Protein Design with Fluoroprolines: 4,4-Difluoroproline Does Not Eliminate the Rate-Limiting Step of Thioredoxin Folding.

C -substituted fluoroprolines (4R)-fluoroproline ((4R)-Flp) and (4S)-fluoroproline ((4S)-Flp) have been used in protein engineering to enhance the thermodynamic stability of peptides and proteins. The electron-withdrawing effect of fluorine can bias the pucker of the pyrrolidine ring, influence the conformational preference of the preceding peptide bond, and can accelerate the cis/trans prolyl peptide bond isomerisation by diminishing its double bond character. The role of 4,4-difluoroproline (Dfp) in the acceleration of the refolding rate of globular proteins bearing a proline (Pro) residue in the cis conformation in the native state remains elusive.

Genetic and environmental influences on serum oxylipins, endocannabinoids, bile acids and steroids.

Lipid bioactivity is a result of direct action and the action of lipid mediators including oxylipins, endocannabinoids, bile acids and steroids. Understanding the factors contributing to biological variation in lipid mediators may inform future approaches to understand and treat complex metabolic diseases. This research aims to determine the contribution of genetic and environmental influences on lipid mediators involved in the regulation of inflammation and energy metabolism.

Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation.

Activation of cyclin-dependent kinases (CDKs) contributes to the uncontrolled proliferation of tumour cells. Genomic alterations that lead to the constitutive activation or overexpression of CDKs can support tumourigenesis including glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. The incurability of GBM highlights the need to discover novel and more effective treatment options.

Targeting JAK-STAT Signalling Alters PsA Synovial Fibroblast Pro-Inflammatory and Metabolic Function.

Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity.

Effect of IL-8 haplotype on temporal profile in circulating concentrations of interleukin 8 and 25(OH) vitamin D in Holstein-Friesian calves.

Interleukin-8 (IL-8) is an inflammatory chemokine released during the primary innate immune response to recruit neutrophils to the site of infection. Two distinct gene promoter haplotypes have been previously reported to segregate in the Holstein-Friesian breed (IL8-h1 and IL8-h2). Our earlier work showed how these divergent IL8 haplotypes influence IL-8 concentration and other immune response parameters at a systemic level.

Towards development of core domain sets for short term and long term studies of calcium pyrophosphate crystal deposition (CPPD) disease: A framework paper by the OMERACT CPPD working group.

Introduction: Although calcium pyrophosphate deposition (CPPD) is common, there are no published outcome domains or validated measurement instruments for CPPD studies. In this paper, we describe the framework for development of the Outcome Measures in Rheumatology (OMERACT) CPPD Core Domain Sets.

Methods: The OMERACT CPPD working group performed a scoping literature review and qualitative interview study.

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

Background: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty.

Methods: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C).

Prediction of caregiver quality of life in amyotrophic lateral sclerosis using explainable machine learning.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative, fatal and currently incurable disease. People with ALS need support from informal caregivers due to the motor and cognitive decline caused by the disease. This study aims to identify caregivers whose quality of life (QoL) may be impacted as a result of caring for a person with ALS.

Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study.

Advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed by the non-enzymatic reaction between amino acids and reducing sugars, or dicarbonyls as intermediate compounds. Experimental studies suggest that AGEs may promote colorectal cancer, but prospective epidemiologic studies are inconclusive. We conducted a case-control study nested within a large European cohort.

Dual Color Imaging from a Single BF-Azadipyrromethene Fluorophore Demonstrated for Lymph Node Identification.

Dual emissions at ~700 and 800 nm have been achieved from a single NIR-AZA fluorophore by establishing parameters in which it can exist in either its isolated molecular or aggregated states. Dual near infrared (NIR) fluorescence color lymph node (LN) mapping with was achieved in a large-animal porcine model, with injection site, channels and nodes all detectable at both 700 and 800 nm using a preclinical open camera system. The fluorophore was also compatible with imaging using two clinical instruments for fluorescence guided surgery.

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

Background: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

Biotic homogenization destabilizes ecosystem functioning by decreasing spatial asynchrony.

Our planet is facing significant changes of biodiversity across spatial scales. Although the negative effects of local biodiversity (α diversity) loss on ecosystem stability are well documented, the consequences of biodiversity changes at larger spatial scales, in particular biotic homogenization, that is, reduced species turnover across space (β diversity), remain poorly known. Using data from 39 grassland biodiversity experiments, we examine the effects of β diversity on the stability of simulated landscapes while controlling for potentially confounding biotic and abiotic factors.

Development of a surgical competency assessment tool for sentinel lymph node dissection by minimally invasive surgery for endometrial cancer.

Introduction: Sentinel lymph node dissection is widely used in the staging of endometrial cancer. Variation in surgical techniques potentially impacts diagnostic accuracy and oncologic outcomes, and poses barriers to the comparison of outcomes across institutions or clinical trial sites. Standardization of surgical technique and surgical quality assessment tools are critical to the conduct of clinical trials.

3-Hydroxytyrosol regulates biofilm growth in Cunninghamella elegans.

In contrast to yeast biofilms, those of filamentous fungi are relatively poorly understood, in particular with respect to their regulation. Cunninghamella elegans is a filamentous fungus that is of biotechnological interest as it catabolises drugs and other xenobiotics in an analogous manner to animals; furthermore, it can grow as a biofilm enabling repeated batch biotransformations. Precisely how the fungus switches from planktonic to biofilm growth is unknown and the aim of this study was to shed light on the possible mechanism of biofilm regulation.

Continuous flow synthesis and antimicrobial evaluation of NHC* silver carboxylate derivatives of SBC3 in vitro and in vivo.

N-heterocyclic silver carbene compounds have been extensively studied and shown to be active agents against a host of pathogenic bacteria and fungi. By incorporating hypothesized virulence targeting substituents into NHC-silver systems via salt metathesis, an atom-efficient complexation process can be used to develop new complexes to target the passive and active systems of a microbial cell. The incorporation of fatty acids and an FtsZ inhibitor have been achieved, and creation of both the intermediate salt and subsequent silver complex has been streamlined into a continuous flow process.

Proceedings of the 2020 GRAPPA Collaborative Research Network (CRN) Meeting.

At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)- Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a pilot investigator-initiated study protocol to test electronic case report forms (eCRFs) and proposed Standardized Operating Procedures (SOPs) to evaluate biomarkers of psoriatic arthritis (PsA) associated with axial disease. The progress on 3 studies was also presented: BioDAM PsA (Biomarkers as Predictors of structural DAMage in PsA; to validate soluble biomarkers as predictors of structural damage in PsA), PreventPsA (examining the development of PsA and risk factors among patients with psoriasis and no arthritis), and PredictORPsA (Predicting Treatment respOnse in patients with eaRly PsA; in collaboration with Pfizer using samples from the Oral Psoriatic Arthritis TriaL [OPAL], to identify biomarkers of treatment response). GRAPPA-CRN funding partnerships and applications are also underway with both the Innovative Medicines Initiative (IMI) in Europe and Accelerating Medicines Partnerships (AMP) 2.

Gastric emptying of solutions containing the natural sweetener erythritol and effects on gut hormone secretion in humans: A pilot dose-ranging study.

Aim: To determine whether a dose-dependent effect in the stimulation of gut hormone release (plasma cholecystokinin [CCK], active glucagon-like peptide-1 [aGLP-1] and peptide tyrosine tyrosine [PYY]) is found for the natural sweetener erythritol.

Materials And Methods: Twelve healthy, lean volunteers received solutions with 10, 25 or 50 g erythritol, or tap water enriched with C-sodium acetate on four study days via a nasogastric tube in this randomized (active treatments), placebo-controlled, double-blind, cross-over trial. Blood samples and breath samples ( C-sodium acetate method for measurement of gastric emptying [GE]) were taken at regular intervals, and sensations of appetite and gastrointestinal symptoms were rated.

Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

Objective: To explore the phenotypic spectrum of -related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.

Methods: Individuals with -related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.

A Roadmap to Inform Development, Validation and Approval of Digital Mobility Outcomes: The Mobilise-D Approach.

Health care has had to adapt rapidly to COVID-19, and this in turn has highlighted a pressing need for tools to facilitate remote visits and monitoring. Digital health technology, including body-worn devices, offers a solution using digital outcomes to measure and monitor disease status and provide outcomes meaningful to both patients and health care professionals. Remote monitoring of physical mobility is a prime example, because mobility is among the most advanced modalities that can be assessed digitally and remotely.

Discriminating Dietary Responses by Combining Transcriptomics and Metabolomics Data in Nutrition Intervention Studies.

Scope: Combining different "omics" data types in a single, integrated analysis may better characterize the effects of diet on human health.

Methods And Results: The performance of two data integration tools, similarity network fusion tool (SNFtool) and Data Integration Analysis for Biomarker discovery using Latent variable approaches for "Omics" (DIABLO; MixOmics), in discriminating responses to diet and metabolic phenotypes is investigated by combining transcriptomics and metabolomics datasets from three human intervention studies: a postprandial crossover study testing dairy foods (n = 7; study 1), a postprandial challenge study comparing obese and non-obese subjects (n = 13; study 2); and an 8-week parallel intervention study that assessed three diets with variable lipid content on fasting parameters (n = 39; study 3). In study 1, combining datasets using SNF or DIABLO significantly improve sample classification.