Identification of tubulin drug binding sites and prediction of relative differences in binding affinities to tubulin isotypes using digital signal processing

Microtubules are involved in numerous cellular processes including chromosome segregation during mitosis and, as a result, their constituent protein, tubulin, has become a successful target of several chemotherapeutic drugs. In general, these drugs bind indiscriminately to tubulin within both cancerous and healthy cells, resulting in unwanted side effects. However, differences between beta-tubulin isotypes expressed in a wide range of cell types may aid in the development of anti-tubulin drugs having increased specificity for only certain types of cells. Here, we describe a digital signal processing (DSP) method that is capable of predicting hot spots for the tubulin family of proteins as well as determining relative differences in binding affinities to these hot spots based only on the primary sequence of 10 human tubulin isotypes. Due to the fact that several drug binding sites have already been characterized within beta-tubulin, we are able to correlate hot spots with the binding sites for known chemotherapy drugs. We have also verified the accuracy of this method using the correlation between the binding affinities of characterized drugs and the tubulin isotypes. Additionally, the DSP method enables the rapid estimation of relative differences in binding affinities within the binding sites of tubulin isotypes that are yet to be experimentally determined.     

A Fuzzy Recommender System for Public Library Catalogs

Recommendation engines are one of the “discovery” products built into integrated library systems. These are a subclass of enterprise systems designed specifically for public and research libraries that incorporate an electronic card catalogue, circulation and inventory management, personnel and payroll systems, etc. The system vendors offer customizations for different contexts of specific library systems, but cannot create a bespoke solution for every customer. Our partner, an Edmonton‐area company, is filling this gap for a consortium of rural libraries in Alberta by creating a mobile app that interfaces with their electronic card catalog. Rural libraries are generally smaller than major urban public libraries, meaning that their holdings are limited overall, and within any given genre. This poses a severe problem for traditional collaborative‐filtering recommender algorithms, as the item sets for recommendations are limited by supply rather than by readers’ interests. The library's relatively small clientele also limits the item sets available for comparison. To deal with this ongoing “cold‐start” problem, we propose a hybridization of collaborative filtering with a content filter using a fuzzy taste vector. Experiments on two benchmark recommender data sets show that this approach is at least as accurate as existing fuzzy recommenders and is particularly effective on sparse data sets.     

Extracting dust from soil: a simple solution to a tricky task

Air quality is commonly assessed by the ambient concentration of airborne particles sized smaller than 10 microm (PM10). However, in addition to concentration, particle shape as well as the type and bioaccessibility of elements adsorbed to this particulate fraction are likely to be related to subsequent respiratory health effects. In order to investigate this relationship, a relatively large mass of the relevant size fraction is needed since sample preparation is necessary prior to analysis. Most existing methods for sampling dust have been developed for analysing the dust directly, without prior handling or digestion. In order to provide sufficient material to be used for subsequent bioaccessibility analysis, these methods require repetitive and time consuming sampling as well as special equipment and procedures which are high in both cost and maintenance. This paper describes an inexpensive and relatively simple procedure for extracting the PM10 fraction from soil to be used for lung bioaccessibility studies. The method described involves dry and wet sieving in order to exclude larger size fractions as far as possible. Vacuum filtering of the wet-sieved soil solution through a 10 microm mesh was then employed to extract the required fraction. In order to avoid frequent blocking of the mesh, Stokes's law was applied in the construction of a tube which enables separation of the solution holding the smallest fraction.     

Comparative modelling of human β tubulin isotypes and implications for drug binding

The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β?tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.     

A balance of tastes. Chefs & dietitians roundtable discussion

The demands from foodservice customers for healthier foods that also taste good have compelled chefs & dietitians to break off their traditional separation of powers & begin forming working partnerships. These new partnerships are producing menus that strike a balance just as new--a balance between the preferences & priorities of both professions. It means a combining of two different but not incompatible perspectives that magnifies both the pleasure & the benefit of the good food they serve. In recognition of these new partnerships, FM convened the first roundtable with chefs & dietitians, all of whom are on the leading edge of this emerging trend. Excerpts of their discussion reflect striking similarities in opinion--as well as differences still to be reconciled.     

Evaluating processor-behavior and three error-detection mechanismsusing physical fault-injection

An approach for assessing the impact of physical injection of transient faults on processor execution is described and evaluated. The fault injection is based on two complementary methods using: (1) heavy-ion radiation; and (2) power supply disturbances. 12000 transient faults were injected into the target microprocessor, a Motorola MC6809E 8-bit CPU, running 3 different workloads. In the evaluation, the control-flow errors were distinguished from those that had no effect on the correct flow of control. The errors that led to wrong results are separated from those that did not affect the correct results. The errors that affected neither the correct control flow nor the correct results are specified. Effects of errors on the registers and signals of the processor are characterized, Workload dependency on error rates is demonstrated. Three error-detection mechanisms, (2 software-based mechanisms and 1 watchdog timer) were combined and used to characterize the detected and undetected errors. More than 87% of all errors and 93% of the control-flow errors could be detected. In a different test, the efficiency of an isolated watchdog timer was evaluated. The coverage of the isolated watchdog timer was only 62%. The results indicate that fault-injection methods, workloads, and programming languages all differently affect the control flow, coverage, latency, and error rates     

The ForeMoSt approach to building valid model-based safety arguments

Software and Systems Modeling - Safety assurance cases (ACs) are structured arguments designed to comprehensively show that a system is safe. ACs are often model-based, meaning that a model of the...