Imaging Parkinson's disease below the neck

Parkinson's disease is a systemic disorder with widespread and early α-synuclein pathology in the autonomic and enteric nervous systems, which is present throughout the gastrointestinal canal prior to diagnosis. Gastrointestinal and genitourinary autonomic symptoms often predate clinical diagnosis by several years. It has been hypothesized that progressive α-synuclein aggregation is initiated in hyperbranched, non-myelinated neuron terminals, and may subsequently spread via retrograde axonal transport. This would explain why autonomic nerves are so prone to formation of α-synuclein pathology. However, the hypothesis remains unproven and in vivo imaging methods of peripheral organs may be essential to study this important research field. The loss of sympathetic and parasympathetic nerve terminal function in Parkinson's disease has been demonstrated using radiotracers such as 123I-meta-iodobenzylguanidin, 18F-dopamine, and 11C-donepezil. Other radiotracer and radiological imaging methods have shown highly prevalent dysfunction of pharyngeal and esophageal motility, gastric emptying, colonic transit time, and anorectal function. Here, we summarize the methodology and main findings of radio-isotope and radiological modalities for imaging peripheral pathology in Parkinson's disease

Uncovering the overlapping community structure of complex networks in nature and society

Many complex systems in nature and society can be described in terms of networks capturing the intricate web of connections among the units they are made of. A key question is how to interpret the global organization of such networks as the coexistence of their structural subunits (communities) associated with more highly interconnected parts. Identifying these a priori unknown building blocks (such as functionally related proteins, industrial sectors and groups of people) is crucial to the understanding of the structural and functional properties of networks. The existing deterministic methods used for large networks find separated communities, whereas most of the actual networks are made of highly overlapping cohesive groups of nodes. Here we introduce an approach to analysing the main statistical features of the interwoven sets of overlapping communities that makes a step towards uncovering the modular structure of complex systems. After defining a set of new characteristic quantities for the statistics of communities, we apply an efficient technique for exploring overlapping communities on a large scale. We find that overlaps are significant, and the distributions we introduce reveal universal features of networks. Our studies of collaboration, word-association and protein interaction graphs show that the web of communities has non-trivial correlations and specific scaling properties.Comment: The free academic research software, CFinder, used for the publication is available at the website of the publication: http://angel.elte.hu/clusterin

Annually resolved North Atlantic marine climate over the last millennium

This is the final version of the article. Available from Nature Publishing Group via the DOI in this record.Owing to the lack of absolutely dated oceanographic information before the modern instrumental period, there is currently significant debate as to the role played by North Atlantic Ocean dynamics in previous climate transitions (for example, Medieval Climate Anomaly-Little Ice Age, MCA-LIA). Here we present analyses of a millennial-length, annually resolved and absolutely dated marine δ(18)O archive. We interpret our record of oxygen isotope ratios from the shells of the long-lived marine bivalve Arctica islandica (δ(18)O-shell), from the North Icelandic shelf, in relation to seawater density variability and demonstrate that solar and volcanic forcing coupled with ocean circulation dynamics are key drivers of climate variability over the last millennium. During the pre-industrial period (AD 1000-1800) variability in the sub-polar North Atlantic leads changes in Northern Hemisphere surface air temperatures at multi-decadal timescales, indicating that North Atlantic Ocean dynamics played an active role in modulating the response of the atmosphere to solar and volcanic forcing.We thank the members of the RV Bjarni Sæmundsson (Cruise No. B05-2006). This work was supported by the NERC-funded ULTRA project (Grant Number NE/H023356/1), NERC-funded CLAM project; (Project No. NE/N001176/1) and EU Millennium Project (Project number 017008). This study is a contribution to the Climate Change Consortium for Wales (C3W). We thank Brian Long (Bangor University) and Dr Julia Becker (Cardiff University) for their technical support, and Dr Manfred Mudelsee for his assistance with the trend analysis. We thank Dr Jessica Tierney and an anonymous reviewer for providing the constructive comments in the reviewing process

Diagnosing the Role of Alfvén Waves in Magnetosphere-Ionosphere Coupling: Swarm Observations of Large Amplitude Nonstationary Magnetic Perturbations During an Interval of Northward IMF

High-resolution multispacecraft Swarm data are used to examine magnetosphere-ionosphere coupling during a period of northward interplanetary magnetic field (IMF) on 31 May 2014. The observations reveal a prevalence of unexpectedly large amplitude (>100 nT) and time-varying magnetic perturbations during the polar passes, with especially large amplitude magnetic perturbations being associated with large-scale downward field-aligned currents. Differences between the magnetic field measurements sampled at 50 Hz from Swarm A and C, approximately 10 s apart along track, and the correspondence between the observed electric and magnetic fields at 16 samples per second, provide significant evidence for an important role for Alfvén waves in magnetosphere-ionosphere coupling even during northward IMF conditions. Spectral comparison between the wave E- and B-fields reveals a frequency-dependent phase difference and amplitude ratio consistent with interference between incident and reflected Alfvén waves. At low frequencies, the E/B ratio is in phase with an amplitude determined by the Pedersen conductance. At higher frequencies, the amplitude and phase change as a function of frequency in good agreement with an ionospheric Alfvén resonator model including Pedersen conductance effects. Indeed, within this Alfvén wave incidence, reflection, and interference paradigm, even quasi-static field-aligned currents might be reasonably interpreted as very low frequency (ω → 0) Alfvén waves. Overall, our results not only indicate the importance of Alfvén waves for magnetosphere-ionosphere coupling but also demonstrate a method for using Swarm data for the innovative experimental diagnosis of Pedersen conductance from low-Earth orbit satellite measurements

In vivo imaging of neuromelanin in Parkinson's disease using 18F-AV-1451 PET.

The tau tangle ligand (18)F-AV-1451 ((18)F-T807) binds to neuromelanin in the midbrain, and may therefore be a measure of the pigmented dopaminergic neuronal count in the substantia nigra. Parkinson's disease is characterized by progressive loss of dopaminergic neurons. Extrapolation of post-mortem data predicts that a ∼30% decline of nigral dopamine neurons is necessary to cause motor symptoms in Parkinson's disease. Putamen dopamine terminal loss at disease onset most likely exceeds that of the nigral cell bodies and has been estimated to be of the order of 50-70%. We investigated the utility of (18)F-AV-1451 positron emission tomography to visualize the concentration of nigral neuromelanin in Parkinson's disease and correlated the findings to dopamine transporter density, measured by (123)I-FP-CIT single photon emission computed tomography. A total of 17 patients with idiopathic Parkinson's disease and 16 age- and sex-matched control subjects had (18)F-AV-1451 positron emission tomography using a Siemens high-resolution research tomograph. Twelve patients with Parkinson's disease also received a standardized (123)I-FP-CIT single photon emission computed tomography scan at our imaging facility. Many of the patients with Parkinson's disease displayed visually apparent decreased (18)F-AV-1451 signal in the midbrain. On quantitation, patients showed a 30% mean decrease in total nigral (18)F-AV-1451 volume of distribution compared with controls (P = 0.004), but there was an overlap of the individual ranges. We saw no significant correlation between symptom dominant side and contralateral nigral volume of distribution. There was no correlation between nigral (18)F-AV-1451 volume of distribution and age or time since diagnosis. In the subset of 12 patients, who also had a (123)I-FP-CIT scan, the mean total striatal dopamine transporter signal was decreased by 45% and the mean total (18)F-AV-1451 substantia nigra volume of distribution was decreased by 33% after median disease duration of 4.7 years (0.5-12.4 years). (18)F-AV-1451 positron emission tomography may be the first radiotracer to reflect the loss of pigmented neurons in the substantia nigra of parkinsonian patients. The magnitude of the nigral signal loss was smaller than the decrease in striatal dopamine transporter signal measured by dopamine transporter single photon emission computed tomography. These findings suggest a more severe loss of striatal nerve terminal function compared with neuronal cell bodies, in accordance with the post-mortem literature

CO(1-0) in z gtrsim 4 Quasar Host Galaxies: No Evidence for Extended Molecular Gas Reservoirs

We present 12CO(J = 1 → 0) observations of the high-redshift quasi-stellar objects (QSOs) BR 1202-0725 (z = 4.69), PSS J2322+1944 (z = 4.12), and APM 08279+5255 (z = 3.91) using the NRAO Green Bank Telescope (GBT) and the MPIfR Effelsberg 100 m telescope. We detect, for the first time, the CO ground-level transition in BR 1202-0725. For PSS J2322+1944 and APM 08279+5255, our observations result in line fluxes that are consistent with previous NRAO Very Large Array (VLA) observations, but they reveal the full line profiles. We report a typical lensing-corrected velocity-integrated intrinsic 12CO(J = 1 → 0) line luminosity of L = 5 × 1010 K km s-1 pc2 and a typical total H2 mass of M(H2) = 4 × 1010 M for the sources in our sample. The CO/FIR luminosity ratios of these high-z sources follow the same trend as seen for low-z galaxies, leading to a combined solution of log LFIR = (1.39 ± 0.05) log LCO - 1.76. It has previously been suggested that the molecular gas reservoirs in some quasar host galaxies may exhibit luminous, extended 12 CO(J = 1 → 0) components that are not observed in the higher J CO transitions. Using the line profiles and the total intensities of our observations and large velocity gradient (LVG) models based on previous results for higher J CO transitions, we derive that emission from all CO transitions is described well by a single gas component in which all molecular gas is concentrated in a compact nuclear region. Thus, our observations and models show no indication of a luminous extended, low surface brightness molecular gas component in any of the high-redshift QSOs in our sample. If such extended components exist, their contribution to the overall luminosity is limited to at most 30%

Separation of Anti-Proliferation and Anti-Apoptotic Functions of Retinoblastoma Protein through Targeted Mutations of Its A/B Domain

BACKGROUND: The human retinoblastoma susceptibility gene encodes a nuclear phosphoprotein RB, which is a negative regulator of cell proliferation. The growth suppression function of RB requires an evolutionarily conserved A/B domain that contains two distinct peptide-binding pockets. At the A/B interface is a binding site for the C-terminal trans-activation domain of E2F. Within the B-domain is a binding site for proteins containing the LxCxE peptide motif. METHODOLOGY/PRINCIPLE FINDINGS: Based on the crystal structure of the A/B domain, we have constructed an RB-K530A/N757F (KN) mutant to disrupt the E2F- and LxCxE-binding pockets. The RB-K530A (K) mutant is sufficient to inactivate the E2F-binding pocket, whereas the RB-N757F (N) mutant is sufficient to inactivate the LxCxE-binding pocket. Each single mutant inhibits cell proliferation, but the RB-KN double mutant is defective in growth suppression. Nevertheless, the RB-KN mutant is capable of reducing etoposide-induced apoptosis. CONCLUSION/SIGNIFICANCE: Previous studies have established that RB-dependent G1-arrest can confer resistance to DNA damage-induced apoptosis. Results from this study demonstrate that RB can also inhibit apoptosis independent of growth suppression

A highly invasive human glioblastoma pre-clinical model for testing therapeutics

Animal models greatly facilitate understanding of cancer and importantly, serve pre-clinically for evaluating potential anti-cancer therapies. We developed an invasive orthotopic human glioblastoma multiforme (GBM) mouse model that enables real-time tumor ultrasound imaging and pre-clinical evaluation of anti-neoplastic drugs such as 17-(allylamino)-17-demethoxy geldanamycin (17AAG). Clinically, GBM metastasis rarely happen, but unexpectedly most human GBM tumor cell lines intrinsically possess metastatic potential. We used an experimental lung metastasis assay (ELM) to enrich for metastatic cells and three of four commonly used GBM lines were highly metastatic after repeated ELM selection (M2). These GBM-M2 lines grew more aggressively orthotopically and all showed dramatic multifold increases in IL6, IL8, MCP-1 and GM-CSF expression, cytokines and factors that are associated with GBM and poor prognosis. DBM2 cells, which were derived from the DBTRG-05MG cell line were used to test the efficacy of 17AAG for treatment of intracranial tumors. The DMB2 orthotopic xenografts form highly invasive tumors with areas of central necrosis, vascular hyperplasia and intracranial dissemination. In addition, the orthotopic tumors caused osteolysis and the skull opening correlated to the tumor size, permitting the use of real-time ultrasound imaging to evaluate antitumor drug activity. We show that 17AAG significantly inhibits DBM2 tumor growth with significant drug responses in subcutaneous, lung and orthotopic tumor locations. This model has multiple unique features for investigating the pathobiology of intracranial tumor growth and for monitoring systemic and intracranial responses to antitumor agents