Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A2A receptors (A2ARs). To ...test if A2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A2AR, we have developed a chimeric rhodopsin-A2AR protein (optoA2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A2AR to confer specific A2AR signaling. The specificity of the optoA2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A2AR. Supporting its physiological relevance, optoA2AR activation and the A2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A2AR signaling and functions depend on intracellular A2AR loops prompts the possibility of targeting the intracellular A2AR-interacting partners to selectively control different neuropsychiatric behaviors.
The breakdown of Dennard scaling has resulted in a decade-long stall of the maximum operating clock frequencies of processors. To mitigate this issue, computing shifted to multi-core devices. This ...introduced the need for programming flows and tools that facilitate the expression of workload parallelism at high abstraction levels. However, not all workloads are easily parallelizable, and the minor improvements to processor cores have not significantly increased single-threaded performance. Simultaneously, Instruction Level Parallelism in applications is considerably underexplored. This article reviews notable approaches that focus on exploiting this potential parallelism via automatic generation of specialized hardware from binary code. Although research on this topic spans over more than 20 years, automatic acceleration of software via translation to hardware has gained new importance with the recent trend toward reconfigurable heterogeneous platforms. We characterize this kind of binary acceleration approach and the accelerator architectures on which it relies. We summarize notable state-of-the-art approaches individually and present a taxonomy and comparison. Performance gains from 2.6× to 5.6× are reported, mostly considering bare-metal embedded applications, along with power consumption reductions between 1.3× and 3.9×. We believe the methodologies and results achievable by automatic hardware generation approaches are promising in the context of emergent reconfigurable devices.
Human and animal studies have converged to suggest that caffeine consumption prevents memory deficits in aging and Alzheimer's disease through the antagonism of adenosine A.sub.2A receptors ...(A.sub.2ARs). To test if A.sub.2AR activation in the hippocampus is actually sufficient to impair memory function and to begin elucidating the intracellular pathways operated by A.sub.2AR, we have developed a chimeric rhodopsin-A.sub.2AR protein (optoA.sub.2AR), which retains the extracellular and transmembrane domains of rhodopsin (conferring light responsiveness and eliminating adenosine-binding pockets) fused to the intracellular loop of A.sub.2AR to confer specific A.sub.2AR signaling. The specificity of the optoA.sub.2AR signaling was confirmed by light-induced selective enhancement of cAMP and phospho-mitogen-activated protein kinase (p-MAPK) (but not cGMP) levels in human embryonic kidney 293 (HEK293) cells, which was abolished by a point mutation at the C terminal of A.sub.2AR. Supporting its physiological relevance, optoA.sub.2AR activation and the A.sub.2AR agonist CGS21680 produced similar activation of cAMP and p-MAPK signaling in HEK293 cells, of p-MAPK in the nucleus accumbens and of c-Fos/phosphorylated-CREB (p-CREB) in the hippocampus, and similarly enhanced long-term potentiation in the hippocampus. Remarkably, optoA.sub.2AR activation triggered a preferential p-CREB signaling in the hippocampus and impaired spatial memory performance, while optoA.sub.2AR activation in the nucleus accumbens triggered MAPK signaling and modulated locomotor activity. This shows that the recruitment of intracellular A.sub.2AR signaling in the hippocampus is sufficient to trigger memory dysfunction. Furthermore, the demonstration that the biased A.sub.2AR signaling and functions depend on intracellular A.sub.2AR loops prompts the possibility of targeting the intracellular A.sub.2AR-interacting partners to selectively control different neuropsychiatric behaviors. Molecular Psychiatry (2015) 20, 1339-1349; doi: 10.1038/mp.2014.182; published online 17 February 2015
Adenosine A(2A) receptors are most abundant in the striatum where they control the striatopallidal pathway thus controlling locomotion. Extra-striatal A(2A) receptors are considerably less abundant ...but their blockade confers robust neuroprotection. We now have investigated if striatal and extra-striatal A(2A) receptors have a different neuronal location to understand their different functions. The binding density of the A(2A) antagonist, (3)H-7-(2-phenylethyl)-5-amino-2-(2-furyl)pyrazolo4,3e1,2,4triazolo1,5-cpyrimidine ((3)HSCH 58261), was enriched in nerve terminals membranes (B(max)=103+/-12 fmol/mg protein) compared with total membranes (B(max)=29+/-4 fmol/mg protein) from the hippocampus, the same occurring with A(2A) receptor immunoreactivity. In contrast, there was no enrichment of (3)HSCH 58261 binding or A(2A) receptor immunoreactivity in synaptosomal compared with total membranes from the striatum. Further subcellular fractionation of hippocampal nerve terminals revealed that A(2A) receptor immunoreactivity was enriched in the active zone of presynaptic nerve terminals, whereas it was predominantly located in the postsynaptic density in the striatum, although a minority of striatal A(2A) receptors were located in the presynaptic active zone. These results indicate that A(2A) receptors in the striatum are not enriched in synapses in agreement with the preponderant role of A(2A) receptors in signal processing in striatopallidal neurons. In contrast, hippocampal A(2A) receptors are enriched in synapses, mainly in the active zone, in accordance with their role in controlling neurotransmitter release. This regional variation in the neuronal distribution of A(2A) receptors reinforces the care required to extrapolate our knowledge from striatal A(2A) receptors to other brain preparations.
High Level Synthesis (HLS) tools targeting Field Programmable Gate Arrays (FPGAs) aim to provide a method for programming these devices via high-level abstractions. Initially, HLS support for FPGAs ...focused on compiling C/C++ to hardware circuits. This raised the issue of determining the programming practices which resulted in the best performing circuits. Recently, to further increase the applicability of HLS approaches, renewed effort was placed on support for HLS of OpenCL code for FPGA, raising the same issues of coding practices and performance portability. This paper explores the performance of OpenCL code compiled for FPGAs for different coding techniques. We evaluate the use of task-kernels versus NDRange kernels, data vectorization, the use of on-chip local memories, and data transfer optimizations by exploiting burst access inference. We present this exploration via a case study of the k-means algorithm, and produce a total of 10 OpenCL implementations of the kernel. To determine the effects of different data set characteristics, and to determine the gains from specialization based on number of attributes, we generated a total of 12 integer data sets. The data sets vary regarding the number of instances, number of attributes (i.e., features), and number of clusters. We also vary the number of processing cores, and present the resulting required resources and operating frequencies. Finally, we execute the same OpenCL code on a 4 GHz Intel i7-6700K CPU, showing that the FPGA achieves speedups up to 1.54 {\times } for four cases, and energy savings up to 80% in all cases.
The use of specialized accelerator circuits is a feasible solution to address performance and energy issues in embedded systems. This paper extends a previous field-programmable gate array-based ...approach that automatically generates pipelined customized loop accelerators (CLAs) from runtime instruction traces. Despite efficient acceleration, the approach suffered from high area and resource requirements when offloading a large number of kernels from the target application. This paper addresses this by enhancing the CLA with dynamic partial reconfiguration (DPR) support. Each kernel to accelerate is implemented as a variant of a reconfigurable area of the CLA which hosts all functional units and configuration memory. Evaluation of the proposed system is performed on a Virtex-7 device. We show, for a set of 21 kernels, that when comparing two CLAs capable of accelerating the same subset of kernels, the one which benefits from DPR can be up to <inline-formula> <tex-math notation="LaTeX">4.3\times </tex-math></inline-formula> smaller. Resorting to DPR allows for the implementation of CLAs which support numerous kernels without a significant decrease in operating frequency and does not affect the initiation intervals at which kernels are scheduled. Finally, the area required by a CLA instance can be further reduced by increasing the IIs of the scheduled kernels.
Malolactic fermentation (MLF) and aging in oak barrels are two oenological processes which modify the composition and sensory characteristics of the wines. However, there are few studies on the MLF ...in barrels.
This work compares wines in which MLF is carried out in steel tanks and then aged in oak barrels, with wines in which MLF has been carried out in barrels.
MLF occurs faster in barrels and while the fundamental structure of the wine is virtually identical, there is less color loss.
Some groups of volatile compounds vary significantly depending on whether MLF takes place in tanks prior to aging or in the oak barrels themselves. It was shown that in this latter case, wines were obtained with slightly higher concentrations of methoxy-phenols and approximately double amount of whisky-lactones and furanic compounds.
•MLF in barrel and tank are compared.•MLF in barrels is faster than in tanks.•MLF-barrels wines maintain higher color intensity.•Some methoxyphenols, whisky-lactones and the furanic compounds are extracted easier in MLF-barrel wines.•MLF-Barrel wines have more intense cherry-red color, aromatic intensity and balsamic flavor, duration and persistence.
Stress initially causes adaptive changes in the brain and can lead to neurodegeneration if continuously present. Noxious brain conditions trigger the release of adenosine that can control brain ...function and neurodegeneration through inhibitory A1 and facilitatory A2A receptors. We tested the effect of restraint stress on the density of adenosine receptors and their effect on the outcome of stress, focusing in a known affected region, the hippocampus. Sub-chronic restraint stress (6 h/day for 7 days) caused a parallel decrease of the density of A1 receptors (15–20%) and an increase (near 250%) of A2A receptor density in rat hippocampal nerve terminals. This indicates that sub-chronic stress unbalances adenosine receptors, up-regulating A2A and down-regulating A1 receptors. Sub-chronic stress did not cause hippocampal neurodegeneration but decreased the immunoreactivity (immunohistochemistry and Western blot) of a synaptic marker, synaptophysin. The blockade of A2A receptors with 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-4,3-e-1,2,4-triazolo1,5-cpyrimidine (0.05 mg/kg, daily i.p. injection) attenuated the loss of synaptophysin immunoreactivity observed in the hippocampus of rats subjected to sub-chronic restraint stress. This ability of A2A receptor antagonists to prevent the earliest stress-induced synaptic modifications provides a neurochemical and morphological correlate for the interest of A2A receptor antagonists to attenuate the burden of chronic stress.
Many embedded applications process large amounts of data using regular computational kernels, amenable to acceleration by specialized hardware coprocessors. To reduce the significant design effort, ...the dedicated hardware may be automatically generated, usually starting from the application's source or binary code. This paper presents a moduloscheduled loop accelerator capable of executing multiple loops and a supporting toolchain. A generation/scheduling procedure, which fully relies on MicroBlaze instruction traces, produces accelerator instances, customized in terms of functional units and interconnections. The accelerators support integer and single-precision floatingpoint arithmetic, and exploit instruction-level parallelism, loop pipelining, and memory access parallelism via two read/write ports. A complete implementation of the proposed architecture is evaluated in a Virtex-7 device. Augmenting a MicroBlaze processor with a tailored accelerator achieves a geometric mean speedup, over software-only execution, of 6.61× for 13 floatingpoint kernels from the Livermore Loops set, and of 4.08× for 11 integer kernels from Texas Instruments' IMGLIB. The proposed customized accelerators are compared with ALU-based ones. The average specialized accelerator requires only 0.47× the number of field-programmable gate array slices of an accelerator with four ALUs. A geometric mean speedup of 1.78× over a four-issue very long instruction word (without floating-point support) was obtained for the integer kernels.
In this article, we examine the production of biogenic amines, histamine, putrescine, tyramine, and cadaverine by 90 strains of Oenococcus oeni isolated from different cellars of Castilla-La Mancha ...(Spain) during wine malolactic fermentation. Amino biogenic capacity of strains was qualitatively analyzed on agar. After that, production of amines on a synthetic medium and on wine, and presence in strains of histidine, ornithine, and tyrosine decarboxylase genes were determined. Only two strains were able to produce histamine or putrescine, both on synthetic medium and wine. The presence of the corresponding genes in these strains was also confirmed. These results suggest that O. oeni does not significantly contribute to the overall biogenic amine content of wines. The main contribution of this work is the isolation of a putrescine-producing O. oeni strain that harbors the ornithine gene, since this gene appears to be rarely present in the genome of O. oeni.
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