8 research outputs found
Point defects in ceramics for detector applications
EThOS - Electronic Theses Online ServiceGBUnited Kingdo
InBetween poetics: im/migrant writing as collective resilience and political consciousness
Point defects in ceramics for detector applications
EThOS - Electronic Theses Online ServiceGBUnited Kingdo
Postoperative Opioid-Free Analgesia in Elective Bowel Resection: Changes Over Time
In the pain management evolution, opioid-free analgesia and multimodal analgesia strategies have emerged as feasible in many surgical settings including colorectal surgery. This was a retrospective cohort study including patients having undergone elective bowel resection between February 2012 and June 2018 aiming to evaluate whether there was reduction in opioid use after implementation of opioid-free analgesia in one medical centre. Trend analysis was conducted using Joinpoint regression employing nine-month intervals. The primary outcome for each interval was the proportion of patients receiving postoperative opioid-free analgesia, defined as forgoing all opioid analgesics after the day of surgery. This study showed a significant increasing trend in opioid-free analgesia in elective bowel resection from 0 to 42.5% over 4.5 years
Systemic Manifestations in Pyridox(am)ine 5'-Phosphate Oxidase Deficiency.
Abstract Objective Pyridoxine is converted to its biologically active form pyridoxal-5-phosphate (P5P) by the enzyme pyridox(am)ine 5′-phosphate oxidase and serves as a cofactor in nearly 200 reactions in the central nervous system. Pyridox(am)ine 5′-phosphate oxidase deficiency leads to P5P dependent epilepsy, typically a neonatal- or infantile-onset epileptic encephalopathy treatable with P5P or in some cases, pyridoxine. Following identification of retinopathy in a patient with pyridox(am)ine 5′-phosphate oxidase deficiency that was reversible with P5P therapy, we describe the systemic manifestations of pyridox(am)ine 5′-phosphate oxidase deficiency. Methods A series of six patients with homozygous mutations of PNPO , the gene coding pyridox(am)ine 5′-phosphate oxidase, were evaluated in our center over the course of two years for phenotyping of neurological and systemic manifestations. Results Five of six were born prematurely, three had anemia and failure to thrive, and two had elevated alkaline phosphatase. A movement disorder was observed in two children, and a reversible retinopathy was observed in the most severely affected infant. All patients had neonatal-onset epilepsy and were on a continuum of developmental delay to profound encephalopathy. Electroencephalographic features included background slowing and disorganization, absent sleep features, and multifocal and generalized epileptiform discharges. All the affected probands carried a homozygous PNPO mutation (c.674 G>T, c.686 G>A and c.352G>A). Conclusion In addition to the well-described epileptic encephalopathy, pyridox(am)ine 5′-phosphate oxidase deficiency causes a range of neurological and systemic manifestations. A movement disorder, developmental delay, and encephalopathy, as well as retinopathy, anemia, and failure to thrive add to the broadening clinical spectrum of P5P dependent epilepsy
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Cryo-EM structure determination of small therapeutic protein targets at 3 Å-resolution using a rigid imaging scaffold.
Cryoelectron microscopy (Cryo-EM) has enabled structural determination of proteins larger than about 50 kDa, including many intractable by any other method, but it has largely failed for smaller proteins. Here, we obtain structures of small proteins by binding them to a rigid molecular scaffold based on a designed protein cage, revealing atomic details at resolutions reaching 2.9 Å. We apply this system to the key cancer signaling protein KRAS (19 kDa in size), obtaining four structures of oncogenic mutational variants by cryo-EM. Importantly, a structure for the key G12C mutant bound to an inhibitor drug (AMG510) reveals significant conformational differences compared to prior data in the crystalline state. The findings highlight the promise of cryo-EM scaffolds for advancing the design of drug molecules against small therapeutic protein targets in cancer and other human diseases
Ubiquitin variants potently inhibit SARS-CoV-2 PLpro and viral replication via a novel site distal to the protease active site.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made it clear that combating coronavirus outbreaks benefits from a combination of vaccines and therapeutics. A promising drug target common to all coronaviruses-including SARS-CoV, MERS-CoV, and SARS-CoV-2-is the papain-like protease (PLpro). PLpro cleaves part of the viral replicase polyproteins into non-structural protein subunits, which are essential to the viral replication cycle. Additionally, PLpro can cleave both ubiquitin and the ubiquitin-like protein ISG15 from host cell substrates as a mechanism to evade innate immune responses during infection. These roles make PLpro an attractive antiviral drug target. Here we demonstrate that ubiquitin variants (UbVs) can be selected from a phage-displayed library and used to specifically and potently block SARS-CoV-2 PLpro activity. A crystal structure of SARS-CoV-2 PLpro in complex with a representative UbV reveals a dimeric UbV bound to PLpro at a site distal to the catalytic site. Yet, the UbV inhibits the essential cleavage activities of the protease in vitro and in cells, and it reduces viral replication in cell culture by almost five orders of magnitude