Synthesis of Small Molecule Derivatives of CK-666 as Potential Inhibitors of the Arp2/3 Complex

The Actin-Related Protein (Arp) 2/3 Complex is an actin nucleating factor intrinsically involved in cellular regulation of actin networks during life-essential processes such as motility. Overexpression of the Arp2/3 complex has indicated as a factor allowing the proliferation of certain metastatic cancers. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. The molecules are designed based off of the structure of known Arp2/3 inhibitor CK-666, which was discovered via high-throughput screening. Details of the synthesis of the tryptamine derivatives are discussed, and the bulk actin polymerization assay used to determine potency of the new compounds is discussed

Heart Treatment in Ancient Egyptian Mummification

Descriptions in the popular and academic literature, of the treatment of the heart as part of the Egyptian mummification tradition, are derived from accounts by classical authors. Our reliance on these normative descriptions, in the absence of Egyptian accounts, has obscured the wide range of mummification practices and the intrasocietal changes occurring in ancient Egypt. It has impeded the study of geographic, chronological, and socio-political variations in ancient Egyptian mortuary practice and ideology. This study focuses on computed tomography (CT) as a non-destructive gold standard for mummies studies, and in the examination of heart treatment indications and variations with time, sex, and status

Another Hole in the Head? Brain Treatment in Ancient Egyptian Mummies

Perhaps the most sensational and best-known feature of Egyptian mummification, the removal of the brain, is commonly attributed to the New Kingdom onward (e.g. [1]). Variability both within and between excerebration techniques, however, is poorly appreciated in the literature [2], and reporting of excerebration is often inconsistent, greatly simplified, or simply absent in descriptions of mummified remains, making detailed comparative studies difficult if not impossible. The goals of this study were to demonstrate: variability in mummy excerebration techniques temporal and status trends in brain treatment the limitations of the literature for large studies This study focuses on computed tomography (CT), as a non-destructive gold standard for mummies studies, in the examination of three primary treatments of the brain in mummification: transnasal craniotomy (TNC) transforaminal craniotomy (TFC) the absence of excerebration in relation to their radiological indications and their variations with time and status

Assessment of Human Trabecular Architecture in the Pubis by Three Radiographic Modalities

This poster discusses technical aspects of an investigation into the use of non-destructive radiological analyses of pubic cancellous bone structure to estimate age-at-death from human skeletal remains. This study stems from findings, in X-ray plain films, of increased rarification and orientation of trabeculae with age [1]; likely in concert with the macroscopic remodelling of the symphyseal surface currently used in estimation of age-at-death. The study uses three non-destructive X-ray imaging modalities: plain film radiography, computed tomography (CT), and micro-CT (μCT). Plain film radiography has greater spatial resolution than CT [2] and is relatively inexpensive, widely available, and, with portable X-ray units, even accessible in the field for archaeological and forensic applications. CT scanners are largely restricted to clinical settings due to the size, sensitivity, and cost of the machine, but offer a greater contrast resolution than plain film radiography [2]. More expensive and more precise, μCTscanners are further restricted in their availability and accessibility, but CT andμCTmodalities provide volumetric data, avoiding the confusion of overlying cortical and cancellous structures and the apparent increases in density with element thickness seen in plain film radiography

Modelling the bioaccumulation of persistent organic pollutants in agricultural food chains for regulatory exposure assessment

New models for estimating bioaccumulation of persistent organic pollutants in the agricultural food chain were developed using recent improvements to plant uptake and cattle transfer models. One model named AgriSim was based on K OW regressions of bioaccumulation in plants and cattle, while the other was a steady-state mechanistic model, AgriCom. The two developed models and European Union System for the Evaluation of Substances (EUSES), as a benchmark, were applied to four reported food chain (soil/air-grass-cow-milk) scenarios to evaluate the performance of each model simulation against the observed data. The four scenarios considered were as follows: (1) polluted soil and air, (2) polluted soil, (3) highly polluted soil surface and polluted subsurface and (4) polluted soil and air at different mountain elevations. AgriCom reproduced observed milk bioaccumulation well for all four scenarios, as did AgriSim for scenarios 1 and 2, but EUSES only did this for scenario 1. The main causes of the deviation for EUSES and AgriSim were the lack of the soil-air-plant pathway and the ambient air-plant pathway, respectively. Based on the results, it is recommended that soil-air-plant and ambient air-plant pathway should be calculated separately and the K OW regression of transfer factor to milk used in EUSES be avoided. AgriCom satisfied the recommendations that led to the low residual errors between the simulated and the observed bioaccumulation in agricultural food chain for the four scenarios considered. It is therefore recommended that this model should be incorporated into regulatory exposure assessment tools. The model uncertainty of the three models should be noted since the simulated concentration in milk from 5th to 95th percentile of the uncertainty analysis often varied over two orders of magnitude. Using a measured value of soil organic carbon content was effective to reduce this uncertainty by one order of magnitude

Pagetʼs Disease (Osteitis Deformans) in Archaeological Remains: A Radiographic Differential

Paget’s disease of bone is a metabolic bone disease of unknown etiology and is the most likely disease to cause secondary bone cancer; a prevalence that increases with age[1]. With the increasing age of modern populations, the importance of better understanding this disease will likewise increase. While in vivo tests for the disease cannot be performed in skeletal samples, radiographic views of archaeological remains can provide insight into the origins and natural history of the disease

\u3cem\u3eIn Vitro\u3c/em\u3e Determination of Potency of Small Molecule Inhibitors of Arp2/3 Complex

Actin is a key protein building block of actin microfilaments, which are constructed and deconstructed in response to cellular signaling pathways to regulate cellular processes such as motility, division, and endocytosis. Arp2/3 Complex is a 7-subunit protein complex that is in involved in cellular construction of branched actin networks, functioning by attaching to the side of a pre-existing actin filament and nucleating a daughter branch. Overexpression of Arp2/3 complex has been linked to the ability of certain metastatic cancers to proliferate. This work describes the synthesis and in vitro biochemical testing of several molecules predicted by computational docking to be inhibitors of Arp2/3 Complex, and therefore of potential interest in clinical applications. A bulk actin polymerization assay is used as the key method to determine the potency of inhibitor candidates. Structure-activity relationships derived from these results are also discussed