'This is what democracy looks like' : New Labour's blind spot and peripheral vision

New Labour in government since 1997 has been roundly criticized for not possessing a clear, coherent and consistent democratic vision. The absence of such a grand vision has resulted, from this critical perspective, in an absence of 'joined-up' thinking about democracy in an evolving multi-level state. Tensions have been all too apparent between the government's desire to exert central direction - manifested in its most pathological form as 'control freakery' - and its democratising initiatives derived from 'third-way' obsessions with 'decentralising', 'empowering' and 'enabling'. The purpose of this article is to examine why New Labour displayed such apparently impaired democratic vision and why it appeared incapable of conceiving of democratic reform 'in the round'. This article seeks to explain these apparent paradoxes, however, through utilising the notion of 'macular degeneration'. In this analysis, the perceived democratic blind spot of New Labour at Westminster is connected to a democratic peripheral vision, which has envisaged innovative participatory and decentred initiatives in governance beyond Westminster

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.

BACKGROUND: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. SCOPE OF REVIEW: Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. MAJOR CONCLUSIONS: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug

The Involvement of IL-17A in the Murine Response to Sub-Lethal Inhalational Infection with Francisella tularensis

Background: Francisella tularensis is an intercellular bacterium often causing fatal disease when inhaled. Previous reports have underlined the role of cell-mediated immunity and IFNc in the host response to Francisella tularensis infection. Methodology/Principal Findings: Here we provide evidence for the involvement of IL-17A in host defense to inhalational tularemia, using a mouse model of intranasal infection with the Live Vaccine Strain (LVS). We demonstrate the kinetics of IL-17A production in lavage fluids of infected lungs and identify the IL-17A-producing lymphocytes as pulmonary cd and Th17 cells. The peak of IL-17A production appears early during sub-lethal infection, it precedes the peak of immune activation and the nadir of the disease, and then subsides subsequently. Exogenous airway administration of IL-17A or of IL-23 had a limited yet consistent effect of delaying the onset of death from a lethal dose of LVS, implying that IL-17A may be involved in restraining the infection. The protective role for IL-17A was directly demonstrated by in vivo neutralization of IL-17A. Administration of anti IL-17A antibodies concomitantly to a sub-lethal airway infection with 0.16LD50 resulted in a fatal disease. Conclusion: In summary, these data characterize the involvement and underline the protective key role of the IL-17A axis in the lungs from inhalational tularemia

A review of acoustic telemetry in Europe and the need for a regional aquatic telemetry network

Background Globally, there are a large and growing number of researchers using biotelemetry as a tool to study aquatic animals. In Europe, this community lacks a formal network structure. The aim of this study is to review the use of acoustic telemetry in Europe and document the contribution of cross-boundary studies and inter-research group collaborations. Based on this, we explore the potential benefits and challenges of a network approach to identify future priorities and best practices for aquatic biotelemetry research in Europe. Results Over the past decade, there was an approximately sevenfold increase in the number of acoustic telemetry studies published on marine and diadromous species in Europe compared to a sixfold increase globally. Over 90% of these studies were conducted on fishes and undertaken in coastal areas, estuaries, or rivers. 75% of these studies were conducted by researchers based in one of five nations (Norway, UK, France, Portugal, and Spain) and, even though 34% were based on collaborations between scientists from several countries, there was only one study with an acoustic receiver array that extended beyond the borders of a single country. In recent years, acoustic telemetry in European waters has evolved from studying behavioural aspects of animals (82.2%), into more holistic approaches addressing management-related issues (10%), tagging methods and effects (5%), and technology and data analysis development (2.8%). Conclusions Despite the increasing number of publications and species tracked, there is a prominent lack of planned and structured acoustic telemetry collaborations in Europe. A formal pan-European network structure would promote the development of (1) a research platform that could benefit the acoustic telemetry community through capacity building, (2) a centralized database, and (3) key deployment sites and studies on priority species requiring research in Europe. A network may increase efficiency, expand the scope of research that can be undertaken, promote European science integration, enhance the opportunities and success of acquiring research funding and, ultimately, foster regional and transatlantic collaborations. It may also help address research priorities such as the large-scale societal challenges arising from climate change impacts and assist the EU’s Marine Strategy Framework Directive via identification of good environmental status of endangered or commercially important species.info:eu-repo/semantics/publishedVersio

Ultrafast Light and Electrons: Imaging the Invisible

In this chapter, the evolutionary and revolutionary developments of microscopic imaging are overviewed with focus on ultrashort light and electrons pulses; for simplicity, we shall use the term “ultrafast” for both. From Alhazen’s camera obscura, to Hooke and van Leeuwenhoek’s optical micrography, and on to three- and four-dimensional (4D) electron microscopy, the developments over a millennium have transformed humans’ scope of visualization. The changes in the length and time scales involved are unimaginable, beginning with the visible shadows of candles at the centimeter and second scales, and ending with invisible atoms with space and time dimensions of sub-nanometer and femtosecond, respectively. With these advances it has become possible to determine the structures of matter and to observe their elementary dynamics as they fold and unfold in real time, providing the means for visualizing materials behavior and biological function, with the aim of understanding emergent phenomena in complex systems. Both light and light-generated electrons are now at the forefront of femtosecond and attosecond science and technology, and the scope of applications has reached beyond the nuclear motion as electron dynamics become accessible

Development of Functional and Molecular Correlates of Vaccine-Induced Protection for a Model Intracellular Pathogen, F. tularensis LVS

In contrast with common human infections for which vaccine efficacy can be evaluated directly in field studies, alternative strategies are needed to evaluate efficacy for slowly developing or sporadic diseases like tularemia. For diseases such as these caused by intracellular bacteria, serological measures of antibodies are generally not predictive. Here, we used vaccines varying in efficacy to explore development of clinically useful correlates of protection for intracellular bacteria, using Francisella tularensis as an experimental model. F. tularensis is an intracellular bacterium classified as Category A bioterrorism agent which causes tularemia. The primary vaccine candidate in the U.S., called Live Vaccine Strain (LVS), has been the subject of ongoing clinical studies; however, safety and efficacy are not well established, and LVS is not licensed by the U.S. FDA. Using a mouse model, we compared the in vivo efficacy of a panel of qualitatively different Francisella vaccine candidates, the in vitro functional activity of immune lymphocytes derived from vaccinated mice, and relative gene expression in immune lymphocytes. Integrated analyses showed that the hierarchy of protection in vivo engendered by qualitatively different vaccines was reflected by the degree of lymphocytes' in vitro activity in controlling the intramacrophage growth of Francisella. Thus, this assay may be a functional correlate. Further, the strength of protection was significantly related to the degree of up-regulation of expression of a panel of genes in cells recovered from the assay. These included IFN-γ, IL-6, IL-12Rβ2, T-bet, SOCS-1, and IL-18bp. Taken together, the results indicate that an in vitro assay that detects control of bacterial growth, and/or a selected panel of mediators, may ultimately be developed to predict the outcome of vaccine efficacy and to complement clinical trials. The overall approach may be applicable to intracellular pathogens in general

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Effective, Broad Spectrum Control of Virulent Bacterial Infections Using Cationic DNA Liposome Complexes Combined with Bacterial Antigens

Protection against virulent pathogens that cause acute, fatal disease is often hampered by development of microbial resistance to traditional chemotherapeutics. Further, most successful pathogens possess an array of immune evasion strategies to avoid detection and elimination by the host. Development of novel, immunomodulatory prophylaxes that target the host immune system, rather than the invading microbe, could serve as effective alternatives to traditional chemotherapies. Here we describe the development and mechanism of a novel pan-anti-bacterial prophylaxis. Using cationic liposome non-coding DNA complexes (CLDC) mixed with crude F. tularensis membrane protein fractions (MPF), we demonstrate control of virulent F. tularensis infection in vitro and in vivo. CLDC+MPF inhibited bacterial replication in primary human and murine macrophages in vitro. Control of infection in macrophages was mediated by both reactive nitrogen species (RNS) and reactive oxygen species (ROS) in mouse cells, and ROS in human cells. Importantly, mice treated with CLDC+MPF 3 days prior to challenge survived lethal intranasal infection with virulent F. tularensis. Similarly to in vitro observations, in vivo protection was dependent on the presence of RNS and ROS. Lastly, CLDC+MPF was also effective at controlling infections with Yersinia pestis, Burkholderia pseudomallei and Brucella abortus. Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens

Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection

Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11bhigh/CD11cmed/autofluorescencelow DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria (∼75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment