Targeted Extracellular Vesicle Gene Therapy for Modulating Alpha-Synuclein Expression in Gut and Spinal Cord

The development of effective disease-modifying therapies to halt Parkinson’s disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alpha-synuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression

On Orbital Period Changes in Nova Outbursts

We propose a new mechanism that produces an orbital period change during a nova outburst. When the ejected material carries away the specific angular momentum of the white dwarf, the orbital period increases. A magnetic field on the surface of the secondary star forces a fraction of the ejected material to corotate with the star, and hence the binary system. The ejected material thus takes angular momentum from the binary orbit and the orbital period decreases. We show that for sufficiently strong magnetic fields on the surface of the secondary star, the total change to the orbital period could even be negative during a nova outburst, contrary to previous expectations. Accurate determinations of pre- and post-outburst orbital periods of recurrent nova systems could test the new mechanism, in addition to providing meaningful constraints on otherwise difficult to measure physical quantities. We apply our mechanism to outbursts of the recurrent nova U Sco.Comment: Accepted for publication in MNRA

Discovery of a New Deeply Eclipsing SU UMa-Type Dwarf Nova, IY UMa (= TmzV85)

We discovered a new deeply eclipsing SU UMa-type dwarf nova, IY UMa, which experienced a superoutburst in 2000 January. Our monitoring revealed two distinct outbursts, which suggest a superoutburst interval of ~800 d, or its half, and an outburst amplitude of 5.4 mag. From time-series photometry during the superoutburst, we determined a superhump and orbital period of 0.07588 d and 0.0739132 d, respectively.Comment: 5 pages, 3 figures, accepted by PASJ lette

Dwarf novae in the Hamburg quasar survey : rarer than expected

Aims. We report the discovery of five new dwarf novae that were spectroscopically identified in the Hamburg Quasar Survey (HQS),and discuss the properties of the sample of new dwarf novae from the HQS. Methods. Follow-up time-resolved spectroscopy and photometry have been obtained to characterise the new systems. Results. The orbital periods determined from analyses of the radial velocity variations and/or orbital photometric variability are Porb 105.1min or Porb 109.9min for HS 0417+7445, Porb = 114.3 ± 2.7min for HS 1016+3412, Porb = 92.66 ± 0.17 min for HS 1340+1524, Porb = 272.317 ± 0.001 min for HS 1857+7127, and Porb = 258.02 ± 0.56 min for HS 2214+2845. HS 1857+7127 is found to be partially eclipsing. In HS 2214+2845 the secondary star of spectral type M3 ± 1 is clearly detected, and we estimate the distance to the system to be d = 390 ± 40 pc. We recorded one superoutburst of HS 0417+7445, identifying the system as a SUUMatype dwarf nova. HS 1016+3412 and HS 1340+1524 have rare outbursts, and their subtype is yet undetermined. HS 1857+7127 frequently varies in brightness and may be a ZCam-type dwarf nova. HS 2214+2845 is a UGem-type dwarf nova with a most likely cycle length of 71 d. Conclusions. To date, 14 new dwarf novae have been identified in the HQS. The ratio of short-period (3 h)systems of this sample is 1.3, much smaller compared to the ratio of 2.7 found for all known dwarf novae. The HQS dwarf novae display typically infrequent or low-amplitude outburst activity, underlining the strength of spectroscopic selection in identifying new CVs independently of their variability. The spectroscopic properties of short-period CVs in the HQS, newly identified and previously known, suggest that most, or possibly all of them are still evolving towards the minimum period. Their total number agrees with the predictions of population models within an order of magnitude. However, the bulk of all CVs is predicted to have evolved past the minimum period, and those systems remain unidentified. This suggests that those post-bounce systems have markedly weaker Hβ emission lines compared to the average known short-period CVs, and undergo no or extremely rare outbursts

Survey of Period Variations of Superhumps in SU UMa-Type Dwarf Novae

We systematically surveyed period variations of superhumps in SU UMa-type dwarf novae based on newly obtained data and past publications. In many systems, the evolution of superhump period are found to be composed of three distinct stages: early evolutionary stage with a longer superhump period, middle stage with systematically varying periods, final stage with a shorter, stable superhump period. During the middle stage, many systems with superhump periods less than 0.08 d show positive period derivatives. Contrary to the earlier claim, we found no clear evidence for variation of period derivatives between superoutburst of the same object. We present an interpretation that the lengthening of the superhump period is a result of outward propagation of the eccentricity wave and is limited by the radius near the tidal truncation. We interpret that late stage superhumps are rejuvenized excitation of 3:1 resonance when the superhumps in the outer disk is effectively quenched. Many of WZ Sge-type dwarf novae showed long-enduring superhumps during the post-superoutburst stage having periods longer than those during the main superoutburst. The period derivatives in WZ Sge-type dwarf novae are found to be strongly correlated with the fractional superhump excess, or consequently, mass ratio. WZ Sge-type dwarf novae with a long-lasting rebrightening or with multiple rebrightenings tend to have smaller period derivatives and are excellent candidate for the systems around or after the period minimum of evolution of cataclysmic variables (abridged).Comment: 239 pages, 225 figures, PASJ accepte

Long-Term Gene Therapy Causes Transgene-Specific Changes in the Morphology of Regenerating Retinal Ganglion Cells

Recombinant adeno-associated viral (rAAV) vectors can be used to introduce neurotrophic genes into injured CNS neurons, promoting survival and axonal regeneration. Gene therapy holds much promise for the treatment of neurotrauma and neurodegenerative diseases; however, neurotrophic factors are known to alter dendritic architecture, and thus we set out to determine whether such transgenes also change the morphology of transduced neurons. We compared changes in dendritic morphology of regenerating adult rat retinal ganglion cells (RGCs) after long-term transduction with rAAV2 encoding: (i) green fluorescent protein (GFP), or (ii) bi-cistronic vectors encoding GFP and ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF) or growth-associated protein-43 (GAP43). To enhance regeneration, rats received an autologous peripheral nerve graft onto the cut optic nerve of each rAAV2 injected eye. After 5–8 months, RGCs with regenerated axons were retrogradely labeled with fluorogold (FG). Live retinal wholemounts were prepared and GFP positive (transduced) or GFP negative (non-transduced) RGCs injected iontophoretically with 2% lucifer yellow. Dendritic morphology was analyzed using Neurolucida software. Significant changes in dendritic architecture were found, in both transduced and non-transduced populations. Multivariate analysis revealed that transgenic BDNF increased dendritic field area whereas GAP43 increased dendritic complexity. CNTF decreased complexity but only in a subset of RGCs. Sholl analysis showed changes in dendritic branching in rAAV2-BDNF-GFP and rAAV2-CNTF-GFP groups and the proportion of FG positive RGCs with aberrant morphology tripled in these groups compared to controls. RGCs in all transgene groups displayed abnormal stratification. Thus in addition to promoting cell survival and axonal regeneration, vector-mediated expression of neurotrophic factors has measurable, gene-specific effects on the morphology of injured adult neurons. Such changes will likely alter the functional properties of neurons and may need to be considered when designing vector-based protocols for the treatment of neurotrauma and neurodegeneration

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference