Of Mice and Math: A Systems Biology Model for Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the US, affecting over 1 in 8 people over the age of 65. There are several well-known pathological changes in the brains of AD patients, namely: the presence of diffuse beta amyloid plaques derived from the amyloid precursor protein (APP), hyper-phosphorylated tau protein, neuroinflammation and mitochondrial dysfunction. Recent studies have shown that cholesterol levels in both the plasma and the brain may play a role in disease pathogenesis, however, this exact role is not well understood. Additional proteins of interest have also been identified (ApoE, LRP-1, IL-1) as possible contributors to AD pathogenesis. To help understand these roles better, a systems biology mathematical model was developed. Basic principles from graph theory and control analysis were used to study the effect of altered cholesterol, ApoE, LRP and APP on the system as a whole. Negative feedback regulation and the rate of cholesterol transfer between astrocytes and neurons were identified as key modulators in the level of beta amyloid. Experiments were run concurrently to test whether decreasing plasma and brain cholesterol levels with simvastatin altered the expression levels of beta amyloid, ApoE, and LRP-1, to ascertain the edge directions in the network model and to better understand whether statin treatment served as a viable treatment option for AD patients. The work completed herein represents the first attempt to create a systems-level mathematical model to study AD that looks at intercellular interactions, as well as interactions between metabolic and inflammatory pathways

First-principles study of defects in wide band gap semiconductors

Wide band gap semiconductors typically exhibit a band gap of more than 2eV and are technologically important for various applications. Such materials are essential for the development of high power, high temperature, and high frequency applications, which are not available with the current silicon based technology. Nonetheless, defects are present and unavoidable in all materials. Their effects on the physical properties of the materials are significant, determining their functionality. A typical example is degradation in devices which is often caused by point defects, which are also responsible for the performance of a device by determining the level of doping that can be achieved. Furthermore, defects may introduce energy levels within the band gap that can act as recombination centers, impeding the performance of solar panels or light-emitting diodes. In some cases, the defects introduce radiative centers responsible for the undesired luminescence of wide band gap semiconductors, such as the yellow luminescence in GaN. Therefore, the study of the effects of the defects in technological materials is essential both in the understanding of the physical properties of the material and the engineering of better devices and systems. In this work, both standard density functional theory and hybrid functional calculations are employed to investigate the material systems of GaN, Ga2O3 , and AlGaN. Specifically, this framework is used to determine the electronic properties and the migration barriers of native and carbon related point defects in GaN. The migration barriers of these defects typically range from 2 to 3eV. The migration barriers of gallium interstitials are lower, ranging from 0.7 to 1.6eV. Furthermore, the study of the migration of vacancies in Ga 2 O 3 and a search for possible p-type dopants is performed. The migration barriers of the oxygen vacancies in Ga2O3 exhibit barriers of typically more than 2eV, which are larger than the barriers of the gallium vacancies which are typically less than 2eV. The acceptor levels introduced by the substitutional dopants were found to be deep levels with activation energies of more than 1eV. Finally, the electronic and thermodynamic properties of the AlGaN alloys are investigated, in order to address the discrepancies observed in literature regarding basic properties of this system such as the band gap bowing parameter. The atomic configuration was found to affect the band gaps significantly, causing the bowing parameter to range from 0 to large positive values

Modeling the Role of the Glymphatic Pathway and Cerebral Blood Vessel Properties in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, affecting over 10% population over the age of 65 years. Clinically, AD is described by the symptom set of short term memory loss and cognitive decline, changes in mentation and behavior, and eventually long-term memory deficit as the disease progresses. On imaging studies, significant atrophy with subsequent increase in ventricular volume have been observed. Pathology on post-mortem brain specimens demonstrates the classic findings of increased beta amyloid (Aβ) deposition and the presence of neurofibrillary tangles (NFTs) within affected neurons. Neuroinflammation, dysregulation of blood-brain barrier transport and clearance, deposition of Aβ in cerebral blood vessels, vascular risk factors such as atherosclerosis and diabetes, and the presence of the apolipoprotein E4 allele have all been identified as playing possible roles in AD pathogenesis. Recent research has demonstrated the importance of the glymphatic system in the clearance of Aβ from the brain via the perivascular space surrounding cerebral blood vessels. Given the variety of hypotheses that have been proposed for AD pathogenesis, an interconnected, multilayer model offers a unique opportunity to combine these ideas into a single unifying model. Results of this model demonstrate the importance of vessel stiffness and heart rate in maintaining adequate clearance of Aβ from the brain

The attitudes and policies of European socialists regarding Spain, Portugal and Greece since 1967

SIGLEAvailable from British Library Document Supply Centre- DSC:D36135/81 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Study and Characterization of a Micromegas Detector Assembly for the cross section measurement of the 237Np(n,f) reaction

93 σ.Η παρούσα διπλωματική εργασία έχει σκοπό την μελέτη και τον χαρακτηρισμό τεσσάρων ανιχνευτών Micromegas τεχνολογίας μαζικής μικροκατασκευής (microbulk), για την χρήση τους στην μέτρηση της ενεργού διατομής της αντίδρασης 237Np(n,f). Η ενεργός διατομή της αντίδρασης 237Np(n,f) μετριέται με σχετική μέτρηση με την χρήση δύο στόχων 238U και ενός στόχου 235U εκτός από τον βασικό στόχο 237Np. Οι ανιχνευτές Micromegas βρίσκονται στο επίκεντρο της έρευνας των τελευταίων ετών λόγω των πολύ καλών ιδιοτήτων τους. Είναι ανιχνευτές αερίου οι οποίοι παρέχουν μεγάλη αξιοπιστία σε καταπονήσεις, χαμηλό κόστος και ευκολία μαζικής παραγωγής. Συγκεκριμένα, οι ανιχνευτές που χρησιμοποιήθηκαν, αξιοποιούν την τεχνολογία microbulk. Το πολυιμίδιο (kapton) και ο χαλκός είναι δύο υλικά με πολύ χαμηλά επίπεδα συγκέντρωσης ραδιενεργών ισοτόπων κάτι που τα κάνει ιδανικά δομικά υλικά ενός ανιχνευτή. Τέλος, η μειωμένη μάζα των ανιχνευτών τους καθιστά ιδανικούς για πειράματα που χρησιμοποιούνται νετρόνια λόγω μειωμένων σκεδάσεων από τα τελευταία. Η μελέτη και ο χαρακτηρισμός των ανιχνευτών πραγματοποιήθηκε στο Εργαστήριο Πειραματικής Φυσικής Υψηλών Ενεργειών του Τομέα Φυσικής της Σχολής Εφαρμοσμένων Μαθηματικών και Φυσικών Επιστημών του Εθνικού Μετσόβιου Πολυτεχνείου. Για τον χαρακτηρισμό των ανιχνευτών χρησιμοποιήθηκαν πηγές 210Po οι οποίες είναι κατάλληλες λόγω της αποδιέγερσης κατά μοναδικό τρόπο με εκπομπή σωματιδίων α. Βασικά χαρακτηριστικά ενός ανιχνευτή Micromegas είναι οι καμπύλες ενίσχυσης και διαφάνειας (trans) του ανιχνευτή. Η πρώτη αφορά στην ενίσχυση που μπορεί να επιτευχθεί συναρτήσει των πεδίων που επικρατούν στις περιοχές του ανιχνευτή. Η δεύτερη αφορά στην δυνατότητα του ανιχνευτή να αξιοποιεί στον βέλτιστο βαθμό τα πεδία που εφαρμόζονται για την καθοδήγηση των παραγόμενων ηλεκτρονίων και την συλλογή του σήματος. Οι στόχοι του πειράματος δεν είναι σημειακές πηγές και θα πρέπει να μελετηθεί ξεχωριστά η συμπεριφορά του ανιχνευτή. Πραγματοποιήθηκαν προσομοιώσεις για την διερεύνηση πιθανούς αλλοίωσης του πεδίου λόγω των στόχων οι οποίοι είναι διηλεκτρικά. Επίσης, εκτελέστηκαν δοκιμές με τους στόχους και διάφορους συνδυασμούς προενισχυτών και ενισχυτών για την επιλογή της καλύτερης δυνατής πειραματικής διάταξης για το πείραμα. Τέλος, η ανιχνευτική διάταξη μεταφέρθηκε στο Ινστιτούτο Πυρηνικής Φυσικής και Στοιχειωδών Σωματιδίων του Εθνικού Κέντρου Έρευνας Φυσικών Επιστημών "Δημόκριτος". Με την χρήση του επιταχυντή 5.5 MV HV TN-11 Tandem δημιουργήθηκαν νετρόνια ενέργειας 4.5-5.3 MeV μέσω της αντίδρασης 2H(d,n)3He και μελετήθηκε η ολική ενεργός διατομή της αντίδρασης 237Np(n,f) σε επιλεγμένα ενεργειακά σημεία.This diploma thesis regards the study and characterization of four Micromegas detectors of the microbulk technology, in order for them to be used in the study of the 237Np(n,f) reaction cross section. The study of the 237Np(n,f) reaction cross section is carried out with relative measurements using two 238U targets and one 235U target besides the 237Np target. The Micromegas detectors are in the leading edge of research during the last years due to the great properties they present. They are gaseous detectors who are very robust, cheap and easy to construct. In particular, the detectors used, utilize the microbulk technology. Kapton and copper are high radiopurity materials, making them ideal construction materials of a detector. Last but not least, the low mass indicate these detectors to be perfect for neutron experiments due to the reduction of neutron scattering. The study and characterization of the detectors took place in the Nuclear Physics Laboratory of the Department of Physics in the School of Applied Mathematical and Physical Sciences of the National Technical University of Athens. For the characterization of the detectors, a 210Po source was used due to the sole decay mode via α emission. The basic properties of a Micromegas detector are the gain and transparency curves. The former regards the achievable gain of the detector versus the electric fields of the detector’s regions. The latter regards the detector’s potential in utilizing the electric fields in order to guide the electrons in the best possible manner. The targets are not point sources and, thus, the detector should be studied further. For the determination of the electric field’s integrity due to the dielectric targets, simulations had to be performed. In addition, several tests were held for the best match of the detector and the electronic equipment. In conclusion, the detector assembly was transfered to the Insitute of Nuclear and Particle Physics of the National Center for Scientific Research "Demokritos". The 4.5-5.3 MeV neutrons were produced in the 5.5 MV HV TN 11 Tandem accelerator via the 2H(d,n)3He reaction and the total cross section of the 237Np(n,f) reaction was studied in specific energies.Αλέξανδρος-Ανδρέας Χ. Κύρτσο

Flow of brain interstitial fluid in response to pulsations of cerebral arteries and arterioles.

<p>Interstitial fluid is generated at the brain endothelium by an unclear process [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139574#pone.0139574.ref030" target="_blank">30</a>] and surrounds neurons, microglia astrocytes and other cells located within the brain parenchyma, bringing nutrition to the cells and removing wastes. Although its chemical composition is similar to cerebrospinal fluid (CSF), the two fluids serve separate purposes. CSF gives the brain buoyancy and buffers against forces applied to the head; CSF is generated by ependymal cells within the choroid plexus [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139574#pone.0139574.ref030" target="_blank">30</a>]. Brain ISF transports waste from the brain parenchyma via a combination of convection and diffusion towards the perivascular space. At the perivascular space, molecules such as Aβ, are either transported by receptors at the blood-brain barrier, or are transported along the glymphatic pathway. A small percentage of molecules transported in the perivascular space are transported into the cerebrospinal fluid at the arachnoid granulations and are cleared from the brain via CSF drainage pathways. The majority (~60%) of Aβ is transported along the glymphatic system to the cervical lymph nodes [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0139574#pone.0139574.ref013" target="_blank">13</a>].</p

Simulation demonstrating effects of normal aging on Aβ levels within the brain parenchyma and local cerebral vessels.

<p>(A) Deposition of Aβ40 occurred much more rapidly than that of Aβ42 with approximately 6 times the amount of Aβ40 deposited within cerebral vessels. This ratio agrees with what has been observed experimentally. The rate of Aβ increase started to decrease over the simulation as the number of neurons declined with aging and from elevations in the Aβ concentration. (B) The number of endothelial cells (blue) decreased slowly as they entered senescence. Microglia (green) decreased about 80% from their initial values, correlating with conversion to dystrophy. Neurons (red) also decreased secondary to natural loss as well as loss from elevated Aβ levels. (C) The total number of LRP-1 receptors decreased to approximately 60% of the initial value in accordance with the loss of brain endothelial cells.</p