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The Human Genome Project (HGP) is regarded by many as one of the major scientific achievements in recent science history, a large-scale endeavour that is changing the way in which biomedical research is done and expected, moreover, to yield considerable benefit for society. Thus, since the completion of the human genome sequencing effort, a debate has emerged over the question whether this effort merits to be awarded a Nobel Prize and if so, who should be the one(s) to receive it, as (according to current procedures) no more than three individuals can be selected. In this article, the HGP is taken as a case study to consider the ethical question to what extent it is still possible, in an era of big science, of large-scale consortia and global team work, to acknowledge and reward individual contributions to important breakthroughs in biomedical fields. Is it still viable to single out individuals for their decisive contributions in order to reward them in a fair and convincing way? Whereas the concept of the Nobel prize as such seems to reflect an archetypical view of scientists as solitary researchers who, at a certain point in their careers, make their one decisive discovery, this vision has proven to be problematic from the very outset. Already during the first decade of the Nobel era, Ivan Pavlov was denied the Prize several times before finally receiving it, on the basis of the argument that he had been active as a research manager (a designer and supervisor of research projects) rather than as a researcher himself. The question then is whether, in the case of the HGP, a research effort that involved the contributions of hundreds or even thousands of researchers worldwide, it is still possible to “individualise” the Prize? The “HGP Nobel Prize problem” is regarded as an exemplary issue in current research ethics, highlighting a number of quandaries and trends involved in contemporary life science research practices more broadly.

Lactic acid bacteria are among the powerhouses of the food industry, colonize the surfaces of plants and animals, and contribute to our health and well-being. The genomic characterization of LAB has rocketed and presently over 100 complete or nearly complete genomes are available, many of which serve as scientific paradigms. Moreover, functional and comparative metagenomic studies are taking off and provide a wealth of insight in the activity of lactic acid bacteria used in a variety of applications, ranging from starters in complex fermentations to their marketing as probiotics. In this new era of high throughput analysis, biology has become big science. Hence, there is a need to systematically store the generated information, apply this in an intelligent way, and provide modalities for constructing self-learning systems that can be used for future improvements. This review addresses these systems solutions with a state of the art overview of the present paradigms that relate to the use of lactic acid bacteria in industrial applications. Moreover, an outlook is presented of the future developments that include the transition into practice as well as the use of lactic acid bacteria in synthetic biology and other next generation applications.

The trend of recent researches, in which synthetic biology and white technology through system approaches based on “Omics technology” are recognized as the ground of biotechnology, indicates the coming of the ‘metagenome era’ that accesses the genomes of all microbes aiming at the understanding and industrial application of the whole microbial resources. The remarkable advance of technologies for digging out and analyzing metagenome is enabling not only practical applications of metagenome but also system approaches on a mixed-genome level based on accumulated information. In this situation, the present review is purposed to introduce the trends and methods of research on metagenome and to examine big science led by related resources in the future.

Background

Big defensin is an antimicrobial peptide composed of a highly hydrophobic N-terminal region and a cationic C-terminal region containing six cysteine residues involved in three internal disulfide bridges. While big defensin sequences have been reported in various mollusk species, few studies have been devoted to their sequence diversity, gene organization and their expression in response to microbial infections.

Findings

Using the high-throughput Digital Gene Expression approach, we have identified in Crassostrea gigas oysters several sequences coding for big defensins induced in response to a Vibrio infection. We showed that the oyster big defensin family is composed of three members (named Cg-BigDef1, Cg-BigDef2 and Cg-BigDef3) that are encoded by distinct genomic sequences. All Cg-BigDefs contain a hydrophobic N-terminal domain and a cationic C-terminal domain that resembles vertebrate β-defensins. Both domains are encoded by separate exons. We found that big defensins form a group predominantly present in mollusks and closer to vertebrate defensins than to invertebrate and fungi CSαβ-containing defensins. Moreover, we showed that Cg-BigDefs are expressed in oyster hemocytes only and follow different patterns of gene expression. While Cg-BigDef3 is non-regulated, both Cg-BigDef1 and Cg-BigDef2 transcripts are strongly induced in response to bacterial challenge. Induction was dependent on pathogen associated molecular patterns but not damage-dependent. The inducibility of Cg-BigDef1 was confirmed by HPLC and mass spectrometry, since ions with a molecular mass compatible with mature Cg-BigDef1 (10.7 kDa) were present in immune-challenged oysters only. From our biochemical data, native Cg-BigDef1 would result from the elimination of a prepropeptide sequence and the cyclization of the resulting N-terminal glutamine residue into a pyroglutamic acid.

Conclusions

We provide here the first report showing that big defensins form a family of antimicrobial peptides diverse not only in terms of sequences but also in terms of genomic organization and regulation of gene expression.

Summary: BigWig and BigBed files are compressed binary indexed files containing data at several resolutions that allow the high-performance display of next-generation sequencing experiment results in the UCSC Genome Browser. The visualization is implemented using a multi-layered software approach that takes advantage of specific capabilities of web-based protocols and Linux and UNIX operating systems files, R trees and various indexing and compression tricks. As a result, only the data needed to support the current browser view is transmitted rather than the entire file, enabling fast remote access to large distributed data sets.

Availability and implementation: Binaries for the BigWig and BigBed creation and parsing utilities may be downloaded at http://hgdownload.cse.ucsc.edu/admin/exe/linux.x86_64/. Source code for the creation and visualization software is freely available for non-commercial use at http://hgdownload.cse.ucsc.edu/admin/jksrc.zip, implemented in C and supported on Linux. The UCSC Genome Browser is available at http://genome.ucsc.edu

Contact: ann@soe.ucsc.edu

Supplementary information: Supplementary byte-level details of the BigWig and BigBed file formats are available at Bioinformatics online. For an in-depth description of UCSC data file formats and custom tracks, see http://genome.ucsc.edu/FAQ/FAQformat.html and http://genome.ucsc.edu/goldenPath/help/hgTracksHelp.html

Radiation hybrid panels are already available for genome mapping in human and mouse. In this study we have used two model organisms (chicken and zebrafish) to show that hybrid panels that contain a full complement of the donor genome can be generated by fusion to hamster cells. The quality of the resulting hybrids has been assessed using PCR and FISH. We confirmed the utility of our panels by establishing the percentage of donor DNA present in the hybrids. Our hybrid resources will allow inexpensive gene mapping and we expect that this technology can be transferred to many other species. Such successes are providing the basis for a new era of mapping tools, in the form of whole genome radiation hybrid panels, and are opening new possibilities for systematic genome analysis in the animal genetics community.

Background

Molecular systematics occupies one of the central stages in biology in the genomic era, ushered in by unprecedented progress in DNA technology. The inference of organismal phylogeny is now based on many independent genetic loci, a widely accepted approach to assemble the tree of life. Surprisingly, this approach is hindered by lack of appropriate nuclear gene markers for many taxonomic groups especially at high taxonomic level, partially due to the lack of tools for efficiently developing new phylogenetic makers. We report here a genome-comparison strategy to identifying nuclear gene markers for phylogenetic inference and apply it to the ray-finned fishes – the largest vertebrate clade in need of phylogenetic resolution.

Results

A total of 154 candidate molecular markers – relatively well conserved, putatively single-copy gene fragments with long, uninterrupted exons – were obtained by comparing whole genome sequences of two model organisms, Danio rerio and Takifugu rubripes. Experimental tests of 15 of these (randomly picked) markers on 36 taxa (representing two-thirds of the ray-finned fish orders) demonstrate the feasibility of amplifying by PCR and directly sequencing most of these candidates from whole genomic DNA in a vast diversity of fish species. Preliminary phylogenetic analyses of sequence data obtained for 14 taxa and 10 markers (total of 7,872 bp for each species) are encouraging, suggesting that the markers obtained will make significant contributions to future fish phylogenetic studies.

Conclusion

We present a practical approach that systematically compares whole genome sequences to identify single-copy nuclear gene markers for inferring phylogeny. Our method is an improvement over traditional approaches (e.g., manually picking genes for testing) because it uses genomic information and automates the process to identify large numbers of candidate makers. This approach is shown here to be successful for fishes, but also could be applied to other groups of organisms for which two or more complete genome sequences exist, which has important implications for assembling the tree of life.

'Genomic tools', such as gene/protein chips, single nucleotide polymorphism and haplotype analyses, are empowering us to generate staggering amounts of correlative data, from human/animal genetics and from normal and disease-affected tissues obtained from complex diseases such as arthritis. These tools are transforming molecular biology into a 'data rich' science, with subjects with an '-omic' suffix. These disciplines have to converge and integrate at a systemic level to examine the structure and dynamics of cellular and organismal function ('functionomics') simultaneously, using a multidimensional approach for cells, tissues, organs, rodents and Zebra fish models, which intertwines various approaches and readouts to study the development and homeostasis of a system. In summary, the postgenomic era of functionomics will facilitate narrowing the bridge between correlative data and causative data, thus integrating 'intercoms' of interacting and interdependent disciplines and forming a unified whole.

In the post-genomic era, we must make maximal use of this technological advancement to broaden our perspective on biology and medicine. Our understanding of the evolutionary process is undermined by looking at it retrospectively, perpetuating a descriptive rather than a mechanistic approach. The reintroduction of developmental biologic principles into evolutionary studies, or evo-devo, allows us to apply embryologic cell-molecular biologic principles to the mechanisms of phylogeny, obviating the artificial space and time barriers between ontogeny and phylogeny. This perspective allows us to consider the continuum between the proximate and ultimate causes of speciation, which was unthinkable when looked at from the descriptive perspective. Using a cell-cell interactive ‘middle-out’ approach, we have gained insight to the evolution of the lung from the swim bladder of fish based on gene regulatory networks that generate both lung ontogeny and phylogeny, i.e. decreased alveolar size, decreased alveolar wall thickness, and increased alveolar wall strength. Vertical integration of cell-cell interactions predicts the adaptivity and maladaptivity of the lung, leading to novel insights for chronic lung disease. Since we have employed principles involved in all of development, this approach is amenable to all biologic structures, functions, adaptations, maladaptations, and diseases, providing an operational basis for preventive medicine.

Analysis of the genome of the elephant shark (Callorhinchus milii), a member of the cartilaginous fishes (class Chondrichthyes), reveals that it encodes all three members of the p53 gene family, p53, p63 and p73, each with clear homology to the equivalent gene in bony vertebrates (class Osteichthyes). Thus, the gene duplication events that lead to the presence of three family members in the vertebrates dates to before the Silurian era. It also encodes Mdm2 and Mdm4 genes but does not encode the p19Arf gene. Detailed comparison of the amino acid sequences of these proteins in the vertebrates reveals that they are evolving at highly distinctive rates, and this variation occurs not only between the three family members but extends to distinct domains in each protein.

Era is an essential GTPase in Escherichia coli, and Era has been implicated in a number of cellular functions. Homologues of Era have been identified in various bacteria and some eukaryotes. Using the era gene as bait in the yeast two-hybrid system to screen E. coli genomic libraries, we discovered that Era interacts with MazG, a protein of unknown function which is highly conserved among bacteria. The direct interaction between Era and MazG was also confirmed in vitro, being stronger in the presence of GDP than in the presence of GTPγS. MazG was characterized as a nucleoside triphosphate pyrophosphohydrolase which can hydrolyze all eight of the canonical ribo- and deoxynucleoside triphosphates to their respective monophosphates and PPi, with a preference for deoxynucleotides. A mazG deletion strain of E. coli was constructed by replacing the mazG gene with a kanamycin resistance gene. Unlike mutT, a gene for another conserved nucleotide triphosphate pyrophosphohydrolase that functions as a mutator gene, the mazG deletion did not result in a mutator phenotype in E. coli.

Background

Big sagebrush (Artemisia tridentata) is one of the most widely distributed and ecologically important shrub species in western North America. This species serves as a critical habitat and food resource for many animals and invertebrates. Habitat loss due to a combination of disturbances followed by establishment of invasive plant species is a serious threat to big sagebrush ecosystem sustainability. Lack of genomic data has limited our understanding of the evolutionary history and ecological adaptation in this species. Here, we report on the sequencing of expressed sequence tags (ESTs) and detection of single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) markers in subspecies of big sagebrush.

Results

cDNA of A. tridentata sspp. tridentata and vaseyana were normalized and sequenced using the 454 GS FLX Titanium pyrosequencing technology. Assembly of the reads resulted in 20,357 contig consensus sequences in ssp. tridentata and 20,250 contigs in ssp. vaseyana. A BLASTx search against the non-redundant (NR) protein database using 29,541 consensus sequences obtained from a combined assembly resulted in 21,436 sequences with significant blast alignments (≤ 1e-15). A total of 20,952 SNPs and 119 polymorphic SSRs were detected between the two subspecies. SNPs were validated through various methods including sequence capture. Validation of SNPs in different individuals uncovered a high level of nucleotide variation in EST sequences. EST sequences of a third, tetraploid subspecies (ssp. wyomingensis) obtained by Illumina sequencing were mapped to the consensus sequences of the combined 454 EST assembly. Approximately one-third of the SNPs between sspp. tridentata and vaseyana identified in the combined assembly were also polymorphic within the two geographically distant ssp. wyomingensis samples.

Conclusion

We have produced a large EST dataset for Artemisia tridentata, which contains a large sample of the big sagebrush leaf transcriptome. SNP mapping among the three subspecies suggest the origin of ssp. wyomingensis via mixed ancestry. A large number of SNP and SSR markers provide the foundation for future research to address questions in big sagebrush evolution, ecological genetics, and conservation using genomic approaches.

With the development of the Human Genome Project, a heated debate emerged on biology becoming ‘big science’. However, biology already has a long tradition of collaboration, as natural historians were part of the first collective scientific efforts: exploring the variety of life on earth. Such mappings of life still continue today, and if field biology is gradually becoming an important subject of studies into big science, research into life in the world's oceans is not taken into account yet. This paper therefore explores marine biology as big science, presenting the historical development of marine research towards the international ‘Census of Marine Life’ (CoML) making an inventory of life in the world's oceans. Discussing various aspects of collaboration – including size, internationalisation, research practice, technological developments, application, and public communication – I will ask if CoML still resembles traditional collaborations to collect life. While showing both continuity and change, I will argue that marine biology is a form of natural history: a specific way of working together in biology that has transformed substantially in interaction with recent developments in the life sciences and society. As a result, the paper does not only give an overview of transformations towards large scale research in marine biology, but also shines a new light on big biology, suggesting new ways to deepen the understanding of collaboration in the life sciences by distinguishing between different ‘collective ways of knowing’.

Introduction

Our objective was to report a case of misdiagnosed temporal lobe necrosis (TLN) in a patient with nasopharyngeal cancer (NPC) after radiation therapy.

Case Presentation

We report a case of a 45 years old Chinese woman who developed moderate to severe headache and dizziness 1 year after 2D radiation therapy for NPC. Subsequent MRI scanning revealed a big enhancing mass in the right temporal lobe. The initial diagnosis was metastatic or intracranial extension of NPC, or a primary intracranial malignancy. She was referred to the neurosurgery department where a maximal surgical resection of the lesion was performed. A diagnosis of TLN was made according to the final histology.

Conclusion

TLN still matters in the IMRT era. The diagnostic quagmire of TLN lies in its close resemblance to neoplasm on clinical presentation and imaging. Reviewing the patient's treatment plan to scrutinize the dose to the temporal lobes is an important prerequisite for diagnosis.

Background

In the big data era, biomedical research continues to generate a large amount of data, and the generated information is often stored in a database and made publicly available. Although combining data from multiple databases should accelerate further studies, the current number of life sciences databases is too large to grasp features and contents of each database.

Findings

We have developed Sagace, a web-based search engine that enables users to retrieve information from a range of biological databases (such as gene expression profiles and proteomics data) and biological resource banks (such as mouse models of disease and cell lines). With Sagace, users can search more than 300 databases in Japan. Sagace offers features tailored to biomedical research, including manually tuned ranking, a faceted navigation to refine search results, and rich snippets constructed with retrieved metadata for each database entry.

Conclusions

Sagace will be valuable for experts who are involved in biomedical research and drug development in both academia and industry. Sagace is freely available at http://sagace.nibio.go.jp/en/.

The University of California, Santa Cruz Genome Browser (http://genome.ucsc.edu) offers online access to a database of genomic sequence and annotation data for a wide variety of organisms. The Browser also has many tools for visualizing, comparing and analyzing both publicly available and user-generated genomic data sets, aligning sequences and uploading user data. Among the features released this year are a gene search tool and annotation track drag-reorder functionality as well as support for BAM and BigWig/BigBed file formats. New display enhancements include overlay of multiple wiggle tracks through use of transparent coloring, options for displaying transformed wiggle data, a ‘mean+whiskers’ windowing function for display of wiggle data at high zoom levels, and more color schemes for microarray data. New data highlights include seven new genome assemblies, a Neandertal genome data portal, phenotype and disease association data, a human RNA editing track, and a zebrafish Conservation track. We also describe updates to existing tracks.

Methanogenic granules from an anaerobic bioreactor that treated wastewater of a beer brewery consisted of different morphological types of granules. In this study, the microbial compositions of the different granules were analyzed by molecular microbiological techniques: cloning, denaturing gradient gel electrophoresis and fluorescent in situ hybridization (FISH), and scanning and transmission electron microscopy. We propose here that the different types of granules reflect the different stages in the life cycle of granules. Young granules were small, black, and compact and harbored active cells. Gray granules were the most abundant granules. These granules have a multilayer structure with channels and void areas. The core was composed of dead or starving cells with low activity. The brown granules, which were the largest granules, showed a loose and amorphous structure with big channels that resulted in fractured zones and corresponded to the older granules. Firmicutes (as determined by FISH) and Nitrospira and Deferribacteres (as determined by cloning and sequencing) were the predominant Bacteria. Remarkably, Firmicutes could not be detected in the brown granules. The methanogenic Archaea identified were Methanosaeta concilii (70 to 90% by FISH and cloning), Methanosarcina mazei, and Methanospirillum spp. The phenotypic appearance of the granules reflected the physiological condition of the granules. This may be valuable to easily select appropriate seed sludges to start up other reactors.

Neanderthals are most often portrayed as big game hunters who derived the vast majority of their diet from large terrestrial herbivores while birds, fish and plants are seen as relatively unimportant or beyond the capabilities of Neanderthals. Although evidence for exploitation of other resources (small mammals, birds, fish, shellfish, and plants) has been found at certain Neanderthal sites, these are typically dismissed as unusual exceptions. The general view suggests that Neanderthal diet may broaden with time, but that this only occurs sometime after 50,000 years ago. We present evidence, in the form of lithic residue and use-wear analyses, for an example of a broad-based subsistence for Neanderthals at the site of Payre, Ardèche, France (beginning of MIS 5/end of MIS 6 to beginning of MIS 7/end of MIS 8; approximately 125–250,000 years ago). In addition to large terrestrial herbivores, Neanderthals at Payre also exploited starchy plants, birds, and fish. These results demonstrate a varied subsistence already in place with early Neanderthals and suggest that our ideas of Neanderthal subsistence are biased by our dependence on the zooarchaeological record and a deep-seated intellectual emphasis on big game hunting.

Era, a Ras-like GTP-binding protein in Escherichia coli, has been shown to be essential for growth. However, its cellular functions still remain elusive. In this study, a genetic screening of an E. coli genomic library was performed to identify those genes which can restore the growth ability of a cold-sensitive mutant, Era(Cs) (E200K), at a restrictive temperature when expressed in a multicopy plasmid. Among eight suppressors isolated, six were located at 1 min of the E. coli genomic map, and the gene responsible for the suppression of Era(Cs) (E200K) was identified as the ksgA gene for 16S rRNA transmethylase, whose mutation causes a phenotype of resistance to kasugamycin, a translation initiation inhibitor. This is the first demonstration of suppression of impaired function of Era by overproduction of a functional enzyme. A possible mechanism of the suppression of the Era cold-sensitive phenotype by KsgA overproduction is discussed.

A report on the Keystone Symposium 'Genome Sequence Variation and the Inherited Basis of Common Disease and Complex Traits', Big Sky, USA, 8-13 January 2006.

A report on the Keystone Symposium 'Genome Sequence Variation and the Inherited Basis of Common Disease and Complex Traits', Big Sky, USA, 8-13 January 2006.

Big projects in biology - such as the human genome project and a number of related and ensuing enterprises - require big funding. A new tradition is growing in which some types of basic research take place within commercial organizations. This article reviews some of the reasons for this and some of the key players, in the USA, Europe and Japan, and highlights some issues to be considered when deciding whether particular research belongs in a company rather than an academic setting.

The role of spliceosomal introns in eukaryotic genomes remains obscure. A large scale analysis of intron presence/absence patterns in many gene families and species is a necessary step to clarify the role of these introns. In this analysis, we used a maximum likelihood method to reconstruct the evolution of 2,961 introns in a dataset of 76 ribosomal protein genes from 22 eukaryotes and validated the results by a maximum parsimony method. Our results show that the trends of intron gain and loss differed across species in a given kingdom but appeared to be consistent within subphyla. Most subphyla in the dataset diverged around 1 billion years ago, when the “Big Bang” radiation occurred. We speculate that spliceosomal introns may play a role in the explosion of many eukaryotes at the Big Bang radiation.

The cancer Biomedical Informatics Grid (caBIG) was launched in 2003 by the US National Cancer Institute with the aim of connecting research teams through the use of shared infrastructure and software to collect, analyse and share data. It was an ambitious project, and the issue it aimed to address was huge and far-reaching. With such developments as the mapping of the human genome and the advancement of new technologies for the analysis of genes and proteins, cancer researchers have never produced so much complex data, nor have they understood so much about cancer on a molecular level. This new ‘molecular understanding’ of cancer, according to the caBIG 2007 ‘Pilot Report’[1], leads to molecular or ‘personalised’ medicine being the way forward in cancer research and treatment, and connects basic research to clinical care in an unprecedented way. But the former ‘silo-like’ nature of research does not lend itself to this brave new world of molecular medicine—individual labs and institutes working in isolation, “in effect, as cottage industries, each collecting and interpreting data using a unique language of their own”[2] will not advance cancer research as it should be advanced. The solution proposed by the NCI in caBIG was to produce an integrated informatics grid (‘caGrid’) to incorporate open source, open access tools to collect, analyse and share data, enabling everyone to use the same methods and language for these tasks.

caBIG is primarily a US-based endeavour, and though the tools are openly available for users worldwide, it is in US NCI-funded cancer centres that they have been actively introduced and promoted with the eventual hope, according to the pilot report, of being able to do the same worldwide. caBIG also has a collaboration in place with the UK organisation NCRI to exchange technologies and research data. The European Association for Cancer Research, a member association for cancer researchers, conducted an online survey in January 2011 to identify the penetration of the ambitious caBIG project into European laboratories. The survey was sent to 6396 researchers based in Europe, with 764 respondents, a total response rate of 11.94%.

Background

Big-fish-little-pond effect (BFLPE) research has demonstrated that students in high-ability environments have lower academic self-concepts than equally able students in low-ability settings. Research has shown low academic self-concepts to be associated with negative educational outcomes. Social comparison processes have been implicated as fundamental to the BFLPE.

Methods

Twenty first-year students in an Australian medical school completed a survey that included academic self-concept and social comparison measures, before and after their first written assessments. Focus groups were also conducted with a separate group of students to explore students' perceptions of competence, the medical school environment, and social comparison processes.

Results

The quantitative study did not reveal any changes in academic self-concept or self-evaluation. The qualitative study suggested that the attributions that students used when discussing performance were those that have been demonstrated to negatively affect self-concept. Students reported that the environment was slightly competitive and they used social comparison to evaluate their performance.

Conclusions

Although the BFLPE was not evident in the quantitative study, results from the qualitative study suggest that the BFLPE might be operating In that students were using attributions that are associated with lower self-concepts, the environment was slightly competitive, and social comparisons were used for evaluation.

Polarized light (PL) sensitivity is relatively well studied in a large number of invertebrates and some fish species, but in most other vertebrate classes, including birds, the behavioural and physiological mechanism of PL sensitivity remains one of the big mysteries in sensory biology. Many organisms use the skylight polarization pattern as part of a sun compass for orientation, navigation and in spatial orientation tasks. In birds, the available evidence for an involvement of the skylight polarization pattern in sun-compass orientation is very weak. Instead, cue-conflict and cue-calibration experiments have shown that the skylight polarization pattern near the horizon at sunrise and sunset provides birds with a seasonally and latitudinally independent compass calibration reference. Despite convincing evidence that birds use PL cues for orientation, direct experimental evidence for PL sensitivity is still lacking. Avian double cones have been proposed as putative PL receptors, but detailed anatomical and physiological evidence will be needed to conclusively describe the avian PL receptor. Intriguing parallels between the functional and physiological properties of PL reception and light-dependent magnetoreception could point to a common receptor system.