Synthesis of 4-Thiazolidinone Small Molecules as Potential Inhibitors of the Arp2/3 Complex

Life-essential cellular processes such as endocytosis, motility, and division rely on a cell’s ability to precisely regulate construction of actin filaments in response to external factors and signals. Intrinsically involved in this process is the Actin Related Protein 2/3 (Arp2/3) Complex, a seven-subunit ATPase that functions by nucleating a daughter branch of actin from the side of a pre-existing microfilament. Active Arp2/3 complex is necessary for the proliferation of certain metastatic cancers, and inhibition of Arp2/3 complex is emerging as a potentially useful treatment strategy for such cancers. We describe synthesis and in vitro assays of 4-thiazolidinones predicted by computational methods to inhibit of Arp2/3 Complex strongly, and therefore serve as potential lead compounds for drug development. Known Arp2/3 inhibitor CK-869 serves as the starting point for derivative synthesis. We discuss the efforts towards the synthesis of new compounds and the biochemical data collected about their potency

Pitched Baseballs and the Seam Shifted Wake

An experiment was conducted to investigate the effect that seams have on the way a baseball moves through the air. An examination of the airflow around a baseball led to the understanding that when seams are in certain areas on the baseball\u27s surface the airflow changes. A subsequent experiment was performed which showed that when these changes in airflow were on one side of the baseball more than the other, the ball moved away from the side with the seams. This movement is in a different direction than the movement direction caused by a ball\u27s spin. These experiments were done using balls moving at 90 mph and spinning at 1200 RPM, a baseball tracking system, and a highspeed camera

Sandstorm: a biosand filter designed for small-scale enterprises

Compared to popular concrete biosand filter designs the Sandstorm biosand filter presented here claims to be lighter, cheaper, faster to make and requires no special tooling or molds. Tested in realistic field conditions in Ethiopia alongside popular concrete biosand filters Sandstorm delivers higher bacteriological removal efficiencies and larger water volumes. Though particularly relevant for implementation in a low-technology, small-scale enterprise model, the design also offers significant scale-up advantages for larger scale implementers due to the advantages of manufacturing speed and transportability. The innovative design follows a partnership between Tearfund UK and Desert Rose Consultancy in Ethiopia

Physical Activity Modulates Corticospinal Excitability of the Lower Limb in Young and Old Adults

Aging is associated with reduced neuromuscular function, which may be due in part to altered corticospinal excitability. Regular physical activity (PA) may ameliorate these age-related declines, but the influence of PA on corticospinal excitability is unknown. The purpose of this study was to determine the influence of age, sex, and PA on corticospinal excitability by comparing the stimulus-response curves of motor evoked potentials (MEP) in 28 young (22.4 ± 2.2 yr; 14 women and 14 men) and 50 old adults (70.2 ± 6.1 yr; 22 women and 28 men) who varied in activity levels. Transcranial magnetic stimulation was used to elicit MEPs in the active vastus lateralis muscle (10% maximal voluntary contraction) with 5% increments in stimulator intensity until the maximum MEP amplitude. Stimulus-response curves of MEP amplitudes were fit with a four-parameter sigmoidal curve and the maximal slope calculated (slopemax). Habitual PA was assessed with tri-axial accelerometry and participants categorized into either those meeting the recommended PA guidelines for optimal health benefits (\u3e10,000 steps/day, high-PA; n = 21) or those not meeting the guidelines (n = 41). The MEP amplitudes and slopemax were greater in the low-PA compared with the high-PA group (P \u3c 0.05). Neither age nor sex influenced the stimulus-response curve parameters (P \u3e 0.05), suggesting that habitual PA influenced the excitability of the corticospinal tract projecting to the lower limb similarly in both young and old adults. These findings provide evidence that achieving the recommended PA guidelines for optimal health may mediate its effects on the nervous system by decreasing corticospinal excitability

Multiscale probability mapping: groups, clusters and an algorithmic search for filaments in SDSS

We have developed a multiscale structure identification algorithm for the detection of overdensities in galaxy data that identifies structures having radii within a user-defined range. Our "multiscale probability mapping" technique combines density estimation with a shape statistic to identify local peaks in the density field. This technique takes advantage of a user-defined range of scale sizes, which are used in constructing a coarse-grained map of the underlying fine-grained galaxy distribution, from which overdense structures are then identified. In this study we have compiled a catalogue of groups and clusters at 0.025 < z < 0.24 based on the Sloan Digital Sky Survey, Data Release 7, quantifying their significance and comparing with other catalogues. Most measured velocity dispersions for these structures lie between 50 and 400 km/s. A clear trend of increasing velocity dispersion with radius from 0.2 to 1 Mpc/h is detected, confirming the lack of a sharp division between groups and clusters. A method for quantifying elongation is also developed to measure the elongation of group and cluster environments. By using our group and cluster catalogue as a coarse-grained representation of the galaxy distribution for structure sizes of <~ 1 Mpc/h, we identify 53 filaments (from an algorithmically-derived set of 100 candidates) as elongated unions of groups and clusters at 0.025 < z < 0.13. These filaments have morphologies that are consistent with previous samples studied.Comment: 22 pages, 14 figures and 6 tables. Accepted for publication in MNRAS. Data products, three-dimensional visualisations and further information about MSPM can be found at http://www.physics.usyd.edu.au/sifa/Main/MSPM/ . v2 contains two additional references. v3 has a slightly altered title and updated reference

Dysregulation of cadherins in the intercalated disc of the spontaneously hypertensive stroke-prone rat

The structural integrity of cardiac cells is maintained by the Ca2+-dependent homophilic cell-cell adhesion of cadherins. N-cadherin is responsible for this adhesion under normal physiological conditions. The role of cadherins in adverse cardiac pathology is less clear. We studied the hearts of the stroke-prone spontaneously hypertensive (SHRSP) rat as a genetic model of cardiac hypertrophy and compared them to Wistar-Kyoto control animals. Western blotting of protein homogenates from 12-week old SHRSP animals indicated that similar levels of [beta], [gamma]-, and [alpha]-catenin and T, N and R-cadherin were expressed in the control and SHRSP animals. However, dramatically higher levels of E-cadherin were detected in SHRSP animals compared to controls at 6, 12 and 18áweeks of age. This was confirmed by quantitative Taqman PCR and immunohistochemistry. E-cadherin was located at the intercalated disc of the myocytes in co-localisation with connexin 43. Adenoviral overexpression of E-cadherin in rat H9c2 cells and primary rabbit myocytes resulted in a significant reduction in myocyte cell diameter and breadth. E-cadherin overexpression resulted in re-localisation of [beta]-catenin to the cell surface particularly to cell-cell junctions. Subsequent immunohistochemistry of the hearts of WKY and SHRSP animals also revealed increased levels of [beta]-catenin in the intercalated disc in the SHRSP compared to WKY. Therefore, remodelling of the intercalated disc in the hearts of SHRSP animals may contribute to the altered function observed in these animal