Development of Second Generation Activity-Based Chemical Probes for Sirtuins

NAD⁺ (nicotinamide adenine dinucleotide)-dependent protein deacylases, namely, the sirtuins, are important cell adaptor proteins that alter cell physiology in response to low calorie conditions. They are thought to mediate the beneficial effects of calorie restriction to extend longevity and improve health profiles. Novel chemical probes are highly desired for a better understanding of sirtuin’s roles in various biological processes. We developed a group of remarkably simple activity-based chemical probes for the investigation of active sirtuin content in complex native proteomes. These probes harbor a thioacyllysine warhead, a diazirine photoaffinity tag, as well as a terminal alkyne bioorthogonal functional group. Compared to their benzophenone-containing counterparts, these new probes demonstrated improved labeling efficiency and sensitivity, shortened irradiation time, and reduced background signal. They were applied to the labeling of individual recombinant proteins, protein mixtures, and whole cell lysate. These cell permeable small molecule probes also enabled the cellular imaging of sirtuin activity change. Taken together, our study provides new chemical biology tools and future drug discovery strategies for perturbing the activity of different sirtuin isoforms.     

Reactions of indium phosphide cluster cations with ammonia and trimethylamine

Chemistry of indium phosphide clusters is studied using the powerful trapped ion cell techniques of Fourier transform ion cyclotron resonance (FTICR) mass spectrometry in conjunction with an external cluster source and ion guide. The external source is capable of generating a wide range of cluster ions which the ion guide loads with high efficiency into the FTICR cell. The differential pumping of the ion guide allows for operation of the FTICR at requisite low pressure conditions while extracting clusters generated in a high pressure environment. Highly selective reactions of indium phosphide clusters are observed with ammonia and trimethylamine. Of all the In_xP⁺_y cluster sizes and stoichiometries studied, only the indium dimer ion reacts exothermically with ammonia. Thermalized In⁺₂ reacts by indium ion transfer to ammonia. Owing to its much higher basicity, trimethylamine is much more reactive. The smaller indium phosphide clusters react by indium ion transfer to trimethylamine. As the clusters become larger, however, the reaction probability decreases to zero.     

Role of design-philosophies in interfacing manufacturing with marketing

Product design involves the mapping of a product's marketing attributes to its engineering and manufacturing features. In practice, it is a non-trivial task for design engineers to determine an appropriate mapping between a product's marketing and manufacturing attributes so as to generate a product design that satisfies customer-needs while being feasible to produce within the technical and financial constraints of the firm's manufacturing domain. In this paper, we hypothesize that in a mature industry, the expertise that guides designers in this mapping process exists in the form of an engineering design-philosophy that governs the design of products in that industry. Clearly, if we are able to discern the design-philosophies that exist in an industry, they can then be used to channrl designers' creativity to be congruent with the commercial objectives of firms in that industry. Using real-world data from the automobile industry, we show the existence of design-philosophies and illustrate methodologies for identifying and interpreting them. We also describe predictive models that allow managers to exploit the knowledge available in these design-philosophies and accurately specify a new product's manufacturing attribute values, given market input regarding the product's desired features. This total approach should save firms valuable product designing time and enable them to generate products that can be successfully produced and sold.     

Transient dynamic response of sandwich shells with transversely compressible core

The present study provides an investigation of the effect of the transverse core compressibility on the dynamic buckling response of sandwich structures. The study utilizes a previous v. Kármán type higher-order model for shallow sandwich shells. An analytical solution is obtained by means of an extended Galerkin procedure in conjunction with an explicit fourth order Runge-Kutta algorithm to solve the transient problem. In an example analysis, it is observed that the transverse core compressibility can have strong effects even on the global response of sandwich structures. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)     

The point-splitting regularization of (2+1)d parity breaking models

The coefficient of the Chern–Simons term in the effective action for massive Dirac fermions in three dimensions is computed by using the point-splitting regularization method. We show that in this framework no ambiguities arise. This is related to the fact that the point-splitting regularization does not introduce additional parity breaking effects, implementing one possible physical criterion in order to uniquely characterize the system.