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"Richardson, Robert"
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The heart of William James
A selection of seventeen essays from the writings of pioneering American psychologist/philosopher William James that provideinsight into his thinking on emotion, war, habit, determinism, religion, and other topics.
Book
Genetic compensation triggered by actin mutation prevents the muscle damage caused by loss of actin protein
The lack of a mutant phenotype in homozygous mutant individuals' due to compensatory gene expression triggered upstream of protein function has been identified as genetic compensation. Whilst this intriguing process has been recognized in zebrafish, the presence of homozygous loss of function mutations in healthy human individuals suggests that compensation may not be restricted to this model. Loss of skeletal α-actin results in nemaline myopathy and we have previously shown that the pathological symptoms of the disease and reduction in muscle performance are recapitulated in a zebrafish antisense morpholino knockdown model. Here we reveal that a genetic actc1b mutant exhibits mild muscle defects and is unaffected by injection of the actc1b targeting morpholino. We further show that the milder phenotype results from a compensatory transcriptional upregulation of an actin paralogue providing a novel approach to be explored for the treatment of actin myopathy. Our findings provide further evidence that genetic compensation may influence the penetrance of disease-causing mutations.
Journal Article
Thoreau and the language of trees
\"Trees were central to Henry David Thoreau's creativity as a writer, his work as a naturalist, his thought and his inner life. His portraits of them were so perfect, it was as if he could to see the sap flowing beneath their bark. When Thoreau wrote that the poet loves the pine tree as his own shadow in the air, he was speaking about himself. In short, he spoke their language. In this original book, Richard Higgins explores Thoreau's deep connections to trees: his keen perception of them, the joy they gave him, the poetry he saw in them, his philosophical view of them, and how they fed his soul. His lively essays show that trees were a thread connecting all parts of Thoreau's being--heart, mind and spirit. Included are one hundred excerpts from Thoreau's writing about trees, paired with sixty-eight of the author's photographs. Thoreau's words are as vivid now as they were in 1890, when an English naturalist wrote that he was unusually able to 'to preserve the flashing forest colors in unfading light.' Thoreau and the Language of Trees shows that Thoreau, with uncanny foresight, believed trees were essential to the preservation of the world\"--Provided by publisher.
BOOK
Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury
In patients with severe acute kidney injury (AKI) but no urgent indication for renal replacement therapy (RRT), the optimal time to initiate RRT remains controversial. While starting RRT preemptively may have benefits, this may expose patients to unnecessary RRT. To study this, we conducted a 12-center open-label pilot trial of critically ill adults with volume replete severe AKI. Patients were randomized to accelerated (12 h or less from eligibility) or standard RRT initiation. Outcomes were adherence to protocol-defined time windows for RRT initiation (primary), proportion of eligible patients enrolled, follow-up to 90 days, and safety in 101 fully eligible patients (57 with sepsis) with a mean age of 63 years. Median serum creatinine and urine output at enrollment were 268 micromoles/l and 356 ml per 24 h, respectively. In the accelerated arm, all patients commenced RRT and 45/48 did so within 12 h from eligibility (median 7.4 h). In the standard arm, 33 patients started RRT at a median of 31.6 h from eligibility, of which 19 did not receive RRT (6 died and 13 recovered kidney function). Clinical outcomes were available for all patients at 90 days following enrollment, with mortality 38% in the accelerated and 37% in the standard arm. Two surviving patients, both randomized to standard RRT initiation, were still RRT dependent at day 90. No safety signal was evident in either arm. Our findings can inform the design of a large-scale effectiveness randomized control trial.
Journal Article
The divergent series. insurgen
Tris and Four are now fugitives on the run, hunted by Jeanine, the leader of the power-hungry Erudite elite. Racing against time, they must find out what Tris's family sacrificed their lives to protect, and why the Erudite leaders will do anything to stop them. Haunted by her past choices but desperate to protect the ones she loves, Tris, with Four at her side, faces one impossible challenge after another as they unlock the truth about the past and ultimately the future of their world.
DVD
Established and emerging GABAA receptor pharmacotherapy for epilepsy
Drugs that modulate the GABA
A
receptor are widely used in clinical practice for both the long-term management of epilepsy and emergency seizure control. In addition to older medications that have well-defined roles for the treatment of epilepsy, recent discoveries into the structure and function of the GABA
A
receptor have led to the development of newer compounds designed to maximise therapeutic benefit whilst minimising adverse effects, and whose position within the epilepsy pharmacologic armamentarium is still emerging. Drugs that modulate the GABA
A
receptor will remain a cornerstone of epilepsy management for the foreseeable future and, in this article, we provide an overview of the mechanisms and clinical efficacy of both established and emerging pharmacotherapies.
Journal Article
Hugo
Orphan, clock keeper, and thief, twelve-year-old Hugo lives in the walls of a busy Paris train station, where his survival depends on secrets and anonymity. But when his world suddenly interlocks with an eccentric girl and the owner of a small toy booth in the train station, Hugo's undercover life, and his most precious secret, are put in jeopardy. A cryptic drawing, a treasured notebook, a stolen key, a mechanical man, and a hidden message all come together to change Hugo's life forever.
DVD
Isolation and characterization of IgG3 glycan-targeting antibodies with exceptional cross-reactivity for diverse viral families
Broadly reactive antibodies that target sequence-diverse antigens are of interest for vaccine design and monoclonal antibody therapeutic development because they can protect against multiple strains of a virus and provide a barrier to evolution of escape mutants. Using LIBRA-seq (linking B cell receptor to antigen specificity through sequencing) data for the B cell repertoire of an individual chronically infected with human immunodeficiency virus type 1 (HIV-1), we identified a lineage of IgG3 antibodies predicted to bind to HIV-1 Envelope (Env) and influenza A Hemagglutinin (HA). Two lineage members, antibodies 2526 and 546, were confirmed to bind to a large panel of diverse antigens, including several strains of HIV-1 Env, influenza HA, coronavirus (CoV) spike, hepatitis C virus (HCV) E protein, Nipah virus (NiV) F protein, and Langya virus (LayV) F protein. We found that both antibodies bind to complex glycans on the antigenic surfaces. Antibody 2526 targets the stem region of influenza HA and the N-terminal domain (NTD) region of SARS-CoV-2 spike. A crystal structure of 2526 Fab bound to mannose revealed the presence of a glycan-binding pocket on the light chain. Antibody 2526 cross-reacted with antigens from multiple pathogens and displayed no signs of autoreactivity. These features distinguish antibody 2526 from previously described glycan-reactive antibodies. Further study of this antibody class may aid in the selection and engineering of broadly reactive antibody therapeutics and can inform the development of effective vaccines with exceptional breadth of pathogen coverage.
Journal Article
Robotic additive manufacturing system for dynamic build orientations
Purpose
This paper aims to present a multi-axis additive robot manufacturing system (ARMS) and demonstrate its beneficial capabilities.
Design/methodology/approach
ARMS was constructed around two robot arms and a fused filament fabrication (FFF) extruder. Quantitative experiments are conducted to investigate the effect of printing at different orientations with respect to gravity, the effect of dynamically changing build orientation with respect to the build tray when printing overhanging features, the effect of printing curved parts using curved, conformal layers. These capabilities are combined to print an integrated demonstrator showing potential practical benefits of the system.
Findings
Orientation with respect to gravity has no effect on print quality; dynamically changing build orientation allows overhangs up to 90° to be cleanly printed without support structures; printing an arch with conformal layers significantly increases its strength compared to conventional printing.
Research limitations/implications
The challenge of automatic slicing algorithms has not been addressed for multi-axis printing. It is shown that ARMS could eventually enable printing of fully-functional prototypes with embedded components.
Originality/value
This work is the first to prove that the surface roughness of an FFF part is independent of print orientation with respect to gravity. The use of two arms creates a novel system with more degrees of freedom than existing multi-axis printers, enabling studies on printing orientation relationships and printing around inserts. It also adds to the emerging body of multi-axis literature by verifying that curved layers improve the strength of an arch which is steeply curved and printed with the nozzle remaining normal to the curvature.
Journal Article
Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death
Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.
Journal Article