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Search Results: 1 - 10 of 149275 matches for " Karen B Avraham "
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MicroRNAs in sensorineural diseases of the ear
Kathy Ushakov,Anya Rudnicki,Karen B. Avraham
Frontiers in Molecular Neuroscience , 2013, DOI: 10.3389/fnmol.2013.00052
Abstract: Non-coding microRNAs (miRNAs) have a fundamental role in gene regulation and expression in almost every multicellular organism. Only discovered in the last decade, miRNAs are already known to play a leading role in many aspects of disease. In the vertebrate inner ear, miRNAs are essential for controlling development and survival of hair cells. Moreover, dysregulation of miRNAs has been implicated in sensorineural hearing impairment, as well as in other ear diseases such as cholesteatomas, vestibular schwannomas, and otitis media. Due to the inaccessibility of the ear in humans, animal models have provided the optimal tools to study miRNA expression and function, in particular mice and zebrafish. A major focus of current research has been to discover the targets of the miRNAs expressed in the inner ear, in order to determine the regulatory pathways of the auditory and vestibular systems. The potential for miRNAs manipulation in development of therapeutic tools for hearing impairment is as yet unexplored, paving the way for future work in the field.
Egr2::Cre Mediated Conditional Ablation of Dicer Disrupts Histogenesis of Mammalian Central Auditory Nuclei
Elena Rosengauer, Heiner Hartwich, Anna Maria Hartmann, Anya Rudnicki, Somisetty Venkata Satheesh, Karen B. Avraham, Hans Gerd Nothwang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049503
Abstract: Histogenesis of the auditory system requires extensive molecular orchestration. Recently, Dicer1, an essential gene for generation of microRNAs, and miR-96 were shown to be important for development of the peripheral auditory system. Here, we investigated their role for the formation of the auditory brainstem. Egr2::Cre-mediated early embryonic ablation of Dicer1 caused severe disruption of auditory brainstem structures. In adult animals, the volume of the cochlear nucleus complex (CNC) was reduced by 73.5%. This decrease is in part attributed to the lack of the microneuronal shell. In contrast, fusiform cells, which similar to the granular cells of the microneural shell are derived from Egr2 positive cells, were still present. The volume reduction of the CNC was already present at birth (67.2% decrease). The superior olivary complex was also drastically affected in these mice. Nissl staining as well as Vglut1 and Calbindin 1 immunolabeling revealed that principal SOC nuclei such as the medial nucleus of the trapezoid body and the lateral superior olive were absent. Only choline acetyltransferase positive neurons of the olivocochlear bundle were observed as a densely packed cell group in the ventrolateral area of the SOC. Mid-embryonic ablation of Dicer1 in the ventral cochlear nucleus by Atoh7::Cre-mediated recombination resulted in normal formation of the cochlear nucleus complex, indicating an early embryonic requirement of Dicer1. Quantitative RT-PCR analysis of miR-96 demonstrated low expression in the embryonic brainstem and up-regulation thereafter, suggesting that other microRNAs are required for proper histogenesis of the auditory brainstem. Together our data identify a critical role of Dicer activity during embryonic development of the auditory brainstem.
Integration of Transcriptomics, Proteomics, and MicroRNA Analyses Reveals Novel MicroRNA Regulation of Targets in the Mammalian Inner Ear
Tal Elkan-Miller,Igor Ulitsky,Ronna Hertzano,Anya Rudnicki,Amiel A. Dror,Danielle R. Lenz,Ran Elkon,Martin Irmler,Johannes Beckers,Ron Shamir,Karen B. Avraham
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0018195
Abstract: We have employed a novel approach for the identification of functionally important microRNA (miRNA)-target interactions, integrating miRNA, transcriptome and proteome profiles and advanced in silico analysis using the FAME algorithm. Since miRNAs play a crucial role in the inner ear, demonstrated by the discovery of mutations in a miRNA leading to human and mouse deafness, we applied this approach to microdissected auditory and vestibular sensory epithelia. We detected the expression of 157 miRNAs in the inner ear sensory epithelia, with 53 miRNAs differentially expressed between the cochlea and vestibule. Functionally important miRNAs were determined by searching for enriched or depleted targets in the transcript and protein datasets with an expression consistent with the dogma of miRNA regulation. Importantly, quite a few of the targets were detected only in the protein datasets, attributable to regulation by translational suppression. We identified and experimentally validated the regulation of PSIP1-P75, a transcriptional co-activator previously unknown in the inner ear, by miR-135b, in vestibular hair cells. Our findings suggest that miR-135b serves as a cellular effector, involved in regulating some of the differences between the cochlear and vestibular hair cells.
Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population
Tom Walsh, Amal Rayan, Judeh Sa'ed, Hashem Shahin, Jeanne Shepshelovich, Ming K Lee, Koret Hirschberg, Mustafa Tekin, Wa'el Salhab, Karen B Avraham, Mary-Claire King, Moien Kanaan
Human Genomics , 2006, DOI: 10.1186/1479-7364-2-4-203
Real-time dynamics in Quantum Impurity Systems: A Time-dependent Numerical Renormalization Group Approach
Frithjof B. Anders,Avraham Schiller
Physics , 2005, DOI: 10.1103/PhysRevLett.95.196801
Abstract: We develop a general approach to the nonequilibrium dynamics of quantum impurity systems for arbitrary coupling strength. The numerical renormalization group is used to generate a complete basis set necessary for the correct description of the time evolution. We benchmark our method with the exact analytical solution for the resonant-level model. As a first application, we investigate the equilibration of a quantum dot subject to a sudden change of the gate voltage and external magnetic field. Two distinct relaxation times are identified for the spin and charge dynamics.
Spin Precession and Real Time Dynamics in the Kondo Model: A Time-Dependent Numerical Renormalization-Group Study
Frithjof B. Anders,Avraham Schiller
Physics , 2006, DOI: 10.1103/PhysRevB.74.245113
Abstract: A detailed derivation of the recently proposed time-dependent numerical renormalization-group (TD-NRG) approach to nonequilibrium dynamics in quantum impurity systems is presented. We demonstrate that the method is suitable for fermionic as well as bosonic baths. A comparison with exact analytical results for the charge relaxation in the resonant-level model and for dephasing in the spin-boson model establishes the accuracy of the method. The real-time dynamics of a single spin coupled to both types of baths is investigated. We use the TD-NRG to calculate the spin relaxation and spin precession of a single Kondo impurity. The short- and long-time dynamics is studied as a function of temperature in the ferromagnetic and antiferromagnetic regimes. The short-time dynamics agrees very well with analytical results obtained at second order in the exchange coupling $J$. In the ferromagnetic regime, the long-time spin decay is described by the scaling variable $x = 2\rho_F J(T) T t$. In the antiferromagnetic regime it is governed for $T < T_K$ by the Kondo time scale $1/T_K$. Here $\rho_F$ is the conduction-electron density of states and $T_K$ is the Kondo temperature. Results for spin precession are obtained by rotating the external magnetic field from the x axis to the z axis.
CLRN1 Is Nonessential in the Mouse Retina but Is Required for Cochlear Hair Cell Development
Scott F. Geller ,Karen I. Guerin,Meike Visel,Aaron Pham,Edwin S. Lee,Amiel A. Dror,Karen B. Avraham,Toshinori Hayashi,Catherine A. Ray,Thomas A. Reh,Olivia Bermingham-McDonogh,William J. Triffo,Shaowen Bao,Juha Isosomppi,Hanna V?stinsalo,Eeva-Marja Sankila,John G. Flannery
PLOS Genetics , 2009, DOI: 10.1371/journal.pgen.1000607
Abstract: Mutations in the CLRN1 gene cause Usher syndrome type 3 (USH3), a human disease characterized by progressive blindness and deafness. Clarin 1, the protein product of CLRN1, is a four-transmembrane protein predicted to be associated with ribbon synapses of photoreceptors and cochlear hair cells, and recently demonstrated to be associated with the cytoskeleton. To study Clrn1, we created a Clrn1 knockout (KO) mouse and characterized the histological and functional consequences of Clrn1 deletion in the retina and cochlea. Clrn1 KO mice do not develop a retinal degeneration phenotype, but exhibit progressive loss of sensory hair cells in the cochlea and deterioration of the organ of Corti by 4 months. Hair cell stereocilia in KO animals were longer and disorganized by 4 months, and some Clrn1 KO mice exhibited circling behavior by 5–6 months of age. Clrn1 mRNA expression was localized in the retina using in situ hybridization (ISH), laser capture microdissection (LCM), and RT–PCR. Retinal Clrn1 transcripts were found throughout development and adulthood by RT–PCR, although expression peaked at P7 and declined to undetectable levels in adult retina by ISH. LCM localized Clrn1 transcripts to the retinas inner nuclear layer, and WT levels of retinal Clrn1 expression were observed in photoreceptor-less retinas. Examination of Clrn1 KO mice suggests that CLRN1 is unnecessary in the murine retina but essential for normal cochlear development and function. This may reflect a redundancy in the mouse retina not present in human retina. In contrast to mouse KO models of USH1 and USH2, our data indicate that Clrn1 expression in the retina is restricted to the Müller glia. This is a novel finding, as most retinal degeneration associated proteins are expressed in photoreceptors, not in glia. If CLRN1 expression in humans is comparable to the expression pattern observed in mice, this is the first report of an inner retinal protein that, when mutated, causes retinal degeneration.
A Myo6 Mutation Destroys Coordination between the Myosin Heads, Revealing New Functions of Myosin VI in the Stereocilia of Mammalian Inner Ear Hair Cells
Ronna Hertzano equal contributor,Ella Shalit equal contributor,Agnieszka K. Rzadzinska equal contributor,Amiel A. Dror,Lin Song,Uri Ron,Joshua T. Tan,Alina Starovolsky Shitrit,Helmut Fuchs,Tama Hasson,Nir Ben-Tal,H. Lee Sweeney,Martin Hrabe de Angelis,Karen P. Steel,Karen B. Avraham
PLOS Genetics , 2008, DOI: 10.1371/journal.pgen.1000207
Abstract: Myosin VI, found in organisms from Caenorhabditis elegans to humans, is essential for auditory and vestibular function in mammals, since genetic mutations lead to hearing impairment and vestibular dysfunction in both humans and mice. Here, we show that a missense mutation in this molecular motor in an ENU-generated mouse model, Tailchaser, disrupts myosin VI function. Structural changes in the Tailchaser hair bundles include mislocalization of the kinocilia and branching of stereocilia. Transfection of GFP-labeled myosin VI into epithelial cells and delivery of endocytic vesicles to the early endosome revealed that the mutant phenotype displays disrupted motor function. The actin-activated ATPase rates measured for the D179Y mutation are decreased, and indicate loss of coordination of the myosin VI heads or ‘gating’ in the dimer form. Proper coordination is required for walking processively along, or anchoring to, actin filaments, and is apparently destroyed by the proximity of the mutation to the nucleotide-binding pocket. This loss of myosin VI function may not allow myosin VI to transport its cargoes appropriately at the base and within the stereocilia, or to anchor the membrane of stereocilia to actin filaments via its cargos, both of which lead to structural changes in the stereocilia of myosin VI–impaired hair cells, and ultimately leading to deafness.
New Product Development—Experience from Distance Learning and Simulation-Based Training  [PDF]
Avraham Shtub
Creative Education (CE) , 2016, DOI: 10.4236/ce.2016.71011
Abstract: This paper presents our experience teaching how to manage New Product Development (NPD) projects to students from several universities—members of an international school network. A combination of lectures, problem solving and hands-on experience provided by a Simulation-Based Learning platform made it possible for students from universities distributed around the globe to work as NPD teams that develop new products in a virtual environment.
The Coulomb Blockade in Quantum Boxes
Eran Lebanon,Avraham Schiller,Frithjof B. Anders
Physics , 2002, DOI: 10.1103/PhysRevB.68.041311
Abstract: The charging of a quantum box connected to a lead by a single-mode point contact is solved for arbitrary temperatures, tunneling amplitudes, and gate voltages, using a variant of Wilson's numerical renormalization group. The charge inside the box and the capacitance of the junction are calculated on equal footing for all physical regimes, including weak tunneling, near perfect transmission, and the crossover regime in between. At the charge plateaus, perturbation theory is found to break down at fairly small tunneling amplitudes. Near perfect transmission, we confirm Matveev's scenario for the smearing of the Coulomb-blockade staircase. A surprising reentrance of the Coulomb-blockade staircase is found for large tunneling amplitudes. At the degeneracy points, we obtain two-channel Kondo behavior directly from the Coulomb-blockade Hamiltonian, without the restriction to two charge configurations or the introduction of an effective cutoff.
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