Biology subjects

Arthur, S.

Publications and source records attributed to Arthur, S..

8 recordsLinked to original sources

bioRxiv2026

Inflammatory burning pain depends on a specific line of nociceptors

The development and persistence of burning pain and heat hyperalgesia following tissue injury and the subsequent inflammatory response, depend on the nuclear enzyme mitogen- and stress-activated kinase 1 (MSK1) expressed in a specific subset of transient receptor potential subfamily V member 1 (TRPV1)-expressing primary sensory neurons termed nociceptors, which are specialised for detecting harmful stimuli. Inflammation up-regulates and activates MSK1, and MSK1 governs TRPV1 expression in the MSK1 and TRPV1 co-expressing mouse and human nociceptors. Importantly, inhibition of inflammatory MSK1-mediated TRPV1 upregulation protects from heat hypersensitivity without affecting other relevant TRPV1 functions, such as the sensation of acute painful heat stimuli or the maintenance of the body core temperature. The newly discovered importance of the interaction between MSK1 and TRPV1 in a specific line of nociceptors provides mechanistic understanding of inflammatory pain and heat hyperalgesia pathogenesis.

neuroscience↗

bioRxiv2025

Adipocyte MKK3 Increases in Human Obesity protecting against Insulin Resistance by p38-beta activation

Obesity is a major global health concern, and a key predisposing factor for insulin resistance and type 2 diabetes mellitus. Adipocytes play a critical role in the development of obesity-induced insulin resistance, with several signaling pathways influencing insulin sensitivity. Among these, p38 MAP kinases are essential for adipose tissue physiology and the regulation of processes such as differentiation, thermogenesis, and inflammation. p38 activation is mediated by the upstream kinases MKK3 and MKK6 in response to inflammatory signals. While MKK6 inhibition promotes browning and thermogenesis and protects against obesity, the role of MKK3 remains unclear. Here, we investigated the function of MKK3 in adipose tissue. In human adipose tissue samples, MKK3 expression was positively correlated with body mass index (BMI) and negatively correlated with glycated hemoglobin, a marker of hyperglycemia. Using whole-body and adipose-specific Mkk3 and p38{beta} knockout mice, we found that Mkk3 activation in adipose tissue during obesity enhances insulin sensitivity. Mechanistically, adipose tissue from Mkk3- or p38{beta}-deficient mice exhibited elevated basal p70S6K activity compared with wild-type controls. This increased p70S6K activity was linked to higher serine phosphorylation of insulin receptor substrate 1 (IRS1) and impaired insulin-stimulated Akt phosphorylation, contributing to worsened insulin resistance. Collectively, our data suggest that activation of the MKK3/p38{beta} signaling axis in adipocytes may protect against high-fat diet-induced insulin resistance and diabetes.

molecular biology↗

bioRxiv2023

Optimising Spectronaut search parameters to improve data quality with minimal proteome coverage reductions in DIA analyses of heterogeneous samples

Data independent acquisition has seen breakthroughs that enable comprehensive proteome profiling using short gradients. As the proteome coverage continues to increase, the quality of the data generated becomes much more relevant. Using Spectronaut, we show that the default search parameters can be easily optimised to minimise the occurrence of false positives across different samples. Using an immunological infection model system to demonstrate the impact of adjusting search settings we analysed mouse macrophages and compared their proteome to macrophages spiked with Candida albicans. This experimental system enabled the identification of false positives since Candida albicans peptides and proteins should not be present in the mouse only samples. We show that adjusting the search parameters reduced false positive identifications by 89% at the peptide and protein level, thereby considerably increasing the quality of the data. We also show that these optimised parameters incur a moderate cost, only reducing the overall number of true positive identifications across each biological replicate by <6.7% at both the peptide and protein level. We believe the value of our updated search parameters extends beyond a two-organism analysis and would be of great value to any DIA experiment analysing heterogenous populations of cell types or tissues.

biochemistry↗

bioRxiv2023

The glucocorticoid dexamethasone impairs the expression of anti-viral mediators in activated macrophages by inhibiting both expression and function of interferon beta.

Glucocorticoids potently inhibit expression of many inflammatory mediators, and have been very widely used to treat both acute and chronic inflammatory diseases for more than seventy years. However, they can have several unwanted effects, amongst which immunosuppression is one of the most common. Here we investigated effects of the synthetic glucocorticoid dexamethasone on the responses of primary mouse bone marrow-derived macrophages to the pro-inflammatory agonist lipopolysaccharide (LPS). At the mRNA level, dexamethasone inhibited the LPS-induced expression of more than 100 genes that are involved in cell-intrinsic defence against viral pathogens. Expression of most of the corresponding proteins was also reduced by dexamethasone. This antiviral disarmament occurred at two distinct levels. First, dexamethasone strongly and dose-dependently inhibited the expression of the type I interferon IFN{beta} by LPS-activated macrophages. IFN{beta} mediates an autocrine positive feedback loop in LPS-treated macrophages, promoting the expression of antiviral genes and other interferon-stimulated genes. Hence reduction of IFN{beta} expression contributes to impaired expression of antiviral genes. Dexamethasone also acted downstream of IFN{beta} to inhibit expression of a subset of interferon-regulated genes. We tested a number of hypotheses based on previous publications, but found that no single mechanism could account for more than a small fraction of the broad suppressive impact of dexamethasone on macrophage type I interferon signaling, underlining the complexity of this pathway. Preliminary experiments indicated that dexamethasone exerted similar inhibitory effects on primary human monocyte-derived or alveolar macrophages.

immunology↗

bioRxiv2021

Salt-inducible kinase (SIK) inhibition is protective in a mouse model of asthma

Interleukin-13 (IL-13) and other Th2 cytokines are important regulators of airway hyper-responsiveness, immune cell infiltration and inflammation in allergic asthma, and are produced when immune cells, such as type 2 innate lymphoid cells (ILC2s) and mast cells, are stimulated with IL-33. Here, we report that the IL-33-dependent secretion of IL-13 from ILC2s is prevented by inhibition of the salt-inducible kinases (SIKs), as we have shown previously in mast cells (Darling NJ et al., 2021, J. Biol. Chem. doi: 10.1016/j.jbc.2021.100428). We also report that a new SIK inhibitor with improved pharmacokinetic properties suppresses the recruitment of eosinophils to the lungs and serum immunoglobulin E (IgE) levels in the Alternaria alternata-induced model of allergic asthma. Our results suggest that drugs targeting SIK isoforms may have therapeutic potential for the treatment of asthma.

immunology↗

bioRxiv2021

Ongoing neural oscillations predict the post-stimulus outcome of closed loop auditory stimulation during slow-wave sleep.

The large slow oscillation (SO, 0.5-2Hz) that characterises slow-wave sleep is crucial to memory consolidation and other physiological functions. Manipulating slow oscillations can enhance sleep and memory, as well as benefitting the immune system. Closed-loop auditory stimulation (CLAS) has been demonstrated to increase the SO amplitude and to boost fast sleep spindle activity (11-16Hz). Nevertheless, not all such stimuli are effective in evoking SOs, even if they are precisely phase-locked. Here, we studied whether it is possible to use ongoing activity patterns to determine which oscillations to stimulate in order to effectively enhance SOs or SO-locked spindle activity. To this end, we trained classifiers using the morphological characteristics of the ongoing SO, as measured by electroencephalography (EEG), to predict whether stimulation would lead to a benefit in terms of the resulting SO and spindle amplitude. Separate classifiers were trained using trials from spontaneous control and stimulated datasets, and we evaluated their performance by applying them to held-out data both within and across conditions. We were able to predict both when large SOs will occur spontaneously, and whether a phase-locked auditory click will effectively enlarge them with an accuracy of ~70%. We were also able to predict when stimulation would elicit spindle activity with an accuracy of ~60%. Finally, we evaluate the importance of the various SO features used to make these predictions. Our results offer new insight into SO and spindle dynamics and provide a new method for online optimisation of stimulation. HIGHLIGHTS- Random forest classifiers can predict spontaneous and stimulated SOs and spindle amplitudes. - Morphological wave features predicted the response of SOs and spindles to CLAS. - SO amplitude during the click is the main predictor for post-stimulus SO amplitude. - Prediction of spindle activity did not differ in accuracy for stimulated vs spontaneous data.

neuroscience↗

bioRxiv2018

Recent trends in Tricolored Blackbird colony size: analysis of the 2008 through 2017 Triennial Statewide Surveys

Tricolored blackbird (Agelaius tricolor) is a colonial breeder, largely restricted to grasslands, wetlands, and agricultural habitats of California. Tricolored blackbird abundance declined considerably during the 20th century. Recent trends have been less clear, however, hindering efforts to evaluate the conservation needs of the species. We assessed trends in tricolored blackbird colony size using the 2008, 2011, 2014, and 2017 Triennial Tricolored Blackbird Statewide Survey, a community-science effort involving hundreds of volunteer observers. After accounting for variation in observer characteristics and survey effort, we found a clear, statistically significant decline in colony size of approximately -5% per year, which translated to a decrease in colony size of approximately -40% between 2008 and 2017. To the extent that colony size is proportional to total abundance, this decline translates to a species half-life of roughly 15 years. We conclude that tricolored blackbird is in considerable need of protection and recovery efforts.

ecology↗

bioRxiv2017

Genome-wide discovery of somatic coding and regulatory variants in Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Many known driver mutations are over-represented in one of its two molecular subgroups, knowledge of which has aided in the development of therapeutics that target these features. The heterogeneity of DLBCL determined through prior genomic analysis suggests an incomplete understanding of its molecular aetiology, with a limited diversity of genetic events having thus far been attributed to the activated B-cell (ABC) subgroup. Through an integrative genomic analysis we uncovered genes and non-coding loci that are commonly mutated in DLBCL including putative regulatory sequences. We implicate recurrent mutations in the 3UTR of NFKBIZ as a novel mechanism of oncogene deregulation and found small amplifications associated with over-expression of FC-{gamma} receptor genes. These results inform on mechanisms of NF-{kappa}B pathway activation in ABC DLBCL and may reveal a high-risk population of patients that might not benefit from standard therapeutics.

genomics↗