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1.  Discrimination between adenocarcinoma and normal pancreatic ductal fluid by proteomic and glycomic analysis 
Journal of proteome research  2013;13(2):395-407.
Sensitive and specific biomarkers for pancreatic cancer are currently unavailable. The high mortality associated with adenocarcinoma of the pancreatic epithelium justifies the broadest possible search for new biomarkers that can facilitate early detection or monitor treatment efficacy. Protein glycosylation is altered in many cancers, leading many to propose that glycoproteomic changes may provide suitable biomarkers. In order to assess this possibility for pancreatic cancer, we have performed an in-depth LC-MS/MS analysis of the proteome and MSn-based characterization of the N-linked glycome of a small set of pancreatic ductal fluid obtained from normal, pancreatitis, intraductal papillary mucinous neoplasm (IPMN), and pancreatic adenocarcinoma patients. Our results identify a set of seven proteins that were consistently increased in cancer ductal fluid compared to normal (AMYP, PRSS1, GP2-1, CCDC132, REG1A, REG1B, and REG3A) and one protein that was consistently decreased (LIPR2). These proteins are all directly or indirectly associated with the secretory pathway in normal pancreatic cells. Validation of these changes in abundance by Western blotting revealed increased REG protein glycoform diversity in cancer. Characterization of the total N-linked glycome of normal, IPMN, and adenocarcinoma ductal fluid clustered samples into three discrete groups based on the prevalence of 6 dominant glycans. Within each group, the profiles of less prevalent glycans were able to distinguish normal from cancer on this small set of samples. Our results emphasize that individual variation in protein glycosylation must be considered when assessing the value of a glycoproteomic marker, but also indicate that glycosylation diversity across human subjects can be reduced to simpler clusters of individuals whose N-linked glycans share structural features.
doi:10.1021/pr400422g
PMCID: PMC3946306  PMID: 24328148
Pancreatic cancer; Proteomics; Biomarker; N-linked glycan; Glycomics
2.  Randomized controlled trial of a minimal versus extended Internet-based intervention for problem drinkers: study protocol 
BMC Public Health  2015;15:21.
Background
Problem drinking causes great harm to the person and to society. Most problem drinkers will never seek treatment. The current trial will test the efficacy of two Internet interventions for problem drinking – one minimal and the other extended – as an alternate means of providing help to those in need.
Methods/Design
A double blinded, four-wave panel design with random assignment to two experimental conditions will be used in this study. Participants will be recruited through a comprehensive recruitment strategy consisting of online and print advertisements asking for people who are ‘interested in helping us develop and evaluate Internet-based interventions for problem drinkers.’ Potential participants will be screened to select problem drinkers who have home access to the Internet. Participants will be sent to a password-protected Internet site and, upon signing in, will be randomized to be provided access to the minimal or extended Internet-based intervention. Six-month, twelve-month, and two-year drinking outcomes will be compared between experimental conditions. The primary hypothesis is that participants in the extended Internet intervention condition will display significantly improved drinking outcomes at twelve months compared to participants in the minimal intervention.
Discussion
The findings of this trial will contribute to the growing literature on Internet interventions for problem drinkers. In addition, findings from this trial will contribute to the scarce literature available evaluating the long-term efficacy of brief interventions for alcohol problems.
Trial registration
Clinical Trials.gov #NCT01874509; First submitted June 17, 2013.
doi:10.1186/s12889-015-1347-8
PMCID: PMC4308920  PMID: 25604206
3.  Treatment dismantling pilot study to identify the active ingredients in personalized feedback interventions for hazardous alcohol use: randomized controlled trial 
Background
There is a considerable body of evidence supporting the effectiveness of personalized feedback interventions for hazardous alcohol use—whether delivered face-to-face, by postal mail, or over the Internet (probably now the primary mode of delivery). The Check Your Drinking Screener (CYD; see www.CheckYourDrinking.net) is one such intervention.
Objectives
The current treatment dismantling study assessed which components of personalized feedback interventions were effective in motivating change in drinking. Specifically, the major objective of this project was to conduct a randomized controlled trial (RCT) comparing the impact of the normative feedback and other personalized feedback components of the CYD intervention in the general population.
Methods
Participants were recruited to take part in an RCT and received either the complete CYD final report, just the normative feedback sections of the CYD, just the personalized feedback components of the CYD, or were assigned to a no-intervention control group. Participants were followed-up at 3 months to assess changes in alcohol consumption.
Results
A total of 741 hazardous drinking participants were recruited for the trial, of which 73 percent provided follow-up data. Analyses using an intent-to-treat approach found some evidence for the impact of the personalized feedback components of the CYD in reducing alcohol consumption on the variables, number of drinks in a week and AUDIT-C (p = .028 and .047 respectively; no impact on highest number of drinks on one occasion; p = .594). However, there was no significant evidence of the impact of the normative feedback components (all p > .3).
Conclusions
Personalized feedback elements alone could provide an active intervention for hazardous drinkers, particularly in situations where normative feedback information was not available.
Trials registration
ClinicalTrials.gov NCT01608763.
Electronic supplementary material
The online version of this article (doi:10.1186/s13722-014-0022-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13722-014-0022-1
PMCID: PMC4288561  PMID: 25539597
Alcohol; Brief intervention; Internet; Randomized controlled trial; Mechanisms of change
4.  Deception in Human Experimental and Public Health Research on Alcohol Problems 
The American journal of bioethics : AJOB  2013;13(11):10.1080/15265161.2013.839757.
doi:10.1080/15265161.2013.839757
PMCID: PMC3822009  PMID: 24161182
5.  Computational prognostic indicators for breast cancer 
Breast cancer remains the leading cause of cancer-related mortality in women. Comprehensive genomics, proteomics, and metabolomics studies are emerging that offer an opportunity to model disease biology, prognosis, and response to specific therapies. Although many biomarkers have been identified through advances in data mining techniques, few have been applied broadly to make patient-specific decisions. Here, we review a selection of breast cancer prognostic indicators and their implications. Our goal is to provide clinicians with a general evaluation of emerging computational methodologies for outcome prediction.
doi:10.2147/CMAR.S46483
PMCID: PMC4103923  PMID: 25050076
computational model; precision prognosis; tumor
6.  Effectiveness of Guided and Unguided Low-Intensity Internet Interventions for Adult Alcohol Misuse: A Meta-Analysis 
PLoS ONE  2014;9(6):e99912.
Background
Alcohol misuse ranks within the top ten health conditions with the highest global burden of disease. Low-intensity, Internet interventions for curbing adult alcohol misuse have been shown effective. Few meta-analyses have been carried out, however, and they have involved small numbers of studies, lacked indicators of drinking within low risk guidelines, and examined the effectiveness of unguided self-help only. We therefore conducted a more thorough meta-analysis that included both guided and unguided interventions.
Methods
Systematic literature searches were performed up to September 2013. Primary outcome was the mean level of alcohol consumption and drinking within low risk guidelines for alcohol consumption at post-treatment.
Findings
We selected 16 randomised controlled trials (with 23 comparisons and 5,612 participants) for inclusion. Results, showed a small but significant overall effect size in favour of Internet interventions (g = 0.20, 95% CI: 0.13–0.27, p<.001). Participants in Internet interventions drunk on average 22 grams of ethanol less than controls and were significantly more likely to be adhering to low-risk drinking guidelines at post-treatment (RD 0.13, 95% CI: 0.09–0.17, p<.001). Subgroup analyses revealed no significant differences in potential moderators for the outcome of alcohol consumption, although there was a near-significant difference between comparisons with waitlist control and those with assessment-only or alcohol information control conditions (p = .056).
Conclusions
Internet interventions are effective in reducing adult alcohol consumption and inducing alcohol users to adhere to guidelines for low-risk drinking. This effect is small but from a public health point of view this may warrant large scale implementation at low cost of Internet interventions for adult alcohol misuse. Moderator analyses with sufficient power are, however, needed in order to assess the robustness of these overall results and to assess whether these interventions may impact on subgroups with different levels of success.
doi:10.1371/journal.pone.0099912
PMCID: PMC4061051  PMID: 24937483
7.  Intervention Adherence is Related to Participant Retention: Implications for Research 
doi:10.2196/jmir.2948
PMCID: PMC4051742  PMID: 24849941
research methods; randomized controlled trials; alcohol; Internet; brief intervention
8.  Effects of Late Gestational High Fat Diet on Body Weight, Metabolic Regulation and Adipokine Expression in Offspring 
International journal of obesity (2005)  2013;37(11):10.1038/ijo.2013.12.
Aims/Hypothesis
Gestational exposures such as dietary changes can alter offspring phenotype through epigenetic modifications and promote increased risk for specific diseases, such as metabolic syndrome. We hypothesized that high fat diet (HFD) during late gestation would lead increased risk for insulin resistance and hyperlipidemia via associated epigenetic alterations in tissue adipocytokine genes.
Methods
Offspring mice of mothers fed a HFD during late gestation (HFDO) were weighed and their food intake measured weekly till age 20 weeks at which time glucose and insulin tolerance tests, plasma lipid and adipocytokine levels were assessed, as well as mRNA expression in visceral fat. Adipocytokine gene methylation levels in visceral fat, liver, and muscle were also assayed.
Results
HFDO mice had increased weight accrual and food intake, and exhibited insulin resistance, hyperlipidemia, and hyperleptinemia, as well as hypoadiponectinemia. Furthermore, increased methylation of adiponectin and leptin receptor, and decreased methylation of leptin genes with unchanged GLP-1 methylation patterns emerged in HFDO mice.
Conclusions
Taken together, late gestational HFD induces increased risk of metabolic syndrome in the progeny, which is coupled with hypoadiponectinemia as well as with leptin resistance, and concomitant presence of selective tissue-based epigenetic changes among adipocytokine genes.
doi:10.1038/ijo.2013.12
PMCID: PMC3701742  PMID: 23399773
high fat diet; obesity; insulin resistance; leptin; adiponectin; epigenetics; DNA methylation; gestation
9.  Embryos, polyps and medusae of the Early Cambrian scyphozoan Olivooides 
The Early Cambrian organism Olivooides is known from both embryonic and post-embryonic stages and, consequently, it has the potential to yield vital insights into developmental evolution at the time that animal body plans were established. However, this potential can only be realized if the phylogenetic relationships of Olivooides can be constrained. The affinities of Olivooides have proved controversial because of the lack of knowledge of the internal anatomy and the limited range of developmental stages known. Here, we describe rare embryonic specimens in which internal anatomical features are preserved. We also present a fuller sequence of fossilized developmental stages of Olivooides, including associated specimens that we interpret as budding ephyrae (juvenile medusae), all of which display a clear pentaradial symmetry. Within the framework of a cnidarian interpretation, the new data serve to pinpoint the phylogenetic position of Olivooides to the scyphozoan stem group. Hypotheses about scalidophoran or echinoderm affinities of Olivooides can be rejected.
doi:10.1098/rspb.2013.0071
PMCID: PMC3619488  PMID: 23446532
Olivooides; cnidarian; scyphozoan; medusa; fossil; embryo
10.  New Connections Between Old Pathways: PDK1 Signaling Promotes Cellular Transformation through PLK1-Dependent MYC Stabilization 
Cancer discovery  2013;3(10):10.1158/2159-8290.CD-13-0581.
Summary
Limited understanding of the functional link between multiple oncogenic pathways is a major barrier in the ongoing effort of cancer biology to design an effective therapeutic approach to treat malignancies characterized by driver oncogenic network signals. In this issue of Cancer Discovery, Tan and colleagues elucidate a novel PDK1-PLK1-MYC signaling pathway connecting two fundamental oncogenic programs, PI3K and MYC. They define the functional role for PDK1-PLK1-MYC signaling in cancer cell survival and tumor formation to demonstrate the therapeutic benefit of inhibiting PDK1 and PLK1 pharmacologically in cancer, tackling the most undruggable tumors defined by elevated levels of the MYC oncoprotein.
doi:10.1158/2159-8290.CD-13-0581
PMCID: PMC3857155  PMID: 24124229
11.  A Novel Method for Curvefitting the Stretched Exponential Function to Experimental Data 
Biomedical engineering research  2013;2(4):153-158.
The stretched exponential function has many applications in modeling numerous types of experimental relaxation data. However, problems arise when using standard algorithms to fit this function: we have observed that different initializations result in distinct fitted parameters. To avoid this problem, we developed a novel algorithm for fitting the stretched exponential model to relaxation data. This method is advantageous both because it requires only a single adjustable parameter and because it does not require initialization in the solution space. We tested this method on simulated data and experimental stress-relaxation data from bone and cartilage and found favorable results compared to a commonly-used Quasi-Newton method. For the simulated data, strong correlations were found between the simulated and fitted parameters suggesting that this method can accurately determine stretched exponential parameters. When this method was tested on experimental data, high quality fits were observed for both bone and cartilage stress-relaxation data that were significantly better than those determined with the Quasi-Newton algorithm.
PMCID: PMC3966632  PMID: 24683538
Cartilage Biomechanics; Osteoarthritis; Curvefitting; Optimization; Polymer Dynamics
12.  Exploratory randomized controlled trial evaluating the impact of a waiting list control design 
Background
Employing waiting list control designs in psychological and behavioral intervention research may artificially inflate intervention effect estimates. This exploratory randomized controlled trial tested this proposition in a study employing a brief intervention for problem drinkers, one domain of research in which waiting list control designs are used.
Methods
All participants (N = 185) were provided with brief personalized feedback intervention materials after being randomly allocated either to be told that they were in the intervention condition and that this was the intervention or to be told that they were in the waiting list control condition and that they would receive access to the intervention in four weeks with this information provided in the meantime.
Results
A total of 157 participants (85%) were followed-up after 4 weeks. Between-group differences were found in one of four outcomes (proportion within safe drinking guidelines). An interaction was identified between experimental manipulation and stage of change at study entry such that participant change was arrested among those more ready to change and told they were on the waiting list.
Conclusions
Trials with waiting list control conditions may overestimate treatment effects, though the extent of any such bias appears likely to vary between study populations. Arguably they should only be used where this threat to valid inference has been carefully assessed.
doi:10.1186/1471-2288-13-150
PMCID: PMC4029562  PMID: 24314204
Randomized controlled trials; Research methods; Waiting list control design; Alternate explanation; Alcohol; Brief intervention
13.  A Prospective Natural History Study of Quitting or Reducing Gambling With or Without Treatment: Protocol 
JMIR Research Protocols  2013;2(2):e51.
Background
Only a small percentage of gamblers ever seek treatment, often due to stigma, embarrassment, or a desire to handle their problems on their own. While the majority of pathological gamblers who achieve remittance do so without accessing formal treatment, factors related to successful resolution have not been thoroughly explored.
Objective
Employing a prospective natural history design, the study will therefore undertake an investigation to explore life events, motivating factors, and strategies used by problem gamblers to quit or reduce their gambling without formal treatment.
Methods
Prospective participants (19 years or older) currently gambling at problematic levels with strong intentions toward quitting gambling will be directed to fill out a Web-based survey. Eligible participants will subsequently complete a survey that will assess: (1) types, frequency, and amount of money spent on gambling, (2) life events experienced in the past 12 months, (3) level of autonomous motivation for change, and (4) use of treatment services. Every 3 months for the duration of one year following the completion of their baseline survey, participants will be sent an email notification requesting them to complete a follow-up survey similar in content to the baseline survey. The four surveys will assess whether participants have experienced changes in their gambling behaviors along with positive or negative life events and motivations for change since the last survey. Individuals who are in the action and maintenance stages of quitting gambling at follow-up will be also asked about their techniques and strategies used to quit or reduce gambling. At 18 months post baseline, participants will be asked to complete a fifth and final follow-up survey that will also assess whether participants have experienced any barriers to change and whether they resolved their gambling to low risk levels.
Results
The study has commenced in May 2013 and is currently in the recruitment stage. The study is scheduled to conclude in 2016.
Conclusions
As this study will examine the active ingredients in natural recovery from gambling problems, the results will inform ways of promoting change among the large number of problem gamblers who do not seek treatment as well as improve treatment for those who do seek help. The information gained will also be useful in identifying effective self-help strategies for those who face challenges in accessing treatment, may be incorporated in standard treatment, provide brief intervention techniques, as well as inform relapse prevention strategies.
doi:10.2196/resprot.2727
PMCID: PMC3868981  PMID: 24297873
gambling; treatment; life events; motivational factors; natural recovery; prospective natural history study; longitudinal study
14.  Disruption of Growth Factor Receptor–Binding Protein 10 in the Pancreas Enhances β-Cell Proliferation and Protects Mice From Streptozotocin-Induced β-Cell Apoptosis 
Diabetes  2012;61(12):3189-3198.
Defects in insulin secretion and reduction in β-cell mass are associated with type 2 diabetes in humans, and understanding the basis for these dysfunctions may reveal strategies for diabetes therapy. In this study, we show that pancreas-specific knockout of growth factor receptor–binding protein 10 (Grb10), which is highly expressed in pancreas and islets, leads to elevated insulin/IGF-1 signaling in islets, enhanced β-cell mass and insulin content, and increased insulin secretion in mice. Pancreas-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high-fat diet and protected mice from streptozotocin-induced β-cell apoptosis and body weight loss. Our study has identified Grb10 as an important regulator of β-cell proliferation and demonstrated that reducing the expression level of Grb10 could provide a novel means to increase β-cell mass and reduce β-cell apoptosis. This is critical for effective therapeutic treatment of both type 1 and 2 diabetes.
doi:10.2337/db12-0249
PMCID: PMC3501856  PMID: 22923474
15.  Effect of remote ischaemic conditioning on contrast-induced nephropathy in patients undergoing elective coronary angiography (ERICCIN): rationale and study design of a randomised single-centre, double-blind placebo-controlled trial 
Clinical Research in Cardiology  2013;103(3):203-209.
Background
Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is an important cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for an effective intervention. Remote ischaemic conditioning (RIC), where non-injurious ischaemia is applied to an arm prior to the administration of contrast, has shown promise in attenuating CIN but its effectiveness in preserving long-term renal function is unknown, which will be studied as part of the effect of remote ischaemic conditioning against contrast-induced nephropathy (ERICCIN) trial. (http://Controlled-trials.com Identifier: ISRCTN49645414.)
Methods
The ERICCIN trial is a single-centre, randomised double-blinded placebo-controlled trial which plans to recruit 362 patients who are at risk of CIN, defined by pre-existent renal impairment (estimated glomerular filtration rate <60 ml/min/1.73 m2), over a period of 2 years. Patients will be randomised to either control or RIC consisting of 4, 5 min 200 mmHg balloon-cuff inflation/deflations, to the upper arm. The primary endpoint will be the development of CIN (>25 % of eGFR, or rise of creatinine of >44 μmol/l) at 48 h. A key secondary endpoint will be whether RIC impacts upon persistent renal impairment over the 3-month follow-up period. Additional secondary endpoints include the measurement of serum neutrophil gelatinase-associated lipocalin and urinary albumin at 6, 48 h and 3 months following administration of contrast.
Implications
Findings from ERICCIN trial will potentially demonstrate that RIC attenuates contrast-induced acute and chronic kidney injury and influence future clinical practice guidelines in at-risk patients undergoing coronary angiographic procedures.
doi:10.1007/s00392-013-0637-3
PMCID: PMC3937541  PMID: 24292557
Remote ischaemic conditioning; Preconditioning; Contrast-induced nephropathy; Acute kidney injury; Clinical trial; Coronary angiography; Percutaneous intervention
16.  Testing models of dental development in the earliest bony vertebrates, Andreolepis and Lophosteus 
Biology Letters  2012;8(5):833-837.
Theories on the development and evolution of teeth have long been biased by the fallacy that chondrichthyans reflect the ancestral condition for jawed vertebrates. However, correctly resolving the nature of the primitive vertebrate dentition is challenged by a dearth of evidence on dental development in primitive osteichthyans. Jaw elements from the Silurian–Devonian stem-osteichthyans Lophosteus and Andreolepis have been described to bear a dentition arranged in longitudinal rows and vertical files, reminiscent of a pattern of successional development. We tested this inference, using synchrotron radiation X-ray tomographic microscopy (SRXTM) to reveal the pattern of skeletal development preserved in the sclerochronology of the mineralized tissues. The tooth-like tubercles represent focal elaborations of dentine within otherwise continuous sheets of the dermal skeleton, present in at least three stacked generations. Thus, the tubercles are not discrete modular teeth and their arrangement into rows and files is a feature of the dermal ornamentation that does not reflect a polarity of development or linear succession. These fossil remains have no bearing on the nature of the dentition in osteichthyans and, indeed, our results raise questions concerning the homologies of these bones and the phylogenetic classification of Andreolepis and Lophosteus.
doi:10.1098/rsbl.2012.0357
PMCID: PMC3440983  PMID: 22628098
Osteichthyes; Andreolepis; Lophosteus; tooth; development; evolution
17.  Claiming Positive Results From Negative Trials: A Cause for Concern in Randomized Controlled Trial Research 
doi:10.2196/jmir.2845
PMCID: PMC3758039  PMID: 23958686
research methods; randomised controlled trials; alcohol; Internet; brief intervention
18.  Use of mobile devices to answer online surveys: implications for research 
BMC Research Notes  2013;6:258.
Background
There is a growing use of mobile devices to access the Internet. We examined whether participants who used a mobile device to access a brief online survey were quicker to respond to the survey but also, less likely to complete it than participants using a traditional web browser.
Findings
Using data from a recently completed online intervention trial, we found that participants using mobile devices were quicker to access the survey but less likely to complete it compared to participants using a traditional web browser. More concerning, mobile device users were also less likely to respond to a request to complete a six week follow-up survey compared to those using traditional web browsers.
Conclusions
With roughly a third of participants using mobile devices to answer an online survey in this study, the impact of mobile device usage on survey completion rates is a concern.
Trial registration
ClinicalTrials.gov: NCT01521078
doi:10.1186/1756-0500-6-258
PMCID: PMC3708744  PMID: 23834999
Internet; Brief intervention; Alcohol; College; University; Mobile device
19.  The Systematic Removal of Participants Post-Randomization Can Lead to Alternate Explanations of the Results 
doi:10.2196/jmir.2631
PMCID: PMC3713941  PMID: 23796473
research methods; randomized controlled trial; confound; alternate explanation
20.  Distinguishing geology from biology in the Ediacaran Doushantuo biota relaxes constraints on the timing of the origin of bilaterians 
The Ediacaran Doushantuo biota has yielded fossils that include the oldest widely accepted record of the animal evolutionary lineage, as well as specimens with alleged bilaterian affinity. However, these systematic interpretations are contingent on the presence of key biological structures that have been reinterpreted by some workers as artefacts of diagenetic mineralization. On the basis of chemistry and crystallographic fabric, we characterize and discriminate phases of mineralization that reflect: (i) replication of original biological structure, and (ii) void-filling diagenetic mineralization. The results indicate that all fossils from the Doushantuo assemblage preserve a complex mélange of mineral phases, even where subcellular anatomy appears to be preserved. The findings allow these phases to be distinguished in more controversial fossils, facilitating a critical re-evaluation of the Doushantuo fossil assemblage and its implications as an archive of Ediacaran animal diversity. We find that putative subcellular structures exhibit fabrics consistent with preservation of original morphology. Cells in later developmental stages are not in original configuration and are therefore uninformative concerning gastrulation. Key structures used to identify Doushantuo bilaterians can be dismissed as late diagenetic artefacts. Therefore, when diagenetic mineralization is considered, there is no convincing evidence for bilaterians in the Doushantuo assemblage.
doi:10.1098/rspb.2011.2280
PMCID: PMC3350665  PMID: 22319125
Ediacaran; Doushantuo; Bilateria; fossilization; diagenesis
21.  A High-Performance Neural Prosthesis Enabled by Control Algorithm Design 
Nature neuroscience  2012;15(12):1752-1757.
Neural prostheses translate neural activity from the brain into control signals for guiding prosthetic devices, such as computer cursors and robotic limbs, and thus offer disabled patients greater interaction with the world. However, relatively low performance remains a critical barrier to successful clinical translation; current neural prostheses are considerably slower with less accurate control than the native arm. Here we present a new control algorithm, the recalibrated feedback intention-trained Kalman filter (ReFIT-KF), that incorporates assumptions about the nature of closed loop neural prosthetic control. When tested with rhesus monkeys implanted with motor cortical electrode arrays, the ReFIT-KF algorithm outperforms existing neural prostheses in all measured domains and halves acquisition time. This control algorithm permits sustained uninterrupted use for hours and generalizes to more challenging tasks without retraining. Using this algorithm, we demonstrate repeatable high performance for years after implantation across two monkeys, thereby increasing the clinical viability of neural prostheses.
doi:10.1038/nn.3265
PMCID: PMC3638087  PMID: 23160043
22.  p19Arf Represses Platelet-Derived Growth Factor Receptor β by Transcriptional and Posttranscriptional Mechanisms 
Molecular and Cellular Biology  2012;32(21):4270-4282.
In addition to cancer surveillance, p19Arf plays an essential role in blocking signals stemming from platelet-derived growth factor receptor β (Pdgfrβ) during eye development, but the underlying mechanisms have not been clear. We now show that without Arf, pericyte hyperplasia in the eye results from enhanced Pdgfrβ-dependent proliferation from embryonic day 13.5 (E13.5) of mouse development. Loss of Arf in the eye increases Pdgfrβ expression. In cultured fibroblasts and pericyte-like cells, ectopic p19Arf represses and Arf knockdown enhances the expression of Pdgfrβ mRNA and protein. Ectopic Arf also represses primary Pdgfrβ transcripts and a plasmid driven by a minimal promoter, including one missing the CCAAT element required for high-level expression. p19Arf uses both p53-dependent and -independent mechanisms to control Pdgfrβ. In vivo, without p53, Pdgfrβ mRNA is elevated and eye development abnormalities resemble the Arf −/− phenotype. However, effects of p53 on Pdgfrβ mRNA do not appear to be due to direct p53 or RNA polymerase II recruitment to the promoter. Although p19Arf controls Pdgfrβ mRNA in a p53-dependent manner, it also blunts Pdgfrβ protein expression by blocking new protein synthesis in the absence of p53. Thus, our findings demonstrate a novel capacity for p19Arf to control Pdgfrβ expression by p53-dependent and -independent mechanisms involving RNA transcription and protein synthesis, respectively, to promote the vascular remodeling needed for normal vision.
doi:10.1128/MCB.06424-11
PMCID: PMC3486135  PMID: 22907756
23.  Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling 
Cell Metabolism  2012;15(4):505-517.
SUMMARY
Rapamycin and derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice leads to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as IGFs, IRS1/2 and AKTs. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increases in genes in this cascade that, in contrast to wild-type mice, were not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 tri-methylation leading to decreases in gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes, such as longevity.
doi:10.1016/j.cmet.2012.03.008
PMCID: PMC3324784  PMID: 22482732
24.  Bridging Cancer Biology with the Clinic: Relative Expression of a GRHL2-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis 
PLoS ONE  2013;8(2):e56195.
Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.
doi:10.1371/journal.pone.0056195
PMCID: PMC3575392  PMID: 23441166
25.  Defective Mitochondrial Morphology and Bioenergetic Function in Mice Lacking the Transcription Factor Yin Yang 1 in Skeletal Muscle 
Molecular and Cellular Biology  2012;32(16):3333-3346.
The formation, distribution, and maintenance of functional mitochondria are achieved through dynamic processes that depend strictly on the transcription of nuclear genes encoding mitochondrial proteins. A large number of these mitochondrial genes contain binding sites for the transcription factor Yin Yang 1 (YY1) in their proximal promoters, but the physiological relevance is unknown. We report here that skeletal-muscle-specific YY1 knockout (YY1mKO) mice have severely defective mitochondrial morphology and oxidative function associated with exercise intolerance, signs of mitochondrial myopathy, and short stature. Gene set enrichment analysis (GSEA) revealed that the top pathways downregulated in YY1mKO mice were assigned to key metabolic and regulatory mitochondrial genes. This analysis was consistent with a profound decrease in the level of mitochondrial proteins and oxidative phosphorylation (OXPHOS) bioenergetic function in these mice. In contrast to the finding for wild-type mice, inactivation of the mammalian target of rapamycin (mTOR) did not suppress mitochondrial genes in YY1mKO mice. Mechanistically, mTOR-dependent phosphorylation of YY1 resulted in a strong interaction between YY1 and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1α (PGC1α), a major regulator of mitochondrial function. These results underscore the important role of YY1 in the maintenance of mitochondrial function and explain how its inactivation might contribute to exercise intolerance and mitochondrial myopathies.
doi:10.1128/MCB.00337-12
PMCID: PMC3434543  PMID: 22711985

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