Recommendations for accelerating open preprint peer review to improve the culture of science.

Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints.

Biomedical publishing: Past historic, present continuous, future conditional.

Academic journals have been publishing the results of biomedical research for more than 350 years. Reviewing their history reveals that the ways in which journals vet submissions have changed over time, culminating in the relatively recent appearance of the current peer-review process. Journal brand and Impact Factor have meanwhile become quality proxies that are widely used to filter articles and evaluate scientists in a hypercompetitive prestige economy. The Web created the potential for a more decoupled publishing system in which articles are initially disseminated by preprint servers and then undergo evaluation elsewhere. To build this future, we must first understand the roles journals currently play and consider what types of content screening and review are necessary and for which papers. A new, open ecosystem involving preprint servers, journals, independent content-vetting initiatives, and curation services could provide more multidimensional signals for papers and avoid the current conflation of trust, quality, and impact. Academia should strive to avoid the alternative scenario, however, in which stratified publisher silos lock in submissions and simply perpetuate this conflation.

Signaling the trustworthiness of science.

Trust in science increases when scientists and the outlets certifying their work honor science's norms. Scientists often fail to signal to other scientists and, perhaps more importantly, the public that these norms are being upheld. They could do so as they generate, certify, and react to each other's findings: for example, by promoting the use and value of evidence, transparent reporting, self-correction, replication, a culture of critique, and controls for bias. A number of approaches for authors and journals would lead to more effective signals of trustworthiness at the article level. These include article badging, checklists, a more extensive withdrawal ontology, identity verification, better forward linking, and greater transparency.

Plan U: Universal access to scientific and medical research via funder preprint mandates.

Preprint servers such as arXiv and bioRxiv represent a highly successful and relatively low cost mechanism for providing free access to research findings. By decoupling the dissemination of manuscripts from the much slower process of evaluation and certification by journals, preprints also significantly accelerate the pace of research itself by allowing other researchers to begin building on new results immediately. If all funding agencies were to mandate posting of preprints by grantees-an approach we term Plan U (for "universal")-free access to the world's scientific output for everyone would be achieved with minimal effort. Moreover, the existence of all articles as preprints would create a fertile environment for experimentation with new peer review and research evaluation initiatives, which would benefit from a reduced barrier to entry because hosting and archiving costs were already covered.

Career Options for Scientists.

Most PhD students in the biological sciences will not go on to become academics. For these individuals, choosing the best career path can be difficult. Fortunately, there are many options that allow them to take advantage of skills they hone during graduate and postdoctoral work.

The Human Phenotype Ontology in 2017.

Deep phenotyping has been defined as the precise and comprehensive analysis of phenotypic abnormalities in which the individual components of the phenotype are observed and described. The three components of the Human Phenotype Ontology (HPO; www.human-phenotype-ontology.org) project are the phenotype vocabulary, disease-phenotype annotations and the algorithms that operate on these. These components are being used for computational deep phenotyping and precision medicine as well as integration of clinical data into translational research. The HPO is being increasingly adopted as a standard for phenotypic abnormalities by diverse groups such as international rare disease organizations, registries, clinical labs, biomedical resources, and clinical software tools and will thereby contribute toward nascent efforts at global data exchange for identifying disease etiologies. This update article reviews the progress of the HPO project since the debut Nucleic Acids Research database article in 2014, including specific areas of expansion such as common (complex) disease, new algorithms for phenotype driven genomic discovery and diagnostics, integration of cross-species mapping efforts with the Mammalian Phenotype Ontology, an improved quality control pipeline, and the addition of patient-friendly terminology.

Signal transduction in cancer.

Cancer is driven by genetic and epigenetic alterations that allow cells to overproliferate and escape mechanisms that normally control their survival and migration. Many of these alterations map to signaling pathways that control cell growth and division, cell death, cell fate, and cell motility, and can be placed in the context of distortions of wider signaling networks that fuel cancer progression, such as changes in the tumor microenvironment, angiogenesis, and inflammation. Mutations that convert cellular proto-oncogenes to oncogenes can cause hyperactivation of these signaling pathways, whereas inactivation of tumor suppressors eliminates critical negative regulators of signaling. An examination of the PI3K-Akt and Ras-ERK pathways illustrates how such alterations dysregulate signaling in cancer and produce many of the characteristic features of tumor cells.

Signal transduction: From the atomic age to the post-genomic era.

We have come a long way in the 55 years since Edmond Fischer and the late Edwin Krebs discovered that the activity of glycogen phosphorylase is regulated by reversible protein phosphorylation. Many of the fundamental molecular mechanisms that operate in biological signaling have since been characterized and the vast web of interconnected pathways that make up the cellular signaling network has been mapped in considerable detail. Nonetheless, it is important to consider how fast this field is still moving and the issues at the current boundaries of our understanding. One must also appreciate what experimental strategies have allowed us to attain our present level of knowledge. We summarize here some key issues (both conceptual and methodological), raise unresolved questions, discuss potential pitfalls, and highlight areas in which our understanding is still rudimentary. We hope these wide-ranging ruminations will be useful to investigators who carry studies of signal transduction forward during the rest of the 21st century.