Backstories - Authorea

by author

by title

by keyword

Proof of Extensive Copy Number Variation in The Human Genome

Stephen W. Scherer

and 1 more

November 09, 2017

This article was originally published at The Winnower and is the backstory behind Redon, R., S. Ishikawa, K. R. Fitch, L. Feuk, G. H. Perry, T. D. Andrews, H. Fiegler, M. H. Shapero, A. R. Carson, W. Chen, E. K. Cho, S. Dallaire, J. L. Freeman, J. R. Gonzalez, M. Gratacos, J. Huang, D. Kalaitzopoulos, D. Komura, J. R. MacDonald, C. R. Marshall, R. Mei, L. Montgomery, K. Nishimura, K. Okamura, F. Shen, M. J. Somerville, J. Tchinda, A. Valsesia, C. Woodwark, F. Yang, J. Zhang, T. Zerjal, J. Zhang, L. Armengol, D. F. Conrad, X. Estivill, C. Tyler-Smith, N. P. Carter, H. Aburatani, C. Lee, K. W. Jones, S. W. Scherer, and M. E. Hurles. 2006. "Global variation in copy number in the human genome." Nature no. 444 (7118):444-54. doi: 10.1038/nature05329A primary message from the Human Genome Project, as well as from earlier studies, was that DNA in the genomes of any two individuals is 99.9 per cent identical. The 0.1 per cent variation was attributed to some three million single nucleotide polymorphisms (SNPs) scattered amongst the chromosomes. Larger genomic changes -- involving losses or gains of thousands or millions of nucleotides, encompassing one or several genes -- were thought to be exceptionally rare, and almost always involved in disease (Check 2005).In the summer of 2004, Charles Lee, a Canadian cytogeneticist at Harvard, collaborating with my Toronto team, and (separately) Michael Wigler's group at Cold Spring Harbor, published data showing that numerous larger gene-sized (or greater) segments of DNA were present in different copy numbers in all individuals (Iafrate et al. 2004, Sebat et al. 2004). These studies, which used microarrays to scan the genomes of a handful of individuals, found about a dozen novel copy number variations (CNVs) per genome. Within the clinical genetics community, uptake of the concept of CNVs was immediate, and as part of our original paper (Iafrate et al. 2004) we established a database (now called the Database of Genomic Variants) to make our results accessible and applicable. The genome sequencing community, however, was busy finishing a "one-size-fits-all' sequence map (Human Genome Sequencing 2004)and starting their venture to map common SNPs, (the HapMap Project) (2005), and did not yet fully recognize the potential importance of the CNV discoveries.Given the limited resolution of the technologies used for the 2004 papers, and the small number of samples analyzed, we recognized that our initial CNV findings were likely just "the tip of the iceberg'. With simple extrapolations from our existing data, we predicted that every genome would likely have thousands of CNVs, as well as insertions and deletions (called indels, which are smaller CNVs (1 to 1,000 nucleotides)). We began to design experiments that might allow us to discover these. As we drafted the first grants in early to mid-2004, we quickly anticipated the challenges ahead: (i) selecting the most appropriate technology (s) for robust CNV detection, (ii) identifying appropriate control samples from world populations, and (iii) securing funding for what would surely be a multi-million dollar CNV genome project. Charles and I found a champion for the project in microarray expert, Nigel Carter (and newly hired scientist Matthew Hurles) at the Welcome Trust Sanger Institute in the United Kingdom, and I was able to win big grants from the Canadian Institutes of Health Research and Genome Canada. We decided to study DNA samples from the same 270 individuals as used in the international HapMap project; these originated from four populations with ancestry in Europe, Africa or Asia.To detect CNVs, we used two complementary genome-wide technologies. The first compared each sample to a reference standard, looking for differences in intensity among a set of more than 26,000 large-insert cloned segments of DNA called bacterial artificial chromosomes. This was done on microarrays that spanned nearly all of the euchromatic genome. The second was a proprietary genotyping approach developed by Keith Jones' team at Affymetrix. Some 500,000 SNPs were assayed, looking for stretches of adjacent SNP loci with atypical or unexpected allele ratios. For this purpose, Hiro Aburatani's group at the University of Tokyo helped by developing new computer algorithms for "calling" CNVs from SNP genotypes.Coverage with these combined microarray approaches allowed detection of CNVs larger than 10kb, and we identified a total of 1,447 alterations among the 270 HapMap samples. CNV regions were estimated to involve an average, per genome, of more than 20 million base pairs -- some 5- to 10-fold more variation per nucleotide than had been suggested by studying SNPs alone. In fact, it was startling to discover that, in the 270 human samples tested, 12% of the genome was copy number variable. These regions encompass about 2,900 genes, or 10% of those known. Some CNVs in the general population are millions of bases in size, involving many genes, yet sometimes with no observable consequence. We also found CNVs that involved genes known to be disease-associated, indicating these genomic events could have significant clinical consequences. We karyotyped all of the cell lines, examined the genetic relationship of SNPs and CNVs, and, with Chris Tyler-Smith of the Sanger Institute and Don Conrad (then a student with Jonathan Pritchard at the University of Chicago), studied properties of CNVs in population and evolutionary genetics. Given all of the striking data generated by our study, we argued strongly, both in the abstract and discussion of the publication (Redon et al. 2006), that CNV assessment should be standard in the design of all studies of the genetic basis of phenotypic variation, including those about disease susceptibility or evolution. In Nature's accompanying News & Views section, geneticist Huntington Willard wrote, "the data suggest that the greatest source of genetic diversity in our species lies not in the millions of SNPs, but rather in larger segments of the genome whose presence or absence calls into question what exactly is a "normal' human genome" (Shianna and Willard 2006).The major obstacle we encountered in publishing this work was the enormity of methods and data generated. The human/clinical genetics community anxiously awaited public release of the data, to enable their own research into genetic diseases. With great effort, we released all of our data at many public sites, including the Database of Genomic Variants, and assembled a massive 233 page Supplemental section in the Nature paper itself. We also coordinated the same-day publication of two accompanying technical papers in Genome Research, detailing the clone-based microarrays and computational tools (Fiegler et al. 2006) and the Affymetrix SNP microarrays and calling algorithms (Komura et al. 2006). Lars Feuk, in my group, took the lead to publish a fourth paper on the same day, in Nature Genetics (Khaja et al. 2006), describing our use of genome assembly comparison to identify smaller CNVs and indels, and balanced alterations like inversions. This set the stage for subsequent copy number and structural variation maps of the human genome, with even higher resolution.In recollection, I believe that we assembled just the right team of junior and senior scientists, who not only recognized the importance of CNV very early on, but also had "fire-in-the-belly' to meet what often were seen as unobtainable goals and timelines. Our core group (Sanger Institute-Lee-Scherer labs) continued to work together and used experience from this foundational study to produce a second-generation CNV map of the genome with higher resolution (Conrad et al. 2010), and to enable studies of the impact of CNVs on gene expression (Stranger et al. 2007), genetic disease (Craddock et al. 2010), and in personal genome analysis (Park et al. 2010).I suppose that when Charles and I originally contemplated what eventually would become widely dubbed as the "Redon et al Nature CNV study", it was simply to add proof of the existence of CNVs, as recognized in 2004, and to show that it was a ubiquitous form of natural genetic variation in humans. This massive study of human genetic variation tied together (for the first time) cytogenetics, submicroscopic copy number variation, and single nucleotide polymorphisms, providing a framework and standard for future studies of the human genome. Ultimately, the sheer magnitude of CNV discovery -- the essence of which we captured in the title "Global variation in copy number in the human genome'-- is what has made this paper a citation classic.References2005. "A haplotype map of the human genome." Nature no. 437 (7063):1299-320. doi: 10.1038/nature04226.Check, E. 2005. "Human genome: patchwork people." Nature no. 437 (7062):1084-6. doi: 10.1038/4371084a.Conrad, D. F., D. Pinto, R. Redon, L. Feuk, O. Gokcumen, Y. Zhang, J. Aerts, T. D. Andrews, C. Barnes, P. Campbell, T. Fitzgerald, M. Hu, C. H. Ihm, K. Kristiansson, D. G. Macarthur, J. R. Macdonald, I. Onyiah, A. W. Pang, S. Robson, K. Stirrups, A. Valsesia, K. Walter, J. Wei, C. Tyler-Smith, N. P. Carter, C. Lee, S. W. Scherer, and M. E. Hurles. 2010. "Origins and functional impact of copy number variation in the human genome." Nature no. 464 (7289):704-12. doi: 10.1038/nature08516.Craddock, N., M. E. Hurles, N. Cardin, R. D. Pearson, V. Plagnol, S. Robson, D. Vukcevic, C. Barnes, D. F. Conrad, E. Giannoulatou, C. Holmes, J. L. Marchini, K. Stirrups, M. D. Tobin, L. V. Wain, C. Yau, J. Aerts, T. Ahmad, T. D. Andrews, H. Arbury, A. Attwood, A. Auton, S. G. Ball, A. J. Balmforth, J. C. Barrett, I. Barroso, A. Barton, A. J. Bennett, S. Bhaskar, K. Blaszczyk, J. Bowes, O. J. Brand, P. S. Braund, F. Bredin, G. Breen, M. J. Brown, I. N. Bruce, J. Bull, O. S. Burren, J. Burton, J. Byrnes, S. Caesar, C. M. Clee, A. J. Coffey, J. M. Connell, J. D. Cooper, A. F. Dominiczak, K. Downes, H. E. Drummond, D. Dudakia, A. Dunham, B. Ebbs, D. Eccles, S. Edkins, C. Edwards, A. Elliot, P. Emery, D. M. Evans, G. Evans, S. Eyre, A. Farmer, I. N. Ferrier, L. Feuk, T. Fitzgerald, E. Flynn, A. Forbes, L. Forty, J. A. Franklyn, R. M. Freathy, P. Gibbs, P. Gilbert, O. Gokumen, K. Gordon-Smith, E. Gray, E. Green, C. J. Groves, D. Grozeva, R. Gwilliam, A. Hall, N. Hammond, M. Hardy, P. Harrison, N. Hassanali, H. Hebaishi, S. Hines, A. Hinks, G. A. Hitman, L. Hocking, E. Howard, P. Howard, J. M. Howson, D. Hughes, S. Hunt, J. D. Isaacs, M. Jain, D. P. Jewell, T. Johnson, J. D. Jolley, I. R. Jones, L. A. Jones, G. Kirov, C. F. Langford, H. Lango-Allen, G. M. Lathrop, J. Lee, K. L. Lee, C. Lees, K. Lewis, C. M. Lindgren, M. Maisuria-Armer, J. Maller, J. Mansfield, P. Martin, D. C. Massey, W. L. McArdle, P. McGuffin, K. E. McLay, A. Mentzer, M. L. Mimmack, A. E. Morgan, A. P. Morris, C. Mowat, S. Myers, W. Newman, E. R. Nimmo, M. C. O'Donovan, A. Onipinla, I. Onyiah, N. R. Ovington, M. J. Owen, K. Palin, K. Parnell, D. Pernet, J. R. Perry, A. Phillips, D. Pinto, N. J. Prescott, I. Prokopenko, M. A. Quail, S. Rafelt, N. W. Rayner, R. Redon, D. M. Reid, Renwick, S. M. Ring, N. Robertson, E. Russell, D. St Clair, J. G. Sambrook, J. D. Sanderson, H. Schuilenburg, C. E. Scott, R. Scott, S. Seal, S. Shaw-Hawkins, B. M. Shields, M. J. Simmonds, D. J. Smyth, E. Somaskantharajah, K. Spanova, S. Steer, J. Stephens, H. E. Stevens, M. A. Stone, Z. Su, D. P. Symmons, J. R. Thompson, W. Thomson, M. E. Travers, C. Turnbull, A. Valsesia, M. Walker, N. M. Walker, C. Wallace, M. Warren-Perry, N. A. Watkins, J. Webster, M. N. Weedon, A. G. Wilson, M. Woodburn, B. P. Wordsworth, A. H. Young, E. Zeggini, N. P. Carter, T. M. Frayling, C. Lee, G. McVean, P. B. Munroe, A. Palotie, S. J. Sawcer, S. W. Scherer, D. P. Strachan, C. Tyler-Smith, M. A. Brown, P. R. Burton, M. J. Caulfield, A. Compston, M. Farrall, S. C. Gough, A. S. Hall, A. T. Hattersley, A. V. Hill, C. G. Mathew, M. Pembrey, J. Satsangi, M. R. Stratton, J. Worthington, P. Deloukas, A. Duncanson, D. P. Kwiatkowski, M. I. McCarthy, W. Ouwehand, M. Parkes, N. Rahman, J. A. Todd, N. J. Samani, and P. Donnelly. 2010. "Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls." Nature no. 464 (7289):713-20. doi: 10.1038/nature08979.Fiegler, H., R. Redon, D. Andrews, C. Scott, R. Andrews, C. Carder, R. Clark, O. Dovey, P. Ellis, L. Feuk, L. French, P. Hunt, D. Kalaitzopoulos, J. Larkin, L. Montgomery, G. H. Perry, B. W. Plumb, K. Porter, R. E. Rigby, D. Rigler, A. Valsesia, C. Langford, S. J. Humphray, S. W. Scherer, C. Lee, M. E. Hurles, and N. P. Carter. 2006. "Accurate and reliable high-throughput detection of copy number variation in the human genome." Genome Res no. 16 (12):1566-74. doi: 10.1101/gr.5630906.Human Genome Sequencing, ConsortiumInternational. 2004. "Finishing the euchromatic sequence of the human genome." Nature no. 431 (7011):931-945. doi: http://www.nature.com/nature/journal/v431/n7011/suppinfo/nature03001_S1.html.Iafrate, A. J., L. Feuk, M. N. Rivera, M. L. Listewnik, P. K. Donahoe, Y. Qi, S. W. Scherer, and C. Lee. 2004. "Detection of large-scale variation in the human genome." Nat Genet no. 36 (9):949-51. doi: 10.1038/ng1416.Khaja, R., J. Zhang, J. R. MacDonald, Y. He, A. M. Joseph-George, J. Wei, M. A. Rafiq, C. Qian, M. Shago, L. Pantano, H. Aburatani, K. Jones, R. Redon, M. Hurles, L. Armengol, X. Estivill, R. J. Mural, C. Lee, S. W. Scherer, and L. Feuk. 2006. "Genome assembly comparison identifies structural variants in the human genome." Nat Genet no. 38 (12):1413-8. doi: 10.1038/ng1921.Komura, Daisuke, Fan Shen, Shumpei Ishikawa, Karen R. Fitch, Wenwei Chen, Jane Zhang, Guoying Liu, Sigeo Ihara, Hiroshi Nakamura, Matthew E. Hurles, Charles Lee, Stephen W. Scherer, Keith W. Jones, Michael H. Shapero, Jing Huang, and Hiroyuki Aburatani. 2006. "Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays." Genome Research no. 16 (12):1575-1584. doi: 10.1101/gr.5629106.Park, Hansoo, Jong-Il Kim, Young Seok Ju, Omer Gokcumen, Ryan E. Mills, Sheehyun Kim, Seungbok Lee, Dongwhan Suh, Dongwan Hong, Hyunseok Peter Kang, Yun Joo Yoo, Jong-Yeon Shin, Hyun-Jin Kim, Maryam Yavartanoo, Young Wha Chang, Jung-Sook Ha, Wilson Chong, Ga-Ram Hwang, Katayoon Darvishi, HyeRan Kim, Song Ju Yang, Kap-Seok Yang, Hyungtae Kim, Matthew E. Hurles, Stephen W. Scherer, Nigel P. Carter, Chris Tyler-Smith, Charles Lee, and Jeong-Sun Seo. 2010. "Discovery of common Asian copy number variants using integrated high-resolution array CGH and massively parallel DNA sequencing." Nat Genet no. 42 (5):400-405. doi: http://www.nature.com/ng/journal/v42/n5/suppinfo/ng.555_S1.html.Redon, R., S. Ishikawa, K. R. Fitch, L. Feuk, G. H. Perry, T. D. Andrews, H. Fiegler, M. H. Shapero, A. R. Carson, W. Chen, E. K. Cho, S. Dallaire, J. L. Freeman, J. R. Gonzalez, M. Gratacos, J. Huang, D. Kalaitzopoulos, D. Komura, J. R. MacDonald, C. R. Marshall, R. Mei, L. Montgomery, K. Nishimura, K. Okamura, F. Shen, M. J. Somerville, J. Tchinda, A. Valsesia, C. Woodwark, F. Yang, J. Zhang, T. Zerjal, J. Zhang, L. Armengol, D. F. Conrad, X. Estivill, C. Tyler-Smith, N. P. Carter, H. Aburatani, C. Lee, K. W. Jones, S. W. Scherer, and M. E. Hurles. 2006. "Global variation in copy number in the human genome." Nature no. 444 (7118):444-54. doi: 10.1038/nature05329.Sebat, J., B. Lakshmi, J. Troge, J. Alexander, J. Young, P. Lundin, S. Maner, H. Massa, M. Walker, M. Chi, N. Navin, R. Lucito, J. Healy, J. Hicks, K. Ye, A. Reiner, T. C. Gilliam, B. Trask, N. Patterson, A. Zetterberg, and M. Wigler. 2004. "Large-scale copy number polymorphism in the human genome." Science no. 305 (5683):525-8. doi: 10.1126/science.1098918.Shianna, K. V., and H. F. Willard. 2006. "Human genomics: in search of normality." Nature no. 444 (7118):428-9. doi: 10.1038/444428a.Stranger, B. E., M. S. Forrest, M. Dunning, C. E. Ingle, C. Beazley, N. Thorne, R. Redon, C. P. Bird, A. de Grassi, C. Lee, C. Tyler-Smith, N. Carter, S. W. Scherer, S. Tavare, P. Deloukas, M. E. Hurles, and E. T. Dermitzakis. 2007. "Relative impact of nucleotide and copy number variation on gene expression phenotypes." Science no. 315 (5813):848-53. doi: 10.1126/science.1136678.

Establishing the Next Generation of the Protein Data Bank

Helen M. Berman

and 1 more

November 09, 2017

This document was originally published at The Winnower and is the backstory behind Berman, H.M., J. Westbrook, Z. Feng, G. Gilliland, T. N. Bhat, H. Weissig, I.N. Shindyalov, and P.E. Bourne. 2000. "The Protein Data Bank." Nucleic Acids Research no. 28 (1):235-242. doi: 10.1093/nar/28.1.235. The Protein Data Bank (PDB) archive was officially launched at Brookhaven National Laboratory (BNL) in 1971 (Protein Data Bank 1971), thirteen years after the first crystal structure of the globular protein myoglobin was published (Kendrew et al. 1958). The PDB was initially established as a repository for the 3D structures of biological macromolecules that were beginning to be determined using X-ray crystallography. In those early days, first under the leadership of Walter Hamilton, and then Tom Koetzle, the PDB served as an archive for the structural biologists who would submit and/or request access to data. The available protein structure coordinates were announced in a newsletter, and scientists who wanted access to these data would send blank magnetic tapes to BNL. Data would be loaded onto these tapes and mailed back to the users; in the 1990's, CD-ROM distribution was introduced. In 1988, when there were almost 300 structures in the PDB, a total of 259 tapes were distributed. A similar number of CD-ROMs were distributed in 1992. As usage of the World Wide Web became more common, a PDB website simplifying access to the data was created under the leadership of Joel Sussman (Peitsch et al. 1995; Stampf, Felder, and Sussman 1995). The PDB user community began to grow and diversify.In 1998, the National Science Foundation issued a Request For Proposals for management of the PDB archive, and a new organization responded with an ambitious proposal. The Research Collaboratory for Structural Bioinformatics (RCSB) group included experts in creating databases for structural biology from Rutgers, The State University of New Jersey, University of California San Diego, and the National Institute of Standards and Technology. Following a competitive review, the RCSB received the award to manage the PDB and the new RCSB PDB was launched at rcsb.org in 1999. This management change was not universally applauded, and there were many misconceptions about what changes may take place. The article published in 2000 in Nucleic Acids Research (Berman et al. 2000) aimed to announce the new systems developed by the RCSB PDB for data deposition, validation, and access, and to clarify any misconceptions.One development described in the article was the use of the Macromolecular Crystallographic Information File dictionary (Fitzgerald et al. 2005) to standardize and process data. PDBx/mmCIF contains specific definitions for every data item and does not have any restrictions with respect to the size and complexity of a structure. Some users were concerned that the PDB file format, created in the 1970s (Bernstein et al. 1977) and used by so many software applications, would no longer be available. However, data now processed and annotated data using the PDBx/mmCIF dictionary could be easily translated into the PDB file format. In fact, data represented in the PDB file format became far more standardized and reliable due to the checking enabled by the use of the formalized data dictionary. Today, the limitations of the original PDB file format are obvious, given its inability to support the increasingly large and complex structures that are being deposited to the archive. As a result, there is community acceptance for PDBx/mmCIF as the official format for PDB data.The Nucleic Acids Research article also described specific validation procedures that were incorporated to assess the quality of the data deposited to the archive. In 1999, some PDB users felt that the archive should only contain data as directly submitted by the authors, since validation procedures could lead to a misrepresentation of author intent. While structural biologists may have expert understanding of the data represented in a PDB entry, this point of view did not take into account the growing number of non-structural biologist users and students to whom data quality is very important. Indeed in the 2000's, there was a huge push for more powerful and standardized validation methods in response to concerns about misconduct and misuse of the data. Now the need for uniform and reliable data across the archive is well recognized.The 2000 article also described partnerships established with the European Bioinformatics Institute and Osaka University for data processing and exchange so as to ensure a single archive. At the time, some believed that multiple data processing centers would only lead to a disorganized data archive. However, the collaboration between data deposition and processing centers only continued to strengthen over the years. These partnerships were formalized in 2003 with the creation of the Worldwide Protein Data Bank (wwPDB; wwpdb.org), whose new mission was to ensure standard representation and processing standards in the PDB archive (Berman, Henrick, and Nakamura 2003). The wwPDB collaboration has worked to standardize data across the archive through targeted "remediation" efforts (Lawson et al. 2008; Henrick et al. 2008) and developed a new system for data deposition and annotation that will be used by all wwPDB data centers (Quesada et al. 2011; Gore, Velankar, and Kleywegt 2012; Young et al. 2013). In addition, the existence of several data centers makes it possible to keep up with an increasing data load.The RCSB PDB was also responsible for the development and support of resources for distribution of the data archive. As noted in the article, the PDB archive contained 10,714 released entries of proteins and nucleic acids as studied by X-ray crystallography, nuclear magnetic resonance (NMR), and other methods in September 1999. This included the distribution of the archive of "flat" data files via FTP, which was still copied onto CD-ROMs and sent via postal mail on a quarterly basis. In addition, the RCSB PDB established a website offering many functionalities. At its core was an integrated system of databases, including a relational database, an object oriented database, a text search engine, and a database of crystallization information. The RCSB PDB website supported a variety of searches for structures across the archive, the production of a large variety of reports, and the ability to visualize and analyze individual structures. Links to related resources were provided. Online mirrors of this website were also maintained among the RCSB PDB partner sites and with international collaborators.The 2000 Nucleic Acids Research article described a Protein Data Bank that was poised to evolve with new science, utilize new technologies to serve the data, and work with its user community to provide the resources required to enable scientific research. The citation is used to reference access through rcsb.org to the ~100,000 entries now available in the PDB archive, as well as to the specialized resources that the RCSB PDB provides for analysis and visualization. A review of citations referencing the 2000 article shows that the vast majority of citations are from users who do not themselves deposit data. These articles are from the wide spectrum of the biological community including biochemists and cell, molecular, and evolutionary biologists. Mathematicians, statisticians and physicists also cite use of the RCSB PDB. Website usage of the RCSB PDB site continues to increase. On average, RCSB.org was accessed by about 319,000 unique visitors from about 190 countries, transferring 1924 GB of data from the website each month in 2013. The initial services provided by the RCSB PDB website continue to be developed and improved in order to support the expanding community of users (Rose et al. 2013; Rose et al. 2011). Increasingly, students and teachers use the RCSB PDB for the educational resources provided, such as a regular Molecule of the Month column. A goal of the RCSB PDB is to create a structural view of biology. That goal is within reach.AcknowledgementsThe RCSB PDB is funded by the NSF (DBI 0829586 ), NIH, and DOE. RCSB PDB is a member of the Worldwide Protein Data Bank.ReferencesBerman, Helen M., Kim Henrick, and Haruki Nakamura. 2003. "Announcing the worldwide Protein Data Bank." Nat Struct Biol no. 10 (12):980. doi: 10.1038/nsb1203-980Berman, Helen M., John D. Westbrook, Zukang Feng, Gary Gilliland, T.N. Bhat, Helge Weissig, Ilya N. Shindyalov, and Phil E. Bourne. 2000. "The Protein Data Bank." Nucleic Acids Res. no. 28:235-242. doi: 10.1093/nar/28.1.235Bernstein, Frances C., Thomas F. Koetzle, Graheme J.B. Williams, Edgar F. Meyer Jr., Michael D. Brice, John R. Rodgers, Olga Kennard, Takehiko Shimanouchi, and Mitsuo Tasumi. 1977. "Protein Data Bank: a computer-based archival file for macromolecular structures." J. Mol. Biol. no. 112:535-542.doi: 10.1016/S0022-2836(77)80200-3Fitzgerald, Paula M. D., John D. Westbrook, Philip E. Bourne, Brian McMahon, Keith D. Watenpaugh, and Helen M. Berman. 2005. "4.5 Macromolecular dictionary (mmCIF)." In International Tables for Crystallography G. Definition and exchange of crystallographic data, edited by S. R. Hall and B. McMahon, 295-443. Dordrecht, The Netherlands: Springer.Gore, S., S. Velankar, and G. J. Kleywegt. 2012. "Implementing an X-ray validation pipeline for the Protein Data Bank." Acta Cryst no. D68:478-483. doi: 10.1107/S0907444911050359Henrick, Kim, Zukang Feng, Wolfgang F. Bluhm, Dimitris Dimitropoulos, Jurgen F. Doreleijers, Shuchismita Dutta, Judith L. Flippen-Anderson, John Ionides, Chisa Kamada, Eugene Krissinel, Catherine L. Lawson, John L. Markley, Haruki Nakamura, Richard Newman, Yukiko Shimizu, Jawahar Swaminathan, Sameer Velankar, Jeramia Ory, Eldon L. Ulrich, Wim Vranken, John Westbrook, Reiko Yamashita, Huanwang Yang, Jasmine Young, Muhammed Yousufuddin, and Helen M. Berman. 2008. "Remediation of the Protein Data Bank Archive." Nucleic Acids Res no. 36 (Database issue):D426-D433. doi: 10.1093/nar/gkm937Kendrew, John C., G. Bodo, Howard M. Dintzis, R.G. Parrish, Harold Wyckoff, and David C. Phillips. 1958. "A three-dimensional model of the myoglobin molecule obtained by x-ray analysis." Nature no. 181:662-666. doi: 10.1038/181662a0Lawson, Catherine L., Shuchismita Dutta, John D. Westbrook, Kim Henrick, and Helen M. Berman. 2008. "Representation of viruses in the remediated PDB archive." Acta Cryst. no. D64:874-882. doi: 10.1107/S0907444908017393.Peitsch, M.C., T.N. Wells, D.R. Stampf, and J.L. Sussman. 1995. "The Swiss-3DImage collection and PDB-Browser on the World-Wide Web." Trends Biochem. Sci. no. 20:82-84. doi: 10.1016/S0968-0004(00)88963-XProtein Data Bank. 1971. "Protein Data Bank." Nature New Biol. no. 233:223. doi:10.1038/newbio233223b0.Quesada, Martha, John Westbrook, Tom Oldfield, Jasmine Young, Jawahar Swaminathan, Zukang Feng, Sameer Velankar, Takanori Matsuura, Eldon Ulrich, Steve Madding, Gerard J. Kleywegt, John L. Markley, Haruki Nakamura, and Helen M. Berman. 2011. "The wwPDB common tool for deposition and annotation." Acta Cryst no. A67:C403-C404.Rose, P. W., B. Beran, C. Bi, W. F. Bluhm, D. Dimitropoulos, D. S. Goodsell, A. Prlic, M. Quesada, G. B. Quinn, J. D. Westbrook, J. Young, B. Yukich, C. Zardecki, H. M. Berman, and P. E. Bourne. 2011. "The RCSB Protein Data Bank: redesigned web site and web services." Nucleic Acids Res no. 39:D392-D401 doi: 10.1093/nar/gkq1021Rose, P. W., C. Bi, W. F. Bluhm, C. H. Christie, D. Dimitropoulos, S. Dutta, R. K. Green, D. S. Goodsell, A. Prlic, M. Quesada, G. B. Quinn, A. G. Ramos, J. D. Westbrook, J. Young, C. Zardecki, H. M. Berman, and P. E. Bourne. 2013. "The RCSB Protein Data Bank: new resources for research and education." Nucleic Acids Res no. 41 (D1):D475-D482. doi: 10.1093/nar/gks1200.Stampf, DR, CE Felder, and JL Sussman. 1995. "PDBBrowse - a graphics interface to the Brookhaven Protein Data Bank." Nature no. 374:572-574. doi: 10.1038/374572a0Young, Jasmine Y., Zukang Feng, Dimitris Dimitropoulos, Raul Sala, John Westbrook, Marina Zhuravleva, Chenghua Shao, Martha Quesada, Ezra Peisach, and Helen M. Berman. 2013. "Chemical annotation of small and peptide-like molecules at the Protein Data Bank." Database no. 2013:bat079.

There's Probably an App For This: How We Identified a Relationship Between Cell Phone...

Andrew Lepp

and 3 more

November 09, 2017

This article was originally published at The Winnower and is the backstory behind Lepp, Andrew, Jacob E. Barkley, and Aryn C. Karpinski. 2014. "The relationship between cell phone use, academic performance, anxiety, and Satisfaction with Life in college students." Computers in Human Behavior no. 31 (0):343-350. doi: 10.1016/j.chb.2013.10.049.We like to say that the idea for this research was hatched over the grill at a backyard barbeque. And that's the truth. It was. We were discussing the widespread use of cell phones across our college campus. We had observed students using phones in every conceivable setting and circumstance - the classroom, the library, the recreation center, on sidewalks, on benches, in cars, in the grass, and under the trees. Of course, we have all seen this. We've probably seen it in ourselves. It is nothing novel anymore. But at the heart of our conversation was the idea that more often than not, the cell phone users were sitting or standing still. We also saw this at the barbeque with our own children if someone tossed them an iPhone. That led us to this hypothesis: despite its inherent mobility, cell phone use disrupts physical activity, encourages sedentary behavior and consequently reduces cardiorespiratory fitness. We developed a study to test this and the findings supported the hypothesized relationships (Lepp et al. 2013). As part of that study, we interviewed 49 college students about their cell phone use. We asked a variety of questions related to the hypothesis, but we also asked students to describe their cell phone use and how cell phone use makes them feel. Of course, many students described feeling happy or connected when using the phone; but to our surprise, an equal number of students described feeling anxious, stressed, annoyed, irritated and regretful. As we looked more closely at the data, it appeared that the students who reported these negative feelings were the students who used the phone the most. Students also reported being distracted by the phone when studying and using the phone in class. This did not surprise us. However, we were intrigued when once again we noticed that these behaviors appeared more frequently among students with the greatest cell phone use. Considering this new information, we hypothesized that cell phone use would be negatively associated with academic performance, positively associated with anxiety, and that together these relationships would link increased cell phone use with decreased happiness (Lepp, Barkley, and Karpinski 2014). Testing this hypothesis led to the article we will discuss below. Thus, it too can be traced, albeit circuitously, to that backyard barbeque.Since very little research has examined these issues, we felt that assessing the hypothesized relationships would make a nice contribution to the extant cell phone literature. We created a survey with the intent of administering it to 500 undergraduate students. The survey included a validated measure of anxiety, a validated measure of happiness (subjective well-being), a self-report measure of cell phone use which we had previously developed and published, and lastly a consent form which would give us permission to access participants' official academic records. This was necessary as participants' actual, cumulative grade point average (GPA) would be our measure of academic performance. After gaining approval from the university's Internal Review Board (IRB) as well as the university Registrar, we were ready to collect data. This was the tricky part. IRB approval required that we carefully explain to each participant how we would access their academic records and how we would keep that information confidential and anonymous. To do this, we needed help from faculty with no direct stake in the project. First, we identified a mix of large classes across campus likely to yield a final sample representative of the larger student body - that is to say, a sample with a wide array of majors and evenly distributed by class standing. Second, we contacted the professors for each class, explained the project and requested thirty minutes of their class time in order to administer the survey. This was a bit awkward since we had nothing to immediately offer in return, only a promise to repay the favor in the future. As it turned out, each of the professors we contacted was interested in the study and freely gave their class time. For this we are very thankful - there is a generous and supportive faculty here at Kent State University and we are privileged to be a part of it.What happened next was relatively easy in comparison to some of our other projects. After a dedicated graduate assistant entered the data into a spreadsheet, a path analysis revealed that each of the hypothesized relationships were significant and in the hypothesized direction. Furthermore, all of the fit indices suggested a very good model. Thus, there was no need to develop and test alternatives. The central finding was this: cell phone use was negatively related to GPA and positively related to anxiety. Following this, GPA was positively related to happiness while anxiety was negatively related to happiness. Thus, for the population studied, high frequency cell phone users tended to have lower GPA, higher anxiety, and diminished happiness relative to their peers who used the cell phone less often. We carefully prepared a manuscript highlighting previous research and presenting our own findings. We submitted it to the journal Computers in Human Behavior. This was our first choice because much of the research we reviewed had been published there, the journal is highly respected, and it has a well-developed online presence. The journal's reviewers and editors provided positive feedback and helpful comments for fine tuning the manuscript. It was accepted with only minor revisions and soon after published online.Along with the online publication, Kent State University issued a press release highlighting our findings. Within an hour of the press release our phones began ringing. First it was local media and by day's end we had a call from TIME magazine. TIME placed a brief article online within 24 hours. In England, the Daily Mail and Guardian soon followed. Then the tweets began. In all, the article stayed in the news for nearly a month and made its way to TV and radio as well. We had a sense this would be of interest to the public but the magnitude of coverage was surprising. To explain this media interest we need only consider the ubiquity of the cell phone. The majority of adults and an increasing number of adolescents and children carry one. Furthermore, with their expanding functionality and Internet connectedness, cell phones have transcended their utilitarian purpose of two-way communication and have entered the realm of pop culture. Cell phones are now marketed as lifestyle enhancers and status symbols. Nevertheless, there is a sense among some that we have become too dependent on the devices (Gibson 2011). Or a sense that after a point, cell phone use may no longer be beneficial. There are now reports of people texting in their sleep (Roberts 2013), experiencing nomophobia (Kung 2012), using the phone as a source of personal identity (Foley, Holzman, and Wearing 2007), and experiencing the phone ringing when it is not (Hu 2013). Add to this our research linking cell phone use with decreased academic performance, increased anxiety and reduced happiness and it raised a red flag. To be clear, our research identifies relationships, not causality. The media was quite vigilant about highlighting this distinction. Even so, it is apparent that the findings hit a nerve and perhaps inspired a brief and critical reflection on our society's cell phone infatuation - a reflection which no doubt was soon interrupted by a text, tweet, Facebook update, or impulse to conquer the next level of Candy Crush Saga.The public was extremely receptive to this research. It does make for intriguing discussion and debate. Yet there were negative comments from the public as well. These voices were accusing us of spending government money to research the obvious. In response: this study was not funded, we never requested funding, and it cost us nothing other than our own time and effort. That said, if you are reading this and happen to be a reviewer for the National Institute of Health - we have some great ideas for expanding this research but they will require your financial assistance.ReferencesFoley, Carmel, Caryn Holzman, and Stephen Wearing. 2007. "Moving Beyond Conspicuous Leisure Consumption: Adolescent Women, Mobile Phones and Public Space." Leisure Studies no. 26 (2):179-192. doi: 10.1080/02614360500418555.Gibson, E. Smartphone dependency: a growing obsession with gadgets. 2011. Available from http://usatoday30.usatoday.com/news/health/medical/health/medical/mentalhealth/story/2011/07/Smartphone-dependency-a-growing-obsession-to-gadgets/49661286/1Hu, E. Phantom Phone Vibrations: So Common They've Changed Our Brains? 2013. Available from http://www.npr.org/blogs/alltechconsidered/2013/09/30/226820044/phantom-phone-vibrations-so-common-they-ve-changed-our-brainsKung, V. . Rise of 'nomophobia': More people fear loss of mobile contact. 2012. Available from http://www.cnn.com/2012/03/06/tech/mobile/nomophobia-mobile-addiction/index.html?sr=sharebar_googleLepp, Andrew, Jacob E. Barkley, and Aryn C. Karpinski. 2014. "The relationship between cell phone use, academic performance, anxiety, and Satisfaction with Life in college students." Computers in Human Behavior no. 31 (0):343-350. doi: 10.1016/j.chb.2013.10.049.Lepp, Andrew, Jacob Barkley, Gabriel Sanders, Michael Rebold, and Peter Gates. 2013. "The relationship between cell phone use, physical and sedentary activity, and cardiorespiratory fitness in a sample of U.S. college students." International Journal of Behavioral Nutrition and Physical Activity no. 10 (1):79. doi: 10.1186/1479-5868-10-79.Roberts, K. Sleeptexting Is the New Sleepwalking. 2013. Available from http://www.theatlantic.com/health/archive/2013/10/sleeptexting-is-the-new-sleepwalking/280591/

I Would Much Rather Write Computer Programs

George Sheldrick

and 1 more

November 09, 2017

This article was originally published at The Winnower and is the backstory behind Sheldrick, G. 2008. "A short history of SHELX." Acta Crystallographica Section A no. 64 (1):112-122. doi:10.1107/S0108767307043930.SHELX is simply a widely used set of crystallographic computer programs that I have spent most of the last 45 years, in my spare time from university teaching, writing and I am by no means finished yet. There are many better programs but for reasons that I have never understood, many crystallographers like to use (and cite) SHELX. You can find more details on the SHELX homepage. I'm not really interested in being highly cited. I would much rather write computer programs!

What Happened When We Tried To Publish a Real Paper Investigating Time Travel

Robert Nemiroff

and 1 more

November 09, 2017

This article was originally published at The Winnower and is the backstory behind: Robert Nemiroff, Teresa Wilson, Searching the Internet for evidence of time travelers, The Winnower 4:e140984.46096 (2014). DOI: 10.15200/winn.140984.46096How is it that a paper that could not get published had the fourth highest reported Altmetric score for all scientific contributions in 2013 (Liu 2014)? This contribution to the Grain has the interesting backstory, written at the request of a Winnower editor. Hang on -- this (long) story includes enthusiastic graduate students, numerous rejection emails, a wife with an encyclopedic knowledge of Doctor Who, a parody by a popular late night talk show host, and an unsolicited offer to buy the movie rights. I could not make this up.First of all, the topic itself is a controversial one, as made clear immediately by the work's title "Searching the Internet for Evidence of Time Travelers" (Nemiroff & Wilson 2014). It is perhaps accepted common knowledge that people who believe in time travelers are crackpots and their ramblings are not to be believed. For the record, I do not believe that traveling back in time is possible, nor do I believe that time travelers are among us. I never did. However, I was not so absolutely sure that I did not check, with the help of students, in as scientifically a manner as possible.Next, a little background about me. I am a (full) professor of physics at a state school in the USA, Michigan Technological University to be precise. I would not have gone on this unusual journey -- a journey that ended up probing the limits of science publishing -- if I did not have tenure. Some people might say that trying to publish an article on such an outrageous topic is an abuse of tenure and an indication that tenure is outdated and should be abolished. Others might say that situations like this are exactly the reason why tenure was invented.THE RESEARCHIt is hard to say when the project really started. Even when I was in grade school I was interested in physics, would read a lot of science fiction, and would sometimes think about the possibility of time travel. I overheard occasional speculation where people would say that if they could travel back in time they would bring back winning lottery numbers, and therefore wondered if some lottery winners were also time travelers. After reading a few accounts, I concluded: generally not. Still, in the back of my mind, I continually wondered if there was any good way to find a real time traveler.In 2009 I read a brief Facebook exchange on the page of a friend highlighting this same topic -- if people from the future were here, how could we tell? Apparently, other people speculated about this as well. I wondered "what if a future-person did an Internet search on something they could not have known about at the time?" I had access only to the log files of an astronomy web site that I help write and administer and so I did a quick search through some log files for queries involving comets that were not known about at the time. I found nothing of note. Past that, I mentioned the idea to a graduate student of mine but nothing much more was done. We had plenty or "real" research projects to work on.During the summers of recent years, I am fortunate enough to have a group of students working with me, including both graduate and undergraduates students. In the summer of 2013, there were five students in all, and at summer's start I tried to come up with projects for each of them. As a group, my students and I would meet twice a week, once at the school and once at my home where we would play poker. The poker was for chips, not money, as pride seems to be a sufficient motivator for students and academics. Part of the idea of meeting over poker-playing was to create a setting where we could all talk about science in an informal setting. At one of these meetings, toward the beginning of the summer, I brought up the question of time travel and challenged my students to come up with ways of searching for time travelers in as scientific and verifiable method as possible.The students LOVED this topic. Every meeting we would talk in increasing depth about how real scientific searches for time travelers might proceed. It was not so easy as it might seem. As expected, investigating lottery winners came up -- but we quickly agreed that it would be pretty difficult to check on them. Idea after idea was suggested and discarded. Disqualifying attributes included taking too much time to investigate, creating too much expensive travel, requiring private or inaccessible information, or not being easily falsifiable. It was easy to come up with bad ways -- was there any good ways that we could actually try?Drawing on my past experience, I suggested the Internet. This quickly became far and away the most popular method to discuss. One reason is that the modern Internet is a mark of the student's generation, and they knew attributes, sites and search methods that I did not. A good tool, we soon decided, was "prescient information" -- information that could not have been known at the time. For example, say in the year 2010 your neighbor keeps asking you if Pope Francis has been elected yet. Repeatedly. "No", you might say, repeatedly, followed sometimes by "who is Pope Francis?" After a while you might ask your friends if they know anything about a "Pope Francis." Were this to persist, one might tweet a query on Twitter. No one would know. The whole name "Pope Francis" did not exist in the public lexicon before March 2013. This "unknowable at the time knowledge" became the basis for the most scientific set of searches for time travelers that we could afford the time and money to do. And the name "Pope Francis" was indeed a factor.So we searched. Graduate student Teresa Wilson soon took the lead. It was a lot of fun! We searched with Google and Bing, we searched Facebook, Google Plus, and Twitter -- everywhere we could for "unknowable at the time knowledge". Eventually we narrowed the focus to two well-thought out search terms to keep things manageable: "Pope Francis" and "Comet ISON". I included my old search strategy of looking for prescient searches in the log files of the Astronomy Picture of the Day web site (Nemiroff & Bonnell 1995). We also posted a request for active communication over the Internet -- for time travelers to contact us before the request was given.We found nothing. We uncovered no "unknowable at the time knowledge" during our limited search of the Internet. Time travel may be discoverable, but we didn't discover it. Still, given the pervasiveness of the Internet and the vastness of the online databases that major web sites like Twitter hold -- ours, it appeared, was the most comprehensive search for time travelers ever. I therefore began writing it up.Now this paper was fun to write. I had been reading about the science and fiction of time travel for 40 years, and here was a chance to use some of this arcane knowledge. I wasn't sure if the result would be publishable. The manuscript, written mostly in 2013 July and August, turned into a strange fusion of two completely different paradigms -- that of classic knowledge about time from people like Einstein and Godel -- and that of modern knowledge about the fast-changing Internet including sites like Google and Facebook. I would send versions of the paper to Wilson to add on to and edit. In my opinion, the resulting manuscript was quite well written.THE SPECTACULAR FAILURE OF EARLY PUBLICATION ATTEMPTSOur first attempt to publish "Searching the Internet for evidence of time travelers", in late September of 2013, was at a classic physics journal that deals with foundational questions at the heart of physics. I have decided not to mention any journal or editor names involved in the rejection of the manuscript. I uploaded the paper to the journal and waited. A few days later, I received an email saying that the journal would not send the manuscript out for review. There was no specific reason given, but the email included a list of attributes that they require in a paper, with the implication was that our manuscript lacked one or more of these attributes. The email was signed by a very famous physicist. I don't really know if this famous physicist ever really read the manuscript -- this email could have been a form-letter email sent out by someone in the front office. I decided to reply -- an effort to reject their apparent rejection -- by asking the famous editor how (s)he really knew, experimentally, that time travel was not possible. I waited. One week. Two weeks. One month. Nothing. No reply.Don't worry, I told Teresa, this work can still be published -- there are other opportunities. I have a friend in the physics department who is on the editorial board of a reputable physics journal and he has asked me, on occasion, if I would consider submitting a paper to that journal. Previously, I had not. Now, I considered it. I gave him the manuscript to read. He knew this would be a "hot potato" but did encourage me to submit it. So I did. About a week later, I received a polite email saying that the manuscript was on a topic inappropriate for this journal. They would not send it out for review and would not consider it further. True to form, I again responded with an impassioned email asking them to reconsider. A few weeks later -- a reply -- but no change. My friend speculated that, quite possibly, there was disagreement among the journal editors about how to handle the manuscript, but that in the end they went with the more conservative course of action. A third physics journal geared more toward the philosophy of physics soon responded similarly.Soon it was December and I had lost hope that the manuscript would be accepted by a journal before Wilson and I presented the main concepts in a poster at the January meeting of the American Astronomical Society (AAS). Possibly because I had attended almost every Winter AAS meeting for the past 20 years and knew so many AAS people, the meeting organizers had accepted the abstract even though it was more physics than astronomy. For this I was grateful. Even though I checked the box indicating that the research was, in my opinion, worthy of press attention, the AAS did not select the paper as a press highlight.Although I anticipated some interesting discussions at the AAS, I was now worried that by presenting only a sketchy poster, others might research, write, and publish on this idea themselves before we ourselves could get it into a journal. I therefore decided to upload the manuscript to a standard web site that posts manuscripts and papers both before and after publication, the arXiv at http://arXig.org/. That way, at the AAS poster, I could at least refer to a finished but unpublished manuscript. Now over the course of my career, I routinely submitted manuscripts and papers that I wrote to the arXiv and received only an occasional email in response. I was grateful, again, that my upload of the manuscript to the arXiv was successful (although they reclassified it), since arXiv does reject manuscript that its editors consider unworthy. The manuscript was uploaded to arXiv.org on 2013 December 26 (Nemiroff & Wilson 2013). My wife and I left on a long car trip the very next day from our home in Michigan to the US east cost to visit relatives, honor a standing speaking engagement I had in New York City the next week, and attend the AAS meeting near Washington, DC the week after.VIRAL EXPLOSIONOn the road, I received an unexpected call from a major US news outlet: NBC. I called them back from a rest stop off Interstate 80. They wanted to know about the time travel paper. "What time travel paper?" I asked. The editor had seen our manuscript on arXiv and wanted to interview me. I was surprised that they even knew about the manuscript on arXiv. Hundreds of manuscripts appear on arXiv daily and it is understood that many of them are not finished works.I replied that I was presenting a poster on the topic at the AAS meeting in two weeks and asked if I could postpone this interview until then. I was surprised at his reply. He said he couldn't wait until the AAS meeting -- the manuscript is already "all over the Internet." Wow. So I gave the interview (Boyle 2014). And soon after, another. The emails poured in. Now almost every time we stopped, I returned someone's email or phone request. I have never had a published paper become so popular, not even papers accompanied by a press release -- and this manuscript was neither published nor promoted by a press release.I decided to ride the publicity wave, trying to see this as an unexpected ride on the amusement park of life, and guessing that I would never have this chance again. I set aside about an hour a day during the next few weeks to do phone interviews and answer email about the time travel manuscript. I referred several interviews to Wilson as well. Apparently, much of the public was seeing this in a different light than journal editors. Most of the coverage was quite positive, but possibly the highest profile report -- on the Colbert Report -- appeared to focus on the seeming silliness of expecting a time traveler to tweet about the future (Colbert 2014). Oh well. Several of the write-ups were excellent, with one high point was the front web page of Der Spiegel where the manuscript was a focal point in a discussion about data sharing being limited by web behemoths like Facebook and Google.At the AAS meeting it turned out that many people who approached our poster already knew about the work. Again, most comments were positive, but then again people with negative comments would be less likely come up and volunteer them. At least three journal editors approached, each separately, and each said that they admired the work but they could never publish something like this in their journal(s). Conversely, one journal editor asked me to submit the manuscript to his journal, but eventually even that journal's editorial board decided the topic was too far afield to send out for review.The most unexpected email I received was from a movie producer who wanted to buy the movie rights. Neither the producer nor I had ever heard, previously, of a scientific manuscript being optioned for movie rights. I discussed the situation with my wife and we debated whether the request was actually some sort of joke. I called back with some questions and so far as we could tell, the offer seemed legitimate. In fact, a Google search showed that the movie producer had a history of making several low-budget independent films. About a month later, after some haggling, he mailed both Wilson and me each a check for $100. Although few actual options are made into movies, I have been in contact with the producer who relates that he is working on a script.LAST TRY FOR AN ESTABLISHED JOURNALGiven encouragement from colleagues, the press, and a movie producer, I decided to try to publish the manuscript in an established journal one last time. Based on some savvy advice from a friend, I agreed to approach a really famous journal that actually had published papers involving the possibility of time travel before. I felt encouraged as I uploaded the manuscript, thinking how cool it would be for this prestigious journal to publish a manuscript that other less prestigious journals had so quickly rejected.So the prestigious journal also rejected the manuscript without review. In their borderline-mocking rejection email, the corresponding editor reported that another editor for this journal had said that the idea behind the manuscript was not even new -- a Doctor Who episode had explored this very concept previously. The precise episode was even mentioned.I was taken aback. Could I have gotten this idea from Doctor Who and not realized it? I could not remember so, and I did not recall even seeing the episode the rejection email referenced. I mentioned this to my wife who surprised me by saying that she herself has seen -- or knew about -- every Dr. Who episode since the modern reboot in 2005, and could say definitively that the main idea of this manuscript was not involved. Still, to be extra sure, we rented the episode in question and watched it in its entirety. My wife was right -- the idea of searching for "unknowable at the time knowledge" over the Internet just was not in this episode. After more thought, my wife gave me the title of the one other Doctor Who episode that might have something relevant to our search in it. So we also rented that episode as well and nothing in it, from start to finish, was relevant to the time travel manuscript.I then responded to the prestigious journal's editor relating my Doctor Who investigation and implying that, given my wife's encyclopedic knowledge of Doctor Who, no episodes at all were directly relevant to the search methods of our manuscript. I then asked them, in light of the manuscript's now verified novelty, to reconsider and send the manuscript out for peer review. In a bid for more respect, I also related that not only had I published in this journal before, but I had been a referee for this journal previously as well. In the response, the editor said that (s)he has now sent the article out to another editor, one who is quite famous in this area, but who also agreed that this paper should be rejected without being sent out for peer review. In this reply, the famous editor said:"I should point out that most stock markets around the planet devote considerable resources to looking for temporally anomalous market behavior --- unusual trading patterns before significant news events. When found, such signals are not typically attributed to time travelers, but more prosaically to insider trading."I agree! This is one reason why we did not look for evidence of time travel in stock market trading. Early on, our group had discussed (briefly) this idea. On one hand, I was glad that finally we had a real criticism to address, but on the other hand, this famous editor's comment indicated to me, once again, that the journal editors did not fully appreciate the novelty, power, simplicity, and falsifiability of our approach. Instead, they gave straw-man criticisms that really meant, in my view, that they did not want to consider a manuscript so unconventional. In my reply, I argued in detail against this criticism and again asked that the manuscript at least be sent out for formal peer review. Alternatively, I asked for a clear reason that the paper was being rejected. Ultimately, however, these arguments went nowhere. The journal editors would do neither, and eventually asked me to stop emailing them on this topic. So I stopped.ON TO THE WINNOWERSoon after the manuscript on arXiv went viral, I received an email from Joshua Nicholson of the Winnower asking if I would write a piece about the manuscript for the web publication's "Grain" section. Apparently, the arXiv manuscript's Altmetric score of over 2,000 had alerted him. I initially replied then that I would but I was still trying to figure out what to do with the manuscript itself. Josh replied that the manuscript could eventually be uploaded to the paper section of the Winnower and opened for public review. I had not heard about the Winnower before, but soon read up on it. Even so, at the time, I tried first for a more established journal. Now that publication in an established journal seemed unlikely, and given that I would not publish this in a "scam" journal even given numerous email advertisements, I took a closer look at the Winnower.The public review inherent in the Winnower's paper section seemed to me to be an excellent idea. I was somewhat skeptical, though, that many authors would submit their papers to this section. A key reason, in my opinion, was the "prisoner's dilemma". Although it would likely benefit the entire community to adopt a public review, it would tax individual authors primarily because of the lack of current reputation of the Winnower. Papers published on the Winnower would not, at least at first, carry the same weight during promotion and tenure deliberations as papers published in a journal with an established reputation.My opinion on this draws on a similar situation that I found myself in several years ago. In 1999, along with a colleague, I started the Astrophysics Source Code Libary (ASCL: Nemiroff & Wallin 1999) based on the idea that opening up the source codes behind peer-reviewed papers would increase falsifiability and benefit the astrophysics community. Since a more healthy astrophysics community is in everyone's interest, I hoped that the ASCL would become quickly popular. I was wrong. In reality, few people contributed their codes, at least at first. I did not appreciate that the extra work and the possibility of revealing poorly written code led to a "prisoner's dilemma" for code authors. Only after a new ASCL editor solicited codes, a new editorial board created policy, and new submission perks were added including having each code appear as a separate citation -- effectively a separate paper that could be cited and included in a publication list -- did the ASCL become popular (Allen et al. 2013). Even now, however, many scientists who would agree that it is a good idea to release paper-enabling source codes still do not submit their own codes to the ASCL.Nevertheless, Wilson and I were out of options, and so if we wanted our manuscript published anywhere besides the arXiv, it would be on the Winnower -- or nothing. Therefore Wilson took the last version of our paper that we submitted to the above-unmentioned prestigious journal and reformatted it for the Winnower. I uploaded the paper in early May of 2014. I might add that we have always welcomed peer review -- now including open peer review -- as evidenced by our pleading with journal editor after journal editor to send our paper out for review. That our manuscript might help advance a more open and healthy system of peer review as deployed on the Winnower was an unexpected perk. If the reader would like to read and even review the paper, please feel free to do so -- this opportunity can be found at the reference at the end of this contribution: Nemiroff & Wilson (2014).WHY DID THE MANUSCRIPT GO VIRAL?We did not know, before hand, that the original manuscript would become so popular. There are several reasons, in retrospect, that likely contributed to its popularity. First, the manuscript incorporates two attractive topics -- time travel and the Internet. Interesting papers on each topic are typically popular in their own right -- but a good paper combining the two -- possibly even more so. By coincidence, however, the manuscript actually touched on a third popular topic -- religion -- by using the search term "Pope Francis". Reporting on a paper that convolved time travel, the Internet, and religion, it turned out, created an irresistible opportunity for many editors and bloggers.On the negative side, the manuscript appears to some, at first sight, like watching a train wreck. It portrays that scientists -- who claim to be worthy of respect -- think that a ludicrous concept like time travel is real. It therefore draws in a reader possibly wondering things like "are the authors crazy?" or "do they also believe in the Easter Bunny and leprechauns?" or "are scientists (again) wasting taxpayer money?" Such readers might be disappointed that no evidence of time travelers was reported, as reading about the self-destruction of haughty scientists might have been more gratifying. On the money-wasted angle, when doing a Reddit interview about the manuscript, I respond to a question about how this research was funded with the fake answer that we used money left over from our study "Does Tax Payer Money Burn Any Better Than Regular Money?" (Nemiroff & Wilson 2014). In reality, this was an unfunded project.I'd like to think, however, that the most important factor in the manuscript's popularity was that it portrayed a really cool idea that was fun to think about. To quote Will Oremus on Slate "[authors] had me at the first line of the abstract: 'Time travel has captured the public imagination for much of the past century, but little has been done to actually search for time travelers. Say, that's a good point!" (Oremus 2014).Although surprised by the degree, I did think the paper would garner some public attention. That is because the paper was motivated by aspects of science that interest the public rather than funding agencies. After the paper's initial submission, I engaged in a short email exchange with Fraser Cain, the publisher of the Universe Today web site. We considered the idea that perhaps there is room in the world of publishing for science motivated primarily BY public interest, instead of IN THE public interest. Such a journal would involve serious peer-reviewed papers about what science really has to say about time-travel, warp drives, and creating black holes in the lab, to mention three ideas that deal with astrophysics. Conversely, the journal could also include some hard science fiction that draws from very modern science discoveries into short fiction pieces as realistically as possible. Other areas of science and engineering should also be included. Possibly publication could be coupled with a small amount of Kickstarter-like funding. Cain and I have not discussed the idea further -- we are both too busy -- but if anyone out there on the Internet wants to explore this idea further, consider me a supporter.REFERENCESAllen, Alice. et al. 2013. The Astrophysics Source Code Library: Where do we go from here? arXiv:1312.5334.Boyle, Alan.2014. Internet Search for Time Travelers Turns Up Nothing ... This Time.http://www.nbcnews.com/science/weird-science/internet-search-time-trave....Colbert, Steven. 2014. Time Travel Research in Cyberspace.http://thecolbertreport.cc.com/videos/b9gbou/time-travel-research-in-cy....Lischka, Konrad. 2014. Spuren aus der Zukunft: US-Forscher suchen Zeitreisende im Netz.http://www.spiegel.de/netzwelt/web/us-forscher-suchen-zeitreisende-im-n....Liu, Jean. 2014. Interactions: January High-Five (2014). Altmetric Blog.http://www.altmetric.com/blog/interactions-january-high-five-2014/.Nemiroff, Robert & Wilson, Teresa. 2014. We searched for time travelers who inadvertently posted unknowable-at-the-time knowledge to the Internet. Ask us anything!http://www.reddit.com/r/IAmA/comments/1va4vq/we_searched_for_time_trave....Nemiroff, Robert J. & Bonnell, Jerry T. 1995. Bulletin of the American Astronomical Society. 27:1291. Astronomy Picture of the Day: http://antwrp.gsfc.nasa.gov/apod/astropix.html.Nemiroff, R. J. & Wallin, J. F. 1999. Bulletin of the American Astronomical Society. 31:885. The Astrophysics Source Code Library: http://www.ascl.net/.Nemiroff, Robert J., & Wilson, Teresa. 2013. Searching the Internet for evidence of time travelers. arxiv.org/abs/1312.7128.Nemiroff, Robert, & Wilson, Teresa. Searching the Internet for evidence of time travelers, The Winnower, https://thewinnower.com/papers/searching-the-internet-for-evidence-of-t....Oremus, Will. 2014. Physics Professors Search Internet for Time Travelers, Don't Find Any. Slate.http://www.slate.com/blogs/future_tense/2014/01/03/professors_search_in....

A Transgender Brazilian Cave Insect

Kazunori Yoshizawa

and 4 more

November 09, 2017

This article was originally published at The Winnower and is the backstory behind Yoshizawa, K., R. L. Ferreira, Y. Kamimura, and C. Lienhard. 2014. "Female penis, male vagina, and their correlated evolution in a cave insect." Curr. Biol. 24: 1006-1010. doi: 10.1016/j.cub.2014.03.022.The penis is, by definition, the male copulatory organ (e.g., New Oxford American Dictionary). Sex-specific features are not restricted to copulatory organs, and many examples of sex-specific elaborations are known, such as the horns of antlers or the decorative feather of peacocks. Evolution and exaggeration of sex-specific elaborations have attracted the attention of many biologists, including Darwin (Darwin 1871). It is now widely accepted that sexual selection promotes the evolution of elaborate sex-specific features (Trivers 1972). Because sexual selection usually acts on the male, sex-specific elaborations are frequent in male, and the male penis is highly diversified morphologically and functionally whereas female genitalia are usually simple (Eberhard 1985).

Understanding Fukushima through Butterfly Biology: Academic Freedom for Scientists an...

Joji M. Otaki

and 1 more

November 09, 2017

This article was originally published at The Winnower and is the backstory to \cite{Hiyama_2012}The impacts of the Great East Japan Earthquake on people living in the Tohoku and Kanto districts and on Japanese society in general were, in many ways, beyond description. The earthquake and the accompanying tsunami destroyed many cities along the east coast of the Tohoku and Kanto districts. However, an additional long-lasting disaster was the nuclear pollution caused by the collapse of the Fukushima Dai-ichi Nuclear Power Plant (NPP). This event was the second worst nuclear accident in the world, next to the Chernobyl accident. At the time of the collapse of the Fukushima Dai-ichi NPP, Japanese government and TEPCO (Tokyo Electric Power Company) could not evacuate people efficiently from the area around the NPP, in part because they did not want to release information on the disaster. From the outset, it appeared that the Japanese government and TEPCO were making every conceivable effort to save the nuclear industry (but not to help people living in Fukushima and vicinity) and to minimize the financial damage and negative publicity resulting from this accident. To achieve their goals, the authorities concealed information that would have put them in a worse position if it had been released. This governmental behavior is not unexpected; similar behavior was seen in the former Soviet Union at the Chernobyl accident. This is understandable in the sense that nuclear policy is strategically sensitive and is involved with making a nation strong militarily and economically. Such restriction of information for political reasons in connection with the governmental alignment with the nuclear industry is, in my opinion, the worst aspect of the use of nuclear energy to produce electricity in any country. Withholding important information hampers the public from making democratic decisions, and it violates the people’s right to know and scientists’ academic freedom.When the shock of the Great East Japan Earthquake hit the country, we were studying butterflies “peacefully” at the University of the Ryukyus, Okinawa, Japan. (I wrote “peacefully”, but Okinawa is the place where the worst ground battle took place between the United States and Japan during World War II, with a massive number of deaths of Okinawan people. Okinawa was formally under United States control from soon after the end of the war until 1972. Even now, most US military bases in Japan are located on Okinawa.) One of our favorite butterflies is the pale grass blue, which is the most abundant butterfly in Japan (including Okinawa but excluding Hokkaido). Although I was trained in olfactory neurobiology at Columbia University, New York, I had been interested in butterfly biology as an amateur lepidopterologist and butterfly physiologist since I was a little child. Thus, I have had a strong interest in using Japanese butterflies for molecular physiological studies. Immediately after returning to Japan from the University of Cambridge, U.K., more than a decade ago, I started working on the pale grass blue butterfly at Kanagawa University and then at the University of the Ryukyus.Originally, I focused on the pale grass blue butterfly from developmental and evolutionary perspectives, i.e., how wing color patterns are determined, constructed, and changed over time, and this is still an important core topic in my laboratory. We have established the standard rearing method for this species. Our methodology was published in 2010, approximately one year before the NPP accident (Hiyama et al., 2010). In this modest but important accomplishment and also in subsequent studies of this butterfly, my student Atsuki Hiyama was a major player. The idea that this butterfly may be useful for environmental monitoring accompanied our previous evolutionary study on this butterfly at the northern margin of its range (Otaki et al., 2010; Hiyama et al., 2012a). Fortunately, this research was appreciated by highly respected and prominent evolutionary biologists (Buckley et al., 2010).When the Fukushima nuclear accident occurred, I believe that everyone felt deeply sorry for people who lived in highly polluted areas. At the same time, everyone was thinking of ways in which they could help. Shortly after the accident, one graduate student of mine, Chiyo Nohara, felt that she wanted to do something. She and A.H. together discussed the possibility of using the pale grass blue. In a regular lab meeting, they proposed to me that the pale grass blue might be used to examine the possible biological impacts of the Fukushima nuclear accident. I agreed instantly because that was what I had been thinking about and because there seemed to be no technical difficulty associated with this project. The technical problems of rearing the butterfly had already been solved by A.H.. Moreover, active students’ proposals based on high motivations are my priority for deciding on research directions in our laboratory. We are not in a research institute, but we are in a university.As expected, we received a variety of opinions, comments, and advice on this matter from other students in our laboratory and from other professors in our university even before starting this research. Many of them discouraged us. Some worried about us because radioactive materials are hazardous to health. Some worried that our research might annoy people living in the polluted areas, the nuclear power industry, and Japanese government, implying that the research would politically dangerous. However, over and above theses considerations, we were terrified by the pollution itself and by the continuing release of radioactive materials. We are also terrified by the possibility of additional earthquakes and further breaches of the NPP. However, we convinced ourselves that we as scientists should contribute to something that provides biological truth on this issue.We soon noticed that we had to collect the first-voltine butterflies that will emerge at the beginning of May 2011. Otherwise, we might miss the real impact of the pollution. The first-voltine individuals were overwintering larvae at the time of the collapse. Most surely, they received massive doses externally. In April, larvae eat new leaves for growth. Therefore, they surely ate radioactive materials on the surface of leaves and inside leaves, resulting in internal exposures. They then pupated and eclosed at the beginning of May. We had to catch them!At that point, I did not know that insects had been characterized as being highly resistant to radiation. A professor who formerly worked at the National Institute of Radiological Sciences advised us that our research plan would be futile, because insects are generally highly resistant to radiation. I thought it over and considered readings on the topic that had been suggested but I came to the conclusion that such a “common sense” conclusion in radiation biology was not supported by solid experimental evidence. As a lepidopterologist, I know that the pale grass blue is quite resilient to environmental stress on the population, but it is also highly sensitive to environmental changes at the individual level. Moreover, if we could not detect anything abnormal after a thorough examination, this would be welcome news for the public because it might mean that the pollution level could be safe, at least for this butterfly.At that point, we also thought that many ecologists and other biologists in Japan would study the biological impacts of this accident because this issue is probably the single most important one in the Japanese ecosystem. In retrospect, a very limited number of laboratories studied this aspect of the Fukushima nuclear accident. In a sense, this is surprising, but in a different sense, this is not unexpected. Most of us are “professional” scientists who live on a particular research topic defined by a study field. I believe that science should be driven, at least partly, by “social demands for knowledge” sensu lato. (People worldwide wanted to know what really occurred in Fukushima.) In short, the Fukushima accident revealed a very discouraging fact; most scientists today in Japan do not care much about their social responsibility except for doing their institutionalized research.Luckily, another graduate student, Seira Kinjo, agreed with us and joined us to work on this project. We had no financial support, but we at least had sufficient human resources. We made a detailed plan for our fieldwork, which would last for a week. When these three graduate students of mine (A.H., C.N., and S.K.) and I entered the polluted areas to collect butterflies approximately two months after the accident, the overall radioactivity was still very high, and highways were physically wavy in some areas. However, we managed to complete our first mission, which covered Tokyo, Ibaraki Prefecture (Tsukuba, Mito, and Takahagi), Fukushima Prefecture (Iwaki, Hirono, Koriyama, Motomiya, and Fukushima), and Miyagi Prefecture (Shiroishi). We subsequently performed several experiments (i.e., morphological examination of the collected butterflies, morphological and physiological examinations of the next generation of butterflies, an internal exposure experiment, and an external exposure experiment) to show the correlation and causality of the NPP accident in relationship to observations of morphological abnormalities and deaths in the butterfly. These experiments were primarily based on the concept that we would reproduce, in the laboratory, what might have occurred in the field. We have been studying butterfly color pattern evolution with this approach. That is, we have been trying to reproduce evolutionary changes in the laboratory at the phenotypic level using Vanessa, Junonia, and Zizeeriabutterflies. We have applied this approach to this case of environmental pollution by radioactive materials. We also completed our second mission in September 2011 to obtain information that would allow the results for May and September 2011 to be compared. We published our results without delay on August 9, 2012 in a new open access journal,Scientific Reports (Hiyama et al., 2012b) to allow free access to our article and contribute to the understanding of the biological status of Fukushima. Coincidentally, the date of publication was the anniversary of the A-bomb attack on Nagasaki. (I am originally from Nagasaki.)Immediately after the publication of this paper, we received a massive number of responses from media, scientists, and the public worldwide. The paper has now 331,433 page views as of March 28, 2015. Some scientists criticized us politely, pointing out some points that we could not demonstrate in the paper. I appreciate their comments. However, other responses were sharp criticisms that lacked any scientific basis. Most likely, these critics firmly believe that nothing biological should happen because of the Fukushima NPP accident. Some of them appear to have read the paper intelligently and to have understood what wepresented, but they still tried to discredit the paper by offering trivial or non-scientific criticisms. The critics likely followed a program of attacking any suggestions that appeared to oppose ideas about the use of nuclear energy. Because free discussion is the core idea in science, I believe that personal attacks in science are inappropriate. Scientific discussion in this sense requires love of others in addition to love of truth. In other words, open discussion is the heart of science, and such discussion should not be personal or political, at least ideally. Otherwise, open discussion would be impossible. Open discussion on Fukushima seems to be rather difficult now.Fortunately, we received many appreciations from international media. The BBC was the very first to e-mail me and covered our story, at least on the Internet and worldwide radio. I was particularly surprised to know that a French newspaper, Le Monde, and a French popular science magazine, Science & Vie, covered our story extensively, given that France is promoting the use of nuclear energy. It was like the experience of a great difference between a fully developed self-governed nation (i.e., France) and an immature nation that is always influenced by other international pressures (i.e., Japan). I simply believe that politics must be built on open knowledge, whether it is for or against nuclear reactors.At the end of 2012, Nature announced its high-scoring papers based on the Altmetrics framework. To our real surprise, our paper was ranked top in the world (Noorden, 2012). I believe that it is a good idea to evaluate papers in terms of multiple aspects, in addition to the conventional impact factors, and in that sense, I welcomed the Altmetric score. In 2013, I presented our results in the Society for Molecular Biology and Evolution in Chicago.Nature covered our story in the news section (Callaway, 2013). Above all, we were generously helped and encouraged by some researchers who logically understand our research (e.g., Møller and Mousseau, 2013; Akimoto, 2014).I note two peculiar aspects of radiation biology. It appears that the basic philosophy of biology is not understood well in this field. (This criticism may only apply to a handful of radiation biologists.) First, in science in general, it is quite difficult to prove “nothing happened”. To prove this proposition, the experimental system should be well defined and investigated thoroughly. Simple failure and rough investigations almost always result in “no results” or “nothing happened”. On the other hand, it is relatively easy to disprove “nothing happened”, because all one has to do is to find anything that happened. Second, there are many simulation studies in radiation biology, and such studies are considered “facts” in this field. In general, biologists are notoriously unconvinced by simulation and other theoretical studies. This is because any simulation may be correct but may be incorrect. That is, any kind of phenomena can be simulated. To be sure, simulations themselves are admissible and often very important, but they should be treated as simulations, not as facts.Nuclear policy is one of the most important types of policy for any modern nation. The Manhattan Project during World War II was a component of the defense effort against Nazi Germany, and numerous nuclear bombs have been produced since then. The nuclear materials are also intended for “peaceful purposes” to justify the development of the nuclear power technologies. Richard Feynman, who was involved in the Manhattan Project and was a Nobel laureate in physics, has stated in a critical essay that nuclear power plants are just enormous machines for boiling water.It is well known that Japan is the only nation in history to be attacked with atomic bombs, and Hiroshima and Nagasaki are famous. Officially, Japan cannot have nuclear bombs on its soil due to a constitutional ban. Therefore, the Japanese government has made many efforts to build and maintain nuclear power plants (instead of producing nuclear bombs explicitly) throughout the nation and, furthermore, to advocate the absolute safety of nuclear power, although Japan has frequent earthquakes. In my opinion, Japan has numerous time bombs waiting to go off that will be triggered by earthquakes or volcanic activity in the future. In this sense, the Fukushima Dai-ichi NPP is just the first bomb to be triggered.In retrospect, we contributed to the knowledge of what really occurred at Fukushima. Our work had the chance to be highlighted because other scientists are so frightened that they ignored the public demand for knowledge. Many more scientists should have become involved in this issue because it was potentially a great accident that might have shaken the entire nation. (Most radioactive materials were dispersed to the Pacific Ocean, and Tokyo was not heavily polluted. We should recognize that Japan was simply lucky; an unlucky situation could have destroyed Tokyo and Japan almost entirely.) Science and technology should not lose the core value that all stems from academic freedom and open discussion. Science should not be used to restrict people’s view of life. Rather, science should open up a new world for people.We are making further progress on this issue now. We responded to comments from all over the world in a correspondence paper (Hiyama et al., 2013). We discussed philosophical aspects of this issue (Taira et al., 2014). We reported how genetic mutants resemble Fukushima aberrations (Iwata et al., 2013). We further evaluated the impacts of ingested radioactive materials for two generations (Nohara et al., 2014a, b). We reported the spatiotemporal dynamics of the impact from 2011 to 2013 (Hiyama et al., 2015). Luckily, we now have a very supportive graduate student from Okinawa, Wataru Taira, who has a good knowledge of butterflies. We also have a few more graduate students, Mayo Iwasaki from Tochigi, Ko Sakauchi from Fukushima, and Masaki Iwata from Miyagi. They are from the Tohoku and Kanto districts. However, I do not know how far we can go in this line of research. We have a very limited financial ability and workforce. University of the Ryukyus was built by the United States when Okinawa was still a part of it, and the University is now one of the local national universities. It seems that the Japanese government is now making a major step toward minimizing the financial ability and academic freedom of local national universities. Please watch us to see how far we can defend academic freedom in Okinawa and Japan in this early phase of the 21st century.REFERENCESAkimoto, S. 2014. “Morphological abnormalities in gall-forming aphids in a radiation-contaminated area near Fukushima Daiichi: selective impact of fallout?” Ecology and Evolution no.4: 355-369. doi: 10.1002/ece3.949Buckley, J., J. R. Bridle, A. Pomiankowski. 2010. “Novel variation associated with species range expansion.” BMC Evolutionary Biology no. 10: 382. doi: 10.1186/1471-2148-10-382Callaway, E. 2013. “Fukushima offers real-time ecolab.” Nature no. 499: 265-266. doi: 10.1038/499265aHiyama, A., M. Iwata, J. M. Otaki. 2010. “Rearing the pale grass blue Zizeeria maha(Lepidoptera, Lycaenidae): Toward the establishment of a lycaenid model system for butterfly physiology and genetics.” Entomological Science no. 13: 293-302. doi: 10.1111/j.1479-8298.2010.00387.xHiyama, A., W. Taira, J. M. Otaki. 2012a. “Color-pattern evolution in response to environmental stress in butterflies.” Frontiers in Genetics no. 3: 15. doi: 10.3389/fgene.2012.00015.Hiyama, A., C. Nohara, S. Kinjo, W. Taira, S. Gima, A. Tanahara, J. M. Otaki. 2012b. “The biological impacts of the Fukushima nuclear accident on the pale grass blue butterfly.” Scientific Reports no. 2: 570. doi: 10.1038/srep00570Hiyama, A., C. Nohara, W. Taira, S. Kinjo, M. Iwata, J. M. Otaki. 2013. “The Fukushima nuclear accident and the pale grass blue butterfly: evaluating biological effects of long-term low-dose exposures.” BMC Evolutionary Biology no. 13: 168. doi: 10.1186/1471-2148-13-168Hiyama A, W. Taira, C. Nohara, M. Iwasaki, S. Kinjo, M. Iwata, J. M. Otaki, 2015. “Spatiotemporal abnormality dynamics of the pale grass blue butterfly: three years of monitoring (2011-2013) after the Fukushima nuclear accident. BMC Evolutionary Biology no. 15: 297. doi: 10.1186/s12862-015-0297-1Iwata M, A. Hiyama, J. M. Otaki. 2013. “System-dependent regulations of colour-pattern development: a mutagenesis study of the pale grass blue butterfly.” Scientific Reports no. 3.doi: 10.1038/srep02379.Møller, A. P., T. A. Mousseau. 2013. “Low-dose radiation, scientific scrutiny, and requirements for demonstrating effects.” BMC Biology no.11: 92. doi: 10.1186/1741-7007-11-92Nohara, C., A. Hiyama, W. Taira, A. Tanahara, J. M. Otaki. 2014a. “The biological impacts of ingested radioactive materials on the pale grass blue butterfly.” Scientific Reports no. 4: 4946. doi: 10.1038/srep04946Nohara, C., W. Taira, A. Hiyama, A. Tanahara, T. Takatsuji, J. M. Otaki. 2014b. “Ingestion of radioactively contaminated diets for two generations in the pale grass blue butterfly.” BMC Evolutionary Biology no. 14: 193. doi: 10.1186/s12862-014-0193-0Noorden, R. V. 2012. “What were the top papers of 2012 on social media?” Nature News Blog 21 Dec 2012. http://blogs.nature.com/news/2012/12/what-were-the-top-papers-of-2012-on-social-media.\nhtmlOtaki, J. M., A. Hiyama, Iwata, M., Kudo, T. 2010. “Phenotypic plasticity in the range-margin population of the lyaenid butterfly Zizeeria maha.” BMC Evolutionary Biology no. 10: 252. doi: 10.1186/1471-2148-10-252Taira W., C. Nohara, A. Hiyama, J. M. Otaki. 2014. “Fukushima’s biological impacts: the case of the pale grass blue butterfly.” Journal of Heredity no.105: 710-722. doi: 10.1093/jhered/esu013