The fast multipole method at exascale

This thesis presents a top to bottom analysis on designing and implementing fast algorithms for current and future systems. We present new analysis, algorithmic techniques, and implementations of the Fast Multipole Method (FMM) for solving N- body problems. We target the FMM because it is broadly applicable to a variety of scientific particle simulations used to study electromagnetic, fluid, and gravitational phenomena, among others. Importantly, the FMM has asymptotically optimal time complexity with guaranteed approximation accuracy. As such, it is among the most attractive solutions for scalable particle simulation on future extreme scale systems. We specifically address two key challenges. The first challenge is how to engineer fast code for today’s platforms. We present the first in-depth study of multicore op- timizations and tuning for FMM, along with a systematic approach for transforming a conventionally-parallelized FMM into a highly-tuned one. We introduce novel opti- mizations that significantly improve the within-node scalability of the FMM, thereby enabling high-performance in the face of multicore and manycore systems. The second challenge is how to understand scalability on future systems. We present a new algorithmic complexity analysis of the FMM that considers both intra- and inter- node communication costs. Using these models, we present results for choosing the optimal algorithmic tuning parameter. This analysis also yields the surprising prediction that although the FMM is largely compute-bound today, and therefore highly scalable on current systems, the trajectory of processor architecture designs, if there are no significant changes could cause it to become communication-bound as early as the year 2015. This prediction suggests the utility of our analysis approach, which directly relates algorithmic and architectural characteristics, for enabling a new kind of highlevel algorithm-architecture co-design. To demonstrate the scientific significance of FMM, we present two applications namely, direct simulation of blood which is a multi-scale multi-physics problem and large-scale biomolecular electrostatics. MoBo (Moving Boundaries) is the infrastruc- ture for the direct numerical simulation of blood. It comprises of two key algorithmic components of which FMM is one. We were able to simulate blood flow using Stoke- sian dynamics on 200,000 cores of Jaguar, a peta-flop system and achieve a sustained performance of 0.7 Petaflop/s. The second application we propose as future work in this thesis is biomolecular electrostatics where we solve for the electrical potential using the boundary-integral formulation discretized with boundary element methods (BEM). The computational kernel in solving the large linear system is dense matrix vector multiply which we propose can be calculated using our scalable FMM. We propose to begin with the two dielectric problem where the electrostatic field is cal- culated using two continuum dielectric medium, the solvent and the molecule. This is only a first step to solving biologically challenging problems which have more than two dielectric medium, ion-exclusion layers, and solvent filled cavities. Finally, given the difficulty in producing high-performance scalable code, productivity is a key concern. Recently, numerical algorithms are being redesigned to take advantage of the architectural features of emerging multicore processors. These new classes of algorithms express fine-grained asynchronous parallelism and hence reduce the cost of synchronization. We performed the first extensive performance study of a recently proposed parallel programming model, called Concurrent Collections (CnC). In CnC, the programmer expresses her computation in terms of application-specific operations, partially-ordered by semantic scheduling constraints. The CnC model is well-suited to expressing asynchronous-parallel algorithms, so we evaluate CnC using two dense linear algebra algorithms in this style for execution on state-of-the-art mul- ticore systems. Our implementations in CnC was able to match and in some cases even exceed competing vendor-tuned and domain specific library codes. We combine these two distinct research efforts by expressing FMM in CnC, our approach tries to marry performance with productivity that will be critical on future systems. Looking forward, we would like to extend this to distributed memory machines, specifically implement FMM in the new distributed CnC, distCnC to express fine-grained paral- lelism which would require significant effort in alternative models.Ph.D

Assembly of dynamic P450-mediated metabolons - order versus chaos

PURPOSE OF REVIEW: We provide an overview of the current knowledge on cytochrome P450-mediated metabolism organized as metabolons and factors that facilitate their stabilization. Essential parameters will be discussed including those that are commonly disregarded using the dhurrin metabolon from Sorghum bicolor as a case study. RECENT FINDINGS: Sessile plants control their metabolism to prioritize their resources between growth and development, or defense. This requires fine-tuned complex dynamic regulation of the metabolic networks involved. Within the recent years, numerous studies point to the formation of dynamic metabolons playing a major role in controlling the metabolic fluxes within such networks. SUMMARY: We propose that P450s and their partners interact and associate dynamically with POR, which acts as a charging station possibly in concert with Cytb5. Solvent environment, lipid composition, and non-catalytic proteins guide metabolon formation and thereby activity, which have important implications for synthetic biology approaches aiming to produce high-value specialized metabolites in heterologous hosts

Molecule diffusion in bacteria and consequences of osmotic stress

Dit proefschrift is een samenvatting van alle experimenten die ik de afgelopen vier jaar heb uitgevoerd. Het grootste deel van deze experimenten is gebaseerd op fluorescentie technieken, voornamelijk fluorescentie microscopie. In de hoofdstukken 2-6 (deel één van mijn proefschrift) richt ik mij op Echerichia coli, een veel gebruikt modelsysteem voor een bacteriële cel. Cellen zijn gevuld met allerlei verschillende macromoleculen die dusdanig dicht op elkaar gepakt zitten dat het vergelijkbaar is met de drukke mensenmassa in een winkelcentrum vlak voor de kerstdagen. Mijn doel was om uit te zoeken hoe snel moleculen in een cel kunnen bewegen onder deze omstandigheden. In hoofdstuk 2 geef ik een samenvatting van de recente literatuur over diffusie van (macro)-moleculen in bacteriën. Fluorescence Recovery After Photobleaching (FRAP) is een veelgebruikte fluorescentie-microscopie methode waarmee de diffusiesnelheid van moleculen bepaald kan worden. In hoofdstuk 3 vergelijk en beoordeel ik twee FRAP methodes voor het meten van de diffusiesnelheid van moleculen in bacteriën. In hoofdstuk 4 beschrijf ik de mobiliteit van grote, middelgrote en kleine moleculen in het celplasma van E. coli onder verschillende omstandigheden. Door de cellen bloot te stellen aan een osmotische verhoging van het milieu was het mogelijk de opeenpakking van moleculen in het celplasma te vergroten. Wanneer bijvoorbeeld de zoutconcentratie in het externe milieu toeneemt, zullen de cellen water verliezen (net als planten die te lang geen water hebben gekregen). Het gevolg hiervan is dat de moleculen in het cytoplasma dichter opeengepakt worden wat resulteert in een afname van hun diffusiesnelheid. Een belangrijke waarneming die ik beschrijf in hoofdstuk 4 is dat de opeenpakking van macromoleculen in het celplasma een veel groter effect heeft op de diffusie van grote moleculen (eiwitten) dan op kleine moleculen (voedingsstoffen)

An investigation of imaging approaches for the study of erbb2 distribution and dynamics in the plasma membrane with respect to the distribution of the tetraspanin cd82

Tetraspanin proteins are known to organise in the plasma membrane and form tetraspanin enriched microdomains. The tetraspanin CD82/KAI 1 has been shown previously by ensemble imaging and biochemical methods to associate with ErbB2, and it has been suggested that CD82 may play a role in regulating the distribution and dynamics ofErbB2 in the plasma membrane [1), [2]. CD82 may also play a role in mediating cellular response to Herceptin. In order to investigate the effect of CD82 on ErbB2 distribution and dynamics in the plasma membrane we applied a number of imaging techniques, in particular super resolution and single molecule approaches. We found little effect of CD82 expression on either ErbB2 diffusion or confinement characteristics in MCF7 and SKBR3 cells, and little difference in either the intrinsic clustering of ErbB2 or clustering in response to treatment with a panel of ErbB targeting molecules. We did however demonstrate and quantify the-importance of optimising both the imaging and analysis conditions for dual colour super-resolution imaging, and demonstrated for the first time the combination of super resolution optical fluctuation imaging and single molecule tracking

Dichotomic role of NAADP/two-pore channel 2/Ca2+ signaling in regulating neural differentiation of mouse embryonic stem cells

Poster Presentation - Stem Cells and Pluripotency: abstract no. 1866The mobilization of intracellular Ca2+stores is involved in diverse cellular functions, including cell proliferation and differentiation. At least three endogenous Ca2+mobilizing messengers have been identified, including inositol trisphosphate (IP3), cyclic adenosine diphosphoribose (cADPR), and nicotinic adenine acid dinucleotide phosphate (NAADP). Similar to IP3, NAADP can mobilize calcium release in a wide variety of cell types and species, from plants to animals. Moreover, it has been previously shown that NAADP but not IP3-mediated Ca2+increases can potently induce neuronal differentiation in PC12 cells. Recently, two pore channels (TPCs) have been identified as a novel family of NAADP-gated calcium release channels in endolysosome. Therefore, it is of great interest to examine the role of TPC2 in the neural differentiation of mouse ES cells. We found that the expression of TPC2 is markedly decreased during the initial ES cell entry into neural progenitors, and the levels of TPC2 gradually rebound during the late stages of neurogenesis. Correspondingly, perturbing the NAADP signaling by TPC2 knockdown accelerates mouse ES cell differentiation into neural progenitors but inhibits these neural progenitors from committing to the final neural lineage. Interestingly, TPC2 knockdown has no effect on the differentiation of astrocytes and oligodendrocytes of mouse ES cells. Overexpression of TPC2, on the other hand, inhibits mouse ES cell from entering the neural lineage. Taken together, our data indicate that the NAADP/TPC2-mediated Ca2+signaling pathway plays a temporal and dichotomic role in modulating the neural lineage entry of ES cells; in that NAADP signaling antagonizes ES cell entry to early neural progenitors, but promotes late neural differentiation.postprin

Improving FRAP and SPT for mobility and interaction measurements of molecules and nanoparticles in biomaterials

An increasing amount of pharmaceutical technologies are being developed in which nanoparticles play a crucial role. The rational development of these technologies requires detailed knowledge of the mobility and interaction of the nanoparticles inside complex biomaterials. The aim of this PhD thesis is to improve fluorescence microscopy based methods that allow to extract this information from time sequences of images. In particular, the fluorescence microscopy techniques Fluorescence Recovery After Photobleaching (FRAP) and Single Particle Tracking (SPT) are considered. FRAP modelling is revisited in order to incorporate the effect of the microscope's scanning laser beam on the shape of the photobleached region. The new model should lead to more straightforward an accurate FRAP measurements. SPT is the main focus of the PhD thesis, starting with an investigation of how motion during image acquisition affects the experimental uncertainty with which the nanoparticle positions are determined. This knowledge is used to develop a method that is able to identify interactions between nanoparticles in high detail, by scanning their trajectories for correlated positions. The method is proven to be useful in the context of drug delivery, where it was used to study the intracellular trafficking of polymeric gene complexes. Besides SPT data analysis, it is also explored how light sheet illumination, which allows to strongly reduce the out of focus fluorescence that degrades the contrast in SPT experiments, can be generated by a planar waveguide that is incorporated on a disposable chip. The potential as platform for diagnostic measurements was demonstrated by using the chip to perform SPT size and concentration measurements of cell-derived membrane vesicles. The results of this PhD thesis are expected to contribute to the effort of making accurate SPT and FRAP measurements of nanoparticle properties in biomaterials more accessible to the pharmaceutical research community