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A New Method for Automated Cell Group Classification from Single Cell RNA Sequencing (scRNAseq)

Genomics (transcriptome, epigenome, genome, etc.) conveys the most comprehensive information of biological systems and cellular entities. Therefore, it is being increasingly used in research and clinics to classify cells from various developmental origin and functional background to aid scientific discover and medical practice. Especially at single cell level, genomic information has the potential to impact treatment options and medical outcome. However, classifying cells by current methods involves a lengthy bioinformatic analysis procedure that requires expertise not only in biology and medicine but in computer science as well, making it a daunting task for many researchers and clinicians, despite the tremendous healthcare value that single cell genomics provides. Thus, a simple and universally applicable approach will facilitate precision medicine and scientific research.

Methods and Applications for Controlling Cellular Viability Using Fluoride-Sensitivity

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

Efficient Production of Cellulase Enzymes Using Transient Agroinfiltration

Researchers at the University of California, Davis have developed a method to produce cellulase enzymes by utilizing a simple agroinfiltration process to transiently express full length cellulases in plant tissue.

Fusion Proteins and Fusion Ribonucleic Acids for Tracking and Manipulating Cellular RNA

There are currently no consolidated systems that can both upregulate and downregulate the translation of specific messenger RNA (mRNA) targets. Known methods to achieve targeted downregulation include anti-sense oligonucleotides (ASO) and short interfering RNAs (siRNA). However, both of these technologies function to destabilize a messenger RNA target and downregulate translation, rather than upregulate translation. There are few known methods to increase mRNA translation and these methods are not well characterized. As such, there is a need to provide compositions and methods for recruiting translational pre-initation complexes in trans and thereby control translation in cells and in gene therapy techniques. Currently, there are no consolidated systems that can both upregulate and downregulate the translation of specific messenger RNA targets.

Modulation Of Engineered Immune Cell Receptor Translation Using Noncoding Sequence Elements

It would be beneficial to control the expression of engineered immune cell receptors for use in cell-based cancer immunotherapy, known as adoptive cell therapy (ACT), or in other cell-based therapies using engineered regulatory T cells (engineered Tregs) to treat immune dysfunction such as autoimmunity or organ transplant rejection. In these therapies, immune cells such as T cells or natural killer (NK) cells are genetically modified to express an engineered cell surface receptor that directs these immune cells to tumor cells or specific tissues expressing a target ligand recognized by the receptor, thereby leading to tumor cell destruction (ACT) or moderated immune reaction (engineered Tregs). However, it has been found that ACT can suffer from severe toxic side effects due to overactivation of engineered immune cells used in ACT such as CAR T-cells, due to signaling by the engineered cell surface receptor. Conversely, overactive immune cells can become exhausted and lose efficacy over time. Present attempts to regulate CAR expression do not account for control exerted at the level of protein synthesis. It would therefore be useful to be able to tune the activity of immune cells engineered for ACT or for treatment of immune dysfunction, by either increasing or decreasing the protein synthesis of the engineered immune cell surface receptor, i.e. the engineered TCR or CAR. This research describes compositions and methods for selectively increasing or decreasing the protein synthesis of engineered immune cell surface receptors using noncoding sequences in the 3’-untranslated region (3’-UTR) of messenger RNAs (mRNAs) encoding the engineered TCRs or CARs. These 3’-UTR sequences are sensitive to regulation by translation initiation factor eIF3 and can be used to modulate the strength and time duration of TCR or CAR protein synthesis.  

Improved Plant Regeneration Method Using GRFs, GIFs or Chimeric GRF-GIF Proteins

Researchers at the University of California, Davis and the Institute of Molecular and Cellular Biology of Rosario in Argentina have collaborated to develop methods for improving plant regeneration efficiency using transformations via a GRF, a GIF, or a GRF-GIF chimera. 

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.

Automated Drosophila Maintenance System

Drosophila spp., also known as fruit flies, are widely used in genetic research. Drosophila lines (e.g. flies with a particular mutation) can only be stored as live animals – they cannot be frozen and remain viable. So to maintain the stocks, the live flies are manually transferred from an old vial to a new vial on a regular basis (every 1-2 weeks). Some Drosophila labs maintain hundreds or even thousands of individual lines and so maintenance of these lines can be very time consuming. A UC Santa Cruz Drosophila researcher has developed a simpler and more efficient method of transferring the flies that requires significantly less hands-on work.

Identification Of Pan-Cancer Small Cell Neuroendocrine Phenotypes And Vulnerabilities

UCLA researchers in the Department of Molecular and Medical Pharmacology have developed a classifier for the identification and treatment of small cell neuroendocrine cancers and small-round-blue cell tumors not previously identified.

DNA Methylation Measurement For Mammals Based On Conserved Loci

UCLA researchers in the Departments of Human Genetics and Biological Chemistry have developed a new approach for measuring DNA methylation levels in mammals based on short and highly conserved nucleotide sequences.  This method facilitates the development of chip for measuring DNA methylation that can be used for cross-species comparisons and used for building universal epigenetic aging clocks (age estimators) that apply to all mammals.

Augmentations to Lentiviral Vectors to Increase Expression

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

Optimized Lentiviral Vector for Stem Cell Gene Therapy of Hemoglobinopathies

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

Technologies that can be Used to Selectively Bind Messenger RNA and Enhance Protein Translation

Control of gene expression is a general approach to treat diseases where there is too much or too little of a gene product. However, while there are many methods which are available to downregulate the expression of messenger RNA transcripts, very few strategies can upregulate the endogenous gene product. The vast majority of gene regulatory drugs which are commercially available or being developed are designed to knockdown gene expression (i.e. siRNAs, miRNAs, anti-sense, etc.). There exist some methods to enhance gene expression, such as the delivery of messenger RNAs; although, therapeutic delivery of such large and charged RNA molecules is technically challenging, inefficient, and may not be practical. There are also classical gene therapy approaches where a gene product is delivered as viral-encoded products (AAV or lentivirus-packaged). However, these methods suffer from not being able to accurately reproduce the correct alternatively spliced isoforms in the right ratios in cells.  

Generation Of Minimal Enhancer Elements Using Massively Parallel Reporter Assays

UCLA researchers in the Department of Microbiology, Immunology and Molecular Genetics have developed a novel method to produce short lentiviral vectors with tissue-specific expression, with a primary focus on lentiviral vectors for treating sickle cell disease and other disorders of hemoglobin.

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.

Method To Implement A Crispr-Cas9 Copycat Gene Drive In Rodents

Currently, alleles at multiple loci in the mouse genome must be combined by Mendelian genetics in crosses of animals to one another to produce a desired compound mutant genotype. For example, to combine homozygous mutations at two loci, animals that are heterozygous for each gene must be produced by breeding, and these are subsequently crossed to one another. Since the frequency of homozygosity for each allele is 1:4 the frequency of homozygosity for both genes is 1:16. Since the average litter of mice is approximately 10 pups, and the generation time from conception to reproductive age is about 3 months, this requires a substantial number of animals and time. With the addition of each new locus (three, four, etc), the cost measured in animals, time, and money increases exponentially. These factors increase substantially more if two or more loci are genetically linked, which requires rare recombination events to combine engineered alleles on the same chromosome. The CRISPR-Cas9 gene drive system stands to revolutionize rodent breeding. If each desired allele is encoded as a gene drive element that contains an sgRNA designed to target the same genomic location in the wild type homologous chromosome, each locus will be “driven” to homozygosity in the presence of Cas9. Therefore, in order to combine three alleles, for example, a mouse with one gene drive element (A) would be crossed to a mouse that encodes Cas9. Offspring of this cross would then be crossed to mice carrying gene drive element B, and these offspring would be crossed to mice carrying gene drive element C. In the presence of Cas9 at each generation, these gene drive elements at three distinct loci will be converted to homozygosity such that 50% of offspring, those that inherit Cas9, will be triple homozygous after three generations, even if they are genetically linked loci. A CRISPR-Cas9 mediated gene drive leverages the native cellular mechanism of homology directed repair to copy a desired allele from one chromosome to another. This process can convert a heterozygous genotype to homozygosity in a single generation. While CRISPR-Cas9 gene drives have been implemented in two species of insects, flies and mosquitos, it has not been reported in any non-insect animal species. 

Biotinylated Ligand-Directed Targeting Lentiviral Vectors

UCLA researchers in the Department of Medicine have developed a novel method to conjugate targeting ligands on lentiviral vectors.  The method allows for selective transduction of mammalian cells types avoiding non-target organs.

4D-seq: Single Cell RNA-sequencing with in situ Spatiotemporal Information

To develop a novel imaging-based single cell RNA-sequencing (scRNA-Seq) platform that allows capturing of spatiotemporal information and cellular behavior of the sequenced cells within tissue.

DARTS: Deep Learning Augmented RNA-seq Analysis of Transcript Splicing

Researchers led by Yi Xing have developed a novel deep learning algorithm to detect alternative splicing patterns in RNA-seq data

Illumination Device for Dynamic Spatiotemporal Control of Photostimulation

A programmable LED device that illuminates multiple spatial locations (termed wells) with user-defined light patterns whose intensity can be modulated as a function of space and time. The devices are used for optogenetic stimulation of tissue culture plates (24-well and 96-well) kept in a heated and humidified tissue culture incubator, as well as photopatterning of hydrogels. In brief, light from LEDs passes through optical elements that ensure uniform illumination of each well. Parameters of the optical system, such as LED configuration, optical diffuser elements, materials, and geometry, were modeled and optimized using the optical ray tracing software Zemax OpticStudio. An electronics subsystem allows programmed control of illumination intensity and temporal sequences, with independent control of each well. Spatial precision is conveyed through a photomask attached to the culture plate. The hardware design also includes a cooling system and vibration isolation to reduce heating and damage to the sample. Lastly, a graphical user interface (GUI) was used to wirelessly program the illumination intensity and temporal sequences for each well. The devices can thus illuminate 24 independent channels with visible, NIR, or UV light with intensity ranges of 0 to 20-100 microwatts per millimeter-squared with 16-bit intensity resolution, and a temporal resolution of 1 millisecond and spatial resolution of 100 microns. In summary, the device allows uniform illumination of multiple wells for multiplexed photoactivation or photopolymerization of various substrates (light-responsive bacterial or mammalian cells grown in tissue culture, hydrogels, dyes, etc) with user-defined patterns. The device can be combined with a robotic handler, microscope, spectrometer, etc, to enable high-throughput illumination and simultaneous recording of the sample.

Haploid-Induction in CRISPR Susceptible Plants

Researchers at the University of California, Davis have developed a method to produce haploid progeny plants from transgenic and wild-type plants that only carry chromosomes from the wild-type gamete.

Method to Direct the Reciprocal Interactions Between the Ureteric Bud and the Metanephric Mesenchyme

Researchers at UCLA have developed an approach to construct an embryonic kidney in vitro for the treatment of end stage renal disease.

A Codon-Optimized Lentiviral Vector For Stem Cell Reprogramming

UCLA researchers in the Department of Medicine and the Department of Surgery have developed a novel lentiviral vector that expresses a codon-optimized sequence of a T cell receptor (TCR) specific for the cancer-testis antigen NY-ESO-1 as well as a positron emission tomography (PET) reporter and suicide gene HSV1-sr39tk for use in adoptive T cell therapy for cancer treatment.

High Throughput Digital Cell Quantification Of Immune Cell Subsets Via Epigenetic Markers

UCLA researchers in the Department of Molecular, Cell, and Developmental Biology have developed a novel high-throughput method for the quantification of immune cell subtype.

Promoting Homologous Recombination In Plants By Targeted cNHEJ Suppression

UCLA researchers in the Department of Molecular, Cell, and Developmental Biology have developed a method to specifically suppress the highly efficient non-homologous end joining (NHEJ) pathway to boost homologous recombination efficiency in plants.

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