Exploring the dimensions of responsible research systems and cultures: a scoping review.

The responsible conduct of research is foundational to the production of valid and trustworthy research. Despite this, our grasp of what dimensions responsible conduct of research (RCR) might contain-and how it differs across disciplines (i.e. how it is conceptualized and operationalized)-is tenuous. Moreover, many initiatives related to developing and maintaining RCR are developed within disciplinary and institutional silos which naturally limits the benefits that RCR practice can have. To this end, we are working to develop a better understanding of how RCR is conceived and realized, both across disciplines and across institutions in Europe. The first step in doing this is to scope existing knowledge on the topic, of which this scoping review is a part. We searched several electronic databases for relevant published and grey literature. An initial sample of 715 articles was identified, with 75 articles included in the final sample for qualitative analysis. We find several dimensions of RCR that are underemphasized or are excluded from the well-established World Conferences on Research Integrity (WCRI) Singapore Statement on Research Integrity and explore facets of these dimensions that find special relevance in a range of research disciplines.

Fly-CURE, a Multi-institutional CURE using Drosophila, Increases Students' Confidence, Sense of Belonging, and Persistence in Research.

The Fly-CURE is a genetics-focused multi-institutional Course-Based Undergraduate Research Experience (CURE) that provides undergraduate students with hands-on research experiences within a course. Through the Fly-CURE, undergraduate students at diverse types of higher education institutions across the United States map and characterize novel mutants isolated from a genetic screen in Drosophila melanogaster. To evaluate the impact of the Fly-CURE experience on students, we developed and validated assessment tools to identify students' perceived research self-efficacy, sense of belonging in science, and intent to pursue additional research opportunities. Our data show gains in these metrics after completion of the Fly-CURE across all student subgroups analyzed, including comparisons of gender, academic status, racial and ethnic groups, and parents' educational background. Importantly, our data also show differential gains in the areas of self-efficacy and interest in seeking additional research opportunities between Fly-CURE students with and without prior research experience, illustrating the positive impact of research exposure (dosage) on student outcomes. Altogether, our data indicate that the Fly-CURE experience has a significant impact on students' efficacy with research methods, sense of belonging to the scientific community, and interest in pursuing additional research experiences.

Can we shift belief in the 'Law of Small Numbers'?

'Sample size neglect' is a tendency to underestimate how the variability of mean estimates changes with sample size. We studied 100 participants, from science or social science backgrounds, to test whether a training task showing different-sized samples of data points (the 'beeswarm' task) can help overcome this bias. Ability to judge if two samples came from the same population improved with training, and 38% of participants reported that they had learned to wait for larger samples before making a response. Before and after training, participants completed a 12-item estimation quiz, including items testing sample size neglect (S-items). Bonus payments were given for correct responses. The quiz confirmed sample size neglect: 20% of participants scored zero on S-items, and only two participants achieved more than 4/6 items correct. Performance on the quiz did not improve after training, regardless of how much learning had occurred on the beeswarm task. Error patterns on the quiz were generally consistent with expectation, though there were some intriguing exceptions that could not readily be explained by sample size neglect. We suggest that training with simulated data might need to be accompanied by explicit instruction to be effective in counteracting sample size neglect more generally.

Performance of the vision, aphasia, neglect (VAN) assessment within a single large EMS system.

BACKGROUND: There is limited evidence on the performance of emergent large-vessel occlusion (LVO) stroke screening tools when used by emergency medical services (EMS) and emergency department (ED) providers. We assessed the validity and predictive value of the vision, aphasia, neglect (VAN) assessment when completed by EMS and in the ED among suspected stroke patients. METHODS: We conducted a retrospective study of VAN performed by EMS providers and VAN inferred from the National Institutes of Health Stroke Scale performed by ED nurses at a single hospital. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of VAN by EMS and in the ED for LVO and a combined LVO and intracerebral hemorrhage (ICH) outcome. RESULTS: From January 2018 to June 2020, 1,547 eligible patients were identified. Sensitivity and specificity of ED VAN were similar for LVO (72% and 74%, respectively), whereas EMS VAN was more sensitive (84%) than specific (68%). PPVs were low for both EMS VAN (26%) and ED VAN (21%) to detect LVO. Due to several VAN-positive ICHs, PPVs were substantially higher for both EMS VAN (44%) and ED VAN (39%) to detect LVO or ICH. EMS and ED VAN had high NPVs (97% and 96%, respectively). CONCLUSIONS: Among suspected stroke patients, we found modest sensitivity and specificity of VAN to detect LVO for both EMS and ED providers. Moreover, the low PPV in our study suggests a significant number of patients with non-LVO ischemic stroke or ICH could be over-triaged with VAN.

Constructing Kinetically Controlled Denaturation Isotherms of Folded Proteins Using Denaturant-Pulse Chaperonin Binding.

Methods to assess the kinetic stability of proteins, particularly those that are aggregation prone, are very useful in establishing ligand induced stabilizing effects. Because aggregation prone proteins are by nature difficult to work with, most solution based methods are compromised by this inherent instability. Here, we describe a label-free method that examines the denaturation of immobilized proteins where the dynamic unfolded protein populations are captured and detected by chaperonin binding.

The regulatory α and ß subunits of phosphorylase kinase directly interact with its substrate, glycogen phosphorylase.

The selective phosphorylation of glycogen phosphorylase (GP) by its only known kinase, phosphorylase kinase (PhK), keeps glycogen catabolism tightly regulated. In addition to the obligatory interaction between the catalytic γ subunit of PhK and the phosphorylatable region of GP, previous studies have suggested additional sites of interaction between this kinase and its protein substrate. Using short chemical crosslinkers, we have identified direct interactions of GP with the large regulatory α and ß subunits of PhK. These newfound interactions were found to be sensitive to ligands that bind PhK.

Emotional arousal when watching drama increases pain threshold and social bonding.

Fiction, whether in the form of storytelling or plays, has a particular attraction for us: we repeatedly return to it and are willing to invest money and time in doing so. Why this is so is an evolutionary enigma that has been surprisingly underexplored. We hypothesize that emotionally arousing drama, in particular, triggers the same neurobiological mechanism (the endorphin system, reflected in increased pain thresholds) that underpins anthropoid primate and human social bonding. We show that, compared to subjects who watch an emotionally neutral film, subjects who watch an emotionally arousing film have increased pain thresholds and an increased sense of group bonding.

Activation of Phosphorylase Kinase by Physiological Temperature.

In the six decades since its discovery, phosphorylase kinase (PhK) from rabbit skeletal muscle has usually been studied at 30 °C; in fact, not a single study has examined functions of PhK at a rabbit's body temperature, which is nearly 10 °C greater. Thus, we have examined aspects of the activity, regulation, and structure of PhK at temperatures between 0 and 40 °C. Between 0 and 30 °C, the activity at pH 6.8 of nonphosphorylated PhK predictably increased; however, between 30 and 40 °C, there was a dramatic jump in its activity, resulting in the nonactivated enzyme having a far greater activity at body temperature than was previously realized. This anomalous change in properties between 30 and 40 °C was observed for multiple functions, and both stimulation (by ADP and phosphorylation) and inhibition (by orthophosphate) were considerably less pronounced at 40 °C than at 30 °C. In general, the allosteric control of PhK's activity is definitely more subtle at body temperature. Changes in behavior related to activity at 40 °C and its control can be explained by the near disappearance of hysteresis at physiological temperature. In important ways, the picture of PhK that has emerged from six decades of study at temperatures of ≤30 °C does not coincide with that of the enzyme studied at physiological temperature. The probable underlying mechanism for the dramatic increase in PhK's activity between 30 and 40 °C is an abrupt change in the conformations of the regulatory ß and catalytic γ subunits between these two temperatures.

A model for activation of the hexadecameric phosphorylase kinase complex deduced from zero-length oxidative crosslinking.

Phosphorylase kinase (PhK) is a hexadecameric (αßγδ)(4) enzyme complex that upon activation by phosphorylation stimulates glycogenolysis. Due to its large size (1.3 MDa), elucidating the structural changes associated with the activation of PhK has been challenging, although phosphoactivation has been linked with an increased tendency of the enzyme's regulatory ß-subunits to self-associate. Here we report the effect of a peptide mimetic of the phosphoryltable N-termini of ß on the selective, zero-length, oxidative crosslinking of these regulatory subunits to form ß-ß dimers in the nonactivated PhK complex. This peptide stimulated ß-ß dimer formation when not phosphorylated, but was considerably less effective in its phosphorylated form. Because this peptide mimetic of ß competes with its counterpart region in the nonactivated enzyme complex in binding to the catalytic γ-subunit, we were able to formulate a structural model for the phosphoactivation of PhK. In this model, the nonactivated state of PhK is maintained by the interaction between the nonphosphorylated N-termini of ß and the regulatory C-terminal domains of the γ-subunits; phosphorylation of ß weakens this interaction, leading to activation of the γ-subunits.