Focused and Deep Brain Magnetic Stimulation Using New Coil Design in Mice

Deep brain transcranial magnetic stimulation (TMS) offers promising treatment for neurological disorders that originate from deeper regions of the brain, such as Parkinson\u27s disease. Coils designed for the human head need significant redesigning to stimulate selective regions of the mouse brain for advanced TMS therapy analysis. We report a focused and deep brain TMS coil for mice that is based on a two coil configuration similar to the \u27Halo coil\u27. A heterogeneous MRI derived head model of mouse was used to obtain an electric field of about 150 V/m in selective deeper regions of the brain. Focality of stimulation was quantified using the ratio of half value volume to half value of depth of electric field. A prototype of the final coil design was fabricated and characterized to compare simulated and physical magnetic field profiles

\u3csup\u3e1\u3c/sup\u3eH, \u3csup\u3e15\u3c/sup\u3eN, \u3csup\u3e13\u3c/sup\u3eC, and \u3csup\u3e13\u3c/sup\u3eCO Assignments of Human Interleukin-4 Using Three-Dimensional Double- and Triple-Resonance Heteronuclear Magnetic Resonance Spectroscopy

The assignment of the 1H, 15N, 13CO, and 13C resonances of recombinant human interleukin-4 (IL-4), a protein of 133 residues and molecular mass of 15.4 kDa, is presented based on a series of 11 three-dimensional (3D) double- and triple resonance heteronuclear NMR experiments. These studies employ uniformly labeled 15N- and 15N/13C-labeled IL-4 with an isotope incorporation of \u3e95% for the protein expressed in yeast. Five independent sequential connectivity pathways via one-, two-, and three-bond heteronuclear J couplings are exploited to obtain unambiguous sequential assignments. Specifically, CO(i)-N(i+l),NH(i+l) correlations are observed in the HNCO experiment, the CαH(i),Cα(i)-N(i+l) correlations in the HCA(CO)N experiment, the Cα(i)-N(i+l),NH(i+ 1) correlations in the HNCA and HN(C0)CA experiments, the CαH(i)-N(i+ l),NH(i+l) correlations in the H(CA)NH and HN(CO)HB experiments, and the Cβ(i)-N(i+ l),NH(i+ 1) correlations in the HN(CO)HB experiments. The backbone intraresidue CαH(i)-15N(i)-NH(i) correlations are provided by the 15N-edited Hartmann-Hahn (HOHAHA) and H(CA)NH experiments, the CβH(i)-15N(i)-NH(i) correlations by the 15N-edited HOHAHA and HNHB experiments, the l3Cα(i)-l5N(i)-NH(i) correlations by the HNCA experiment, and the CαH(1)-13Cα(i)-13CO(i) correlations by the HCACO experiment. Aliphatic side-chain spin systems are assigned by 3D 1H-13C-13C-1H correlated (HCCH-COSY) and total correlated (HCCH-TOCSY) spectroscopy. Because of the high resolution afforded by these experiments, as well as the availability of multiple sequential connectivity pathways, ambiguities associated with the limited chemical shift dispersion associated with helical proteins are readily resolved. Further, in the majority of cases (88%), four or more sequential correlations are observed between successive residues. Consequently, the interpretation of these experiments readily lends itself to semiautomated analysis which significantly simplifies and speeds up the assignment process. The assignments presented in this paper provide the essential basis for studies aimed at determining the high-resolution three-dimensional structure of IL-4 in solution

Integration, Effectiveness and Adaptation in Social Systems

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66951/2/10.1177_009539977500600402.pd

Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Aβ deposits represent a neuropathological hallmark of Alzheimer's disease (AD). Both soluble and insoluble Aβ species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Aβ production or accumulation remains a priority. NFκB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Aβ. We therefore explored whether the known NFκB inhibitor celastrol could represent a suitable compound for decreasing Aβ production and accumulation <it>in vivo</it>.</p> <p>Methods</p> <p>The effect of celastrol on amyloid precursor protein (APP) processing, Aβ production and NFκB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Aβ accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol.</p> <p>Results</p> <p><it>In vitro</it>, celastrol dose dependently prevented NFκB activation and inhibited BACE-1 expression. Celastrol potently inhibited Aβ_1-40and Aβ_1-42production by reducing the β-cleavage of APP, leading to decreased levels of APP-CTFβ and APPsβ. <it>In vivo</it>, celastrol appeared to reduce the levels of both soluble and insoluble Aβ_1-38, Aβ_1-40and Aβ_1-42. In addition, a reduction in Aβ plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol.</p> <p>Conclusions</p> <p>Overall our data suggest that celastrol is a potent Aβ lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFκB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.</p

Discrete multivortex solitons

We introduce discrete multivortex solitons in a ring of nonlinear oscillators coupled to a central site. Regular clusters of discrete vortices appear as a result of mode collisions and we show that their stability is determined by global symmetries rather than the stability of constituent vortices. Stable multivortex solitons support complex vortex dynamics including charge flipping and spiraling.Comment: 3 pages, 3 figure

Generic Business Model Types for Enterprise Mashup Intermediaries

The huge demand for situational and ad-hoc applications desired by the mass of business end users led to a new kind of Web applications, well-known as Enterprise Mashups. Users with no or limited programming skills are empowered to leverage in a collaborative manner existing Mashup components by combining and reusing company internal and external resources within minutes to new value added applications. Thereby, Enterprise Mashup environments interact as intermediaries to match the supply of providers and demand of consumers. By following the design science approach, we propose an interaction phase model artefact based on market transaction phases to structure required intermediary features. By means of five case studies, we demonstrate the application of the designed model and identify three generic business model types for Enterprise Mashups intermediaries (directory, broker, and marketplace). So far, intermediaries following a real marketplace business model don’t exist in context of Enterprise Mashups and require further research for this emerging paradigm

Decoherence-Free Subspaces for Multiple-Qubit Errors: (I) Characterization

Coherence in an open quantum system is degraded through its interaction with a bath. This decoherence can be avoided by restricting the dynamics of the system to special decoherence-free subspaces. These subspaces are usually constructed under the assumption of spatially symmetric system-bath coupling. Here we show that decoherence-free subspaces may appear without spatial symmetry. Instead, we consider a model of system-bath interactions in which to first order only multiple-qubit coupling to the bath is present, with single-qubit system-bath coupling absent. We derive necessary and sufficient conditions for the appearance of decoherence-free states in this model, and give a number of examples. In a sequel paper we show how to perform universal and fault tolerant quantum computation on the decoherence-free subspaces considered in this paper.Comment: 18 pages, no figures. Major changes. Section on universal fault tolerant computation removed. This section contained a crucial error. A new paper [quant-ph/0007013] presents the correct analysi

Ultrafast x-ray-induced nuclear dynamics in diatomic molecules using femtosecond x-ray-pump-x-ray-probe spectroscopy

Citation: Lehmann, C. S., Picon, A., Bostedt, C., Rudenko, A., Marinelli, A., Moonshiram, D., . . . Southworth, S. H. (2016). Ultrafast x-ray-induced nuclear dynamics in diatomic molecules using femtosecond x-ray-pump-x-ray-probe spectroscopy. Physical Review A, 94(1), 7. doi:10.1103/PhysRevA.94.013426The capability of generating two intense, femtosecond x-ray pulses with a controlled time delay opens the possibility of performing time-resolved experiments for x-ray-induced phenomena. We have applied this capability to study the photoinduced dynamics in diatomic molecules. In molecules composed of low-Z elements, K-shell ionization creates a core-hole state in which the main decay mode is an Auger process involving two electrons in the valence shell. After Auger decay, the nuclear wave packets of the transient two-valence-hole states continue evolving on the femtosecond time scale, leading either to separated atomic ions or long-lived quasibound states. By using an x-ray pump and an x-ray probe pulse tuned above the K-shell ionization threshold of the nitrogen molecule, we are able to observe ion dissociation in progress by measuring the time-dependent kinetic energy releases of different breakup channels. We simulated the measurements on N-2 with a molecular dynamics model that accounts for K-shell ionization, Auger decay, and the time evolution of the nuclear wave packets. In addition to explaining the time-dependent feature in the measured kinetic energy release distributions from the dissociative states, the simulation also reveals the contributions of quasibound states

Hetero-site-specific X-ray pump-probe spectroscopy for femtosecond intramolecular dynamics

Citation: Picon, A., Lehmann, C. S., Bostedt, C., Rudenko, A., Marinelli, A., Osipov, T., . . . Southworth, S. H. (2016). Hetero-site-specific X-ray pump-probe spectroscopy for femtosecond intramolecular dynamics. Nature Communications, 7, 6. doi:10.1038/ncomms11652New capabilities at X-ray free-electron laser facilities allow the generation of two-colour femtosecond X-ray pulses, opening the possibility of performing ultrafast studies of X-ray-induced phenomena. Particularly, the experimental realization of hetero-site-specific X-ray-pump/X-ray-probe spectroscopy is of special interest, in which an X-ray pump pulse is absorbed at one site within a molecule and an X-ray probe pulse follows the X-ray-induced dynamics at another site within the same molecule. Here we show experimental evidence of a hetero-site pump-probe signal. By using two-colour 10-fs X-ray pulses, we are able to observe the femtosecond time dependence for the formation of F ions during the fragmentation of XeF2 molecules following X-ray absorption at the Xe site

Non-standard embedding and five-branes in heterotic M-Theory

We construct vacua of M-theory on S^1/Z_2 associated with Calabi-Yau three-folds. These vacua are appropriate for compactification to N=1 supersymmetry theories in both four and five dimensions. We allow for general E_8 x E_8 gauge bundles and for the presence of five-branes. The five-branes span the four-dimensional uncompactified space and are wrapped on holomorphic curves in the Calabi-Yau space. Properties of these vacua, as well as of the resulting low-energy theories, are discussed. We find that the low-energy gauge group is enlarged by gauge fields that originate on the five-brane world-volumes. In addition, the five-branes increase the types of new E_8 x E_8 breaking patterns allowed by the non-standard embedding. Characteristic features of the low-energy theory, such as the threshold corrections to the gauge kinetic functions, are significantly modified due to the presence of the five-branes, as compared to the case of standard or non-standard embeddings without five-branes.Comment: 34 pages, Latex 2e with amsmath, typos removed, factors corrected, refs improve