Environmental-Based Characterization of SoC-Based Instrumentation Systems for Stratified Testing

This paper proposes a novel environmental-based method for evaluating the good yield rate (GYR) of systems-on-chip (SoC) during fabrication. Testing and yield evaluation at high confidence are two of the most critical issues for the success of SoC as a viable technology. The proposed method relies on different features of fabrication, which are quantified by the so-called Fabrication environmental parameters (EPs). EPs can be highly correlated to the yield, so they are analyzed using statistical methods to improve its accuracy and ultimately direct the test process to an efficient execution. The novel contributions of the proposed method are: 1) to establish an adequate theoretical foundation for understanding the fabrication process of SoCs together with an assurance of the yield at a high confidence level and 2) to ultimately provide a realistic approach to SoC testing with an accurate yield evaluation. Simulations are provided to demonstrate that the proposed method significantly improves the confidence interval of the estimated yield as compared with existing testing methodologies such as random testing (RT)

How do metalloenzymes propagate and control chemical reactions?

Enzymes control and propagate a dizzying array of chemical reactions, including radical reactions and reactions cleaving carbon-carbon bonds. Metalloenzymes, which contain a metal cofactor, are particularly adept at propagating these reactions. This thesis focuses on several metalloenzymes; each an example of a different unique reaction control strategy. Both experimental and computational methodologies have been employed in order to identify specific residues or features which contribute to each enzyme\u27s ability to control the reaction. Emphasis is made on special properties of the metal Manganese. Controlling residues include not only first shell or active site residues, but also residues more distant from the active-site. Further, manipulation of such residues can be used to alter reactivity at non -active-sites, or to alter the apparent electrostatics of the protein (in the case of substitution of hydrogen with fluorine). Electron Paramagnetic Resonance (EPR) and other forms of magnetic spectroscopy can be used to evaluate subtle differences imposed by substitution for controlling residues to a metal center, which gives further insight into the electronic contributions of given residues, as well as the electronic properties of metal cofactors. In summary, the catalysis by Mn-dependent and other metal-dependent metalloenzymes can be investigated through multiple kinetic and spectroscopic avenues, unveiling suprising and novel themes in enzymatic catalysis, such as mechano-chemical switches and super long-distance metallo-interactions

Theoretical investigation of the Co-C bond activation in methylcobalamin and adenosylcobalamin-dependent systems: mechanistic insights.

The vitamin B12 derivates, otherwise known as cobalamin (Cbl), are ubiquitous organometallic cofactors. The biologically active forms of Cbl, such as methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl), act as cofactors in different physiological reactions for both prokaryotes and eukaryotes. A crucial aspect of the Cbl-mediated systems is the activation of the organometallic Co-C bond that plays a critical role in its catalytic activity. One of the most remarkable features of this Co-C bond is its unusual activation in AdoCbl-dependent enzymatic reactions, where a trillion-fold rate acceleration of the Co-C bond cleavage is observed inside the enzyme compared to the isolated AdoCbl. Although several hypotheses have been proposed previously, none can fully explain the trillion-fold rate acceleration that is observed for the Co-C bond cleavage. Thus, the factor(s) responsible for the unusual activation of the Co-C bond in the AdoCbl-dependent enzyme remains elusive. Nonetheless, this Co-C bond of MeCbl and AdoCbl cofactors is also known for its unique ability to be activated both thermally and photolytically within the enzymatic environment as well as in solutions. Even though the photochemistry of Cbl-dependent systems has been known for almost five decades, it has recently received a lot of attention due to its potential role in light-activated drug delivery, biomimetic catalysis, and a variety of other applications. Therefore, with these applications in mind, understanding the mechanistic insight into the activation of the Co-C bond is paramount for gaining a comprehensive knowledge of these reactions. In this dissertation, the mechanistic details of the activation of the Co-C in the photolysis and native catalysis of MeCbl and AdoCbl-dependent systems have been investigated using hybrid quantum mechanics/molecular mechanics (QM/MM) simulations, density functional theory (DFT), and time-dependent density functional theory (TD-DFT) methodologies. Overall, this dissertation is divided into six chapters. Chapter one gives an introduction, a historical overview of B12 chemistry, and possible applications in therapeutics and optogenetics. Chapters two and three discuss the photoactivation of the Co-C bond in MeCbl-dependent methionine synthase (MetH) and explore the role of the enzymatic environment on photoreaction. The photochemical data of isolated MeCbl cofactor in solution were also discussed and compared with the enzymatic environment to understand the effect of protein binding on the photolysis of Co-C bonds. The influence of mutation on the photolysis of Co-C is discussed in chapter three. Overall, in these two chapters, it was shown that the enzymatic environment affects the photolysis of the Co-C bond by modulating the electronically excited state. Chapter four provides an in-depth insight into the aerobic photolysis of MeCbl, with emphasis placed on the mechanistic details of the insertion of O2 in the activated Co-C bond. It was shown that the photochemical properties of MeCbl can also be modulated in the presence of molecular oxygen, i.e., in aerobic conditions. While chapters two to four cover the light-activation of the Co-C bond, chapter five focused on the activation of the Co-C bond during the native catalysis of AdoCbl-dependent methylmalonyl CoA mutase (MCM). The QM/MM methodology has been used to investigate the factor(s) responsible for the unusual activation of the Co-C bond that is observed in the enzyme as compared to AdoCbl in solution. While there are at least three previously reported hypotheses for the activation of the Co-C5ʹ bond including, substrate-induced conformational changes, electrostatic interaction between the Ado group and the enzyme, and involvement of tyrosine residue, none of these can explain this unusual activation. Thus, how the arrival of the substrate triggers the activation of the Co-C5ʹ bond remains an open issue

Theory and Background of Multi-Criteria Analysis: Toward a policy-led approach for mega transport project infrastructure appraisal

The aims of this paper are twofold. Firstly, to present a review and critical analysis of the varying forms and functions of Multi-Criteria Analysis presented in the literature, and secondly, drawing from this, to introduce methods and processes by which policy leadership can be introduced into such processes for the appraisal of large-scale transport infrastructure projects to form a policy-led multi-criteria analysis. Following the discussion in the first paper of this Special Issue, ‘Presenting the Case for the Application of Multi-Criteria Analysis to Mega Transport Project Infrastructure Appraisal’, this contribution commences by outlining further the generic features and challenges of multi-criteria analysis approaches to project appraisal whilst emphasizing the difference among various frameworks and attendant processes for such approaches. It also highlights the important role/value of the multi-criteria mapping of stakeholder policies and agendas affecting project decision-making as a means of defining and scoping the boundaries of the project exercise under study and the trade-off decision-spaces for stakeholder dialogues and negotiations in their search to arrive at mutually agreed actions and outcomes. The paper discusses how multi-criteria analysis frameworks can be tailor-designed for particular agencies and stakeholders developed around problems, challenges and issues. This is done in the acknowledgement that such exercises, especially when applied to mega infrastructure project appraisal, typically attract a multiple-institutional response and where ultimately an institutional leader (or partnership of stakeholders) exists/emerges that impose its/their priorities on others. Alternatively, the approach can be tailor-made for specific institutions with its imbedded hierarchy of policies and priorities that frame the stakeholder decision space within which other parties can participate and trade off interests. The first part of the paper highlights the important role of scenarios of policy-making contexts and policy leadership indicating the new risks, uncertainties and opportunities these may offer in multi-criteria analysis exercises, indicating that some/many past processes have been conducted outside of any real reference to such matters. In so doing, such applications have them silently and implicitly adopt scenarios and policy assumptions that are not transparent frequently reflecting, it is alleged, ‘business as usual’ circumstances in contexts when the signs are very much that these trends will not/cannot prevail. The authors contend that without explicit policy leadership there is a danger that certain institutional stakeholder priorities will be imposed over others by the most powerful without adequate dialogue. Understanding that this matters a great deal in contexts when project stakeholder powers shifts occur is very significant. Examples of such circumstances are when national governments become, less or more powerful and economically affluent, when relative legislative and regulation powers become less or more binding and powerful, and when a major private sector investor upon which a project depends goes bankrupt. The second half of the paper builds on these observations to offer a generic multi-criteria analysis framework and attendant processes that imbed policy leadership firmly within multi-stakeholder decision-making (termed Policy-led Multi-criteria Analysis). The framework developed is to be applied to mega transport projects via the use of suitable appraisal criteria in the pursuit of sustainable development goals, which seek to address both quantitative and qualitative dimensions and concerns of multiple stakeholders, with particular emphasis on the processes required to identify and incorporate suitable policy leadership, including feedback between appraisal and policy