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Class 2 CRISPR/Cas COMPOSITIONS AND METHODS OF USE

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} 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 systems 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, so there is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).   Researchers have shown that Class 2 CRISPR Cas protein and their variants can be used in a complex for specific binding and cleavage of DNA. The Class 2 CRISPR Cas complex utilizes a novel RNA and a guide RNA to perform double stranded cleavage of DNA and the complex is expected to have a wide variety of applications in genome editing and nucleic acid manipulation. 

CRISPR CASY COMPOSITIONS AND METHODS OF USE

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} 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 systems 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, so there is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).   Previously UC Berkeley researchers discovered a new type of Cas protein, CasY (also referred to as Cas 12d protein).  CasY is short compared to previously identified CRISPR-Cas endonucleases, and thus use of this protein as an alternative provides the advantage that the nucleotide sequence encoding the protein is relatively short.  CasY utilizes a guide RNA to perform double stranded cleavage of DNA. The researchers introduced CRISPR-CasY into E. coli, finding that they could block genetic material introduced into the cell.  Further research results indicated that CRISPR-CasY operates in a manner analogous to CRISPR-Cas9, but utilizing an entirely distinct protein architecture containing different catalytic domains.   CasY is also expected to function under different conditions (e.g., temperature) given the environment of the organisms that CasY was expressed in.  Similar to CRISPR Cas9, CasY enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation. Recent studies have shown that the CasY complex utilizes a novel RNA, in addition to the guide RNA, to perform double stranded cleavage of DNA. Similar to CRISPR Cas9, CasY enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.   

Cas12c/C2C3 Compositions and Methods of Use

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} 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 systems 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, so there is a need in the art for additional Class 2 CRISPR/Cas systems (e.g., Cas protein plus guide RNA combinations).   Researchers have shown that a Cas12c protein (also referred to as a Cas12c polypeptide or a C2c3 polypeptide) complex as well as Cas12c variants can be used for specific binding and cleavage of DNA. The Cas12c complex utilizes a novel RNA and a guide RNA to perform double stranded cleavage of DNA. Similar to CRISPR Cas9, Cas12c enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.   

Methods and Compositions for Selective Testing of Mammalian Proteomics From Mixed Biological Environments

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} Studies of heterochronic parabiosis (surgical joining of young and old animals) suggest both productive tissue repair and the key signal transduction pathways that control stem cell activation are restored to ‘youth’ in the old parabionts by young systemic factors.  It would be beneficial from academic and clinical stand-points to determine which proteins in tissues of parabiotically connected animals are derived from the circulation of young versus old partner. Such a database of systemic proteins that end up in specific tissues would suggest potentially rejuvenating (young blood) and inhibitory (old blood) molecules with direct effects in a given tissue. While biochemical fractionation of serum and plasma can provide some characterization of the molecular differences between young and old circulatory milieu, this technique is fraught with the risk of missing proteins that act in complexes with each other and other macromolecules. UC Berkeley researchers have discovered methods and compositions that overcome these problems by relying on tRNA synthase that specifically recognizes and incorporates Bio-Orthogonal Non-Canonical Amino acid Tagging (“BONCAT”) into proteins. To facilitate detection by proteomics, we have selected the BONCAT method over the cell type-specific labeling with amino acid precursors where proteomes are tagged with heavy isotope—labeled precursors; and over the incorporation of Met analogs azidohomoalanine and homopropargylglycine, which do not allow one to selectively profile young versus old proteomes in settings of parabiosis. The researchers have also developed a novel transgenic mouse strain which demonstrate the survival and vigor of these animals as well as the effective proteome labeling of cells in vitro and all examined tissues in vivo.

THERMOSTABLE RNA-GUIDED ENDONUCLEASES AND METHODS OF USE THEREOF (GeoCas9)

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} 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. The programmable nature of these 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 CRISPR-Cas systems with improved cleavage and manipulation under a variety of conditions and ones that are particularly thermostable under those conditions.     UC researchers discovered a new type of RNA-guided endonuclease (GeoCas9) and variants of GeoCas9.  GeoCas9 was found to be stable and enzymatically active in a temperature range of from 15°C to 75°C and has extended lifetime in human plasma.  With evidence that GeoCas9 maintains cleavage activity at mesophilic temperatures, the ability of GeoCas9 to edit mammalian genomes was then assessed.  The researchers found that when comparing the editing efficiency for both GeoCas9 and SpyCas9, similar editing efficiencies by both proteins were observed, demonstrating that GeoCas9 is an effective alternative to SpyCas9 for genome editing in mammalian cells.  Similar to CRISPR-Cas9, GeoCas9 enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.   

Xanthene-Based Dyes For Voltage Imaging

Rapid changes in the membrane potential of excitable cells (e.g., neurons and cardiomyocytes) play a central role in defining the cellular signaling and physiological profiles of these specialized cells. Typically, the membrane potential is monitored and measured via patch clamp electrophysiology, which involves the use of a micro-electrode attached to or near the cell of interests.  Unfortunately, the use of an electrode is highly invasive, limits records to the soma of a single cell and is extremely low throughput. Researchers at the University of California, Berkeley have designed and synthesized a voltage sensitive indicator that can provide excitation and emission profiles greater than 700 nm, and as such, represents an important method for visualizing membrane potential in living cells.

Au(III) Complexes For [18F] Trifluoromethylation

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} The biological properties of trifluoromethyl compounds (e.g, CF3) have led to their ubiquity in pharmaceuticals, yet their chemical properties have made their preparation a substantial challenge, necessitating innovative chemical solutions.  For example, strong, non-interacting C-F bonds lend metabolic stability while simultaneously limiting the ability of chemical transformations to forge the relevant linkages and install the CF3 unit.  When these same synthetic considerations are extended toward the synthesis of trifluoromethylated positron emission tomography (PET) tracers, the situation becomes more complex.   UC Berkeley researchers discovered an unusual alternative mechanism, in which borane abstracts fluoride from the CF3 group in a gold complex. The activated CF2 fragment can then bond to a wide variety of other carbon substituents added to the same gold center. Return of the fluoride liberates a trifluoromethylated compound from the metal. This mechanism would be useful for the introduction of radioactive fluoride substituents for potential tracers to be used for positron emission tomography applications.

Monolithically Integrated Implantable Flexible Antenna for Electrocorticography and Related Biotelemetry Devices

A sub-skin-depth (nanoscale metallization) thin film antenna is shown that is monolithically integrated with an array of neural recording electrodes on a flexible polymer substrate. The structure is intended for long-term biometric data and power transfer such as electrocorticographic neural recording in a wireless brain-machine interface system. The system includes a microfabricated thin-film electrode array and a loop antenna patterned in the same microfabrication process, on the same or on separate conductor layers designed to be bonded to an ultra-low power ASIC.

Configurations for Integrated MRI-linear Accelerators

Researchers at Stanford and University of California, Berkeley, have developed an integrated MRI-Linac hybrid system that can increase the efficacy of image-guided radiotherapy (IGRT). This system allows more aggressive treatment strategies that employ dose escalation, tighter geometric margins and sharper dose gradients which can improve clinical outcomes. This radiotherapy treatment apparatus includes a treatment beam (charged by Linac, particle, proton, or electron beam), a magnetic field disposed parallel collinear to the treatment beam, and a target that is disposed along the treatment beam. MRI is ideal for IGRT, however, there is magnetic field and RF interference between the linear accelerator and MRI scanner. The configurations of this system overcome this issue.

Contraceptive Compounds

Steroid hormones regulate human physiology and cellular metabolism by either slowly changing gene expression, or by a binding to a plasma membrane receptor, which leads to the activation of ion channels. The latter represents a fast signaling event that plays role in sperm activation or insulin secretion. For example, the female hormone progesterone (P4) activates the principal calcium channel of sperm (CatSper) via this fast pathway. By testing different steroids and steroid-like molecules, UC Berkeley researchers discovered that pregnenolone sulfate (PS), a sulfated steroid hormone similar in structure to P4, is another steroid hormone that can activate CatSper in human spermatozoa. In addition, the researchers discovered two specific and nontoxic compounds found in plants that antagonize physiological function of P4 and PS, and prevent spermatozoa from reaching full fertilizing potential. These compounds can serve as contraceptives since they reduced the number of hyperactive spermatozoa, thus preventing sperm from reaching and fertilizing an egg.  

Sensitive Detection Of Chemical Species Using A Bacterial Display Sandwich Assay

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Endocrine disrupting compounds are found in increasing amounts in our environment, originating from pesticides, plasticizers, and pharmaceuticals, among other sources. These compounds have been implicated in diseases such as obesity, diabetes, and cancer. The list of chemicals that disrupt normal hormone function is growing at an alarming rate, making it crucially important to find sources of contamination and identify new compounds that display this ability. However, there is currently no broad-spectrum, rapid test for these compounds, as they are difficult to monitor because of their high potency and chemical dissimilarity.   To address this, UC Berkeley researchers have developed a new detection system and method for the sensitive detection of trace compounds using electrochemical methods.  This platform is both fast and portable, and it requires no specialized skills to perform. This system enables both the detection of many detrimental compounds and signal amplification from impedance measurements due to the binding of bacteria to a modified electrode. The researchers were able to test the system finding sub-ppb levels of estradiol and ppm levels of bisphenol A in complex solutions. This approach should be broadly applicable to the detection of chemically diverse classes of compounds that bind to a single receptor.  

Sparse 3D Holographic Spatio-Temporal Focusing

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Several techniques are available to trigger neural activity in brain tissue on demand which are needed to study how the brain exchanges and processes information, which is useful in research and treatment applications.  The most promising solutions are all optical. Brain cells are modified with bio-compatible engineered proteins making ion-specific channels located at the neurons' cell membrane photosensitive. At this point, external triggering of action-potentials with light becomes possible.  What is needed are instruments and methods that provide specificity, improve spatial and temporal resolution, are non-invasive and bio-compatible, provide high speed and low delay, have large operating volumes.   UC Berkeley researchers have developed a new system and methods that meet the above qualities.  This new technology enables all-optical activation of individual neurons in live brain tissue and can narrowly concentrate light on individual neurons anywhere within a large 3D volume. The invention enables precise triggering of action-potentials with single neuron spatial resolution in the entire volume of interest, offering a significant improvement over existing technology.  The technology can be used as an add-on system in the optical path in a commercial microscope.  

Heterochronic Blood Exchange As A Modality To Influence Myogenesis, Neurogenesis, And Liver Regeneration

One reason for waning capabilities with advancing age is a progressive decline in organ function. Heterochronic parabiosis rejuvenates the performance of old tissues' stem cells at some expense to the young, but whether this is through shared circulatory factors or shared organ systems is unclear; and parabiosis is not a clinically adaptable approach. The old heterochronic partners have access to young organs, environmental enrichment and youthful hormones/pheromones, while the young parabiont maintains an additional aged body with deteriorating organs. In contrast to the permanent anastomosis of parabiosis, UC Berkeley researchers have used a small animal blood exchange where animals are connected and disconnected at will, removing the influence of shared organs, adaptation to being joined, etc. The effects of heterochronic blood exchange were examined with respect to all three germ layer derivatives: injured-regenerating muscle, ongoing liver cell proliferation and brain - hippocampal neurogenesis, and in the presence and absence of muscle injury.  The influence of heterochronic blood exchange on myogenesis, neurogenesis and hepatogenesis was fast, within a few days.  These findngs suggest a rapid translation of blood apheresis (FDA approved for other diseases, but not for the degenerative pathologies) for therapy to attenuate and reverse liver fibrosis and adiposity, muscle wasting and neuro-degeneration.  

Mechano-Nps (Node Pore Sensing)

The mechanical properties of cells derive from the structure and dynamics of their intracellular components, including the cytoskeleton, cell membrane, nucleus, and other organelles.  These, in turn, emerge from cell specific genetic, epigenetic, and biochemical programs, providing a link between cellular mechanics and the underlying molecular state.  Differences in mechanical properties reflect on cellular properties with clinical implications, including the metastatic potential, cell-cycle stage, and differentiation state of cells.  Yet, many mechanical aspects of various cells and sub-cell organelles remain unknown due to absence of appropriate analysis platforms. Atomic-force microscopy (AFM) and micropipette aspiration are the gold standards for performing mechanical measurements of cells, as they both provide controlled loading conditions and quantify such cellular properties as elastic modulus and cortical tension.  They are, however, burdened by slow throughput, capable of analyzing only just a few cells/hr.  Likewise, optical tweezers and microplate rheometry also suffer from low throughput.  Various microfluidic based platforms have been proposed for the high-throughput mechanical analysis of cells, including hydrodynamic stretching cytometry, suspended microchannel resonators (SMR), and real-time deformability cytometry (RT-DC).  Although each of these methods can analyze populations of cells in a relatively short time, they focus only on a single cellular property.  Consequently, these platforms, and the low-throughput traditional methods that under-sample, can neither identify cellular heterogeneity nor classify mechanical sub-phenotypes within a population. Investigators at UC Berkeley have developed a microfluidic platform, “mechano-node-pore sensing” (mechano-NPS), a rapid and multi-parametric cell screening platform, that simultaneously quantifies cell diameter, transit time through a contraction channel, transverse deformation under constant strain, and recovery time after deformation.  This platform efficiently reveals malignant-dependent mechanical phenotypes of cancer and normal epithelial cells, discriminates between sub-lineages of cells with accuracy comparable to flow cytometry, and determines the effects of chronological age and malignant progression on cell elasticity and recovery from deformation – based solely on a cell’s mechanical properties.

Voltage-Sensitive Dyes In Living Cells

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Comprehensively mapping and recording the electrical inputs and outputs of multiple neurons simultaneously with cellular spatial resolution and millisecond time resolution remains an outstanding challenge in the field of neurobiology. Traditionally, electrophysiology is used to directly measure membrane potential changes. While this technique yields sensitive results, it is invasive and only permits single-cell recording.  VoltageFluor dyes rely on photoinduced electron transfer to effectively report membrane potential changes in cells. This approach allows for fast, sensitive and non-invasive recording of neuronal activity in cultured mammalian neurons and in ex-vivo tissue slices. However, one major limitation of small-molecule dye imaging is the inability to target the dye to specific cells of interest.   UC Berkeley researchers have developed latent voltage sensitive dyes that require a fluorogenic activation step. This new class of VoltageFluor dyes are only weakly fluorescent until being activated in defined cell types via biological processes. In particular, the VoltageFluor dyes described herein comprise a bioreversible group that quenches the fluorescence of the VoltageFluor dye, that upon selective removal by the action of biological processes (e.g., enzymes) thereby activates the fluorescence of the VoltageFluor dye. The researchers found that the new dye facilitated the observation of spontaneous activity in rat hippocampal neurons.  

CARDIAC TISSUE MODELS AND METHODS OF USE THEREOF

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Tissue engineering approaches have the potential to increase the physiologic relevance of human iPS-derived cells, such as cardiomyocytes (iPS-CM). However, forming Engineered Heart Muscle (EHM) typically requires >1 million cells per tissue. Existing miniaturization strategies involve complex approaches not amenable to mass production, limiting the ability to use EHM for iPS-based disease modeling and drug screening. Micro-scale cardiospheres are easily produced, but do not facilitate assembly of elongated muscle or direct force measurements.   UC Berkeley researchers have developed a 3D filamentous fiber matrix that combines features of EHM and cardiospheres: Micro-Heart Muscle (μHM) arrays, in which elongated muscle fibers are formed in an easily fabricated template, with as few as 2,000 iPS-CM per individual tissue. Within μHM, iPS-CM exhibit uniaxial contractility and alignment, robust sarcomere assembly, and reduced variability and hypersensitivity in drug responsiveness, compared to monolayers with the same cellular composition. μHM mounted onto standard force measurement apparatus exhibited a robust Frank-Starling response to external stretch, and a dose-dependent inotropic response to the β-adrenergic agonist isoproterenol.  

Modulation Of Lymphatic Valve And Vessel Formation To Treat Diseases, Such As Trasplant Rejection

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; 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;} Lymphatic Valve formation is associated with lymphangiogenesis, a pathological event that occurs in many diseases after inflammatory, infections, immunogenic or traumatic insults. These valves play critical roles in directing lymph flow inside the lymphatic vessels. The Lymphatic pathway is a primary mediator of immune responses, including transplant rejection. The current regimen of pharmacotherapy with corticosteroids is of limited efficacy and is fraught with serious side effects.   Researchers at the University of California, Berkeley have identified Itga-9 is critically involved in lymphatic valve formation after pathological insults, and itga-9 blockade can reduce the number of lymphatic valves formed inside the pathological lymphatic vessels. Moreover, Itga-9 interference can be used to modulate immune responses and transplant rejection. Additionally, ITga-9 can be used to improve the therapeutic effects of other anti-lymphangiogenic molecules, such as VEGFR-3. When used in combination, the formulation of both valves and lymphatic vessels are greatly suppressed and better therapeutic outcomes can be achieved for severe diseases, such as high-risk transplant rejection.  

Method For Imaging Neurotransmitters In Vitro and In Vivo Using Functionalized Carbon Nanotubes

Neurotransmitters play a central role in complex neural networks by serving as chemical units of neuronal communication.  Quantitative optical methods for the detection of changes in neurotransmitter levels has the potential to profoundly increase our understanding of how the brain works. Therapeutic drugs that target neurotransmitter release are used ubiquitously to treat a vast array of brain and behavioral disorders.  For example, new methods in this sphere could provide a new platform by which to validate the function of drugs that alter modulatory neurotransmission, or to screen antipsychotic and antidepressant drugs.  However, currently in neuroscience, few optical methods exist that can detect neurotransmitters with high spatial and temporal resolution in vitro or in vivo.  Brain tissue also readily scatters visible wavelengths of light currently used to perform biological imaging, and neuronal tissue and has an abundance of biomolecules that are chemically or structurally similar and therefore hard to specifically distinguish.  Furthermore, neurotransmission relevant processes occur at challenging spatial  and temporal scales.    UC Berkeley investigators have developed polymer-functionalized carbon nanotubes for in vitro and in vivo quantification of extracellular modulatory neurotransmitter levels using optical detectors. The method uses the fluorescent optical properties of polymer-functionalized carbon nanotubes to selectively report changes in concentration of specific neurotransmitters. The scheme is novel in that the detection method applies to wide variety of specific neurotransmitters, it is an optical method and therefore gives greater spatial information, and enables the potential for imaging of one or more neurotransmitters. The optical method also produces less damage to the surrounding tissue than methods that implant electrodes or cells and allows high resolution localization with other methods of optical investigation. The invention takes advantage of favorable fluorescence properties of carbon nanotubes, such as carbon nanotube emission in the near infrared and infinite fluorescence lifetime.  The near infrared emission scatters less than shorter wavelengths, enabling greater signal recovery from deeper tissue, and allows greater compatibility with other techniques. The optical properties also enable long term potentially even chronic use. 

Highly Stable Nanoscale Disk Assemblies Of The Tobacco Mosaic Virus For Applications In Drug Delivery And Disease Imaging

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} Self-assembling protein nanomaterials derived from viruses have properties that make them useful for applications in drug delivery, disease imaging and diagnostics. These properties include uniform sizes and shapes, biodegradability, and multiple sets of functional handles for chemical manipulation. Intact virus nanoparticles have been functionalized for applications in drug delivery in vivo, however, the injection of replication-competent viruses into subjects have limited their clinical appeal. The development of spherical and rod-shaped virus nanoparticles has in both cases resulted in differential tumor accumulation, demonstrating the need to further expand the shape library of protein nanomaterials. However, expressing non-spherical virus-based protein nanomaterials without the genetic material that functions as a backbone to the assembly architecture can lead to significant challenges including poly-diversity in size and shape, and change in assembly behavior in response to different conditions such as pH and ionic strength.   UC Berkeley researchers have developed a self-assembling nanoscale disk derived from a mutant of a recombinantly expressed viral coat protein. The disks display highly stable double-disk assembly states. The researchers functionalized the disks with the chemotherapy drug doxorubicin (DOX) and further modified the disks for improved solubility.  The functionalized disks displayed cytotoxic properties similar to those of DOX alone when incubated with U87MG glioblastoma cells, but the unmodified disks did not cause any cytotoxicity.

RNA-directed Cleavage and Modification of DNA using CasY (CRISPR-CasY)

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} 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.  Current CRISPR Cas technologies are based on systems from cultured bacteria, leaving untapped the vast majority of organisms that have not been isolated.  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 Cas protein, CasY.  CasY is short compared to previously identified CRISPR-Cas endonucleases, and thus use of this protein as an alternative provides the advantage that the nucleotide sequence encoding the protein is relatively short.  CasY utilizes a guide RNA to perform double stranded cleavage of DNA. The researchers introduced CRISPR-CasY into E. coli, finding that they could block genetic material introduced into the cell.  Further research results indicated that CRISPR-CasY operates in a manner analogous to CRISPR-Cas9, but utilizing an entirely distinct protein architecture containing different catalytic domains.   CasY is also expected to function under different conditions (e.g., temperature) given the environment of the organisms that CasY was expressed in.  Similar to CRISPR Cas9, CasY enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation.   

RNA-directed Cleavage and Modification of DNA using CasX (CRISPR-CasX)

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} 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.  Current CRISPR Cas technologies are based on systems from cultured bacteria, leaving untapped the vast majority of organisms that have not been isolated.  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 Cas protein, CasX, from groundwater samples. CasX is short compared to previously identified CRISPR-Cas endonucleases, and thus use of this protein as an alternative provides the advantage that the nucleotide sequence encoding the protein is relatively short.  CasX utilizes a tracrRNA and a guide RNA to perform double stranded cleavage of DNA. The researchers introduced CRISPR-CasX into E. coli, finding that they could block genetic material introduced into the cell.  Further research results indicated that CRISPR-CasX operates in a manner analogous to CRISPR-Cas9, but utilizing an entirely distinct protein architecture containing different catalytic domains.   CasX is also expected to function under different conditions (e.g., temperature) given the environment of the organisms that CasX was expressed in.  Similar to CRISPR Cas9, CasX enzymes are expected to have a wide variety of applications in genome editing and nucleic acid manipulation. 

Compositions and Methods for Inhibiting Stem Cell Aging

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} By 2050 the number of people in the world that will be aged 65 or older is expected to nearly triple to about 1.5 billion, representing 16% of the world’s population. One aspect of aging involves a diminished capacity to repair tissues after injury. This diminished capacity is evident in certain conditions that occur with aging, such as anemia, sarcopenia (loss of muscle mass), and osteoporosis. Deterioration of adult stem cells accounts for much of aging-associated compromised tissue maintenance. Adult stem cells mostly reside in a metabolically inactive quiescent state to preserve their integrity, but convert to a metabolically active proliferative state to replenish the tissue. The signals that trigger stem cells to exit the cell cycle and re-enter quiescence, and the signal transduction leading to the transition remain elusive however.   UC Berkeley researchers have developed methods of reducing or inhibiting or reversing stem cell aging or preventing and/or reversing tissue degeneration or injury by increasing the activity and/or the level of SIRT2 in an adult stem cell or reducing the level of a nucleotide-binding domain and leucine-rich repeat- containing-3 (NLRP3) polypeptide in an adult stem cell.  

CB6 for Highly Sensitive Molecular Detection Using HyperCEST NMR

Hyperpolarized 129Xe chemical exchange saturation transfer (HyperCEST) nuclear magnetic resonance (NMR), used to detect cancer markers, small molecule analytes, and cell surface glycans, relies on the targeted delivery of xenon hosts to a region of interest or small chemical shift difference between bound and unbound xenon sensors. Cryptophane-A (CryA) xenon hosts, used in the past, are hydrophobic, costly, and difficult to functionalize. CB6 is an excellent xenon host for activated 129Xe NMR detection because it produces a distinctive signal, has better exchange parameters for HyperCEST when compared to CryA, is soluble in most buffers and biological environments, and is commercially available. One major limitation of CB6 sensors is the difficult chemical functionalization to generalize them for diverse spectroscopic applications. To address this problem, researchers at Lawrence Berkeley National Laboratory and University of California, Berkeley, have designed, synthesized, and implemented a chemically-activated cucurbit[6]uril (CB6) platform for 129Xe HyperCEST NMR that blocks 129Xe@CB6 interactions with greater control to eliminate background signals until the CB6 reaches a region of interest, where it is then released to produce a 129Xe @CB6 signal. This technology will enable detection of increasingly lower concentrations of targets as the molecular systems become more optimized. 

Enzymatic Synthesis Of Cyclic Dinucleotides

96 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} GGDEF domain-containing enzymes are diguanylate cyclases that produce cyclic di-GMP (cdiG), a second messenger that modulates the key bacterial lifestyle transition from a motile to sessile biofilm-forming state. The ubiquity of genes encoding GGDEF proteins in bacterial genomes has established the dominance of cdiG signaling in bacteria. A subfamily of GGDEF enzymes synthesizes the asymmetric signaling molecule cyclic AMP-GMP. Hybrid CDN-producing and promiscuous substrate-binding (Hypr) GGDEF enzymes are widely distributed and found in other deltaproteobacteria and have roles that include regulation of cAG signaling.  GGDEF enzymes that produce cyclic dinucleotides are especially of interest.    UC Berkeley researcher have developed a new method of preparing and using cyclic dinucleotides (CDNs) by contacting a CDN producing-enzyme (e.g., a GGDEF enzyme) with a precursor of a CDN under conditions sufficient to convert the precursor into a CDN. This method produces a variety of non-naturally occurring, asymmetric and symmetric CDNs and can be performed in vitro or in a genetically modified host cell. Also provided are CDN compositions that find use in a variety of applications such as modulating an immune response in an individual.  

Novel, Programmable Nucleic Acid Binding And Cleaving CRISPR Proteins Which Can Sense And Respond To The Cellular Environment

96 800x600 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:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman",serif;} RNA-programmed Cas9 has proven to be a versatile tool for genome engineering in multiple cell types and organisms. Guided by a dual-RNA complex or a chimeric single-guide RNA, Cas9 (or variants of Cas9) can generate site-specific double-stranded or single-stranded breaks within target nucleic acids. Target nucleic acids can include double-stranded DNA and single-stranded DNA as well as RNA. When cleavage of a DNA occurs within a cell (e.g., genomic DNA in a eukaryotic cell), the cell can repair the break in the target DNA by non-homologous end joining or homology directed repair. Thus, CRISPR/Cas systems provide a facile means of modifying genomic information. Because the effectiveness of many Cas9 protein fusions is less than optimal (likely due to steric incompatibility), there is a need for variants of RNA-guide polypeptides (e.g., variant Cas9 proteins) that provide for, for example, conditionally active proteins and/or more efficient fusion proteins.   UC Berkeley researchers have created circularly permutated Cas9 proteins (cpCas9 proteins) with entirely new N- and C- termini at defined sites around the Cas9 protein structure.  The cpCas9 proteins were found to increase the effectiveness of Cas9 fusion proteins because they reduce the constraints imposed by the naturally existing N- and C-termini. The researchers have shown their RNA-guided polypeptides provide increased target nucleic acid editing accuracy (increased in some cases with single nucleotide resolution). Multiple different cpCas9 proteins were developed, each of which provides new N- and C- termini at unique positions within the structure of the Cas9 protein. Thus, depending on the fusion partner of choice, an appropriate cpCas9 can be selected that will place the fused partner at a desired position. This ability to position a fusion partner relative to the structure of the protein while allowing fusion to an N- and/or C-terminus, provides RNA-guided polypeptides that are better suited to avoid off-target effects.  

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