Positive Magneto-Resistance in Quasi-1D Conductors

We present here a simple qualitative model that interpolates between the high and low temperature properties of quasi-1D conductors. At high temperatures we argue that transport is governed by inelastic scattering whereas at low temperatures the conductance decays exponentially with the electron dephasing length. The crossover between these regimes occurs at the temperature at which the elastic and inelastic scattering times become equal. This model is shown to be in quantitative agreement with the organic conductor $TTT_2I_{3-\delta}$. Within this model, we also show that on the insulating side, the positive magnetoresistance of the form $(H/T)^2$ observed in $TTT_2I_{3-\delta}$ and other quasi-1D conductors can be explained by the role spin-flip scattering plays in the electron dephasing rate.Comment: 4 pages, Latex, no figure

Multiwalled carbon nanotube: Luttinger liquid or not?

We have measured IV-curves of multiwalled carbon nanotubes using end contacts. At low voltages, the tunneling conductance obeys non-Ohmic power law, which is predicted both by the Luttinger liquid and the environment-quantum-fluctuation theories. However, at higher voltages we observe a crossover to Ohm's law with a Coulomb-blockade offset, which agrees with the environment-quantum-fluctuation theory, but cannot be explained by the Luttinger-liquid theory. From the high-voltage tunneling conductance we determine the transmission line parameters of the nanotubes.Comment: RevTeX, 4 pages, 2 EPS-figures, submitted to Phys. Rev. Let

Localized and Delocalized Charge Transport in Single-Wall Carbon-Nanotube Mats

We measured the complex dielectric constant in mats of single-wall carbon-nanotubes between 2.7 K and 300 K up to 0.5 THz. The data are well understood in a Drude approach with a negligible temperature dependence of the plasma frequency (omega_p) and scattering time (tau) with an additional contribution of localized charges. The dielectric properties resemble those of the best ''metallic'' polypyrroles and polyanilines. The absence of metallic islands makes the mats a relevant piece in the puzzle of the interpretation of tau and omega_p in these polymers.Comment: 4 pages including 4 figure

Strong localization of electrons in quasi-one-dimensional conductors

We report on the experimental study of electron transport in sub-micron-wide ''wires'' fabricated from Si $\delta$-doped GaAs. These quasi-one-dimensional (Q1D) conductors demonstrate the crossover from weak to strong localization with decreasing the temperature. On the insulating side of the crossover, the resistance has been measured as a function of temperature, magnetic field, and applied voltage for different values of the electron concentration, which was varied by applying the gate voltage. The activation temperature dependence of the resistance has been observed with the activation energy close to the mean energy spacing of electron states within the localization domain. The study of non-linearity of the current-voltage characteristics provides information on the distance between the critical hops which govern the resistance of Q1D conductors in the strong localization (SL) regime. We observe the exponentially strong negative magnetoresistance; this orbital magnetoresistance is due to the universal magnetic-field dependence of the localization length in Q1D conductors. The method of measuring of the single-particle density of states (DoS) in the SL regime has been suggested. Our data indicate that there is a minimum of DoS at the Fermi level due to the long-range Coulomb interaction.Comment: 12 pages, 11 figures; the final version to appear in Phys. Rev.

Combining multiomics and drug perturbation profiles to identify muscle-specific treatments for spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify potentially novel treatments to alleviate muscle pathology combining transcriptomics, proteomics, and perturbational data sets. This revealed potential drug candidates for repurposing in SMA. One of the candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including lifespan, weight, and key molecular networks in skeletal muscle. Our work highlights the potential of multiple and parallel data-driven approaches for the development of potentially novel treatments for use in combination with SMN restoration therapies

Interventions targeting glucocorticoid-Krüppel-like factor 15-branched-chain amino acid signaling improve disease phenotypes in spinal muscular atrophy mice

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling

A New Evolutionary Algorithm-Based Home Monitoring Device for Parkinson’s Dyskinesia

Parkinson’s disease (PD) is a neurodegenerative movement disorder. Although there is no cure, symptomatic treatments are available and can significantly improve quality of life. The motor, or movement, features of PD are caused by reduced production of the neurotransmitter dopamine. Dopamine deficiency is most often treated using dopamine replacement therapy. However, this therapy can itself lead to further motor abnormalities referred to as dyskinesia. Dyskinesia consists of involuntary jerking movements and muscle spasms, which can often be violent. To minimise dyskinesia, it is necessary to accurately titrate the amount of medication given and monitor a patient’s movements. In this paper, we describe a new home monitoring device that allows dyskinesia to be measured as a patient goes about their daily activities, providing information that can assist clinicians when making changes to medication regimens. The device uses a predictive model of dyskinesia that was trained by an evolutionary algorithm, and achieves AUC>0.9 when discriminating clinically significant dyskinesia

Loss of Nuclear Activity of the FBXO7 Protein in Patients with Parkinsonian-Pyramidal Syndrome (PARK15)

Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15

Early-stage [123I]beta-CIT SPECT and long-term clinical follow-up in patients with an initial diagnosis of Parkinson's disease

beta-CIT binding in both caudate nuclei was lower than in the group of patients with IPD. In addition, putamen to caudate binding ratios were higher in the group of APS patients. In spite of these differences, individual binding values showed considerable overlap between the groups. CONCLUSION: [(123)I]beta-CIT SPECT scanning in early-stage, untreated parkinsonian patients revealed a relative sparing of the caudate nucleus in patients with IPD as compared to patients later (re)diagnosed with APS. Nevertheless, the pattern of striatal involvement appears to have little predictive value for a later re-diagnosis of APS in individual case