Mapping the complexity of transcription control in higher eukaryotes.

Recent genomic analyses suggest the importance of combinatorial regulation by broadly expressed transcription factors rather than expression domains characterized by highly specific factors.

Stochastic E2F activation and reconciliation of phenomenological cell-cycle models.

The transition of the mammalian cell from quiescence to proliferation is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include various forms of the transition probability (TP) model and the growth control (GC) model, which lack mechanistic details. The GC model was further proposed as an alternative explanation for the concept of the restriction point, which we recently demonstrated as being controlled by a bistable Rb-E2F switch. Here, through a combination of modeling and experiments, we show that these different lines of models in essence reflect different aspects of stochastic dynamics in cell cycle entry. In particular, we show that the variable activation of E2F can be described by stochastic activation of the bistable Rb-E2F switch, which in turn may account for the temporal variability in cell cycle entry. Moreover, we show that temporal dynamics of E2F activation can be recast into the frameworks of both the TP model and the GC model via parameter mapping. This mapping suggests that the two lines of phenomenological models can be reconciled through the stochastic dynamics of the Rb-E2F switch. It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states.

High-throughput isolation and mapping of C. elegans mutants susceptible to pathogen infection.

We present a novel strategy that uses high-throughput methods of isolating and mapping C. elegans mutants susceptible to pathogen infection. We show that C. elegans mutants that exhibit an enhanced pathogen accumulation (epa) phenotype can be rapidly identified and isolated using a sorting system that allows automation of the analysis, sorting, and dispensing of C. elegans by measuring fluorescent bacteria inside the animals. Furthermore, we validate the use of Amplifluor as a new single nucleotide polymorphism (SNP) mapping technique in C. elegans. We show that a set of 9 SNPs allows the linkage of C. elegans mutants to a 5-8 megabase sub-chromosomal region.

Molecular mapping of movement-associated areas in the avian brain: a motor theory for vocal learning origin.

Vocal learning is a critical behavioral substrate for spoken human language. It is a rare trait found in three distantly related groups of birds-songbirds, hummingbirds, and parrots. These avian groups have remarkably similar systems of cerebral vocal nuclei for the control of learned vocalizations that are not found in their more closely related vocal non-learning relatives. These findings led to the hypothesis that brain pathways for vocal learning in different groups evolved independently from a common ancestor but under pre-existing constraints. Here, we suggest one constraint, a pre-existing system for movement control. Using behavioral molecular mapping, we discovered that in songbirds, parrots, and hummingbirds, all cerebral vocal learning nuclei are adjacent to discrete brain areas active during limb and body movements. Similar to the relationships between vocal nuclei activation and singing, activation in the adjacent areas correlated with the amount of movement performed and was independent of auditory and visual input. These same movement-associated brain areas were also present in female songbirds that do not learn vocalizations and have atrophied cerebral vocal nuclei, and in ring doves that are vocal non-learners and do not have cerebral vocal nuclei. A compilation of previous neural tracing experiments in songbirds suggests that the movement-associated areas are connected in a network that is in parallel with the adjacent vocal learning system. This study is the first global mapping that we are aware for movement-associated areas of the avian cerebrum and it indicates that brain systems that control vocal learning in distantly related birds are directly adjacent to brain systems involved in movement control. Based upon these findings, we propose a motor theory for the origin of vocal learning, this being that the brain areas specialized for vocal learning in vocal learners evolved as a specialization of a pre-existing motor pathway that controls movement.

Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm.

Functional neuroimaging studies of episodic memory retrieval generally measure brain activity while participants remember items encountered in the laboratory ("controlled laboratory condition") or events from their own life ("open autobiographical condition"). Differences in activation between these conditions may reflect differences in retrieval processes, memory remoteness, emotional content, retrieval success, self-referential processing, visual/spatial memory, and recollection. To clarify the nature of these differences, a functional MRI study was conducted using a novel "photo paradigm," which allows greater control over the autobiographical condition, including a measure of retrieval accuracy. Undergraduate students took photos in specified campus locations ("controlled autobiographical condition"), viewed in the laboratory similar photos taken by other participants (controlled laboratory condition), and were then scanned while recognizing the two kinds of photos. Both conditions activated a common episodic memory network that included medial temporal and prefrontal regions. Compared with the controlled laboratory condition, the controlled autobiographical condition elicited greater activity in regions associated with self-referential processing (medial prefrontal cortex), visual/spatial memory (visual and parahippocampal regions), and recollection (hippocampus). The photo paradigm provides a way of investigating the functional neuroanatomy of real-life episodic memory under rigorous experimental control.

The neuropsychology of autobiographical memory.

This special issue of Cortex focuses on the relative contribution of different neural networks to memory and the interaction of 'core' memory processes with other cognitive processes. In this article, we examine both. Specifically, we identify cognitive processes other than encoding and retrieval that are thought to be involved in memory; we then examine the consequences of damage to brain regions that support these processes. This approach forces a consideration of the roles of brain regions outside of the frontal, medial-temporal, and diencephalic regions that form a central part of neurobiological theories of memory. Certain kinds of damage to visual cortex or lateral temporal cortex produced impairments of visual imagery or semantic memory; these patterns of impairment are associated with a unique pattern of amnesia that was distinctly different from the pattern associated with medial-temporal trauma. On the other hand, damage to language regions, auditory cortex, or parietal cortex produced impairments of language, auditory imagery, or spatial imagery; however, these impairments were not associated with amnesia. Therefore, a full model of autobiographical memory must consider cognitive processes that are not generally considered 'core processes,' as well as the brain regions upon which these processes depend.

Quantitative mapping of trimethyltin injury in the rat brain using magnetic resonance histology.

The growing exposure to chemicals in our environment and the increasing concern over their impact on health have elevated the need for new methods for surveying the detrimental effects of these compounds. Today's gold standard for assessing the effects of toxicants on the brain is based on hematoxylin and eosin (H&E)-stained histology, sometimes accompanied by special stains or immunohistochemistry for neural processes and myelin. This approach is time-consuming and is usually limited to a fraction of the total brain volume. We demonstrate that magnetic resonance histology (MRH) can be used for quantitatively assessing the effects of central nervous system toxicants in rat models. We show that subtle and sparse changes to brain structure can be detected using magnetic resonance histology, and correspond to some of the locations in which lesions are found by traditional pathological examination. We report for the first time diffusion tensor image-based detection of changes in white matter regions, including fimbria and corpus callosum, in the brains of rats exposed to 8 mg/kg and 12 mg/kg trimethyltin. Besides detecting brain-wide changes, magnetic resonance histology provides a quantitative assessment of dose-dependent effects. These effects can be found in different magnetic resonance contrast mechanisms, providing multivariate biomarkers for the same spatial location. In this study, deformation-based morphometry detected areas where previous studies have detected cell loss, while voxel-wise analyses of diffusion tensor parameters revealed microstructural changes due to such things as cellular swelling, apoptosis, and inflammation. Magnetic resonance histology brings a valuable addition to pathology with the ability to generate brain-wide quantitative parametric maps for markers of toxic insults in the rodent brain.

Improvement in visual search with practice: mapping learning-related changes in neurocognitive stages of processing.

Practice can improve performance on visual search tasks; the neural mechanisms underlying such improvements, however, are not clear. Response time typically shortens with practice, but which components of the stimulus-response processing chain facilitate this behavioral change? Improved search performance could result from enhancements in various cognitive processing stages, including (1) sensory processing, (2) attentional allocation, (3) target discrimination, (4) motor-response preparation, and/or (5) response execution. We measured event-related potentials (ERPs) as human participants completed a five-day visual-search protocol in which they reported the orientation of a color popout target within an array of ellipses. We assessed changes in behavioral performance and in ERP components associated with various stages of processing. After practice, response time decreased in all participants (while accuracy remained consistent), and electrophysiological measures revealed modulation of several ERP components. First, amplitudes of the early sensory-evoked N1 component at 150 ms increased bilaterally, indicating enhanced visual sensory processing of the array. Second, the negative-polarity posterior-contralateral component (N2pc, 170-250 ms) was earlier and larger, demonstrating enhanced attentional orienting. Third, the amplitude of the sustained posterior contralateral negativity component (SPCN, 300-400 ms) decreased, indicating facilitated target discrimination. Finally, faster motor-response preparation and execution were observed after practice, as indicated by latency changes in both the stimulus-locked and response-locked lateralized readiness potentials (LRPs). These electrophysiological results delineate the functional plasticity in key mechanisms underlying visual search with high temporal resolution and illustrate how practice influences various cognitive and neural processing stages leading to enhanced behavioral performance.

Mapping the structure of perceptual and visual-motor abilities in healthy young adults.

The ability to quickly detect and respond to visual stimuli in the environment is critical to many human activities. While such perceptual and visual-motor skills are important in a myriad of contexts, considerable variability exists between individuals in these abilities. To better understand the sources of this variability, we assessed perceptual and visual-motor skills in a large sample of 230 healthy individuals via the Nike SPARQ Sensory Station, and compared variability in their behavioral performance to demographic, state, sleep and consumption characteristics. Dimension reduction and regression analyses indicated three underlying factors: Visual-Motor Control, Visual Sensitivity, and Eye Quickness, which accounted for roughly half of the overall population variance in performance on this battery. Inter-individual variability in Visual-Motor Control was correlated with gender and circadian patters such that performance on this factor was better for males and for those who had been awake for a longer period of time before assessment. The current findings indicate that abilities involving coordinated hand movements in response to stimuli are subject to greater individual variability, while visual sensitivity and occulomotor control are largely stable across individuals.

Mapping the semantic structure of cognitive neuroscience.

Cognitive neuroscience, as a discipline, links the biological systems studied by neuroscience to the processing constructs studied by psychology. By mapping these relations throughout the literature of cognitive neuroscience, we visualize the semantic structure of the discipline and point to directions for future research that will advance its integrative goal. For this purpose, network text analyses were applied to an exhaustive corpus of abstracts collected from five major journals over a 30-month period, including every study that used fMRI to investigate psychological processes. From this, we generate network maps that illustrate the relationships among psychological and anatomical terms, along with centrality statistics that guide inferences about network structure. Three terms--prefrontal cortex, amygdala, and anterior cingulate cortex--dominate the network structure with their high frequency in the literature and the density of their connections with other neuroanatomical terms. From network statistics, we identify terms that are understudied compared with their importance in the network (e.g., insula and thalamus), are underspecified in the language of the discipline (e.g., terms associated with executive function), or are imperfectly integrated with other concepts (e.g., subdisciplines like decision neuroscience that are disconnected from the main network). Taking these results as the basis for prescriptive recommendations, we conclude that semantic analyses provide useful guidance for cognitive neuroscience as a discipline, both by illustrating systematic biases in the conduct and presentation of research and by identifying directions that may be most productive for future research.

Chromatin accessibility mapping identifies mediators of basal transcription and retinoid-induced repression of OTX2 in medulloblastoma.

Despite an emerging understanding of the genetic alterations giving rise to various tumors, the mechanisms whereby most oncogenes are overexpressed remain unclear. Here we have utilized an integrated approach of genomewide regulatory element mapping via DNase-seq followed by conventional reporter assays and transcription factor binding site discovery to characterize the transcriptional regulation of the medulloblastoma oncogene Orthodenticle Homeobox 2 (OTX2). Through these studies we have revealed that OTX2 is differentially regulated in medulloblastoma at the level of chromatin accessibility, which is in part mediated by DNA methylation. In cell lines exhibiting chromatin accessibility of OTX2 regulatory regions, we found that autoregulation maintains OTX2 expression. Comparison of medulloblastoma regulatory elements with those of the developing brain reveals that these tumors engage a developmental regulatory program to drive OTX2 transcription. Finally, we have identified a transcriptional regulatory element mediating retinoid-induced OTX2 repression in these tumors. This work characterizes for the first time the mechanisms of OTX2 overexpression in medulloblastoma. Furthermore, this study establishes proof of principle for applying ENCODE datasets towards the characterization of upstream trans-acting factors mediating expression of individual genes.

Application of the Intervention Mapping protocol to develop Keys, a family child care home intervention to prevent early childhood obesity.

BACKGROUND: Many families rely on child care outside the home, making these settings important influences on child development. Nearly 1.5 million children in the U.S. spend time in family child care homes (FCCHs), where providers care for children in their own residences. There is some evidence that children in FCCHs are heavier than those cared for in centers. However, few interventions have targeted FCCHs for obesity prevention. This paper will describe the application of the Intervention Mapping (IM) framework to the development of a childhood obesity prevention intervention for FCCHs METHODS: Following the IM protocol, six steps were completed in the planning and development of an intervention targeting FCCHs: needs assessment, formulation of change objectives matrices, selection of theory-based methods and strategies, creation of intervention components and materials, adoption and implementation planning, and evaluation planning RESULTS: Application of the IM process resulted in the creation of the Keys to Healthy Family Child Care Homes program (Keys), which includes three modules: Healthy You, Healthy Home, and Healthy Business. Delivery of each module includes a workshop, educational binder and tool-kit resources, and four coaching contacts. Social Cognitive Theory and Self-Determination Theory helped guide development of change objective matrices, selection of behavior change strategies, and identification of outcome measures. The Keys program is currently being evaluated through a cluster-randomized controlled trial CONCLUSIONS: The IM process, while time-consuming, enabled rigorous and systematic development of intervention components that are directly tied to behavior change theory and may increase the potential for behavior change within the FCCHs.

Is the Species Flock Concept Operational? The Antarctic Shelf Case

There has been a significant body of literature on species flock definition but not so much about practical means to appraise them. We here apply the five criteria of Eastman and McCune for detecting species flocks in four taxonomic components of the benthic fauna of the Antarctic shelf: teleost fishes, crinoids (feather stars), echinoids (sea urchins) and crustacean arthropods. Practical limitations led us to prioritize the three historical criteria (endemicity, monophyly, species richness) over the two ecological ones (ecological diversity and habitat dominance). We propose a new protocol which includes an iterative fine-tuning of the monophyly and endemicity criteria in order to discover unsuspected flocks. As a result nine « full » species flocks (fulfilling the five criteria) are briefly described. Eight other flocks fit the three historical criteria but need to be further investigated from the ecological point of view (here called « core flocks »). The approach also shows that some candidate taxonomic components are no species flocks at all. The present study contradicts the paradigm that marine species flocks are rare. The hypothesis according to which the Antarctic shelf acts as a species flocks generator is supported, and the approach indicates paths for further ecological studies and may serve as a starting point to investigate the processes leading to flock-like patterning of biodiversity. © 2013 Lecointre et al.

Mapping 2-D defects in a conductive half-space by eigenfunction expansions in K-space of Fourier-Laplace transforms

info:eu-repo/semantics/published