Grid-enabled high throughput in-silico screening against influenza A neuraminidase

PCSV, présenté par H.-C. Lee, à paraître dans les proceedingsEncouraged by the success of first EGEE biomedical data challenge against malaria[1], the second data challenge was kicked off in April, 2006, fighting against avian flu. In the paper, we demonstrated how to adopt a world-wide deployed Grid infrastructure to efficiently produce a large scale virtual screening to speed up the drug design process. The 6-weeks activity of molecular docking on the Grid has covered over 100 years of computing power required for discovering new drug for avian flu. Around 600 Gigabytes of output has also been produced and archived on the Grid for further biological analysis and test

ARC 2014 over-clocking KLT designs on FPGAs under process, voltage, and temperature variation

Karhunen-Loeve Transformation is a widely used algorithm in signal processing that often implemented with high-throughput requisites. This work presents a novel methodology to optimise KLT designs on FPGAs that outperform typical design methodologies, through a prior characterisation of the arithmetic units in the datapath of the circuit under various operating conditions. Limited by the ever-increasing process variation, the delay models available in synthesis tools are no longer suitable for extreme performance optimisation of designs, and as they are generic, they need to consider the worst-case performance for a given fabrication process. Hence, they heavily penalise the maximum possible achieved performance of a design by leaving safety margin. This work presents a novel unified optimisation framework which contemplates a prior characterisation of the embedded multipliers on the target FPGA device under process, voltage, and temperature variation. The proposed framework allows a design space exploration leading to designs without any latency overheads that achieve high throughput while producing less errors than typical methodologies, operating with the same throughput. Experimental results demonstrate that the proposed methodology outperforms the typical implementation in three real-life design strategies: high performance, low power, and temperature variation; and it produced circuit designs that performed up to 18dB better when over-clocked.</jats:p

A generator-produced gallium-68 radiopharmaceutical for PET imaging of myocardial perfusion

Lipophilic cationic technetium-99m-complexes are widely used for myocardial perfusion imaging (MPI). However, inherent uncertainties in the supply chain of molybdenum-99, the parent isotope required for manufacturing 99Mo/99mTc generators, intensifies the need for discovery of novel MPI agents incorporating alternative radionuclides. Recently, germanium/gallium (Ge/Ga) generators capable of producing high quality 68Ga, an isotope with excellent emission characteristics for clinical PET imaging, have emerged. Herein, we report a novel 68Ga-complex identified through mechanism-based cell screening that holds promise as a generator-produced radiopharmaceutical for PET MPI

4-Phenylbutyrate Attenuates the ER Stress Response and Cyclic AMP Accumulation in DYT1 Dystonia Cell Models

Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3′, 5′-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3′, 5′-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway

Binding, thermodynamics, and selectivity of a non-peptide antagonist to the melanocortin-4 receptor

The melanocortin-4 receptor (MC4R) is a potential drug target for treatment of obesity, anxiety, depression, and sexual dysfunction. Crystal structures for MC4R are not yet available, which has hindered successful structure-based drug design. Using microsecond-scale molecular-dynamics simulations, we have investigated selective binding of the non-peptide antagonist MCL0129 to a homology model of human MC4R (hMC4R). This approach revealed that, at the end of a multi-step binding process, MCL0129 spontaneously adopts a binding mode in which it blocks the agonistic-binding site. This binding mode was confirmed in subsequent metadynamics simulations, which gave an affinity for human hMC4R that matches the experimentally determined value. Extending our simulations of MCL0129 binding to hMC1R and hMC3R, we find that receptor subtype selectivity for hMC4R depends on few amino acids located in various structural elements of the receptor. These insights may support rational drug design targeting the melanocortin systems

Atypical Self-Focus Effect on Interoceptive Accuracy in Anorexia Nervosa

Background: Interoceptive abilities are known to be affected in anorexia nervosa (AN). Previous studies could show that private self-focus can enhance interoceptive accuracy (IAcc) in healthy participants. As body dissatisfaction is high in AN, confrontation with bodily features such as the own face might have a directly opposed effect in AN. Whether patients with AN can benefit from self-focus in their IAcc and whether this pattern changes over the time-course of cognitive behavioral therapy was investigated in this study. Methods: 15 patients with AN from the Psychosomatic Clinic in Windach were assessed three times in the time course of a standardized cognitive-behavioral therapy. They were compared to 15 controls, recruited from Ulm University and tested in a comparable setting. Both groups performed the heartbeat perception task assessing interoceptive accuracy (IAcc) under two conditions either enhancing (Self) or decreasing (Other) self-focused attention. Furthermore, body dissatisfaction was assessed by a subscale of the Eating Disorder Inventory 2. Results: Patients with AN scored higher in IAcc when watching others’ faces as compared to one’s own face while performing the heartbeat perception task. The opposite pattern was observed in controls. IAcc remained reduced in AN as compared to controls in the time-course of cognitive-behavioral therapy, while body-dissatisfaction improved in AN. High body dissatisfaction was related to poorer IAcc in the Self condition. Conclusions: Our findings suggest that using self-focused attention reduces IAcc in AN while the opposite pattern was observed in controls. Confronting anorexic patients with bodily features might increase body-related avoidance and therefore decrease interoceptive accuracy. The current study introduces a new perspective concerning the role of interoceptive processes in AN and generates further questions regarding the therapeutic utility of methods targeting self-focus in the treatment of AN

Molecular Diversity and Potential Anti-neuroinflammatory Activities of Cyathane Diterpenoids from the Basidiomycete Cyathus africanus

Ten new polyoxygenated cyathane diterpenoids, named neocyathins A-J (1-10), together with four known diterpenes (11-14), were isolated from the liquid culture of the medicinal basidiomycete fungus Cyathus africanus. The structures and configurations of these new compounds were elucidated through comprehensive spectroscopic analyses including 1D NMR, 2D NMR (HSQC, HMBC, NOESY) and HRESIMS, and electronic circular dichroism (ECD) data. Neuroinflammation is implicated in the pathogenesis of various neurodegenerative diseases, such as Alzheimers' disease (AD). All isolated compounds were evaluated for the potential anti-neuroinflammatory activities in BV2 microglia cells. Several compounds showed differential effects on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated and Aβ1-42-treated mouse microglia cell line BV-2. Molecular docking revealed that bioactive compounds (e.g., 11) could interact with iNOS protein other than COX-2 protein. Collectively, our results suggested that this class of cyathane diterpenoids might serve as important lead compounds for drug discovery against neuroinflammation in AD.published_or_final_versio

Optimal response and covariate-adaptive biased-coin designs for clinical trials with continuous multivariate or longitudinal responses

Adaptive randomization of the sequential construction of optimum experimental designs is used to derive biased-coin designs for longitudinal clinical trials with continuous responses. The designs, coming from a very general rule, target pre-specified allocation proportions for the ranked treatment effects. Many of the properties of the designs are similar to those of well understood designs for univariate responses. A numerical study illustrates this similarity in a comparison of four designs for longitudinal trials. Designs for multivariate responses can likewise be found, requiring only the appropriate information matrix. Some new results in the theory of optimum experimental design for multivariate responses are presented

The Role of the Circadian Clock in Fat Body Transcriptomics and Metabolomics

Drosophila melanogaster circadian rhythms oscillate based on many different factors and are dictated by the central brain clock, input pathways that take in outside information, and output pathways. These output pathways include peripheral tissues that can affect many different behaviors. An example of one of these tissues is the fat body, which may play a role in feeding/fasting rhythms. The mechanism used to control this behavior is not well known. By determining a connection between the central brain clock and peripheral tissues such as the fat body, the way that physiological processes such as metabolism, energy storage, and behavioral outputs are controlled can be better understood. Long term, this project aims to identify connections between metabolic rhythms utilizing metabolomics and transcriptomic of the fat body. To do so, the best, most specific driver with which to manipulate the fat body must be identified, and the expression of any other tissues must be identified. Using the GAL4-UAS system, the manipulation or selective inactivation of fat body tissues can be accomplished by certain drivers. Takeout-GAL4 is well-known as a fat body driver but may show expression in other tissues which must be identified in more detail. Lsp is another driver that must be characterized and compared to Takeout-GAL4. By characterizing each driver in detail, the most selective one can be utilized in later experiments to learn more about circadian relation to metabolism

Simulation results of coherent light in a modified microring resonator

By using short Gaussian pulses from a monochromatic light source as input ones, we simulate the photon distribution and analyze the output signals of a nonlinear microring resonator with two nonlinear side rings. Such a configuration is called a Panda ring resonator, which is a modified add-drop filter with two alongside phase modulators. We consider the directional couplers, which are characterized by two parameters, i.e., the power coupling coefficient (k) and the power coupling loss (γ). The nonlinear refractive index (n 2 ) of the phase modulator affects the center ring and reveals more interesting aspects. The simulation model is constructed, and the results obtained with the use of a combination of the Lumerical FDTD and MODE programs are presented. The photon is conceptually interpreted in terms of a wave packet and discussed for possible applications