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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.  

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.

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. 

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.  

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.  

Directed Evolution Of AAV Vectors That Undergo Retrograde Axonal Transport

Brain functions such as perception, cognition, and the control of movement depend on the coordinated action of large-scale neuronal networks, which are composed of local circuit modules that are linked together by long-range connections.  Such long­ range connections are formed by specialized projection neurons that often comprise several intermingled classes, each projecting to a different downstream target within the network. Projection neurons have also been implicated in the spread of several neurodegenerative diseases. Selective targeting of projection neurons for transgene delivery is important both for gaining insights into brain function and for therapeutic intervention in neurodegenerative diseases.   Viral vectors constitute an important class of tools for introducing transgenes into specific neuronal populations, but their potential for biological investigation and gene therapy is hampered by excessive virulence.  Other viruses can infect neurons when administered directly to the nervous system, with "pseudorabies", adenoviruses and lentiviruses used most commonly in animal research. However, these viruses mediate only modest levels of transgene expression, have potential for toxicity, and are currently not easily scalable for clinical or large animal studies.  Recombinant adeno-associated viruses (rAAVs) are an effective platform for in vivo gene therapy, as they mediate high-level transgene expression, are non-toxic, and evoke minimal immune responses.  rAAVs have allowed retrograde access to projection neurons, but their natural propensity for retrograde transport is low, hampering efforts to address the role of projection neurons in circuit computations or disease progression.    UCB and HHMI researchers have produced a new rAAV variant (rAAV2-retro) that permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde labeling reagents.  The rAAV2-retro gene delivery system can be used on its own or in conjunction with Cre recombinase driver lines to achieve long-term, high-level transgene expression that is sufficient for effective functional interrogation of neural circuit function, as well as for CRISPR/Cas9-mediated and other genome editing in targeted neuronal populations.  As such, this designer variant of adeno-associated virus allows for efficient mapping, monitoring, and manipulation of projection neurons.

C2c2 - A Dual Function Programmable RNA Endoribonuclease

Bacterial adaptive immune systems employ CRISPRs and CRISPR-associated (Cas) proteins for RNA-guided nucleic acid cleavage. Although generally targeted to DNA substrates, the Type VI CRISPR system directs interference complexes against single-stranded RNA substrates and in Type VI CRISPR systems, the single-subunit C2c2 protein functions as an RNA-guided RNA endonuclease.   UC Berkeley researchers have discovered that the CRISPR-C2c2 has two distinct RNase activities that enable both single stranded target RNA detection and multiplexed guide-RNA processing.  These dual RNase functions were found to be chemically and mechanistically different from each other and from the CRISPR RNA processing behavior of the evolutionarily unrelated CRISPR enzyme Cpf1.  Methods for detecting the single stranded target RNA were also discovered using a C2c2 guide RNA and a C2c2 protein in a sample have a plurality of RNAs as well as methods of cleaving a precursor C2c2 guide RNA into two or more C2c2 guide RNAs.  

System and Methods to Track Single Molecules

Tracking single molecules inside cells reveals the dynamics of biological processes, including receptor trafficking, signaling and cargo transport. However, individual molecules often cannot be resolved inside cells due to their high density in the cellular environment, plus it is difficult to see spatial and temporal features, such as signal transduction events at the cell surface or on intracellular compartments, with single molecule resolution. To address these problems, researchers at the University of California, Berkeley, have developed the PhotoGate device and methods in order to control the number of fluorescent particles in a region of interest. By deploying PhotoGate and applying patterned photobleaching, they have demonstrated the tracking of single particles at surface densities two orders of magnitude higher than the single-molecule detection limit. Additional experimentation enabled the observation of ligand-induced dimerization of epidermal growth factor receptors on a live cell membrane, and also measurements of the binding and the dissociation rate of single adaptor protein from early endosomes in the crowded environment of the cytoplasm. The innovative approach enables tracking of single particles at high spatial and temporal resolution, and for mapping of molecular trajectories, as well as determining complex stoichiometry and dynamics, and drives the art towards video-rate imaging of live cells with molecular (1–5 nm) resolution.

Versatile Cas9-Mediated Integration Technology

Many advancements to the Cas9 system (both the Cas9 nuclease and the sgRNA sequence) have been made to increase and optimize its efficiency and specificity.  Since many diseases and traits in humans have a complex genetic basis, multiple genomic targets must be simultaneously edited in order for diseases to be cured or for traits to be impacted.  Thus in order for CRISPR/Cas9 to be an effective gene therapeutic technology, huge swathes of the genome must be edited simultaneously, efficiently, and accurately. To address many of these issues, UC Berkeley researchers have developed a system method to rapidly manipulate multiple loci. This system allows for either sequential (maintaining inducible Cas9 present in the genome) or simultaneous (scarless excision) manipulation of Cas9 itself and can be applied to any organism currently utilizing the CRISPR technology.  The system can also be applied conveniently to create genomic libraries, artificial genome sequences, and highly programmable strains or cell lines that can be rapidly (and repeatedly) manipulated at multiple loci with extremely high efficiency.  

ENGINEERED MICROORGANISMS FOR PRODUCTION OF COMMODITY CHEMICALS AND CELLULAR BIOMASS

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;} Citrus pulp and sugar beet pulp are pectin-rich agricultural wastes that are globally produced in significant amounts and have the potential to contribute towards the greater bioeconomy as a source of raw, inexpensive carbohydrate biomass. There is currently limited use for these waste streams. In some cases, pulps are dried, pelleted, and repurposed as an inexpensive livestock feed, however this application is barely profitable due to high production costs. There is a need for technologies that can cost-effectively transform pectin-rich waste streams into value-added products of commercial interest.   UC Berkeley researchers developed an efficient microbial strain technology and metabolic fermentation methods for the bioconversion of pectin-rich waste streams to useful bio-based commodity chemicals and biofuels. In addition to the beneficial environmental impact of utilizing a waste-stream, the fermentation technologies achieve three design goals set to optimize the productivity of bioconversions and economic viability. First, the technology allows for anaerobic fermentation, eliminating the need for culture oxygenation. This lowers operating costs by simplifying the metabolic requirements of high-density fermentation cultures. Second, co- utilization of the major component monosaccharides in the hydrolysate broth allows for productive conversion of the predominant, energy- rich biomass sugars. Third, fermentations can be conducted at low pH, discouraging contaminant growth and eliminating the need to buffer the hydrolysate mixture.  

CRISPR genome editing of Zygotes (CRISPR-EZ)

0 0 1 214 1224 UC Berkeley 10 2 1436 14.0 Normal 0 false false false EN-US JA 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:Cambria; mso-ascii-font-family:Cambria; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Cambria; mso-hansi-theme-font:minor-latin;} Easily accessible and efficient methodologies to edit the genomes of organisms are an immense resource to the biological and biomedical research community. Traditionally, engineering of the mammalian genome is achieved by homologous recombination (HR)-mediated sequence substitution in embryonic stem cells (ESCs), a time consuming process that occurs at low frequency. Taking genetically engineering in mice for example, after extensive screening for ESC colonies with the desired genetic modifications, ESCs are microinjected into mouse blastocysts to generate chimeras capable of germline transmission. Such chimera mice are then crossed to wild-type mice to generate heterozygous offspring (F1), which are then intercrossed to yield homozygous mutant mice (F2) that can be subjected to phenotypic analyses. Despite the wide use of this technology to generate transgenic mice, the low efficiency of HR in ESCs, the laborious process of screening, the technical difficulty of microinjection, and the nature of the mouse life cycle make this approach a lengthy and costly process.   UC Berkeley researchers developed methods for modifying the genome of a mammalian zygote by introducing a ribonucleoprotein complex (RNP) to the zygote via electroporation.  Suitable genome editing nucleases were found to be CRISPR/Cas endonucleases (e.g., class 2 CRISPR/Cas endonucleases such as a type II, type V, or type VI CRISPR/Cas endonucleases.  

Salmonella-Based Gene Delivery Vectors and their Preparation

Nucleic acid-based gene interference technologies, including ribozymes and small interfering RNAs (siRNAs), represent promising gene-targeting strategies for specific inhibition of mRNA sequences of choice. A fundamental challenge to use nucleic acid-based gene interfering approaches for gene therapy is to deliver the gene interfering agents to appropriate cells in a way that is tissue/cell specific, efficient and safe. Many of the currently used vectors are based on attenuated or modified viruses, or synthetic vectors in which complexes of DNA, proteins, and/or lipids are formed in particles, and tissue-specific vectors have been only partially obtained by using carriers that specifically target certain cell types. As such, efficient and targeted delivery of M1GS sequences to specific cell types and tissues in vivo is central to developing this technology for gene targeting applications. Invasive bacteria, such as Salmonella, possess the ability to enter and transfer genetic material to human cells, leading to the efficient expression of transferred genes. Attenuated Salmonella strains have earlier been shown to function as a carrier system for delivery of nucleic acid-based vaccines and anti-tumor transgenes. Salmonella-based vectors are low cost and easy to prepare. Furthermore, they can be administrated orally in vivo, a non-invasive delivery route with significant advantage. Thus, Salmonella may represent a promising gene delivery agent for gene therapy. Scientists at UC Berkeley have developed a novel attenuated strain of Salmonella, SL101, which exhibited high gene transfer activity and low cytotoxicity/pathogenicity while efficiently delivering ribozymes, for expression in animals. Using MCMV infection of mice as the model, they demonstrated that oral inoculation of SL101 in animals efficiently delivered RNase P-based ribozyme sequence into specific organs, leading to substantial expression of ribozyme and effective inhibition of viral infection and pathogenesis. This strategy could easily be adopted deliver other gene targeting technologies.

Fluorescent Biosensor for Cyclic GMP-AMP (cGAMP)

The cGAS-cGAMP-STING pathway is an important immune surveillance pathway which gets activated in presence of cytoplasmic DNA either due to a microbial infection or a patho-physiological condition, including cancer and autoimmune disorders. Sensing 2’3’ cGAMP level is important in diagnostics perspective as well as in basic understanding of their regulation.  Small molecule activators of this pathway have also been shown to activate an anti-cancer immune response and thus an important use for pharmaceutical applications. However, a high throughput method to screen for such potential drugs is still not available. UC Berkeley researchers have designed a RNA-based fluorescent biosensor for directly detecting 2’3’ cGAMP. The biosensor was able to detect 2’3’ cGAMP and assay cGAS activity in vitro and thus would be useful for high throughput screening of small molecule modulators of cGAS activity.  The biosensor was sensitive enough to quantify 2’3’ cGAMP in dsDNA- stimulated mammalian cell extracts. 

Methods and Materials to Treat Lymphangiogenesis

The lymphatic vascular network penetrates most tissues in the body and plays important roles in a broad spectrum of functions, including immune surveillance, fat absorption and interstitial fluid homeostasis. Numerous disorders have been found to be associated with lymphatic dysfunction, such as cancer metastasis, inflammatory and immune diseases, infection, transplant rejection, obesity, hypertension and lymphedema. However, to date, there is still little effective treatment for most lymphatic disorders. Researchers at UC Berkeley (UCB) are working to advance the understanding of the mechanisms underlying pathologic lymphatic processes, such as lymphangiogenesis (LG), for new preventive measures and treatments. MicroRNAs are a class of small noncoding RNAs that negatively regulate gene expression by binding to complimentary sequences of target messenger RNA. UCB researchers are specifically investigating the role of microRNA 184 (miR-184) in corneal LG in vivo and dermal lymphatic endothelial cells (LECs) in vitro. Using preclinical animal models combined with human cell cultures, the researchers have discovered that miR-184 which is naturally expressed in the cornea is critically involved in LG and could potentially be used as an inhibitor of LG. Further research and understanding of these data may produce targets for miR-184 for new approaches to prevent or treat lymphatic disease which occurs both inside and outside the eye.

Method For Detecting Protein-Specific Glycosylation

O-GlcNAc modification is a common form of post-translational modification that mediates cellular activity and stem cell programming by modifying transcription factors. Multiple human diseases, including cancer and diabetes, have been linked to aberrant O-GlcNAcylation of specific proteins.Despite the importance of this modification, current methods for detection require advanced instrumentation and expertise as well as arduously enriched or purified samples. The “Glyco-seq” method developed by UC Berkeley researchers is highly sensitive, easy to use, and enables O-GlcNAc detection on proteins of interest in cell lysate. 

Novel 3D Stem Cell Culture Systems

Many disorders result in tissue degeneration, including Parkinson’s disease, heart attacks, and liver failure. One promising approach to treat these disorders is cell replacement therapy, which would implant new cells or tissues to replace those damaged by disease. Cell replacement therapy relies on stem cells, which are able to differentiate into a wide number of mature cell types. However, cell replacement therapies require large numbers of cells to clinically develop and commercialize, and the current stem cell culture methods are problematic in multiple ways, including low cell yields in 2D and poorly defined culture components. By culturing stem cells three-dimensionally, instead of two-dimensionally, far larger numbers of cells can be generated. Current three-dimensional culturing systems, however, often exert harmful shear stresses and pressures on the cells, have harsh cell recovery steps, do thus not generate large cell yields.   UC Berkeley researchers have developed new materials intended for use in fully chemically defined processes for large-scale growth and differentiation of stem cells. These materials prevent harsh cell recovery steps, and can be used in a defined, highly tunable, and three-dimensional cell culture system. 

Combination Therapeutic for the Treatment of Melanoma

The incidence of skin cancer over the past three decades have been more than all other cancers combined.  Melanoma, a malignant form of skin cancer originating in the melanin containing melanocytes, accounts for less than 2 percent of all diagnosed skin cancer cases, but causes 77% of all skin cancer deaths.   UC Berkelely researchers combination of a first and second compound of a composition of the present disclosure can provide a synergistic enhancement in inhibiting proliferation of a cancer cell (e.g., melanoma).  The first compound is either indole-3-carbinol or 1-benzyl indole-3-carbinol.  In some cases, the synergistic effect is provided by two compounds targeting the same protein, (e.g., an oncogenic BRAF polypeptide). In such cases, the two compounds target distinct sites on the oncogenic BRAF polypeptide.  In other cases, the synergistic effect can be provided by two compounds targeting different pathways that impinge upon a common downstream component. 

Self-Inactivating Targeted DNA Nucleases For Gene Therapy

The clinical application of targeted nucleases - such as zinc-finger nucleases, TALENs, and CRISPR/Cas9 – are exciting genome editing platforms. Delivery of nucleases to cells and tissues using as viral methods, however, can leave the nucleases stably present in the target cells, even after editing has been accomplished. One major safety concern is off-target effects (i.e. cutting a non-intended site), which pose a safety risk.  Another safety concern for gene therapies is the long-term expression of a foreign protein potentially provoking inflammatory reactions, another safety risk.   To avoid these potential detrimental outcomes, researchers at UC Berkeley have modified the delivered nuclease DNA which will cleave the host genome target DNA site and also excise its own DNA from the stable delivered construct.  The researchers have shown that there is no trace of any active delivered DNA remaining, thus mitigating the harmful side effects from nuclease based gene therapy.

3D System For Differentiation Of Oligodendocyte Precusors From Pluripotent Stem Cells

Cell replacement therapies using have long been thought to have the potential to treat demyelinating diseases such as multiple sclerosis or hypomyelinating leukodystrophies - as well as spinal cord and other CNS injuries that involve inflammation and loss of myelin. While pluripotent stem cells represent a potential source of readily available regenerative tissue, they require labor-intensive culturing to differentiate into target cell types.  Since Oligodendrocyte precursors cells (OPCs) can migrate, engraft and differentiate when experimentally transplanted onto unmyelinated axons, OPCs have been seen as the future of cell replacement therapies for demyelinating diseases.  However, as there is currently no reliable and sustainable source of transplantable OPCs, their therapeutic potential cannot be harnessed.   Researchers at the UC Berkeley have created a 3-dimensional, chemically defined biomaterial system for the large-scale differentiation of OPCs. By systematically optimized chemical cues, this strategy rapidly generated Olig2 and NKX2.2-positive cells with the same efficiency of other protocols, but in a shorter period of time (approximately 18 days instead of 30). This shortened 3D differentiation protocol, which results in up to 2-4 times more cells, enables a significant reduction in the cost of production of pre-OPCs. 

Wearable Sensor Arrays for Detailed Sweat Profiles

Wearable technologies can play a significant role in realizing personalized medicine through continuously monitoring an individual’s physical and physiological states. Most currently developed wearable technologies are capable only in tracking the physical activities of an individual and fail to provide insight into the individual’s state of health. Human sweat contains the physiologically rich information needed to infer an individual’s sate of health and is an excellent candidate for non-invasive monitoring. The wearable sweat sensors can serve as an ideal platform for a wide range of real-time healthcare monitoring such as exercise-induced dehydration and medical diagnosis.

Bioorthogonal Reaction Of N-Oxides And Boron Reagents

The development of prodrugs, molecules activated in the body to reveal therapeutic function in order to limit off-target toxicity or enhance properties such as biodistribution are highly sought for biologic therapeutics as it does not solely depend on endogeneous processes such as hydrolysis or enzymatic cleavage. While prodrugs constitute a rich area of application of bioorthogonal chemistry conceptually, these approaches suffer from slow reaction kinetics. Researchers developed a new tool for small molecule activation of biomolecules. using N-oxides and boron reagents. The mechanism features fast reaction kinetics that rival the fastest reactions currently in the literature while introducing functionality that has yet to gain significant attention. Due to the benignity of the reaction conditions toward live cells and its intracellular compatibility, this reaction holds much promise.

Superresolution Microscopy And Ultrahigh-Throughput Spectroscopy

Current super-resolution microscopy (SRM) methods have excellent spatial resolution, but no spectral information. Issues such as heavy color crosstalk, compromised image quality, and difficulties in aligning 3D coordinates of different color channels mean that high-quality multicolor 3D SRM remains a challenge. Another current imaging technique, single-molecule spectroscopy, is also limited in use because current methods are low throughput, have low spatial resolution, and cannot be used effectively for densely labeled biological samples.   UC Berkeley researchers have developed a 3-D super-resolution microscopy and single molecule spectroscopy system that addresses the issues inherent to both of these imaging techniques. By synchronously measuring the fluorescence spectra and positions of millions of single molecules within minutes, both spectrally resolved SRM and ultrahigh-throughput single-molecule spectroscopy are made possible.

Novel Target For Contraceptives And Painkillers

The steroid progesterone (P4) is a major component of follicular fluid and is released by ovaries and cumulus cells surrounding the oocyte.  P4 is known to cause rapid and robust elevation of sperm cytoplasmic calcium levels through binding to a non-genomic receptor.  This rise in intracellular calcium leads to changes in sperm motility and primes the cell for acrosomal exocytosis, which is required for fertilization.     UC Berkeley researchers have identified an enzyme as a P4 non-genomic receptor.  The enzyme was found to possess progesterone-stimulated endocannabinoid hydrolase activity, and regulate human sperm activation.  The technology includes methods of modulating the level and/or activity of the enzyme in a cell in an individual. 

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