SPG10 is a rare cause of spastic paraplegia in European families

Background: SPG10 is an autosomal dominant form of hereditary spastic paraplegia (HSP), which is caused by mutations in the neural kinesin heavy chain KIF5A gene, the neuronal motor of fast anterograde axonal transport. Only four mutations have been identified to date.Objective: To determine the frequency of SPG10 in European families with HSP and to specify the SPG10 phenotype.Patients and methods: 80 index patients from families with autosomal dominant HSP were investigated for SPG10 mutations by direct sequencing of the KIF5A motor domain. Additionally, the whole gene was sequenced in 20 of these families.Results: Three novel KIF5A mutations were detected in German families, including one missense mutation (c.759G>T, p.K253N), one in frame deletion (c.768_770delCAA, p.N256del) and one splice site mutation (c.217G>A). Onset of gait disturbance varied from infancy to 30 years of age. All patients presented clinically with pure HSP, but a subclinical sensory--motor neuropathy was detected by neurophysiology studies.Conclusions: SPG10 accounts for approximately 3% of European autosomal dominant HSP families. All mutations affect the motor domain of kinesin and thus most likely impair axonal transport. Clinically, SPG10 is characterised by spastic paraplegia with mostly subclinical peripheral neuropathy

Aging Effect in Ceramic Superconductors

A three-dimensional lattice of the Josephson junctions with a finite self-conductance is employed to model ceramic superconductors. Using Monte Carlo simulations it is shown that the aging disappears in the strong screening limit. In the weeak screening regime aging is present even at low temperatures. For intermediate values of the self-inductance aging occurs at intermediate temperatures interval but is suppressed entirely at high and low temperatures. Our results are in good agreement with experiments.Comment: 5 pages, 5 eps figures, to appear in Physical Review Letter

Paramagnetic Meissner Effect in Multiply-Connected Superconductors

We have measured a paramagnetic Meissner effect in Nb-Al2O3-Nb Josephson junction arrays using a scanning SQUID microscope. The arrays exhibit diamagnetism for some cooling fields and paramagnetism for other cooling fields. The measured mean magnetization is always less than 0.3 flux quantum (in terms of flux per unit cell of the array) for the range of cooling fields investigated. We demonstrate that a new model of magnetic screening, valid for multiply-connected superconductors, reproduces all of the essential features of paramagnetism that we observe and that no exotic mechanism, such as d-wave superconductivity, is needed for paramagnetism.Comment: 4 pages, 3 figures, LaTe

The origin of paramagnetic magnetization in field-cooled YBa2Cu3O7 films

Temperature dependences of the magnetic moment have been measured in YBa_2Cu_3O_{7-\delta} thin films over a wide magnetic field range (5 <= H <= 10^4 Oe). In these films a paramagnetic signal known as the paramagnetic Meissner effect has been observed. The experimental data in the films, which have strong pinning and high critical current densities (J_c ~ 2 \times 10^6 A/cm^2 at 77 K), are quantitatively shown to be highly consistent with the theoretical model proposed by Koshelev and Larkin [Phys. Rev. B 52, 13559 (1995)]. This finding indicates that the origin of the paramagnetic effect is ultimately associated with nucleation and inhomogeneous spatial redistribution of magnetic vortices in a sample which is cooled down in a magnetic field. It is also shown that the distribution of vortices is extremely sensitive to the interplay of film properties and the real experimental conditions of the measurements.Comment: RevTex, 8 figure

Polyphenol Content and Antioxidant Activity of Sour Cherries From Serbia

The aim of this study was to evaluate the content of phenolics: the total phenols (TP), flavonoids (TF), anthocyanins (TA), as well as the total antioxidant\ud capacity (TAC) in three sour cherry cultivars (Prunus cerasus L.) introduced to the southeast Serbia climate conditions. Among the investigated sour cherries,\ud „Oblačinska“ cultivar contained the highest amounts of all groups of phenolics, followed by „Cigančica“ > „Marela“. A significant difference were observed in the phenolic content among different cultivars and growing seasons (p  0.05), and the phenolic compounds were significantly higher in the growing season 2009. The examined cultivars possess a high antioxidant capacity, and all phenolics of highy correlation with TAC. The following compounds were identified and quantified using HPLC-DAD: 4 anthocyanins, the most abundant of which was cyanidin-3-glucoside in “Marela” and “Oblačinska”, and cyanidin-3-glucosylrutinoside in „Cigančica“, and 4 hydroxycinnamic acids, the most abundant of which was neochlorogenic acid in all sour cherry cultivars. The growing and ripening process on the tree of sour cherry cv. „Oblačinska“ was evaluated also. The results showed significant increases in total phenols during the ripening, the total anthocyanins and total antioxidant capacity and 4 quantified anthocyanins, however the neochlorogenic acid decreased during the ripening. The study indicated that the growing and climate conditions in southeast Serbia are convenient for introducing sour cherry cultivars.\u

Non-Fermi liquid behavior of SrRuO_3 -- evidence from infrared conductivity

The reflectivity of the itinerant ferromagnet SrRuO_3 has been measured between 50 and 25,000 cm-1 at temperatures ranging from 40 to 300 K, and used to obtain conductivity, scattering rate, and effective mass as a function of frequency and temperature. We find that at low temperatures the conductivity falls unusually slowly as a function of frequency (proportional to \omega^{-1/2}), and at high temperatures it even appears to increase as a function of frequency in the far-infrared limit. The data suggest that the charge dynamics of SrRuO_3 are substantially different from those of Fermi-liquid metals.Comment: 4 pages, 3 postscript figure

Induced paramagnetic states by localized π\pi -loops in grain boundaries

Recent experiments on high-temperature superconductors show paramagnetic behavior localized at grain boundaries (GB). This paramagnetism can be attributed to the presence unconventional d-wave induced $\pi$-junctions. By modeling the GB as an array of $\pi$ and conventional Josephson junction we determine the conditions of the occurrence of the paramagnetic behavior.Comment: 4 pages, 4 figures, submitted to Phys. Rev. Let

Pseudogap formation of four-layer BaRuO3_3 and its electrodynamic response changes

We investiaged the optical properties of four-layer BaRuO$_{3}$, which shows a fermi-liquid-like behavior at low temperature. Its optical conductivity spectra clearly displayed the formation of a pseudogap and the development of a coherent peak with decreasing temperature. Temperature-dependences of the density $n$ and the scattering rate $1/\tau$ of the coherent component were also derived. As the temperature decreases, both $n$ and $1/\tau$ decrease for four-layer BaRuO$_{3}$. These electrodynamic responses were compared with those of nine-layer BaRuO$_{3}$, which also shows a pseudogap formation but has an insulator-like state at low temperature. It was found that the relative rates of change of both $n$ and $1/\tau$ determine either metallic or insulator-like responses in the ruthenates. The optical properties of the four-layer ruthenate were also compared with those of other pseudogap systems, such as high $T_{c}$ cuprates and heavy electron systems.Comment: 7 figures. submitted to Phys. Rev.

Evaluation of tolerance to lentiviral LV-RPE65 gene therapy vector after subretinal delivery in non-human primates.

Several approaches have been developed for gene therapy in RPE65-related Leber congenital amaurosis. To date, strategies that have reached the clinical stages rely on adeno-associated viral vectors and two of them documented limited long-term effect. We have developed a lentiviral-based strategy of RPE65 gene transfer that efficiently restored protein expression and cone function in RPE65-deficient mice. In this study, we evaluated the ocular and systemic tolerances of this lentiviral-based therapy (LV-RPE65) on healthy nonhuman primates (NHPs), without adjuvant systemic anti-inflammatory prophylaxis. For the first time, we describe the early kinetics of retinal detachment at 2, 4, and 7 days after subretinal injection using multimodal imaging in 5 NHPs. We revealed prolonged reattachment times in LV-RPE65-injected eyes compared to vehicle-injected eyes. Low- (n = 2) and high-dose (n = 2) LV-RPE65-injected eyes presented a reduction of the outer nuclear and photoreceptor outer segment layer thickness in the macula, that was more pronounced than in vehicle-injected eyes (n = 4). All LV-RPE65-injected eyes showed an initial perivascular reaction that resolved spontaneously within 14 days. Despite foveal structural changes, full-field electroretinography indicated that the overall retinal function was preserved over time and immunohistochemistry identified no difference in glial, microglial, or leucocyte ocular activation between low-dose, high-dose, and vehicle-injected eyes. Moreover, LV-RPE65-injected animals did not show signs of vector shedding or extraocular targeting, confirming the safe ocular restriction of the vector. Our results evidence a limited ocular tolerance to LV-RPE65 after subretinal injection without adjuvant anti-inflammatory prophylaxis, with complications linked to this route of administration necessitating to block this transient inflammatory event

Amyloid Precursor-Like Protein 2 deletion-induced retinal synaptopathy related to congenital stationary night blindness: structural, functional and molecular characteristics.

Amyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO). Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, APLP2-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the APP-KO photoreceptor ribbon synapses and bipolar cells were intact. The APLP2-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the APLP2-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including CACNA1F, GRM6, TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, VSX1 and OTX2. These findings demonstrate that APLP2 couples retina development and synaptic genes and present the first evidence that APLP2 expression may be linked to synaptic disease