Molecular and Device Engineering Towards the Study of Potential Anti-MRSA Agents

At the intersection of bio-device engineering and bio-pharmaceutical studies, our project involved the design of a hydraulic manifold to be used in isothermal titration calorimetry (ITC), with the ultimate goal of using ITC to study the thermodynamic binding parameters of potential anti-Methicillin Resistant Staphylococcus aureus (MRSA) agents to our drug target, Sortase A. The hydraulic manifold redesign included the analysis of materials such as high density polyethylene (HDPE), polytetrafluorethylene (PTFE, ‘Teflon’), and polycarbonate as well as the implementation of a new construct of the manifold itself. Sortase A is a transpeptidase found in Gram-positive bacteria and catalyses the attachment of virulent surface proteins to the cell wall by recognizing a specific amino acid motif (LPXTG). The ability of the bacterium to communicate with and infect host cells is linked to the Sortase A mechanism. We have identified pyridostigmine bromide as the primary drug target based upon the analysis of ITC data

Determination of pulsation periods and other parameters of 2875 stars classified as MIRA in the All Sky Automated Survey (ASAS)

We have developed an interactive PYTHON code and derived crucial ephemeris data of 99.4% of all stars classified as 'Mira' in the ASAS data base, referring to pulsation periods, mean maximum magnitudes and, whenever possible, the amplitudes among others. We present a statistical comparison between our results and those given by the AAVSO International Variable Star Index (VSX), as well as those determined with the machine learning automatic procedure of Richards et al. 2012. Our periods are in good agreement with those of the VSX in more than 95% of the stars. However, when comparing our periods with those of Richards et al, the coincidence rate is only 76% and most of the remaining cases refer to aliases. We conclude that automatic codes require still more refinements in order to provide reliable period values. Period distributions of the target stars show three local maxima around 215, 275 and 330 d, apparently of universal validity, their relative strength seems to depend on galactic longitude. Our visual amplitude distribution turns out to be bimodal, however 1/3 of the targets have rather small amplitudes (A $<$ 2.5$^{m}$) and could refer to semi-regular variables (SR). We estimate that about 20% of our targets belong to the SR class. We also provide a list of 63 candidates for period variations and a sample of 35 multiperiodic stars which seem to confirm the universal validity of typical sequences in the double period and in the Petersen diagramsComment: 14 pages, 14 figures, and 8 tables. Accepted to The Astrophysical Journal Supplement Series, September 201

Bayesian changepoint analysis for atomic force microscopy and soft material indentation

Material indentation studies, in which a probe is brought into controlled physical contact with an experimental sample, have long been a primary means by which scientists characterize the mechanical properties of materials. More recently, the advent of atomic force microscopy, which operates on the same fundamental principle, has in turn revolutionized the nanoscale analysis of soft biomaterials such as cells and tissues. This paper addresses the inferential problems associated with material indentation and atomic force microscopy, through a framework for the changepoint analysis of pre- and post-contact data that is applicable to experiments across a variety of physical scales. A hierarchical Bayesian model is proposed to account for experimentally observed changepoint smoothness constraints and measurement error variability, with efficient Monte Carlo methods developed and employed to realize inference via posterior sampling for parameters such as Young's modulus, a key quantifier of material stiffness. These results are the first to provide the materials science community with rigorous inference procedures and uncertainty quantification, via optimized and fully automated high-throughput algorithms, implemented as the publicly available software package BayesCP. To demonstrate the consistent accuracy and wide applicability of this approach, results are shown for a variety of data sets from both macro- and micro-materials experiments--including silicone, neurons, and red blood cells--conducted by the authors and others.Comment: 20 pages, 6 figures; submitted for publicatio

Ebola virus VP35 induces high-level production of recombinant TPL-2–ABIN-2–NF-κB1 p105 complex in co-transfected HEK-293 cells

Activation of PKR (double-stranded-RNA-dependent protein kinase) by DNA plasmids decreases translation, and limits the amount of recombinant protein produced by transiently transfected HEK (human embryonic kidney)-293 cells. Co-expression with Ebola virus VP35 (virus protein 35), which blocked plasmid activation of PKR, substantially increased production of recombinant TPL-2 (tumour progression locus 2)–ABIN-2 [A20-binding inhibitor of NF-κB (nuclear factor κB) 2]–NF-κB1 p105 complex. VP35 also increased expression of other co-transfected proteins, suggesting that VP35 could be employed generally to boost recombinant protein production by HEK-293 cells

Structured deterministic models applied to malaria and other endemic diseases

This thesis includes modeling studies on three structured deterministic models. These models are used to study the disease dynamics of malaria or the joint disease dynamics of HIV and HSV-2. Each of the models includes multiple components containing individuals in various epidemiological classes for the purpose of addressing questions that are of interests to biologists and epidemiologists. Some of the compartments have a continuous age-structure, which is necessary for studying the specific biological questions under investigation.^ In Chapter 2 a chronological-age structured deterministic model for malaria is presented. The model includes the human and mosquito populations with the human population structured by chronological age. The model consists of both PDEs and ODEs. The infected human population is divided into symptomatic infectious, asymptomatic infectious and asymptomatic chronic infected individuals. The original PDE model is reduced to an ODE model with aging. The basic reproduction number R0 is derived for both settings of the model. A novel assumption of the model based on biological evidence is that the infectiousness of chronic infected individuals can be triggered by bites from even susceptible mosquitoes. The model analysis indicates that this assumption contributes greatly to the R0 and therefore needs to be further studied and understood. Numerical simulations for n =2 age groups and a sensitivity/uncertainty analysis show that it is important to both asymptomatic infectious individuals and asymptomatic chronic infections. Age-targeted control strategies are also discussed.^ In Chapter 3 a deterministic malaria model is presented to study the effects of a pre-erythrocytic vaccine on malaria dynamics. The model includes two vaccinated classes, the first for initial vaccination dose(s) and the second for a booster dose. Vaccinated individuals in both compartments are structured by vaccine-age. A vaccine-age dependent transition between vaccinated classes makes it possible to model a minimum vaccine-age required for receiving the booster vaccination. The control reproduction number R is derived and shown to determine the local stability of the disease free equilibrium. Global stability of the disease free equilibrium is shown analytically under certain assumptions and conditions for the existence of endemic equilibria are identified. Numerical results suggest that the incorporation of two vaccination classes, as opposed to only one, allows for a greater accuracy in predicting threshold vaccination coverages for disease eradication. The model also exhibits backward bifurcation, indicating thatR=1 is no longer the threshold value for disease eradication. The effect of waning vaccine efficacy (vaccine-age dependent) on disease prevalence is also investigated. ^ Chapter 4 presents a deterministic model for the joint dynamics of HIV and HSV-2 to study the effect that the presence of HSV-2 may have on the prevalence of HIV. An infection-age is used to incorporate the epidemiological characteristic of HSV-2 that infected individuals change between the acute and the latent stages, and treatment may affect the lengths of these stages. The model is also structured by gender and includes one male and two female populations with different activity levels. The basic reproduction number for each disease, as well as the invasion reproduction numbers are derived. Due to the model complexity, the derivation of these reproduction numbers and their biological interpretations are very challenging, which is one of the novel aspects of this study. Numerical simulations are performed to confirm and extend the analytical results. A sensitivity analysis is also conducted. Model results demonstrate that strategies for reducing co-infections with HIV and HSV-2, particularly treating the high-risk group of females may have an important impact on the HIV disease dynamics

Das Computerprogramm als Erfahrungsgegenstand

Was ist eigentlich ein Computerprogramm? Technikphilosophische Überlegungen deuten darauf hin, dass unter diesen Begriff sehr unterschiedliche Gegenstände fallen können. Bisherige ontologische Analysen zergliedern aus diesem Grund den Begriff, um beispielsweise zwischen der Semantik eines Programms und greifbaren technischen Artefakten zu unterscheiden. Derartige Analysen bieten eine große Klarheit und Präzision bei der Begriffsverwendung, da die Unterscheidungen der zuvor zergliederten Begriffsanteile in den Vordergrund treten. Gleichzeitig führt dieses Vorgehen jedoch dazu, dass die Zusammenhänge, Verbindungen und wechselseitigen Beeinflussungen der einzelnen Bedeutungen, welche im "Programm"-Begriff gebündelt sind verdeckt werden können. Um diesem Nachteil zu begegnen, wird in dieser Arbeit ein mehrdimensionaler Programmbegriff entwickelt, der eine Unterscheidung zwischen verschiedenen Bedeutungsebenen des Programmbegriffs vornimmt, gleichzeitig aber deren Zusammenhang herausarbeitet. Dafür werden der Begriffsbestimmung epistemologische Überlegungen vorangestellt, die der Frage nachgehen, wie Computerprogramme überhaupt von Menschen wahrgenommen werden können, wie Programme Gegenstände menschlicher Erfahrung werden. Ausgehend von Immanuel Kants Transzendentalphilosophie und Edmund Husserls Grundlegung der Phänomenologie wird ein Zugang zu dieser Erfahrung von Computerprogrammen entwickelt. Dabei wird herausgearbeitet, dass die Programme auf vier voneinander unterscheidbare Arten als Gegenstand konstituiert werden. Die daraus resultierenden Bedeutungsebenen des vorgestellten Programmbegriffs sind jeweils Programme als räumlich-zeitliche, syntaktische, semantische und eingebettete Gegenstände. Der Zusammenhang zwischen diesen Begriffsdimensionen zeigt sich dabei als Eigenschaft der Wahrnehmung von Programmen: Je nachdem, als was ein Programm konstituiert wird, können die jeweils anderen Begriffbedeutungen von "Programm" appräsentiert, also mitgegeben, sein. Dieser Zusammenhang ist in hohem Maße gesellschaftlich und technisch bedingt. Um diese Bedingtheit zu untersuchen wird dies anschließend als Assoziation im Sinne von Bruno Latours Akteur-Netzwerk-Theorie untersucht. Der hier entwickelte Programmbegriff eignet sich, um die Bedeutung von Computerprogrammen im Rahmen technikphilosophischer und techniksoziologischer Forschung zu analysieren. Die Anwendbarkeit des mehrdimensionalen Programmbegriffs zur Analyse menschlicher Bezüge zur Computertechnologie wird in der vorliegenden Arbeit an drei Fallbeispielen im Umfeld der Softwareentwicklung aufgezeigt. Im Mittelpunkt dieser Überlegungen stehen die wechselseitigen Verhältnisse von Mensch, Technik und Gesellschaft zueinander. Abschließend zeigt ein Ausblick weitere Bereiche, in denen mithilfe des entwickelten Begriffs aussichtsreiche Untersuchungen durchgeführt werden können