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Programmable System that Mixes Large Numbers of Small Volume, High-Viscosity, Fluid Samples Simultaneously

Researchers at the University of California, Davis have developed a programmable machine that shakes and repeatedly inverts large numbers of small containers - such as vials and flasks – in order to mix high-viscosity fluids.

(SD2021-057) Electro-optical mechanically flexible microprobes for minimally invasive interfacing with intrinsic neural circuits

Microelectrodes are the gold standard for measuring the activity of individual neurons at high temporal resolution in any nervous system region and central to defining the role of neural circuits in controlling behavior.Microelectrode technologies such as the Utah or Michigan arrays, have allowed tracking of distributed neural activity with millisecond precision. However, their large footprint and rigidity lead to tissue damage and inflammation that hamper long-term recordings. State of the art Neuropixel and carbon fiber probes have improved on these previous devices by increasing electrode density and reducing probe dimensions and rigidity.Although these probes have advanced the field of recordings, next-generation devices should enable targeted stimulation in addition to colocalized electrical recordings. Optogenetic techniques enable high-speed modulation of cellular activity through targeted expression and activation of light-sensitive opsins. However, given the strong light scattering and high absorption properties of neural tissue optogenetic interfacing with deep neural circuits typically requires the implantation of large-diameter rigid fibers, which can make this approach more invasive than its electrical counterpart.Approaches to integrating optical and electrical modalities have ranged from adding fiber optics to existing Utah arrays to the Optetrode or other integrated electro-optical coaxial structures. These technologies have shown great promise for simultaneous electrical recordings and optical stimulation in vivo. However, the need to reduce the device footprint to minimize immune responses for long-term recordings is still present.

(SD2020-497) Light-activated tetrazines enable live-cell spatiotemporal control of bioorthogonal reactions

Bioorthogonal ligations encompass coupling chemistries that have considerable utility in living systems. Among the numerous bioorthogonal chemistries described to date, cycloaddition reactions between tetrazines and strained dienophiles are widely used in proteome, lipid, and glycan labeling due to their extremely rapid kinetics. In addition, a variety of functional groups can be released after the cycloaddition reaction, and drug delivery triggered by in vivo tetrazine ligation is in human phase I clinical trials. While applications of tetrazine ligations are growing in academia and industry, it has so far not been possible to control this chemistry to achieve the high degrees of spatial and temporal precision necessary for modifying mammalian cells with single-cell resolution.

2-D Polymer-Based Device for Serial X-Ray Crystallography

Researchers at the University of California, Davis have developed a single-use chip for the identification of protein crystals using X-ray based instruments.

One-Pot Multienzyme Synthesis of Sialidase Reagents, Probes and Inhibitors

Researchers at the University of California, Davis, have developed an environmentally friendly one-pot multienzyme (OPME) method for synthesizing sialidase reagents, probes, and inhibitors.

Optimized Virus-like Particles for Cas9 RNPs & Transgene/HDR Template Delivery

The inventors have developed optimized methods for using virus-like particles for the co-delivery of Cas9 ribonucleoprotein complexes and: a lentiviral genome that encodes a large transgene, such as a chimeric angtigen receptor (CAR) transgene a lentiviral genome that does not encode a sgRNA expression cassette a method for nucleofecting VLPs + homology directed repair (HDR) donor template together to enhance HDR in treated cells  

Directed Pseudouridylation Of Cellular Rna Via Delivery Of Crispr/Cas And Esgrna Guide Combinations

resent strategies aimed to target and manipulate RNA in living cells mainly rely on the use of antisense oligonucleotides (ASO) or engineered RNA binding proteins (RBP). Although ASO therapies have been shown great promise in eliminating pathogenic transcripts or modulating RBP binding, they are synthetic in construction and thus cannot be encoded within DNA. This complicates potential gene therapy strategies, which would rely on regular administration of ASOs throughout the lifetime of the patient. Furthermore, they are incapable of modulating the genetic sequence of RNA. Although engineered RBPs such as PUF proteins can be designed to recognize target transcripts and fused to RNA modifying effectors to allow for specific recognition and manipulation, these constructs require extensive protein engineering for each target and may prove to be laborious and costly. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;}

MODULATORS OF TYPE VI-D CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF

UC researchers have discovered anti-CRISPR (Acr) polypeptides that inhibit activity of a CRISPR-Cas effector polypeptide, for example, Type VI-D CRISPR-Cas effector polypeptides, nucleic acids encoding the Acr polypeptides, and systems and kits comprising the polypeptides and/or nucleic acids encoding the Acr polypeptides. The inhibitor is a small protein from a phage and is capable of strongly inhibiting gene editing in human cells.

XYZeq – Spatially-Resolved Single Cell Sequencing

Researchers at UCSF have developed XYZeq, a method for coupling a cell’s spatial location with single-cell sequencing. Single-cell genomic techniques have emerged as powerful approaches to further our understanding of disease states and cellular heterogeneity. Single-cell imaging methods gain spatial information, but lack throughput and detailed transcriptomic information. Current single-cell sequencing approaches require dissociation of cells during preparation, as a result cannot record a cell’s physical location. UCSF researchers eliminate this step using XYZeq, a new scRNA-seq process that incorporates the benefits of single-cell imaging techniques with single-cell sequencing, without an imaging step. XYZeq simultaneously discerns the location and gene expression of a single cell residing within a complex tissue microenvironment. The technology has been validated in a laboratory setting.

Targeted Identification Of Rna Bases That Hydrogen Bond With Protein

Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:8.0pt; mso-para-margin-left:0in; line-height:107%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri",sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:"Times New Roman"; mso-bidi-theme-font:minor-bidi;} RNA binding proteins are increasingly implicated in genetic and somatic diseases.  Higher resolution methods to identify their RNA targets and how the proteins may interact with specific bases within them are needed to develop drugs that interfere with the regulation or misregulation of RBPs via their binding sites.

Engineered/Variant Hyperactive CRISPR CasPhi Enzymes And Methods Of Use Thereof

The CRISPR-Cas system is now understood to confer bacteria and archaea with acquired immunity against phage and viruses. CRISPR-Cas systems consist of Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a CRISPR array, which includes direct repeats flanking short spacer sequences that guide Cas proteins to their targets.  Class 2 CRISPR-Cas are streamlined versions in which a single Cas protein bound to RNA is responsible for binding to and cleavage of a targeted sequence. The programmable nature of these minimal systems has facilitated their use as a versatile technology that is revolutionizing the field of genome manipulation.  There is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).     UC Berkeley researchers discovered a new type of CasPhi/12j protein.  Site-specific binding and/or cleavage of a target nucleic acid (e.g., genomic DNA, ds DNA, RNA, etc.) can occur at locations (e.g., target sequence of a target locus) determined by base-pairing complementarity between the Cas12 guide RNA (the guide sequence of the Cas12 guide RNA) and the target nucleic acid.  Similar to CRISPR Cas9, the compact Cas12 enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.  

High-yielding Extraction of Single-Stranded Nucleic Acids with Carbon Nanotubes

PCR amplification is widely used in basic biological research and medical diagnostic tests for various infectious diseases, and is a powerful tool for nucleic acid detection. Nucleic acid extraction is an important part of the overall workflow in PCR-based viral infection test, since its function is to separate out viral nucleic acid from the many other biological components in a nasal swab-derived sample. UC Berkeley researchers have developed a method for single-stranded nucleic acid extraction from complex biofluids with DNA-wrapped carbon nanotubes. Large viral single-stranded nucleic acids can be captured by corresponding DNA-wrapped carbon nanotubes and can be concentrated for subsequent polymerase chain reaction (PCR) amplification. This method can extract nucleic acids without complicated manufacturing and experimental processes, can generate higher extraction yields than a conventional commercial PCR kit, and fits into the current PCR workflow while requiring minimal chemical reagents.  

Improved guide RNA and Protein Design for CasX-based Gene Editing Platform

The inventors have developed two new CasX gene-editing platforms (DpbCasXv2 and PlmCasXv2) through rationale structural engineering of the CasX protein and gRNA, which yield improved in vitro and in vivo behaviors. These platforms dramatically increase DNA cleavage activity and can be used as the basis for further improving CasX tools.The RNA-guided CRISPR-associated (Cas) protein CasX has been reported as a fundamentally distinct, RNA-guided platform compared to Cas9 and Cpf1. Structural studies revealed structural differences within the nucleotide-binding loops of CasX, with a compact protein size less than 1,000 amino acids, and guide RNA (gRNA) scaffold stem. These structural differences affect the active ternary complex assembly, leading to different in vivo and in vitro behaviors of these two enzymes.

A Broadly Neutralizing Molecule Against Clostridium Difficile Toxin B

Researchers at UCI have developed a family of recombinant protein therapeutics against Clostridium difficile designed to provide broad-spectrum protection and neutralization against all isoforms of its main toxin, TcdB. These antitoxin molecules feature fragments of TcdB’s human receptors which compete for TcdB binding, significantly improving upon existing antibody therapeutics for Clostridium difficile infections.

Rapid Generation Of A Droplet Compound Library

The present invention features a device for rapidly formatting a chemical compound library into microfluidic droplets, addressing the challenge of interfacing between the macroscale and the microscale regimes of the production of reagent libraries of chemical compounds.

Method And Device For Patterning Cells At Defined Interface

The present invention features a method and device that addresses the need for a low-cost and easy-to-use method and device to pattern a sharp interface between two or more cell populations or, more generally, two or more coatings wherein their interfacing properties are of interest. As a result, the present invention enables new types of experiments that analyze cell-cell interactions and the study of tissue biology in general. 

High Efficiency Single Cell Indexing Of Droplets Via Interfacial Shearing With Downstream Droplet Sorting

The invention is an integrated device that provides a high efficiency single cell encapsulation solution. The two core modules of the invention are responsible for generating the cell encapsulating droplet, then sorting the generated droplets to eliminate the empty ones. Such a two-step process yields a high throughput, single cell indexed droplets, with an overall encapsulation efficiency reaching 80%, which is crucial for various applications ranging from genomics and proteomics to pharmacology.

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-VariPhi”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasVariPhi) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

3D-Bioprinted All-Inclusive Bioanalytical Platforms for Cell Studies

Common drug screen models, such as animals and 2D cell cultures, do not properly recapitulate human organ structure and environment. Using 3D bioprinting technology, researchers at UCI have developed all-inclusive customized organ-on-a-chip-like platforms. These platforms produce cell models that properly mimic the microenvironment of cells for drug screening and cell-therapeutic response studies.

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-Omega”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasOmega) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (“Cas-Theta”)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of proteins (CasTheta) that utilize a guide RNA to perform RNA-directed cleavage of nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. 

CRISPR-CAS EFFECTOR POLYPEPTIDES AND METHODS OF USE THEREOF (CasGamma)

CRISPR-Cas systems include Cas proteins, which are involved in acquisition, targeting and cleavage of foreign DNA or RNA, and a guide RNA(s), which includes a segment that binds Cas proteins and a segment that binds to a target nucleic acid. For example, Class 2 CRISPR-Cas systems comprise a single Cas protein bound to a guide RNA, where the Cas protein binds to and cleaves a targeted nucleic acid. The programmable nature of these systems has facilitated their use as a versatile technology for use in modification of target nucleic acid.   UC Berkeley researchers have discovered a novel family of compact proteins (CasGamma) with a RuvC-like domain in the C-terminal end of the protein. These proteins are able to cleave nucleic acids. Viral and microbial (cellular) genomes were assembled from a variety of environmental and animal microbiome sources, and variants of a novel and previously unknown Cas protein family were uncovered from the sequences decoded. These CasGamma proteins utilize a guide RNA to perform RNA-directed cleavage of nucleic acids.  

Mapping Ciliary Activity Using Phase Resolved Spectrally Encoded Interferometric Microscopy

Researchers at UCI have developed an imaging technique that can monitor and measure small mobile structures called cilia in our airways and in the oviduct. This invention will serve as a stepping stone for study of respiratory diseases, oviduct ciliary colonoscopy and future clinical translations.

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