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1.  Hexokinase-II positively regulates glucose starvation induced autophagy through TORC1 inhibition 
Molecular cell  2014;53(4):521-533.
Summary
Hexokinase-II (HK-II) catalyzes the first step of glycolysis and also functions as a protective molecule, however, its role in protective autophagy has not been determined. Results showed that inhibition of HK-II diminished, while overexpression of HK-II potentiated, autophagy induced by glucose deprivation in cardiomyocyte and non-cardiomyocyte cells. Immunoprecipitation studies revealed that HK-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and this binding was increased by glucose deprivation. The TOS motif, a scaffold sequence responsible for binding TORC1 substrates, is present in HK-II and mutating it blocked its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate. We suggest that HK-II binds TORC1 as a decoy substrate and provides a previously unrecognized mechanism for switching cells from a metabolic economy based on plentiful energy, to one of conservation, under starvation.
doi:10.1016/j.molcel.2013.12.019
PMCID: PMC3943874  PMID: 24462113
2.  The FOCUS trial: cognitive remediation plus standard treatment versus standard treatment for patients at ultra-high risk for psychosis: study protocol for a randomised controlled trial 
Trials  2015;16:25.
Background
Cognitive deficits are a distinct feature among people at ultra-high risk (UHR) for psychosis and pose a barrier to functional recovery. Insufficient evidence exists on how to ameliorate these cognitive deficits in patients at UHR for psychosis and hence improve daily living and quality of life. The aim of the trial is to investigate whether cognitive remediation can improve cognitive and psychosocial function in patients at UHR for psychosis.
Methods
The FOCUS trial (Function and Overall Cognition in Ultra-high risk States) is a randomised, parallel group, observer-blinded clinical trial enrolling 126 patients meeting the standardised criteria of being at UHR for psychosis. Patients are recruited from psychiatric in- and outpatient facilities in the Copenhagen catchment area. Patients are randomised to one of the two treatment arms: cognitive remediation plus standard treatment versus standard treatment. The cognitive remediation consists of 24 weekly group-based and manualised sessions targeting neurocognition and social cognition. In addition to the group sessions, the patients will be offered 12 individual sessions aiming at maximising the transfer of the effects of the cognitive training to their everyday lives. Follow-up assessments will be conducted at 6 and 12 months after randomisation. The primary outcome is the composite score on the Brief Assessment of Cognition in Schizophrenia at cessation of treatment after 6 months. Secondary outcomes are social and daily functioning, psychosis-like symptoms, negative symptomatology, and depressive symptomatology as measured with the Personal and Social Performance Scale, Brief Psychiatric Rating Scale-Expanded Version, Scale for the Assessment of Negative Symptoms, and the Montgomery-Åsberg Depression Rating Scale.
Discussion
This is the first trial to evaluate the effects of neurocognitive and social cognitive remediation in UHR patients. The FOCUS trial results will provide evidence on the effect of targeted and comprehensive cognitive rehabilitation on cognition, daily living, and symptomatology as well as long-term outcome in preventing transition to psychosis in UHR patients.
Trial registration
ClinicalTrials.gov NCT 02098408. Date of registration 18 March 2014.
doi:10.1186/s13063-014-0542-8
PMCID: PMC4318160  PMID: 25623736
At-risk mental state; Ultra-high risk for psychosis; Prodromal schizophrenia; Prodromal intervention; Cognitive remediation; Cognitive training; Social cognitive training; Neurocognitive training
3.  Self-association of the APC tumor suppressor is required for the assembly, stability, and activity of the Wnt signaling destruction complex 
Molecular Biology of the Cell  2014;25(21):3424-3436.
The colon cancer tumor suppressor adenomatous polyposis coli (APC) negatively regulates Wnt signaling in the β-catenin destruction complex by binding to β-catenin and facilitating its phosphorylation and degradation. APC self-association plays an integral role in the assembly, stability, and activity of the destruction complex.
The tumor suppressor adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β, and CK1 that targets β-catenin/Armadillo (β-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. Whereas APC functions in the complex through its ability to bind both β-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC self-association domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates β-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in β-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
doi:10.1091/mbc.E14-04-0885
PMCID: PMC4214788  PMID: 25208568
4.  5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence in Meningioma: Qualitative and Quantitative Measurements In Vivo 
Neurosurgery  2014;10(0 1):74-83.
BACKGROUND
The use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence has shown promise as a surgical adjunct for maximizing the extent of surgical resection in gliomas. To date, the clinical utility of 5-ALA in meningiomas is not fully understood, with most descriptive studies using qualitative approaches to 5-ALA-PpIX.
OBJECTIVE
To assess the diagnostic performance of 5-ALA-PpIX fluorescence during surgical resection of meningioma.
METHODS
ALA was administered to 15 patients with meningioma undergoing PpIX fluorescence-guided surgery at our institution. At various points during the procedure, the surgeon performed qualitative, visual assessments of fluorescence by using the surgical microscope, followed by a quantitative fluorescence measurement by using an intra-operative probe. Specimens were collected at each point for subsequent neuropathological analysis. Clustered data analysis of variance was used to ascertain a difference between groups, and receiver operating characteristic analyses were performed to assess diagnostic capabilities.
RESULTS
Red-pink fluorescence was observed in 80% (12/15) of patients, with visible fluorescence generally demonstrating a strong, homogenous character. Quantitative fluorescence measured diagnostically significant PpIX concentrations (CPpIx) in both visibly and nonvisibly fluorescent tissues, with significantly higher CPpIx in both visibly fluorescent (P < .001) and tumor tissue (P = .002). Receiver operating characteristic analyses also showed diagnostic accuracies up to 90% for differentiating tumor from normal dura.
CONCLUSION
ALA-induced PpIX fluorescence guidance is a potential and promising adjunct in accurately detecting neoplastic tissue during meningioma resective surgery. These results suggest a broader reach for PpIX as a biomarker for meningiomas than was previously noted in the literature.
doi:10.1227/NEU.0000000000000117
PMCID: PMC4237006  PMID: 23887194
5-Aminolevulinic acid; Biophotonics; Brain tumor; Fluorescence-guided surgery; Meningioma Optical spectroscopy; Protoporphyrin IX
5.  Fragmentation of Care and the Use of Head Computed Tomography in Patients With Ischemic Stroke 
Background
Computed tomographic (CT) scans are central diagnostic tests for ischemic stroke. Their inefficient use is a negative quality measure tracked by the Centers for Medicare and Medicaid Services.
Methods and Results
We performed a retrospective analysis of Medicare fee-for-service claims data for adults admitted for ischemic stroke from 2008 to 2009, with 1-year follow-up. The outcome measures were risk-adjusted rates of high-intensity CT use (≥4 head CT scans) and risk- and price-adjusted Medicare expenditures in the year after admission. The average number of head CT scans in the year after admission, for the 327 521 study patients, was 1.94, whereas 11.9% had ≥4. Risk-adjusted rates of high-intensity CT use ranged from 4.6% (Napa, CA) to 20.0% (East Long Island, NY). These rates were 2.6% higher for blacks than for whites (95% confidence interval, 2.1%–3.1%), with considerable regional variation. Higher fragmentation of care (number of different doctors seen) was associated with high-intensity CT use. Patients living in the top quintile regions of fragmentation experienced a 5.9% higher rate of high-intensity CT use, with the lowest quintile as reference; the corresponding odds ratio was 1.77 (95% confidence interval, 1.71–1.83). Similarly, 1-year risk- and price-adjusted expenditures exhibited considerable regional variation, ranging from $31 175 (Salem, MA) to $61 895 (McAllen, TX). Regional rates of high-intensity CT scans were positively associated with 1-year expenditures (r=0.56; P<0.01).
Conclusions
Rates of high-intensity CT use for patients with ischemic stroke reflect wide practice patterns across regions and races. Medicare expenditures parallel these disparities. Fragmentation of care is associated with high-intensity CT use.
doi:10.1161/CIRCOUTCOMES.113.000745
PMCID: PMC4236029  PMID: 24714599
Medicare; multidetector computed tomography; stroke
6.  Genome-wide admixture and ecological niche modelling reveal the maintenance of species boundaries despite long history of interspecific gene flow 
Molecular Ecology  2014;23(8):2046-2059.
The maintenance of species boundaries despite interspecific gene flow has been a continuous source of interest in evolutionary biology. Many hybridizing species have porous genomes with regions impermeable to introgression, conferring reproductive barriers between species. We used ecological niche modelling to study the glacial and postglacial recolonization patterns between the widely hybridizing spruce species Picea glauca and P. engelmannii in western North America. Genome-wide estimates of admixture based on a panel of 311 candidate gene single nucleotide polymorphisms (SNP) from 290 genes were used to assess levels of admixture and introgression and to identify loci putatively involved in adaptive differences or reproductive barriers between species. Our palaeoclimatic modelling suggests that these two closely related species have a long history of hybridization and introgression, dating to at least 21 000 years ago, yet species integrity is maintained by a combination of strong environmental selection and reduced current interspecific gene flow. Twenty loci showed evidence of divergent selection, including six loci that were both Fst outliers and associated with climatic gradients, and fourteen loci that were either outliers or showed associations with climate. These included genes responsible for carbohydrate metabolism, signal transduction and transcription factors.
doi:10.1111/mec.12710
PMCID: PMC4228761  PMID: 24597663
admixture; ecological niche modelling; outlier loci; spruce
7.  Temporal Pattern of Cocaine Intake Determines Tolerance vs Sensitization of Cocaine Effects at the Dopamine Transporter 
Neuropsychopharmacology  2013;38(12):2385-2392.
The dopamine transporter (DAT) is responsible for terminating dopamine (DA) signaling and is the primary site of cocaine's reinforcing actions. Cocaine self-administration has been shown previously to result in changes in cocaine potency at the DAT. To determine whether the DAT changes associated with self-administration are due to differences in intake levels or temporal patterns of cocaine-induced DAT inhibition, we manipulated cocaine access to produce either continuous or intermittent elevations in cocaine brain levels. Long-access (LgA, 6 h) and short-access (ShA, 2 h) continuous self-administration produced similar temporal profiles of cocaine intake that were sustained throughout the session; however, LgA had greater intake. ShA and intermittent-access (IntA, 6 h) produced the same intake, but different temporal profiles, with ‘spiking' brain levels in IntA compared with constant levels in ShA. IntA consisted of 5-min access periods alternating with 25-min timeouts, which resulted in bursts of high responding followed by periods of no responding. DA release and uptake, as well as the potency of cocaine for DAT inhibition, were assessed by voltammetry in the nucleus accumbens slices following control, IntA, ShA, and LgA self-administration. Continuous-access protocols (LgA and ShA) did not change DA parameters, but the ‘spiking' protocol (IntA) increased both release and uptake of DA. In addition, high continuous intake (LgA) produced tolerance to cocaine, while ‘spiking' (IntA) produced sensitization, relative to ShA and naive controls. Thus, intake and pattern can both influence cocaine potency, and tolerance seems to be produced by high intake, while sensitization is produced by intermittent temporal patterns of intake.
doi:10.1038/npp.2013.136
PMCID: PMC3799057  PMID: 23719505
Addiction & Substance Abuse; Animal models; Catecholamines; cocaine; Dopamine; dopamine transporter; nucleus accumbens; self-administration; voltammetry; self-administration; cocaine; voltammetry; dopamine; dopamine transporter; nucleus accumbens
8.  Conflation of Cocaine Seeking and Cocaine Taking Responses in IV Self-administration Experiments in Rats: Methodological and Interpretational Considerations 
Neuroscience and biobehavioral reviews  2013;37(0):10.1016/j.neubiorev.2013.04.017.
IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self-administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies.
doi:10.1016/j.neubiorev.2013.04.017
PMCID: PMC3838507  PMID: 23669047
cocaine; self-administration; addiction; consummatory behavior; appetitive behavior; drug seeking; drug taking; schedules of reinforcement; motivation; reward
9.  Human Herpes Simplex Virus Type 1 in Confiscated Gorilla 
Emerging Infectious Diseases  2014;20(11):1883-1886.
In 2007, we detected human herpes simplex virus type 1, which caused stomatitis, in a juvenile confiscated eastern lowland gorilla (Gorilla beringei graueri) that had a high degree of direct contact with human caretakers. Our findings confirm that pathogens can transfer between nonhuman primate hosts and humans.
doi:10.3201/eid2011.140075
PMCID: PMC4214296  PMID: 25341185
gorilla; herpes simplex virus; zoonoses; nonhuman primate; great ape; herpesvirus; Gorilla beringei,viruses
10.  Nipping Cue Reactivity in the Bud: Baclofen Prevents Limbic Activation Elicited by Subliminal Drug Cues 
The Journal of Neuroscience  2014;34(14):5038-5043.
Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen—a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals—could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing—that which occurs outside of awareness—before it evolves into a less manageable state.
doi:10.1523/JNEUROSCI.4977-13.2014
PMCID: PMC3972727  PMID: 24695721
addiction; baclofen; cocaine; cues; fMRI; subliminal
11.  The group II metabotropic glutamate receptor agonist, LY379268, decreases methamphetamine self-administration in rats 
Drug and alcohol dependence  2013;132(3):414-419.
Background
Given the problems associated with the escalation in methamphetamine (METH) use, the identification of more effective treatment strategies is essential. Group II metabotropic glutamate receptors (mGluRs) have been suggested to be a novel therapeutic target for psychostimulant addiction. We sought to test the ability of the selective group II mGluR agonist LY379268 to reduce METH self-administration in rats.
Methods
Rats were trained to self-administer METH on a progressive ratio (PR) schedule. Animals were then switched to fixed ratio responding and given daily extended access (6 h/day) to METH self-administration for 14 days. Rats were then re-tested on the PR schedule. The effect of LY379268 on METH-reinforced PR responding was determined before and after 14 days of extended access. To test for non-specific effects, a separate group of animals received LY379268 prior to a sucrose pellet-reinforced PR schedule.
Results
Animals escalated their daily intake of METH during extended access. PR responding did not change as a function of extended access. LY379268 significantly attenuated METH reinforced responding, both before and after extended access. The degree of attenuation did not change as a function of extended access. LY379268 had no effect on sucrose pellet-reinforced responding at any dose.
Conclusions
LY379268 selectively reduced the motivation to self-administer METH. In contrast to data with other compounds, the sensitivity to the effects of LY379268 did not change following extended access to METH self-administration. Group II mGluR agonists, therefore, may represent a relatively new class of compounds for the development of pharmacotherapies for METH addiction.
doi:10.1016/j.drugalcdep.2013.07.024
PMCID: PMC3804156  PMID: 23953655
methamphetamine; LY369268; self-administration; extended-access
12.  Comprehensive analysis of forty yeast microarray datasets reveals a novel subset of genes (APha-RiB) consistently negatively associated with ribosome biogenesis 
BMC Bioinformatics  2014;15(1):322.
Background
The scale and complexity of genomic data lend themselves to analysis using sophisticated mathematical techniques to yield information that can generate new hypotheses and so guide further experimental investigations. An ensemble clustering method has the ability to perform consensus clustering over the same set of genes from different microarray datasets by combining results from different clustering methods into a single consensus result.
Results
In this paper we have performed comprehensive analysis of forty yeast microarray datasets. One recently described Bi-CoPaM method can analyse expressions of the same set of genes from various microarray datasets while using different clustering methods, and then combine these results into a single consensus result whose clusters’ tightness is tunable from tight, specific clusters to wide, overlapping clusters. This has been adopted in a novel way over genome-wide data from forty yeast microarray datasets to discover two clusters of genes that are consistently co-expressed over all of these datasets from different biological contexts and various experimental conditions. Most strikingly, average expression profiles of those clusters are consistently negatively correlated in all of the forty datasets while neither profile leads or lags the other.
Conclusions
The first cluster is enriched with ribosomal biogenesis genes. The biological processes of most of the genes in the second cluster are either unknown or apparently unrelated although they show high connectivity in protein-protein and genetic interaction networks. Therefore, it is possible that this mostly uncharacterised cluster and the ribosomal biogenesis cluster are transcriptionally oppositely regulated by some common machinery. Moreover, we anticipate that the genes included in this previously unknown cluster participate in generic, in contrast to specific, stress response processes. These novel findings illuminate coordinated gene expression in yeast and suggest several hypotheses for future experimental functional work. Additionally, we have demonstrated the usefulness of the Bi-CoPaM-based approach, which may be helpful for the analysis of other groups of (microarray) datasets from other species and systems for the exploration of global genetic co-expression.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2105-15-322) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2105-15-322
PMCID: PMC4262117  PMID: 25267386
Ribosome biogenesis; Stress response; Co-expression; Co-regulation; Genome-wide analysis; Budding yeast; (Binarisation of consensus partition matrices) Bi-CoPaM
13.  The INTERVAL trial to determine whether intervals between blood donations can be safely and acceptably decreased to optimise blood supply: study protocol for a randomised controlled trial 
Trials  2014;15(1):363.
Background
Ageing populations may demand more blood transfusions, but the blood supply could be limited by difficulties in attracting and retaining a decreasing pool of younger donors. One approach to increase blood supply is to collect blood more frequently from existing donors. If more donations could be safely collected in this manner at marginal cost, then it would be of considerable benefit to blood services. National Health Service (NHS) Blood and Transplant in England currently allows men to donate up to every 12 weeks and women to donate up to every 16 weeks. In contrast, some other European countries allow donations as frequently as every 8 weeks for men and every 10 weeks for women. The primary aim of the INTERVAL trial is to determine whether donation intervals can be safely and acceptably decreased to optimise blood supply whilst maintaining the health of donors.
Methods/Design
INTERVAL is a randomised trial of whole blood donors enrolled from all 25 static centres of NHS Blood and Transplant. Recruitment of about 50,000 male and female donors started in June 2012 and was completed in June 2014. Men have been randomly assigned to standard 12-week versus 10-week versus 8-week inter-donation intervals, while women have been assigned to standard 16-week versus 14-week versus 12-week inter-donation intervals. Sex-specific comparisons will be made by intention-to-treat analysis of outcomes assessed after two years of intervention. The primary outcome is the number of blood donations made. A key secondary outcome is donor quality of life, assessed using the Short Form Health Survey. Additional secondary endpoints include the number of ‘deferrals’ due to low haemoglobin (and other factors), iron status, cognitive function, physical activity, and donor attitudes. A comprehensive health economic analysis will be undertaken.
Discussion
The INTERVAL trial should yield novel information about the effect of inter-donation intervals on blood supply, acceptability, and donors’ physical and mental well-being. The study will generate scientific evidence to help formulate blood collection policies in England and elsewhere.
Trial registration
Current Controlled Trials ISRCTN24760606, 25 January 2012.
doi:10.1186/1745-6215-15-363
PMCID: PMC4177700  PMID: 25230735
whole blood donation; randomised controlled trial; donation frequency; blood supply; donor well-being
14.  Estimating the prevalence of researcher misconduct: a study of UK academics within biological sciences 
PeerJ  2014;2:e562.
Misconduct in academic research is undoubtedly increasing, but studies estimating the prevalence of such behaviour suffer from biases inherent in researching sensitive topics. We compared the unmatched-count technique (UCT) and the crosswise-model (CM), two methods specifically designed to increase honest reporting to sensitive questions, with direct questioning (DQ) for five types of misconduct in the biological sciences. UCT performed better than CM and either outperformed or produced similar estimates to DQ depending on the question. Estimates of academic misconduct increased with decreasing seriousness of the behaviour, from c. 0% for data fabrication to >68% for inappropriate co-authorship. Results show that research into even minor issues of misconduct, is sensitive, suggesting that future studies should consider using specialised questioning techniques as they are more likely to yield accurate figures.
doi:10.7717/peerj.562
PMCID: PMC4168756  PMID: 25250215
Unmatched-count technique; Crosswise-model; Sensitive question; Ethics; List experiment
15.  Magnetic Resonance Imaging Confirms Loss of Blood- Brain Barrier Integrity in a Mouse Model of Disseminated Candidiasis 
NMR in biomedicine  2013;26(9):1125-1134.
Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood- brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI imaging using the extracellular vascular contrast agent Gd-DTPA demonstrated that integrity of the blood- brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by administering ultra-small iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across brain microvasculature, these imaging methods provide useful tools to further study the pathogenesis of C. albicans infections, define the roles of Candida virulence genes in kidney versus brain infection, and assess new therapeutic measures for drug development.
doi:10.1002/nbm.2926
PMCID: PMC3744627  PMID: 23606437
Candida albicans; murine disseminated candidiasis; blood- brain barrier; magnetic resonance imaging; extracellular vascular contrast agent Gd-DTPA; ultra small iron oxide particles; intravital two photon microscopy
16.  A Novel Survey Tool to Assess Pulmonary and Critical Care Fellows' Attitudes Regarding Acquiring Teaching Skills During Fellowship Training 
Background
Important components of fellowship training include learning teaching skills and career development. Pulmonary and critical care medicine (PCCM) fellows' opinions of the importance of developing teaching skills and interest in careers in medical education have not been previously described, and there are no tools to assess interest in acquiring teaching skills.
Objective
We describe the development and initial psychometric validation of a survey tool to assess trainees' attitudes toward and interest in acquiring teaching skills.
Methods
A survey tool to assess attitudes toward teaching and medical education skills was designed and psychometrically characterized. We then anonymously surveyed fellows in 1 PCCM program to assess their perceptions of and attitudes regarding acquiring teaching skills.
Results
The survey tool demonstrated acceptable psychometric properties. The survey showed that most fellows felt that acquiring teaching skills was “very important,” and nearly half reported being “interested” or “very interested” in pursuing careers as medical educators. However, fellows disagreed with the feedback they received from attending physicians with regard to their teaching abilities (10% disagreed with feedback at the beginning of the year, 36% disagreed at the end of the year; P  =  .03).
Conclusions
Our survey demonstrates acceptable psychometric properties and performance characteristics in a single-site study of PCCM fellows during 1 academic year. Fellows are interested in improving their teaching skills but do not know how to become better teachers. Added research in multiple settings should explore the generalizability of our findings.
doi:10.4300/JGME-D-12-00153.1
PMCID: PMC3771185  PMID: 24404319
17.  Tai chi mind-body exercise in patients with COPD: study protocol for a randomized controlled trial 
Trials  2014;15(1):337.
Background
Chronic obstructive pulmonary disease (COPD) is a chronic, progressively debilitating condition that is prevalent in the US and worldwide. Patients suffer from progressive dyspnea and exercise intolerance. Physical exercise is beneficial, but conventional pulmonary rehabilitation programs are underutilized. There remains a need for novel interventions that improve symptoms, quality-of-life, and functional capacity. Tai chi is an increasingly popular mind-body exercise that includes physical exercise, breathing training, mindful awareness, and stress management--components that are essential to the self-management of COPD. There are, however, limited data on the effectiveness of tai chi as a therapeutic intervention in this population.
Methods/Design
The Primary Aims are to evaluate the efficacy, safety, and feasibility of a 12-week tai chi program for patients with COPD. We utilize a randomized controlled trial design, with participants assigned in a 2:1 ratio to either a group tai chi program (N = 63) or a time/attention-matched education control (N = 31). Our primary outcomes are COPD-specific quality-of-life and exercise capacity. Secondary outcomes include dyspnea, mood, functional status, self-efficacy, and lung function. Cardiopulmonary exercise testing is done in a subset of patients (N = 50). To explore optimal training duration, a subgroup of patients in tai chi are randomly assigned to complete an additional 12 weeks training (total 24 weeks) (Exploratory Aim 1). To explore the impact of a simplified seated intervention including only a subset of tai chi’s training components, a third randomly assigned group (N = 31) receives a 12- week mind-body breathing program (N = 31) (Exploratory Aim 2).
Discussion
Results of the BEAM study (Breathing, Education, Awareness, Movement) will provide preliminary evidence regarding the value of tai chi for improving quality of life and exercise capacity in patients with COPD, including information regarding optimal duration. They will also inform the feasibility and potential benefit of an alternative mind-body breathing intervention, and provide insight regarding how isolated mind-body exercise components contribute to the overall effects of tai chi. Should the results be positive, tai chi and related mind-body practices may offer a novel exercise option that is potentially accessible to a large proportion of patients with COPD.
Trial registration
This trial is registered in Clinical Trials.gov, ID number NCT01551953. Date of Registration March 1 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-337) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-337
PMCID: PMC4158042  PMID: 25168853
Exercise; mind-body therapies; chronic obstructive pulmonary disease
18.  Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation 
Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S biosynthetic enzymes cystathionine β-synthase and cystathionine γ-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation.
doi:10.1016/j.matbio.2013.02.009
PMCID: PMC3706541  PMID: 23499828
Thrombospondin-1; CD47; Hydrogen sulfide; T lymphocytes; Extracellular signal-regulated kinase; Redox signaling
19.  Paradoxical tolerance to cocaine after initial supersensitivity in drug-use prone animals 
The European journal of neuroscience  2013;38(4):2628-2636.
There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a “drug-use prone” phenotype that is defined by rapid acquisition of cocaine self-administration. Here, we show that response to novelty can also predict neurochemical and behavioral effects of acute and repeated cocaine. We used cocaine self-administration under a fixed-ratio one schedule followed by fast scan cyclic voltammetry in brain slices to measure sub-second dopamine release and uptake parameters in drug-use prone and resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had dopamine transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self-administration more rapidly, and after five days of extended access cocaine self-administration, high responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we show that tolerance to cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.
doi:10.1111/ejn.12266
PMCID: PMC3748159  PMID: 23725404
Dopamine; Individual Differences; Voltammetry; Self-Administration; Dopamine Transporter; Rat
20.  The Sequential Application of Macroalgal Biosorbents for the Bioremediation of a Complex Industrial Effluent 
PLoS ONE  2014;9(7):e101309.
Fe-treated biochar and raw biochar produced from macroalgae are effective biosorbents of metalloids and metals, respectively. However, the treatment of complex effluents that contain both metalloid and metal contaminants presents a challenging scenario. We test a multiple-biosorbent approach to bioremediation using Fe-biochar and biochar to remediate both metalloids and metals from the effluent from a coal-fired power station. First, a model was derived from published data for this effluent to predict the biosorption of 21 elements by Fe-biochar and biochar. The modelled outputs were then used to design biosorption experiments using Fe-biochar and biochar, both simultaneously and in sequence, to treat effluent containing multiple contaminants in excess of water quality criteria. The waste water was produced during ash disposal at an Australian coal-fired power station. The application of Fe-biochar and biochar, either simultaneously or sequentially, resulted in a more comprehensive remediation of metalloids and metals compared to either biosorbent used individually. The most effective treatment was the sequential use of Fe-biochar to remove metalloids from the waste water, followed by biochar to remove metals. Al, Cd, Cr, Cu, Mn, Ni, Pb, Zn were reduced to the lowest concentration following the sequential application of the two biosorbents, and their final concentrations were predicted by the model. Overall, 17 of the 21 elements measured were remediated to, or below, the concentrations that were predicted by the model. Both metalloids and metals can be remediated from complex effluent using biosorbents with different characteristics but derived from a single feedstock. Furthermore, the extent of remediation can be predicted for similar effluents using additive models.
doi:10.1371/journal.pone.0101309
PMCID: PMC4111303  PMID: 25061756
21.  Hippocampal interictal epileptiform activity disrupts cognition in humans 
Neurology  2013;81(1):18-24.
Objective:
We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.
Methods:
Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.
Results:
Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p < 0.05) or bilateral (p < 0.001). Bilateral IED during the memory maintenance period had a similar effect (p < 0.01), particularly with spike-wave complexes of longer duration (p < 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.
Conclusions:
Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur.
doi:10.1212/WNL.0b013e318297ee50
PMCID: PMC3770206  PMID: 23685931
22.  Age-Associated Induction of Cell Membrane CD47 Limits Basal and Temperature-Induced Changes in Cutaneous Blood Flow 
Annals of surgery  2013;258(1):184-191.
Objective
We tested the hypothesis that the matricellular protein thrombospondin-1 (TSP1), through binding to and activation of the cell receptor CD47, inhibits basal and thermal-mediated cutaneous blood flow.
Background Data
Abnormal and decreased cutaneous blood flow in response to temperature changes or vasoactive agents is a feature of cardiovascular disease and aging. The reasons for decreased cutaneous blood flow remain incompletely understood. Further, a role for matricellular proteins in the regulation skin blood flow has never been proposed.
Methods
C57BL/6 wild type, TSP1- and CD47-null 12 and 72 week old male mice underwent analysis of skin blood flow (SkBF) via laser Doppler in response to thermal stress and vasoactive challenge.
Results
Young and aged TSP1- and CD47-null mice displayed enhanced basal and thermal sensitive SkFB changes compared to age matched wild type controls. Nitric oxide-mediated increases in SkBF were also greater in null mice. TSP1 and CD47 were expressed in skin from young wild type mice, and both were significantly upregulated in aged animals. Tissue 3',5'-cyclic guanosine monophosphate (cGMP), a potent vasodilator, was greater in skin samples from null mice compared to wild type regardless of age. Finally, treating wild type animals with a CD47 monoclonal antibody, that inhibits TSP1 activation of CD47, enhanced SkBF in both young and aged animals.
Conclusions
The above results suggest that secreted TSP1, via its cognate receptor CD47, acutely modulates SkBF. These data further support therapeutically targeting CD47 to mitigate age-associated loss of SkBF and maximize wound healing.
doi:10.1097/SLA.0b013e31827e52e1
PMCID: PMC3626753  PMID: 23275312
23.  Long-term seizure, cognitive, and psychiatric outcome following trans–middle temporal gyrus amygdalohippocampectomy and standard temporal lobectomy 
Journal of neurosurgery  2013;119(1):16-23.
Object
Previous comparisons of standard temporal lobectomy (STL) and selective amygdalohippocampectomy (SelAH) have been limited by inadequate long-term follow-up, variable definitions of favorable outcome, and inadequate consideration of psychiatric comorbidities.
Methods
The authors performed a retrospective analysis of seizure, cognitive, and psychiatric outcomes in a noncontemporaneous cohort of 69 patients with unilateral refractory temporal lobe epilepsy and MRI evidence of mesial temporal sclerosis after either an STL or an SelAH and examined seizure, cognitive, and psychiatric outcomes.
Results
The mean duration of follow-up for STL was 9.7 years (range 1–18 years), and for trans–middle temporal gyrus SelAH (mtg-SelAH) it was 6.85 years (range 1–15 years). There was no significant difference in seizure outcome when “favorable” was defined as time to loss of Engel Class I or II status; better seizure outcome was seen in the STL group when “favorable” was defined as time to loss of Engel Class IA status (p = 0.034). Further analysis revealed a higher occurrence of seizures solely during attempted medication withdrawal in the mtg-SelAH group than in the STL group (p = 0.016). The authors found no significant difference in the effect of surgery type on any cognitive and most psychiatric variables. Standard temporal lobectomy was associated with significantly higher scores on assessment of postsurgical paranoia (p = 0.048).
Conclusions
Overall, few differences in seizure, cognitive, and psychiatric outcome were found between STL and mtg-SelAH on long-term follow-up. Longer exposure to medication side effects after mtg-SelAH may adversely affect quality of life but is unlikely to cause additional functional impairment. In patients with high levels of presurgical psychiatric disease, mtg-SelAH may be the preferred surgery type.
doi:10.3171/2013.3.JNS12714
PMCID: PMC4074539  PMID: 23621601
middle temporal gyrus amygdalohippocampectomy; standard temporal lobectomy; seizure outcome; cognitive outcome; psychiatric outcome; epilepsy
24.  Bioremediation of a Complex Industrial Effluent by Biosorbents Derived from Freshwater Macroalgae 
PLoS ONE  2014;9(6):e94706.
Biosorption with macroalgae is a promising technology for the bioremediation of industrial effluents. However, the vast majority of research has been conducted on simple mock effluents with little data available on the performance of biosorbents in complex effluents. Here we evaluate the efficacy of dried biomass, biochar, and Fe-treated biomass and biochar to remediate 21 elements from a real-world industrial effluent from a coal-fired power station. The biosorbents were produced from the freshwater macroalga Oedogonium sp. (Chlorophyta) that is native to the industrial site from which the effluent was sourced, and which has been intensively cultivated to provide a feed stock for biosorbents. The effect of pH and exposure time on sorption was also assessed. These biosorbents showed specificity for different suites of elements, primarily differentiated by ionic charge. Overall, biochar and Fe-biochar were more successful biosorbents than their biomass counterparts. Fe-biochar adsorbed metalloids (As, Mo, and Se) at rates independent of effluent pH, while untreated biochar removed metals (Al, Cd, Ni and Zn) at rates dependent on pH. This study demonstrates that the biomass of Oedogonium is an effective substrate for the production of biosorbents to remediate both metals and metalloids from a complex industrial effluent.
doi:10.1371/journal.pone.0094706
PMCID: PMC4053327  PMID: 24919058
25.  Pulsed-light imaging for fluorescence guided surgery under normal room lighting 
Optics letters  2013;38(17):3249-3252.
Fluorescence guided surgery (FGS) is an emerging technology that has demonstrated improved surgical outcomes. However, dim lighting conditions required bycurrent FGS systems are disruptive to standard surgical workflow. We present a novel FGS system capable of imaging fluorescence under normal room lightby using pulsed excitation and gated acquisition. Images from tissue-simulating phantoms confirm visual detection down to 0.25 μM of protopor-phyrin IX under 125 μW/cm2 of ambient light, more than an order of magnitude lower than that measured with the Zeiss Pentero in the dark. Resection of orthotopic brain tumors in mice also suggests that the pulsed-light system provides superior sensitivity in vivo.
PMCID: PMC4051311  PMID: 23988926
(110.0110) Imaging systems; (110.2970) Image detection systems; (170.1610) Clinical applications; (170.3890) Medical optics instrumentation; (230.3670) Light-emitting diodes

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