Metacomputing in practice: a distributed compute server for pharmaceutical industry

We describe a distributed high-performance compute server that has been implemented for running compute-intensive applications on a mixture of HPC systems interconnected by Inter-and Intranet. With a practical industrial background, our work focusses on high availability, efficient job load balancing, security, and the easy integration of HPC computing into the daily work-flow at pharmaceutical companies.

The work was done in the course of the ESPRIT project P A Distributed Pharmaceutical Application Server The client software is implemented in Java. All results are displayed in a web browser and can be forwarded to the next stage of applications used in the drug design cycle. The server software handles the job load balancing between the participating HPC nodes and is capable of managing multi-site applications.

Our environment currently supports four key applications that are used in rational drug design and drug target identification. They range from the automatic functional annotation of protein sequences to three-dimensional protein structure prediction tools and protein comparison applications.     

Computer simulation of the enteric neural circuits mediating an ascending reflex: roles of fast and slow excitatory outputs of sensory neurons

Recent electrophysiological studies of the properties of intestinal reflexes and the neurons that mediate them indicate that the intrinsic sensory neurons may transmit to second order neurons via either fast (30-50 ms duration) or slow (10-60 s duration) excitatory synaptic potentials or both. Which of these possible modes of transmission is involved in the initiation of motility reflexes has not been determined and it is not clear and what the consequences of the different forms of synaptic transmission would be for the properties of the reflex pathways. In the present study, this question has been addressed by the use off a suite of computer programs, Plexus, which was written to simulate the activity of the neurons of the enteric nervous system during intestinal reflexes. The programs construct a simulated enteric nerve circuit based on anatomical and physiological data about the number, functions and interconnections of neurons involved in the control of motility. The membrane potentials of neurons are calculated individually from physiological data about the reversal potentials and membrane conductances for Na+, K+ and Cl-. Synaptic potentials are simulated by changes in specific conductances based on physiological data. The results of each simulation are monitored by recording the membrane potentials of up to 16 separate defined neurons and by recording the summed activity of whole classes of neurons as a function of time and location in the stimulated network. The present series of experiments simulated the behaviour of a network consisting of 18,898 sensory neurons and 3708 ascending interneurons after 75% of the sensory neurons lying in the anal 10 mm of a 30 mm long segment of small intestine were stimulated once. The results were compared with electrophysiological data recorded from myenteric neurons during ascending reflexes evoked either by distension or mechanical stimulation of the mucosa. When transmission from sensory neurons to ascending interneurons was via fast excitatory synaptic potentials, the latencies and durations of the simulated responses were too brief to match the electrophysiologically recorded responses. When transmission from sensory neurons was via slow excitatory synaptic potentials, the latencies were very similar to those recorded physiologically, but the durations of the stimulated responses were much longer than seen in physiological experiments. The latencies and durations of simulated and physiologically recorded responses matched only when the firing of ascending interneurons was limited to the beginning of a slow excitatory synaptic (in this study by limiting the duration of the decrease in K+ conductance). The simulation provided several physiologically testable predictions, indicating that Plexus is an important tool for the investigation of the properties and behaviour of the enteric nervous system.     

Essential dynamics of lipase binding sites: the effect of inhibitors of different chain length

The biochemical activity of enzymes, such as lipases, is often associated with structural changes in the enzyme resulting in selective and stereospecific reactions with the substrate. To investigate the effect of a substrate and its chain length on the dynamics of the enzyme, we have performed molecular dynamics simulations of the native Rhizomucor miehei lipase (Rml) and lipase-dialkylphosophate complexes, where the length of the alkyl chain ranges from two to 10 carbon atoms. Simulations were performed in water and trajectories of 400 ps were used to analyse the essential motions in these systems. Our results indicate that the internal motions of the Rml and Rml complexes occur in a subspace of only a few degrees of freedom. A high flexibility is observed in solvent-exposed segments, which connect beta-sheets and helices. In particular, loop regions Gly35-Lys50 and Thr57-Asn63 fluctuate extensively in the native enzyme. Upon activation and binding of the inhibitor, involving the displacement of the active site loop, these motions are considerably suppressed. With increasing chain length of the inhibitor, the fluctuations in the essential subspace increase, levelling off at a chain length of 10, which corresponds to the size of the active-site groove.      

One-step integration method for digital differential analysers

A scheme is proposed whereby the normal multistep iteration procedure used in digital integrators can be truncated to a single step, with a subsequent increase in iteration rate. It appears to be of most use for improving the implementation of Adam's method.     

Domain swapping in G-protein coupled receptor dimers

Computer simulations were performed on models of the beta2-adrenergic receptor dimer, including 5,6-domain swapped dimers which have been proposed as the active, high affinity form (here the dimer interface lies between helices 5 and 6). The calculations suggest that the domain swapped dimer is a high energy structure in both the apo dimer and in the presence of propranolol. In the presence of agonist the energy of the domain swapped dimer is significantly lowered. Analysis of the dimer structure suggests that the agonist-induced conformational change optimizes the helix-helix interactions at the 5-6 interface. An antagonist on the other hand has little effect on these interactions. These observations are consistent with the hypothesis that the agonist functions by shifting the equilibrium in favour of the domain swapped dimer. Indirect support for the domain swapping hypothesis was obtained from the correlated mutations amongst the external residues of the known beta2-adrenergic receptors. These occur mainly at the 5-6 interface at precisely the locations predicted by the simulations; site-directed mutagenesis data in support of a functional role for these lipid-facing correlated residues is presented. The article includes a review of the experimental evidence for G-protein coupled receptor dimerization. Many other aspects of G-protein coupled receptor activation are discussed in terms of this domain swapping hypothesis     

Second-, minute- and hour-metronomes of intestinal pacemakers

Chromosomal translocations affecting the 6p24 region have been associated with orofacial clefting. Here we present a female patient with cleft palate, severe growth retardation, developmental delay, frontal bossing, hypertelorism, antimongoloid slant, bilateral ptosis, flat nasal bridge, hypoplastic nasal alae, protruding upper lip, microretrognathia, bilateral, low set, and posteriorly rotated ears, bilateral microtia, narrow ear canals, short neck, and a karyotype of 46,XX,t(6;9)(p24;p23). The translocation chromosomes were analysed in detail by FISH and the 6p24 breakpoint was mapped within 50-500 kb of other breakpoints associated with orofacial clefting, in agreement with the assignment of such a locus in 6p24. The chromosome 9 translocation breakpoint was identified to be between D9S156 and D9S157 in 9p23-p22, a region implicated in the 9p deletion syndrome.     

Design and test results of a pulsed quadrupole magnet with 2 µs rise time

Major polarization losses will be encountered during acceleration of polarized protons in the Brookhaven AGS due to eight intrinsic depolarizing resonances. Pulsing a set of 12 vertical tune shift quadrupole magnets with a 2μs rise time, 3 ms fall, and 60 ms repetition rate should reduce these losses. [1] This requires a gradient of 1.87 T/M over the 8.89 × 12.7 cm vacuum chamber.     

Optical properties of styrene-isoprene two-block copolymers

Four styrene-isoprene two-block copolymers of high molecular weight (M_w5 × 10⁵–2.5 × 10⁶) containing ～50% polystyrene have been prepared in a high state of purity. Their optical properties were studied in solution by transmission and diffraction techniques. It is shown that these properties can be related to the sizes of the domains present due to phase separation.     

化纤及其产品的贸易格局正在改变

虽说未来的化纤生产领域将逐渐被中国和亚洲其他国家所主导，但仍有部分产品亚洲化纤生产商是不具备能力涉足的，这部分产品依然由欧洲和北关的化纤生产商控制。针对这一由欧洲和北美生产商控制的市场，应利用化纤产品的核心创新技术，并联合当地相关方面的专家学者进行不断的研究和开发。