Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with increased risk for developing Parkinson's disease (PD). Previously, we found that LRRK2 G2019S mutation carriers have increased ...mitochondrial DNA (mtDNA) damage and after zinc finger nuclease-mediated gene mutation correction, mtDNA damage was no longer detectable. While the mtDNA damage phenotype can be unambiguously attributed to the LRRK2 G2019S mutation, the underlying mechanism(s) is unknown. Here, we examine the role of LRRK2 kinase function in LRRK2 G2019S-mediated mtDNA damage, using both genetic and pharmacological approaches in cultured neurons and PD patient-derived cells. Expression of LRRK2 G2019S induced mtDNA damage in primary rat midbrain neurons, but not in cortical neuronal cultures. In contrast, the expression of LRRK2 wild type or LRRK2 D1994A mutant (kinase dead) had no effect on mtDNA damage in either midbrain or cortical neuronal cultures. In addition, human LRRK2 G2019S patient-derived lymphoblastoid cell lines (LCL) demonstrated increased mtDNA damage relative to age-matched controls. Importantly, treatment of LRRK2 G2019S expressing midbrain neurons or patient-derived LRRK2 G2019S LCLs with the LRRK2 kinase inhibitor GNE-7915, either prevented or restored mtDNA damage to control levels. These findings support the hypothesis that LRRK2 G2019S-induced mtDNA damage is LRRK2 kinase activity dependent, uncovering a novel pathological role for this kinase. Blocking or reversing mtDNA damage via LRRK2 kinase inhibition or other therapeutic approaches may be useful to slow PD-associated pathology.
Abstract Parkinson's disease associated mutations in leucine rich repeat kinase 2 ( LRRK2 ) impair mitochondrial function and increase the vulnerability of induced pluripotent stem cell ...(iPSC)-derived neural cells from patients to oxidative stress. Since mitochondrial DNA (mtDNA) damage can compromise mitochondrial function, we examined whether LRRK2 mutations can induce damage to the mitochondrial genome. We found greater levels of mtDNA damage in iPSC-derived neural cells from patients carrying homozygous or heterozygous LRRK2 G2019S mutations, or at-risk individuals carrying the heterozygous LRRK2 R1441C mutation, than in cells from unrelated healthy subjects who do not carry LRRK2 mutations. After zinc finger nuclease-mediated repair of the LRRK2 G2019S mutation in iPSCs, mtDNA damage was no longer detected in differentiated neuroprogenitor and neural cells. Our results unambiguously link LRRK2 mutations to mtDNA damage and validate a new cellular phenotype that can be used for examining pathogenic mechanisms and screening therapeutic strategies.
The aims of this study were to 1) compare active drag (Da) calculation between a single land-based measurement of frontal surface area (FSA) and in-water FSA measures obtained at key events of the ...arm pull (1, right upper-limb catch; 2, right upper-limb insweep; 3, right upper-limb exit and left upper-limb catch; 4, left upper-limb insweep; and 5, left upper-limb exit and right upper-limb catch) at front crawl swimming, and 2) compare mechanical power variables computed based on these two approaches.
Seventeen swimmers (11, male; 6, female; 16.15 ± 0.94 yr old) were recruited. The FSA was measured based on two approaches: (i) nonvariation, that is, assuming a constant value, and (ii) variation, that is, calculated in each key event of the front crawl swim. Active drag based on a nonvariation of the FSA was measured using the Velocity Perturbation method. Active drag based on a variation approach was measured in each key event of the front crawl according to the law of linear motion. Paired t-test (P ≤ 0.05), simple linear regression models, and Bland-Altman plots between assessment methods (variation vs nonvariation) were computed.
The FSA (variation) was higher than when assuming a nonvariation (0.1110 ± 0.010 vs 0.0968 ± 0.010 m, Δ = 15.69%, t = 4.40, P < 0.001, d = 0.95). Active drag (variation) was also significantly higher than when assuming a nonvariation (88.44 ± 25.92 vs 75.41 ± 15.11 N, Δ = 16.09%, t = 3.66, P = 0.002, d = 0.61).
Besides the FSA, swim velocity also changes during the front crawl arm pull. The variation of both variables had a significant effect on the active drag measurement and consequently on mechanical power and total power input variables.
While young muscle is capable of restoring the original architecture of damaged myofibers, aged muscle displays a markedly reduced regeneration. We show that expression of the "anti-aging" protein, ...α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myofiber regeneration, revealing a critical role for α-Klotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.
Preserving the availability and integrity of the power grid critical infrastructures in the face of fast-spreading intrusions requires advances in detection techniques specialized for such ...large-scale cyber-physical systems. In this paper, we present a security-oriented cyber-physical state estimation (SCPSE) system, which, at each time instant, identifies the compromised set of hosts in the cyber network and the maliciously modified set of measurements obtained from power system sensors. SCPSE fuses uncertain information from different types of distributed sensors, such as power system meters and cyber-side intrusion detectors, to detect the malicious activities within the cyber-physical system. We implemented a working prototype of SCPSE and evaluated it using the IEEE 24-bus benchmark system. The experimental results show that SCPSE significantly improves on the scalability of traditional intrusion detection techniques by using information from both cyber and power sensors. Furthermore, SCPSE was able to detect all the attacks against the control network in our experiments.
I show that the lensing masses of the Sloan Lens Advanced Camera Surveys sample of strong gravitational lenses are consistent with the stellar masses determined from population synthesis models using ...the Salpeter initial mass function. This is true in the context of both General Relativity and modified Newtonian dynamics (MOND), and is in agreement with the expectation of MOND that there should be little classical discrepancy within the high surface brightness regions probed by strong gravitational lensing. There is also dynamical evidence from this sample supporting the claim that the mass-to-light ratio of the stellar component increases with the velocity dispersion.
Modified Newtonian dynamics (MOND) is an empirically motivated modification
of Newtonian gravity or inertia suggested by Milgrom as an alternative to
cosmic dark matter. The basic idea is that at ...accelerations below
a
o
10
−8
cm/s
2
cH
o
/6 the effective gravitational attraction
approaches
,
where
g
n
is the usual Newtonian acceleration. This
simple algorithm yields flat rotation curves for spiral galaxies and a
mass-rotation velocity relation of the form
M
∝
V
4
that forms the basis for the observed
luminosity-rotation velocity relation-the Tully-Fisher law. We
review the phenomenological success of MOND on scales ranging from dwarf
spheroidal galaxies to superclusters and demonstrate that the evidence for dark
matter can be equally well interpreted as evidence for MOND. We discuss the
possible physical basis for an acceleration-based modification of Newtonian
dynamics as well as the extention of MOND to cosmology and structure
formation.
Abstract DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the ...role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration — and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2 O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.
The universal Faber–Jackson relation Sanders, R. H
Monthly notices of the Royal Astronomical Society,
September 2010, Letnik:
407, Številka:
2
Journal Article
Recenzirano
Odprti dostop
In the context of modified Newtonian dynamics, the Fundamental Plane, as the observational signature of the Newtonian virial theorem, is defined by high-surface-brightness objects that deviate from ...being purely isothermal: the line-of-sight velocity dispersion should slowly decline with radius as observed in luminous elliptical galaxies. All high-surface-brightness objects (e.g. globular clusters, ultra-compact dwarfs) will lie, more or less, on the Fundamental Plane defined by elliptical galaxies, but low-surface-brightness objects (dwarf spheroidals) would be expected to deviate from this relation. This is borne out by observations. With Milgrom's modified Newtonian dynamics (MOND), the Faber–Jackson relation (L∝σ4), ranging from globular clusters to clusters of galaxies and including both high- and low-surface-brightness objects, is the more fundamental and universal scaling relation in spite of its larger scatter. The Faber–Jackson relation reflects the presence of an additional dimensional constant (the MOND acceleration a0) in the structure equation.
Objective: To test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. Methods: In total, ...630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Δ9-tetrahydrocannabinol (Δ9-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to12 months in the follow up study reported here. Results: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Δ9-THC mean reduction 1·82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI −0.99 to 1.19), placebo −0.23 (n = 176, 95% CI −1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. Conclusions: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.
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