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Potent and Effective Anti-Metastatic EphA2 Agonists

Prof. Maurizio Pellecchia and his colleagues at the University of California, Riverside have developed peptide-based EphA2 agonistic agents that have nanomolar activities. These agents, having the same mechanism of action as the natural (ephrinA1-Fc) ligands, effectively degrade EphA2 receptors and  delay cell migration in key cancer cell lines.  These agonistic agents may be effective therapeutics that may result in less unwanted side effects that have been observed in the clinic with ADCs targeting EphA2. Fig. 1 Top, X-ray structure of EphA2 in complex with UCR agent.. Bottom, Treatment with ephrinA1-Fc or UCR agent 135H12 on an orthotopic mouse model of prostate cancer with PC-3-GFP cells (n = 5 mice per treatment group). The mean fluorescence intensity related to metastases detected at day 7 from mice in each group, control (the solvent formulation used for 135H12), ephrinA1-Fc treated, 135H12 treated. Error bars represent standard deviation. ** p < 0.01.

Composition and Methods of a Nuclease Chain Reaction for Nucleic Acid Detection

This invention leverages the nuclease activity of CRISPR proteins for the direct, sensitive detection of specific nucleic acid sequences. This all-in-one detection modality includes an internal Nuclease Chain Reaction (NCR), which possesses an amplifying, feed-forward loop to generate an exponential signal upon detection of a target nucleic acid.Cas13 or Cas12 enzymes can be programmed with a guide RNA that recognizes a desired target sequence, activating a non-specific RNase or DNase activity. This can be used to release a detectable label. On its own, this approach is inherently limited in sensitivity and current methods require an amplification of genetic material before CRISPR-base detection. 

COMPOSITIONS AND METHODS FOR IDENTIFYING HOST CELL TARGET PROTEINS FOR TREATING RNA VIRUS INFECTIONS

Viral infection is a multistep process involving complex interplay between viral life cycle and host immunity. One defense mechanism that hosts use to protect cells against the virus are nucleic-acid-mediated surveillance systems, such as RNA interference-driven gene silencing and CRISPR-Cas mediated gene editing. Another important stage for host cells to combat virus replication is translational regulation, which is particular important for the life cycle of RNA viruses, such as Hepatitis C virus and Coronavirus.  While efforts to characterize structural features of viral RNA have led to a better understanding of translational regulation, no systematical approaches to identify important host genes for controlling viral translation have been developed and little is known about how to regulate host-virus translational interaction to prevent and treat infections caused by RNA viruses.   UC Berkeley researchers have developed a high-throughput platform using CRISPR-based target interrogation to identify new therapeutics targets or repurposed drug targets for blocking viral RNA translation.  The new kits can also be used to identify important domains within target proteins that are required for regulating (viral RNA translation) and can inform drug design and development for treating RNA viruses.

Methods and Applications for Controlling Cellular Viability Using Fluoride-Sensitivity

This technology employs fluoride-sensitivity to overcome the limitations of existing selection methods.

Brown Adipose Tissue Myosin II Activators for Metabolic Therapy

The inventors have uncovered a novel brown adipose tissue (BAT) activation pathway based on cellular tension generated by actomyosin. Initial tests of predicted myosin II activators show the ability to increase the expression of uncoupling protein 1 (UCP1), a pivotal determinant of uncoupled respiration, in murine and human brown and beige cells. This strategy could be the foundation for a novel strategy to treat obesity-associated disorders such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease.

Reacting Molecules and Colloids Electrophoretically

Researchers in UCLA's Department of Chemistry and Biochemistry have harnessed gel electrophoresis in order to direct and program controlled collisional reactions between pulse-like bands of molecules and/or colloidal reagent species.

Temporal Control over DNA-Patterned Signaling Ligands In Vitro Using Sequence-Targeting Nucleases

UC Berkeley researchers have created a new technique that can rapidly “print” two-dimensional arrays of cells and proteins that mimic a wide variety of cellular environments in the body, be it the brain tissue surrounding a neural stem cell, the lining of the intestine or liver or the cellular configuration inside a tumor.  In the new technique, each cell or protein is tethered to a substrate with a short string of DNA. While similar methods have been developed that attach tethered cells or proteins one by one.  By repeating the process, up to 10 different kinds of cells or proteins can be tethered to the surface in an arbitrary pattern. This technique could help scientists develop a better understanding of the complex cell-to-cell messaging that dictates a cell’s final fate, from neural stem cell differentiating into a brain cell to a tumor cell with the potential to metastasize to an embryonic stem cell becoming an organ cell.

Enzymatic Modification Of Amino Acids And Their Products

The inventors report the structural characterization of BesD, a recently discovered radical halogenase from the FeII/-ketogluturate family that chlorinates the free amino acid lysine. They also identify and characterize additional halogenases that produce mono- and di-chlorinated as well as brominated and azidated amino acids. The substrate selectivity of this new family of radical halogenases takes advantage of the central role of amino acids in metabolism and enables engineering biosynthetic pathways to afford a wide variety of compound classes, such as heterocycles, diamines, -keto acids, and peptides. 

Improved Cas12a Proteins for Accurate and Efficient Genome Editing

Mutated versions of Cas12a that remove its non-specific ssDNA cleavage activity without affecting site-specific double-stranded DNA cutting activity. These mutant proteins, in which a short amino acid sequence is deleted or changed, provide improved genome editing tools that will avoid potential off-target editing due to random ssDNA nicking.

Traceless Linker for Aliphatic Amines that Rapidly and Quantitatively Fragment

The inventors have developed a traceless linker (TRAILER), which can for the first time modify aliphatic amines and release them rapidly and quantitatively after disulfide reduction. TRAILER can reversibly modify the lysine residues on the Cas9 protein, with the cell penetrating peptide Arg10, and is able to generate a self-delivering Cas9 RNP that can edit cells without transfection reagents.Reduction sensitive linkers have the potential to transform the field of drug delivery due to their ease of use and selective cleavage in intracellular environments. However, despite their compelling attributes, using reduction sensitive linkers for biomolecule conjugation reactions has been challenging in the past, because linkers have not been developed that can efficiently modify aliphatic amines and release them rapidly and completely after reduction. Previous efforts to develop reduction sensitive self-immolative linkers for aliphatic amines have been stymied due to their poor leaving group ability and high pKa values. 

Phenotypic Profiling Of Hepatocellular Carcinoma Circulating Tumor Cells For Treatment Selection

Researchers in the UCLA Departments of Surgery and Molecular and Medical Pharmacology have developed a novel blood-based assay that can capture and characterize circulating tumor cells indicative of both early- and late-staged hepatocellular carcinoma (HCC).

Lipid Bilayer Formation Using Sessile Droplets

UCLA researchers in the Department of Bioengineering have developed a method to form a biologically functional lipid bilayer in a high-throughput and automated fashion.

Development Of A Method For Endocrine Network Discovery Uncovers Peptide Therapeutic Targets

UCLA researchers in the Division of Cardiology at the Geffen School of Medicine have developed a bioinformatics methodology to identify and functionally annotate novel endocrine pathways.

Tissue Projection Electrophoretic Separation Of Protein

A range of related immunoblotting methods have enabled the identification and semi-quantitative characterization of e.g., DNA (Southern blot), RNA (northern blot), proteins (Western blot), and protein-protein interactions (far-western blot); by coupling biomolecule separations and assays.  However, there are a wide number of alternative splicing events, post-translational modifications, and co-translational modifications (e.g., phosphorylation, glycosylation, and protein cleavage) that give rise to proteoforms and protein complexes with distinct function and subsequent cell behavior that cannot be analyzed with conventional methods such as immunohistochemistry (IHC). Analytical variability (lack of isoform- or complex-specific antibody probes), biological variability (small cell subpopulations diluted in bulk analysis), and lack of multiplexing (measurement of multiple proteins from the same tissues) can all render proteoforms and protein complexes undetectable by current technologies.     UC Berkeley researchers have created electrophoretic separation platform that is capable of measuring proteoforms and protein complexes lacking specific antibodies alongside spatial information, at the cellular level.  This platform maintains the architecture of 2D tissue slices while projecting a protein separation in the 3rd dimension. The platform mitigates artifacts induced by tissue dissociation processes, as the intact tissue is lysed and subject to a protein separation. The platform is also compatible with differential detergent fractionation methods for further separation of proteins (e.g. separation by localization within the cell, by cell type, by protein complex formation, or by cellular vs. matrix proteins), opening the door for a novel, refined classification taxonomy using enhanced biomarker signatures for diagnostics and treatment selection in oncology among a wide range of additional future applications.  

Protein-Coated Microparticles For Protein Standardization In Single-Cell Assays

Single-cell analysis offers powerful capabilities of identification of rare sub-populations of cells, understanding heterogeneity of cancerous tumors, and tracking cell differentiation and reprogramming. Despite great potentials for uncovering new biological systems and targeting diseases with precision medicine, single-cell approaches are composed of complex device processes that can cause bias in measurement.  In deep sequencing, technical variation in single cell expression data occurs during capture and pre-amplification steps. Similarly, in single-cell protein assays, technical variability can obscure functionally relevant variance.    To better control protein measurement quality in single-cell assays, researchers at the University of California, Berkeley developed a novel method to loading and release protein standard. This method utilizes the surface of modified and functionalized microparticles as vehicles to capture target proteins with desired concentrations. Chelation-assisted click chemistry is applied to demonstrate that protein standards with different molecular masses can be loaded and bounded in a single-cell protein assay. Microparticles are introduced into single-cell devices by either passive gravity, magnetic attraction, or other physicochemical forces. These protein standards from microparticles provide a reference to measure protein mass sizes from individual cells and a quality control for any biases in device fabrication, cell lysis, protein solubility, protein capture, and protein readouts (i.e. antibody probing).   

Living Bioreactor for Stoichiometric Protein Production

Living bioreactors are powerful systems for producing a variety of valuable compounds. The versatility of such bioreactors is one of the more useful aspects of the system. Large quantities of compounds or cellular components can be produced efficiently, with minimal cost. Alternately, these systems can be used to produce pathway components that are necessary in the production of secondary products. A common problem with such systems is that they are limited by non-uniform production of pathway components, or require an isolation process to ensure the components are in the appropriate quantity and sequence in the process. Inventors at Texas A&M and UC San Francisco have developed a novel technique to address these issues. The technology effectively results in a stoichiometric production of protein components that are produced in an array, ready for secondary production.

Rapid Screening and Identification of Antigenic Components in Tissues and Organs

Researchers at the University of California, Davis have developed an approach to rapidly screen and identify antigenic components in tissues and organs.

Versatile Labeling of Protein N-Termini for Site-specific Bioconjugation

Improved subtiligase variants allow broad and versatile site-specific chemical modification or conjugation of proteins on their N-termini.

Process For Sorting Dispersed Colloidal Structures

Researchers from the Chemistry and Biochemistry department at UCLA have developed method of separating and/or sorting specific target structures from other non-target structures in a complex mixture using custom-made target-specific colloidal particles.

Low Cost Wireless Spirometer Using Acoustic Modulation

The present invention relates to portable Spirometry system that uses sound to transmit pulmonary airflow information to a receiver.

Microfluidic Component Package

The present invention describes a component package that enables a microfluidic device to be fixed to a Printed Circuit Board (PCB) or other substrate, and embedded within a larger microfluidic system.

Improved Cell-Free Protein Synthesis For Protein Microarray

Researchers at UC Irvine have developed a cell-free (CF) protein synthesis system to solubilize and synthesize highly hydrophobic membrane proteins that would typically aggregate using current CF synthesis systems. With such high amounts of synthesized proteins, researchers intend to build protein microarrays for diagnostic purposes.

Enhanced Cell/Bead Encapsulation Via Acoustic Focusing

The invention consists of a multi-channel, droplet-generating microfluidic device with a strategically placed feature.The feature vibrates in order to counteract particle-trapping micro-vortices formed within the device.Counteracting these vortices allows for single particle encapsulation in the droplets formed by the device and thereby makes this technology a good candidate for use in single cell diagnostics and drug delivery systems.

Mesenchymal Stem Cell Derived Exosomes for Treating Peripheral Artery Disease

Researchers at the University of California, Davis have developed a method to isolate exosomes from mesenchymal stem cells that contain signaling molecules that induce angiogenesis. The isolated exosomes can be used for treating peripheral arterial disease.

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