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1.  Do you see what I hear? Vantage point preference and visual dominance in a time-space synaesthete 
Time-space synaesthetes “see” time units organized in a spatial form. While the structure might be invariant for most synaesthetes, the perspective by which some view their calendar is somewhat flexible. One well-studied synaesthete L adopts different viewpoints for months seen vs. heard. Interestingly, L claims to prefer her auditory perspective, even though the month names are represented visually upside down. To verify this, we used a spatial-cueing task that included audiovisual month cues. These cues were either congruent with L's preferred “auditory” viewpoint (auditory-only and auditory + month inverted) or incongruent (upright visual-only and auditory + month upright). Our prediction was that L would show enhanced cueing effects (larger response time difference between valid and invalid targets) following the audiovisual congruent cues since both elicit the “preferred” auditory perspective. Also, when faced with conflicting cues, we predicted L would choose the preferred auditory perspective over the visual perspective. As we expected, L did show enhanced cueing effects following the audiovisual congruent cues that corresponded with her preferred auditory perspective, but that the visual perspective dominated when L was faced with both viewpoints simultaneously. The results are discussed with relation to the reification hypothesis of sequence space synaesthesia (Eagleman, 2009).
doi:10.3389/fpsyg.2013.00695
PMCID: PMC3797398  PMID: 24137140
synaesthesia; spatial-cueing; spatial perception; attention; mental vantage points; orienting; reification
2.  The C-Terminal Putative Nuclear Localization Sequence of BReast cancer Metastasis Suppressor 1, BRMS1, Is Necessary for Metastasis Suppression 
PLoS ONE  2013;8(2):e55966.
Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that suppresses metastasis in multiple human and murine carcinoma cell lines. BRMS1 interacts with several nuclear proteins including SIN3:HDAC chromatin remodeling complexes that are involved in repressing transcription. However, recent reports suggest BRMS1 may function in the cytoplasm. BRMS1 has two predicted nuclear localization sequences (NLS) that are located near the C-terminus (amino acids 198–205 and 238–244, NLS1 and NLS2 respectively). We hypothesized that nuclear localization sequences of BRMS1 were essential for BRMS1 mediated metastasis suppression. Replacement of NLS2 with NLS1 (BRMS1NLS1,1), truncation at 238 (BRMS1ΔNLS2), or switching the location of NLS1 and NLS2 (BRMS1NLS2,1) did not affect nuclear localization; but, replacement of NLS1 with NLS2 (BRMS1NLS2,2) or truncation at 197 (BRMS1ΔNLS which removes both NLS) promoted cytoplasmic localization. MDA-MB-231 human metastatic breast cancer cells transduced with BRMS1NLS1,1, BRMS1NLS2,2 or BRMS1NLS2,1 were evaluated for metastasis suppression in an experimental xenograft mouse model. Interestingly, while NLS2 was not necessary for nuclear localization, it was found to be important for metastasis suppression since BRMS1NLS2,2 suppressed metastasis by 85%. In contrast, BRMS1NLS2,1 and BRMS1NLS1,1 did not significantly suppress metastasis. Both BRMS1 and BRMS1NLS2,2 co-immunoprecipitated with SIN3A in the nucleus and cytoplasm; however, BRMS1NLS1,1 and BRMS1NLS2,1 were associated with SIN3A in the nucleus only. Moreover, BRMS1 and BRMS1NLS2,2, but not BRMS1NLS1,1 and BRMS1NLS2,1, down-regulated the pro-metastatic microRNA, miR-10b. Together, these data demonstrate an important role for NLS2 in the cytoplasm that is critical for metastasis suppression and is distinct from nuclear localization.
doi:10.1371/journal.pone.0055966
PMCID: PMC3563580  PMID: 23390556
3.  Use and Quality of Mental Health Services for Haitian Youth 
Ethnicity & health  2011;16(6):567-582.
Objective
To describe the mental health service use of Haitian, African American, and non-Latino White youth in a community mental health setting. Groups are compared on adherence to treatment guidelines for attention-deficit/hyperactivity disorder (ADHD) and depressive disorders.
Design
Retrospective review of outpatient mental health charts (n=252) from five community sites in an urban area of the Northeastern United States. We recorded total number and treatment type of sessions during the first six months of treatment. Guideline-adherent treatments were compared and predicted after controlling for clinical need.
Results
Most Haitian and African American youth stopped treatment by six months, with the majority attending less than eight sessions. One third of Haitian and African American patients attended just one session. Haitians patients who presented with less severe symptoms and dysfunction were more likely to have single-session treatments. Guideline-adherent treatment for ADHD and depression was less likely for Haitians. Older patients were more likely to receive adequate depression treatment. Haitian youth were relatively underinsured, had more family separations documented, and received Adjustment Disorder diagnoses more often.
Conclusions
Haitian youth use outpatient mental health services in similar proportion to African American youth, and at lower rates than White youth. Guideline-adherent treatment for ADHD and depression is limited by low retention in care for Black youth. Low insurance coverage is likely an important contributor to reduced use of services, especially for Haitians. These findings are discussed in the context of providing culturally sensitive mental health care to diverse communities.
doi:10.1080/13557858.2011.586024
PMCID: PMC3226766  PMID: 22050537
mental health services; Haitian; cross-cultural; treatment guidelines; youth
4.  A Deliberate and Rigorous Approach to Development of Patient-centered Technologies 
Seminars in oncology nursing  2011;27(3):183-191.
Objectives
Many technologies intended for patient use are never developed or evaluated with principles of user-centered design. In this review, we explore different approaches to assessing usability and acceptability, drawn from selected exemplar studies in the health sciences literature.
Data sources
Peer-reviewed research manuscripts were selected from Medline and other data sources accessible through pubmed.gov. We also present a framework for developing patient-centered technologies that we recently employed.
Conclusions
While there are studies utilizing principles of user-centered design, many more do not report formative usability testing results and may only report post-hoc satisfaction surveys. Consequently, adoption by user groups may be limited.
Implications for Nursing Practice
We encourage nurses in practice to look for and examine usability testing results prior to considering implementation of any patient-centered technology.
doi:10.1016/j.soncn.2011.04.003
PMCID: PMC3189856  PMID: 21783009
Usability; Acceptability; Patient-centered; Informatics
5.  Broadening of activity with flow across neural structures 
Perception  2008;37(3):401-407.
Synfire chains have long been suggested as a substrate for perception and information processing in the nervous system. However, embedding activation chains in a densely connected nervous matrix risks spread of signal that will obscure or obliterate the message. We used computer modeling and physiological measurements in rat hippocampus to assess this problem of activity broadening. We simulated a series of neural modules with feedforward propagation and random connectivity within each module and from one module to the next. We found that activity broadened as it propagated from one module to the next. This occurred over a wide array of parameters with greater broadening seen due to increasing excitatory-excitatory synaptic strength. Activity broadening correlated positively with propagation velocity. Multi-electrode measurements of activity propagation in disinhibited CA1 slice demonstrated broadening of about 50% over 1 mm. Such broadening is a problem for information transfer that must be dealt with in a fully functioning nervous system.
PMCID: PMC2679216  PMID: 18491717
6.  Computer simulation of epilepsy: implications for seizure spread and behavioral dysfunction 
Epilepsy & behavior : E&B  2005;7(3):336-344.
Hippocampal area CA3 has been one of the most intensively studied brain regions for computer models of epileptiform activity. As physiological studies begin to extend outward to other hippocampal and parahippocampal areas, we must extend these models to understand more complex circuitry containing diverse elements. Study of subiculum is of particular interest in this context, as it is a structure of intermediate complexity, with an inchoate columnar and laminar organization. In addition to helping us understand seizures, modeling of these structures will also help us understand the genesis of physiological activity patterns that are below threshold for seizure generation. Such modeling can also serve as a basis for speculation regarding the non-ictal behavioral consequences of epilepsy.
doi:10.1016/j.yebeh.2005.06.011
PMCID: PMC2656282  PMID: 16105749
7.  Data-mining through simulation 
Data integration is particularly difficult in neuroscience: we must organize vast amounts of data around only a few fragmentary functional hypotheses. It has often been noted that computer simulation, by providing explicit hypotheses for a particular system and bridging across different levels of organization, can provide an organizational focus which can be leveraged to form substantive hypotheses. Simulations lend meaning to data and can be updated and adapted as further data comes in. The use of simulation in this context suggests the need for simulator adjuncts to manage and evaluate data. We have developed a neural query system (NQS) within the NEURON simulator, providing a relational database system, a query function and basic data-mining tools. NQS is used within the simulation context to manage, verify and evaluate model parameterizations. More importantly, it is used for data-mining of simulation data and comparison to neurophysiology.
doi:10.1007/978-1-59745-520-6_9
PMCID: PMC2633476  PMID: 18368365
simulation; computer modeling; neural networks; neuronal networks; databasing; query systems; data-mining; knowledge discovery; inductive database
8.  Adapting the Learning-Cycle to Enrich Undergraduate Neuroscience Education for All Students 
A learning-cycle approach to science instruction is not new to science educators (Karplus, 1977; Kolb, 1984; Bergquist, 1991; Zollman, 1990; Allard and Barman, 1994). Somewhat less known, however, is the usefulness of this approach for creating lab activities for a broad audience of undergraduates. The following paper presents a brief overview of a laboratory activity that can be adapted for use by instructors of introductory neuroscience courses. The three-hour activity is geared towards tapping key elements of the learning-cycle approach, with a particular emphasis on the exploration phase of the model. Students work as members of small teams to explore a contemporary issue involving memory and gain hands-on experience from the outset, to which conceptual information is then added during lecture the following week. The approach is in marked contrast to the more traditional practice in the sciences where laboratory activities generally serve to punctuate already presented lecture material.
PMCID: PMC3592666  PMID: 23493626
problem-based learning; undergraduate neuroscience education; laboratory experiences; non-science majors
9.  Hemispheric differences in protein kinase C βII levels in the rat amygdala: baseline asymmetry and lateralized changes associated with cue and context in a classical fear conditioning paradigm 
Neuroscience  2006;144(3):797-807.
The amygdala is critically important for fear learning, and specific kinases have been implicated as contributors to the mechanisms that underlie learning. We examined levels of protein kinase C βII (PKC βII) in the left and right lateral and basolateral nuclei (LA/BLA) of the amygdala from animals that were classically fear conditioned with tones as cues and footshocks. Groups consisted of animals that received neither tones nor shocks, paired tones and shocks, or unpaired tones and shocks. At 1 hour after conditioning, some animals from each group were used for biochemical measurements of PKC βII levels and other animals were given probe trials to assess freezing behavior to cue and context. The levels of PKC βII were greater in the left hemisphere in animals receiving neither tones nor shocks and animals receiving paired tones and shocks. PKC βII levels were greater in the right hemisphere of animals receiving randomly presented tones and shocks. Freezing times to cue were long (>80% of probe trial time) in both the paired tone/shock and randomly unpaired tone/shock groups. Freezing times to context were long in the unpaired tone/shock group, but not the paired tone/shock group. Correlational analyses showed that freezing times to context, but not cue, precisely predicted the right/left relation of PKC βII levels in the LA/BLA: the greater the time spent freezing to context, the greater the increase in right hemisphere PKC βII levels. We conclude that fear conditioning causes hemisphere and input specific increases in PKC βII in the rat LA/BLA.
doi:10.1016/j.neuroscience.2006.10.017
PMCID: PMC1892597  PMID: 17118565
10.  Intrinsic Connectivity of the Rat Subiculum: II. Properties of Synchronous Spontaneous Activity and a Demonstration of Multiple Generator Regions 
Brain structures that can generate epileptiform activity possess excitatory interconnections among principal cells and a subset of these neurons that can be spontaneously active (“pacemaker” cells). We describe electrophysiological evidence for excitatory interactions among rat subicular neurons. Subiculum was isolated from presubiculum, CA1, and entorhinal cortex in ventral horizontal slices. Nominally zero magnesium perfusate, picrotoxin (100 μM), or NMDA (20 μM) was used to induce spontaneous firing in subicular neurons. Synchronous population activity and the spread of population events from one end of subiculum to the other in isolated subicular subslices indicate that subicular pyramidal neurons are coupled together by excitatory synapses. Both electrophysiological classes of subicular pyramidal cells (bursting and regular spiking) exhibited synchronous activity, indicating that both cell classes are targets of local excitatory inputs. Burst firing neurons were active in the absence of synchronous activity in field recordings, indicating that these cells may serve as pacemaker neurons for the generation of epileptiform activity in subiculum. Epileptiform events could originate at either proximal or distal segments of the subiculum from ventral horizontal slices. In some slices, events originated in both proximal and distal locations and propagated to the other location. Finally, propagation was supported over axonal paths through the cell layer and in the apical dendritic zone. We conclude that subicular burst firing and regular spiking neurons are coupled by means of glutamatergic synapses. These connections may serve to distribute activity driven by topographically organized inputs and to synchronize subicular cell activity.
PMCID: PMC1592136  PMID: 11406829
parahippocampal region; hippocampus; limbic cortex; excitatory synapse
11.  Intrinsic Connectivity of the Rat Subiculum: I. Dendritic Morphology and Patterns of Axonal Arborization by Pyramidal Neurons 
The dendritic and axonal morphology of rat subicular neurons was studied in single cells labeled with Neurobiotin. Electrophysiological classification of cells as intrinsic burst firing or regular spiking neurons was correlated with morphologic patterns and cell locations. Every cell had dendritic branches that reached the outer molecular layer, with most cells having branches that reached the hippocampal fissure. All but two pyramidal cells had axon collaterals that entered the deep white matter (alveus). Branching patterns of apical dendrites varied as a function of the cell’s soma location along the fissure–alveus axis of the cell layer. The first major dendritic branch point for most cells occurred at the superficial edge of the cell layer giving deep cells long primary apical dendrites and superficial cells short or absent primary apical dendrites. In contrast, basal dendritic arbors were similar across cells regardless of cell position. Apical and basal dendrites of all cells had numerous spines. Superficial and deep cells also differed in axonal collateralization. Deep cells (mostly intrinsically bursting [IB] class) had one or more ascending axon collaterals that typically remained within the region circumscribed by their apical dendrites. Superficial cells (mostly regular spiking [RS] class) tended to have axon collaterals that reached longer distances in the cell layer. Numerous varicosities and axonal extensions were present on axon collaterals in the cell layer and in the apical dendritic region, suggesting intrinsic connectivity. Axonal varicosities and extensions were found on axons that entered presubiculum, entorhinal cortex or CA1, supporting the notion that these were projection cells. Local collaterals were distinctly thinner than collaterals that would leave the subiculum, suggesting little or no myelin on local collaterals and some myelin on efferent fibers. We conclude that both IB and RS classes of subicular principal cells make synaptic contacts in and apical to the cell layer. Based on the patterns of axonal arborization, we suggest that subiculum has at least a crude columnar and laminar architecture, with ascending collaterals of deep cells forming columns and broader axonal arbors of superficial cells serving to distribute activity across multiple columns.
PMCID: PMC1592135  PMID: 11406828
parahippocampal region; hippocampus; limbic cortex; excitatory synapse
12.  Mpt5p, a Stress Tolerance- and Lifespan-Promoting PUF Protein in Saccharomyces cerevisiae, Acts Upstream of the Cell Wall Integrity Pathway▿  
Eukaryotic Cell  2006;6(2):262-270.
Pumilio family (PUF) proteins affect specific genes by binding to, and inhibiting the translation or stability of, their transcripts. The PUF domain is required and sufficient for this function. One Saccharomyces cerevisiae PUF protein, Mpt5p (also called Puf5p or Uth4p), promotes stress tolerance and replicative life span (the maximum number of doublings a mother cell can undergo before entering into senescence) by an unknown mechanism thought to partly overlap with, but to be independent of, the cell wall integrity (CWI) pathway. Here, we found that mpt5Δ mutants also display a short chronological life span (the time cells stay alive in saturated cultures in synthetic medium), a defect that is suppressed by activation of CWI signaling. We found that Mpt5p is an upstream activator of the CWI pathway: mpt5Δ mutants display the appropriate phenotypes and genetic interactions, display low basal activity of the pathway, and are defective in activation of the pathway upon thermal stress. A set of mRNAs that specifically bind to Mpt5p was recently reported. One such putative target, LRG1, encodes a GTPase-activating protein for Rho1p that directly links Mpt5p to CWI signaling: Lrg1p inhibits CWI signaling, LRG1 mRNA contains a consensus Mpt5p-binding site in its putative 3′ untranslated region, loss of Lrg1p suppresses the temperature sensitivity and CWI signaling defects of mpt5Δ mutants, and LRG1 mRNA abundance is inhibited by Mpt5p. We conclude that Mpt5p is required for normal replicative and chronological life spans and that the CWI pathway is a key and direct downstream target of this PUF protein.
doi:10.1128/EC.00188-06
PMCID: PMC1797943  PMID: 17172436
13.  Advice or exercise for chronic whiplash disorders? Design of a randomized controlled trial 
Background
Whiplash-associated disorder (or "whiplash") is a common condition incurring considerable expense in social and economic terms. A lack of research on effective therapy for patients with chronic whiplash associated disorders prompted the design of the current study. The primary aim of this randomised controlled trial is to determine the effects of a physical activity program for people with chronic (symptoms of > 3 months duration) whiplash. A secondary aim is to determine if pain severity, level of disability and fear of movement/(re)injury predict response to a physical activity program.
Methods / Design
This paper presents the rationale and design of a randomised controlled trial examining the effects of advice and individualized sub-maximal exercise programs in the treatment of whiplash associated disorders.
Discussion
This paper highlights the design, methods and operational aspects of a significant clinical trial in the area of whiplash and chronic pain.
doi:10.1186/1471-2474-4-18
PMCID: PMC194710  PMID: 12932301
Whiplash; Exercise; Advice; Therapy; Neck Pain; Disability.
14.  Small Molecule Inhibitors of the Neuropilin-1 Vascular Endothelial Growth Factor A (VEGF-A) Interaction† 
Journal of Medicinal Chemistry  2010;53(5):2215-2226.
We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1−ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.
doi:10.1021/jm901755g
PMCID: PMC2841442  PMID: 20151671

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