Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.

Seeing like an epidemiologist? Mobilising people against COVID-19.

Diaries and other materials in the Mass Observation Archive have been characterised as intersubjective and dialogic. They have been used to study top-down and bottom-up processes, including how ordinary people respond to sociological constructs and, more broadly, the footprint of social science in the 20th century. In this article, we use the Archive's COVID-19 collections to study how attempts to govern the pandemic by mobilising ordinary people to see like an epidemiologist played out in the United Kingdom during 2020. People were asked to think in terms of populations and groups; rates, trends, and distributions; the capacity of public services; and complex systems of causation. How did they respond? How did they use the statistics, charts, maps, concepts, identities, and roles they were given? We find evidence of engagement with science plural; confident and comfortable engagement with epidemiological terms and concepts; sceptical and reluctant engagement with epidemiological subject positions; use of both scientific and moral literacy to negotiate regulations and guidance; and use of scientific literacy to compare and judge government performance. Governing the pandemic through scientific literacy was partially successful, but in some unexpected ways.

Archiving the COVID-19 pandemic in Mass Observation and Middletown.

The COVID-19 pandemic generated debates about how pandemics should be known. There was much discussion of what role the human sciences could play in knowing - and governing - the pandemic. In this article, we focus on attempts to know the pandemic through diaries, other biographical writing, and related forms like mass photography. In particular, we focus on the archiving of such forms by Mass Observation in the UK and the Everyday Life in Middletown (EDLM) project in the USA, and initial analyses of such material by scholars from across the human sciences. Our main argument is that archiving the pandemic was informed by, and needs viewing through, the history of the human sciences - including the distinctive histories and human sciences of Mass Observation and Middletown. The article finishes by introducing a Special Section that engages with archiving the pandemic in two senses: the archiving of diaries and related forms by Mass Observation and the EDLM project, and the archiving of initial encounters between researchers and this material by History of the Human Sciences. The Special Section seeks to know the pandemic from the human sciences in the present and to archive knowing the pandemic from the human sciences for the future.

Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities.

Beyond compliance: Good citizenship during the COVID-19 pandemic.

In the UK, discussion of good citizenship during the COVID-19 pandemic largely focused on compliance and non-compliance with government rules. In this paper, we offer an alternative point of focus. Pandemic governance proceeded not only through rules/morality, but also through freedom/ethics. Good citizenship, therefore, involved practical reasoning in response to situations. We demonstrate this using diaries and other forms of writing collected by Mass Observation during the first six months of the pandemic. Responses to government rules and guidance varied by situation. Many people found governance through freedom/ethics confusing and burdensome. Faced with ethical dilemmas, they managed risks and responsibilities by deliberating, weighing justifications, and sometimes falling back on rules of thumb or heuristics. Discussion of good citizenship during future emergencies would benefit from a greater focus on situations, dilemmas, and justifications.

The Impact of Individualizing Sodium Bicarbonate Supplementation Strategies on World-Class Rowing Performance.

Contemporary meta-analyses have generally demonstrated a positive effect of sodium bicarbonate (NaHCO3) supplementation on exercise performance. However, despite these claims, there is limited data on contrasting individualized and standardized timing of NaHCO3 ingestion prior to exercise to further enhance performance outcomes. Purpose: To determine whether NaHCO3 ingestion timing impacts 2,000-m rowing time-trial (TT) performance in elite-level rowers (Senior National team including Olympic/World Championships level) adhering to their own individualized pre-race strategies (e.g. nutrition, warm-up, etc.). Methods: Twenty three (n = 23) rowers across two research centers (using the exact same methods/protocols) completed three trials: NaHCO3 loading profile at rest to determine the individual's time-to-peak bicarbonate concentration [ HCO 3 - ], followed by two randomized 0.3 g·kgBM-1 NaHCO3 supplementation experimental trials conducted at different time points [consensus timing (CON): TT performed 60 min post-NaHCO3 ingestion; and individualized peak (IP): TT performed at the rower's individual peak [ HCO 3 - ] determined from the profiling trial post-NaHCO3 ingestion]. Results: There was a significant mean difference of +2.9 [± 0.4 mmol·L-1 HCO 3 - for IP vs. CON (95% CI 2.0 to 3.8 mmol·L-1); p = 0.02; d = 1.08] at pre warm-up, but not immediately prior to the TT (post warm-up). Performance times were significantly different between IP (367.0 ± 10.5 s) vs. CON (369.0 ± 10.3 s); p = 0.007; d = 0.15). Conclusions: The present study demonstrated a small but significant performance effect of an individualized NaHCO3 ingestion strategy. Similarities after warm-up between pre-TT sHCO 3 - values (CON ~ + 5.5 mmol·L-1; IP ~ + 6 mmol·L-1), however, would suggest this effect was not a result of any meaningful differences in blood alkalinity.

Moving healthcare professionals - a whole system approach to embed physical activity in clinical practice.

BACKGROUND: Healthcare professionals are key informants to support individual behaviour change, and although there has been some progress in empowering clinicians to promote physical activity and health at work, an effective strategy overarching the whole medical educational journey is still lacking. This report provides an overview from the Moving Healthcare Professionals programme (MHPP), a whole-system educational approach to embed prevention and physical activity promotion into clinical practice. METHODS: The MHPP model integrates educational resources into three core domains of medical education: undergraduate education, postgraduate education and continuing professional development. The interventions are designed to spiral through existing educational approaches rather than as additional special study modules or bolt-on courses, thus reducing self-selection bias in exposure. Interventions include spiral undergraduate education materials, e-learning, embedded post-graduate resources and face-to-face peer-to-peer education. RESULTS: To date the MHPP model has been applied in two key areas, physical activity and health and work. The physical activity programme in a partnership between Public Health England and Sport England has delivered face-to-face training to 17,105 healthcare professionals, embedded materials in almost three quarters of English medical schools and overseen > 95,000 e-learning modules completed over two and half years. Evaluation of the individual elements of the model is ongoing and aims to show improvements in knowledge, skills and practice. Further evaluation is planned to assess patient impact. CONCLUSIONS: The MHPP model offers a coherent whole-system approach to embed public health action into existing healthcare education models, and as such provides a framework for rapid change as well as upstream implementation to support the clinicians of today and tomorrow.

Active 10 - A new approach to increase physical activity in inactive people in England.

Public health physical activity (PA) guidelines are failing to increase levels of population PA, requiring a new approach. A national integrated marketing campaign was developed based on published literature and ethnographic research to get inactive lower socioeconomic 40-60 year olds to walk briskly for bouts of 10 or more minutes per day and move towards recommended levels of PA. National and local communications campaigns and partnerships promoted key messages and directed people to a free mobile phone app that provided the user with time, intensity and periodicity of walking, and included goal setting and encouragement to support behaviour change. Campaigns in the summers of 2017 and 2018 achieved around 500,000 downloads of the mobile phone app, with evaluation suggesting increases in brand and app awareness, and those taking action. Active 10 is a promising example of a physical activity promotion campaign based on evidence-based messages tailored for a target audience to change social norms rather than guidelines, an approach recognised as an effective population intervention for increasing walking.

The Decline in Diffuse Support for National Politics: The Long View on Political Discontent in Britain.

This research note considers how to track long-term trajectories of political discontent in Britain. Many accounts are confined to using either survey data drawn from recent decades or imperfect behavioral measures such as voting or party membership as indicators of political disengagement. We instead develop an approach that provides the long view on political disaffection. We first consider time-series data available from repeated survey measures. We next replicate historic survey questions to observe change in public opinion relative to earlier points in time. Finally, we use Stimson's (1991) dyad-ratios algorithm to construct an over-time index of political discontent that combines data from multiple poll series. This reveals rising levels of political discontent for both specific and diffuse measures of mass opinion. Our method and findings offer insights into the rising tide of disillusionment afflicting many contemporary democracies.

Molecular hybridization yields triazole bronchodilators for the treatment of COPD.

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Oral and inhaled p38 MAPK inhibitors: effects on inhaled LPS challenge in healthy subjects.

BACKGROUND: Inhaled LPS causes neutrophilic airway inflammation in healthy subjects. We compared the effects of p38 MAPK inhibitors and fluticasone propionate on the LPS response. METHODS: Three randomised, double-blind, placebo-controlled, single dose crossover studies were performed. Active treatments were the oral p38 MAPK inhibitor PH-797804 30 mg (study 1), PH-797804 30 mg and the inhaled p38 MAPK inhibitor PF-03715455 20 mg (study 2) and inhaled fluticasone propionate 500 µg (study 3). The primary endpoint was sputum neutrophil percentage. RESULTS: Sputum neutrophil percentage post-LPS challenge was significantly inhibited (15.1 and 15.3% reduction) by PH-797804 compared to placebo in studies 1 and 2 (p = 0.0096 and 0.0001, respectively), and by PF-03715455 (8.0% reduction, p = 0.031); fluticasone propionate had no effect. PH-797804 significantly inhibited the increase in inflammatory mediators (IL-6, MCP-1, MIP1ß and CC16) in sputum supernatant, while PF-03715455 had no effect. PH-797804 and PF-03715455 both inhibited IL-6, MCP-1, MIP1ß, CC16 and CRP levels in plasma, with PH-797804 having greater effects. Fluticasone propionate had no effect on sputum supernatant or plasma biomarkers. CONCLUSIONS: PH-797804 had the greatest impact on neutrophilic airway inflammation. Oral administration of p38 MAPK inhibitors may optimise pulmonary anti-inflammatory effects.

Direct and indirect measurement of neuromuscular fatigue in Canadian football players.

This study assessed the effects of a fatiguing game simulation (G-Sim) on the balance of collegiate Canadian football players. The purpose of the study was to evaluate postural control as a potential tool for monitoring neuromuscular fatigue (NMF) in collision-based team sports. Fifteen male Canadian football players were recruited (mean±SD: age 21.8±1.6 years, weight 97.6±14.7 kg). Indirect NMF measures (postural sway and countermovement jump (CMJ)) were performed 24 h before (TBase), immediately before (TPre) and after (TPost), and 24 h (T24) and 48 h after (T48) a Canadian football G-Sim. Peak isometric knee extensor torque of a maximal voluntary contraction (MVC) and electrically evoked tetani at 20 Hz (P20) and 80 Hz (P80) were also recorded as direct NMF measures at TBase, TPre, TPost, and T48. At TPost, we observed significant declines in MVC, P20, and the MVC/P80 ratio (-15.3%, -15.7%, and -12.1%, respectively; n=12) along with reductions in CMJ takeoff velocity and peak power (-6.9% and -6.5%, respectively; n=12) and larger area of the center of pressure trajectory (95.2%; n=10) during a 60-s postural sway task. All variables were no longer different than baseline by T48. Acute neuromuscular impairment in this cohort is likely attributable to alterations in excitation-contraction coupling due to structural damage and central activation failure. Congruency between the direct and indirect measures of NMF suggests monitoring postural sway has the potential to identify both neuromuscular and somatosensory alterations induced by acute game-induced fatigue in collision-based team sports players.

Velocity-specific strength recovery after a second bout of eccentric exercise.

A bout of eccentric exercise (ECC) has the protective effect of reducing muscle damage during a subsequent bout of ECC known as the "repeated bout effect" (RBE). The purpose of this study was to determine if the RBE is greater when both bouts of ECC are performed using the same vs. different velocity of contraction. Thirty-one right-handed participants were randomly assigned to perform an initial bout of either fast (3.14 rad·s [180°·s]) or slow (0.52 rad·s [30°·s]) maximal isokinetic ECCs of the elbow flexors. Three weeks later, the participants completed another bout of ECC at the same velocity (n = 16), or at a different velocity (n = 15). Indirect muscle damage markers were measured before, immediately after, and at 24, 48, and 72 hours postexercise. Measures included maximal voluntary isometric contraction (MVC) strength (dynamometer), muscle thickness (MT; ultrasound), delayed onset muscle soreness (DOMS; visual analog scale), biceps and triceps muscle activation amplitude (electromyography), voluntary activation (interpolated twitch), and twitch torque. After the repeated bout, MVC strength recovered faster compared with the same time points after the initial bout for only the same velocity group (p = 0.017), with no differences for all the other variables. Irrespective of velocity, MT and DOMS were reduced after the repeated bout compared with that of the initial bout at 24, 48, and 72 hours with a corresponding increase in TT at 72 hours (p < 0.05). Faster recovery of isometric strength associated with a repeated bout of ECC was evident when the velocity was matched between bouts, suggesting that specificity effects contribute to the RBE. The current findings support the idea of multiple mechanisms contributing to the RBE.

Quantification of training load in Canadian football: application of session-RPE in collision-based team sports.

The session-rating of perceived exertion (Session-RPE) method for quantifying internal training load (TL) has proven to be a highly valuable and accurate monitoring tool in numerous team sports. However, the influence of frequent impact during Canadian football on the validity of this subjective rating tool remains unclear. The aim of this study was to validate Session-RPE application to a prolonged, intermittent, high-intensity collision-based team sport through correlation of internal TL data collected using 2 criterion heart rate-based measures known as Polar Training-Impulse (TRIMP) and Edwards' TL. Twenty male participants (age = 22.0 ± 1.4 years) from the competitive roster of the University of Saskatchewan Canadian football team were recruited. Session-RPE, Polar TRIMP, and Edwards' TL data were collected daily over the 2011 Canadian Interuniversity Sport pre-competitive and competitive season (11 weeks; 713 total practice sessions). On average, each player contributed 36 sessions of data to the analysis. Statistically significant correlations (p < 0.01) between Session-RPE with Polar TRIMP (r = 0.65-0.91) and with Edwards' TL (r = 0.69-0.91) were found for all individual players. This study provides confirmation that Session-RPE is an inexpensive and simple tool, which is highly practical and accurately measures an individual's response (internal TL) to the Canadian football practice. Furthermore, when considering the number of individuals involved worldwide in collision-based team sports, this tool has the potential to impact a large proportion of the global sporting community.

Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-ß2-agonist for the treatment of chronic obstructive pulmonary disease.

Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a ß(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.

Gastric cancer-related information on the Internet: incomplete, poorly accessible, and overly commercial.

BACKGROUND: Patients increasingly use the Internet for gastric cancer information. However, the quality of the information is questionable. We evaluated the accuracy, completeness, accessibility, reliability, and readability of gastric cancer websites. METHODS: The Internet was searched for the terms "gastric cancer" or "stomach cancer" using general search engines. Websites were evaluated for completeness (CS) and accuracy (AS) using predefined quality appraisal instruments (QAIs), reliability using an integrity score (IS), readability using the Flesch-Kincaid (FK) grade level, and accessibility using automated accessibility appraisal tools. Site sponsor and the presence of quality labels were noted. RESULTS: Fifty-one websites were evaluated. The mean CS was 100.3 (SD ±44.9), AS was 107.22 (SD ±47.9), IS was 15.3 (SD ±3.7), and the mean readability grade level was 10.4 (SD ±2.5). Only 5 websites had the minimum mandatory basic accessibility. Commercial sites and sites with quality labels had significantly more accessibility violations. CONCLUSIONS: Internet gastric cancer information is overtly commercial, generally incomplete, and poorly accessible.

Inhalation by design: dual pharmacology ß-2 agonists/M3 antagonists for the treatment of COPD.

This paper describes the successful design and development of dual pharmacology ß-2 agonists-M3 antagonists, for the treatment of chronic obstructive pulmonary disorder using the principles of 'inhalation by design'. A key feature of this work is the combination of balanced potency and pharmacodynamic duration with desirable pharmacokinetic and material properties, whilst keeping synthetic complexity to a minimum.

Phenotypic modulation of human urinary tract stroma-derived fibroblasts by transforming growth factor beta3.

OBJECTIVES: Animal models have described critical roles for transforming growth factor beta (TGFbeta) isoforms in modulating urinary tract stroma phenotype. TGFbeta3 is of particular interest because it may regulate TGFbeta1 and TGFbeta2 expression, but its modulatory affect has not been so well characterized in human cells. In this study, we aim to determine whether TGFbeta3 treatment induced differentiation of human urinary tract stroma-derived fibroblasts to a smooth muscle-like phenotype. METHODS: We established cultures of human urinary tract stroma-derived fibroblasts and studied the effects of TGFbeta3 treatment using proliferation assays, cell cycle analysis, immunocytochemistry, and Western blotting for expression of differentiation marker and downstream regulators, and fura-2 fluorescence to study the effects on intracellular calcium. RESULTS: TGFbeta3 treatment induced proliferation that peaked at 72 hours, followed by enhanced expression of alpha-smooth muscle actin (alpha-SMA) with a maximal 3.4-fold increase at 168 hours. TGFbeta3 treatment decreased resting [Ca(2+)](i) by 70% and caused a 95% decrease in stimulated internal Ca(2+) release regulated by the sarcoplasmic/endoplasmic calcium-ATPase pump. These effects were associated with upregulation of nuclear activator of T cells -1 (NFAT), a known regulator of cell differentiation. CONCLUSIONS: TGFbeta3 treatment causes a time-specific response in the presence of serum, whereby fibroblasts initially proliferate and subsequently differentiate to a smooth muscle-like phenotype. This sequence was associated with stabilization of [Ca(2+)](i) stores, suggesting a role in the induction of hyperplasia and reduction of contractility; phenomena associated with a number of urinary tract pathologies.

Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: improving metabolic stability and reducing ion channel activity.

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI.