A randomized trial of a lab-embedded discourse intervention to improve research ethics.

We report a randomized trial of a research ethics training intervention designed to enhance ethics communication in university science and engineering laboratories, focusing specifically on authorship and data management. The intervention is a project-based research ethics curriculum that was designed to enhance the ability of science and engineering research laboratory members to engage in reason giving and interpersonal communication necessary for ethical practice. The randomized trial was fielded in active faculty-led laboratories at two US research-intensive institutions. Here, we show that laboratory members perceived improvements in the quality of discourse on research ethics within their laboratories and enhanced awareness of the relevance and reasons for that discourse for their work as measured by a survey administered over 4 mo after the intervention. This training represents a paradigm shift compared with more typical module-based or classroom ethics instruction that is divorced from the everyday workflow and practices within laboratories and is designed to cultivate a campus culture of ethical science and engineering research in the very work settings where laboratory members interact

Scientific Utopia III: crowdsourcing science

Most scientific research is conducted by small teams of investigators who together formulate hypotheses, collect data, conduct analyses, and report novel findings. These teams operate independently as vertically integrated silos. Here we argue that scientific research that is horizontally distributed can provide substantial complementary value, aiming to maximize available resources, promote inclusiveness and transparency, and increase rigor and reliability. This alternative approach enables researchers to tackle ambitious projects that would not be possible under the standard model. Crowdsourced scientific initiatives vary in the degree of communication between project members from largely independent work curated by a coordination team to crowd collaboration on shared activities. The potential benefits and challenges of large-scale collaboration span the entire research process: ideation, study design, data collection, data analysis, reporting, and peer review. Complementing traditional small science with crowdsourced approaches can accelerate the progress of science and improve the quality of scientific research

Preregistering Qualitative Research: A Delphi Study

Preregistrations—records made a priori about study designs and analysis plans and placed in open repositories—are thought to strengthen the credibility and transparency of research. Different authors have put forth arguments in favor of introducing this practice in qualitative research and made suggestions for what to include in a qualitative preregistration form. The goal of this study was to gauge and understand what parts of preregistration templates qualitative researchers would find helpful and informative. We used an online Delphi study design consisting of two rounds with feedback reports in between. In total, 48 researchers participated (response rate: 16%). In round 1, panelists considered 14 proposed items relevant to include in the preregistration form, but two items had relevance scores just below our predefined criterion (68%) with mixed argument and were put forth again. We combined items where possible, leading to 11 revised items. In round 2, panelists agreed on including the two remaining items. Panelists also converged on suggested terminology and elaborations, except for two terms for which they provided clear arguments. The result is an agreement-based form for the preregistration of qualitative studies that consists of 13 items. The form will be made available as a registration option on Open Science Framework (osf.io). We believe it is important to assure that the strength of qualitative research, which is its flexibility to adapt, adjust and respond, is not lost in preregistration. The preregistration should provide a systematic starting point

Systematizing Confidence in Open Research and Evidence (SCORE)

Assessing the credibility of research claims is a central, continuous, and laborious part of the scientific process. Credibility assessment strategies range from expert judgment to aggregating existing evidence to systematic replication efforts. Such assessments can require substantial time and effort. Research progress could be accelerated if there were rapid, scalable, accurate credibility indicators to guide attention and resource allocation for further assessment. The SCORE program is creating and validating algorithms to provide confidence scores for research claims at scale. To investigate the viability of scalable tools, teams are creating: a database of claims from papers in the social and behavioral sciences; expert and machine generated estimates of credibility; and, evidence of reproducibility, robustness, and replicability to validate the estimates. Beyond the primary research objective, the data and artifacts generated from this program will be openly shared and provide an unprecedented opportunity to examine research credibility and evidence

Enhanced tonic GABAA inhibition in typical absence epilepsy

The cellular mechanisms underlying typical absence seizures, which characterize various idiopathic generalized epilepsies, are not fully understood, but impaired GABAergic inhibition remains an attractive hypothesis. In contrast, we show here that extrasynaptic GABAA receptor–dependent ‘tonic’ inhibition is increased in thalamocortical neurons from diverse genetic and pharmacological models of absence seizures. Increased tonic inhibition is due to compromised GABA uptake by the GABA transporter GAT–1 in the genetic models tested, and GAT–1 is critical in governing seizure genesis. Extrasynaptic GABAA receptors are a requirement for seizures in two of the best characterized models of absence epilepsy, and the selective activation of thalamic extrasynaptic GABAA receptors is sufficient to elicit both electrographic and behavioural correlates of seizures in normal animals. These results identify an apparently common cellular pathology in typical absence seizures that may have epileptogenic significance, and highlight novel therapeutic targets for the treatment of absence epilepsy.peer-reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Novel Pathways Linking Mammalian Septins and the DNA Damage Response

A cellular response to damaged DNA, known as the DNA damage response (DDR), has evolved to combat damage that occurs from exposure to genotoxic agents or byproducts of normal cellular metabolism. Upon recognition of DNA damage, the cell arrests the cell cycle and repairs damaged DNA to maintain genome integrity. However, if the damage is severe, cells undergo apoptosis or initiate cellular senescence. The DDR is a highly coordinated event linking many pathways involved in various cellular processes. A previous study from this lab implicated mammalian septins in the DDR, although through an unknown mechanism. These cytoskeletal proteins function as signaling platforms and diffusion barriers and associate with various proteins including the adaptor proteins SOCS7 and NCK. In response to multiple types of DNA damage, NCK relocalizes from the cytoplasm to the nucleus, using the nucleocytoplasmic shuttling protein SOCS7. The nuclear accumulation of NCK in response to UV irradiation is dependent on the kinase activity of ATR, a member of the PIKK family that is activated early in the DDR. Depletion of NCK results in elevated phosphorylation of the transcription factor p53 and an early induction of apoptosis. Depletion of SOCS7, which blocks the nuclear accumulation of NCK, also increases phosphorylation of p53 and also results in an early induction of apoptosis. This indicates the anti-apoptotic role of NCK is dependent on its nuclear translocation during the DDR. Another septin interacting protein was identified using a proteomic approach. This novel nuclease called Septin Associated Nuclease 1 (SAN1) possesses unique 5’ exonuclease activity mediated by a FEN1-related nuclease domain necessary for the proper repair of DNA interstrand crosslinks (ICL). Depletion of SAN1 results in a low rate of homologous recombination (HR) due to a decrease in end-resection of double-strand breaks generated during ICL repair. Additionally, SAN1 is mostly localized in the cytoplasm but accumulates in the nucleus following treatment with ICL-inducing agents. However, in the absence of septins, SAN1 becomes mislocalized and distributed throughout the cell. Depletion of septins also results in a decrease in HR and end-resection. This suggests septins are necessary for the proper response to ICL by regulating SAN1 localization and activation. Taken together, these data demonstrate that mammalian septins play a role in the DDR and highlight an unexpected link between cytoskeletal elements and DNA damage signaling