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1.  Experimental taphonomy of Artemia reveals the role of endogenous microbes in mediating decay and fossilization 
Exceptionally preserved fossils provide major insights into the evolutionary history of life. Microbial activity is thought to play a pivotal role in both the decay of organisms and the preservation of soft tissue in the fossil record, though this has been the subject of very little experimental investigation. To remedy this, we undertook an experimental study of the decay of the brine shrimp Artemia, examining the roles of autolysis, microbial activity, oxygen diffusion and reducing conditions. Our findings indicate that endogenous gut bacteria are the main factor controlling decay. Following gut wall rupture, but prior to cuticle failure, gut-derived microbes spread into the body cavity, consuming tissues and forming biofilms capable of mediating authigenic mineralization, that pseudomorph tissues and structures such as limbs and the haemocoel. These observations explain patterns observed in exceptionally preserved fossil arthropods. For example, guts are preserved relatively frequently, while preservation of other internal anatomy is rare. They also suggest that gut-derived microbes play a key role in the preservation of internal anatomy and that differential preservation between exceptional deposits might be because of factors that control autolysis and microbial activity. The findings also suggest that the evolution of a through gut and its bacterial microflora increased the potential for exceptional fossil preservation in bilaterians, providing one explanation for the extreme rarity of internal preservation in those animals that lack a through gut.
PMCID: PMC4455810  PMID: 25972468
Cambrian explosion; palaeobiology; taphonomy; bilateria; metazoa
2.  Encoder-Decoder Optimization for Brain-Computer Interfaces 
PLoS Computational Biology  2015;11(6):e1004288.
Neuroprosthetic brain-computer interfaces are systems that decode neural activity into useful control signals for effectors, such as a cursor on a computer screen. It has long been recognized that both the user and decoding system can adapt to increase the accuracy of the end effector. Co-adaptation is the process whereby a user learns to control the system in conjunction with the decoder adapting to learn the user's neural patterns. We provide a mathematical framework for co-adaptation and relate co-adaptation to the joint optimization of the user's control scheme ("encoding model") and the decoding algorithm's parameters. When the assumptions of that framework are respected, co-adaptation cannot yield better performance than that obtainable by an optimal initial choice of fixed decoder, coupled with optimal user learning. For a specific case, we provide numerical methods to obtain such an optimized decoder. We demonstrate our approach in a model brain-computer interface system using an online prosthesis simulator, a simple human-in-the-loop pyschophysics setup which provides a non-invasive simulation of the BCI setting. These experiments support two claims: that users can learn encoders matched to fixed, optimal decoders and that, once learned, our approach yields expected performance advantages.
Author Summary
Brain-computer interfaces are systems which allow a user to control a device in their environment via their neural activity. The system consists of hardware used to acquire signals from the brain of the user, algorithms to decode the signals, and some effector in the world that the user will be able to control, such as a cursor on a computer screen. When the user can see the effector under control, the system is closed-loop, such that the user can learn based on discrepancies between intended and actual kinematic outcomes. During training sessions where the user has specified objectives, the decoding algorithm can be updated as well based on discrepancies between what the user is supposed to be doing and what was decoded. When both the user and the decoding algorithm are simultaneously co-adapting, performance can improve. We propose a mathematical framework which contextualizes co-adaptation as a joint optimization of the user’s control scheme and the decoding algorithm, and we relate co-adaptation to optimal, fixed (non-adaptive) choices of decoder. We use simulation and human psychophysics experiments intended to model the BCI setting to demonstrate the utility of this approach.
PMCID: PMC4451011  PMID: 26029919
3.  Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles 
BMC Medical Genomics  2015;8(Suppl 2):S6.
Therapy-related, secondary acute myeloid leukemia (t-AML) is an increasingly frequent complication of intensive chemotherapy. This malignancy is often characterized by abnormalities of chromosome 7, including large deletions or chromosomal loss. A variety of studies suggest that decreased expression of the EZH2 gene located at 7q36.1 is critical in disease pathogenesis. This histone methyltransferase has been implicated in transcriptional repression through modifying histone H3 on lysine 27 (H3k27). However, the critical target genes of EZH2 and their regulatory roles remain unclear.
To characterize the subset of EZH2 target genes that might contribute to t-AML pathogenesis, we developed a novel computational analysis to integrate tissue-specific histone modifications and genome-wide transcriptional regulation. Initial integrative analysis utilized a novel "seq2gene" strategy to explore largely the target genes of chromatin immuneprecipitation sequencing (ChIP-seq) enriched regions. By combining seq2gene with our Phenotype-Genotype-Network (PGNet) algorithm, we enriched genes with similar expression profiles and genomic or functional characteristics into "biomodules".
Initial studies identified SEMA3A (semaphoring 3A) as a novel oncogenic candidate that is regulated by EZH2-silencing, using data derived from both normal and leukemic cell lines as well as murine cells deficient in EZH2. A microsatellite marker at the SEMA3A promoter has been associated with chemosensitivity and radiosensitivity. Notably, our subsequent studies in primary t-AML demonstrate an expected up-regulation of SEMA3A that is EZH2-modulated. Furthermore, we have identified three biomodules that are co-expressed with SEMA3A and up-regulated in t-AML, one of which consists of previously characterized EZH2-repressed gene targets. The other two biomodules include MAPK8 and TATA box targets. Together, our studies suggest an important role for EZH2 targets in t-AML pathogenesis that warrants further study.
These developed computational algorithms and systems biology strategies will enhance the knowledge discovery and hypothesis-driven analysis of multiple next generation sequencing data, for t-AML and other complex diseases.
PMCID: PMC4460748  PMID: 26043758
computational biology; t-AML; EZH2; H3K27me3; SEMA3A
4.  Protein and nucleotide biosynthesis are coupled through a single rate limiting enzyme, PRPS2, to drive cancer 
Cell  2014;157(5):1088-1103.
Cancer cells must integrate multiple biosynthetic demands to drive indefinite proliferation. An outstanding question is how these key cellular processes such as metabolism and protein synthesis cross-talk to fuel cancer cell growth. Here we uncover the mechanism by which the MYC oncogene coordinates the production of the two most abundant classes of cellular macromolecules, proteins and nucleic acids in cancer cells. We find that a single rate-limiting enzyme, phosphoribosyl-pyrophosphate synthetase 2 (PRPS2), promotes increased nucleotide biosynthesis in MYC-transformed cells. Remarkably, Prps2 couples protein and nucleotide biosynthesis through a specialized cis-regulatory element within the Prps2 5′UTR, which is controlled by the oncogene and translation initiation factor eIF4E downstream Myc activation. We demonstrate with a Prps2 knockout mouse that the nexus between protein and nucleotide biosynthesis controlled by PRPS2 is crucial for Myc-driven tumorigenesis. Together, these studies identify a translationally-anchored anabolic circuit critical for cancer cell survival and an unexpected vulnerability for “undruggable” oncogenes, such as Myc.
PMCID: PMC4140650  PMID: 24855946
5.  Web-Based Alcohol Screening and Brief Intervention for University Students 
JAMA  2014;311(12):1218-1224.
Unhealthy alcohol use is a leading contributor to the global burden of disease, particularly among young people. Systematic reviews suggest efficacy of web-based alcohol screening and brief intervention and call for effectiveness trials in settings where it could be sustainably delivered.
To evaluate a national web-based alcohol screening and brief intervention program.
A multisite, double-blind, parallel-group, individually randomized trial was conducted at 7 New Zealand universities. In April and May of 2010, invitations containing hyperlinks to the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) screening test were e-mailed to 14 991 students aged 17 to 24 years.
Participants who screened positive (AUDIT-C score ≥4) were randomized to undergo screening alone or to 10 minutes of assessment and feedback (including comparisons with medical guidelines and peer norms) on alcohol expenditure, peak blood alcohol concentration, alcohol dependence, and access to help and information.
A fully automated 5-month follow-up assessment was conducted that measured 6 primary outcomes: consumption per typical occasion, drinking frequency, volume of alcohol consumed, an academic problems score, and whether participants exceeded medical guidelines for acute harm (binge drinking) and chronic harm (heavy drinking). A Bonferroni-corrected significance threshold of .0083 was used to account for the 6 comparisons and a sensitivity analysis was used to assess possible attrition bias.
Of 5135 students screened, 3422 scored 4 or greater and were randomized, and 83% were followed up. There was a significant effect on 1 of the 6 prespecified outcomes. Relative to control participants, those who received intervention consumed less alcohol per typical drinking occasion (median 4 drinks [interquartile range {IQR}, 2-8] vs 5 drinks [IQR 2-8]; rate ratio [RR], 0.93 [99.17% CI, 0.86-1.00]; P = .005) but not less often (RR, 0.95 [99.17% CI, 0.88-1.03]; P = .08) or less overall (RR, 0.95 [99.17% CI, 0.81-1.10]; P = .33). Academic problem scores were not lower (RR, 0.91 [99.17% CI, 0.76-1.08]; P = .14) and effects on the risks of binge drinking (odds ratio [OR], 0.84 [99.17% CI, 0.67-1.05]; P = .04) and heavy drinking (OR, 0.77 [99.17% CI, 0.56-1.05]; P = .03) were not significantly significant. In a sensitivity analysis accounting for attrition, the effect on alcohol per typical drinking occasion was no longer statistically significant.
A national web-based alcohol screening and brief intervention program produced no significant reductions in the frequency or overall volume of drinking or academic problems. There remains a possibility of a small reduction in the amount of alcohol consumed per typical drinking occasion.
PMCID: PMC4413370  PMID: 24668103
6.  The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun 
Nature medicine  2012;18(11):1643-1650.
Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling–related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling–related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure.
PMCID: PMC4401084  PMID: 23086477
7.  Investigating Myc-Dependent Translational Regulation in Normal and Cancer Cells 
There is an increasing realization that a primary role for Myc in driving cellular growth and cell cycle progression relies on Myc’s ability to increase the rate of protein synthesis. Myc induces myriad changes in both global and specific mRNA translation. Herein, we present three assays that allow researchers to measure changes in protein synthesis at the global level as well as alterations in the translation of specific mRNAs. Metabolic labeling of cells with 35S-containing methionine and cysteine is presented as a method to measure the overall rate of global protein synthesis. The bicistronic reporter assay is employed to determine levels of cap-dependent and cap-independent translation initiation in the cell. Finally, isolation of polysome-associated mRNAs followed by next-generation sequencing, microarray or quantitative real-time PCR (qRT-PCR) analysis is utilized to detect changes in the abundance of specific mRNAs that are regulated upon Myc hyperactivation. The protocols described in this chapter can be used to understand how and to what extent Myc-dependent regulation of translation influences normal cellular functions as well as tumorigenesis.
PMCID: PMC4390065  PMID: 24006066
Myc; Translation; Protein synthesis; Ribosome
8.  Systematic computation with functional gene-sets among leukemic and hematopoietic stem cells reveals a favorable prognostic signature for acute myeloid leukemia 
BMC Bioinformatics  2015;16(1):97.
Genes that regulate stem cell function are suspected to exert adverse effects on prognosis in malignancy. However, diverse cancer stem cell signatures are difficult for physicians to interpret and apply clinically. To connect the transcriptome and stem cell biology, with potential clinical applications, we propose a novel computational “gene-to-function, snapshot-to-dynamics, and biology-to-clinic” framework to uncover core functional gene-sets signatures. This framework incorporates three function-centric gene-set analysis strategies: a meta-analysis of both microarray and RNA-seq data, novel dynamic network mechanism (DNM) identification, and a personalized prognostic indicator analysis. This work uses complex disease acute myeloid leukemia (AML) as a research platform.
We introduced an adjustable “soft threshold” to a functional gene-set algorithm and found that two different analysis methods identified distinct gene-set signatures from the same samples. We identified a 30-gene cluster that characterizes leukemic stem cell (LSC)-depleted cells and a 25-gene cluster that characterizes LSC-enriched cells in parallel; both mark favorable-prognosis in AML. Genes within each signature significantly share common biological processes and/or molecular functions (empirical p = 6e-5 and 0.03 respectively). The 25-gene signature reflects the abnormal development of stem cells in AML, such as AURKA over-expression. We subsequently determined that the clinical relevance of both signatures is independent of known clinical risk classifications in 214 patients with cytogenetically normal AML. We successfully validated the prognosis of both signatures in two independent cohorts of 91 and 242 patients respectively (log-rank p < 0.0015 and 0.05; empirical p < 0.015 and 0.08).
The proposed algorithms and computational framework will harness systems biology research because they efficiently translate gene-sets (rather than single genes) into biological discoveries about AML and other complex diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s12859-015-0510-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4376348  PMID: 25887548
Functional gene-set; Dynamic network biomarker; Relative effect analysis; Leukemic stem cell; AML outcome
9.  On-Chip Picosecond Pulse Detection and Generation Using Graphene Photoconductive Switches 
Nano Letters  2015;15(3):1591-1596.
We report on the use of graphene for room temperature on-chip detection and generation of pulsed terahertz (THz) frequency radiation, exploiting the fast carrier dynamics of light-generated hot carriers, and compare our results with conventional low-temperature-grown gallium arsenide (LT-GaAs) photoconductive (PC) switches. Coupling of picosecond-duration pulses from a biased graphene PC switch into Goubau line waveguides is also demonstrated. A Drude transport model based on the transient photoconductance of graphene is used to describe the mechanism for both detection and generation of THz radiation.
PMCID: PMC4370719  PMID: 25710079
Graphene; on-chip; THz detection; GaAs; Goubau line; photoconductive switch
10.  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.
PMCID: PMC3946306  PMID: 24328148
Pancreatic cancer; Proteomics; Biomarker; N-linked glycan; Glycomics
11.  Randomized controlled trial of a minimal versus extended Internet-based intervention for problem drinkers: study protocol 
BMC Public Health  2015;15:21.
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.
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.
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 #NCT01874509; First submitted June 17, 2013.
PMCID: PMC4308920  PMID: 25604206
12.  Treatment dismantling pilot study to identify the active ingredients in personalized feedback interventions for hazardous alcohol use: randomized controlled trial 
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 is one such intervention.
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.
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.
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).
Personalized feedback elements alone could provide an active intervention for hazardous drinkers, particularly in situations where normative feedback information was not available.
Trials registration 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.
PMCID: PMC4288561  PMID: 25539597
Alcohol; Brief intervention; Internet; Randomized controlled trial; Mechanisms of change
13.  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.
PMCID: PMC3822009  PMID: 24161182
14.  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.
PMCID: PMC4103923  PMID: 25050076
computational model; precision prognosis; tumor
15.  Effectiveness of Guided and Unguided Low-Intensity Internet Interventions for Adult Alcohol Misuse: A Meta-Analysis 
PLoS ONE  2014;9(6):e99912.
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.
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.
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).
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.
PMCID: PMC4061051  PMID: 24937483
16.  Intervention Adherence is Related to Participant Retention: Implications for Research 
PMCID: PMC4051742  PMID: 24849941
research methods; randomized controlled trials; alcohol; Internet; brief intervention
17.  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.
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.
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.
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.
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.
PMCID: PMC3701742  PMID: 23399773
high fat diet; obesity; insulin resistance; leptin; adiponectin; epigenetics; DNA methylation; gestation
18.  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.
PMCID: PMC3619488  PMID: 23446532
Olivooides; cnidarian; scyphozoan; medusa; fossil; embryo
19.  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.
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.
PMCID: PMC3857155  PMID: 24124229
20.  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
21.  Exploratory randomized controlled trial evaluating the impact of a waiting list control design 
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.
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.
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.
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.
PMCID: PMC4029562  PMID: 24314204
Randomized controlled trials; Research methods; Waiting list control design; Alternate explanation; Alcohol; Brief intervention
22.  A Prospective Natural History Study of Quitting or Reducing Gambling With or Without Treatment: Protocol 
JMIR Research Protocols  2013;2(2):e51.
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.
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.
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.
The study has commenced in May 2013 and is currently in the recruitment stage. The study is scheduled to conclude in 2016.
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.
PMCID: PMC3868981  PMID: 24297873
gambling; treatment; life events; motivational factors; natural recovery; prospective natural history study; longitudinal study
23.  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.
PMCID: PMC3501856  PMID: 22923474
24.  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.
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. ( Identifier: ISRCTN49645414.)
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.
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.
PMCID: PMC3937541  PMID: 24292557
Remote ischaemic conditioning; Preconditioning; Contrast-induced nephropathy; Acute kidney injury; Clinical trial; Coronary angiography; Percutaneous intervention
25.  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.
PMCID: PMC3440983  PMID: 22628098
Osteichthyes; Andreolepis; Lophosteus; tooth; development; evolution

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