The exaggerated benefits of failure.

Commencement speakers, business leaders, and the popular press tell us that failure has at least one benefit: It fuels success. Does it? Across 11 studies, including a field study of medical professionals, predictors overestimated the rate at which people course correct following failure (Studies 1-4). Predictors overestimated the likelihood that professionals who fail a professional exam (e.g., the bar exam, the medical boards) pass a retest (Studies 1a, 1b, and 2a), the likelihood that patients improve their health after a crisis (e.g., heart attack, drug overdose; Studies 2b and 6), and the probability, more generally, of learning from one's mistakes (Studies 3-5). This effect was specific to overestimating success following failure (Study 4) and erasing mention of an initial failure that had actually occurred corrected the problem (Studies 2a and 2b). The success overestimate was due, at least in part, to the belief that people attend to failure more than they do (Studies 5 and 6). Correcting this overestimate had policy implications. Citizens apprised of the sobering true rate of postfailure success increased their support for rehabilitative initiatives aimed at helping struggling populations (e.g., people with addiction, ex-convicts) learn from past mistakes (Studies 7a-7c). (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Working together with people with intellectual disability to make a difference: a protocol for a mixed-method co-production study to address inequities in cervical screening participation.

Introduction: Cervical cancer is one of the most preventable cancers yet remains a disease of inequity for people with intellectual disability, in part due to low screening rates. The ScreenEQUAL project will use an integrated knowledge translation (iKT) model to co-produce and evaluate accessible cervical screening resources with and for this group. Methods: Stage 1 will qualitatively explore facilitators and barriers to screening participation for people with intellectual disability, families and support people, healthcare providers and disability sector stakeholders (n ≈ 20 in each group). An accessible multimodal screening resource, accompanying supporting materials for families and support people, and trauma-informed healthcare provider training materials will then be co-produced through a series of workshops. Stage 2 will recruit people with intellectual disability aged 25 to 74 who are due or overdue for screening into a single-arm trial (n = 48). Trained support people will provide them with the co-produced resource in accessible workshops (intervention) and support them in completing pre-post questions to assess informed decision-making. A subset will participate in qualitative post-intervention interviews including optional body-mapping (n ≈ 20). Screening uptake in the 9-months following the intervention will be measured through data linkage. Family members and support people (n = 48) and healthcare providers (n = 433) will be recruited into single-arm sub-studies. Over a 4-month period they will, respectively, receive the accompanying supporting materials, and the trauma-informed training materials. Both groups will complete pre-post online surveys. A subset of each group (n ≈ 20) will be invited to participate in post-intervention semi-structured interviews. Outcomes and analysis: Our primary outcome is a change in informed decision-making by people with intellectual disability across the domains of knowledge, attitudes, and screening intention. Secondary outcomes include: (i) uptake of screening in the 9-months following the intervention workshops, (ii) changes in health literacy, attitudes and self-efficacy of family members and support people, and (iii) changes in knowledge, attitudes, self-efficacy and preparedness of screening providers. Each participant group will evaluate acceptability, feasibility and usability of the resources. Discussion: If found to be effective and acceptable, the co-produced cervical screening resources and training materials will be made freely available through the ScreenEQUAL website to support national, and potentially international, scale-up.

van der Waals Parameter Scanning with Amber Nucleic Acid Force Fields: Revisiting Means to Better Capture the RNA/DNA Structure through MD.

Molecular dynamics simulations can be used in combination with experimental techniques to uncover the intricacies of biomolecular structure, dynamics, and the resulting interactions. However, many noncanonical nucleic acid structures have proven to be challenging to replicate in accurate agreement with experimental data, often attributed to known force field deficiencies. A common force field criticism is the handling of van der Waals (vdW) parameters, which have not been updated since the regular use of Ewald's methods became routine. This work dives into the effects of minute vdW radii shifts on RNA tetranucleotide, B-DNA, and Z-DNA model systems described by commonly used Amber force fields. Using multidimensional replica exchange molecular dynamics (M-REMD), the GACC RNA tetranucleotide demonstrated changes in the structural distribution between the NMR minor and anomalous structure populations based on the O2' vdW radii scanning. However, no significant change in the NMR Major conformation population was observed. There were minimal changes in the B-DNA structure but there were more substantial improvements in Z-DNA structural descriptions, specifically with the Tumuc1 force field. This occurred with both LJbb vdW radii adjustments and incorporation of the CUFIX nonbonded parameter modifications. Though the limited vdW modifications tested did not provide a universal fix to the challenge of simulating the various known nucleic acid structures, they do provide direction and a greater understanding for future force field development efforts.

Assessment of A- to B- DNA Transitions Utilizing the Drude Polarizable Force Field.

In addition to the well-characterized B-form of DNA, duplex DNA can adopt various conformations, such as A or Z-DNA. Though less common, these structures can be induced biologically through protein or ligand interactions or experimentally with niche environmental conditions, such as high salt concentrations or in mixed water-ethanol. Reproducing these alternate structures through molecular dynamics simulations in recent years has been quite challenging with the currently available force fields, simulation techniques, and time scales. In this study, the Drude polarizable force field is tested for its ability to facilitate transitions between A-DNA and B-DNA or maintain A-DNA. Though transitions away from B-DNA were observed in high concentrations of ethanol, the resulting structures had hybrid properties taken from both B-DNA and A-DNA structures. This was also true for A-DNA in ethanol, which lost some of the A-DNA properties that it was expected to maintain. When B-DNA was tested in high salt environments, the resulting B-DNA structures showed no distinguishable differences with the increasing salt concentrations tested. These results with the Drude FF and recent results with additive force fields suggest that at present the current additive and polarizable force fields do not facilitate a complete transition between B- to A-DNA conformations under the conditions simulated. At present, the Drude FF favors A-B DNA hybrid structures when simulated in nonphysiological conditions.

Benchmarking the Drude Polarizable Force Field Using the r(GACC) Tetranucleotide.

Polarizable force fields, in particular, the Drude polarizable force field (Drude FF), may hold the key to more accurately modeling biomolecules with molecular dynamics simulations by explicitly accounting for atomic polarizability. Previous work has shown promising results in simulating duplex nucleic acids and protein structures with excellent agreement with experimental values. However, benchmarking the Drude polarizable force field with highly flexible, single-stranded structures has yet to be achieved. In this work, the r(GACC) tetranucleotide is simulated over a multimicrosecond time scale, starting with various different initial conformations. Despite the starting conformation, including starting from the expected dominant A-form major conformation, the experimental structural distribution is not matched. In fact, the major NMR conformation is never resampled. Instead, the r(GACC) tetranucleotide becomes stabilized in anomalous structures that are inconsistent with the NMR data and that favor base-pairing and electrostatic interactions over base stacking. These structures are maintained for lengthy time scales (>1 µs) themselves, suggesting a misbalance of forces in the Drude polarizable force field itself. This model system is suggestive of the fact that currently the Drude polarizable force field does not appear to produce the sensitive balance of forces required to accurately model other single-stranded or noncanonical RNA structures.

Structures and Dynamics of DNA Mini-Dumbbells Are Force Field Dependent.

Flexible nucleic acid structures can be challenging to accurately resolve with currently available experimental structural determination techniques. As an alternative, molecular dynamics (MD) simulations can provide a window into understanding the unique dynamics and population distributions of these biomolecules. Previously, molecular dynamics simulations of noncanonical (non-duplex) nucleic acids have proven difficult to accurately model. With a new influx of improved nucleic acid force fields, achieving an in-depth understanding of the dynamics of flexible nucleic acid structures may be achievable. In this project, currently available nucleic acid force fields are evaluated using a flexible yet stable model system: the DNA mini-dumbbell. Prior to MD simulations, nuclear magnetic resonance (NMR) re-refinement was accomplished using improved refinement techniques in explicit solvent to yield DNA mini-dumbbell structures with better agreement between the newly determined PDB snapshots, with the NMR data itself, as well as the unrestrained simulation data. Starting from newly determined structures, a total aggregate of over 800 µs of production data between 2 DNA mini-dumbbell sequences and 8 force fields was collected to compare to these newly refined structures. The force fields tested spanned from traditional Amber force fields: bsc0, bsc1, OL15, and OL21 to Charmm force fields: Charmm36 and the Drude polarizable force field, as well as force fields from independent developers: Tumuc1 and CuFix/NBFix. The results indicated slight variations not only between the different force fields but also between the sequences as well. Given our previous experiences with high populations of potentially anomalous structures in RNA UUCG tetraloops and in various tetranucleotides, we expected the mini-dumbbell system to be challenging to accurately model. Surprisingly, many of the recently developed force fields generated structures in good agreement with experiments. Yet, each of the force fields provided a different distribution of potentially anomalous structures.

Animating History: Digitally Mapping the United States Telegraph System.

Digital humanities is a booming field. This article introduces a new digital map that shows the development of the telegraph system in the United States from its inception in 1844 to 1862. This interactive map locates offices and lines, and it displays data that put the telegraph system in its political, social, and environmental contexts. As far as the authors know, this is the first born-digital map of a telegraph system anywhere in the world. Readers are invited to explore the freely available map, and historians of technology are encouraged to use digital maps for their research and teaching. Digital maps are ideal for visualizing systems and networks, two concepts that have dominated the history of technology for several decades. The ability to display time-sensitive data for several variables at the same time is especially useful.

The COVID-19 pandemic and food assistance organizations' responses in New York's Capital District.

This research examines the impact of COVID-19 on food security in New York state and the innovative approaches employed by food assistance organizations to help address the changing and increasing demand for their services from March 2020 to May 2021. We examine the case study of New York's Capital District region through a qualitative approach. We find that there was a sharp increase in utilization of emergency services during spring of 2020, which tapered off in the summer and fall of 2020 but remained above the levels of need seen the previous year. Food assistance organizations quickly adapted to the increased demand for their services and changing conditions to reduce gaps in local food distribution chains: They reorganized and tapped into new sources for volunteers, networked with public and private organizations, and coordinated work with other regional food pantries for maximum impact. The flexibility of food assistance organizations to address the disruptions brought about by the COVID-19 pandemic highlights their critical roles in the U.S. food security environment. While organizations are aware of their shortcomings, constraints, and overall role in the American food system, the majority also expressed that the pandemic presented an opportunity to treat a complex problem together and to enact change. Several stakeholders also shared their hope that strengthening their networks and innovations may facilitate post-pandemic recovery, bring about systemic changes to address root causes of food insecurity, and better serve the communities most vulnerable to hunger and service disruptions.

You Think Failure Is Hard? So Is Learning From It.

Society celebrates failure as a teachable moment. But do people actually learn from failure? Although lay wisdom suggests people should, a review of the research suggests that this is hard. We present a unifying framework that points to emotional and cognitive barriers that make learning from failure difficult. Emotions undermine learning because people find failure ego-threatening. People tend to look away from failure and not pay attention to it to protect their egos. Cognitively, people also struggle because the information in failure is less direct than the information in success and thus harder to extract. Beyond identifying barriers, this framework suggests inroads by which barriers might be addressed. Finally, we explore implications. We outline what, exactly, people miss out on when they overlook the information in failure. We find that the information in failure is often high-quality information that can be used to predict success.

Functional elements of the cis-regulatory lincRNA-p21.

The p53-induced long noncoding RNA (lncRNA) lincRNA-p21 is proposed to act in cis to promote p53-dependent expression of the neighboring cell cycle gene, Cdkn1a/p21. The molecular mechanism through which the transcribed lincRNA-p21 regulatory locus activates p21 expression remains poorly understood. To elucidate the functional elements of cis-regulation, we generate a series of genetic models that disrupt DNA regulatory elements, the transcription of lincRNA-p21, or the accumulation of mature lincRNA-p21. Unexpectedly, we determine that full-length transcription, splicing, and accumulation of lincRNA-p21 are dispensable for the chromatin organization of the locus and for cis-regulation. Instead, we find that production of lincRNA-p21 through conserved regions in exon 1 of lincRNA-p21 promotes cis-activation. These findings demonstrate that the activation of nascent transcription from this lncRNA locus, but not the generation or accumulation of a mature lncRNA transcript, is necessary to enact local gene expression control.

Surprised elaboration: When White men get longer sentences.

We present a new consequence of stereotypes: they affect the length of communications. People say more about events that violate common stereotypes than those that confirm them, a phenomenon we dub surprised elaboration. Across two public data sets, government officials wrote longer reports when negative events befell White people (stereotype-inconsistent) than when the same events befell Black or Hispanic people (stereotype-consistent). Officers authored longer missing child reports of White (vs. Black or Hispanic) children (Study 1a), and medical examiners wrote longer reports of unidentified White (vs. Black or Hispanic) bodies (Study 1b). In follow-up experiments, communicators found stereotype-inconsistent events more surprising and this prompted them to elaborate (Study 2). Surprised elaboration occurred for negative events (i.e., crimes, misdemeanors) and also positive ones (i.e., weddings; Study 3). We found that surprised elaboration has policy implications. Observers preferred to funnel government and media resources toward White victims, since their case reports were longer, even when longer reports were not more informative (Studies 4-6). Together, these studies introduce surprised elaboration, a new theoretical phenomenon with implications for public policy. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Riboflavin Stabilizes Abasic, Oxidized G-Quadruplex Structures.

The G-quadruplex is a noncanonical fold of DNA commonly found at telomeres and within gene promoter regions of the genome. These guanine-rich sequences are highly susceptible to damages such as base oxidation and depurination, leading to abasic sites. In the present work, we address whether a vacancy, such as an abasic site, in a G-quadruplex serves as a specific ligand recognition site. When the G-tetrad is all guanines, the vacant (abasic) site is recognized and bound by free guanine nucleobase. However, we aim to understand whether the preference for a specific ligand recognition changes with the presence of a guanine oxidation product 8-oxo-7,8-dihydroguanine (OG) adjacent to the vacancy in the tetrad. Using molecular dynamics simulation, circular dichroism, and nuclear magnetic resonance, we examined the ability for riboflavin to stabilize abasic site-containing G-quadruplex structures. Through structural and free energy binding analysis, we observe riboflavin's ability to stabilize an abasic site-containing G-quadruplex only in the presence of an adjacent OG-modified base. Further, when compared to simulation with the vacancy filled by free guanine, we observe that the free guanine nucleobase is pushed outside of the tetrad by OG to interact with other parts of the structure, including loop residues. These results support the preference of riboflavin over free guanine to fill an OG-adjacent G-quadruplex abasic vacancy.

A mechanistic view of long noncoding RNAs in cancer.

Long noncoding RNAs (lncRNAs) have emerged as important modulators of a wide range of biological processes in normal and disease states. In particular, lncRNAs have garnered significant interest as novel players in the molecular pathology of cancer, spurring efforts to define the functions, and elucidate the mechanisms through which cancer-associated lncRNAs operate. In this review, we discuss the prevalent mechanisms employed by lncRNAs, with a critical assessment of the methodologies used to determine each molecular function. We survey the abilities of cancer-associated lncRNAs to enact diverse trans functions throughout the nucleus and in the cytoplasm and examine the local roles of cis-acting lncRNAs in modulating the expression of neighboring genes. In linking lncRNA functions and mechanisms to their roles in cancer biology, we contend that a detailed molecular understanding of lncRNA functionality is key to elucidating their contributions to tumorigenesis and to unlocking their therapeutic potential. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease.

Megastudies improve the impact of applied behavioural science.

Policy-makers are increasingly turning to behavioural science for insights about how to improve citizens' decisions and outcomes1. Typically, different scientists test different intervention ideas in different samples using different outcomes over different time intervals2. The lack of comparability of such individual investigations limits their potential to inform policy. Here, to address this limitation and accelerate the pace of discovery, we introduce the megastudy-a massive field experiment in which the effects of many different interventions are compared in the same population on the same objectively measured outcome for the same duration. In a megastudy targeting physical exercise among 61,293 members of an American fitness chain, 30 scientists from 15 different US universities worked in small independent teams to design a total of 54 different four-week digital programmes (or interventions) encouraging exercise. We show that 45% of these interventions significantly increased weekly gym visits by 9% to 27%; the top-performing intervention offered microrewards for returning to the gym after a missed workout. Only 8% of interventions induced behaviour change that was significant and measurable after the four-week intervention. Conditioning on the 45% of interventions that increased exercise during the intervention, we detected carry-over effects that were proportionally similar to those measured in previous research3-6. Forecasts by impartial judges failed to predict which interventions would be most effective, underscoring the value of testing many ideas at once and, therefore, the potential for megastudies to improve the evidentiary value of behavioural science.

The p53 transcriptional response across tumor types reveals core and senescence-specific signatures modulated by long noncoding RNAs.

The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However, knowledge of the downstream mediators of p53 reactivation in different oncogenic contexts has been limited. Here, we utilized a panel of murine cancer cell lines from three distinct tumor types susceptible to alternative outcomes following p53 restoration to define unique and shared p53 transcriptional signatures. While we found that the majority of p53-bound sites and p53-responsive transcripts are tumor-type specific, analysis of shared targets identified a core signature of genes activated by p53 across all contexts. Furthermore, we identified repression of E2F and Myc target genes as a key feature of senescence. Characterization of p53-induced transcripts revealed core and senescence-specific long noncoding RNAs (lncRNAs) that are predominantly chromatin associated and whose production is coupled to cis-regulatory activities. Functional investigation of the contributions of p53-induced lncRNAs to p53-dependent outcomes highlighted Pvt1b, the p53-dependent isoform of Pvt1, as a mediator of p53-dependent senescence via Myc repression. Inhibition of Pvt1b led to decreased activation of senescence markers and increased levels of markers of proliferation. These findings shed light on the core and outcome-specific p53 restoration signatures across different oncogenic contexts and underscore the key role of the p53-Pvt1b-Myc regulatory axis in mediating proliferative arrest.

Ancillary Ligand in Ternary CuII Complexes Guides Binding Selectivity toward Minor-Groove DNA.

Copper-containing compounds known as Casiopeínas are biologically active molecules which show promising antineoplastic effects against several cancer types. Two possible hypotheses regarding the mode of action of the Casiopeínas have emerged from the experimental evidence: the generation of reactive oxygen species or the ability of the compounds to bind and interact with nucleic acids. Using robust molecular dynamics simulations, we investigate the interaction of four different Casiopeínas with the DNA duplex d(GCACGAACGAACGAACGC). The studied copper complexes contain either 4-7- or 5-6-substituted dimethyl phenanthroline as the primary ligand and either glycinate or acetylacetonate as the secondary ligand. For statistical significance and to reduce bias in the simulations, four molecules of each copper compound were manually placed at a distance of 10 Å away from the DNA and 20 independent molecular dynamics simulations were performed, each reaching at least 30 µs. This time scale allows us to reproduce expected DNA terminal base-pair fraying and also to observe intercalation/base-pair eversion events generated by the compounds interacting with DNA. The results reveal that the secondary ligand is the guide toward the mode of binding between the copper complex and DNA in which glycinate prefers minor-groove binding and acetylacetonate produces base-pair eversion and intercalation. The CuII complexes containing glycinate interact within the DNA minor groove which are stabilized principally by the hydrogen bonds formed between the amino group of the aminoacidate moiety, whereas the compounds with the acetylacetonate do not present a stable network of hydrogen bonds and the ligand interactions enhance DNA breathing dynamics that result in base-pair eversion.

Not Learning From Failure-the Greatest Failure of All.

Our society celebrates failure as a teachable moment. Yet in five studies (total N = 1,674), failure did the opposite: It undermined learning. Across studies, participants answered binary-choice questions, following which they were told they answered correctly (success feedback) or incorrectly (failure feedback). Both types of feedback conveyed the correct answer, because there were only two answer choices. However, on a follow-up test, participants learned less from failure feedback than from success feedback. This effect was replicated across professional, linguistic, and social domains-even when learning from failure was less cognitively taxing than learning from success and even when learning was incentivized. Participants who received failure feedback also remembered fewer of their answer choices. Why does failure undermine learning? Failure is ego threatening, which causes people to tune out. Participants learned less from personal failure than from personal success, yet they learned just as much from other people's failure as from others' success. Thus, when ego concerns are muted, people tune in and learn from failure.

A large-scale field experiment shows giving advice improves academic outcomes for the advisor.

Common sense suggests that people struggling to achieve their goals benefit from receiving motivational advice. What if the reverse is true? In a preregistered field experiment, we tested whether giving motivational advice raises academic achievement for the advisor. We randomly assigned n = 1,982 high school students to a treatment condition, in which they gave motivational advice (e.g., how to stop procrastinating) to younger students, or to a control condition. Advice givers earned higher report card grades in both math and a self-selected target class over an academic quarter. This psychologically wise advice-giving nudge, which has relevance for policy and practice, suggests a valuable approach to improving achievement: one that puts people in a position to give.

Self-Control and Academic Achievement.

Self-control refers to the alignment of thoughts, feelings, and actions with enduringly valued goals in the face of momentarily more alluring alternatives. In this review, we examine the role of self-control in academic achievement. We begin by defining self-control and distinguishing it from related constructs. Next, we summarize evidence that nearly all students experience conflict between academic goals that they value in the long run and nonacademic goals that they find more gratifying in the moment. We then turn to longitudinal evidence relating self-control to academic attainment, course grades, and performance on standardized achievement tests. We use the process model of self-control to illustrate how impulses are generated and regulated, emphasizing opportunities for students to deliberately strengthen impulses that are congruent with, and dampen impulses that are incongruent with, academic goals. Finally, we conclude with future directions for both science and practice.

Dear Abby: Should I Give Advice or Receive It?

Typically, individuals struggling with goal achievement seek advice. However, in the present investigation ( N = 2,274), struggling individuals were more motivated by giving advice than receiving it. In a randomized, controlled, double-blind field experiment, middle-school students who gave motivational advice to younger students spent more time on homework over the following month than students who received motivational advice from expert teachers (Experiment 1). This phenomenon was replicated across self-regulatory domains: Strugglers who gave advice, compared with those who received expert advice, were more motivated to save money, control their tempers, lose weight, and seek employment (Experiments 2 and 3). Nevertheless, across domains, people erroneously predicted the opposite, expecting themselves and others to be less motivated by giving advice than receiving it (Experiments 2 and 3). Why are people blind to the motivational power of giving? Giving advice motivated givers by raising their confidence-a reality that predictors fail to anticipate (Experiment 4).