Raising argument strength using negative evidence: A constraint on models of induction

Both intuitively, and according to similarity-based theories of induction, relevant evidence raises argument strength when it is positive and lowers it when it is negative. In three experiments, we tested the hypothesis that argument strength can actually increase when negative evidence is introduced. Two kinds of argument were compared through forced choice or sequential evaluation: single positive arguments (e.g., “Shostakovich’s music causes alpha waves in the brain; therefore, Bach’s music causes alpha waves in the brain”) and double mixed arguments (e.g., “Shostakovich’s music causes alpha waves in the brain, X’s music DOES NOT; therefore, Bach’s music causes alpha waves in the brain”). Negative evidence in the second premise lowered credence when it applied to an item X from the same subcategory (e.g., Haydn) and raised it when it applied to a different subcategory (e.g., AC/DC). The results constitute a new constraint on models of induction

Characterisation of the pathogenic effects of the in vivo expression of an ALS-linked mutation in D-amino acid oxidase: Phenotype and loss of spinal cord motor neurons

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset neuromuscular disorder characterised by selective loss of motor neurons leading to fatal paralysis. Current therapeutic approaches are limited in their effectiveness. Substantial advances in understanding ALS disease mechanisms has come from the identification of pathogenic mutations in dominantly inherited familial ALS (FALS). We previously reported a coding mutation in D-amino acid oxidase (DAOR199W) associated with FALS. DAO metabolises D-serine, an essential co-agonist at the N-Methyl-D-aspartic acid glutamate receptor subtype (NMDAR). Using primary motor neuron cultures or motor neuron cell lines we demonstrated that expression of DAOR199W, promoted the formation of ubiquitinated protein aggregates, activated autophagy and increased apoptosis. The aim of this study was to characterise the effects of DAOR199W in vivo, using transgenic mice overexpressing DAOR199W. Marked abnormal motor features, e.g. kyphosis, were evident in mice expressing DAOR199W, which were associated with a significant loss (19%) of lumbar spinal cord motor neurons, analysed at 14 months. When separated by gender, this effect was greater in females (26%; p< 0.0132). In addition, we crossed the DAOR199W transgenic mouse line with the SOD1G93A mouse model of ALS to determine whether the effects of SOD1G93A were potentiated in the double transgenic line (DAOR199W/SOD1G93A). Although overall survival was not affected, onset of neurological signs was significantly earlier in female double transgenic animals than their female SOD1G93A littermates (125 days vs 131 days, P = 0.0239). In summary, some significant in vivo effects of DAOR199W on motor neuron function (i.e. kyphosis and loss of motor neurons) were detected which were most marked in females and could contribute to the earlier onset of neurological signs in double transgenic females compared to SOD1G93A littermates, highlighting the importance of recognizing gender effects present in animal models of ALS

The COLO-COHORT (Colorectal Cancer Cohort) study: Protocol for a multi-centre, observational research study and development of a consent-for-contact research platform

Aim The COLO-COHORT study aims to produce a multi-factorial risk prediction model for colorectal neoplasia that can be used to target colonoscopy to those at greatest risk of colorectal neoplasia, ensuring that people are not investigated unnecessarily and maximizing the use of limited endoscopy resources. The study will also explore the link between neoplasia and the human gut microbiome. Additionally, the study aims to generate a cohort of colonoscopy patients who are ‘research ready’ through the development of a consent-for-contact (C4C) platform, to facilitate a range of colorectal cancer prevention studies to be conducted at scale and speed. Methods and analysis This is a multi-centre observational study involving sites across the UK. Recruitment is over a 6-year period (2019–2025). Patients recruited to the study are those attending for colonoscopy. Patients are recruited into two groups, namely observational group A (10 000 patients) and C4C group B (10 000 patients), known as COLO-SPEED (Colorectal Cancer Screening Prevention Endoscopy and Early Diagnosis; https://colospeed.uk). Patients complete a health questionnaire, provide anthropometric measurements and submit biosamples (blood and stool—depending on the part of the study they are recruited into). Patients' colonoscopy and histology findings are also recorded. Models of factors associated with the presence of neoplasia at colonoscopy will be developed using logistic or multinomial regression. For internal validation, model discrimination and calibration will be assessed and bootstrapping and cross-validation approaches used. To enable long-term follow-up for outcomes related to colorectal cancer and polyps, patients are asked to consent to follow-up through data linkage with national databases. Dissemination In keeping with good research practice, following analysis by the study team the study investigators will make the anonymized dataset available to other researchers. The C4C platform will also be accessible to other researchers. The study findings will be submitted for publication in peer-reviewed journals and lay summaries will be disseminated to participants and the wider public

Promiscuous drugs compared to selective drugs (promiscuity can be a virtue)

BACKGROUND: The word selectivity describes a drug's ability to affect a particular cell population in preference to others. As part of the current state of art in the search for new therapeutic agents, the property of selectivity is a mode of action thought to have a high degree of desirability. Consequently there is a growing activity in this area of research. Selectivity is generally a worthy property in a drug because a drug having high selectivity may have a dramatic effect when there is a single agent that can be targeted against the appropriate molecular-driver involved in the pathogenesis of a disease. An example is chronic myeloid leukemia (CML). CML has a specific chromosomal abnormality, the Philadelphia chromosome, that results in a single gene that produces an abnormal protein DISCUSSION: There is a burgeoning understanding of the cellular mechanisms that control the etiology and pathogeneses of diseases. This understanding both enables and motivates the development of drugs that induce a specific action in a selected cell population; i.e., a targeted treatment. Consequently, drugs that can target distinct molecular targets involved in pathologic/pathogenetic processes, or signal-transduction pathways, are being developed. However, in most cases, diseases involve multiple abnormalities. A disease may be associated with more than one dysfunctional protein and these may be out-of-balance with each other. Likewise a drug might strongly target a protein that shares a similar active domain with other proteins. A drug may also target pleiotropic cytokines, or other proteins that have multi-physiological functions. In this way multiple normal cellular pathways can be simultaneously influenced. Long term experience with drugs supposedly designed for only a single target, but which unavoidably involve other functional effects, is uncovering the fact that molecular targeting is not medically flawless. SUMMARY: We contend that an ideal drug may be one whose efficacy is based not on the inhibition of a single target, but rather on the rebalancing of the several proteins or events, that contribute to the etiology, pathogeneses, and progression of diseases, i.e., in effect a promiscuous drug. Ideally, if this could be done at minimum drug concentration, side effects could be minimized. Corollaries to this argument are that the growing fervor for researching truly selective drugs may be imprudent when considering the totality of responses; and that the expensive screening techniques used to discover these, may be both medically and financially inefficient

Maternal Undernutrition Significantly Impacts Ovarian Follicle Number and Increases Ovarian Oxidative Stress in Adult Rat Offspring

BACKGROUND: We have shown recently that maternal undernutrition (UN) advanced female pubertal onset in a manner that is dependent upon the timing of UN. The long-term consequence of this accelerated puberty on ovarian function is unknown. Recent findings suggest that oxidative stress may be one mechanism whereby early life events impact on later physiological functioning. Therefore, using an established rodent model of maternal UN at critical windows of development, we examined maternal UN-induced changes in offspring ovarian function and determined whether these changes were underpinned by ovarian oxidative stress. METHODOLOGY/PRINCIPAL FINDINGS: Our study is the first to show that maternal UN significantly reduced primordial and secondary follicle number in offspring in a manner that was dependent upon the timing of maternal UN. Specifically, a reduction in these early stage follicles was observed in offspring born to mothers undernourished throughout both pregnancy and lactation. Additionally, antral follicle number was reduced in offspring born to all mothers that were UN regardless of whether the period of UN was restricted to pregnancy or lactation or both. These reductions were associated with decreased mRNA levels of genes critical for follicle maturation and ovulation. Increased ovarian protein carbonyls were observed in offspring born to mothers UN during pregnancy and/or lactation and this was associated with peroxiredoxin 3 hyperoxidation and reduced mRNA levels; suggesting compromised antioxidant defence. This was not observed in offspring of mothers UN during lactation alone. CONCLUSIONS: We propose that maternal UN, particularly at a time-point that includes pregnancy, results in reduced offspring ovarian follicle numbers and mRNA levels of regulatory genes and may be mediated by increased ovarian oxidative stress coupled with a decreased ability to repair the resultant oxidative damage. Together these data are suggestive of maternal UN potentially contributing to premature ovarian ageing in offspring

Geographical gradient of the <em>eIF4E</em> alleles conferring resistance to potyviruses in pea (<em>Pisum</em>) germplasm

<div><p>Background</p><p>The eukaryotic translation initiation factor 4E was shown to be involved in resistance against several potyviruses in plants, including pea. We combined our knowledge of pea germplasm diversity with that of the <i>eIF4E</i> gene to identify novel genetic diversity.</p><p>Methodology/Principal findings</p><p>Germplasm of 2803 pea accessions was screened for <i>eIF4E</i> intron 3 length polymorphism, resulting in the detection of four <i>eIF4E^A-B-C-S</i> variants, whose distribution was geographically structured. The <i>eIF4E^A</i> variant conferring resistance to the P1 PSbMV pathotype was found in 53 accessions (1.9%), of which 15 were landraces from India, Afghanistan, Nepal, and 7 were from Ethiopia. A newly discovered variant, <i>eIF4E^B</i>, was present in 328 accessions (11.7%) from Ethiopia (29%), Afghanistan (23%), India (20%), Israel (25%) and China (39%). The <i>eIF4E^C</i> variant was detected in 91 accessions (3.2% of total) from India (20%), Afghanistan (33%), the Iberian Peninsula (22%) and the Balkans (9.3%). The <i>eIF4E^S</i> variant for susceptibility predominated as the wild type. Sequencing of 73 samples, identified 34 alleles at the whole gene, 26 at cDNA and 19 protein variants, respectively. Fifteen alleles were virologically tested and 9 alleles (<i>eIF4E^{A-1-2-3-4-5-6-7}</i>, <i>eIF4E^B-1</i>, <i>eIF4E^C-2</i>) conferred resistance to the P1 PSbMV pathotype.</p><p>Conclusions/Significance</p><p>This work identified novel <i>eIF4E</i> alleles within geographically structured pea germplasm and indicated their independent evolution from the susceptible <i>eIF4E^S1</i> allele. Despite high variation present in wild <i>Pisum</i> accessions, none of them possessed resistance alleles, supporting a hypothesis of distinct mode of evolution of resistance in wild as opposed to crop species. The Highlands of Central Asia, the northern regions of the Indian subcontinent, Eastern Africa and China were identified as important centers of pea diversity that correspond with the diversity of the pathogen. The series of alleles identified in this study provides the basis to study the co-evolution of potyviruses and the pea host.</p></div

The SAMI Galaxy Survey: Early Data Release

We present the Early Data Release of the Sydney–AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey. The SAMI Galaxy Survey is an ongoing integral field spectroscopic survey of _3400 low-redshift (z < 0:12) galaxies, covering galaxies in the field and in groups within the Galaxy And Mass Assembly (GAMA) survey regions, and a sample of galaxies in clusters. In the Early Data Release, we publicly release the fully calibrated datacubes for a representative selection of 107 galaxies drawn from the GAMA regions, along with information about these galaxies from the GAMA catalogues. All datacubes for the Early Data Release galaxies can be downloaded individually or as a set from the SAMI Galaxy Survey website. In this paper we also assess the quality of the pipeline used to reduce the SAMI data, giving metrics that quantify its performance at all stages in processing the raw data into calibrated datacubes. The pipeline gives excellent results throughout, with typical sky subtraction residuals in the continuum of 0.9–1.2 per cent, a relative flux calibration uncertainty of 4.1 per cent (systematic) plus 4.3 per cent (statistical), and atmospheric dispersion removed with an accuracy of 0:0009, less than a fifth of a spaxel

The SAMI Galaxy Survey: Early Data Release

We present the Early Data Release of the Sydney–AAO Multi-object Integral field spectrograph (SAMI) Galaxy Survey. The SAMI Galaxy Survey is an ongoing integral field spectroscopic survey of _3400 low-redshift (z < 0:12) galaxies, covering galaxies in the field and in groups within the Galaxy And Mass Assembly (GAMA) survey regions, and a sample of galaxies in clusters. In the Early Data Release, we publicly release the fully calibrated datacubes for a representative selection of 107 galaxies drawn from the GAMA regions, along with information about these galaxies from the GAMA catalogues. All datacubes for the Early Data Release galaxies can be downloaded individually or as a set from the SAMI Galaxy Survey website. In this paper we also assess the quality of the pipeline used to reduce the SAMI data, giving metrics that quantify its performance at all stages in processing the raw data into calibrated datacubes. The pipeline gives excellent results throughout, with typical sky subtraction residuals in the continuum of 0.9–1.2 per cent, a relative flux calibration uncertainty of 4.1 per cent (systematic) plus 4.3 per cent (statistical), and atmospheric dispersion removed with an accuracy of 0:0009, less than a fifth of a spaxel

Depicting the tree of life in museums: guiding principles from psychological research

The Tree of Life is revolutionizing our understanding of life on Earth, and, accordingly, evolutionary trees are increasingly important parts of exhibits on biodiversity and evolution. The authors argue that in using these trees to effectively communicate evolutionary principles, museums need to take into account research results from cognitive, developmental, and educational psychology while maintaining a focus on visitor engagement and enjoyment. Six guiding principles for depicting evolutionary trees in museum exhibits distilled from this research literature were used to evaluate five current or recent museum trees. One of the trees was then redesigned in light of the research while preserving the exhibit’s original learning goals. By attending both to traditional factors that influence museum exhibit design and to psychological research on how people understand diagrams in general and Tree of Life graphics in particular, museums can play a key role in fostering 21st century scientific literacy

Inappropriate stereotypical inferences? An adversarial collaboration in experimental ordinary language philosophy

This paper trials new experimental methods for the analysis of natural language reasoning and the (re)development of critical ordinary language philosophy in the wake of J.L. Austin. Philosophical arguments and thought experiments are strongly shaped by default pragmatic inferences, including stereotypical inferences. Austin suggested that contextually inappropriate stereotypical inferences are at the root of some philosophical paradoxes and problems, and that these can be resolved by exposing those verbal fallacies. This paper builds on recent efforts to empirically document inappropriate stereotypical inferences that may drive philosophical arguments. We demonstrate that previously employed questionnaire-based output measures do not suffice to exclude relevant confounds. We then report an experiment that combines reading time measurements with plausibility ratings. The study seeks to provide evidence of inappropriate stereotypical inferences from appearance verbs that have been suggested to lie at the root of the influential ‘argument from illusion’. Our findings support a diagnostic reconstruction of this argument. They provide the missing component for proof of concept for an experimental implementation of critical ordinary language philosophy that is in line with the ambitions of current ‘evidential’ experimental philosophy