Computational Models of Dopamine Diffusion and Receptor Binding in the Striatum

The neuromodulator dopamine (DA) has complex effects on the activity of striatal neurons by changing their excitability and strength of synaptic inputs in the context of motor control, action-selection, reinforcement learning, and addiction. DA is volume transmitted, it leaves the synaptic cleft and diffuses through the extracellular space in the striatum. The spatial and temporal distribution of DA created by this diffusion have not been extensively studied yet. In this thesis a computational model based on diffusion in a porous medium was developed to study the spatiotemporal distribution of DA in the striatum. During the development of the model a second interesting problem was identified: DA receptors have slow kinetics. Due to these slow kinetics the DA receptors do not directly follow the DA concentration, but can integrate over longer timespans. Taking into account realistic kinetics it is shown that the different DA receptors do not have markedly different responses to different timescales of DA signals. The full model incorporates inhomogenous DA uptake, DA axonal tree morphologies, detailed receptor kinetics and spike trains based on rat cell recording. The thesis shows that spatiotemporal DA maps of a healthy striatum are highly variable in space and time but the death of dopaminergic axons, as seen in Parkinsons Disease, reduces the variability of the DA maps and makes them more homogenous. Furthermore, the DA receptor maps are shown to be correlated to anatomical features, synaptic positions and locations of reduced local DA uptake, and therefore have a component that is stable in time. The code of the full model has been made available at https://bitbucket.org/Narur/dope-amine/src/, so that others may also find out that dopamine is a dope amine

Spectral turning bands for efficient Gaussian random fields generation on GPUs and accelerators

A random field (RF) is a set of correlated random variables associated with different spatial locations. RF generation algorithms are of crucial importance for many scientific areas, such as astrophysics, geostatistics, computer graphics, and many others. Current approaches commonly make use of 3D fast Fourier transform (FFT), which does not scale well for RF bigger than the available memory; they are also limited to regular rectilinear meshes. We introduce random field generation with the turning band method (RAFT), an RF generation algorithm based on the turning band method that is optimized for massively parallel hardware such as GPUs and accelerators. Our algorithm replaces the 3D FFT with a lower‐order, one‐dimensional FFT followed by a projection step and is further optimized with loop unrolling and blocking. RAFT can easily generate RF on non‐regular (non‐uniform) meshes and efficiently produce fields with mesh sizes bigger than the available device memory by using a streaming, out‐of‐core approach. Our algorithm generates RF with the correct statistical behavior and is tested on a variety of modern hardware, such as NVIDIA Tesla, AMD FirePro and Intel Phi. RAFT is faster than the traditional methods on regular meshes and has been successfully applied to two real case scenarios: planetary nebulae and cosmological simulations

Opening a new window to other worlds with spectropolarimetry

A high level of diversity has already been observed among the planets of our own Solar System. As such, one expects extrasolar planets to present a wide range of distinctive features, therefore the characterisation of Earth- and super Earth-like planets is becoming of key importance in scientific research. The SEARCH (Spectropolarimetric Exoplanet AtmospheRe CHaracerisation) mission proposal of this paper represents one possible approach to realising these objectives. The mission goals of SEARCH include the detailed characterisation of a wide variety of exoplanets, ranging from terrestrial planets to gas giants. More specifically, SEARCH will determine atmospheric properties such as cloud coverage, surface pressure and atmospheric composition, and may also be capable of identifying basic surface features. To resolve a planet with a semi major axis of down to 1.4AU and 30pc distant SEARCH will have a mirror system consisting of two segments, with elliptical rim, cut out of a parabolic mirror. This will yield an effective diameter of 9 meters along one axis. A phase mask coronagraph along with an integral spectrograph will be used to overcome the contrast ratio of star to planet light. Such a mission would provide invaluable data on the diversity present in extrasolar planetary systems and much more could be learned from the similarities and differences compared to our own Solar System. This would allow our theories of planetary formation, atmospheric accretion and evolution to be tested, and our understanding of regions such as the outer limit of the Habitable Zone to be further improved.Comment: 23 pages, accepted for publication in Experimental Astronom

Toxic epidermal necrolysis and Stevens-Johnson syndrome

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease

Evaluation of the National Swiss Skin Cancer Screening Campaign 2013: Do We Do the Right Thing

BACKGROUND Skin cancer prevention and screening programs are performed in many countries. Their benefit is discussed controversially. OBJECTIVE Our aim is to evaluate the Skin Cancer Screening Program 2013 in Switzerland by following up screenees upon interventions. METHODS Quality was assessed by personal follow-up via phone/e-mail of every patient that had been screened during this campaign and histological follow-up of all participants with suspicious skin lesions. RESULTS Of the 1,087 screenees requiring interventions, 263 agreed to participate in the follow-up. We were able to obtain 66 histology reports. During this campaign 33 malignant lesions (8 melanomas) were removed. CONCLUSION The overall melanoma detection rate in our free Skin Cancer Screening Program is comparable to those in European public activities. The costs of free screening programs compare favorably with the prevented potential therapeutic costs of late-stage melanoma. The low response rate of screenees agreeing to be followed up limits conclusions of this study

Evaluation of the National Swiss Skin Cancer Screening Campaign 2013: Do We Do the Right Thing?

BACKGROUND Skin cancer prevention and screening programs are performed in many countries. Their benefit is discussed controversially. OBJECTIVE Our aim is to evaluate the Skin Cancer Screening Program 2013 in Switzerland by following up screenees upon interventions. METHODS Quality was assessed by personal follow-up via phone/e-mail of every patient that had been screened during this campaign and histological follow-up of all participants with suspicious skin lesions. RESULTS Of the 1,087 screenees requiring interventions, 263 agreed to participate in the follow-up. We were able to obtain 66 histology reports. During this campaign 33 malignant lesions (8 melanomas) were removed. CONCLUSION The overall melanoma detection rate in our free Skin Cancer Screening Program is comparable to those in European public activities. The costs of free screening programs compare favorably with the prevented potential therapeutic costs of late-stage melanoma. The low response rate of screenees agreeing to be followed up limits conclusions of this study

Pulmonary targeting of Adeno-associated viral vectors by next-generation sequencing-guided screening of random capsid displayed peptide libraries

Vectors mediating strong, durable, and tissue-specific transgene expression are mandatory for safe and effective gene therapy. In settings requiring systemic vector administration, the availability of suited vectors is extremely limited. Here, we present a strategy to select vectors with true specificity for a target tissue from random peptide libraries displayed on adeno-associated virus (AAV) by screening the library under circulation conditions in a murine model. Guiding the in vivo screening by next-generation sequencing, we were able to monitor the selection kinetics and to determine the right time point to discontinue the screening process. The establishment of different rating scores enabled us to identify the most specifically enriched AAV capsid candidates. As proof of concept, a capsid variant was selected that specifically and very efficiently delivers genes to the endothelium of the pulmonary vasculature after intravenous administration. This technical approach of selecting target-specific vectors in vivo is applicable to any given tissue of interest and therefore has broad implications in translational research and medicine