Transcription is a fundamental cellular process and the first step in gene regulation. Although RNA polymerase (RNAP) is highly processive, in growing cells the progression of transcription can be hindered by obstacles on the DNA template, such as damaged DNA. The authors recent findings highlight a trade‐off between transcription fidelity and DNA break repair. While a lot of work has focused on the interaction between transcription and nucleotide excision repair, less is known about how transcription influences the repair of DNA (...) breaks. The authors suggest that when the cell experiences stress from DNA breaks, the control of RNAP processivity affects the balance between preserving transcription integrity and DNA repair. Here, how the conflict between transcription and DNA double‐strand break (DSB) repair threatens the integrity of both RNA and DNA are discussed. In reviewing this field, the authors speculate on cellular paradigms where this equilibrium is well sustained, and instances where the maintenance of transcription fidelity is favored over genome stability. (shrink)

Powerful new social science data resources are emerging. One particularly important source is administrative data, which were originally collected for organisational purposes but often contain information that is suitable for social science research. In this paper we outline the concept of reproducible research in relation to micro-level administrative social science data. Our central claim is that a planned and organised workflow is essential for high quality research using micro-level administrative social science data. We argue that it is essential for researchers (...) to share research code, because code sharing enables the elements of reproducible research. First, it enables results to be duplicated and therefore allows the accuracy and validity of analyses to be evaluated. Second, it facilitates further tests of the robustness of the original piece of research. Drawing on insights from computer science and other disciplines that have been engaged in e-Research we discuss and advocate the use of Git repositories to provide a useable and effective solution to research code sharing and rendering social science research using micro-level administrative data reproducible. (shrink)

'Knowledge-First' constitutes what is widely regarded as one of the most significant innovations in contemporary epistemology in the past 25 years. Knowledge-first epistemology is the idea that knowledge per se should not be analysed in terms of its constituent parts (e.g., justification, belief), but rather that these and other notions should be analysed in terms of the concept of knowledge. This volume features a substantive introduction and 13 original essays from leading and up-and-coming philosophers on the topic of knowledge-first philosophy. (...) The contributors' essays range from foundational issues to applications of this project to other disciplines including the philosophy of mind, the philosophy of perception, ethics and action theory. Knowledge First: Approaches in Epistemology and Mind aims to provide a relatively open-ended forum for creative and original scholarship with the potential to contribute and advance debates connected with this philosophical project. (shrink)

Recent work in the philosophy of mind and cognitive science (e.g., Clark and Chalmers 1998; Clark 2010a; Clark 2010b; Palermos 2014) can help to explain why certain kinds of assertions—made on the basis of information stored in our gadgets rather than in biological memory—are properly criticisable in light of misleading implicatures, while others are not.

Should we regard Jennifer Lackey’s ‘Creationist Teacher’ as understanding evolution, even though she does not, given her religious convictions, believe its central claims? We think this question raises a range of important and unexplored questions about the relationship between understanding, factivity and belief. Our aim will be to diagnose this case in a principled way, and in doing so, to make some progress toward appreciating what objectual understanding—i.e., understanding a subject matter or body of information—demands of us. Here is the (...) plan. After some ground clearing in §1, §2 outlines and motivates a plausible working model—moderate factivity—for characterising the sense in which objectual understanding should be regarded as factive. §3 shows how the datum that we can understand false theories can, despite initial suggestions to the contrary, be assimilated straightforwardly within the moderate factivity model. §4 highlights how the inverse kind of case to that explored in §3—viz., a variant of Lackey’s creationist teacher case—poses special problems for moderate factivity. With reference to recent work on moral understanding by Hills, §5 proposes a solution to the problem, and §6 attempts to diagnose why it is that we might originally have been led to draw the wrong conclusion. (shrink)

We show that the contemporary debate surrounding the question “What is the norm of assertion?” presupposes what we call the quantitative view, i.e. the view that this question is best answered by determining how much epistemic support is required to warrant assertion. We consider what Jennifer Lackey ( 2010 ) has called cases of isolated second-hand knowledge and show—beyond what Lackey has suggested herself—that these cases are best understood as ones where a certain type of understanding , rather than knowledge, (...) constitutes the required epistemic credential to warrant assertion. If we are right that understanding (and not just knowledge) is the epistemic norm for a restricted class of assertions, then this straightforwardly undercuts not only the widely supposed quantitative view, but also a more general presupposition concerning the universalisability of some norm governing assertion—the presumption (almost entirely unchallenged since Williamson’s 1996 paper) that any epistemic norm that governs some assertions should govern assertions—as a class of speech act—uniformly. (shrink)

Consideration of the experimental activities carried out in one discipline, through the lens of another, can lead to novel insights. Here, we comment from a biological perspective upon experiments in quantum mechanics proposed by physicists that are likely to feasible in the near future. In these experiments, an entire living organism would be knowingly placed into a coherent quantum state for the first time, i.e. would be coerced into demonstrating quantum phenomena. The implications of the proposed experiment for a biologist (...) depend to an extent upon the outcomes. If successful, then the organism will have been temporarily in a state where it has an unmeasurable metabolism—not because a metabolic rate is undetectable, but because any attempt to measure it would automatically bring the organism out of the state. We argue that this would in essence represent a new category of cryptobiosis. Further, the organism would not necessarily retain all of the characteristics commonly attributed to living systems, unlike the currently known categories of cryptobiosis. If organisms can survive having previously been in a coherent state, then we must accept that living systems do not necessarily need to remain in a decoherent state at all times. This would be something new to biologists, even if it might seem trivial to physicists. It would have implications concerning the physical extremes organisms can tolerate, the search for extraterrestrial life, and our philosophical view of animation. (shrink)

The scope of Philosophy in Multiple Voices provides the reader with eight philosophical streams of thought-African-American, Afro-Caribbean, Asian-American, Feminist, Latin-American, Lesbian, Native-American and Queer-that introduce readers to alternative, complex philosophical questions concerning gendered, sexed, racial and ethnic identities, canon formation, and meta-philosophy. The overriding theme of the text is that philosophy is pluralistic in voice, rich in diversity, and ought to valorize democratic intellectual spaces of philosophical engagement.

The study of anarchism as a philosophical, political, and social movement has burgeoned both in the academy and in the global activist community in recent years. Taking advantage of this boom in anarchist scholarship, Nathan J. Jun and Shane Wahl have compiled twenty-six cutting-edge essays on this timely topic in New Perspectives on Anarchism.

This paper examines farmer intentions to adapt to global climate change by analyzing responses to a climate change scenario presented in a survey given to large-scale farmers across the US Corn Belt in 2012. Adaptive strategies are evaluated in the context of decision making and farmers’ intention to increase their use of three production practices promoted across the Corn Belt: no-till farming, cover crops, and tile drainage. This paper also provides a novel conceptual framework that bridges a typology of adaptation (...) with concepts that help predict intentionality in behavior change models. This conceptual framework was developed to facilitate examination of adaptive decision making in the context of agriculture. This research effort examines key factors that influence farmers’ intentions to increase their use of the practices evaluated given a climate change scenario. Twenty-two covariates are examined across three models developed for no-till farming, cover crops, and tile drainage. Findings highlight that farmers who believed they should adjust their practices to protect their farm from the negative impacts of increased weather variability were more likely to indicate that they would increase their use of each of the practices in response to climate change. Additionally, visiting with other farmers to observe their practices was positively associated with farmers’ intentions to increase their use of the adaptive strategies examined. Farmers who were currently using no-till farming, cover crops, and tile drainage were also more likely to plan to increase their use of these practices in response to increased weather variability associated with climate change. However, farmers who reported high levels of confidence in their current practices were less likely to plan on changing their use of these practices in response to climatic changes. (shrink)

This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. ?Social context? refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is (...) introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences. (shrink)

This article argues that we could improve the design of research protocols by developing an awareness of and a responsiveness to the social contexts of all the actors in the research enterprise, including subjects, investigators, sponsors, and members of the community in which the research will be conducted. “Social context” refers to the settings in which the actors are situated, including, but not limited to, their social, economic, political, cultural, and technological features. The utility of thinking about social contexts is (...) introduced and exemplified by the presentation of a hypothetical case in which one central issue is limitation of the probability of injury to subjects by selection of individuals who are not expected to live long enough for the known risks of the study to become manifest as harms. Benefits of such considerations may include enhanced subject satisfaction and cooperation, community acceptance, and improved data quality, among other desirable consequences. (shrink)

Darwinian Evolution and Classical Liberalism brings together a collection of new essays that examine the multifaceted ferment between Darwinian biology and classical liberalism.

The co-occurrence of stress-induced posttraumatic stress disorder and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to systematically (...) highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin, Neuropeptide-Y, and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation. (shrink)

Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that (...) has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. (shrink)

The US neutrino community gathered at the Workshop on the Intermediate Neutrino Program at Brookhaven National Laboratory February 4-6, 2015 to explore opportunities in neutrino physics over the next five to ten years. Scientists from particle, astroparticle and nuclear physics participated in the workshop. The workshop examined promising opportunities for neutrino physics in the intermediate term, including possible new small to mid-scale experiments, US contributions to large experiments, upgrades to existing experiments, R&D plans and theory. The workshop was organized into (...) two sets of parallel working group sessions, divided by physics topics and technology. Physics working groups covered topics on Sterile Neutrinos, Neutrino Mixing, Neutrino Interactions, Neutrino Properties and Astrophysical Neutrinos. Technology sessions were organized into Theory, Short-Baseline Accelerator Neutrinos, Reactor Neutrinos, Detector R&D and Source, Cyclotron and Meson Decay at Rest sessions.This report summarizes discussion and conclusions from the workshop. (shrink)

Using a sample of 652 college students, we examined several implications of the hypothesis that the shape of the human penis evolved to enable males to substitute their semen for those of their rivals. The incidence of double mating by females appears sufficient to make semen displacement adaptive (e.g., one in four females acknowledge infidelity, one in eight admit having sex with two or more males in a 24-hour period, and one in 12 report involvement in one or more sexual (...) threesomes with two males). We also document several changes in post-ejaculatory behavior (e.g., reduced thrusting, penis withdrawal, loss of an erection) which may have evolved to minimize displacement of the male’s own semen. Consistent with predictions derived from a theoretical model (Gallup and Burch 2006), we discovered that most females report waiting at least 48 hours following an instance of infidelity before resuming sex with their in-pair partners. (shrink)

This paper describes the application of eight statistical and machine-learning methods to derive computer models for predicting mortality of hospital patients with pneumonia from their findings at initial presentation. The eight models were each constructed based on 9847 patient cases and they were each evaluated on 4352 additional cases. The primary evaluation metric was the error in predicted survival as a function of the fraction of patients predicted to survive. This metric is useful in assessing a model’s potential to assist (...) a clinician in deciding whether to treat a given patient in the hospital or at home. We examined the error rates of the models when predicting that a given fraction of patients will survive. We examined survival fractions between 0.1 and 0.6. Over this range, each model’s predictive error rate was within 1% of the error rate of every other model. When predicting that approximately 30°K of the patients will survive, all the models have an error rate of less than 1.5%. The models are distinguished more by the number of variables and parameters that they contain than by their error rates; these differences suggest which models may be the most amenable to future implementation as paper-based guidelines. (shrink)

For all of the emphasis on quality improvement—as well as the acknowledged overlap between assessment of the quality of healthcare services and clinical ethics—the quality of clinical ethics consultation has received scant attention, especially in terms of empirical measurement. Recognizing this need, the second edition of Core Competencies for Health Care Ethics Consultation identified four domains of ethics quality: (1) ethicality, (2) stakeholders’ satisfaction, (3) resolution of the presenting conflict/dilemma, and (4) education that translates into knowledge. This study is the (...) first, to our knowledge, to directly measure all of these domains. Here we describe the quality improvement process undertaken at a tertiary care academic medical center, as well as the tools developed to measure the quality of ethics consultation, which include post-consultation satisfaction surveys and weekly case conferences. The information gained through these tools helps to improve not only the process of ethics consultation, but also the measurement and assurance of quality. (shrink)

Live donor kidney transplantation is the best treatment option for most patients with late-stage chronic kidney disease; however, the rate of living kidney donation has declined in the United States. A consensus conference was held June 5-6, 2014 to identify best practices and knowledge gaps pertaining to live donor kidney transplantation and living kidney donation. Transplant professionals, patients, and other key stakeholders discussed processes for educating transplant candidates and potential living donors about living kidney donation; efficiencies in the living donor (...) evaluation process; disparities in living donation; and financial and systemic barriers to living donation. We summarize the consensus recommendations for best practices in these educational and clinical domains, future research priorities, and possible public policy initiatives to remove barriers to living kidney donation. (shrink)

Background The allocation of scarce deceased donor kidneys is a complex process. Transplant providers are increasingly relying on constructs such as frailty and cognitive function to guide kidney transplant (KT) candidate selection. Patient views of the ethical issues surrounding the use of such constructs are unclear. We sought to assess KT candidates’ attitudes and beliefs about the use of frailty and cognitive function to guide waitlist selection.Methods KT candidates were randomly recruited from an ongoing single-center cohort study of frailty and (...) cognitive function. Semi-structured interviews were conducted, and thematic analysis was performed. Inductively derived themes were mapped onto bioethics principles.Results Twenty interviews were conducted (65% contact rate, 100% participation rate) (60% male; 70% White). With respect to the use of frailty and cognitive function in waitlisting decisions, four themes emerged in which participants: (1) valued maximizing a scarce resource (utility); (2) prioritized equal access to all patients (equity); (3) appreciated a proportional approach to the use of equity and utility (precautionary utility); and (4) sought to weigh utility- and equity-based concerns regarding social support. While some participants believed frailty and cognitive function were useful constructs to maximize utility, others believed their use would jeopardize equity. Patients were uncomfortable with using single factors such as frailty or cognitive impairment to deny someone access to transplantation; participants instead encouraged using the constructs to identify opportunities for intervention to improve frailty and cognitive function prior to KT.Conclusions KT candidates’ values mirrored the current allocation strategy, seeking to balance equity and utility in a just manner, albeit with conflicting viewpoints on the appropriate use of frailty and cognitive impairment in waitlisting decisions. (shrink)

BackgroundPeople with upper extremity amputations report receiving insufficient information about treatment options. Furthermore, patients commonly report not knowing what questions to ask providers. A question prompt sheet, or list of questions, can support patient-centered care by empowering patients to ask questions important to them, promoting patient-provider communication, and increasing patient knowledge. This study assessed information needs among people with UE amputations about UE vascularized composite allotransplantation and developed a UE VCA-QPS.MethodsThis multi-site, cross-sectional, mixed-methods study involved in-depth and semi-structured interviews with (...) people with UE amputations to assess information needs and develop a UE VCA-QPS. Qualitative data were analyzed by thematic analysis; quantitative data were analyzed by descriptive statistics. The initial UE VCA-QPS included 130 items across 18 topics.ResultsEighty-nine people with UE amputations participated. Most were male, had a mean age of 46 years, and had a unilateral and below-elbow amputation. Participants desired information about UE VCA eligibility, evaluation process, surgery, risks, rehabilitation, and functional outcomes. After refinement, the final UE VCA-QPS included 35 items, across 9 topics. All items were written at a ≤ 6th grade reading level. Most semi-structured interview participants reported being ‘completely’ or ‘very’ likely to use a UE VCA-QPS.ConclusionPeople with UE amputations have extensive information needs about UE VCA. The UE VCA-QPS aims to address patients’ information needs and foster patient-centered care. Future research should assess whether the UE VCA-QPS facilitates patient-provider discussion and informed decision-making for UE VCA. (shrink)

BackgroundKinarm Standard Tests is a suite of upper limb tasks to assess sensory, motor, and cognitive functions, which produces granular performance data that reflect spatial and temporal aspects of behavior. We have previously used principal component analysis to reduce the dimensionality of multivariate data using the Kinarm End-Point Lab. Here, we performed PCA using data from the Kinarm Exoskeleton Lab, and determined agreement of PCA results across EP and EXO platforms in healthy participants. We additionally examined whether further dimensionality reduction (...) was possible by using PCA across behavioral tasks.MethodsHealthy participants were assessed using the Kinarm EXO and EP. Four behavioral tasks were performed that quantified arm sensory and motor function, including position sense [Arm Position Matching ] and three motor tasks [Visually Guided Reaching, Object Hit, and Object Hit and Avoid ]. The number of components to include per task was determined from scree plots and parallel analysis, and rotation type was decided on a per-task basis. To assess agreement, we compared principal components across platforms using distance correlation. We additionally considered inter-task interactions in EXO data by performing PCA across all six behavioral assessments.ResultsBy applying PCA on a per task basis to data collected using the EXO, the number of behavioral parameters were substantially reduced by 58–75% while accounting for 76–87% of the variance. These results compared well to the EP analysis, and we found good-to-excellent agreement values between PCs from the EXO and those from the EP. Finally, we were able to reduce the dimensionality of the EXO data across tasks down to 16 components out of a total of 76 behavioral parameters, which represents a reduction of 79% while accounting for 73% of the total variance.ConclusionPCA of Kinarm robotic assessment appears to capture similar relationships between kinematic features in healthy individuals and is agnostic to the robotic platform used for collection. Further work is needed to investigate the use of PCA-based data reduction for the characterization of neurological deficits in clinical populations. (shrink)

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls. Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents. Probands were more likely to carry an additional large copy-number variant when compared to matched controls. The clinical (...) features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease. © 2010 Nature America, Inc. All rights reserved. (shrink)

Importance Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials.Objective To examine cancer clinical trial (CCT) participants’ perceptions of informed consent processes and variations in perceptions by cancer type.Design and Setting and Participants Cross-sectional survey from mixed-methods study at National Cancer Institute–designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or genitourinary, hematologic-lymphatic (...) malignancies, lung cancer, and breast or gynecological cancer (N = 334).Main Outcome Measures Percentages satisfied with consent process and information provided; and assessing participation’s perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type.Results Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did—47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT.Conclusions and Relevance Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making. (shrink)

Plato: Symposium, translated by B. Jowett. Phaedo, translated by B. Jowett. Sophist, translated by B. Jowett.--Aristotle: De anima, translated by R. D. Hicks. Metaphysics (selections) translated by H. Tredennick. Nichomachean ethics (selections) translated by H. Rackham.--R. Descartes: Meditations, translated by E. S. Haldane and G. R. T. Ross.--G. Berkeley: Three dialogues between Hylas and Philonus.--D. Hume: Dialogues concerning natural religion.--I. Kant: Prolegomena to every future, translated by C. J. Friedrich. Metaphysical foundations of morals, translated by C. J. Friedrich.

Saigle, Dubljevic, and Racine (2018) claim that Libet-style experiments are insufficient to challenge that agents have free will. They support this with evidence from experimen- tal psychology that the folk concept of freedom is consis- tent with monism, that our minds are identical to our brains. However, recent literature suggests that evidence from experimental psychology is less than determinate in this regard, and that folk intuitions are too unrefined as to provide guidance on metaphysical issues like monism. In light of (...) this, it is worthwhile to examine the authors’ insuf- ficiency claim under the assumption that monism is false and dualism true (our minds are not identical to our brains). We conclude that, were dualism true, then Libet- style experiments would tell us no more about freedom and moral responsibility than what the authors initially claimed, thus further bolstering their point that Libet-style experiments are ill-suited to speak to the free will of agents. In what follows we first discuss some of the reasons to be skeptical of using folk intuitions to make claims about the nature of freedom and moral responsibility. We then draw from the work of E. J. Lowe to demonstrate that Libet-style experiments would likely give the same results regardless of the truth of monism or dualism. (shrink)

Beginning with Sir William Hamilton's revitalisation of philosophy in Scotland in the 1830s, Gordon Graham takes up the theme of George Davie's The Democratic Intellect and explores a century of debates surrounding the identity and continuity of the Scottish philosophical tradition. Gordon Graham identifies a host of once-prominent but now neglected thinkers - such as Alexander Bain, J. F. Ferrier, Thomas Carlyle, Alexander Campbell Fraser, John Tulloch, Henry Jones, Henry Calderwood, David Ritchie and Andrew Seth Pringle-Pattison - whose (...) reactions to Hume and Reid stimulated new currents of ideas. Graham concludes by considering the relation between the Scottish philosophical tradition and the 20th-century philosopher John Macmurray. (shrink)