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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.  

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.  

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. 

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.  

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.  

Diagnostic Colorimetric Assay

0 0 1 183 1047 UC Berkeley 8 2 1228 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:11.0pt; font-family:"Times New Roman";} Hyper-accumulation of copper in biological fluids and tissues is a hallmark of pathologies such as Wilson’s and Menkes diseases, various neurodegenerative diseases, and toxic environmental exposure. Diseases characterized by copper hyper accumulation are currently challenging to identify due to costly diagnostic tools that involve extensive technical workup.   To solve these problems, UC Berkeley researches developed a simple yet highly selective and sensitive diagnostic tool along with new materials that can enable monitoring of copper levels in biological fluid samples without complex and expensive instrumentation.  The diagnostic tool includes a robust three-dimensional porous aromatic framework (PAF) densely functionalized with thioether groups for selective capture and concentration of copper from biofluids as well as aqueous samples.  The PAF exhibits high selectivity for copper over other biologically relevant metals, with a saturation capacity reaching over 600 mg/g.  The researchers were able to use the diagnostic tool, which included a colorimetric indicator, to identify aberrant elevations of copper in urine samples from mice with Wilson’s disease and also traced exogenously added copper in serum. 

Methods and Compositions for Increasing Desiccation Tolerance In a Cell

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 impact of desiccation on microorganisms such as yeasts, bacteria, and plants are extremely important in a variety of industries ranging from the food and beverage industry that rely heavily on yeast and agricultural crops.  Microorganisms can survive for a certain period of time when water is limited, but may not be able to survive severe environmental conditions when desiccation tolerance is low. The market potential in stabilization of cells and cell products is estimated to be some $500 billion worldwide. For example, it has been reported that fewer than one in a million yeast cells from low-density logarithmic cultures of Saccharomyces cerevisiae survive desiccation. Therefore, given the exceedingly large number of microorganisms used in a variety of industries, even minor increases in survival can result in significant improvements in final output. For example, applications such as freeze-drying cells for the medical industry are used to preserve cell structure and function for long term storage. Additionally, the largest market for freeze-drying is the food industry.   UC Berkeley researchers have developed methods and compositions for increasing desiccation tolerance in a cell by contacting the cell with one or more agents that generates synergistic amounts of trehalose and a hydrophilin protein within the cell.  Cells with increased desiccation tolerance have also been developed.  

Optical Phase Retrieval Systems Using Color-Multiplexed Illumination

Light is a wave, having both an amplitude and phase. Our eyes and cameras, however, only see real values (i.e. intensity), so cannot measure phase directly. Phase is important, especially in biological imaging, where cells are typically transparent (i.e. invisible) but yet impose phase delays. When we can measure the phase delays, we get back important shape and density maps.   Researchers at the University of California, Berkeley have developed a new method for recovering both phase and amplitude of an arbitrary sample in an optical microscope from a single image, using patterned partially coherent illumination. The hardware requirements are compatible with most modern microscopes via a simple condenser insert, or by replacing the entire illumination pathway with a programmable LED array, providing flexibility, portability, and affordability, while eliminating many of the trade-offs required by other methods. This enables quantitative imaging of phase from a single image, using partially coherent illumination, and in a way that is flexible and amenable to a variety of existing microscopy systems. 

PHOTO-INDUCED ELECTRON TRANSFER VOLTAGE SENSITIVE DYES

The development of fluorescent indicators for sensing membrane potential can be a challenge.  Traditional methods to measure membrane potential rely on invasive electrodes, however, voltage imaging with fluorescent probes (VF) is an attractive solution because voltage imaging circumvents problems of low- throughput, low spatial resolution, and high invasiveness. Previously reported VF probes/dyes have proven useful in a number of imaging contexts. However, the design scheme for VF dyes remains elusive, due in part to our incomplete understanding of the biophysical properties influencing voltage sensitivity in our VoltageFluor scaffolds.   UC Berkeley researchers have discovered new VF dyes, which are a small molecule platform for voltage imaging that operates via a photoinduced electron transfer (PeT) quenching mechanism to directly image transmembrane voltage changes.   The dyes further our understanding of the roles that membrane voltage plays, not only in excitable cells, such as neurons and cardiomyocytes, but also in non-excitable cells in the rest of the body.

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.

Chemical Cocktail For Deriving Myogenic Cells

In postnatal life, growth and repair of skeletal muscle fibers are mediated by the satellite cells. These cells divide at a slow rate to sustain both self-renewal and growth of skeletal muscle tissue. In response to muscle injury, satellite cells divide and fuse to repair or replace the damaged muscular fibers. However, the self-renewal potential of adult satellite cells is limited and is compromised with aging, excessive trauma, or genetic defect as in certain severe muscular dystrophies such as Duchenne muscular dystrophy. In such cases, external interventions are needed.             UC Berkeley researchers have developed a chemical cocktail that allows large number of myogenic stem cells to be derived from, but no limited to, mouse dermal fibroblasts. These myogenic stem cells could then be transplanted into diseased or injured skeletal muscle to promote regeneration and recovery. In addition, the chemicals could be directly delivered into diseased or injured skeletal muscle to promote regeneration in vivo.  The mixture allows large number of patient-specific skeletal muscle cells to be obtained conveniently from non-invasive skin biopsy techniques. The in vitro culture of these skeletal muscle cells can then be used for disease modeling and drug screening purposes.

Miniature Cleaning Device and Method for Ion Traps

For decades, quantum mechanics have been studied as a powerful new resource to accelerate and safeguard critical computational processes. A trapped ion quantum computer is one proposed approach, where qubit states based on trapped ions are connected through a common network of electromagnetic fields, gates and algorithms. One problem pertains to electric field noise arising from system electrodes which can destroy the stored quantum information. Specialized instruments, such as ion guns, are commonly used to treat unwanted electric field noise, but these devices require bulky port hardware and often cause undesirable and irreversible damage to surfaces. To address these problems, researchers at the University of California, Berkeley, have researched alternatives to traditional ion gun means. They have developed an innovative cleaning method and apparatus which is nonobstructing, and has greater directionality and overall control. The researchers have demonstrated the ultra-small (footprint = 2cm) and platform-friendly cleaning system for quantum information processing chips, in prototype stage.

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.  

Atom Probe Tomography Method and Algorithm

Most cluster analysis parameters in atom probe tomography (APT) are selected ad hoc. This can often lead to data misinterpretation and misleading results by instrument technicians and researchers. Moreover, arbitrary cluster parameters can have suboptimal consequences on data quality and integrity, leading to inefficiencies for downstream data users. To address these problems, researchers at the University of California, Berkeley, have developed a framework and specific cluster analysis methods to efficiently extract knowledge from better APT data. By using parameter selection protocols with theoretical explanations, this technology allows for a more optimized and robust multivariate statistical analysis technique from the start, thus improving the quality of analysis and outcomes for both upstream and downstream data users.

Rapid Methods for Multi-layer Microfluidic Structures

Microfluidics has rapidly advanced in the fields of chemical and biological research since 1980s due to its unique ability to make low-cost, high-throughput platforms. The most far-reaching breakthrough in microfluidics has been the development of soft-lithography using rigid micromachined molds to shape elastomeric polymers. Among polymeric materials, Polydimethylsiloxane (PDMS) is commonly used due to its numerous ideal properties, including its ease in manufacturing, reasonable cost, as well as strength, transparency, and especially biocompatibility. However, traditional PDMS methods for fabricating microfluidic devices have a unique set of challenges, including long and expensive process times, and feature sophistication limits (e.g. restricted to rectilinear features). To address these challenges, researchers at UC Berkeley have developed novel 3D printing techniques for fully-integrated, multi-layer microfluidic objects to achieve greater system-level functionalities. For demonstration, UC researchers created complex, high-quality geometries in PDMS without the need for a microscope, including thin membranes and rounded channels and while accounting for surface roughness. Their novel processes could enable assembly of microfluidic components into sophisticated 3D architectures, which may provide a new platform for rapidly creating complex microfluidic devices in volume.

Sleep Circuit Neurons

Rapid eye movement (REM) sleep is a distinct brain state characterized by activated electroencephalogram and complete skeletal muscle paralysis, and is associated with vivid dreams. The medulla contains neurons that are active during REM sleep, but whether they play a causal role in REM sleep generation was unclear.   UC Berkelely researchers have discovered that a GABAergic (γ-aminobutyric-acid-releasing) pathway originating from the ventral medulla powerfully promotes REM sleep.  The researchers inserted am optogenetic switch into the ventral medulla of mice and the GABAergic neurons rapidly and reliably initiated REM sleep episodes and prolonged their durations, whereas inactivating these neurons had the opposite effects.  The researcheres showed these neurons triggered all aspects of REM sleep, including muscle paralysis and the typical cortical activation that makes the brain look more awake than in non-REM sleep.  

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.  

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. 

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. 

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