"Cognitive Penetrability" - Ch 3 of Seemings and Epistemic Justification

In this chapter I introduce the thesis that perceptual appearances are cognitively penetrable and analyse cases made against phenomenal conservatism hinging on this thesis. In particular, I focus on objections coming from the externalist reliabilist camp and the internalist inferentialist camp. I conclude that cognitive penetrability doesn’t yield lethal or substantive difficulties for phenomenal conservatism

"Phenomenal Conservatism" - Ch 2 of Seemings and Epistemic Justification

In this chapter I introduce and analyse the tenets of phenomenal conservatism, and discuss the problem of the nature of appearances. After that, I review the asserted epistemic merits phenomenal conservatism and the principal arguments adduced in support of it. Finally, I survey objections to phenomenal conservatism and responses by its advocates. Some of these objections will be scrutinised and appraised in the next chapters

An Open Science Peer Review Oath

One of the foundations of the scientific method is to be able to reproduce experiments and corroborate the results of research that has been done before. However, with the increasing complexities of new technologies and techniques, coupled with the specialisation of experiments, reproducing research findings has become a growing challenge. Clearly, scientific methods must be conveyed succinctly, and with clarity and rigour, in order for research to be reproducible. Here, we propose steps to help increase the transparency of the scientific method and the reproducibility of research results: specifically, we introduce a peer-review oath and accompanying manifesto. These have been designed to offer guidelines to enable reviewers (with the minimum friction or bias) to follow and apply open science principles, and support the ideas of transparency, reproducibility and ultimately greater societal impact. Introducing the oath and manifesto at the stage of peer review will help to check that the research being published includes everything that other researchers would need to successfully repeat the work. Peer review is the lynchpin of the publishing system: encouraging the community to consciously (and conscientiously) uphold these principles should help to improve published papers, increase confidence in the reproducibility of the work and, ultimately, provide strategic benefits to authors and their institutions

Post-publication peer review, in all its guises, is here to stay

Over the past few years there has been a rise in the use of post-publication peer review (PPPR) to complement pre-publication review and improve existing and future research published in the scientific literature. PPPR is not a new concept; post-publication evaluation and discussion of research has always happened organically through written or spoken dialogue. It is a cornerstone of the practice of science and it is how the extensive knowledge base we have today has been built up over time. However, with a greater volume of research now being undertaken and scientific dissemination becoming more digitised, the discussion and evaluation of science has started to migrate from private forums to the Internet, a universal platform where scientists can quickly make their thoughts on specific papers more widely available to a much broader audience

Germline mutations and somatic inactivation of <i>TRIM28</i> in Wilms tumour

<div><p>Wilms tumour is a childhood tumour that arises as a consequence of somatic and rare germline mutations, the characterisation of which has refined our understanding of nephrogenesis and carcinogenesis. Here we report that germline loss of function mutations in <i>TRIM28</i> predispose children to Wilms tumour. Loss of function of this transcriptional co-repressor, which has a role in nephrogenesis, has not previously been associated with cancer. Inactivation of <i>TRIM28</i>, either germline or somatic, occurred through inactivating mutations, loss of heterozygosity or epigenetic silencing. <i>TRIM28</i>-mutated tumours had a monomorphic epithelial histology that is uncommon for Wilms tumour. Critically, these tumours were negative for TRIM28 immunohistochemical staining whereas the epithelial component in normal tissue and other Wilms tumours stained positively. These data, together with a characteristic gene expression profile, suggest that inactivation of <i>TRIM28</i> provides the molecular basis for defining a previously described subtype of Wilms tumour, that has early age of onset and excellent prognosis.</p></div

Somatic genetic changes in Wilms tumours.

<p>The left side shows the number of somatic non-synonymous and truncating mutations for each tumour detected by MuTect2. The single somatic variant in W117 is the <i>TRIM28</i> mutation. The right side shows the fractional length of aberrant copy number segments as determined by ADTEx.</p

DNA sequence and methylation of <i>TRIM28</i>.

<p>(<b>A</b>) Family 1. 2-bp deletion (c.525_526del) in the blood of case 39 (39B), the kidney of case 37 (37K) and the blood of their mother (37M). The father (37F) was unaffected. The tumours from cases 37 and 39 (37T and 39T) showed loss of heterozygosity. (<b>B</b>) Family 2. Germline deletion/insertion (c.1746_1747delinsC) in blood DNA from case 399 (399N) with loss of heterozygosity in tumours 399T and 249T. (<b>C</b>) Somatic deletion/insertion mutation (c.1935delinsGA) in W117 tumour (W117T) and reference sequence in the adjacent kidney (W117K). (<b>D</b>) The proportion of methylated CpGs in exon 1 of <i>TRIM28</i> in W117T as measured by targeted bisulfite PCR. For each CpG site the black portion of the bar shows the proportion of methylated reads.</p

Genetic, epigenetic and clinical features of monomorphic epithelial Wilms tumours.

<p>Genetic, epigenetic and clinical features of monomorphic epithelial Wilms tumours.</p

Dendrogram from unsupervised hierarchical clustering of gene expression of 17 Wilms tumours.

<p>IGF2, refers to <i>IGF2</i> status where blue = loss of imprinting, and red = loss of heterozygosity at <i>IGF2</i>. Rests refers to the presence of nephrogenic rests (NR) were blue = intralobar NR, red perilobar NR and purple NR of unknown type. For each gene, red boxes indicate the presence of mutation, whereas the grey box denotes gene deletion.</p

Comparison of gene expression between S1 and other Wilms tumours.

<p>The upper panels show the five most down-regulated and five most up-regulated genes in the S1 subgroup (n = 11) compared to S2-S5 tumours (n = 213) in the study of Gadd et al. [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007399#pgen.1007399.ref030" target="_blank">30</a>]. The lower panels show expression of these genes in <i>TRIM28</i>-mutated tumours and 13 other tumours from this study. Red circles, S1 or <i>TRIM28</i>-mutated tumours. Blue circles, favourable histology tumours. Note that two tumours with anaplastic histology, both of which had <i>TP53</i> mutations, are not included to maintain comparability with the favourable histology tumours reported by Gadd et al. [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1007399#pgen.1007399.ref030" target="_blank">30</a>].</p