A molecular‐level perspective on the frequency, distribution, and consequences of messenger RNA modifications

Cells use chemical modifications to alter the sterics, charge, and conformations of large biomolecules, modulating their biogenesis, function, and stability. Until recently post‐transcriptional RNA modifications were thought to be largely limited to nonprotein coding RNA species. However, this dogma has rapidly transformed with the discovery of a host of modifications in protein coding messenger RNAs (mRNAs). Recent advancements in genome‐wide sequencing technologies have enabled the identification of mRNA modifications as a potential new frontier in gene regulation—leading to the development of the epitranscriptome field. As a result, there has been a flurry of multiple groundbreaking discoveries, including new modifications, nucleoside modifying enzymes (“writers” and “erasers”), and RNA binding proteins that recognize chemical modifications (“readers”). These discoveries opened the door to understanding how post‐transcriptional mRNA modifications can modulate the mRNA lifecycle, and established a link between the epitranscriptome and human health and disease. Despite a rapidly growing recognition of their importance, fundamental questions regarding the identity, prevalence, and functional consequences of mRNA modifications remain to be answered. Here, we highlight quantitative studies that characterize mRNA modification abundance, frequency, and interactions with cellular machinery. As the field progresses, we see a need for the further integration of quantitative and reductionist approaches to complement transcriptome wide studies in order to establish a molecular‐level framework for understanding the consequences of mRNA chemical modifications on biological processes.This article is categorized under:RNA Structure and Dynamics > RNA Structure, Dynamics and ChemistryRNA Processing > RNA Editing and ModificationThe integration of biochemical, structural, and transcriptome wide approaches is shaping a quantitative framework for understanding the biological consequences of mRNA modifications.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155973/1/wrna1586.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155973/2/wrna1586_am.pd

The practical, ethical and legal reasons why patients should not be transferred between NHS trusts for phage therapy

Bacteriophages (phages) are naturally occurring viruses of bacteria that have a long history of use as antimicrobials, known as phage therapy. The antibiotic resistance crisis has driven renewed interest in phage therapy, which has been used on an unlicensed compassionate basis in various Western contexts. The option to use unlicensed medicines exists to allow clinicians to respond to genuine clinical needs arising in their own patients. However, in the UK some clinicians may, in the absence of suitable patients of their own, seek to transfer patients from other NHS trusts into their own Trust. This article sets out why patient transfer is not necessary and the practical, ethical and legal reasons why patients should not be transferred between NHS Trusts for phage therapy. Phage preparations should always be transported to the patient and the patient treated in the Trust in which they would have received care in the absence of phage. We enclose suggested best practice guidelines for adoption across the UK that will protect patient safety and safeguard clinicians and Trusts from potential litigation

The cysteine proteome

AbstractThe cysteine (Cys) proteome is a major component of the adaptive interface between the genome and the exposome. The thiol moiety of Cys undergoes a range of biologic modifications enabling biological switching of structure and reactivity. These biological modifications include sulfenylation and disulfide formation, formation of higher oxidation states, S-nitrosylation, persulfidation, metalation, and other modifications. Extensive knowledge about these systems and their compartmentalization now provides a foundation to develop advanced integrative models of Cys proteome regulation. In particular, detailed understanding of redox signaling pathways and sensing networks is becoming available to allow the discrimination of network structures. This research focuses attention on the need for atlases of Cys modifications to develop systems biology models. Such atlases will be especially useful for integrative studies linking the Cys proteome to imaging and other omics platforms, providing a basis for improved redox-based therapeutics. Thus, a framework is emerging to place the Cys proteome as a complement to the quantitative proteome in the omics continuum connecting the genome to the exposome

Brain Imaging for Judges: An Introduction to Law and Neuroscience

It has become increasingly common for brain images to be proffered as evidence in civil and criminal litigation.1 This article offers some general guidelines to judges about how to understand brain-imaging studies—or at least avoid misunderstanding them. (An appendix annotating a published brain imaging study, in order to illustrate and explain, with step-by step commentary, is available in the full text online.2) Brain images are offered in legal proceedings for a variety of purposes, as Professors Carter Snead and Gary Marchant have usefully surveyed.3 On the civil side, neuro imaging has been offered in constitutional, personal injury, disability benefit, and contract cases, among others. For example, in Entertainment Software Ass’n v. Blagojevich,4 the court considered whether a brain-imaging study could be used to show that exposure to violent video games increases aggressive thinking and behavior in adolescents. In Fini v. General Motors Corp.,5 brain scans were proffered to help determine the extent of head injuries from a car accident. In Boyd v. Bert Bell/Pete Rozelle NFL Players Retirement Plan,6 a former professional football player proffered brain scans in an effort to prove entitlement to neuro-degenerative disability benefits. And in Van Middlesworth v. Century Bank & Trust Co.,7 involving a dispute over the sale of land, the defendant introduced brain images to prove mental incompetency, resulting in a voidable contract

Copy Number Alterations and Methylation in Ewing's Sarcoma

Ewing's sarcoma is the second most common bone malignancy affecting children and young adults. The prognosis is especially poor in metastatic or relapsed disease. The cell of origin remains elusive, but the EWS-FLI1 fusion oncoprotein is present in the majority of cases. The understanding of the molecular basis of Ewing's sarcoma continues to progress slowly. EWS-FLI1 affects gene expression, but other factors must also be at work such as mutations, gene copy number alterations, and promoter methylation. This paper explores in depth two molecular aspects of Ewing's sarcoma: copy number alterations (CNAs) and methylation. While CNAs consistently have been reported in Ewing's sarcoma, their clinical significance has been variable, most likely due to small sample size and tumor heterogeneity. Methylation is thought to be important in oncogenesis and balanced karyotype cancers such as Ewing's, yet it has received only minimal attention in prior studies. Future CNA and methylation studies will help to understand the molecular basis of this disease

Brain Imaging for Legal Thinkers: A Guide for the Perplexed

It has become increasingly common for brain images to be proffered as evidence in criminal and civil litigation. This Article - the collaborative product of scholars in law and neuroscience - provides three things. First, it provides the first introduction, specifically for legal thinkers, to brain imaging. It describes in accessible ways the new techniques and methods that the legal system increasingly encounters. Second, it provides a tutorial on how to read and understand a brain-imaging study. It does this by providing an annotated walk-through of the recently-published work (by three of the authors - Buckholtz, Jones, and Marois) that discovered the brain activity underlying a person\u27s decisions: a) whether to punish someone; and b) how much to punish. The annotation uses the \u27Comment\u27 feature of the Word software to supply contextual and step-by-step commentary on what unfamiliar terms mean, how and why brain imaging experiments are designed as they are, and how to interpret the results. Third, the Article offers some general guidelines about how to avoid misunderstanding brain images in legal contexts and how to identify when others are misusing brain images. The Article is a product of the \u27Law and Neuroscience Project\u27, supported by the MacArthur Foundation

Uncovering the components of the Francisella tularensis virulence stealth strategy

Over the last decade, studies on the virulence of the highly pathogenic intracellular bacterial pathogen Francisella tularensis have increased dramatically. The organism produces an inert LPS, a capsule, escapes the phagosome to grow in the cytosol (FPI genes mediate phagosomal escape) of a variety of host cell types that include epithelial, endothelial, dendritic, macrophage, and neutrophil. This review focuses on the work that has identified and characterized individual virulence factors of this organism and we hope to highlight how these factors collectively function to produce the pathogenic strategy of this pathogen. In addition, several recent studies have been published characterizing F. tularensis mutants that induce host immune responses not observed in wild type F. tularensis strains that can induce protection against challenge with virulent F. tularensis. As more detailed studies with attenuated strains are performed, it will be possible to see how host models develop acquired immunity to Francisella. Collectively, detailed insights into the mechanisms of virulence of this pathogen are emerging that will allow the design of anti-infective strategies

Physical and biological controls on fine sediment transport and storage in rivers

Excess fine sediment, comprising particles <2 mm in diameter, is a major cause of ecological degradation in rivers. The erosion of fine sediment from terrestrial or aquatic sources, its delivery to the river, and its storage and transport in the fluvial environment are controlled by a complex interplay of physical, biological and anthropogenic factors. Whilst the physical controls exerted on fine sediment dynamics are relatively well-documented, the role of biological processes and their interactions with hydraulic and physico-chemical phenomena has been largely overlooked. The activities of biota, from primary producers to predators, exert strong controls on fine sediment deposition, infiltration and resuspension. For example, extracellular polymeric substances (EPS) associated with biofilms increase deposition and decrease resuspension. In lower energy rivers, aquatic macrophyte growth and senescence are intimately linked to sediment retention and loss, whereas riparian trees are dominant ecosystem engineers in high energy systems. Fish and invertebrates also have profound effects on fine sediment dynamics through activities that drive both particle deposition and erosion depending on species composition and abiotic conditions. The functional traits of species present will determine not only these biotic effects but also the responses of river ecosystems to excess fine sediment. We discuss which traits are involved and put them into context with spatial processes that occur throughout the river network. Whilst strides towards better understanding of the impacts of excess fine sediment have been made, further progress to identify the most effective management approaches is urgently required through close communication between authorities and scientists

Sorting Guilty Minds

Because punishable guilt requires that bad thoughts accompany bad acts, the Model Penal Code (MPC) typically requires that jurors infer the past mental state of a criminal defendant. More specifically, jurors must sort that mental state into one of four specific categories - purposeful, knowing, reckless, or negligent - which in turn defines the nature of the crime and the extent of the punishment. The MPC therefore assumes that ordinary people naturally sort mental states into these four categories with a high degree of accuracy, or at least can reliably do so when properly instructed. It also assumes that ordinary people will order these categories of mental state, by increasing amount of punishment, in the same severity hierarchy that the MPC prescribes. The MPC, now turning 50 years old, has previously escaped the scrutiny of comprehensive empirical research on these assumptions underlying its culpability architecture. Our new empirical studies, reported here, find that most of the mens rea assumptions embedded in the MPC are reasonably accurate as a behavioral matter. Even without the aid of the MPC definitions, subjects were able to regularly and accurately distinguish among purposeful, negligent, and blameless conduct. Nevertheless, our subjects failed to distinguish reliably between knowing and reckless conduct. This failure can have significant sentencing consequences in some types of crimes, especially homicide

A point process framework for modeling electrical stimulation of the auditory nerve

Model-based studies of auditory nerve responses to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe auditory nerve spiking while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of the auditory nerve that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semi-analytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data and explain differences in auditory nerve responses to high and low pulse rate stimulation. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds.Comment: 1 title page, 27 manuscript pages, 14 figures, 1 table, 1 appendi