k2U: A General Framework from k-Point Effective Schedulability Analysis to Utilization-Based Tests

To deal with a large variety of workloads in different application domains in real-time embedded systems, a number of expressive task models have been developed. For each individual task model, researchers tend to develop different types of techniques for deriving schedulability tests with different computation complexity and performance. In this paper, we present a general schedulability analysis framework, namely the k2U framework, that can be potentially applied to analyze a large set of real-time task models under any fixed-priority scheduling algorithm, on both uniprocessor and multiprocessor scheduling. The key to k2U is a k-point effective schedulability test, which can be viewed as a "blackbox" interface. For any task model, if a corresponding k-point effective schedulability test can be constructed, then a sufficient utilization-based test can be automatically derived. We show the generality of k2U by applying it to different task models, which results in new and improved tests compared to the state-of-the-art. Analogously, a similar concept by testing only k points with a different formulation has been studied by us in another framework, called k2Q, which provides quadratic bounds or utilization bounds based on a different formulation of schedulability test. With the quadratic and hyperbolic forms, k2Q and k2U frameworks can be used to provide many quantitive features to be measured, like the total utilization bounds, speed-up factors, etc., not only for uniprocessor scheduling but also for multiprocessor scheduling. These frameworks can be viewed as a "blackbox" interface for schedulability tests and response-time analysis

Unraveling the Mechanisms of Isoprenoid Biosynthetic Enzymes: Mechanistic Studies of the Early Stage Enzymes

Isoprenoids (or terpenoids) are a large and structurally diverse class of biomolecules that are essential for the survival of all forms of life. Despite the vast differences in their final structures and functions, the early steps of isoprenoid biosynthesis in all organisms follow one of only two known biosynthetic pathways: the mevalonate pathway or the methyl erythritol phosphate (MEP) pathway. Interestingly, while humans utilize the mevalonate pathway, many human pathogens rely exclusively on the MEP pathway for the biosynthesis of their isoprenoid compounds. This has led to a number of mechanistic studies of the MEP-specific pathway enzymes, with the ultimate goal of developing small molecule inhibitors as potential drugs. In addition to their therapeutic value, many of the MEP pathway enzymes also catalyze unusual chemical transformations that are not well understood. In this review, we will highlight the recent work by us and others towards the elucidation of the catalytic mechanisms of several key enzymes involved in the early stages of isoprenoid biosynthesis. These include 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) and 1-hydroxy-2-methyl-2-(E)-butenyl-4-diphosphate reductase (IspH) of the MEP pathway, and the type II isopentenyl diphosphate:dimethylallyl diphosphate isomerase (IDI-2) from Staphylococcus aureus. The functions of these enzymes are validated or identified as potential drug targets

Mutations in the PKM2 exon-10 region are associated with reduced allostery and increased nuclear translocation.

PKM2 is a key metabolic enzyme central to glucose metabolism and energy expenditure. Multiple stimuli regulate PKM2's activity through allosteric modulation and post-translational modifications. Furthermore, PKM2 can partner with KDM8, an oncogenic demethylase and enter the nucleus to serve as a HIF1α co-activator. Yet, the mechanistic basis of the exon-10 region in allosteric regulation and nuclear translocation remains unclear. Here, we determined the crystal structures and kinetic coupling constants of exon-10 tumor-related mutants (H391Y and R399E), showing altered structural plasticity and reduced allostery. Immunoprecipitation analysis revealed increased interaction with KDM8 for H391Y, R399E, and G415R. We also found a higher degree of HIF1α-mediated transactivation activity, particularly in the presence of KDM8. Furthermore, overexpression of PKM2 mutants significantly elevated cell growth and migration. Together, PKM2 exon-10 mutations lead to structure-allostery alterations and increased nuclear functions mediated by KDM8 in breast cancer cells. Targeting the PKM2-KDM8 complex may provide a potential therapeutic intervention

Traceable GISAXS measurements for pitch determination of a 25 nm self-assembled polymer grating

The feature sizes of only a few nanometers in modern nanotechnology and next-generation microelectronics continually increase the demand for suitable nanometrology tools. Grazing incidence small-angle X-ray scattering (GISAXS) is a versatile technique to measure lateral and vertical sizes in the nm-range, but the traceability of the obtained parameters, which is a prerequisite for any metrological measurement, has not been demonstrated so far. In this work, the first traceable GISAXS measurements, demonstrated with a self-assembled block copolymer grating structure with a nominal pitch of 25 nm, are reported. The different uncertainty contributions to the obtained pitch value of 24.83(9) nm are discussed individually. The main uncertainty contribution results from the sample-detector distance and the pixel size measurement, whereas the intrinsic asymmetry of the scattering features is of minor relevance for the investigated grating structure. The uncertainty analysis provides a basis for the evaluation of the uncertainty of GISAXS data in a more general context, for example in numerical data modeling.Comment: 9 pages, 6 figures; submitted to Journal of Applied Crystallograph