Targeting the Progression of Parkinson’s Disease

By the time a patient first presents with symptoms of Parkinson’s disease at the clinic, a significant proportion (50-70%) of the cells in the substantia nigra (SN) has already been destroyed. This degeneration progresses until, within a few years, most of the cells have died. Except for rare cases of familial PD, the initial trigger for cell loss is unknown. However, we do have some clues as to why the damage, once initiated, progresses unabated. It would represent a major advance in therapy to arrest cell loss at the stage when the patient first presents at the clinic. Current therapies for Parkinson’s disease focus on relieving the motor symptoms of the disease, these unfortunately lose their effectiveness as the neurodegeneration and symptoms progress. Many experimental approaches are currently being investigated attempting to alter the progression of the disease. These range from replacement of the lost neurons to neuroprotective therapies; each of these will be briefly discussed in this review. The main thrust of this review is to explore the interactions between dopamine, alpha synuclein and redox-active metals. There is abundant evidence suggesting that destruction of SN cells occurs as a result of a self-propagating series of reactions involving dopamine, alpha synuclein and redox-active metals. A potent reducing agent, the neurotransmitter dopamine has a central role in this scheme, acting through redox metallo-chemistry to catalyze the formation of toxic oligomers of alpha-synuclein and neurotoxic metabolites including 6-hydroxydopamine. It has been hypothesized that these feed the cycle of neurodegeneration by generating further oxidative stress. The goal of dissecting and understanding the observed pathological changes is to identify therapeutic targets to mitigate the progression of this debilitating disease

Characterization and identification of dityrosine cross-linked peptides using tandem mass spectrometry

The use of mass spectrometry coupled with chemical cross-linking of proteins has become a powerful tool for proteins structure and interactions studies. Unlike structural analysis of proteins using chemical reagents specific for lysine or cysteine residues, identification of gas-phase fragmentation patterns of endogenous dityrosine cross-linked peptides have not been investigated. Dityrosine cross-linking in proteins and peptides are clinical markers of oxidative stress, aging, and neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. In this study, we investigated and characterized the fragmentation pattern of a synthetically prepared dityrosine cross-linked dimer of Aβ(1–16) using ESI tandem mass spectrometry. We then detailed the fragmentation pattern of dityrosine cross-linked Aβ(1–16), using collision induced dissociation (CID), higher-energy collision induced dissociation (HCD), electron transfer dissociation (ETD), and electron capture dissociation (ECD). Application of these generic fragmentation rules of dityrosine cross-linked peptides allowed for the identification of dityrosine cross-links in peptides of Aβ and α-synuclein generated in vitro by enzymatic peroxidation. We report, for the first time, the dityrosine cross-linked residues in human hemoglobin and α-synuclein under oxidative conditions. Together these tools open up the potential for automated analysis of this naturally occurring post-translation modification in neurodegenerative diseases as well as other pathological conditions

Resonant scattering on impurities in the Quantum Hall Effect

We develop a new approach to carrier transport between the edge states via resonant scattering on impurities, which is applicable both for short and long range impurities. A detailed analysis of resonant scattering on a single impurity is performed. The results are used for study of the inter-edge transport by multiple resonant hopping via different impurities' sites. It is shown that the total conductance can be found from an effective Schroedinger equation with constant diagonal matrix elements in the Hamiltonian, where the complex non-diagonal matrix elements are the amplitudes of a carrier hopping between different impurities. It is explicitly demonstrated how the complex phase leads to Aharonov-Bohm oscillations in the total conductance. Neglecting the contribution of self-crossing resonant-percolation trajectories, one finds that the inter-edge carrier transport is similar to propagation in one-dimensional system with off-diagonal disorder. We demonstrated that each Landau band has an extended state $\bar E_N$, while all other states are localized. The localization length behaves as $L_N^{-1}(E)\sim (E-\bar E_N)^2$.Comment: RevTex 41 pages; 3 Postscript figure on request; Final version accepted for publication in Phys. Rev. B. A new section added contained a comparison with other method

Follow-up plasma apolipoprotein E levels in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL) cohort

Introduction: Alzheimer's disease (AD) is a growing socioeconomic problem worldwide. Early diagnosis and prevention of this devastating disease have become a research priority. Consequently, the identification of clinically significant and sensitive blood biomarkers for its early detection is very important. Apolipoprotein E (APOE) is a well-known and established genetic risk factor for late-onset AD; however, the impact of the protein level on AD risk is unclear. We assessed the utility of plasma ApoE protein as a potential biomarker of AD in the large, well-characterised Australian Imaging, Biomarkers and Lifestyle Study of Ageing (AIBL) cohort. Methods: Total plasma ApoE levels were measured at 18-month follow-up using a commercial bead-based enzyme-linked immunosorbent assay: the Luminex xMAP human apolipoprotein kit. ApoE levels were then analysed between clinical classifications (healthy controls, mild cognitive impairment (MCI) and AD) and correlated with the data available from the AIBL cohort, including but not limited to APOE genotype and cerebral amyloid burden. Results: A significant decrease in ApoE levels was found in the AD group compared with the healthy controls. These results validate previously published ApoE protein levels at baseline obtained using different methodology. ApoE protein levels were also significantly affected, depending on APOE genotypes, with ε2/ε2 having the highest protein levels and ε4/ε4 having the lowest. Plasma ApoE levels were significantly negatively correlated with cerebral amyloid burden as measured by neuroimaging. Conclusions: ApoE is decreased in individuals with AD compared with healthy controls at 18-month follow-up, and this trend is consistent with our results published at baseline. The influence of APOE genotype and sex on the protein levels are also explored. It is clear that ApoE is a strong player in the aetiology of this disease at both the protein and genetic levels

Predicting evolution and visualizing high-dimensional fitness landscapes

The tempo and mode of an adaptive process is strongly determined by the structure of the fitness landscape that underlies it. In order to be able to predict evolutionary outcomes (even on the short term), we must know more about the nature of realistic fitness landscapes than we do today. For example, in order to know whether evolution is predominantly taking paths that move upwards in fitness and along neutral ridges, or else entails a significant number of valley crossings, we need to be able to visualize these landscapes: we must determine whether there are peaks in the landscape, where these peaks are located with respect to one another, and whether evolutionary paths can connect them. This is a difficult task because genetic fitness landscapes (as opposed to those based on traits) are high-dimensional, and tools for visualizing such landscapes are lacking. In this contribution, we focus on the predictability of evolution on rugged genetic fitness landscapes, and determine that peaks in such landscapes are highly clustered: high peaks are predominantly close to other high peaks. As a consequence, the valleys separating such peaks are shallow and narrow, such that evolutionary trajectories towards the highest peak in the landscape can be achieved via a series of valley crossingsComment: 12 pages, 7 figures. To appear in "Recent Advances in the Theory and Application of Fitness Landscapes" (A. Engelbrecht and H. Richter, eds.). Springer Series in Emergence, Complexity, and Computation, 201

Plasma high‐density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data

Plasma p217+tau versus NAV4694 amyloid and MK6240 tau PET across the Alzheimer's continuum

Introduction We evaluated a new Simoa plasma assay for phosphorylated tau (P-tau) at aa217 enhanced by additional p-tau sites (p217+tau). Methods Plasma p217+tau levels were compared to 18F-NAV4694 amyloid beta (Aβ) positron emission tomography (PET) and 18F-MK6240 tau PET in 174 cognitively impaired (CI) and 223 cognitively unimpaired (CU) participants. Results Compared to Aβ− CU, the plasma levels of p217+tau increased 2-fold in Aβ+ CU and 3.5-fold in Aβ+ CI. In Aβ− the p217+tau levels did not differ significantly between CU and CI. P217+tau correlated with Aβ centiloids P = .67 (CI, P = .64; CU, P = .45) and tau SUVRMT P = .63 (CI, P = .69; CU, P = .34). Area under curve (AUC) for Alzheimer's disease (AD) dementia versus Aβ− CU was 0.94, for AD dementia versus other dementia was 0.93, for Aβ+ versus Aβ− PET was 0.89, and for tau+ versus tau− PET was 0.89. Discussion Plasma p217+tau levels elevate early in the AD continuum and correlate well with Aβ and tau PET

About levitation of superconducting rings for magnetic system of multipole plasma trap

In order to continue works on creation of the plasma trap with levitating magnetic coils the analytical function of the potential energy U(x,θ) of the system of two coaxial superconducting rings (and the upper ring is fixed at that), which trapped given fluxes of the same sign, in the homogeneous gravity field versus the coordinate x of the free ring and the deflection angle θ of its axis from the vertical has been obtained under approximation of thin rings. For manufactured HTSC rings, which trapped fluxes of the same sign, with the help of calculations of the dependence U(x,θ) in Mathcad system, such values of magnetic fluxes trapped by rings have been obtained under which equilibrium states of the free ring in the field of the fixed ring, stable to the shift of the levitating ring plane along the common axis and to the deflection of its axis from the vertical, exist. The existence of the determined by calculations equilibrium state for HTSC rings under trapped fluxes of the same sign, stable to the vertical shifts of the levitating ring and to the deflection of its axis from the vertical, has been proved experimentally.В продолжение работ по созданию плазменной ловушки с левитирующими магнитными катушками в приближении тонких колец получено аналитическое выражение для потенциальной энергии U (x,θ) системы из двух коаксиальных сверхпроводящих колец (причем, верхнее из них закреплено), захвативших заданные потоки одного знака, в однородном поле силы тяжести как функции координаты x свободного кольца и угла отклонения θ его оси от вертикали. Для изготовленных ВТСП-колец, захвативших потоки одного знака, с помощью расчетов в системе Mathcad зависимости U (x,θ) были найдены такие значения захваченных кольцами магнитных потоков, при которых существуют равновесные состояния свободного кольца в поле закрепленного кольца, устойчивые по отношению к смещению плоскости левитирующего кольца вдоль общей оси и к отклонению его оси от вертикали. Существование найденного из расчетов равновесного состояния для ВТСП- колец при захваченных потоках одного знака, устойчивого по отношению к вертикальным смещениям левитирующего кольца и к отклонению его оси от вертикали, было подтверждено экспериментально.У продовження робіт зі створення плазмової пастки з левітуючими магнітними котушками в наближенні тонких кілець отримано аналітичний вираз для потенційної енергії U (x, θ) системи з двох коаксіальних надпровідних кілець (причому, верхнє з них закріплено), що захопили задані потоки одного знаку, в однорідному полі сили тяжіння як функції координати x вільного кільця і кута відхилення θ його осі від вертикалі. Для виготовлених ВТНП-кілець, які захопили потоки одного знаку, за допомогою розрахунків в системі Mathcad залежності U (x, θ), були знайдені такі значення захоплених кільцями магнітних потоків, при яких існують рівноважні стани вільного кільця в полі закріпленого кільця, стійкі по відношенню до зміщення площини левітуючого кільця уздовж загальної осі та до відхилення його осі від вертикалі. Існування знайденого з розрахунків рівноважного стану для ВТНП-кілець при захоплених потоках одного знаку, стійкого по відношенню до вертикальних зсувів левітуючого кільця та до відхилення його осі від вертикалі, було підтверджено експериментально

About stability of levitating states of superconducting myxini of plasma traps-Galateas

To develop a plasma trap with levitating superconducting magnetic coils it is necessary to carry out the search of their stable levitating states. With this purpose, based upon the superconductor property to conserve the trapped magnetic flux, in the uniform gravitational field the analytical dependence of the potential energy of one or two superconducting rings, having trapped the given magnetic fluxes, in the field of the fixed ring with the constant current from the coordinates of the free rings and the deflection angle of their axes from the common axis of the magnetic system has been obtained in the thin ring approximation. Under magnetic fluxes of the same polarity in coils the existence of the found from the calculations equilibrium levitating states for the manufactured HTSC rings stable relative to the vertical shifts of levitating rings and to the deflection angle of their axes from the vertical has been confirmed experimentally.Для разработки плазменной ловушки с левитирующими сверхпроводящими магнитными катушками нужно выполнить поиск их устойчивых левитирующих состояний. С этой целью, исходя из свойства сверхпроводников сохранять захваченный магнитный поток, в однородном поле силы тяжести в приближении тонких колец получена аналитическая зависимость потенциальной энергии одного либо двух сверхпроводящих колец, захвативших заданные магнитные потоки, в поле закрепленного кольца с постоянным током от координат свободных колец и углов отклонения их осей от общей оси системы. При совпадающих по знаку потоках в кольцах существование найденных из расчетов равновесных левитирующих состояний для изготовленных ВТСП колец, устойчивых по отношению к вертикальным смещениям левитирующих колец и к отклонению их осей от вертикали, было подтверждено экспериментально.Для розробки плазмової пастки з левітуючими надпровідними магнітними котушками потрібно виконати пошук їх стійких левітуючих станів. З цією метою, виходячи з властивості надпровідників зберігати захоплений магнітний потік, в однорідному полі сили тяжіння в наближенні тонких кілець отримана аналітична залежність потенційної енергії одного або двох надпровідних кілець, які захопили задані магнітні потоки, у полі закріпленого кільця з постійним струмом від координат вільних кілець і кутів відхилення їх осей від загальної осі системи. При співпадаючих за знаком потоках у кільцях існування знайдених з розрахунків рівноважних левітуючих станів для виготовлених ВТНП кілець, стійких по відношенню до вертикальних зміщень левітуючих кілець і до відхилення їх осей від вертикалі, було підтверджено експериментально

The Measurement of Solar Diameter and Limb Darkening Function with the Eclipse Observations

The Total Solar Irradiance varies over a solar cycle of 11 years and maybe over cycles with longer period. Is the solar diameter variable over time too? We introduce a new method to perform high resolution astrometry of the solar diameter from the ground, through the observations of eclipses by reconsidering the definition of the solar edge. A discussion of the solar diameter and its variations must be linked to the Limb Darkening Function (LDF) using the luminosity evolution of a Baily's Bead and the profile of the lunar limb available from satellite data. This approach unifies the definition of solar edge with LDF inflection point for eclipses and drift-scan or heliometric methods. The method proposed is applied for the videos of the eclipse in 15 January 2010 recorded in Uganda and in India. The result shows light at least 0.85 arcsec beyond the inflection point, and this suggests to reconsider the evaluations of the historical eclipses made with naked eye.Comment: 16 pages, 11 figures, accepted in Solar Physics. arXiv admin note: text overlap with arXiv:astro-ph/0601109 by other author