Effective transvascular delivery of nanoparticles across the blood-brain tumor barrier into malignant glioma cells

<p>Abstract</p> <p>Background</p> <p>Effective transvascular delivery of nanoparticle-based chemotherapeutics across the blood-brain tumor barrier of malignant gliomas remains a challenge. This is due to our limited understanding of nanoparticle properties in relation to the physiologic size of pores within the blood-brain tumor barrier. Polyamidoamine dendrimers are particularly small multigenerational nanoparticles with uniform sizes within each generation. Dendrimer sizes increase by only 1 to 2 nm with each successive generation. Using functionalized polyamidoamine dendrimer generations 1 through 8, we investigated how nanoparticle size influences particle accumulation within malignant glioma cells.</p> <p>Methods</p> <p>Magnetic resonance and fluorescence imaging probes were conjugated to the dendrimer terminal amines. Functionalized dendrimers were administered intravenously to rodents with orthotopically grown malignant gliomas. Transvascular transport and accumulation of the nanoparticles in brain tumor tissue was measured <it>in vivo </it>with dynamic contrast-enhanced magnetic resonance imaging. Localization of the nanoparticles within glioma cells was confirmed <it>ex vivo </it>with fluorescence imaging.</p> <p>Results</p> <p>We found that the intravenously administered functionalized dendrimers less than approximately 11.7 to 11.9 nm in diameter were able to traverse pores of the blood-brain tumor barrier of RG-2 malignant gliomas, while larger ones could not. Of the permeable functionalized dendrimer generations, those that possessed long blood half-lives could accumulate within glioma cells.</p> <p>Conclusion</p> <p>The therapeutically relevant upper limit of blood-brain tumor barrier pore size is approximately 11.7 to 11.9 nm. Therefore, effective transvascular drug delivery into malignant glioma cells can be accomplished by using nanoparticles that are smaller than 11.7 to 11.9 nm in diameter and possess long blood half-lives.</p

The Brain's Router: A Cortical Network Model of Serial Processing in the Primate Brain

The human brain efficiently solves certain operations such as object recognition and categorization through a massively parallel network of dedicated processors. However, human cognition also relies on the ability to perform an arbitrarily large set of tasks by flexibly recombining different processors into a novel chain. This flexibility comes at the cost of a severe slowing down and a seriality of operations (100–500 ms per step). A limit on parallel processing is demonstrated in experimental setups such as the psychological refractory period (PRP) and the attentional blink (AB) in which the processing of an element either significantly delays (PRP) or impedes conscious access (AB) of a second, rapidly presented element. Here we present a spiking-neuron implementation of a cognitive architecture where a large number of local parallel processors assemble together to produce goal-driven behavior. The precise mapping of incoming sensory stimuli onto motor representations relies on a “router” network capable of flexibly interconnecting processors and rapidly changing its configuration from one task to another. Simulations show that, when presented with dual-task stimuli, the network exhibits parallel processing at peripheral sensory levels, a memory buffer capable of keeping the result of sensory processing on hold, and a slow serial performance at the router stage, resulting in a performance bottleneck. The network captures the detailed dynamics of human behavior during dual-task-performance, including both mean RTs and RT distributions, and establishes concrete predictions on neuronal dynamics during dual-task experiments in humans and non-human primates

Hypofrontality in Schizophrenia. A meta-analysis of functional imaging studies

The definitive version is available at www.blackwell-synergy.com '--Copyright Blackwell PublishingObjective: Hypofrontality is not a well-replicated finding in schizophrenia either at rest or under conditions of task activation. Method: Studies comparing whole brain and frontal blood flow/ metabolism in schizophrenic patients and normal controls were pooled.Voxel-based studies were also combined to examine the pattern of prefrontal activation in schizophrenia. Results: Whole brain flow/metabolism was reduced in schizophrenia to only a small extent.Restin g and activation frontal flow/metabolism were both reduced with a medium effect size.Duration of illness significantly moderated resting hypofrontality, but the moderating effects of neuroleptic treatment were consistent with an influence on global flow/metabolism only.Pooling of voxel-based studies did not suggest an abnormal pattern of activation in schizophrenia. Conclusion: Meta-analysis supports resting hypofrontality in schizophrenia.Task-activated hypofrontality is also supported, but there is little from voxel-based studies to suggest that this is associated with an altered pattern of regional functional architecture.Peer reviewe

ASL-LEX: A lexical database of American Sign Language

ASL-LEX is a lexical database that catalogues information about nearly 1,000 signs in American Sign Language (ASL). It includes the following information: subjective frequency ratings from 25–31 deaf signers, iconicity ratings from 21–37 hearing non-signers, videoclip duration, sign length (onset and offset), grammatical class, and whether the sign is initialized, a fingerspelled loan sign or a compound. Information about English translations is available for a subset of signs (e.g., alternate translations, translation consistency). In addition, phonological properties (sign type, selected fingers, flexion, major and minor location, and movement) were coded and used to generate sub-lexical frequency and neighborhood density estimates. ASL-LEX is intended for use by researchers, educators, and students who are interested in the properties of the ASL lexicon. An interactive website where the database can be browsed and downloaded is available at http://asl-lex.org