Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

Fast parallel algorithms for short-range molecular dynamics

Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

Neurotrophins: roles in neuronal development and function.

Trk receptors are a family of three receptor tyrosine kinases, each of which can be activated by one or more of four neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophins 3 and 4 (NT3 and NT4). Neurotrophin signaling through these receptors regulates cell survival, proliferation, the fate of neural precursors, axon and dendrite growth and patterning, and the expression and activity of functionally important proteins, such as ion channels and neurotransmitter receptors. In the adult nervous system, the Trk receptors regulate synaptic strength and plasticity. The cytoplasmic domains of Trk receptors contain several sites of tyrosine phosphorylation that recruit intermediates in intracellular signaling cascades. As a result, Trk receptor signaling activates several small G proteins, including Ras, Rap-1, and the Cdc-42-Rac-Rho family, as well as pathways regulated by MAP kinase, PI 3-kinase and phospholipase-C-gamma (PLC-gamma). Trk receptor activation has different consequences in different cells, and the specificity of downstream Trk receptor-mediated signaling is controlled through expression of intermediates in these signaling pathways and membrane trafficking that regulates localization of different signaling constituents. Perhaps the most fascinating aspect of Trk receptor-mediated signaling is its interplay with signaling promoted by the pan-neurotrophin receptor p75NTR. p75NTR activates a distinct set of signaling pathways within cells that are in some instances synergistic and in other instances antagonistic to those activated by Trk receptors. Several of these are proapoptotic but are suppressed by Trk receptor-initiated signaling. p75NTR also influences the conformations of Trk receptors; this modifies ligand-binding specificity and affinity with important developmental consequences.

Trk receptors: roles in neuronal signal transduction.

The neurotrophins are a family of proteins that are essential for the development of the vertebrate nervous system. Each neurotrophin can signal through two different types of cell surface receptor — the Trk receptor tyrosine kinases and the p75 neurotrophin receptor. Given the wide range of activities that are now associated with neurotrophins, it is probable that additional regulatory events and signalling systems are involved. Here, I review recent findings that neurotrophins, in addition to promoting survival and differentiation, exert various effects through surprising interactions with other receptors and ion channels.

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Neurotrophins and their receptors: a convergence point for many signalling pathways.

The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

Physiology of the neurotrophins

Binding of brain-derived neurotrophic factor to the nerve growth factor receptor

Neurotrophins have long been known to promote the survival and differentiation of vertebrate neurons. However, these growth factors can also induce cell death through the p75 neurotrophin receptor (p75(NTR)), a member of the tumor necrosis factor receptor superfamily. Consistent with a function in controlling the survival and process formation of neurons, p75(NTR) is mainly expressed during early neuronal development. In the adult, p75(NTR) is re-expressed in various pathological conditions, including epilepsy, axotomy and neurodegeneration. Potentially toxic peptides, including the amyloid beta- (Abeta-) peptide that accumulates in Alzheimer's disease, are ligands for p75(NTR). Recent work also implicates p75(NTR) in the regulation of both synaptic transmission and axonal elongation. It associates with the Nogo receptor, a binding protein for axonal growth inhibitors, and appears to be the transducing subunit of this receptor complex.

The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system.

The neurotrophins nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 promote the survival of subpopulations of vertebrate neurons in vitro, but so far only nerve growth factor has been demonstrated to be essential for normal neuronal development; no neurotrophin has previously been shown to function in normal glial cell development. We found recently that neurotrophin-3 promotes the survival of pure oligodendrocyte precursor cells in vitro, and, although by itself it induces only a small percentage of these cells to synthesize DNA, in combination with platelet-derived growth factor it induces the majority of them to do so. Neither of these factors, however, has been shown to contribute to oligodendrocyte precursor cell proliferation in vivo or to stimulate pure populations of these cells to proliferate (as opposed to synthesize DNA) in vitro. Here we show that neurotrophin-3 and platelet-derived growth factor collaborate to promote clonal expansion of oligodendrocyte precursor cells in vitro and to drive the intrinsic clock that times oligodendrocyte development. We also show that neurotrophin-3 helps stimulate the proliferation of oligodendrocyte precursor cells in vivo and is thus required for normal oligodendrocyte development.

A crucial role for neurotrophin-3 in oligodendrocyte development.

We have studied the effects of different neurotrophins on the survival and proliferation of rat cerebellar granule cells in culture. These neurons express trkB and trkC, the putative neuronal receptors for brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) respectively. Binding studies using iodinated BDNF and NT-3 demonstrated that both BDNF and NT-3 bind to the cerebellar granule neurons with a similar affinity of approximately 2 x 10(-9) M. The number of receptors per granule cell was surprisingly high, approximately 30 x 10(-4) and 2 x 10(5) for BDNF and NT-3, respectively. Both NT-3 and BDNF elevated c-fos mRNA in the granule neurons, but only BDNF up-regulated the mRNA encoding the low-affinity neurotrophin receptor (p75). In contrast to NT-3, BDNF acted as a survival factor for the granule neurons. BDNF also induced sprouting of the granule neurons and significantly protected them against neurotoxicity induced by high (1 mM) glutamate concentrations. Cultured granule neurons also expressed low levels of BDNF mRNA which were increased by kainic acid, a glutamate receptor agonist. Thus, BDNF, but not NT-3, is a survival factor for cultured cerebellar granule neurons and activation of glutamate receptor(s) up-regulates BDNF expression in these cells.

Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity.

The correlation between functional and structural neuronal plasticity is by now well documented. However, the molecular mechanisms translating patterns of neuronal activity into specific changes in the structure of neurons remain unclear. Neurotrophins can be released in an activity-dependent manner, and they are capable of controlling both neuronal morphology and functional synaptic changes. They are thus attractive molecules to be studied in the context of synaptic plasticity. In the CNS, most of the work so far has focused on the role of BDNF and of its tyrosine kinase B receptor (TrkB), but relatively little is known about the function of the pan-neurotrophin receptor p75NTR. In this study, we show in loss-of-function experiments that postnatal hippocampal pyramidal cells in two mutant lines of p75NTR have a higher spine density and greater dendritic complexity than wild-type (WT) mice. Conversely, in a gain-of-function approach, p75NTR overexpression in WT neurons significantly reduces dendritic complexity, as well as spine density in all dendritic compartments. These results show that p75NTR negatively modulates dendritic morphology in adult hippocampal pyramidal neurons and documents a new case of functional antagonism between Trk and p75NTR signaling.

https://www.jneurosci.org/content/jneuro/25/43/9989.full.pdf

Georg Dechant

Papers

Binding of brain-derived neurotrophic factor to the nerve growth factor receptor

The neurotrophin receptor p75(NTR): novel functions and implications for diseases of the nervous system.

A crucial role for neurotrophin-3 in oligodendrocyte development.

Brain-derived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamate-induced neurotoxicity.

The p75 Neurotrophin Receptor Negatively Modulates Dendrite Complexity and Spine Density in Hippocampal Neurons