Genetic Inactivation of Trpml3 Does Not Lead to Hearing and Vestibular Impairment in Mice

TRPML3, a member of the transient receptor potential (TRP) family, is an inwardly rectifying, non-selective Ca2+-permeable cation channel that is regulated by extracytosolic Na+ and H+ and can be activated by a variety of small molecules. The severe auditory and vestibular phenotype of the TRPML3(A419P) varitint-waddler mutation made this protein particularly interesting for inner ear biology. To elucidate the physiological role of murine TRPML3, we conditionally inactivated Trpml3 in mice. Surprisingly, lack of functional TRPML3 did not lead to circling behavior, balance impairment or hearing loss

Effects of music therapy in the treatment of children with delayed speech development - results of a pilot study

<p>Abstract</p> <p>Background</p> <p>Language development is one of the most significant processes of early childhood development. Children with delayed speech development are more at risk of acquiring other cognitive, social-emotional, and school-related problems. Music therapy appears to facilitate speech development in children, even within a short period of time. The aim of this pilot study is to explore the effects of music therapy in children with delayed speech development.</p> <p>Methods</p> <p>A total of 18 children aged 3.5 to 6 years with delayed speech development took part in this observational study in which music therapy and no treatment were compared to demonstrate effectiveness. Individual music therapy was provided on an outpatient basis. An ABAB reversal design with alternations between music therapy and no treatment with an interval of approximately eight weeks between the blocks was chosen. Before and after each study period, a speech development test, a non-verbal intelligence test for children, and music therapy assessment scales were used to evaluate the speech development of the children.</p> <p>Results</p> <p>Compared to the baseline, we found a positive development in the study group after receiving music therapy. Both phonological capacity and the children's understanding of speech increased under treatment, as well as their cognitive structures, action patterns, and level of intelligence. Throughout the study period, developmental age converged with their biological age. Ratings according to the Nordoff-Robbins scales showed clinically significant changes in the children, namely in the areas of client-therapist relationship and communication.</p> <p>Conclusions</p> <p>This study suggests that music therapy may have a measurable effect on the speech development of children through the treatment's interactions with fundamental aspects of speech development, including the ability to form and maintain relationships and prosodic abilities. Thus, music therapy may provide a basic and supportive therapy for children with delayed speech development. Further studies should be conducted to investigate the mechanisms of these interactions in greater depth.</p> <p>Trial registration</p> <p>The trial is registered in the German clinical trials register; Trial-No.: DRKS00000343</p

Controlled Collisions for Multiparticle Entanglement of Optically Trapped Atoms

Entanglement lies at the heart of quantum mechanics and in recent years has been identified as an essential resource for quantum information processing and computation. Creating highly entangled multi-particle states is therefore one of the most challenging goals of modern experimental quantum mechanics, touching fundamental questions as well as practical applications. Here we report on the experimental realization of controlled collisions between individual neighbouring neutral atoms trapped in the periodic potential of an optical lattice. These controlled interactions act as an array of quantum gates between neighbouring atoms in the lattice and their massively parallel operation allows the creation of highly entangled states in a single operational step, independent of the size of the system. In the experiment, we observe a coherent entangling-disentangling evolution in the many-body system depending on the phase shift acquired during the collision between neighbouring atoms. This dynamics is indicative of highly entangled many-body states that present novel opportunities for theory and experiment.Comment: 17 pages, including 5 figures, accepted for publication in Natur

Cooperative coupling of ultracold atoms and surface plasmons

Cooperative coupling between optical emitters and light fields is one of the outstanding goals in quantum technology. It is both fundamentally interesting for the extraordinary radiation properties of the participating emitters and has many potential applications in photonics. While this goal has been achieved using high-finesse optical cavities, cavity-free approaches that are broadband and easy to build have attracted much attention recently. Here we demonstrate cooperative coupling of ultracold atoms with surface plasmons propagating on a plane gold surface. While the atoms are moving towards the surface they are excited by an external laser pulse. Excited surface plasmons are detected via leakage radiation into the substrate of the gold layer. A maximum Purcell factor of $\eta_\mathrm{P}=4.9$ is reached at an optimum distance of $z=250~\mathrm{nm}$ from the surface. The coupling leads to the observation of a Fano-like resonance in the spectrum.Comment: 9 pages, 4 figure

Protein Conformation and Supercharging with DMSO from Aqueous Solution

The efficacy of dimethyl sulfoxide (DMSO) as a supercharging reagent for protein ions formed by electrospray ionization from aqueous solution and the mechanism for supercharging were investigated. Addition of small amounts of DMSO to aqueous solutions containing hen egg white lysozyme or equine myoglobin results in a lowering of charge, whereas a significant increase in charge occurs at higher concentrations. Results from both near-UV circular dichroism spectroscopy and solution-phase hydrogen/deuterium exchange mass spectrometry indicate that DMSO causes a compaction of the native structure of these proteins at low concentration, but significant unfolding occurs at ~63% and ~43% DMSO for lysozyme and myoglobin, respectively. The DMSO concentrations required to denature these two proteins in bulk solution are ~3–5 times higher than the concentrations required for the onset of supercharging, consistent with a significantly increased concentration of this high boiling point supercharging reagent in the ESI droplet as preferential evaporation of water occurs. DMSO is slightly more basic than m-nitrobenzyl alcohol and sulfolane, two other supercharging reagents, based on calculated proton affinity and gas-phase basicity values both at the B3LYP and MP2 levels of theory, and all three of these supercharging reagents are significantly more basic than water. These results provide additional evidence that the origin of supercharging from aqueous solution is the result of chemical and/or thermal denaturation that occurs in the ESI droplet as the concentration of these supercharging reagents increases, and that proton transfer reactivity does not play a significant role in the charge enhancement observed

Alpha-Synuclein Cell-to-Cell Transfer and Seeding in Grafted Dopaminergic Neurons In Vivo

Several people with Parkinson’s disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10–22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in cell and animal models. In cell culture, α-synuclein has been found to transfer from one cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient cell. In animal models, transfer of α-synuclein from host brain cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the transferred α-synuclein. We now demonstrate frequent transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying cell-to-cell transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the transferred α-synuclein. Finally, we show that, at least in a subset of the studied cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit cell-to-cell transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology

The Efficacy of Generating Three Independent Anti-HIV-1 siRNAs from a Single U6 RNA Pol III-Expressed Long Hairpin RNA

RNA Interference (RNAi) effectors have been used to inhibit rogue RNAs in mammalian cells. However, rapidly evolving sequences such as the human immunodeficiency virus type 1 (HIV-1) require multiple targeting approaches to prevent the emergence of escape variants. Expressed long hairpin RNAs (lhRNAs) have recently been used as a strategy to produce multiple short interfering RNAs (siRNAs) targeted to highly variant sequences. We aimed to characterize the ability of expressed lhRNAs to generate independent siRNAs that silence three non-contiguous HIV-1 sites by designing lhRNAs comprising different combinations of siRNA-encoding sequences. All lhRNAs were capable of silencing individual target sequences. However, silencing efficiency together with concentrations of individual lhRNA-derived siRNAs diminished from the stem base (first position) towards the loop side of the hairpin. Silencing efficacy against HIV-1 was primarily mediated by siRNA sequences located at the base of the stem. Improvements could be made to first and second position siRNAs by adjusting spacing arrangements at their junction, but silencing of third position siRNAs remained largely ineffective. Although lhRNAs offer advantages for combinatorial RNAi, we show that good silencing efficacy across the span of the lhRNA duplex is difficult to achieve with sequences that encode more than two adjacent independent siRNAs

Photoactivatable drugs for nicotinic optopharmacology

Photoactivatable pharmacological agents have revolutionized neuroscience, but the palette of available compounds is limited. We describe a general method for caging tertiary amines by using a stable quaternary ammonium linkage that elicits a red shift in the activation wavelength. We prepared a photoactivatable nicotine (PA-Nic), uncageable via one- or two-photon excitation, that is useful to study nicotinic acetylcholine receptors (nAChRs) in different experimental preparations and spatiotemporal scales

Search for Charged Higgs Bosons in e+e- Collisions at \sqrt{s} = 189 GeV

A search for pair-produced charged Higgs bosons is performed with the L3 detector at LEP using data collected at a centre-of-mass energy of 188.6 GeV, corresponding to an integrated luminosity of 176.4 pb^-1. Higgs decays into a charm and a strange quark or into a tau lepton and its associated neutrino are considered. The observed events are consistent with the expectations from Standard Model background processes. A lower limit of 65.5 GeV on the charged Higgs mass is derived at 95 % confidence level, independent of the decay branching ratio Br(H^{+/-} -> tau nu)