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Fujii H.,Kitasato University | Takahashi T.,Discovery Labs | Nagase H.,Kitasato University | Nagase H.,University of Tsukuba
Expert Opinion on Therapeutic Patents | Year: 2013

Introduction: The δ opioid receptor mediates various pharmacological effects such as antinociceptive and antidepressant effects, whereas it does not appear to induce μ opioid-like side effects such as dependence, respiratory depression and constipation. Therefore, the δ opioid receptor is a promising drug target. Areas covered: This review covers literature and patents concerning non-peptidic δ opioid receptor agonists, antagonists, modulators and ligands from 2000 to 2012. Pharmacological effects induced by δ receptor agonists or antagonists are also discussed. Expert opinion: Potential therapeutic effects by δ receptor agonists are antinociceptive, antidepressant, anxiolytic, cardioprotective and neuroprotective effects. Among them, anxiolytic effects are of particular interest because the anxiolytic effects by a δ receptor agonist have been observed in humans. Although non-peptidic δ receptor agonists were reported to show convulsive effects via the δ opioid receptor, some δ receptor agonists are known to produce no convulsive behaviors. Therefore, it may be possible to eliminate convulsion induced by a δ receptor agonist. Many δ receptor antagonists were also reported but there is little new information about pharmacological effects by a δ receptor antagonist. Although detailed results were not revealed, two δ receptor antagonists with μ receptor agonistic or antagonistic properties are in the late stages of the clinical trial. © 2013 Informa UK, Ltd.


The number of poorly water-soluble drug candidates in drug discovery has recently increased. Limited solubility often causes poor and variable oral absorption. Therefore, it is critical to predict poor absorption of a candidate compound at the drug discovery stage. Herein is a summary of our strategy for improving oral absorption of poorly water-soluble drugs using a computer-based simulation.


Chetty S.,University of California at Berkeley | Chetty S.,Harvard Stem Cell Institute | Friedman A.R.,University of California at Berkeley | Taravosh-Lahn K.,University of California at Berkeley | And 19 more authors.
Molecular Psychiatry | Year: 2014

Stress can exert long-lasting changes on the brain that contribute to vulnerability to mental illness, yet mechanisms underlying this long-term vulnerability are not well understood. We hypothesized that stress may alter the production of oligodendrocytes in the adult brain, providing a cellular and structural basis for stress-related disorders. We found that immobilization stress decreased neurogenesis and increased oligodendrogenesis in the dentate gyrus (DG) of the adult rat hippocampus and that injections of the rat glucocorticoid stress hormone corticosterone (cort) were sufficient to replicate this effect. The DG contains a unique population of multipotent neural stem cells (NSCs) that give rise to adult newborn neurons, but oligodendrogenic potential has not been demonstrated in vivo. We used a nestin-CreER/YFP transgenic mouse line for lineage tracing and found that cort induces oligodendrogenesis from nestin-expressing NSCs in vivo. Using hippocampal NSCs cultured in vitro, we further showed that exposure to cort induced a pro-oligodendrogenic transcriptional program and resulted in an increase in oligodendrogenesis and decrease in neurogenesis, which was prevented by genetic blockade of glucocorticoid receptor (GR). Together, these results suggest a novel model in which stress may alter hippocampal function by promoting oligodendrogenesis, thereby altering the cellular composition and white matter structure. © 2014 Macmillan Publishers Limited.


Jansen J.M.,Novartis | Cornell W.,Discovery Labs | Tseng Y.J.,National Taiwan University | Amaro R.E.,University of California at San Diego
Journal of Molecular Graphics and Modelling | Year: 2012

Teach-Discover-Treat (TDT) is an initiative to promote the development and sharing of computational tools solicited through a competition with the aim to impact education and collaborative drug discovery for neglected diseases. Collaboration, multidisciplinary integration, and innovation are essential for successful drug discovery. This requires a workforce that is trained in state-of-the-art workflows and equipped with the ability to collaborate on platforms that are accessible and free. The TDT competition solicits high quality computational workflows for neglected disease targets, using freely available, open access tools. © 2012 Elsevier Inc.


Witkin J.M.,Discovery Labs
CNS & neurological disorders drug targets | Year: 2013

Curcumin, the major constituent of the spice tumeric produces a plethora of biological actions that have translated in vivo into behavioral and neurochemical effects in rodents that are also produced by clinically-used antidepressants. The present study was designed to provide a systematic replication of prior behavioral, pharmacological, and neurochemical experiments. In particular, the ability of curcumin to engender anti-immobility effects in the mouse forced-swim assay was established. Although prior work had shown curcumin to function as an inhibitor of the monoamine metabolizing enzyme, monoamine oxidase (MAO), neither MAOA nor MAOB was inhibitied by curcumin in the present study. Curcumin had also been reported previously to function as a cannabinoid CB1 receptor inverse agonist/antagonist. However, in our hands, curcumin did not potently alter GTP-γ.-35S binding indicative of functional CB1 antagonism (Kb = 2080 nM). Moreover, curcumin was not able to prevent the hypothermic effects of the cannabinoid receptor agonist (-)-cis-3-[2-Hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP 55,940). Nonetheless, the anti-immobility effects of curcumin did not occur in CB1 -/- mice. Finally, a broad array of protein receptors and enzymes were evaluated in vitro for their potential interaction with and/or functional engagement with curcumin. Of the more than 100 targets screened, curcumin had very low potency in most. Of those targets with appreciable activity, curcumin had affinities for the human cloned muscarinic receptor subtypes (Ki = 1.3-3.1 uM). Moreover, the plasma and brain levels of curcumin at behaviorally-active doses were below quantitative limits. Given these findings, it is concluded that the prominent antidepressant-like behavioral effects of curcumin, replicated here and in multiple acute and chronic rodent models detailed in the literature, are the result of as yet undisclosed mechanisms of action. The scientific and patient communities await the full scale clinical evaluation of a sufficiently bioavailable curcumin analog in major depressive disorder.


Smith D.D.,Discovery Labs
2015 IEEE Compound Semiconductor Integrated Circuit Symposium, CSICS 2015 | Year: 2015

A new oscillation mode has been observed in bulk planar InP Gunn diode devices with integrated metallic gratings. The grating mode oscillation is distinct from the transit mode of normal Gunn diodes. Its characteristics depend on doping concentration: In 1e17/cc material, the grating mode is consistent with the Smith-Purcell mode [1]. In 5e16/cc material, the grating-mode frequency is 5-10 times higher than the transit frequency with comparable power. It is currently believed that the low-doped mode is attributable to the limited-space-charge accumulation (LSA) mode. This work has led to new design concepts which are expected to result in robust 100-300GHz sources by 2016. © 2015 IEEE.


News Article | December 9, 2013
Site: www.zdnet.com

As demand increases for computers that can carry out hyperscale workloads — lightweight computing tasks carried out on a very large scale — server OEMs are having to broaden what they offer to avoid becoming irrelevant to an important part of their market. Hyperscale workloads are commonplace at web giants such as Facebook and Google, which already source the majority of their servers and datacentre infrastructure themselves, Google behind closed doors and Facebook in collaboration with its Open Compute partners , rather than buying the stock server offerings from large manufacturers such as HP, Dell and IBM. And as demand for scalable compute power suited to these type of tasks increases, driven in part by the fast-growing public cloud services industry, the big OEMs are offering new types of servers. One new product line is HP's Moonshot server, small servers, sometimes known as microservers , that can be packed into dense clusters targeted at carrying out specific computing workloads. Moonshot servers are tailored towards workloads that need to be carried out in parallel on a very large scale or hyperscale, such as serving content for widely-used web sites and apps. A key concern for hyperscale tasks, due to the massive scale at which these workloads are carried out, is minimising power consumption. Power draw in Moonshot servers is kept down by using low-energy system on a chips (SoCs), such as the Intel Atom or ARM-based systems, by stripping circuitry from the main board that isn't needed for a specific computing workload and by sharing power, cooling and networking between servers. Moonshot is designed to be a "low-powered server technology to provide scale-out architecture for these new types of applications and workloads that are coming to market, specifically in the hyperscale segment," said Paul Morgan, HP's hyperscale business manager for industry standard servers. "We call them application-defined servers, as opposed to general-purpose servers. With Moonshot we take the application first, and then custom build the cartridge specifically for that application. In doing that we get the best price per performance per watt." HP released its first Moonshot server in April this year , an Intel Atom Centerton S1200-based cartridge — HP's name for Moonshot server boards — which could be packed into 450 server cluster sitting in a single rack containing 10 4.3U Moonshot chassis. Today HP has revealed three new boards — based on chip designs from AMD, ARM and Intel — and aimed at workloads beyond its first generation Moonshot server, which was designed to serve static elements on web pages. The Intel and AMD cartridges are available to buy from today, while the ARM cartridge will be available in HP's Discovery Labs for customers to test and will ship to customers next year. The three new cartridges are aimed at serving: This Moonshot server cartridge, known as the HP ProLiant m700, is designed for serving hosted desktops to client PCs, and will support Windows 7 and Windows 8 at launch. Each rack of these cartridges will support about 1,800 hosted desktop users, with each OS hosted on a separate server node. Each m700 cartridge has four nodes, each functioning as a separate server. Each Moonshot 4.3U chassis holds about 45 cartridges and 10 of these chassis fit in a rack. "If you look at a per user perspective we're able to bring down the TCO significantly, just on the power savings alone, since these Moonshot servers run at a fraction of the power of traditional x86 servers,"  Morgan said. Each node on the m700 board has an SoC based on the 64-bit AMD Opteron-X processor, a quad core chip with an integrated 128-core Radeon HD 8000 graphics processing unit. The AMD processor is the 11W-22W Opteron X2150, which runs at up to 1.9GHz and has 2MB of level-2 cache. Each of the four nodes on the board includes 8GB of DDR3 SO-DIMM ECC memory running at 1600MHz. The cartridge has up to 32GB of solid state storage per node, with HP planning to increase the storage in future versions of the board. The board is the basis of the HP's ConvergedSystem 100 for Hosted Desktops, available worldwide from today starting at $137,999 for 180 users. This Intel Atom Avoton-based cartridge, known as the HP ProLiant m300, is designed to serve dynamic content in web sites and apps, such as Flash animations or interactive menus driven by Ajax. The ability to serve dynamic content on websites comes from the "six to seven times" performance gain in this cartridge over the Intel Atom Centerton-based SoC Intel used for its first Moonshot server. Each cartridge has a single server node powered by an Intel Avoton SoC with a 64-bit, eight-core processor running at up to 2.4GHz and up to 32GB of DRAM. The Avoton family's TDP, a measurement related to the maximum expected power consumption of the chip, ranges from 6W to 20W. The new Intel cartridge includes a SAS or SATA small form factor ProLiant Generation 8 drive, available in sizes up to a 1TB hard drive or as a 200GB SSD. HP will continue to offer the Centerton-based cartridge for serving static content over the web. The third cartridge, the HP ProLiant m800, is aimed at telecoms providers, which make extensive use of digital signal processing (DSP) for audio processing and compression, and in data transmission. This is the first Moonshot cartridge powered by an ARM-based SoC. At the heart of the SoC is a Texas Instruments 66AK2H chip based on a 32-bit Arm A15 core, with each core containing eight digital signal processors. There are four SoCs on each cartridge, each functioning as a separate server node, and with with each node having up to 16GB of DRAM and up to 32GB of solid state storage. A total of 45 cartridges can be placed in a 4.3U chassis to give a total of 180 cores and 1,440 digital signal processors. "A 4.3U chassis is going to be the densest DSP solution in the market today," Morgan said, adding that it would replace legacy DSP systems that are typically "large, heavy and power hungry". The shared network infrastructure in the Moonshot chassis is also upgraded from today. Connections between the chassis and the cartridges are increased from 45 to 180 1Gbps lines — in order to provide a 1Gbps connection for each of the 180 server nodes in chassis housing four-node server clusters. The chassis uplink module has also been upgraded from 6 x 10 Gigabit Ethernet (GbE) to 4 x 40 GbE. HP plans to release Moonshot cartridges targeted at different applications on a regular basis and next year will bring out more cartridges built on ARM-based SoCs, including its first cartridge based on a 64-bit ARM chip and SoCs from Calxeda and Applied Micro. "We're not going to stop here. You'll see a host of other flavours coming out for lots of different other use cases. It's going to broaden the workloads and applications we can drive and support," Morgan said. HP is using feedback from customers to decide what computing workloads the next generation of Moonshot servers should focus on, and therefore what the designs of the cartridges should be, said Angela Cross, HP UK and Ireland country management for industry standard servers and software. "We create the cartridge to suit the app, rather than try and make the application suit the server," she said. "We've just turned on our head our usual development cycle and therefore can invite the customer in to ask 'What would you like?'." Morgan said the proviso that cartridges will generally be targeted at the needs of a particular industry or very large organisation to ensure the cartridge is economically viable, but said HP will be able to release new Moonshot servers rapidly to capitalise on changing compute demands. "There's a huge amount of flexibility that we can drive because we're not launching a whole physical new server, that core underlying infrastructure is already there for us, so to launch a new Moonshot server only takes three or four months," he said. The market for microservers is predicted to grow to be a small but significant portion of the market, accounting for about one fifth of server sales by 2015/16 . HP expects Moonshot will add to, rather than cannibalise, its existing server sales. "It's not a replacement for blades, this is for scale-out hyperscale-type architecture like a single application scaled across hundreds or thousands of nodes," Morgan said. HP wouldn't reveal sales figures for its first generation Moonshot servers since the launched in April this year but said it has had 150 customers testing their workloads on and certifying Moonshot systems in its Discovery Labs. And while Morgan won't name names he said customers operating at the scale of Facebook were showing interest in Moonshot servers. "We have many of those large, what I call T1 hyperscale customers looking at Moonshot," he said.


News Article | November 2, 2011
Site: arstechnica.com

Hewlett-Packard has teamed up with ARM chipmaker Calxeda to make power-sipping systems for the cloud, and is working on similar servers based on Intel Atom. But can low-power systems really deliver high-performance results? HP is building “extreme low-energy” servers based on Calxeda’ EnergyCore ARM server-on-a-chip processor, and plans future servers based on Intel Atom and other low-power processors. HP’s Redstone Development Platform, named after the rocket used in NASA’s Mercury program, is targeted at cloud services and on-demand computing applications. HP rolled out the new technology at an event in Austin yesterday. The servers are part of a set of efforts at HP called “Project Moonshot,” a program to advance energy-efficient computing for data centers.  Moonshot’s goals parallel those of the Open Compute Project in some respects, such as creating hardware that helps reduce the power consumption of cloud data centers. But it takes a significantly different approach to those goals, opting to pack thousands of low-power systems together. Redstone packs 288 Calxeda servers into a 4U server chassis. The server system cards are plugged into trays and connected through a passive backplane architecture that provides power, network, and storage connections. By putting over 2,000 servers in a single standard data center rack, which Calxeda CEO Barry Evans said "delivers the throughput of some 700 traditional servers," the Redstone platform could significantly reduce the space requirements of Web hosting and cloud services providers. And since each server node only consumes 5 watts of power—including 4GB of memory and an SSD storage device—Redstone could provide dramatic energy savings as well. While there’s no roadmap for general availability of products based on Redstone yet, HP has formed a new partner program around the technology that will include AMD, ARM Holdings, Calxeda, Canonical, and Red Hat. HP is making the Redstone platform available to customers on a limited basis to a small selection of customers in the first half of 2012, and will also allow customers to evaluate the technology in one of the “Discovery Labs” that the company is opening—the first, in Houston, will open its doors to HP customers in January. The goal of the carefully managed exposure of the technology to customers will be figuring out what applications will run well on Redstone—and what architectural changes may have to be made software to make it run well on the platform. That may prove to be a difficult question to answer. While the move to use low-power “physicalized” servers might work well for some applications, there are questions about how effective and efficient they really are for big cloud providers who’ve already invested in designing their own hardware—like Facebook, Google, and Amazon. While the ARM and Atom architectures HP is focusing on initially for Redstone are highly power-efficient, they also may have too much latency for some cloud applications. In an article published last year in IEEE Micro, Google Senior Vice President of Operations Urs Hölze wrote that even though they are more power efficient, there are a number of disadvantages to using “wimpy processors,” as he called them: software has to be explicitly parallelized to run effectively across them, which adds to software development costs; the overhead of splitting things up across multiple processors can reduce performance; and there’s the likelihood of lower utilization of the processors, and thus a loss of efficiency. “Once a chip’s single-core performance lags by more than a factor to two or so behind the higher end of current-generation commodity processors,” Hölze wrote, “making a business case for switching to the wimpy system becomes increasingly difficult because application programmers will see it as a significant performance regression: their single-threaded request handlers are no longer fast enough to meet latency targets.” Researchers working on Microsoft’s Gargoyle project came to similar conclusions in their comparisons of search engine workloads, comparing the performance of Xeon and Atom processors. While Atom processors were inherently more power efficient, the cost of that efficiency was too high. “At their respective sustainable throughputs, Atom’s latency is nearly 3x greater than that of the Xeon,” the researchers wrote. There’s also the question of whether compressing computing power into a smaller form factor is that much of a priority. Amazon Vice President James Hamilton said last week at the Open Compute Summit that floor space only accounts for four percent of his data center costs, while server hardware accounts for 57 percent.  “There’s no way you want to pay more for servers just to save on floor space,” he said.


News Article | April 8, 2013
Site: www.eweek.com

HP executives expect to roll out more Moonshot servers in the second half of the year for such environments at Web workloads, cloud computing and massive data centers, as well as analytics and telecommunications. Future systems will be optimized for high-performance computing, financial services, facial recognition, video analysis and other workloads. They will be powered by chips from a range of vendors , including Intel—which this week is showing off the next-generation microserver Atom chip, dubbed "Avoton""—Advanced Micro Devices and ARM partners AppliedMicro, Calxeda and Texas Instruments. That broad offering of architectures is a key part of what HP is doing with Project Moonshot, Potter said. Not only will the company be able to accelerate by three times the rate that it releases new servers—thanks to no longer being tied solely to Intel's 18- to 24-month cycle—but it allows a level of customization that the industry hasn't seen before, both crucial factors when dealing with the emerging workloads coming into the data center, he said. "General-purpose [chips don't] really fit their needs," Potter told eWEEK.Along with the Moonshot systems, HP also is rolling out its Pathfinder Innovation Ecosystem, an initiative aimed at enabling software developers to build applications that can be optimized for the systems. In addition, HP's Discovery Labs enables customers and partners to access Moonshot systems housed in HP's data center to test and benchmark solutions."Only someone like HP can [create a place] where people can come together and innovate," Potter said. Both Donatelli and Potter said the new systems will be complementary to the company's x86-based traditional ProLiant systems. Donatelli noted that the x86 server market is a $40 billion space. "x86 will be here a long time [and] Moonshot will be here a long time," he said. "It's just that you'll see rapid growth in Moonshot." The Moonshot systems come as HP undergoes a multi-year turnaround program under Whitman following several years of upheaval, management instability and disappointing financial numbers. However, Roger Kay, principal analyst with Endpoint Technologies Associates, said Whitman is bringing stability back to the company, and it's beginning to work. "Ms. Whitman has kept HP on a relatively even keel over the past 18 months, and things at the company are beginning to look up," Kay wrote in an April 8 column in Forbes.com . "From a November 2012 low of $11.35, the stock is up into the low 20s, about a double. … HP still has many arrows in its quiver.  It just needs the time and stability to pull each one out with a steady hand, set it to the bowstring, pull back, and fire."


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