Therapeutic glucocorticoids have been widely used in rheumatic diseases since they became available over 60 years ago. Despite the advent of more specific biologic therapies, a notable proportion of ...individuals with chronic rheumatic diseases continue to be treated with these drugs. Glucocorticoids are powerful, broad-spectrum anti-inflammatory agents, but their use is complicated by an equally broad range of adverse effects. The specific cellular mechanisms by which glucocorticoids have their therapeutic action have been difficult to identify, and attempts to develop more selective drugs on the basis of the action of glucocorticoids have proven difficult. The actions of glucocorticoids seem to be highly cell-type and context dependent. Despite emerging data on the effect of tissue-specific manipulation of glucocorticoid receptors in mouse models of inflammation, the cell types and intracellular targets of glucocorticoids in rheumatic diseases have not been fully identified. Although showing some signs of decline, the use of systemic glucocorticoids in rheumatology is likely to continue to be widespread, and careful consideration is required by rheumatologists to balance the beneficial effects and deleterious effects of these agents.
Osteoporosis associated with long-term glucocorticoid therapy remains a common and serious bone disease. Additionally, in recent years it has become clear that more subtle states of endogenous ...glucocorticoid excess may have a major impact on bone health. Adverse effects can be seen with mild systemic glucocorticoid excess, but there is also evidence of tissue-specific regulation of glucocorticoid action within bone as a mechanism of disease. This review article examines (1) the role of endogenous glucocorticoids in normal bone physiology, (2) the skeletal effects of endogenous glucocorticoid excess in the context of endocrine conditions such as Cushing disease/syndrome and autonomous cortisol secretion (subclinical Cushing syndrome), and (3) the actions of therapeutic (exogenous) glucocorticoids on bone. We review the extent to which the effect of glucocorticoids on bone is influenced by variations in tissue metabolizing enzymes and glucocorticoid receptor expression and sensitivity. We consider how the effects of therapeutic glucocorticoids on bone are complicated by the effects of the underlying inflammatory disease being treated. We also examine the impact that glucocorticoid replacement regimens have on bone in the context of primary and secondary adrenal insufficiency. We conclude that even subtle excess of endogenous or moderate doses of therapeutic glucocorticoids are detrimental to bone. However, in patients with inflammatory disorders there is a complex interplay between glucocorticoid treatment and underlying inflammation, with the underlying condition frequently representing the major component underpinning bone damage.
Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific ...treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.
Colony growth on solid media is a simple and effective measure for high-throughput genomic experiments such as yeast two-hybrid, synthetic dosage lethality and Synthetic Physical Interaction screens. ...The development of robotic pinning tools has facilitated the experimental design of these assays, and different imaging software can be used to automatically measure colony sizes on plates. However, comparison to control plates and statistical data analysis is often laborious and pinning issues or plate specific growth effects can lead to the detection of false-positive growth defects.
We have developed ScreenGarden, a shinyR application, to enable easy, quick and robust data analysis of plate-based high throughput assays. The code allows comparisons of different formats of data and different sized arrays of colonies. A comparison of ScreenGarden with previous analysis tools shows that it performs, at least, equivalently. The software can be run either via a website or offline via the RStudio program; the code is available and can be modified by expert uses to customise the analysis.
ScreenGarden provides a simple, fast and effective tool to analyse colony growth data from genomic experiments.
This paper provides an overview of recent progress made in the area of cellulose nanofibre-based nanocomposites. An introduction into the methods used to isolate cellulose nanofibres (nanowhiskers, ...nanofibrils) is given, with details of their structure. Following this, the article is split into sections dealing with processing and characterisation of cellulose nanocomposites and new developments in the area, with particular emphasis on applications. The types of cellulose nanofibres covered are those extracted from plants by acid hydrolysis (nanowhiskers), mechanical treatment and those that occur naturally (tunicate nanowhiskers) or under culturing conditions (bacterial cellulose nanofibrils). Research highlighted in the article are the use of cellulose nanowhiskers for shape memory nanocomposites, analysis of the interfacial properties of cellulose nanowhisker and nanofibril-based composites using Raman spectroscopy, switchable interfaces that mimic sea cucumbers, polymerisation from the surface of cellulose nanowhiskers by atom transfer radical polymerisation and ring opening polymerisation, and methods to analyse the dispersion of nanowhiskers. The applications and new advances covered in this review are the use of cellulose nanofibres to reinforce adhesives, to make optically transparent paper for electronic displays, to create DNA-hybrid materials, to generate hierarchical composites and for use in foams, aerogels and starch nanocomposites and the use of all-cellulose nanocomposites for enhanced coupling between matrix and fibre. A comprehensive coverage of the literature is given and some suggestions on where the field is likely to advance in the future are discussed.
Seasonal snowpacks, characterized by their snow water equivalent (SWE), can play a major role in the hydrological cycle of montane environments with months of snow accretion followed by episodes of ...melt controlling flood risk and water resource availability downstream. Quantifying the temporal and spatial patterns of snowpack accumulation and its subsequent melt and runoff is an internationally significant challenge, particularly within mountainous regions featuring complex terrain with limited or absent observational data. Here we report a new approach to snowpack characterization using open-source global satellite and modelled data products (precipitation and SWE) greatly enhancing the utility of the widely used Soil and Water Assessment Tool (SWAT). The paper focusses on the c. 23,000 km2 Chenab river basin (CRB) in the headwaters of the Indus Basin, globally important because of its large and growing population and increasing water insecurity due to climate change. We used five area-weighted averaged satellite, gridded and reanalysis precipitation datasets: ERA5-Land, CMORPH, TRMM, APHRODITE and CPC UPP. As well as comparison to local weather station data, these were used in SWAT to model streamflow for evaluation against observed streamflow at the basin outlet. ERA5-Land data provided the best streamflow match-ups and was used to infer snowpack (SWE) dynamics at basin and sub-basin scales. Snow reference data were derived from remote sensing and modelled SWE re-analysis products: ULCA-SWE and KRA-SWE, respectively. Beyond conventional auto-calibration and single-variable approaches we undertook multi-variable calibration using R-SWAT to manually adjust snow parameters alongside observed streamflow data. Characterization of basin-wide patterns of snowpack build-up and melt (SWE dynamics) were greatly strengthened using KRA-SWE data accompanied by improved streamflow simulation in sub-basins dominated by seasonal snow cover. UCLA-SWE data also improved SWE estimations using R-SWAT but weakened the performance of simulated streamflow due to under capture of seasonal runoff from permanent snow/ice fields in the CRB. This research highlights the utility and value of remote sensing and modelling data to drive better understanding of snowpack dynamics and their contribution to runoff in the absence of in situ snowpack data in high-altitude environments. An improved understanding of snow-bound water is vital in natural hazard risk assessment and in better managing worldwide water resources in the populous downstream regions of mountain-fed large rivers under threat from climate change.
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•Electrochemiluminescence based biosensors for a variety of applications within veterinary science are presented.•Disease detection within livestock and domestic animals is ...reviewed.•Monitoring of transmission of veterinary disease and treatments into the food supply chain is discussed.
Veterinary science or veterinary medicine is a diverse and significant field. Concerned not only with the diagnosis and treatment of domestic animals and livestock, but it also places focus upon zoonotic diseases, the development and effectiveness of potential vaccines and the possibility of transmission of veterinary medication or viruses into animal food products. Electrochemiluminescence (ECL) is a powerful analytical technique, which despite its significant intrinsic benefits has not seen enormous adoption into the wider analytical chemical community. In contrast, the veterinary science sector has reaped the merit of ECL as far back as the late 90′s and continue to benefit from development of the technique a further three decades later. ECL offers the superb sensitivity, low running costs, rapid results and high reliability required within the veterinary science sector, as such its employment in this area shouldn’t be surprising. To this end this article aims to summarise the standing of ECL within the veterinary science field, in an attempt increase the awareness of its successful employment within this area to the electro-analytical and wider analytical chemistry communities. Where it is hope veterinary science will gain recognition as possible end user targets for academic and industrial electrochemical researchers.
Biological systems such as proteins, viruses, and DNA have been most often reported to be used as templates for the synthesis of functional nanomaterials, but the properties of widely available ...biopolymers, such as cellulose, have been much less exploited for this purpose. Here, we report for the first time that cellulose nanocrystals (CNC) have the capacity to assist in the synthesis of metallic nanoparticle chains. A cationic surfactant, cetyltrimethylammonium bromide (CTAB), was critical to nanoparticle stabilization and CNC surface modification. Silver, gold, copper, and platinum nanoparticles were synthesized on CNCs, and the nanoparticle density and particle size were controlled by varying the concentration of CTAB, the pH of the salt solution, and the reduction time.
We report the case of a positive COVID‐19 patient who presented to our hospital for a maculopapular skin rash which appeared 7 days after the onset of COVID‐19 symptoms. He was 34 years old and ...nothing relevant was recorded at his previous anamnesis. The patient was hospitalized for 3 days and received systemic therapy with steroid, antihistamines, tocilizumab, and hydroxicloroquine. On the third day of the hospitalization the cutaneous rash had almost completely disappeared.
The transition from mitosis into the first gap phase of the cell cycle in budding yeast is controlled by the Mitotic Exit Network (MEN). The network interprets spatiotemporal cues about the ...progression of mitosis and ensures that release of Cdc14 phosphatase occurs only after completion of key mitotic events. The MEN has been studied intensively; however, a unified understanding of how localisation and protein activity function together as a system is lacking. In this paper, we present a compartmental, logical model of the MEN that is capable of representing spatial aspects of regulation in parallel to control of enzymatic activity. We show that our model is capable of correctly predicting the phenotype of the majority of mutants we tested, including mutants that cause proteins to mislocalise. We use a continuous time implementation of the model to demonstrate that Cdc14 Early Anaphase Release (FEAR) ensures robust timing of anaphase, and we verify our findings in living cells. Furthermore, we show that our model can represent measured cell-cell variation in Spindle Position Checkpoint (SPoC) mutants. This work suggests a general approach to incorporate spatial effects into logical models. We anticipate that the model itself will be an important resource to experimental researchers, providing a rigorous platform to test hypotheses about regulation of mitotic exit.
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