QCD on the connection machine: beyond *LISP

We report on the status of code development for a simulation of quantum chromodynamics (QCD) with dynamical Wilson fermions on the Connection Machine model CM-2. Our original code, written in Lisp, gave performance in the near-GFLOPS range. We have rewritten the most time-consuming parts of the code in the low-level programming systems CMIS, including the matrix multiply and the communication. Current versions of the code run at approximately 3.6 GFLOPS for the fermion matrix inversion, and we expect the next version to reach or exceed 5 GFLOPS

Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

background: There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples. methods: About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample. results: We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC). conclusions: We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression

Reciprocal regulation of PKA and rac signaling

Activated G protein-coupled receptors (GPCRs) and receptor tyrosine kinases relay extracellular signals through spatial and temporal controlled kinase and GTPase entities. These enzymes are coordinated by multifunctional scaffolding proteins for precise intracellular signal processing. The cAMP-dependent protein kinase A (PKA) is the prime example for compartmentalized signal transmission downstream of distinct GPCRs. A-kinase anchoring proteins tether PKA to specific intracellular sites to ensure precision and directionality of PKA phosphorylation events. Here, we show that the Rho-GTPase Rac contains A-kinase anchoring protein properties and forms a dynamic cellular protein complex with PKA. The formation of this transient core complex depends on binary interactions with PKA subunits, cAMP levels and cellular GTP-loading accounting for bidirectional consequences on PKA and Rac downstream signaling. We show that GTP-Rac stabilizes the inactive PKA holoenzyme. However, β-adrenergic receptor-mediated activation of GTP-Rac–bound PKA routes signals to the Raf-Mek-Erk cascade, which is critically implicated in cell proliferation. We describe a further mechanism of how cAMP enhances nuclear Erk1/2 signaling: It emanates from transphosphorylation of p21-activated kinases in their evolutionary conserved kinase-activation loop through GTP-Rac compartmentalized PKA activities. Sole transphosphorylation of p21-activated kinases is not sufficient to activate Erk1/2. It requires complex formation of both kinases with GTP-Rac1 to unleash cAMP-PKA–boosted activation of Raf-Mek-Erk. Consequently GTP-Rac functions as a dual kinase-tuning scaffold that favors the PKA holoenzyme and contributes to potentiate Erk1/2 signaling. Our findings offer additional mechanistic insights how β-adrenergic receptor-controlled PKA activities enhance GTP-Rac–mediated activation of nuclear Erk1/2 signaling

Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4)

PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the Hsp20 by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window

Matrix model approach to the flux lattice melting in 2D2D superconductors

We investigate a gauged matrix model in the large $N$ limit which is closely related to the superconductor fluctuation and the flux lattice melting in two dimensions. With the use of saddle point method the free energy is expanded up to eighth order for the coupling constant $g$. In the case that the coefficient of quadratic term of the Ginzburg-Landau matrix model is negative, a critical point $g=g_c$ is obtained in the large $N$ limit and the relation between this phase transition and the 2D flux lattice melting transition is discussed.Comment: REVTeX file, 20 pages + 3 figures attached as uu-encoded ps-file

Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density

Sponges as natural environmental DNA samplers

At a time of unprecedented impacts on marine biodiversity, scientists are rapidly becoming persuaded by the potential of screening large swathes of the oceans through the retrieval, amplification and sequencing of trace DNA fragments left behind by marine organisms; an approach known as ‘environmental DNA’ (eDNA) [1]. In trying to circumvent the many challenges associated with water filtration and DNA isolation from environmental samples, significant investment is being made in high-tech solutions, such as automated underwater vehicles and robots [2]. Here, instead, we explored a simpler, alternative option, based on the recovery of eDNA from sponges (phylum Porifera), the planet’s most effective water-filterers. We obtained sponge samples from Mediterranean and Antarctic surveys, extracted total DNA from their tissues, and obtained tens of thousands of fish DNA reads via metabarcoding, which were able to clearly distinguish samples from the two regions. One Antarctic sample yielded hundreds of reads from chinstrap penguin (Pygoscelis antarcticus) and Weddell seal (Leptonychotes weddellii). We argue that this ‘natural sampler DNA’ (nsDNA) approach is poised to become a powerful, affordable, universal tool for aquatic biodiversity monitoring globally

Dynamic Critical Behavior of the Swendsen-Wang Algorithm: The Two-Dimensional 3-State Potts Model Revisited

We have performed a high-precision Monte Carlo study of the dynamic critical behavior of the Swendsen-Wang algorithm for the two-dimensional 3-state Potts model. We find that the Li-Sokal bound ($\tau_{int,E} \geq const \times C_H$) is almost but not quite sharp. The ratio $\tau_{int,E} / C_H$ seems to diverge either as a small power ($\approx 0.08$) or as a logarithm.Comment: 35 pages including 3 figures. Self-unpacking file containing the LaTeX file, the needed macros (epsf.sty, indent.sty, subeqnarray.sty, and eqsection.sty) and the 3 Postscript figures. Revised version fixes a normalization error in \xi (with many thanks to Wolfhard Janke for finding the error!). To be published in J. Stat. Phys. 87, no. 1/2 (April 1997