Gergely Nagy

Electro-thermal and Logi-thermal Simulators aimed at the Temperature-aware Design of Complex Integrated Circuits

With the increasing power dissipation increasing attention has been paid to the thermal issues in electronics design on system, board, package and chip level, including electrothermal simulation of even rather complex integrated circuits. Two distinct algorithmic directions can be distinguished in electro-thermal simulation: the simulator coupling and the simultaneous iteration or direct method. In our view the direct method is well suited for electro-thermal simulation of analog circuit blocks while simulator coupling can be used to implement logi-thermal simulation. In case of complex designs containing digital and analog blocks the two approaches can also be combined. Ideally thermal, electro-thermal and logi-thermal simulation of a circuit is performed already in the phase of conceptual design when only a rough idea exists about the final physical realization of the circuit. In any case, effect of the thermal boundary conditions of the die+package, cooling via the electrical connections to the die and the granularity of the simulation should be carefully considered.

Preventive DNA repair by sanitizing the cellular (deoxy)nucleoside triphosphate pool

The occurrence of modified bases in DNA is attributed to some major factors: incorporation of altered nucleotide building blocks and chemical reactions or radiation effects on bases within the DNA structure. Several enzyme families are involved in preventing the incorporation of noncanonical bases playing a ‘sanitizing’ role. The catalytic mechanism of action of these enzymes has been revealed for a number of representatives in clear structural and kinetic detail. In this review, we focus in detail on those examples where clear evidence has been produced using high‐resolution structural studies. Comparing the protein fold and architecture of the enzyme active sites, two main classes of sanitizing deoxyribonucleoside triphosphate pyrophosphatases can be assigned that are distinguished by the site of nucleophilic attack. In enzymes associated with attack at the α‐phosphorus, it is shown that coordination of the γ‐phosphate group is also ensured by multiple interactions. By contrast, enzymes catalyzing attack at the β‐phosphorus atom mainly coordinate the α‐ and the β‐phosphate only. Characteristic differences are also observed with respect to the role of the metal ion cofactor (Mg2+) and the coordination of nucleophilic water. Using different catalytic mechanisms embedded in different protein folds, these enzymes present a clear example of convergent evolution.

Composite Aromatic Boxes for Enzymatic Transformations of Quaternary Ammonium Substrates

Cation-π interactions to cognate ligands in enzymes have key roles in ligand binding and enzymatic catalysis. We have deciphered the key functional role of both charged and aromatic residues within the choline binding subsite of CTP:phosphocholine cytidylyltransferase and choline kinase from Plasmodium falciparum. Comparison of quaternary ammonium binding site structures revealed a general composite aromatic box pattern of enzyme recognition sites, well distinguished from the aromatic box recognition site of receptors.

Advancing the thermal stability of 3D ICs using logi-thermal simulation

3D-ICs have emerged in the past few years. While they solve a large number of problems related to scaling, they also create new ones. Removing the heat from the layers far from the cooling facilities is a great challenge still under intensive research. This paper shows how logi-thermal simulation can be used to predict the operation parameters of large digital systems realized in 3D-ICs. The method can be effectively used to guide place-and-route algorithms and to find the thermal bottlenecks.

Simulation framework for multilevel power estimation and timing analysis of digital systems allowing the consideration of thermal effects

This paper presents a simulation framework that considers the self-heating of digital blocks and thus helps designers, verification engineers and test engineers to predict or detect thermally sensitive regions and possible signal integrity issues in complex digital designs.

Vibration combined high Temperature Cycle Tests for capacitive MEMS accelerometers

In this paper vibration combined high temperature cycle tests for packaged capacitive SOI-MEMS accelerometers are presented. The aim of these tests is to provide useful Design for reliability information for MEMS designers. A high temperature test chamber and a chopper-stabilized read-out circuitry were designed and realized at BME-DED. Twenty thermal cycles of combined temperature cycle test and fatigue vibration test has been carried out on 5 samples. Statistical evaluation of the test results showed that degradation has started in 3 out of the 5 samples.

Molecular Mechanism for the Thermo-Sensitive Phenotype of CHO-MT58 Cell Line Harbouring a Mutant CTP:Phosphocholine Cytidylyltransferase

Control and elimination of malaria still represents a major public health challenge. Emerging parasite resistance to current therapies urges development of antimalarials with novel mechanism of action. Phospholipid biosynthesis of the Plasmodium parasite has been validated as promising candidate antimalarial target. The most prevalent de novo pathway for synthesis of phosphatidylcholine is the Kennedy pathway. Its regulatory and often also rate limiting step is catalyzed by CTP:phosphocholine cytidylyltransferase (CCT). The CHO-MT58 cell line expresses a mutant variant of CCT, and displays a thermo-sensitive phenotype. At non-permissive temperature (40°C), the endogenous CCT activity decreases dramatically, blocking membrane synthesis and ultimately leading to apoptosis. In the present study we investigated the impact of the analogous mutation in a catalytic domain construct of Plasmodium falciparum CCT in order to explore the underlying molecular mechanism that explains this phenotype. We used temperature dependent enzyme activity measurements and modeling to investigate the functionality of the mutant enzyme. Furthermore, MS measurements were performed to determine the oligomerization state of the protein, and MD simulations to assess the inter-subunit interactions in the dimer. Our results demonstrate that the R681H mutation does not directly influence enzyme catalytic activity. Instead, it provokes increased heat-sensitivity by destabilizing the CCT dimer. This can possibly explain the significance of the PfCCT pseudoheterodimer organization in ensuring proper enzymatic function. This also provide an explanation for the observed thermo-sensitive phenotype of CHO-MT58 cell line.

NLS copy-number variation governs efficiency of nuclear import--case study on dUTPases.

Nucleocytoplasmic trafficking of large macromolecules requires an active transport machinery. In many cases, this is initiated by binding of the nuclear localization signal (NLS) peptide of cargo proteins to importin‐α molecules. Fine orchestration of nucleocytoplasmic trafficking is of particularly high importance for proteins involved in maintenance of genome integrity, such as dUTPases, which are responsible for prevention of uracil incorporation into the genome. In most eukaryotes, dUTPases have two homotrimeric isoforms: one of these contains three NLSs and is present in the cell nucleus, while the other is located in the cytoplasm or the mitochondria. Here we focus on the unusual occurrence of a pseudo‐heterotrimeric dUTPase in Drosophila virilis that contains one NLS, and investigate its localization pattern compared to the homotrimeric dUTPase isoforms of Drosophila melanogaster. Although the interaction of individual NLSs with importin‐α has been well characterized, the question of how multiple NLSs of oligomeric cargo proteins affect their trafficking has been less frequently addressed in adequate detail. Using the D. virilis dUTPase as a fully relevant physiologically occurring model protein, we show that NLS copy number influences the efficiency of nuclear import in both insect and mammalian cell lines, as well as in D. melanogaster and D. virilis tissues. Biophysical data indicate that NLS copy number determines the stoichiometry of complexation between importin‐α and dUTPases. The main conclusion of our study is that, in D. virilis, a single dUTPase isoform efficiently reproduces the cellular dUTPase distribution pattern that requires two isoforms in D. melanogaster.

New simulation approaches supporting temperature-aware design of digital ICs

Regarding thermal issues in digital IC design a major concern is how timing integrity is affected by the elevated junction temperature and temperature gradients on the chip surface. To predict this in a thermal aware design process one needs a dedicated simulation tool in which the logic simulation of the circuit is coupled to the thermal simulation of the chip and its environment. This paper presents two approaches to this so called logithermal simulation. In one of our approaches we rely completely on industry standard EDA tools, standard EDA file formats and interfaces. In the other solution which provides us total freedom in the abstraction level of circuit description and simulation accuracy we use our own logic simulation engine. In both cases the logic simulation engine is connected to our own thermal simulation engines which also use compact thermal models of the IC package during simulation. This paper describes certain implementation aspects and features of our logithermal simulation solutions, with emphasizes on modeling the thermal properties of the IC packaging.

Consideration of thermal effects in logic simulation

This paper presents a method that considers thermal effects in logic simulations. The aim is to develop a tool that is capable of modeling the thermal behavior of a digital circuit and, at the same time, yields results almost at the speed of ordinary logic simulators. The importance of such a simulation is that thermal effects can be the cause of signal integrity problems. The structure and the basic operation of the simulator are discussed as well as the issues that need to be addressed throughout the development. A detailed description of the implementation of the tightly integrated thermal and logic simulation is also given.