Faculty Bibliography

Medulloblastoma is the most common malignant brain tumor in children, but the cells from which it arises remain unclear. Here we examine the origin of medulloblastoma resulting from mutations in the Sonic hedgehog (Shh) pathway. We show that activation of Shh signaling in neuronal progenitors causes medulloblastoma by 3 months of age. Shh pathway activation in stem cells promotes stem cell proliferation but only causes tumors after commitment to-and expansion of-the neuronal lineage. Notably, tumors initiated in stem cells develop more rapidly than those initiated in progenitors, with all animals succumbing by 3-4 weeks. These studies suggest that medulloblastoma can be initiated in progenitors or stem cells but that Shh-induced tumorigenesis is associated with neuronal lineage commitment

Semicircular canals have been sensors of angular acceleration for 450 million years. This vertebrate adaptation enhances survival by implementing postural and visual stabilization during motion in a three-dimensional environment. We used an integrated neuroethological approach in larval Xenopus to demonstrate that semicircular canal dimensions, and not the function of other elements, determines the onset of angular acceleration detection. Before angular vestibuloocular function in either the vertical or horizontal planes, at stages 47 and 48, respectively, each individual component of the vestibuloocular system was shown to be operational: extraocular muscles could be activated, central neural pathways were complete, and canal hair cells were capable of evoking graded responses. For Xenopus, a minimum semicircular canal lumen radius of 60 microm was necessary to permit endolymph displacement sufficient for sensor function at peak accelerations of 400 degrees /s(2). An intra-animal comparison demonstrated that this size is reached in the vertical canals earlier in development than in the horizontal canals, corresponding to the earlier onset of vertical canal-activated ocular motor behavior. Because size constitutes a biophysical threshold for canal-evoked behavior in other vertebrates, such as zebrafish, we suggest that the semicircular canal lumen and canal circuit radius are limiting the onset of vestibular function in all small vertebrates. Given that the onset of gravitoinertial acceleration detection precedes angular acceleration detection by up to 10 d in Xenopus, these results question how the known precise spatial patterning of utricular and canal afferents in adults is achieved during development

Animals process information about many stimulus features simultaneously, swiftly (in a few 100 ms), and robustly (even when individual neurons do not themselves respond reliably). When the brain carries, codes, and certainly when it decodes information, it must do so through some coarse-grained projection mechanism. How can a projection retain information about network dynamics that covers multiple features, swiftly and robustly? Here, by a coarse-grained projection to event trees and to the event chains that comprise these trees, we propose a method of characterizing dynamic information of neuronal networks by using a statistical collection of spatial-temporal sequences of relevant physiological observables (such as sequences of spiking multiple neurons). We demonstrate, through idealized point neuron simulations in small networks, that this event tree analysis can reveal, with high reliability, information about multiple stimulus features within short realistic observation times. Then, with a large-scale realistic computational model of V1, we show that coarse-grained event trees contain sufficient information, again over short observation times, for fine discrimination of orientation, with results consistent with recent experimental observation

RATIONALE: Interventional clinical trials involving children with septic shock would benefit from an efficient preenrollment stratification strategy. OBJECTIVES: To test the predictive value of interleukin (IL)-8 for 28-day mortality in pediatric septic shock. METHODS: A training data set (n = 40) identified a serum IL-8 of greater than 220 pg/ml as having a 75% sensitivity and specificity for predicting 28-day mortality. This cutoff was then subjected to a series of validation steps. MEASUREMENTS AND MAIN RESULTS: Subjects were drawn from two large, independent pediatric septic shock databases. Prospective application of the IL-8 cutoff to validation data set 1 (n = 139) demonstrated 78% sensitivity and 64% specificity for 28-day mortality. A serum IL-8 level of 220 pg/ml or less, however, had a negative predictive value for 28-day mortality of 95% in validation data set 1, which was subsequently applied to an independently generated data set of children with septic shock (validation set 2, n = 193). A serum IL-8 level of 220 pg/ml or less had a negative predictive value for 28-day mortality of 94% when applied to validation set 2. CONCLUSIONS: A serum IL-8 level of 220 pg/ml or less, obtained within 24 hours of admission, predicts a high likelihood of survival in children with septic shock. We propose that IL-8 can be used to exclude such patients from interventional clinical trials and ultimately derive a study population with a more favorable risk to benefit ratio when subjected to a study agent

Next-generation sequencing is limited to short read lengths and by high error rates. We systematically analyzed sources of noise in the Illumina Genome Analyzer that contribute to these high error rates and developed a base caller, Alta-Cyclic, that uses machine learning to compensate for noise factors. Alta-Cyclic substantially improved the number of accurate reads for sequencing runs up to 78 bases and reduced systematic biases, facilitating confident identification of sequence variants

Impulsive acts and decisions are a part of everyday normal behavior. However, in its pathological forms, impulsivity can be a debilitating disorder often associated with a number of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). This article reviews recent progress in our understanding of the neurobiology of impulsivity using examples from recent investigations in experimental animals. Evidence is reviewed from several well-established paradigms with putative utility in assessing distinct forms of impulsive behavior in rodents, including the 5-choice serial reaction time (5CSRT) task and the delay discounting paradigm. We discuss, in particular, recent psychopharmacological and in-vivo neurochemical data in task-performing rats showing functional heterogeneity of the forebrain dopamine (DA), noradrenaline (NA), serotonin (5-HT) and acetylcholine (ACh) systems and identify how these systems normally function to facilitate flexible goal-directed behavior in situations that tax basic attentional functions and inhibitory response control mechanisms. We also discuss future research needs in terms of understanding the functional diversity of different sub-regions of prefrontal cortex (PFC) and how these systems normally interact with the striatum and main nuclei of origin of DA and NA neurons. Finally, we argue in line with others that animal paradigms are unlikely to model all aspects of complex psychiatric conditions such as ADHD but components of such syndromes may be amenable to investigation using sophisticated animal models based on highly-defined psychiatric endophenotypes.