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The logic structures implemented in Field Programmable Gate Arrays (FPGAs) are often critical and their correct operation is vital. FPGA devices are often used in areas where there is increased ionising radiation (space, medical diagnostics, aviation or nuclear power). There is therefore a need for mechanisms to correct radiation-induced errors. A common approach is the redundant implementation of particularly critical parts of the logic structure. By triplicating selected fragments, it is possible not only to detect potential errors but also to correct them. Such an approach is called triple modular redundancy (TMR), and its essence lies in the use of specialised voting circuits called voters, which allow the erroneous results of individual subcircuits to be eliminated by voting. The triplicate circuit under consideration, together with the voter, constitutes the mitigation structure. It becomes necessary to develop a test environment to assess the correct operation of these circuits. Also key is the efficiency of the implementation of these structures, which can be related to the occupation of logical resources or the power consumption of a given implementation. This paper demonstrates the essence of implementing a test environment to test the correctness of the mitigation of logic structures using TMR voters. An error injector mechanism using the Pseudo-Random Bit Sequence (PRBS) register is proposed, which introduces an element of randomness into the testing process. The aim of this research is to determine the implementation efficiency of the proposed test environment. In the experimental part, the implementation costs of the proposed solution were examined. The results indicate that between 66 and 109 LUT blocks were required to implement the error injector, corresponding to a relatively small increase in dynamic power consumption: by 22% for combinational circuits and by 37% for sequential circuits. [ABSTRACT FROM AUTHOR]

Designs of timer function blocks (FBs) are presented in the article. The developed modules are IEC 61131-3. An analysis of IEC 61131-3 in terms of timer functionality and implementation options is presented. Three types are presented, timer-on, timer-off, and timer-pulse, with each type designed to be fully hardware or software-like. Both designs, hardware or software-like, can operate as multi-channel timers. Particularly noteworthy is the software-like design, for which a solution without edge detectors was achieved. Such a feature was obtained by reversing the method of time determination by counting the difference between the start and end times and by using specific features of the D flip-flops, that is, clock-enable inputs. The presented timers were written in Verilog language and implemented in an FPGA chip. Thanks to the universal design of the interface, the proposed FBs can be used for the hardware support of existing programmable logic controllers (PLCs) or as an integral part of newly built PLC CPUs. The idea of a CPU architecture with hardware support is proposed. The paper presents the results of the implementation in an FPGA of the Kintex UltraScale+ family from AMD-Xilinx. [ABSTRACT FROM AUTHOR]

Pharmacokinetic properties of our first-generation HIF-2α antagonist PT2385, including modest solubility, resulted in a high recommended phase 2 dose (RP2D) of 800 mg BID and motivated the pursuit of novel scaffolds which could improve solubility and formulation parameters with the goal of improved pharmacokinetics. Herein we disclose our successful efforts to identify such HIF-2α antagonists through an optimization strategy characterized by: (1) increasing the fraction of sp3 hybridized carbons (Fsp3), (2) replacing the aromatic portion of the indane core with pyridine heterocycles, and (3) improving a putative Olp→π*Ar interaction, an underutilized electrostatic contact in medicinal chemistry. These efforts emphasize the importance of employing multiple strategies in parameter optimization. In isolation, modifications to areas (1) and (2) improved solubility, but with the compromise of reduced potency. In area (3), understanding the importance of an Olp→π*Ar interaction, as documented through a wealth of crystal structures and retrospective calculations, proved essential in guiding SAR and identifying the trifluoromethyl group as a suitable replacement of the sulfone. Only by combining these three strategies could inhibitors with substantially improved solubility and comparable potency be discovered. Finally, the overall improvement in pharmacokinetic properties of the newly identified inhibitors is highlighted through a battery of ADME and in vivo data, including use of pharmacodynamic biomarkers indicative of HIF-2α antagonism. [ABSTRACT FROM AUTHOR]

The kinetic characterization of recombinant human acidic mammalian chitinase (AMCase) is described. AMCase, a member of the family 18 glycosyl hydrolases, is one of the important proteins involved in Th2-mediated inflammation and is implicated in asthma and allergic diseases.

Various studies are presented that provide important mechanistic insights into kinase activity and phosphorylation-mediated regulation of the novel protein kinase C isoform, protein kinase C theta. The results aid the design and discovery of protein kinase C theta antagonists as therapeutics for modulating T-cell-mediated immune and respiratory diseases.

Research has been conducted on the hypothetical protein YdcE from Escherichia coli. The crystal structure analysis of this protein demonstrate that it is a dimer and that it has structural diversity within the 4-oxalocrotonate tautomerase family.

Research has been conducted on the amino-terminal proline 4-oxalocrotonate tautomerase. The replacement of Phe-50 with Tyr, Ala, Val and Ile has been performed to investigate the effect of the hydrophobic environment on the pK (sub)a of Pro-1.

Macrophage migration inhibitory factor (MIF) exhibits catalytic activity similar to phenylpyruvate tautomerase (PPT) and may be the same protein. The Lys-32 residue in the active site lowers the pK(sub)a of the catalytic base Pro-1.

The biological role of macrophage inhibiting factor (MIF) as an inhibitor of monocyte chemotaxis and random migration was investigated. This was done by examining MIF's ability to act as a tautomerase and by determining the physiological significance of this characteristic. Results showed that MIF inhibits the movement of monocytes when a chemotactic gradient exists. It was also demonstrated that this migration inhibitory property was elicited by the chemotactic gradient of monocyte chemotactic protein 1.

A study reports on the effects of the mutations of active site arginine residues on pH-rate profile and on the pKa values of the general base catalyst Pro-1 in 4-oxalcrotonate tautomerase as determined by direct 15N nuclear magnetic resonance titrations. It is concluded that no arginine residue is responsible for either the essential acid group with pKa of 9.0 in the pH-rate profile or the unusually low pKa of Pro-1. Experimental procedures and results are presented.

The crystal structure of a complex between murine macrophage migration inhibitory factor (MIF) and (E)-2-fluoro-p-hydroxycinnamate, a competitive inhibitor of the tautomerase activity, was determined to 1.8 angstroms resolution. Findings showed that MIF processes the enol isomers more efficiently than the keto isomers mainly because of a decrease in K(sub m). A mechanism is suggested for the MIF-catalyzed tautomerization reaction.

The crystal structure of 2-oxo-3-pentynoate-inactivated 4-oxalocrotonate tautomerase was investigated using molecular replacement techniques to determine the mechanism of enzyme inactivation and catalysis. Results reveal that the active site of 4-oxalocrotonate tautomerase is located at a hydrophobic region around the proline residue at position 1. The crystal structure of the enzyme-inhibitor complex was used as the basis for the proposed catalytic reaction.

The compound 2-oxo-3-pentynoate was synthesized and tested as an inhibitor of the enzyme 4-oxalocrotonate tautomerase from Pseudomonas putida. The enzyme was found to be speedily and irreversibly inactivated by the acetylenic product analogue in a time-dependent manner. It indicated saturation kinetics and was protected from inactivation by the presence of substrate. These findings indicated that inactivation occurs at the active site.

4-oxalocrotonate tautomerase is functional in the isomerization of unconjugated alpha-keto acids. Four mutants of 4-OT have been constructed, where the amino-terminal proline is replaced with glycine, alanine and leucine, resulting in an active enzyme. The quantity of protein obtained only allowed for kinetic analysis. Results indicated that proton transfer between C3 and C5 is partly due to the rigidity of the pyrrolidine ring and the basicity of the secondary amine.

The amino acids between positions 14 and 119 at the carboxy-terminal end in the enzyme carbamoyl phosphate synthetase from Escherichia coli are necessary for catalytic activity of the enzyme. The activity is affected by allosteric effects of ornithine and UMP which can be reduced by substitutions in the glycine residue at position 968. The enzyme has two subunits, a small one that hydrolyzes glutamine to glutamate and ammonia, and a large subunit that catalyzes the formation of carbamoyl phosphate with binding sites for ornithine and UMP.