurium strains that lack or overproduce this enzyme are highly attentuated; thus therapeutic agents that block this enzyme are candidates for a new class of antimicrobials. Moreover, mice immunized with strains that do not produce this enzyme survived a wild type challenge of 10+4 above the LD50 (lethal dose required to kill 50% of the animals); thus these mutant strains can serve as live attenuated vaccines. Since DNA adenine methylases ("Dam") is present in many pathogens that cause serious health problems worldwide, including cholera, dysentery, meningitis, typhoid fever and the plague, Dams are potentially excellent targets for both vaccines and antimicrobials). "Cross-Protective Vaccines Against Emerging Infectious Agents"    M. Mahan, UC Santa Barbara BioDiscovery Symposium, MAY 2006 "Cross-Protective Vaccines Against Emerging Infectious Agents"    VIDEO PRESENTATION   by Michael Mahan    Windows Media    Quicktime (more...)

DNase II, an endonuclease, has recently been shown to play a role in many different cellular activities. Mammalian DNase II enzymes and the Caenorhabditis elegans homolog NUC-1 have been shown to be critically important during engulfment-mediated clearance of apoptotic DNA. NUC-1 has been demonstrated to participate in apoptotic DNA degradation in nematodes while the mammalian enzyme appears to be critical for full degradation of engulfed apoptotic DNA. Both DNase I and DNase II have also been implicated in tumor cell necrosis induced by specific vitamin regimens. Furthermore, DNase II has been observed to play a major role in chromatin cleavage during terminal differentiation in lens cells. Finally, DNase II has been implicated by researchers at the University of California in isotype switch recombination; the process of varying antibody isotypes by targeted rearrangement of the antibody genes in mature B cells. (more...)

Amino acid-N-carboxyanhydride (NCA) polymerizations employing conventional initiators (e.g. hexylamine or sodium methoxide) are plagued by chain-breaking transfer and termination reactions which prevent the formation of block copolymers. The mechanisms of NCA polymerization have been under intensive study to find a method for enhancing control over chain growth in these reactions. These investigations have been severely hindered by the complexity of the polymerizations, which can proceed through multiple pathways. (more...)

Surgical tissue adhesives provide an alternative to suturing, packing, or stapling planes of tissue together. Use of adhesives for wound closure is desirable since adhesives can be very fast acting and assure complete closure. Marine adhesives (such as those used by barnacles) can function over wide temperature ranges, fluctuating salinities, humidities, and under strong currents. These glues are able to rapidly form permanent bonds to a wide variety of substances with complex and often irregular coatings. In contrast, the success of synthetic adhesives in wet environments requires carefully cleaned adherents that must often be chemically treated or partially dried or both. (more...)

Gels based on high molecular weight polyethylene glycol (PEG) have been used for many biological applications because of their low immunogenicity. Conventional gels incorporate solid-phase components, constraining their manipulation and use in a variety of areas such as molecular drug delivery. Gels that can function without solid-phase components would help to overcome many of these difficulties. (more...)

In eukaryotes, the methylation state of a gene specifically affects its transcription. Proper function of the methylation enzyme is crucial for viable development and normal cellular activity. Increased activity of the enzyme cytosine-C5 DNA methyltransferase (DCMTase) has been directly associated with neoplastic development and excess methylation by DCMTase may constitute a key step in carcinogenesis. Currently, the drugs available for inhibiting DCMTase bind irreversibly to the enzyme and have toxic side effects. (more...)

The hormone prolactin (PRL) exerts various effects in a wide range of physiological processes. Research suggests that PRL may promote cellular proliferation in both breast cancer and prostate cancer cells. University of California researchers have developed a modified PRL analog (S179D) that acts as a strong antagonist to PRL in cell proliferation assays. S179D consists of a wild-type PRL with a single amino acid substitution. This substitution alters the activity of the molecule such that it antagonizes the growth-promoting effects of unmodified PRL in experimental breast cancer and prostate cancer cell lines. Research results indicate that the modified S179D retains some functions of normal PRL. In other words, S179D may be a selective inhibitor of cell proliferation in certain systems, which suggests that it could potentially be used as a cancer therapeutic that did not wholly disrupt PRL metabolism throughout the body. The University of California holds a soon-to-issue United States Patent claiming S179D and related PRL mutants. The University is searching for commercial partners that are interested in investigating the potential of S179D as a therapeutic. Examples Figure 1.  Effects of S179D on the proliferation of MCF-7 breast cancer cells Normal MCF-7 cells produce PRL, making it difficult to study the effects of exogenous PRL. In this study, MCF-7 breast cancer cells were developed that are deficient in PRL production so that the effects of exogenously applied hormone could be elucidated. Cells were cultured in media containing wild-type human PRL at 100 ng/ml. Cell numbers were measured at 48 hours, and the percent increase over the number of cells in the vehicle only control was calculated. In the absence of S179D, wild type PRL induced a near doubling in the number of MCF-7 cells. When treated with either of two forms of S179D (A or B), the growth-promoting effects of PRL were significantly reduced in a dose-dependent manner. Figure 2.  In one experiment, the administration of S179D prior to cancer cell injection was effective in decreasing both the incidence and size of tumors in mice injected with prostate cancer cells (A and B). In a second experiment, mice previously injected with prostate cancer cells were treated with S179D, which was effective in reducing tumor size (C). 2A.  At day 1, nude mice were implanted with minipumps administering control vehicle, wild type PRL, or S179D. On day 4, mice were injected with DU145 human prostate cancer cells. On day 22, mice were assayed for tumor incidence and size. S179D significantly reduced the incidence of tumors. 2B.  PRL slightly increased tumor size while S179D significantly reduced tumor size. 2C.  In a separate experiment, mice were injected on day 1 with DU145 human prostate cancer cells. At day 18, mice were implanted with minipumps administering control vehicle, wild type PRL, or S179D. On day 42, tumor size was measured. PRL promoted increased tumor size while S179D significantly reduced the size of well-established tumors. References X. Xu, E. Kreye, C.B. Kuo, and A.M. Walker. A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were gown in nude mice. Cancer Research 61:6098 (2001) M.D. Schroeder, J.L. Brockman, A.M. Walker, and L.A. Schuler. Inhibition of Prolactin (PRL)-Induced Proliferative Signals in Breast Cancer Cells by a Molecular Mimic of Phosphorylated PRL, S179D-PRL. Endocrinology 144: 5300 ' 5307 (2003) T.J. Chen, C.B. Kuo, F.F. Tsai, J.W. Liu, D.Y. Chen, and A.M. Walker. Development of Recombinant Human Prolactin Receptor Antagonists by Molecular Mimicry of the Phosphorylated Hormone. Endocrinology 139: 609-616 (1998).   (more...)

PATENT ABSTRACT: Aqueous compositions, test kits and methods can be used to detect hydrogen peroxide or vanadium bromoperoxidase by generating a chemiluminescent signal in the presence of the analyte. Signal generation as well as reaction kinetics are improved by using a composition which comprises a 2,3-dihydro-1,4-phthalazinedione derivative; a halogen, pseudohalogen, halogen-providing or pseudohalogen-providing source; and a peroxide or peroxide-generating reagent composition. (more...)

University of California scientists have synthesized novel oligonucleotide analogs for use in antisense and related applications. Unlike ordinary DNA and RNA strands, the U.C. analogs incorporate modifications to the sugar-phosphate backbone that alter electrostatic properties of the strand. These changes enable U.C. analogs to resist attack by nucleases, restriction enzymes, and topoisomerases, thus making the analog much more stable in vivo than existing antisense agents. Also, these changes enhance the binding affinity of the analogs to complementary RNA single strands and DNA double strands, which improves performance of the analogs in most applications. It is expected that the U.C. analogs will be strongly preferred over existing agents for antisense therapy to suppress expression of undesirable genes, particularly in antiviral and anticancer roles. The RNA analog might prove especially valuable in fighting retroviruses such as HIV (the etiologic agent that triggers AIDS), where such an analog could inhibit reverse transcriptase and other essential viral genes in vivo. With their superior stability and binding affinity, the U.C. analogs are also likely to find use as oligonucleotide probes in hybridization protocols, encompassing a wide variety of possible diagnostic and biotechnological applications. (more...)

Compounds that bind to DNA could be used to target drugs to DNA and to regulate expression of genes. Indeed, many compounds have been discovered (e.g. Distamycin) which bind to the minor groove of DNA, but the bond is too weak for reliable medical application. Scientists at the University of California have discovered a class of novel compounds that have a high binding affinity for DNA (Keq>=109 M-1). The compounds bind in the minor grooves of the double helix and extend into the major groove to a substituent which interacts strongly in the major groove, particularly at the phosphodiester linkages. The side groups of the compounds also may bind metal ions. These novel compounds have multiple therapeutic and diagnostic applications. The compounds inhibit mammalian topoisomerase, a molecule that unwinds and rewinds the DNA double helix during replication. They function by competing for binding sites, altering the conformation of the DNA, and changing the affinity of DNA manipulating enzymes for sites on the double helix. Further, these compounds could be effective to arrest cell growth and act as anti-cancer agents. Since these compounds detect nucleic acid with high sensitivity, they may be used for diagnostic purposes. For instance, they may be used to assay for the presence of DNA or RNA markers of a disease in a sample of infectious material. Protein, mass produced by recombinant DNA technology, may be checked for the presence of minute quantities of DNA or RNA. For therapeutic treatments, the compounds may be combined with pharmaceutical carriers and made into a liquid, tablet, powder, suppository, or ointment. Besides oral or topical application of the dose, the compounds may be introduced intravenously or by injection directly into the peritoneal cavity, lymphatic system, or malignant tumors. (more...)

Monoclonal antibodies (mAbs) are an essential tool in numerous research, therapeutic, and diagnostic applications, as mAbs can be customized to bind a desired antigen. While this is highly advantageous in generating very high binding specificity, the actual process of producing mAb-producing hybridomas is difficult and time-consuming, and involves mAb protein chains (immunoglobins) derived from animal sources that are not always suitable for use in humans. Researchers at the University of California have developed a set of vectors for use in an alternative method for producing purified, humanized antibodies, based on the expression of recombinant human immunoglobulins in cell culture. These vectors, which are being made available for bailment as tangible research property, can be used to express PCR-generated variable regions or variable regions cloned directly from a cell line in conjunction with the constant regions. Thus, expression of the UC vectors can provide complete heavy or light chains or libraries of heavy or light chains expressing variable regions of interest. This expression system eliminates the need for hybridomas, and makes possible the facile production of human mAb proteins that are suitable for in vivo or in vitro use. They include gene sequences for the kappa light chain and for the IgG-1, IgG-2, IgG-3, IgG-4, and IgA heavy chains, along with various selectable markers (his, neo, and gpt). In the case of the kappa and gamma-1 chains, more than one vector is available. This range of vectors permits the design of antibody-specific therapeutic and diagnostic agents based on human immunoglobulins. Such recombinant antibodies avoid allergic reactions typical of mAbs, and may also be useful in various specialized research applications where conventional techniques for generating antigen-specific beta lymphocyte cell strains, etc., are not practical. (more...)