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1.  Antiviral Mechanisms of Human Defensins 
Journal of molecular biology  2013;425(24):10.1016/j.jmb.2013.09.038.
Defensins are an effector component of the innate immune system with broad antimicrobial activity. Humans express two types of defensins, α- and β-defensins, which have antiviral activity against both enveloped and non-enveloped viruses. The diversity of defensin-sensitive viral species reflects a multitude of antiviral mechanisms. These include direct defensin targeting of viral envelopes, glycoproteins, and capsids in addition to inhibition of viral fusion and post-entry neutralization. Binding and modulation of host cell surface receptors and disruption of intracellular signaling by defensins can also inhibit viral replication. In addition, defensins can function as chemokines to augment and alter adaptive immune responses, revealing an indirect antiviral mechanism. Nonetheless, many questions regarding the antiviral activities of defensins remain. Although significant mechanistic data is known for α-defensins, molecular details for β-defensin inhibition are mostly lacking. Importantly, the role of defensin antiviral activity in vivo has not been addressed due to the lack of a complete defensin knockout model. Overall, the antiviral activity of defensins is well established as are the variety of mechanisms by which defensins achieve this inhibition; however, additional research is needed to fully understand the role of defensins in viral pathogenesis.
PMCID: PMC3842434  PMID: 24095897
virus; defensin; antimicrobial peptides; innate immunity
2.  Detection of Pleiotropy through a Phenome-Wide Association Study (PheWAS) of Epidemiologic Data as Part of the Environmental Architecture for Genes Linked to Environment (EAGLE) Study 
PLoS Genetics  2014;10(12):e1004678.
We performed a Phenome-wide association study (PheWAS) utilizing diverse genotypic and phenotypic data existing across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC), and accessed by the Epidemiological Architecture for Genes Linked to Environment (EAGLE) study. We calculated comprehensive tests of association in Genetic NHANES using 80 SNPs and 1,008 phenotypes (grouped into 184 phenotype classes), stratified by race-ethnicity. Genetic NHANES includes three surveys (NHANES III, 1999–2000, and 2001–2002) and three race-ethnicities: non-Hispanic whites (n = 6,634), non-Hispanic blacks (n = 3,458), and Mexican Americans (n = 3,950). We identified 69 PheWAS associations replicating across surveys for the same SNP, phenotype-class, direction of effect, and race-ethnicity at p<0.01, allele frequency >0.01, and sample size >200. Of these 69 PheWAS associations, 39 replicated previously reported SNP-phenotype associations, 9 were related to previously reported associations, and 21 were novel associations. Fourteen results had the same direction of effect across more than one race-ethnicity: one result was novel, 11 replicated previously reported associations, and two were related to previously reported results. Thirteen SNPs showed evidence of pleiotropy. We further explored results with gene-based biological networks, contrasting the direction of effect for pleiotropic associations across phenotypes. One PheWAS result was ABCG2 missense SNP rs2231142, associated with uric acid levels in both non-Hispanic whites and Mexican Americans, protoporphyrin levels in non-Hispanic whites and Mexican Americans, and blood pressure levels in Mexican Americans. Another example was SNP rs1800588 near LIPC, significantly associated with the novel phenotypes of folate levels (Mexican Americans), vitamin E levels (non-Hispanic whites) and triglyceride levels (non-Hispanic whites), and replication for cholesterol levels. The results of this PheWAS show the utility of this approach for exposing more of the complex genetic architecture underlying multiple traits, through generating novel hypotheses for future research.
Author Summary
The Epidemiological Architecture for Genes Linked to Environment (EAGLE) study performed a Phenome-Wide Association Study (PheWAS) to investigate comprehensive associations between a wide range of phenotypes and single-nucleotide polymorphisms using the diverse genotypic and phenotypic data that exists across multiple populations in the National Health and Nutrition Examination Surveys (NHANES), conducted by the Centers for Disease Control and Prevention (CDC). In this study, we replicated known genotype-phenotype associations, identified genotypes associated with phenotypes related to previously reported associations, and most importantly, identified a series of novel genotype-phenotype associations. We also identified potential pleiotropy; that is, SNPs associated with more than one phenotype. We explored the features of these PheWAS results, characterizing any potential functionality of the SNPs of this study, determining association results that were found in more than one racial/ethnic group for the same SNP and phenotype, identifying novel direction of effect relationships for SNPs demonstrating potential pleiotropy, and investigating the association results in the context of gene-based biological networks. Through considering the SNP associations on multiple phenotypic outcomes, as well as through exploring pleiotropy, we may be able to leverage the results of PheWAS to uncover more of the complex underlying genomic architecture of complex traits.
PMCID: PMC4256091  PMID: 25474351
3.  The Epithelial Cell-derived Atopic Dermatitis Cytokine TSLP Activates Neurons to Induce Itch 
Cell  2013;155(2):285-295.
Atopic dermatitis (AD) is a chronic itch and inflammatory disorder of the skin that affects one in ten people. Patients suffering from severe AD eventually progress to develop asthma and allergic rhinitis, in a process known as the “atopic march.” Signaling between epithelial cells and innate immune cells via the cytokine Thymic Stromal Lymphopoietin (TSLP) is thought to drive AD and the atopic march. Here we report that epithelial cells directly communicate to cutaneous sensory neurons via TSLP to promote itch. We identify the ORAI1/NFAT calcium signaling pathway as an essential regulator of TSLP release from keratinocytes, the primary epithelial cells of the skin. TSLP then acts directly on a subset of TRPA1-positive sensory neurons to trigger robust itch behaviors. Our results support a new model whereby calcium-dependent TSLP release by keratinocytes activates both primary afferent neurons and immune cells to promote inflammatory responses in the skin and airways.
PMCID: PMC4041105  PMID: 24094650
4.  Carbamazepine Potentiates the Effectiveness of Morphine in a Rodent Model of Neuropathic Pain 
PLoS ONE  2014;9(9):e107399.
Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) which may aggravate preexisting pain conditions. Accumulating evidence indicates that M3G signaling through neuronal Toll-like receptor 4 (TLR4) may be central to this proalgesic signaling event. These events are known to include elevated neuronal excitability, increased voltage-gated sodium (NaV) current, tactile allodynia and decreased opioid analgesic efficacy. Using an in vitro ratiometric-based calcium influx analysis of acutely dissociated small and medium-diameter neurons derived from lumbar dorsal root ganglion (DRG), we observed that M3G-sensitive neurons responded to lipopolysaccharide (LPS) and over 35% of these M3G/LPS-responsive cells exhibited sensitivity to capsaicin. In addition, M3G-exposed sensory neurons significantly increased excitatory activity and potentiated NaV current as measured by current and voltage clamp, when compared to baseline level measurements. The M3G-dependent excitability and potentiation of NaV current in these sensory neurons could be reversed by the addition of carbamazepine (CBZ), a known inhibitor of several NaV currents. We then compared the efficacy between CBZ and morphine as independent agents, to the combined treatment of both drugs simultaneously, in the tibial nerve injury (TNI) model of neuropathic pain. The potent anti-nociceptive effects of morphine (5 mg/kg, i.p.) were observed in TNI rodents at post-injury day (PID) 7–14 and absent at PID21–28, while administration of CBZ (10 mg/kg, i.p.) alone failed to produce anti-nociceptive effects at any time following TNI (PID 7–28). In contrast to either drug alone at PID28, the combination of morphine and CBZ completely attenuated tactile hyperalgesia in the rodent TNI model. The basis for the potentiation of morphine in combination with CBZ may be due to the effects of a latent upregulation of NaV1.7 in the DRG following TNI. Taken together, our observations demonstrate a potential therapeutic use of morphine and CBZ as a combinational treatment for neuropathic pain.
PMCID: PMC4164621  PMID: 25221944
5.  Gender moderates the influence of psychosocial factors and drug use on HAART adherence in the context of HIV and childhood sexual abuse 
AIDS care  2014;26(8):959-967.
This study aimed to examine gender moderation within a stress and coping model of HIV medication adherence in adults with a history of childhood sexual abuse (CSA). Sequelae of CSA, including negative coping, psychological distress, and drug use, interfere with adherence to highly active antiretroviral treatment (HAART). These obstacles to adherence are likely moderated by gender. Gender may particularly influence the mediational effect of drug use on adherence. Participants included 206 adults living with HIV/AIDS and CSA. Categorical/continuous variable methodology (CVM) in a structural equation modeling (SEM) framework was used to test a multigroup model with women and men. Gender significantly moderated several effects in the model. For women, the effect of psychological distress on HAART adherence was mediated by drug use, and the effect of drug use on viral load was mediated by HAART adherence. Among men, drug use did not significantly impact adherence. Since gender appears to moderate the effect of drug use on medication adherence, it is particularly important to address drug use within the context of HIV disease management in women with a history of CSA. Further, interventions to increase HAART adherence should take trauma history, gender, and drug abuse into account when assessing efficacy.
PMCID: PMC4156823  PMID: 24410324
medication adherence; CSA = childhood sexual abuse; HIV = human immunodeficiency virus; drug abuse; SEM = structural equation modeling; gender difference
6.  Association of the FTO Obesity Risk Variant rs8050136 With Percentage of Energy Intake From Fat in Multiple Racial/Ethnic Populations 
American Journal of Epidemiology  2013;178(5):780-790.
Common obesity risk variants have been associated with macronutrient intake; however, these associations' generalizability across populations has not been demonstrated. We investigated the associations between 6 obesity risk variants in (or near) the NEGR1, TMEM18, BDNF, FTO, MC4R, and KCTD15 genes and macronutrient intake (carbohydrate, protein, ethanol, and fat) in 3 Population Architecture using Genomics and Epidemiology (PAGE) studies: the Multiethnic Cohort Study (1993–2006) (n = 19,529), the Atherosclerosis Risk in Communities Study (1987–1989) (n = 11,114), and the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) Study, which accesses data from the Third National Health and Nutrition Examination Survey (1991–1994) (n = 6,347). We used linear regression, with adjustment for age, sex, and ethnicity, to estimate the associations between obesity risk genotypes and macronutrient intake. A fixed-effects meta-analysis model showed that the FTO rs8050136 A allele (n = 36,973) was positively associated with percentage of calories derived from fat (βmeta = 0.2244 (standard error, 0.0548); P = 4 × 10−5) and inversely associated with percentage of calories derived from carbohydrate (βmeta = −0.2796 (standard error, 0.0709); P = 8 × 10−5). In the Multiethnic Cohort Study, percentage of calories from fat assessed at baseline was a partial mediator of the rs8050136 effect on body mass index (weight (kg)/height (m)2) obtained at 10 years of follow-up (mediation of effect = 0.0823 kg/m2, 95% confidence interval: 0.0559, 0.1128). Our data provide additional evidence that the association of FTO with obesity is partially mediated by dietary intake.
PMCID: PMC3755639  PMID: 23820787
energy intake; fat mass and obesity-associated (FTO) gene; obesity; percent calories from fat; race/ethnicity
7.  Pharmacy Students’ Perceptions of Natural Science and Mathematics Subjects 
Objective. To determine the level of importance pharmacy students placed on science and mathematics subjects for pursuing a career in pharmacy.
Method. Two hundred fifty-four students completed a survey instrument developed to investigate students’ perceptions of the relevance of science and mathematics subjects to a career in pharmacy. Pharmacy students in all 4 years of a master of pharmacy (MPharm) degree program were invited to complete the survey instrument.
Results. Students viewed chemistry-based and biology-based subjects as relevant to a pharmacy career, whereas mathematics subjects such as physics, logarithms, statistics, and algebra were not viewed important to a career in pharmacy.
Conclusion. Students’ experience in pharmacy and year of study influenced their perceptions of subjects relevant to a pharmacy career. Pharmacy educators need to consider how they can help students recognize the importance of scientific knowledge earlier in the pharmacy curriculum.
PMCID: PMC4140484  PMID: 25147390
science; mathematics; pharmacy students; career
8.  (Biphenyl-4-yl)methylammonium Chlorides: Potent Anticonvulsants That Modulate Na+ Currents 
Journal of medicinal chemistry  2013;56(14):10.1021/jm4007092.
We have reported that compounds containing a bi-aryl linked unit (Ar-X-Ar′) modulated Na+ currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na+ currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models and in the maximal electroshock seizure test the activity of (3′-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A– differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na+ currents.
PMCID: PMC3842382  PMID: 23772678
9.  Defensins and Viral Infection: Dispelling Common Misconceptions 
PLoS Pathogens  2014;10(7):e1004186.
PMCID: PMC4102581  PMID: 25033215
10.  The genetic basis of music ability 
Music is an integral part of the cultural heritage of all known human societies, with the capacity for music perception and production present in most people. Researchers generally agree that both genetic and environmental factors contribute to the broader realization of music ability, with the degree of music aptitude varying, not only from individual to individual, but across various components of music ability within the same individual. While environmental factors influencing music development and expertise have been well investigated in the psychological and music literature, the interrogation of possible genetic influences has not progressed at the same rate. Recent advances in genetic research offer fertile ground for exploring the genetic basis of music ability. This paper begins with a brief overview of behavioral and molecular genetic approaches commonly used in human genetic analyses, and then critically reviews the key findings of genetic investigations of the components of music ability. Some promising and converging findings have emerged, with several loci on chromosome 4 implicated in singing and music perception, and certain loci on chromosome 8q implicated in absolute pitch and music perception. The gene AVPR1A on chromosome 12q has also been implicated in music perception, music memory, and music listening, whereas SLC6A4 on chromosome 17q has been associated with music memory and choir participation. Replication of these results in alternate populations and with larger samples is warranted to confirm the findings. Through increased research efforts, a clearer picture of the genetic mechanisms underpinning music ability will hopefully emerge.
PMCID: PMC4073543  PMID: 25018744
music; music ability; music perception; music production; genetic; genome; review
11.  Predictors of Lapse in First Week of Smoking Abstinence in PTSD and Non-PTSD Smokers 
Nicotine & Tobacco Research  2012;15(6):1122-1129.
Retrospective research suggests smokers with posttraumatic stress disorder (PTSD) lapse more quickly after their quit date. Ecological momentary assessment (EMA) research is needed to confirm the presence of early smoking lapse in PTSD and form conceptualizations that inform intervention.
Smokers with (n = 55) and without (n = 52) PTSD completed alarm-prompted EMA of situational and psychiatric variables the week before and after a quit date, and self-initiated EMA following smoking lapses. Blood samples at baseline and on the quit date allowed assessment of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA(S)).
PTSD was related to shorter time to lapse (hazard ratio [HR] = 1.677, 95% CI: 1.106–2.544). Increased smoking abstinence self-efficacy was related to longer time to lapse (HR = 0.608, 95% CI: 0.430–0.860). Analyses of participants’ real-time reports revealed that smokers with PTSD were more likely to attribute first-time lapses to negative affect ( = 5.412, p = .020), and trauma reminders (Fisher’s exact p = .003**). Finally, the quit date decrease in DHEA(S) was related to shorter time to lapse (HR = 1.009, 95% CI: 1.000–1.018, p < .05).
Results provide evidence of shorter time to first smoking lapse in PTSD, and add to evidence that early lapse occasions are more strongly related to trauma reminders, negative affect, and cravings in smokers with PTSD.
PMCID: PMC3646653  PMID: 23178322
12.  Lack of Associations of Ten Candidate Coronary Heart Disease Risk Genetic Variants and Subclinical Atherosclerosis in Four U.S. Populations: the Population Architecture using Genomics and Epidemiology (PAGE) Study 
Atherosclerosis  2013;228(2):390-399.
A number of genetic variants have been discovered by recent genome-wide association studies for their associations with clinical coronary heart disease (CHD). However, it is unclear whether these variants are also associated with the development of CHD as measured by subclinical atherosclerosis phenotypes, ankle brachial index (ABI), carotid artery intima-media thickness (cIMT) and carotid plaque.
Ten CHD risk single nucleotide polymorphisms (SNPs) were genotyped in individuals of European American (EA), African American (AA), American Indian (AI), and Mexican American (MA) ancestry in the Population Architecture using Genomics and Epidemiology (PAGE) study. In each individual study, we performed linear or logistic regression to examine population-specific associations between SNPs and ABI, common and internal cIMT, and plaque. The results from individual studies were meta-analyzed using a fixed effect inverse variance weighted model.
None of the ten SNPs was significantly associated with ABI and common or internal cIMT, after Bonferroni correction. In the sample of 13,337 EA, 3,809 AA, and 5,353 AI individuals with carotid plaque measurement, the GCKR SNP rs780094 was significantly associated with the presence of plaque in AI only (OR = 1.32, 95% confidence interval: 1.17, 1.49, P = 1.08 × 10−5), but not in the other populations (P = 0.90 in EA and P = 0.99 in AA). A 9p21 region SNP, rs1333049, was nominally associated with plaque in EA (OR = 1.07, P = 0.02) and in AI (OR = 1.10, P = 0.05).
We identified a significant association between rs780094 and plaque in AI populations, which needs to be replicated in future studies. There was little evidence that the index CHD risk variants identified through genome-wide association studies in EA influence the development of CHD through subclinical atherosclerosis as assessed by cIMT and ABI across ancestries.
PMCID: PMC3717342  PMID: 23587283
ankle brachial index; carotid artery intima-media thickness; carotid plaque; coronary heart disease; genetic association study; multiethnic populations; subclinical atherosclerosis
13.  SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons 
Channels  2013;7(3):153-159.
The axon/dendrite specification collapsin response mediator protein 2 (CRMP2) bidirectionally modulates N-type voltage-gated Ca2+ channels (CaV2.2). Here we demonstrate that small ubiquitin-like modifier (SUMO) protein modifies CRMP2 via the SUMO E2-conjugating enzyme Ubc9 in vivo. Removal of a SUMO conjugation site KMD in CRMP2 (K374A/M375A/D376A; CRMP2AAA) resulted in loss of SUMOylated CRMP2 without compromising neurite branching, a canonical hallmark of CRMP2 function. Increasing SUMOylation levels correlated inversely with calcium influx in sensory neurons. CRMP2 deSUMOylation by SUMO proteases SENP1 and SENP2 normalized calcium influx to those in the CRMP2AAA mutant. Thus, our results identify a novel role for SUMO modification in CRMP2/CaV2.2 signaling pathway.
PMCID: PMC3710342  PMID: 23510938
SUMO; CRMP2; Ubc9; CaV2.2; calcium influx; sensory neurons
14.  Moral Development of First-Year Pharmacy Students in the United Kingdom 
Objective. To investigate the moral development of pharmacy students over their first academic year of study at a university in the United Kingdom.
Methods. Pharmacy students completed Defining Issues Test (DIT) at the start of their first year (phase 1) and again at the end of their first year (phase 2) of the program.
Results. Pharmacy students (N=116) had significantly higher moral reasoning at the beginning of their first year than by the end of it. Scores differed by students’ gender and age; however, these findings differed between phase 1 and phase 2.
Conclusion. First-year pharmacy students in the United Kingdom scored lower on moral reasoning than did pharmacy students in the United States and Canada.
PMCID: PMC3965144  PMID: 24672069
moral development; pharmacy students; moral reasoning
15.  Differential regulation of collapsin response mediator protein 2 (CRMP2) phosphorylation by GSK3ß and CDK5 following traumatic brain injury 
Aberrant ion channel function has been heralded as a main underlying mechanism driving epilepsy and its symptoms. However, it has become increasingly clear that treatment strategies targeting voltage-gated sodium or calcium channels merely mask the symptoms of epilepsy without providing disease-modifying benefits. Ion channel function is likely only one important cog in a highly complex machine. Gross morphological changes, such as reactive sprouting and outgrowth, may also play a role in epileptogenesis. Mechanisms responsible for these changes are not well-understood. Here we investigate the potential involvement of the neurite outgrowth-promoting molecule collapsin response mediator protein 2 (CRMP2). CRMP2 activity, in this respect, is regulated by phosphorylation state, where phosphorylation by a variety of kinases, including glycogen synthase kinase 3 β (GSK3β) renders it inactive. Phosphorylation (inactivation) of CRMP2 was decreased at two distinct phases following traumatic brain injury (TBI). While reduced CRMP2 phosphorylation during the early phase was attributed to the inactivation of GSK3β, the sustained decrease in CRMP2 phosphorylation in the late phase appeared to be independent of GSK3β activity. Instead, the reduction in GSK3β-phosphorylated CRMP2 was attributed to a loss of priming by cyclin-dependent kinase 5 (CDK5), which allows for subsequent phosphorylation by GSK3β. Based on the observation that the proportion of active CRMP2 is increased for up to 4 weeks following TBI, it was hypothesized that it may drive neurite outgrowth, and therefore, circuit reorganization during this time. Therefore, a novel small-molecule tool was used to target CRMP2 in an attempt to determine its importance in mossy fiber sprouting following TBI. In this report, we demonstrate novel differential regulation of CRMP2 phosphorylation by GSK3β and CDK5 following TBI.
PMCID: PMC4035569  PMID: 24904280
CRMP2; GSK3β; CDK5; phosphorylation; mossy fiber sprouting; TIMM staining; epileptogenesis; (S)-Lacosamide
16.  Neurobiological, Cognitive, and Emotional Mechanisms in Melodic Intonation Therapy 
Singing has been used in language rehabilitation for decades, yet controversy remains over its effectiveness and mechanisms of action. Melodic Intonation Therapy (MIT) is the most well-known singing-based therapy; however, speculation surrounds when and how it might improve outcomes in aphasia and other language disorders. While positive treatment effects have been variously attributed to different MIT components, including melody, rhythm, hand-tapping, and the choral nature of the singing, there is uncertainty about the components that are truly necessary and beneficial. Moreover, the mechanisms by which the components operate are not well understood. Within the literature to date, proposed mechanisms can be broadly grouped into four categories: (1) neuroplastic reorganization of language function, (2) activation of the mirror neuron system and multimodal integration, (3) utilization of shared or specific features of music and language, and (4) motivation and mood. In this paper, we review available evidence for each mechanism and propose that these mechanisms are not mutually exclusive, but rather represent different levels of explanation, reflecting the neurobiological, cognitive, and emotional effects of MIT. Thus, instead of competing, each of these mechanisms may contribute to language rehabilitation, with a better understanding of their relative roles and interactions allowing the design of protocols that maximize the effectiveness of singing therapy for aphasia.
PMCID: PMC4040885  PMID: 24917811
Melodic Intonation Therapy; singing; language rehabilitation; aphasia; mechanisms; neuroplasticity; cognitive; mood
17.  The functionalized amino acid (S)-Lacosamide subverts CRMP2-mediated tubulin polymerization to prevent constitutive and activity-dependent increase in neurite outgrowth 
Activity-dependent neurite outgrowth is a highly complex, regulated process with important implications for neuronal circuit remodeling in development as well as in seizure-induced sprouting in epilepsy. Recent work has linked outgrowth to collapsin response mediator protein 2 (CRMP2), an intracellular phosphoprotein originally identified as axon guidance and growth cone collapse protein. The neurite outgrowth promoting function of CRMP2 is regulated by its phosphorylation state. In this study, depolarization (potassium chloride)-driven activity increased the level of active CRMP2 by decreasing its phosphorylation by GSK3β via a reduction in priming by Cdk5. To determine the contribution of CRMP2 in activity-driven neurite outgrowth, we screened a limited set of compounds for their ability to reduce neurite outgrowth but not modify voltage-gated sodium channel (VGSC) biophysical properties. This led to the identification of (S)-lacosamide ((S)-LCM), a stereoisomer of the clinically used antiepileptic drug (R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. Whereas (S)-LCM was ineffective in targeting VGSCs, the presumptive pharmacological targets of (R)-LCM, (S)-LCM was more efficient than (R)-LCM in subverting neurite outgrowth. Biomolecular interaction analyses revealed that (S)-LCM bound to wildtype CRMP2 with low micromolar affinity, similar to (R)-LCM. Through the use of this novel tool, the activity-dependent increase in neurite outgrowth observed following depolarization was characterized to be reliant on CRMP2 function. Knockdown of CRMP2 by siRNA in cortical neurons resulted in reduced CRMP2-dependent neurite outgrowth; incubation with (S)-LCM phenocopied this effect. Other CRMP2-mediated processes were unaffected. (S)-LCM subverted neurite outgrowth not by affecting the canonical CRMP2-tubulin association but rather by impairing the ability of CRMP2 to promote tubulin polymerization, events that are perfunctory for neurite outgrowth. Taken together, these results suggest that changes in the phosphorylation state of CRMP2 are a major contributing factor in activity-dependent regulation of neurite outgrowth.
PMCID: PMC4109617  PMID: 25104922
CRMP2; activity-dependent; neurite outgrowth; (S)-Lacosamide; GSK3β; Cdk5
18.  Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation 
ACS Chemical Neuroscience  2012;3(12):1037-1049.
Four compounds that contained the N-benzyl 2-amino-3-methoxypropionamide unit were evaluated for their ability to modulate Na+ currents in catecholamine A differentiated CAD neuronal cells. The compounds differed by the absence or presence of either a terminal N-acetyl group or a (3-fluoro)benzyloxy moiety positioned at the 4′-benzylamide site. Analysis of whole-cell patch-clamp electrophysiology data showed that the incorporation of the (3-fluoro)benzyloxy unit, to give the (3-fluoro)benzyloxyphenyl pharmacophore, dramatically enhanced the magnitude of Na+ channel slow inactivation. In addition, N-acetylation markedly increased the stereoselectivity for Na+ channel slow inactivation. Furthermore, we observed that Na+ channel frequency (use)-dependent block was maintained upon inclusion of this pharmacophore. Confirmation of the importance of the (3-fluoro)benzyloxyphenyl pharmacophore was shown by examining compounds where the N-benzyl 2-amino-3-methoxypropionamide unit was replaced by a N-benzyl 2-amino-3-methylpropionamide moiety, as well as examining a series of compounds that did not contain an amino acid group but retained the pharmacophore unit. Collectively, the data indicated that the (3-fluoro)benzyloxyphenyl unit is a novel pharmacophore for the modulation of Na+ currents.
PMCID: PMC3526970  PMID: 23259039
Benzyloxyphenyl pharmacophore; voltage-gated sodium channels; slow inactivation; anticonvulsant activity; hyperexcitable neurons; epilepsy
19.  Pitch and Plasticity: Insights from the Pitch Matching of Chords by Musicians with Absolute and Relative Pitch 
Brain Sciences  2013;3(4):1615-1634.
Absolute pitch (AP) is a form of sound recognition in which musical note names are associated with discrete musical pitch categories. The accuracy of pitch matching by non-AP musicians for chords has recently been shown to depend on stimulus familiarity, pointing to a role of spectral recognition mechanisms in the early stages of pitch processing. Here we show that pitch matching accuracy by AP musicians was also dependent on their familiarity with the chord stimulus. This suggests that the pitch matching abilities of both AP and non-AP musicians for concurrently presented pitches are dependent on initial recognition of the chord. The dual mechanism model of pitch perception previously proposed by the authors suggests that spectral processing associated with sound recognition primes waveform processing to extract stimulus periodicity and refine pitch perception. The findings presented in this paper are consistent with the dual mechanism model of pitch, and in the case of AP musicians, the formation of nominal pitch categories based on both spectral and periodicity information.
PMCID: PMC4061894  PMID: 24961624
pitch; absolute pitch; concurrent pitch; neurocognitive model; recognition
20.  The musical environment and auditory plasticity: hearing the pitch of percussion 
Although musical skills clearly improve with training, pitch processing has generally been believed to be biologically determined by the behavior of brain stem neural mechanisms. Two main classes of pitch models have emerged over the last 50 years. Harmonic template models have been used to explain cross-channel integration of frequency information, and waveform periodicity models have been used to explain pitch discrimination that is much finer than the resolution of the auditory nerve. It has been proposed that harmonic templates are learnt from repeated exposure to voice, and so it may also be possible to learn inharmonic templates from repeated exposure to inharmonic music instruments. This study investigated whether pitch-matching accuracy for inharmonic percussion instruments was better in people who have trained on these instruments and could reliably recognize their timbre. We found that adults who had trained with Indonesian gamelan instruments were better at recognizing and pitch-matching gamelan instruments than people with similar levels of music training, but no prior exposure to these instruments. These findings suggest that gamelan musicians were able to use inharmonic templates to support accurate pitch processing for these instruments. We suggest that recognition mechanisms based on spectrotemporal patterns of afferent auditory excitation in the early stages of pitch processing allow rapid priming of the lowest frequency partial of inharmonic timbres, explaining how music training can adapt pitch processing to different musical genres and instruments.
PMCID: PMC3807563  PMID: 24187543
inharmonic; pitch; recognition; plasticity; percussion; instrument
21.  In Vitro Grown Pollen Tubes of Nicotiana alata Actively Synthesise a Fucosylated Xyloglucan 
PLoS ONE  2013;8(10):e77140.
Nicotiana alata pollen tubes are a widely used model for studies of polarized tip growth and cell wall synthesis in plants. To better understand these processes, RNA-Seq and de novo assembly methods were used to produce a transcriptome of N. alata pollen grains. Notable in the reconstructed transcriptome were sequences encoding proteins that are involved in the synthesis and remodelling of xyloglucan, a cell wall polysaccharide previously not thought to be deposited in Nicotiana pollen tube walls. Expression of several xyloglucan-related genes in actively growing pollen tubes was confirmed and xyloglucan epitopes were detected in the wall with carbohydrate-specific antibodies: the major xyloglucan oligosaccharides found in N. alata pollen grains and tubes were fucosylated, an unusual structure for the Solanaceae, the family to which Nicotiana belongs. Finally, carbohydrate linkages consistent with xyloglucan were identified chemically in the walls of N. alata pollen grains and pollen tubes grown in culture. The presence of a fucosylated xyloglucan in Nicotiana pollen tube walls was thus confirmed. The consequences of this discovery to models of pollen tube growth dynamics and more generally to polarised tip-growing cells in plants are discussed.
PMCID: PMC3792914  PMID: 24116212
22.  Moderating variables of music training-induced neuroplasticity: a review and discussion 
A large body of literature now exists to substantiate the long-held idea that musicians' brains differ structurally and functionally from non-musicians' brains. These differences include changes in volume, morphology, density, connectivity, and function across many regions of the brain. In addition to the extensive literature that investigates these differences cross-sectionally by comparing musicians and non-musicians, longitudinal studies have demonstrated the causal influence of music training on the brain across the lifespan. However, there is a large degree of inconsistency in the findings, with discordance between studies, laboratories, and techniques. A review of this literature highlights a number of variables that appear to moderate the relationship between music training and brain structure and function. These include age at commencement of training, sex, absolute pitch (AP), type of training, and instrument of training. These moderating variables may account for previously unexplained discrepancies in the existing literature, and we propose that future studies carefully consider research designs and methodologies that control for these variables.
PMCID: PMC3766835  PMID: 24058353
music training; neuroplasticity; imaging; training age; sex; absolute pitch; training type
23.  Consumer Perspectives on Genetic Testing for Psychiatric Disorders: The Attitudes of Veterans with Posttraumatic Stress Disorder and Their Families 
The perspectives of patients with posttraumatic stress disorder (PTSD) on genetic research have not yet been investigated in the genetics research literature. To provide a basis for research on attitudes toward genetic research in PTSD, we surveyed the U.S. Military Afghanistan/Iraq-era veterans with PTSD and their social support companions to investigate the attitudes and knowledge about genetics and genetic testing. One hundred forty-six veterans (76 with PTSD and 70 without PTSD) participated in this study. Each veteran participant had a corresponding companion (primarily spouses, but also relatives and friends) who they identified as a primary member of their social support network. Participants and companions completed self-report measures on knowledge of genetics and attitudes toward genetic testing for PTSD. Results indicated that, relative to veterans without PTSD, veterans with PTSD had similar levels of genetic knowledge, but less-favorable attitudes toward genetic testing. Differences persisted after controlling for age and genetics knowledge. No differences between companions of those with and without PTSD were observed. Results suggest that the perspective of those with PTSD regarding genetic testing is in need of further investigation, especially if potentially beneficial genetic testing for PTSD is to be utilized in the target population.
PMCID: PMC3438836  PMID: 22891755
24.  The Ion Channel TRPA1 Is Required for Chronic Itch 
Chronic itch is a debilitating condition that affects one in 10 people. Little is known about the molecules that mediate chronic itch in primary sensory neurons and skin. We demonstrate that the ion channel TRPA1 is required for chronic itch. Using a mouse model of chronic itch, we show that scratching evoked by impaired skin barrier is abolished in TRPA1-deficient animals. This model recapitulates many of the pathophysiological hallmarks of chronic itch that are observed in prevalent human diseases such as atopic dermatitis and psoriasis, including robust scratching, extensive epidermal hyperplasia, and dramatic changes in gene expression in sensory neurons and skin. Remarkably, TRPA1 is required for both transduction of chronic itch signals to the CNS and for the dramatic skin changes triggered by dry-skin-evoked itch and scratching. These data suggest that TRPA1 regulates both itch transduction and pathophysiological changes in the skin that promote chronic itch.
PMCID: PMC3752436  PMID: 23719797
25.  Therapeutic revascularisation of ischaemic tissue: the opportunities and challenges for therapy using vascular stem/progenitor cells 
Ischaemia-related diseases such as peripheral artery disease and coronary heart disease constitute a major issue in medicine as they affect millions of individuals each year and represent a considerable economic burden to healthcare systems. If the underlying ischaemia is not sufficiently resolved it can lead to tissue damage, with subsequent cell death. Treating such diseases remains difficult and several strategies have been used to stimulate the growth of blood vessels and promote regeneration of ischaemic tissues, such as the use of recombinant proteins and gene therapy. Although these approaches remain promising, they have limitations and results from clinical trials using these methods have had limited success. Recently, there has been growing interest in the therapeutic potential of using a cell-based approach to treat vasodegenerative disorders. In vascular medicine, various stem cells and adult progenitors have been highlighted as having a vasoreparative role in ischaemic tissues. This review will examine the clinical potential of several stem and progenitor cells that may be utilised to regenerate defunct or damaged vasculature and restore blood flow to the ischaemic tissue. In particular, we focus on the therapeutic potential of endothelial progenitor cells as an exciting new option for the treatment of ischaemic diseases.
PMCID: PMC3580469  PMID: 22897941

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