Post-transcriptional Processing of mRNA in Neurons: The Vestiges of the RNA World Drive Transcriptome Diversity

Neurons are morphologically complex cells that rely on the compartmentalization of protein expression to develop and maintain their extraordinary cytoarchitecture. This formidable task is achieved, at least in part, by targeting mRNA to subcellular compartments where they are rapidly translated. mRNA transcripts are the conveyor of genetic information from DNA to the translational machinery, however, they are also endowed with additional functions linked to both the coding sequence (open reading frame, or ORF) and the flanking 5′ and 3′ untranslated regions (UTRs), that may harbor coding-independent functions. In this review, we will highlight recent evidences supporting new coding-dependent and -independent functions of mRNA and discuss how nuclear and cytoplasmic post-transcriptional modifications of mRNA contribute to localization and translation in mammalian cells with specific emphasis on neurons. We also describe recently developed techniques that can be employed to study RNA dynamics at subcellular level in eukaryotic cells in developing and regenerating neurons

Harms and wrongs in epistemic practice

This volume has its roots in two recent developments within mainstream analytic epistemology: a growing recognition over the past two or three decades of the active and social nature of our epistemic lives; and, more recently still, the increasing appreciation of the various ways in which the epistemic practices of individuals and societies can, and often do, go wrong. The theoretical analysis of these breakdowns in epistemic practice, along with the various harms and wrongs that follow as a consequence, constitutes an approach to epistemology that we refer to as non-ideal epistemology. In this introductory chapter we introduce and contextualise the ten essays that comprise this volume, situating them within four broad sub-fields: vice epistemology, epistemic injustice, inter-personal epistemic practices, and applied epistemology. We also provide a brief overview of several other important growth areas in non-ideal epistemology

Cytoplasmic cleavage of IMPA1 3' UTR is necessary for maintaining axon integrity

The 3′ untranslated regions (3′ UTRs) of messenger RNAs (mRNAs) are non-coding sequences involved in many aspects of mRNA metabolism, including intracellular localization and translation. Incorrect processing and delivery of mRNA cause severe developmental defects and have been implicated in many neurological disorders. Here, we use deep sequencing to show that in sympathetic neuron axons, the 3′ UTRs of many transcripts undergo cleavage, generating isoforms that express the coding sequence with a short 3′ UTR and stable 3′ UTR-derived fragments of unknown function. Cleavage of the long 3′ UTR of Inositol Monophosphatase 1 (IMPA1) mediated by a protein complex containing the endonuclease argonaute 2 (Ago2) generates a translatable isoform that is necessary for maintaining the integrity of sympathetic neuron axons. Thus, our study provides a mechanism of mRNA metabolism that simultaneously regulates local protein synthesis and generates an additional class of 3′ UTR-derived RNAs

Regulation of NGF Signaling by an Axonal Untranslated mRNA

Neurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner

Motivational approaches to intellectual vice

Despite the now considerable literature on intellectual virtue, there remains relatively little philosophical discussion of intellectual vice. What discussion there is has been shaped by a powerful assumption—that, just as intellectual virtue requires that we are motivated by epistemic goods, intellectual vice requires that we aren't. In this paper, I demonstrate that this assumption is false: motivational approaches cannot explain a range of intuitive cases of intellectual vice. The popularity of the assumption is accounted for by its being a manifestation of a more general understanding of vice as an inversion or mirror image of virtue. I call this the inversion thesis, and argue that the failure of the motivational approach to vice exposes its limitations. I conclude by suggesting that recognizing these limitations can help to encourage philosophical interest in intellectual vice

Independence in complaints procedures: lessons from community care

This article looks at internal complaints procedures and considers the role of independent elements in procedures which are designed to be simple, informal and low cost. Taking the example of local authority community care services as a case study, the article discusses research which looked at the views of complainants, potential complainants and those who run the procedure. Most people do not make formal complaints at all and very few people seek an independent review of their complaint. When they do seek such a review, they expect it to be transparently independent of the body complained about. The article concludes that the current system of local authority complaints review panels or committees does not provide the independent element that complainants seek

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

A communal catalogue reveals Earth’s multiscale microbial diversity

Our growing awareness of the microbial world’s importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth’s microbial diversity