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"Reynolds, H"
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Going places
Rafael has looked forward to the Going Places contest and builds his go-cart from a kit in record time, but his neighbor, Maya, has a much more interesting and creative idea for her entry and Rafael decides to help.
Book
Spontaneous traveling waves naturally emerge from horizontal fiber time delays and travel through locally asynchronous-irregular states
Studies of sensory-evoked neuronal responses often focus on mean spike rates, with fluctuations treated as internally-generated noise. However, fluctuations of spontaneous activity, often organized as traveling waves, shape stimulus-evoked responses and perceptual sensitivity. The mechanisms underlying these waves are unknown. Further, it is unclear whether waves are consistent with the low rate and weakly correlated “asynchronous-irregular” dynamics observed in cortical recordings. Here, we describe a large-scale computational model with topographically-organized connectivity and conduction delays relevant to biological scales. We find that spontaneous traveling waves are a general property of these networks. The traveling waves that occur in the model are sparse, with only a small fraction of neurons participating in any individual wave. Consequently, they do not induce measurable spike correlations and remain consistent with locally asynchronous irregular states. Further, by modulating local network state, they can shape responses to incoming inputs as observed in vivo.
Spontaneous traveling cortical waves shape neural responses. Using a large-scale computational model, the authors show that transmission delays shape locally asynchronous spiking dynamics into traveling waves without inducing correlations and boost responses to external input, as observed in vivo.
Journal Article
Playing from the heart
\"When a young boy begins to play on his family's piano, reveling in the fun of plunking the keys, his father signs him up for lessons so that he can learn to play properly. With his father's encouragement, Raj learns notes, then scales, then songs, and finally classical pieces that his father can recognize and be proud of. But the more Raj practices and the more skilled he becomes, the less he enjoys playing, until he grows up and stops playing altogether. But when his father becomes ill and asks Raj to play for him, will Raj remember how to play from the heart?\"--Provided by publisher.
Book
The role of ligand efficiency metrics in drug discovery
Key Points
Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity.
The application of ligand efficiency metrics has been widely reported in the selection and optimization of fragments, hits and leads. In particular, optimization of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets.
Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physicochemical properties, are a practical means of estimating target 'druggability'. This is exemplified with 480 target–assay pairs from the primary literature. Across these targets, correlations between biological activity
in vitro
and physicochemical properties are generally weak, which shows that increasing activity by increasing physicochemical properties is not always necessary.
An analysis of 46 recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values and lipophilic ligand efficiency values for their target. Compared with 'only-in-class' oral drugs, only 1.5% of all molecules per target — on average — possess superior combined ligand efficiency and lipophilic ligand efficiency values.
Optimizing ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the ability to develop drug candidates.
Ligand efficiency metrics quantify the molecular properties required to gain binding affinity for a drug target. This article discusses the application of such metrics in the selection and optimization of fragments, hits and leads, highlighting how optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to increase the quality of drug candidates.
The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates.
Journal Article
ATTENTIONAL MODULATION OF VISUAL PROCESSING
▪ Abstract Single-unit recording studies in the macaque have carefully documented the modulatory effects of attention on the response properties of visual cortical neurons. Attention produces qualitatively different effects on firing rate, depending on whether a stimulus appears alone or accompanied by distracters. Studies of contrast gain control in anesthetized mammals have found parallel patterns of results when the luminance contrast of a stimulus increases. This finding suggests that attention has co-opted the circuits that mediate contrast gain control and that it operates by increasing the effective contrast of the attended stimulus. Consistent with this idea, microstimulation of the frontal eye fields, one of several areas that control the allocation of spatial attention, induces spatially local increases in sensitivity both at the behavioral level and among neurons in area V4, where endogenously generated attention increases contrast sensitivity. Studies in the slice have begun to explain how modulatory signals might cause such increases in sensitivity.
Journal Article
Sydney & Simon : to the moon!
Twin mice Sydney and Simon compete to create the most interesting project about the Earth's moon for their elementary school, and win the first prize--a chance to meet a real astronaut.
Book
Waves traveling over a map of visual space can ignite short-term predictions of sensory input
Recent analyses have found waves of neural activity traveling across entire visual cortical areas in awake animals. These traveling waves modulate the excitability of local networks and perceptual sensitivity. The general computational role of these spatiotemporal patterns in the visual system, however, remains unclear. Here, we hypothesize that traveling waves endow the visual system with the capacity to predict complex and naturalistic inputs. We present a network model whose connections can be rapidly and efficiently trained to predict individual natural movies. After training, a few input frames from a movie trigger complex wave patterns that drive accurate predictions many frames into the future solely from the network’s connections. When the recurrent connections that drive waves are randomly shuffled, both traveling waves and the ability to predict are eliminated. These results suggest traveling waves may play an essential computational role in the visual system by embedding continuous spatiotemporal structures over spatial maps.
Waves of neural activity travel across single regions in the visual cortex, but their computational role is unclear. Here, the authors present a neural network model demonstrating that waves traveling over retinotopic maps can enable short-term predictions of future inputs.
Journal Article
The dot
Vashti believes that she cannot draw, but her art teacher's encouragement leads her to change her mind.
Book
The Oldest of Old Male C57B/6J Mice Are Protected from Sarcopenic Obesity: The Possible Role of Skeletal Muscle Protein Kinase B Expression
The impact of aging on body composition and glucose metabolism is not well established in C57BL/6J mice, despite being a common pre-clinical model for aging and metabolic research. The purpose of this study was to examine the effect of advancing age on body composition, in vivo glucose metabolism, and skeletal muscle AKT expression in young (Y: 4 months old, n = 7), old (O: 17–18 months old, n = 10), and very old (VO: 26–27 month old, n = 9) male C57BL/6J mice. Body composition analysis, assessed by nuclear magnetic resonance, demonstrated O mice had a significantly greater fat mass and body fat percentage when compared to Y and VO mice. Furthermore, VO mice had a significantly greater lean body mass than both O and Y mice. We also found that the VO mice had greater AKT protein levels in skeletal muscle compared to O mice, an observation that explains a portion of the increased lean body mass in VO mice. During glucose tolerance (GT) testing, blood glucose values were significantly lower in the VO mice when compared to the Y and O mice. No age-related differences were observed in insulin tolerance (IT). We also assessed the glucose response to AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). The change in blood glucose following AICAR administration was significantly reduced in VO mice compared to Y and AG mice. Our findings indicate that lean body mass and AKT2 protein expression in muscle are significantly increased in VO mice compared to O mice. The increase in AKT2 likely plays a role in the greater lean body mass observed in the oldest of old mice. Finally, despite the increased GT, VO mice appear to be resistant to AMPK-mediated glucose uptake.
Journal Article