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1.  Incorporating genomic, transcriptomic and clinical data: a prognostic and stem cell-like MYC and PRC imbalance in high-risk neuroblastoma 
BMC Systems Biology  2017;11(Suppl 5):92.
Background
Previous studies suggested that cancer cells possess traits reminiscent of the biological mechanisms ascribed to normal embryonic stem cells (ESCs) regulated by MYC and Polycomb repressive complex 2 (PRC2). Several poorly differentiated adult tumors showed preferentially high expression levels in targets of MYC, coincident with low expression levels in targets of PRC2. This paper will reveal this ESC-like cancer signature in high-risk neuroblastoma (HR-NB), the most common extracranial solid tumor in children.
Methods
We systematically assembled genomic variants, gene expression changes, priori knowledge of gene functions, and clinical outcomes to identify prognostic multigene signatures. First, we assigned a new, individualized prognostic index using the relative expressions between the poor- and good-outcome signature genes. We then characterized HR-NB aggressiveness beyond these prognostic multigene signatures through the imbalanced effects of MYC and PRC2 signaling. We further analyzed Retinoic acid (RA)-induced HR-NB cells to model tumor cell differentiation. Finally, we performed in vitro validation on ZFHX3, a cell differentiation marker silenced by PRC2, and compared cell morphology changes before and after blocking PRC2 in HR-NB cells.
Results
A significant concurrence existed between exons with verified variants and genes showing MYCN-dependent expression in HR-NB. From these biomarker candidates, we identified two novel prognostic gene-set pairs with multi-scale oncogenic defects. Intriguingly, MYC targets over-represented an unfavorable component of the identified prognostic signatures while PRC2 targets over-represented a favorable component. The cell cycle arrest and neuronal differentiation marker ZFHX3 was identified as one of PRC2-silenced tumor suppressor candidates. Blocking PRC2 reduced tumor cell growth and increased the mRNA expression levels of ZFHX3 in an early treatment stage. This hypothesis-driven systems bioinformatics work offered novel insights into the PRC2-mediated tumor cell growth and differentiation in neuroblastoma, which may exert oncogenic effects together with MYC regulation.
Conclusion
Our results propose a prognostic effect of imbalanced MYC and PRC2 moderations in pediatric HR-NB for the first time. This study demonstrates an incorporation of genomic landscapes and transcriptomic profiles into the hypothesis-driven precision prognosis and biomarker discovery. The application of this approach to neuroblastoma, as well as other cancer more broadly, could contribute to reduced relapse and mortality rates in the long term.
Electronic supplementary material
The online version of this article (doi:10.1186/s12918-017-0466-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12918-017-0466-5
PMCID: PMC5629556  PMID: 28984200
Neuroblastoma; MYC; PRC2; ZFHX3; Somatic mutation
2.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
3.  An integrated genomic approach to the assessment and treatment of acute myeloid leukemia 
Seminars in oncology  2011;38(2):215-224.
Traditionally, new scientific advances have been applied quickly to the leukemias based on the ease with which relatively pure samples of malignant cells can be obtained. Currently, our arsenal of approaches used to characterize an individual’s acute myeloid leukemia combines hematopathologic evaluation, flow cytometry, cytogenetic analysis, and molecular studies focused on a few key genes. The advent of high-throughput methods capable of full genome evaluation presents new options for a revolutionary change in the way we diagnose, characterize, and treat AML. Next-generation DNA sequencing techniques allow full sequencing of a cancer genome or transcriptome, with the hope that this will be affordable for routine clinical care within the decade. Microarray-based testing will define gene and miRNA expression, DNA methylation patterns, chromosomal imbalances, and predisposition to disease and chemosensitivity. The vision for the future entails an integrated and automated approach to these analyses, bringing the possibility of formulating an individualized treatment plan within days of a patient’s initial presentation. With these expectations comes the hope that such an approach will lead to decreased toxicities and prolonged survival for our patients.
doi:10.1053/j.seminoncol.2011.01.003
PMCID: PMC5591437  PMID: 21421111
4.  Long-term effectiveness of mailed nicotine replacement therapy: study protocol of a randomized controlled trial 5-year follow-up 
BMC Public Health  2017;18:28.
Background
Our group recently completed a randomized controlled trial, evaluating the efficacy of providing 5 weeks of free nicotine replacement therapy (NRT; in the form of the nicotine patch) by expedited postal mail without behavioral assistance to regular adult smokers interested in receiving it. The findings revealed that mailed provision of nicotine patches resulted in more than a doubling of quit rates at a six-month follow-up compared to a no intervention control group. While this trial provided evidence for the effectiveness of mailed nicotine patches in promoting cessation, the findings speak only to the short term effectiveness of this approach. As relapse to smoking is known to occur beyond the 6 month period, it is important to evaluate whether the net benefit of NRT in naturalistic settings can be maintained long-term. The present study aims to perform a 5-year follow-up survey of participants in the original trial to evaluate the long-term effectiveness of mailed NRT.
Methods/Design
Trained interviewers will contact participants in the randomized controlled trial 5 years post-enrollment. A total of 924 participants will be eligible to be contacted. Interviewers will first assess participants’ smoking status and their level of nicotine dependence. Participants reporting not currently smoking will be asked whether they have smoked tobacco, even a puff, in the last 30 days (primary outcome measure: 30-day point prevalence abstinence), past 6 months (secondary outcome measure: prolonged 6-month abstinence), and since the 8-week follow-up survey (secondary outcome measure: > 4 year continuous abstinence). Interviewers will be blind to experimental condition at the time the primary outcome measure will be assessed. It is hypothesized that participants who received nicotine patches at baseline will display significantly higher quit rates at the 5-year follow-up as compared to participants who did not receive nicotine patches at baseline.
Discussion
If the study finds that the mailed distribution of free NRT is effective at promoting long-term cessation, it would provide further evidence to move forward with policies designed to make NRT treatment readily and freely available to smokers who request it.
Trial registration
ClinicalTrials.gov: NCT01429129, Registered 2 September 2011; NCT03097445, Registered 25 March 2017.
doi:10.1186/s12889-017-4586-z
PMCID: PMC5516338
Smoking; Tobacco; Nicotine dependence; Smoking cessation; Nicotine replacement therapy; Nicotine patches; Free distribution
5.  Impact of large-scale distribution and subsequent use of free nicotine patches on primary care physician interaction 
BMC Public Health  2017;18:4.
Background
Large-scale distribution efforts of free nicotine replacement therapy (NRT) have been documented to be cost-effective interventions for increasing smoking quit rates. However, despite nearly a dozen studies evaluating their effectiveness, none have examined whether free NRT provision promotes further primary care help-seeking and the impact that it may have on cessation efforts.
Methods
In the context of a randomized controlled trial, a secondary analysis was conducted on 1000 adult regular smokers randomized to be mailed a 5-week supply of nicotine patches or to a no intervention control group. Recipients and users of free nicotine patches at an 8 week follow-up were successfully case matched to controls based on age, gender, baseline level of nicotine dependence and intent to quit (n = 201 per group). Differences in physician interaction between the two groups were evaluated at both 8 week and 6 month follow-ups. The impact of physician interaction on self-reported smoking abstinence at each follow-up was also examined.
Results
Although no differences in physician interaction were noted between groups at the 8 week follow-up, at the 6 month follow-up, nicotine patch users reported greater frequency of discussing smoking with their physician (43.9%), as compared to the control group (30.3%) (p = 0.011). Across both groups, over 90% of those that discussed smoking with a physician were encouraged to quit and approximately 70% were provided with additional support. Separate ANOVAs revealed no significant impact of physician interaction on cessation (p > 0.05), regardless of group or follow-up period, however, at the 6 month follow-up, nicotine patch users who discussed cessation with a physician had made serious quit attempts at significantly greater rates (72.6%), compared to controls (49.1%) (p = 0.007).
Conclusions
Irrespective of group, the majority of smokers in the present study did not discuss cessation with their physician. Recipients and users of nicotine patches however, were more likely to discuss smoking with their physician, suggesting that the provision of free NRT particularly to those who are likely to use it may facilitate opportunities for benefits beyond the direct pharmacological effects of the medication.
Trial registration
clinicaltrials.gov, NCT01429129. Registered: 2 September 2011.
doi:10.1186/s12889-017-4548-5
PMCID: PMC5504597  PMID: 28693456
Smoking cessation; Nicotine replacement therapy; Primary care physicians; Tobacco; Health professionals
6.  Open data and digital morphology 
Over the past two decades, the development of methods for visualizing and analysing specimens digitally, in three and even four dimensions, has transformed the study of living and fossil organisms. However, the initial promise that the widespread application of such methods would facilitate access to the underlying digital data has not been fully achieved. The underlying datasets for many published studies are not readily or freely available, introducing a barrier to verification and reproducibility, and the reuse of data. There is no current agreement or policy on the amount and type of data that should be made available alongside studies that use, and in some cases are wholly reliant on, digital morphology. Here, we propose a set of recommendations for minimum standards and additional best practice for three-dimensional digital data publication, and review the issues around data storage, management and accessibility.
doi:10.1098/rspb.2017.0194
PMCID: PMC5394671  PMID: 28404779
digital data; three-dimensional models; phenotype; computed tomography; visualization; functional analysis
7.  A c-Myc-regulated stem cell-like signature in high-risk neuroblastoma: A systematic discovery (Target neuroblastoma ESC-like signature) 
Scientific Reports  2017;7:41.
c-Myc dysregulation is hypothesized to account for the ‘stemness’ – self-renewal and pluripotency – shared between embryonic stem cells (ESCs) and adult aggressive tumours. High-risk neuroblastoma (HR-NB) is the most frequent, aggressive, extracranial solid tumour in childhood. Using HR-NB as a platform, we performed a network analysis of transcriptome data and presented a c-Myc subnetwork enriched for genes previously reported as ESC-like cancer signatures. A subsequent drug-gene interaction analysis identified a pharmacogenomic agent that preferentially interacted with this HR-NB-specific, ESC-like signature. This agent, Roniciclib (BAY 1000394), inhibited neuroblastoma cell growth and induced apoptosis in vitro. It also repressed the expression of the oncogene c-Myc and the neural ESC marker CDK2 in vitro, which was accompanied by altered expression of the c-Myc-targeted cell cycle regulators CCND1, CDKN1A and CDKN2D in a time-dependent manner. Further investigation into this HR-NB-specific ESC-like signature in 295 and 243 independent patients revealed and validated the general prognostic index of CDK2 and CDKN3 compared with CDKN2D and CDKN1B. These findings highlight the very potent therapeutic benefits of Roniciclib in HR-NB through the targeting of c-Myc-regulated, ESC-like tumorigenesis. This work provides a hypothesis-driven systems computational model that facilitates the translation of genomic and transcriptomic signatures to molecular mechanisms underlying high-risk tumours.
doi:10.1038/s41598-017-00122-x
PMCID: PMC5427913  PMID: 28246384
8.  Upper Trunk Brachial Plexus Palsy Following Chiropractic Manipulation 
Introduction
Upper trunk brachial plexus palsy can result from high-energy trauma and has never been reported following spinal manipulation.
Background
The case is presented of a patient who developed an acute brachial plexus upper trunk palsy following spinal manipulative therapy.
Discussion
Discussion is made on the incidence of complications following manipulation and recommendations to prospectively capture all serious complications.
Concluding remarks
Risks exist with spinal manipulative therapy. Neurological injury can occur. Risk assessment and re-examination should occur at every visit. Large rigorous prospective studies are required to identify the true incidence of serious complications resulting from manipulative therapy and the benefit:risk ratio.
doi:10.3389/fneur.2016.00211
PMCID: PMC5127815  PMID: 27965621
brachial plexus injury; upper trunk; Erb’s palsy; manipulation; chiropractic
9.  PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing 
Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious. Using the human β-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA–mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. In primary erythroid progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5. Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.
doi:10.1038/nsmb.1568
PMCID: PMC5120857  PMID: 19234465
10.  Tensor Analysis Reveals Distinct Population Structure that Parallels the Different Computational Roles of Areas M1 and V1 
PLoS Computational Biology  2016;12(11):e1005164.
Cortical firing rates frequently display elaborate and heterogeneous temporal structure. One often wishes to compute quantitative summaries of such structure—a basic example is the frequency spectrum—and compare with model-based predictions. The advent of large-scale population recordings affords the opportunity to do so in new ways, with the hope of distinguishing between potential explanations for why responses vary with time. We introduce a method that assesses a basic but previously unexplored form of population-level structure: when data contain responses across multiple neurons, conditions, and times, they are naturally expressed as a third-order tensor. We examined tensor structure for multiple datasets from primary visual cortex (V1) and primary motor cortex (M1). All V1 datasets were ‘simplest’ (there were relatively few degrees of freedom) along the neuron mode, while all M1 datasets were simplest along the condition mode. These differences could not be inferred from surface-level response features. Formal considerations suggest why tensor structure might differ across modes. For idealized linear models, structure is simplest across the neuron mode when responses reflect external variables, and simplest across the condition mode when responses reflect population dynamics. This same pattern was present for existing models that seek to explain motor cortex responses. Critically, only dynamical models displayed tensor structure that agreed with the empirical M1 data. These results illustrate that tensor structure is a basic feature of the data. For M1 the tensor structure was compatible with only a subset of existing models.
Author Summary
Neuroscientists commonly measure the time-varying activity of neurons in the brain. Early studies explored how such activity directly encodes sensory stimuli. Since then neural responses have also been found to encode abstract parameters such as expected reward. Yet not all aspects of neural activity directly encode identifiable parameters: patterns of activity sometimes reflect the evolution of underlying internal computations, and may be only obliquely related to specific parameters. For example, it remains debated whether cortical activity during movement relates to parameters such as reach velocity, to parameters such as muscle activity, or to underlying computations that culminate in the production of muscle activity. To address this question we exploited an unexpected fact. When activity directly encodes a parameter it tends to be mathematically simple in a very particular way. When activity reflects the evolution of a computation being performed by the network, it tends to be mathematically simple in a different way. We found that responses in a visual area were simple in the first way, consistent with encoding of parameters. We found that responses in a motor area were simple in the second way, consistent with participation in the underlying computations that culminate in movement.
doi:10.1371/journal.pcbi.1005164
PMCID: PMC5096707  PMID: 27814353
11.  Reorganization between preparatory and movement population responses in motor cortex 
Nature Communications  2016;7:13239.
Neural populations can change the computation they perform on very short timescales. Although such flexibility is common, the underlying computational strategies at the population level remain unknown. To address this gap, we examined population responses in motor cortex during reach preparation and movement. We found that there exist exclusive and orthogonal population-level subspaces dedicated to preparatory and movement computations. This orthogonality yielded a reorganization in response correlations: the set of neurons with shared response properties changed completely between preparation and movement. Thus, the same neural population acts, at different times, as two separate circuits with very different properties. This finding is not predicted by existing motor cortical models, which predict overlapping preparation-related and movement-related subspaces. Despite orthogonality, responses in the preparatory subspace were lawfully related to subsequent responses in the movement subspace. These results reveal a population-level strategy for performing separate but linked computations.
Single neuron responses are highly complex and dynamic yet they are able to flexibly represent behaviour through their collective activity. Here the authors demonstrate that population activity patterns of motor cortex neurons are orthogonal during successive task epochs that are linked through a simple linear function.
doi:10.1038/ncomms13239
PMCID: PMC5095296  PMID: 27807345
12.  Randomized Controlled Trial of a Brief Versus Extended Internet Intervention for Problem Drinkers 
Purpose
Brief Internet interventions have been shown to reduce alcohol consumption. This trial intended to compare the effects of one such brief intervention to an extended Internet intervention for problem drinkers.
Method
Using online advertising, 490 participants, 18 years or older, were recruited and randomized to receive a brief (CheckYourDrinking.net) versus an extended (AlcoholHelpCentre.net) Internet intervention and were followed up at 6, 12, and 24 months. The per protocol primary analysis assessed difference between condition at the 12-month follow-up.
Results
The follow-up rate at 12 months was 83.3 %. ANCOVAs of the primary (Alcohol Use Disorder Identification Test (AUDIT)-C) and secondary outcome variables (drinks in a typical week, highest number of drinks on one occasion—baseline drinking as covariate) revealed no significant (p > 0.05) differences between the interventions. Similarly, combined analyses of the 6-, 12-, and 24-month follow-up revealed no significant differences between interventions at all time points.
Conclusion
The present study does not provide support for the added benefit of an extended Internet intervention for problem drinkers over a brief Internet intervention.
doi:10.1007/s12529-016-9604-5
PMCID: PMC5608868  PMID: 27770293
Alcohol; Internet intervention; Randomized controlled trial; RCT; Problem drinking
13.  Proceedings of the 13th annual conference of INEBRIA 
Watson, Rod | Morris, James | Isitt, John | Barrio, Pablo | Ortega, Lluisa | Gual, Antoni | Conner, Kenneth | Stecker, Tracy | Maisto, Stephen | Paroz, Sophie | Graap, Caroline | Grazioli, Véronique S | Daeppen, Jean-Bernard | Collins, Susan E | Bertholet, Nicolas | McNeely, Jennifer | Kushnir, Vlad | Cunningham, John A. | Crombie, Iain K | Cunningham, Kathryn B | Irvine, Linda | Williams, Brian | Sniehotta, Falko F | Norrie, John | Melson, Ambrose | Jones, Claire | Briggs, Andrew | Rice, Peter | Achison, Marcus | McKenzie, Andrew | Dimova, Elena | Slane, Peter W | Grazioli, Véronique S. | Collins, Susan E. | Paroz, Sophie | Graap, Caroline | Daeppen, Jean-Bernard | Baggio, Stéphanie | Dupuis, Marc | Studer, Joseph | Gmel, Gerhard | Magill, Molly | Grazioli, Véronique S. | Tait, Robert J. | Teoh, Lucinda | Kelty, Erin | Geelhoed, Elizabeth | Mountain, David | Hulse, Gary K. | Renko, Elina | Mitchell, Shannon G. | Lounsbury, David | Li, Zhi | Schwartz, Robert P. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla | Hosler, Colleen | Dusek, Kristi | Brown, Barry S. | Finnell, Deborah S. | Holloway, Aisha | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | Wallhed Finn, Sara | Andreasson, Sven | Dvorak, Robert D. | Kramer, Matthew P. | Stevenson, Brittany L. | Sargent, Emily M. | Kilwein, Tess M. | Harris, Sion K. | Sherritt, Lon | Copelas, Sarah | Knight, John R. | Mdege, Noreen D | McCambridge, Jim | Bischof, Gallus | Bischof, Anja | Freyer-Adam, Jennis | Rumpf, Hans-Juergen | Fitzgerald, Niamh | Schölin, Lisa | Toner, Paul | Böhnke, Jan R. | Veach, Laura J. | Currin, Olivia | Dongre, Leigh Z. | Miller, Preston R. | White, Elizabeth | Williams, Emily C. | Lapham, Gwen T. | Bobb, Jennifer J. | Rubinsky, Anna D. | Catz, Sheryl L. | Shortreed, Susan | Bensley, Kara M. | Bradley, Katharine A. | Milward, Joanna | Deluca, Paolo | Khadjesari, Zarnie | Watson, Rod | Fincham-Campbell, Stephanie | Drummond, Colin | Angus, Kathryn | Bauld, Linda | Baumann, Sophie | Haberecht, Katja | Schnuerer, Inga | Meyer, Christian | Rumpf, Hans-Jürgen | John, Ulrich | Gaertner, Beate | Barrault-Couchouron, Marion | Béracochéa, Marion | Allafort, Vincent | Barthélémy, Valérie | Bonnefoi, Hervé | Bussières, Emmanuel | Garguil, Véronique | Auriacombe, Marc | Saint-Jacques, Marianne | Dorval, Michel | M’Bailara, Katia | Segura-Garcia, Lidia | Ibañez-Martinez, Nuria | Mendive-Arbeloa, Juan Manuel | Anoro-Perminger, Manel | Diaz-Gallego, Pako | Piñar-Mateos, Mª Angeles | Colom-Farran, Joan | Deligianni, Marianthi | Yersin, Bertrand | Adam, Angeline | Weisner, Constance | Chi, Felicia | Lu, Wendy | Sterling, Stacy | Kraemer, Kevin L. | McGinnis, Kathleen A. | Fiellin, David A. | Skanderson, Melissa | Gordon, Adam J. | Robbins, Jonathan | Zickmund, Susan | Korthuis, P. Todd | Edelman, E. Jennifer | Hansen, Nathan B. | Cutter, Christopher J. | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Maisto, Stephen A. | Bedimo, Roger | Gilbert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria | Simberkoff, Michael | Justice, Amy C. | Bryant, Kendall J. | Berman, Anne H | Shorter, Gillian W | Bray, Jeremy W | Barbosa, Carolina | Johansson, Magnus | Hester, Reid | Campbell, William | Souza Formigoni, Maria Lucia O. | Andrade, André Luzi Monezi | Sartes, Laisa Marcorela Andreoli | Sundström, Christopher | Eék, Niels | Kraepelien, Martin | Kaldo, Viktor | Fahlke, Claudia | Hernandez, Lynn | Becker, Sara J. | Jones, Richard N. | Graves, Hannah R. | Spirito, Anthony | Diestelkamp, Silke | Wartberg, Lutz | Arnaud, Nicolas | Thomasius, Rainer | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Malan, Zelra | Mash, Bob | Everett-Murphy, Katherine | Grazioli, Véronique S. | Studer, Joseph | Mohler-Kuo, M. | Bertholet, Nicolas | Gmel, Gerhard | Doi, Lawrence | Cheyne, Helen | Jepson, Ruth | Luna, Vanesa | Echeverria, Leticia | Morales, Silvia | Barroso, Teresa | Abreu, Ângela | Aguiar, Cosma | Stewart, Duncan | Abreu, Angela | Brites, Riany M. | Jomar, Rafael | Marinho, Gerson | Parreira, Pedro | Seale, J. Paul | Johnson, J. Aaron | Henry, Dena | Chalmers, Sharon | Payne, Freida | Tuck, Linda | Morris, Akula | Gonçalves, Cátia | Besser, Bettina | Casajuana, Cristina | López-Pelayo, Hugo | Balcells, María Mercedes | Teixidó, Lídia | Miquel, Laia | Colom, Joan | Hepner, Kimberly A. | Hoggatt, Katherine. J. | Bogart, Andy | Paddock, Susan. M. | Hardoon, Sarah L | Petersen, Irene | Hamilton, Fiona L | Nazareth, Irwin | White, Ian R. | Marston, Louise | Wallace, Paul | Godfrey, Christine | Murray, Elizabeth | Sovinová, Hana | Csémy, Ladislav
doi:10.1186/s13722-016-0062-9
PMCID: PMC5032602  PMID: 27654147
14.  Online interventions for problem gamblers with and without co-occurring mental health symptoms: Protocol for a randomized controlled trial 
BMC Public Health  2016;16:624.
Background
Comorbidity between problem gambling and depression or anxiety is common. Further, the treatment needs of people with co-occurring gambling and mental health symptoms may be different from those of problem gamblers who do not have a co-occurring mental health concern. The current randomized controlled trial (RCT) will evaluate whether there is a benefit to providing access to mental health Internet interventions (G + MH intervention) in addition to an Internet intervention for problem gambling (G-only intervention) in participants with gambling problems who do or do not have co-occurring mental health symptoms.
Methods
Potential participants will be screened using an online survey to identify participants meeting criteria for problem gambling. As part of the baseline screening process, measures of current depression and anxiety will be assessed. Eligible participants agreeing (N = 280) to take part in the study will be randomized to one of two versions of an online intervention for gamblers – an intervention that just targets gambling issues (G-only) versus a website that contains interventions for depression and anxiety in addition to an intervention for gamblers (G + MH). It is predicted that problem gamblers who do not have co-occurring mental health symptoms will display no significant difference between intervention conditions at a six-month follow-up. However, for those with co-occurring mental health symptoms, it is predicted that participants receiving access to the G + MH website will display significantly reduced gambling outcomes at six-month follow-up as compared to those provided with G-only website.
Discussion
The trial will produce information on the best means of providing online help to gamblers with and without co-occurring mental health symptoms.
Trial registration
ClinicalTrials.gov NCT02800096; Registration date: June 14, 2016.
doi:10.1186/s12889-016-3291-7
PMCID: PMC4957312  PMID: 27449527
Clinical trial; Randomized controlled trial; Brief intervention; Gambling disorders; Comorbidity; Depression; Anxiety; Online intervention; Internet intervention; Trial protocol
15.  Community Structure of a Mental Health Internet Support Group: Modularity in User Thread Participation 
JMIR Mental Health  2016;3(2):e20.
Background
Little is known about the community structure of mental health Internet support groups, quantitatively. A greater understanding of the factors, which lead to user interaction, is needed to explain the design information of these services and future research concerning their utility.
Objective
A study was conducted to determine the characteristics of users associated with the subgroup community structure of an Internet support group for mental health issues.
Methods
A social network analysis of the Internet support group BlueBoard (blueboard.anu.edu.au) was performed to determine the modularity of the community using the Louvain method. Demographic characteristics age, gender, residential location, type of user (consumer, carer, or other), registration date, and posting frequency in subforums (depression, generalized anxiety, social anxiety, panic disorder, bipolar disorder, obsessive compulsive disorder, borderline personality disorder, eating disorders, carers, general (eg, “chit chat”), and suggestions box) of the BlueBoard users were assessed as potential predictors of the resulting subgroup structure.
Results
The analysis of modularity identified five main subgroups in the BlueBoard community. Registration date was found to be the largest contributor to the modularity outcome as observed by multinomial logistic regression. The addition of this variable to the final model containing all other factors improved its classification accuracy by 46.3%, that is, from 37.9% to 84.2%. Further investigation of this variable revealed that the most active and central users registered significantly earlier than the median registration time in each group.
Conclusions
The five subgroups resembled five generations of BlueBoard in distinct eras that transcended discussion about different mental health issues. This finding may be due to the activity of highly engaged and central users who communicate with many other users. Future research should seek to determine the generalizability of this finding and investigate the role that highly active and central users may play in the formation of this phenomenon.
doi:10.2196/mental.4961
PMCID: PMC4906237  PMID: 27242012
internet; support group; social network; modularity; mental health; super user
16.  Neuroprosthetic Decoder Training as Imitation Learning 
PLoS Computational Biology  2016;12(5):e1004948.
Neuroprosthetic brain-computer interfaces function via an algorithm which decodes neural activity of the user into movements of an end effector, such as a cursor or robotic arm. In practice, the decoder is often learned by updating its parameters while the user performs a task. When the user’s intention is not directly observable, recent methods have demonstrated value in training the decoder against a surrogate for the user’s intended movement. Here we show that training a decoder in this way is a novel variant of an imitation learning problem, where an oracle or expert is employed for supervised training in lieu of direct observations, which are not available. Specifically, we describe how a generic imitation learning meta-algorithm, dataset aggregation (DAgger), can be adapted to train a generic brain-computer interface. By deriving existing learning algorithms for brain-computer interfaces in this framework, we provide a novel analysis of regret (an important metric of learning efficacy) for brain-computer interfaces. This analysis allows us to characterize the space of algorithmic variants and bounds on their regret rates. Existing approaches for decoder learning have been performed in the cursor control setting, but the available design principles for these decoders are such that it has been impossible to scale them to naturalistic settings. Leveraging our findings, we then offer an algorithm that combines imitation learning with optimal control, which should allow for training of arbitrary effectors for which optimal control can generate goal-oriented control. We demonstrate this novel and general BCI algorithm with simulated neuroprosthetic control of a 26 degree-of-freedom model of an arm, a sophisticated and realistic end effector.
Author Summary
There are various existing methods for rapidly learning a decoder during closed-loop brain computer interface (BCI) tasks. While many of these methods work well in practice, there is no clear theoretical foundation for parameter learning. We offer a unification of closed-loop decoder learning setting as an imitation learning problem. This has two major consequences: first, our approach clarifies how to derive “intention-based” algorithms for any BCI setting, most notably more complex settings like control of an arm; and second, this framework allows us to provide theoretical results, building from an existing literature on the regret of related algorithms. After first demonstrating algorithmic performance in simulation on the well-studied setting of a user trying to reach targets by controlling a cursor on a screen, we then simulate a user controlling an arm with many degrees of freedom in order to grasp a wand. Finally, we describe how extensions in the online-imitation learning literature can improve BCI in additional settings.
doi:10.1371/journal.pcbi.1004948
PMCID: PMC4871564  PMID: 27191387
17.  Pauci Immune crescentic glomerulonephritis in a patient with T-cell lymphoma and argyria 
BMC Nephrology  2016;17:49.
Background
Silver is a transition metal, toxic when ingested in significant amounts, causing argyria (skin deposition) and argyrosis (eye deposition). It is excreted mainly via the gastrointestinal tract with only small amounts eliminated by the kidneys, and rarely have cases of nephrotoxicity due to silver been reported. Here we present the case of a woman who used colloidal silver as an alternative remedy for a T cell lymphoma, who subsequently developed argyria and a pauci-immune crescentic glomerulonephritis with evidence of extensive glomerular basement membrane silver deposition.
Case Presentation
A 47 year old woman of Indo-Asian descent with a T-cell lymphoma who refused conventional chemotherapy for 18 months but self-medicated with a remedy containing colloidal silver, was admitted with acute dialysis-dependent kidney injury. A kidney biopsy demonstrated a pauci-immune crescentic glomerulonephritis with deposition of silver particles in the mesangium and along the glomerular basement membranes. The patient was treated with intravenous methylprednisolone and intravenous cyclophosphamide and recovered independent renal function.
Conclusion
Chronological evolution of the the pauci-immune glomerulonephritis suggests that a cellular immune-mediated process was induced, potentially mediated by lymphomatous T cells directed at the glomerular basement membrane, following silver deposition. Immunosuppressive therapy improved the situation and allowed cessation of haemodialysis, supporting the hypothesis of an immune-mediated process.
doi:10.1186/s12882-016-0259-x
PMCID: PMC4869364  PMID: 27189346
Glomerulonephritis; Silver; Toxicity; Immunosuppression; AKI; Argyria
18.  Internet-Based Brief Intervention to Prevent Unhealthy Alcohol Use among Young Men: A Randomized Controlled Trial 
PLoS ONE  2015;10(12):e0144146.
Introduction
Alcohol use is one of the leading modifiable morbidity and mortality risk factors among young adults.
Study Design
2 parallel-group randomized controlled trial with follow-up at 1 and 6 months.
Setting/Participants
Internet based study in a general population sample of young men with low-risk drinking, recruited between June 2012 and February 2013.
Intervention: Internet-based brief alcohol primary prevention intervention (IBI). The IBI aims at preventing an increase in alcohol use: it consists of normative feedback, feedback on consequences, calorific value alcohol, computed blood alcohol concentration, indication that the reported alcohol use is associated with no or limited risks for health. Intervention group participants received the IBI. Control group (CG) participants completed only an assessment.
Main Outcome Measures
Alcohol use (number of drinks per week), binge drinking prevalence. Analyses were conducted in 2014–2015.
Results
Of 4365 men invited to participate, 1633 did so; 896 reported low-risk drinking and were randomized (IBI: n = 451; CG: n = 445). At baseline, 1 and 6 months, the mean (SD) number of drinks/week was 2.4(2.2), 2.3(2.6), 2.5(3.0) for IBI, and 2.4(2.3), 2.8(3.7), 2.7(3.9) for CG. Binge drinking, absent at baseline, was reported by 14.4% (IBI) and 19.0% (CG) at 1 month and by 13.3% (IBI) and 13.0% (CG) at 6 months. At 1 month, beneficial intervention effects were observed on the number of drinks/week (p = 0.05). No significant differences were observed at 6 months.
Conclusion
We found protective short term effects of a primary prevention IBI.
Trial Registration
Controlled-Trials.com ISRCTN55991918
doi:10.1371/journal.pone.0144146
PMCID: PMC4671673  PMID: 26642329
19.  From Help-Seekers to Influential Users: A Systematic Review of Participation Styles in Online Health Communities 
Background
Understanding how people participate in and contribute to online health communities (OHCs) is useful knowledge in multiple domains. It is helpful for community managers in developing strategies for building community, for organizations in disseminating information about health interventions, and for researchers in understanding the social dynamics of peer support.
Objective
We sought to determine if any patterns were apparent in the nature of user participation across online health communities.
Methods
The current study involved a systematic review of all studies that have investigated the nature of participation in an online health community and have provided a quantifiable method for categorizing a person based on their participation style. A systematic search yielded 20 papers.
Results
Participatory styles were classified as either multidimensional (based on multiple metrics) or unidimensional (based on one metric). With respect to the multidimensional category, a total of 41 different participation styles were identified ranging from Influential Users who were leaders on the board to Topic-Focused Responders who focused on a specific topic and tended to respond to rather than initiate posts. However, there was little overlap in participation styles identified both across OHCs for different health conditions and within OHCs for specific health conditions. Five of the 41 styles emerged in more than one study (Hubs, Authorities, Facilitators, Prime Givers, and Discussants), but the remainder were reported in only one study. The focus of the unidimensional studies was on level of engagement and particularly on high-engaged users. Eight different metrics were used to evaluate level of engagement with the greatest focus on frequency of posts.
Conclusions
With the exception of high-engaged users based on high post frequency, the current review found little evidence for consistent participatory styles across different health communities. However, this area of research is in its infancy, with most of the studies included in the review being published in the last 2 years. Nevertheless, the review delivers a nomenclature for OHC participation styles and metrics and discusses important methodological issues that will provide a basis for future comparative research in the area. Further studies are required to systematically investigate a range of participatory styles, to investigate their association with different types of online health communities and to determine the contribution of different participatory styles within and across online health communities.
doi:10.2196/jmir.4705
PMCID: PMC4704975  PMID: 26627369
online health community; participation style; social network; participation inequality; systematic review
20.  Dimensionality reduction for large-scale neural recordings 
Nature neuroscience  2014;17(11):1500-1509.
Most sensory, cognitive and motor functions depend on the interactions of many neurons. In recent years, there has been rapid development and increasing use of technologies for recording from large numbers of neurons, either sequentially or simultaneously. A key question is what scientific insight can be gained by studying a population of recorded neurons beyond studying each neuron individually. Here, we examine three important motivations for population studies: single-trial hypotheses requiring statistical power, hypotheses of population response structure and exploratory analyses of large data sets. Many recent studies have adopted dimensionality reduction to analyze these populations and to find features that are not apparent at the level of individual neurons. We describe the dimensionality reduction methods commonly applied to population activity and offer practical advice about selecting methods and interpreting their outputs. This review is intended for experimental and computational researchers who seek to understand the role dimensionality reduction has had and can have in systems neuroscience, and who seek to apply these methods to their own data.
doi:10.1038/nn.3776
PMCID: PMC4433019  PMID: 25151264
21.  Excitation, detection, and electrostatic manipulation of terahertz-frequency range plasmons in a two-dimensional electron system 
Scientific Reports  2015;5:15420.
Terahertz frequency time-domain spectroscopy employing free-space radiation has frequently been used to probe the elementary excitations of low-dimensional systems. The diffraction limit, however, prevents its use for the in-plane study of individual laterally-defined nanostructures. Here, we demonstrate a planar terahertz frequency plasmonic circuit in which photoconductive material is monolithically integrated with a two-dimensional electron system. Plasmons with a broad spectral range (up to ~ 400 GHz) are excited by injecting picosecond-duration pulses, generated and detected by a photoconductive semiconductor, into a high mobility two-dimensional electron system. Using voltage modulation of a Schottky gate overlying the two-dimensional electron system, we form a tuneable plasmonic cavity, and observe electrostatic manipulation of the plasmon resonances. Our technique offers a direct route to access the picosecond dynamics of confined electron transport in a broad range of lateral nanostructures.
doi:10.1038/srep15420
PMCID: PMC4614073  PMID: 26487263
22.  DEVELOPMENTAL PALEOBIOLOGY OF THE VERTEBRATE SKELETON 
Journal of paleontology  2014;88(4):676-683.
Studies of the development of organisms can reveal crucial information on homology of structures. Developmental data are not peculiar to living organisms, and they are routinely preserved in the mineralized tissues that comprise the vertebrate skeleton, allowing us to obtain direct insight into the developmental evolution of this most formative of vertebrate innovations. The pattern of developmental processes is recorded in fossils as successive stages inferred from the gross morphology of multiple specimens and, more reliably and routinely, through the ontogenetic stages of development seen in the skeletal histology of individuals. Traditional techniques are destructive and restricted to a 2-D plane with the third dimension inferred. Effective non-invasive methods of visualizing paleohistology to reconstruct developmental stages of the skeleton are necessary.
In a brief survey of paleohistological techniques we discuss the pros and cons of these methods. The use of tomographic methods to reconstruct development of organs is exemplified by the study of the placoderm dentition. Testing evidence for the presence of teeth in placoderms, the first jawed vertebrates, we compare the methods that have been used. These include inferring the development from morphology, and using serial sectioning, microCT or synchrotron X-ray tomographic microscopy (SRXTM) to reconstruct growth stages and directions of growth. The ensuing developmental interpretations are biased by the methods and degree of inference. The most direct and reliable method is using SRXTM data to trace sclerochronology. The resulting developmental data can be used to resolve homology and test hypotheses on the origin of evolutionary novelties.
doi:10.1666/13-107
PMCID: PMC4545513  PMID: 26306050
23.  Single-trial dynamics of motor cortex and their applications to brain-machine interfaces 
Nature Communications  2015;6:7759.
Increasing evidence suggests that neural population responses have their own internal drive, or dynamics, that describe how the neural population evolves through time. An important prediction of neural dynamical models is that previously observed neural activity is informative of noisy yet-to-be-observed activity on single-trials, and may thus have a denoising effect. To investigate this prediction, we built and characterized dynamical models of single-trial motor cortical activity. We find these models capture salient dynamical features of the neural population and are informative of future neural activity on single trials. To assess how neural dynamics may beneficially denoise single-trial neural activity, we incorporate neural dynamics into a brain–machine interface (BMI). In online experiments, we find that a neural dynamical BMI achieves substantially higher performance than its non-dynamical counterpart. These results provide evidence that neural dynamics beneficially inform the temporal evolution of neural activity on single trials and may directly impact the performance of BMIs.
In online experiments with monkeys the authors demonstrate, for the first time, that incorporating neural dynamics substantially improves brain–machine interface performance. This result is consistent with a framework hypothesizing that motor cortex is a dynamical machine that generates movement.
doi:10.1038/ncomms8759
PMCID: PMC4532790  PMID: 26220660
24.  Critical appraisal of tubular putative eumetazoans from the Ediacaran Weng'an Doushantuo biota 
Molecular clock analyses estimate that crown-group animals began diversifying hundreds of millions of years before the start of the Cambrian period. However, the fossil record has not yielded unequivocal evidence for animals during this interval. Some of the most promising candidates for Precambrian animals occur in the Weng'an biota of South China, including a suite of tubular fossils assigned to Sinocyclocyclicus, Ramitubus, Crassitubus and Quadratitubus, that have been interpreted as soft-bodied eumetazoans comparable to tabulate corals. Here, we present new insights into the anatomy, original composition and phylogenetic affinities of these taxa based on data from synchrotron radiation X-ray tomographic microscopy, ptychographic nanotomography, scanning electron microscopy and electron probe microanalysis. The patterns of deformation observed suggest that the cross walls of Sinocyclocyclicus and Quadratitubus were more rigid than those of Ramitubus and Crassitubus. Ramitubus and Crassitubus specimens preserve enigmatic cellular clusters at terminal positions in the tubes. Specimens of Sinocyclocyclicus and Ramitubus have biological features that might be cellular tissue or subcellular structures filling the spaces between the cross walls. These observations are incompatible with a cnidarian interpretation, in which the spaces between cross walls are abandoned parts of the former living positions of the polyp. The affinity of the Weng'an tubular fossils may lie within the algae.
doi:10.1098/rspb.2015.1169
PMCID: PMC4528530  PMID: 26180072
Doushantuo; Ediacaran; tubular fossils; exceptional fossilization
25.  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.
doi:10.1098/rspb.2015.0476
PMCID: PMC4455810  PMID: 25972468
Cambrian explosion; palaeobiology; taphonomy; bilateria; metazoa

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