Development and application of novel scaffolds in drug discovery:the MCR approach

The research André Boltjes described in his thesis covers the application of MCR methodologies aimed at expansion of the scaffold library and implementation of these scaffolds for the development of pharmaceutical relevant, drug-like compounds and diagnostic probes. Scaffold design was achieved either by clever application of bifunctional MCR components, or implementation of underexplored starting materials. Applicability of the scaffolds was found to be quite broad, covering biological targets such as anti-cancer and kinases, application as a new class of MRI contrast agents and peptidomimetics for yet to be discovered targets. Moreover, the thorough review of one the youngest MCRs, the GBB-3CR, revealed affinity of the associated GBB-scaffold for a wide variety of biological targets. This scaffold is still underexplored, thus exhibits high potential for drug discovery. Additionally Boltjes worked on the improvement of IMCRs by addressing limitations in availability and/or problematic application of isocyanides. The approach was demonstrated through the example of the synthesis of praziquantel and covers an important procedure of both a MCR approach to synthesize a marketed drug in less reaction steps into a more optimized reaction, as well as in situ formation of the isocyanide compound through readily available formamides. Overall the MCR scaffold design described in this thesis was successfully linked by Boltjes to new potential targets and the resulting compounds were applied as drug-like compounds and introduced beyond the scope of drug discovery

Tendon Reliability for Overall Knee Function

https://openriver.winona.edu/urc2018/1111/thumbnail.jp

Color inversion and detail effects on face recognition

Two separate studies were completed to demonstrate the importance of color location and focus on face recognition. The first study manipulated Gaussian Blur (GB) and inversion (IN). GB is the process of taking an image out of focus, the higher the cycle the more out of focus the image will appear. IN is the process of changing the dark color with light color and the light color with dark color, like a colored photographic negative. In the study, twenty celebrity faces (10 female and 10 male) were exposed to six different manipulations: three levels of GB and two levels of IN (present and absent). Each of the 41 participants was exposed to all 120 images. Results showed that as the GB increased, there was a decrease in performance. When IN was present, there was also a decrease in performance. However, when GB and IN were used in combination, performance did not decrease further. The second study manipulated higher levels of GB and Glowing Edge (GE). GE is the process of highlighting the contours of the face in different colors. One hundred twenty participants were randomly exposed to one of the six conditions following one practice list. The results were measured using a between subjects design which showed an interaction between GB and GE, indicating both were a contributor to face recognition. It was demonstrated that facial recognition is contingent upon proper color location

An Ugi Reaction/Intramolecular Cyclization/Oxidation Cascade towards Tetrazole-Linked Dibenzoxazepines

A series of tetrazole-linked dibenzo[ b, f ][1,4]oxazepines is synthesized through a short sequence involving an Ugi tetrazole reaction. The intermediate tetrazole undergoes a potassium carbonate mediated S NAr cyclization, followed by oxidation to afford the target tricyclic heterocyclic scaffold. The optimization, scope and limitations of this two-step and efficient methodology are investigated. A 1000-member library of tetrazole-linked dibenzo[ b, f ][1,4]oxazepines is generated and the physicochemical properties are analyzed. great

The effect of interferons and viral proteins on antigen-presenting cells in chronic hepatitis B

__Abstract__ The innate immune system forms the so-called first line of defense against invading pathogens like viruses. Innate immune cells include phagocytes like monocytes, macrophages and dendritic cells (DC). Phagocytes sample their environments, binding and taking up viral pathogens. By means of surface and intracellular recognition receptors these cells are able to recognize and react to viral pathogens by producing molecules like cytokines that attract and activate other immune cells. Furthermore, they can present pathogen-derived antigens to T cells. Therefore, they are also called antigen-presenting cells (APC). APC can induce T effector cell, but also B cell, activation and differentiation at the site of inflammation, ultimately leading to the induction of virus-specific T and B cell responses. Also in HBV infection, APC are key players in the initiation and regulation of antiviral immune responses, ensuing in combined cellular and humoral immunity that ultimately allows control of HBV infection. This thesis focuses on specific aspects of the role of APC in chronic HBV infection. Interferons, a family of cytokines, are used as antiviral therapy in chronic HBV infection, but what the exact effects of IFN on APC are and how this influences the role of APC in HBV infection remains elusive. Furthermore, APC are constantly exposed to viral proteins, but reports on their interaction with APC are scarce while literature on their effects on APC seem contradictive and/or insufficient. Therefore, we investigated effects of IFN and viral proteins on APC in chronic HBV infection to further define the role of APC in HBV infection

Monocytes from chronic HBV patients react in vitro to HBsAg and TLR by producing cytokines irrespective of stage of disease

Individuals who are chronically infected with the hepatitis B virus (HBV) are highly heterogenous with respect to serum levels of HBV DNA, HBV particles and viral proteins. Since circulating leukocytes, such as monocytes, are constantly exposed to these viral components, it is likely that the functionality of these cells is affected. However, at present, little information is available on the consequences of the interaction between monocytes and viral components. Therefore, we examined the in vitro effects of HBV surface antigen (HBsAg) on monocytes and evaluated whether these effects were reflected in vivo. We observed that in vitro HBsAg exposure of monocytes induced robust production of IL-6 and TNF. However, between chronic HBV patients with distinct levels of serum HBsAg, HBV early antigen (HBeAg), and HBV DNA, TLR-induced monocyte cytokine production did not differ. Importantly, HBsAg-induced cytokine production by monocytes was similar between patients and healthy controls showing that earlier in vivo exposure to HBsAg does not affect the in vitro response. Additionally, we show that IL-10 is able to inhibit cytokine production by HBsAg-induced monocytes. In conclusion, we demonstrate that monocytes can recognize and respond to HBsAg, resulting in vigorous pro-inflammatory cytokine production in vitro. However, phenotype and function of the monocyte compartment in chronic HBV patients are not influenced by differences in levels of serum viral components, suggesting that regulatory mechanisms are active to avoid excessive in vivo monocyte activation

Common Variants Associated With OSMR Expression Contribute to Carotid Plaque Vulnerability, but Not to Cardiovascular Disease in Humans

Background and Aims: Oncostatin M (OSM) signaling is implicated in atherosclerosis, however the mechanism remains unclear. We investigated the impact of common genetic variants in OSM and its receptors, OSMR and LIFR, on overall plaque vulnerability, plaque phenotype, intraplaque OSMR and LIFR expression, coronary artery calcification burden and cardiovascular disease susceptibility. Methods and Results: We queried Genotype-Tissue Expression data and found that rs13168867 (C allele) was associated with decreased OSMR expression and that rs10491509 (A allele) was associated with increased LIFR expression in arterial tissues. No variant was significantly associated with OSM expression. We associated these two variants with plaque characteristics from 1,443 genotyped carotid endarterectomy patients in the Athero-Express Biobank Study. After correction for multiple testing, rs13168867 was significantly associated with an increased overall plaque vulnerability (β = 0.118 ± s.e. = 0.040, p = 3.00 × 10−3, C allele). Looking at individual plaque characteristics, rs13168867 showed strongest associations with intraplaque fat (β = 0.248 ± s.e. = 0.088, p = 4.66 × 10−3, C allele) and collagen content (β = −0.259 ± s.e. = 0.095, p = 6.22 × 10−3, C allele), but these associations were not significant after correction for multiple testing. rs13168867 was not associated with intraplaque OSMR expression. Neither was intraplaque OSMR expression associated with plaque vulnerability and no known OSMR eQTLs were associated with coronary artery calcification burden, or cardiovascular disease susceptibility. No associations were found for rs10491509 in the LIFR locus. Conclusions: Our study suggests that rs1316887 in the OSMR locus is associated with increased plaque vulnerability, but not with coronary calcification or cardiovascular disease risk. It remains unclear through which precise biological mechanisms OSM signaling exerts its effects on plaque morphology. However, the OSM-OSMR/LIFR pathway is unlikely to be causally involved in lifetime cardiovascular disease susceptibility

A pathway to solving the Wi-Fi tragedy of the commons in apartment blocks

Surprisingly little research has quantified the severity of Wi-Fi congestion in densely populated areas. We performed a high-fidelity 3D simulation of the performance of a realistic Wi-Fi deployment in a typical apartment block. Our results show that congestion leads to significant loss of performance, and that current channel selection procedures have only little effect. Also the strategy that is mostly applied today, i.e. to deploy additional repeaters and access points (APs), fails. As this is a typical example of the “Tragedy of the Commons”, some form of collaboration between AP operators is needed to solve the problem. New channel selection algorithms that optimize Wi-Fi performance on a system level then become possible which, for instance, minimize the mutual interference impact on all APs involved. We validate that such an algorithm indeed leads to an optimized as well as fair assignment, which is a necessary first step towards solving the Tragedy