Biology subjects

Day, J.

Publications and source records attributed to Day, J..

12 recordsLinked to original sources

bioRxiv2026

A faster incubation explains Usutu leading West Nile in temperate Europe

Usutu virus (USUV) is a mosquito-borne flavivirus that has recently expanded northwards in Europe and become endemic in the UK. USUV emergence often precedes the closely related West Nile virus (WNV), potentially reflecting differences in epidemiological parameters. One key parameter is the extrinsic incubation period (EIP), the time taken for a mosquito to become infectious after a blood meal. Here we present the first quantitative estimate of the temperature dependent EIP for USUV in the vector Culex pipiens molestus. We were able to quantify the shortening of the USUV EIP from 68.06 days (95% CrI: 38.62 to 141.04) at 17 {degrees}C to 12.35 days (95% CrI: 8.10 to 17.09) at 25{degrees}C. This was achieved by re-analysing laboratory data with a bespoke Bayesian model that accounted for important features of the experimental design. Under UK summer temperatures, the median EIP of USUV is 37.75% (95% CrI: 3.38 to 55.68) shorter than that of WNV, and the potential transmission season of USUV is both longer and geographically more extensive. Under RCP8.5 climate projections, WNV transmission suitability could match or exceed current USUV levels between 2055 and 2065, highlighting the future threat to the UK from emerging mosquito borne pathogens. Our findings support USUV as a precursor for WNV in Europe and provide a robust characterisation of a key epidemiological parameter of USUV, enabling accurate modelling of its transmission dynamics.

ecology↗

bioRxiv2025

Expression of the Close homolog of L-1 and embigin identifies activated myofibroblasts.

AbstractFibrosis is driven by the emergence of myofibroblasts, which are the primary producers of the extracellular matrix proteins that form fibrotic lesions. Despite this critical role, detecting myofibroblasts remains challenging due to the paucity of selective markers. We therefore screened for novel myofibroblast-specific markers, discovering that the expression of the close homolog of L1 (ChL-1) and embigin (Emb) distinguish activated myofibroblasts from their quiescent precursors. We report that ChL-1+/Emb+ fibroblasts: (1) emerge during cardiac inflammation, (2) have elevated expression of collagens and inflammatory factors and (3) localise to fibrotic zones - consistent with activated myofibroblasts. Mechanistically, Chl1+/Emb+ myofibroblasts differentiate from resident fibroblasts which upregulate these markers in response to proinflammatory cytokines, such as IL-1 and IL-17. Moreover, we show that embigin could be exploited to target antibody-based therapies to myofibroblasts and confirm this protein as a conserved marker of activated fibroblasts in multiple tissues and settings. Collectively, these findings identify ChL-1 and embigin as novel myofibroblast surface-markers that could be used to identify, enumerate and target this pathogenic population.

cell biology↗

bioRxiv2024

Video-based biomechanical analysis captures disease-specific movement signatures of different neuromuscular diseases

BackgroundAssessing human movement is essential for diagnosing and monitoring movement-related conditions like neuromuscular disorders. Timed function tests (TFTs) are among the most widespread assessments due to their speed and simplicity, but they cannot capture disease-specific movement patterns. Conversely, biomechanical analysis can produce sensitive disease-specific biomarkers but is traditionally confined to laboratory settings. Recent advances in smartphone video-based biomechanical analysis enable quantification of 3D movement with the ease and speed required for clinical settings. However, the potential of this technology to offer more sensitive assessments of human function than TFTs remains untested. MethodsTo compare video-based analysis against TFTs, we collected an observational dataset from 129 individuals: 28 with facioscapulohumeral muscular dystrophy, 58 with myotonic dystrophy, and 43 controls with no diagnosed neuromuscular condition. We used OpenCap, a free open-source software tool, to capture smartphone video-based biomechanics of nine different movements in a median time of 16 minutes per participant. From these recordings we extracted 34 interpretable movement features. Using these features, we evaluated the ability of video-based biomechanics to reproduce four TFTs (10-meter walk, 10-meter run, timed up-and-go, and 5-time sit-to-stand) while capturing additional disease-specific signatures of movement. ResultsVideo-based biomechanical analysis reproduced all four TFTs (r > 0.98) with similar test-retest reliability. In addition, video metrics outperformed TFTs at disease classification (p = 0.021). Unlike TFTs, video-based biomechanical analysis identified disease-specific signatures of movement such as differences in gait kinematics that are not evident in TFTs. ConclusionVideo-based biomechanical analysis can complement existing functional movement assessments by capturing more sensitive, disease-specific outcomes from human movement. This technology enables digital health solutions for assessing and monitoring motor function, complementing traditional clinical outcome measures to enhance care, management, and clinical trial design for movement-related conditions. DescriptionThis study demonstrates that smartphone video-based biomechanical analysis can accurately replicate traditional timed function tests (TFTs) -- commonly used to diagnose and assess movement-related conditions like neuromuscular disorders -- while also capturing disease-specific movement patterns that TFTs fail to detect. By enabling sensitive and interpretable assessments in clinical settings, this approach offers a scalable and objective tool to enhance diagnosis, monitoring, and clinical trial design for neuromuscular disorders.

bioengineering↗

bioRxiv2024

Mastication while rested does not improve sustained attention in healthy participants conducting short-duration cognitive tasks

Sustained attention is important for optimal neurobehavioral performance, but many biological and environmental factors (e.g., circadian rhythm, distraction, etc.) may cause sustained attention deficits. It has been suggested that mastication (chewing) may ameliorate such deficits. As part of a continuing program to study the effects of mastication under varying conditions of fatigue and cognitive demand, this trial used a randomized, within-subjects, cross-over design to investigate the effect of mastication (gum chewing) on levels of sustained attention. To initially provide data that was ecologically valid for the average person, participants were not sleep deprived or otherwise challenged. Fifty-eight healthy adults (aged 18 - 45 years; 38 females) completed a 5 h in-laboratory daytime study during which time they completed two, 40 min test bouts. Participants completed the Psychomotor Vigilance Test (PVT), the Sustained Attention to Response Task (SART), the Karolinska Sleepiness Scale (KSS) and the Positive and Negative Affect Schedule (PANAS). During one of the two test bouts, participants were instructed to chew a piece of gum at a steady, comfortable rate. The statistical analyses were conducted blind. The primary outcome variable used for analyses was PVT lapses using the transformation square root of lapses plus square root of lapses plus 1 in addition to PVT mean reciprocal response time. Secondary outcome variables were PVT time-on-task slope and SART error score. Using rested participants and moderately fatiguing tasks, we were unable to detect any significant improvement in PVT or SART performance, or in KSS or PANAS ratings. A follow-up study under conditions of sleep deprivation and/or with longer task duration may provide further insight into the countermeasure potential of mastication.

physiology↗

bioRxiv2023

An immunohistochemical atlas of necroptotic pathway expression

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo. HighlightsO_LI13 automated immunohistochemistry protocols for detecting the necroptotic pathway C_LIO_LINecroptotic pathway expression is confined to fast-cycling immune barriers C_LIO_LINecroptotic pathway expression changes at sites of immunoinflammatory challenge C_LIO_LIImmunodetection of necrosomes in IBD patients is a putative new diagnostic tool C_LI

cell biology↗

bioRxiv2022

MLKL deficiency protects against low-grade, sterile inflammation in aged mice

MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl-/- and Ripk3-/- mice on a congenic C57BL/6J genetic background. We show that genetic deletion of Mlkl, but not Ripk3, in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. Mlkl-/- female mice were also protected against age-related, low-grade chronic sterile inflammation, with a reduced number of inflammatory infiltrates present in the connective and muscle tissue at 17 months relative to wild-type littermates. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans.

immunology↗

bioRxiv2022

Extensions of mean-field approximations for environmentally-transmitted pathogen networks

Many pathogens spread via environmental transmission, without requiring host- to-host direct contact. While models for environmental transmission exist, many are simply constructed intuitively with structures analogous to standard models for direct transmission. As model insights are generally sensitive to the underlying model assumptions, it is important that we are able understand the details and consequences of these assumptions. We construct a simple network model for an environmentally-transmitted pathogen and rigorously derive systems of ordinary differential equations (ODEs) based on different assumptions. We explore two key assumptions, namely homogeneity and independence, and demonstrate that relaxing these assumptions can lead to more accurate ODE approximations. We compare these ODE models to a stochastic implementation of the network model over a variety of parameters and network structures, demonstrating that with fewer restrictive assumptions we are able to achieve higher accuracy in our approximations and highlighting more precisely the errors produced by each assumption. We show that less restrictive assumptions lead to more complicated systems of ODEs and the potential for unstable solutions. Due to the rigour of our derivation, we are able to identify the reason behind these errors and propose potential resolutions.

microbiology↗

bioRxiv2020

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology

Between 6-20% of the cellular proteome is under circadian control to tune cell function with cycles of environmental change. For cell viability, and to maintain volume within narrow limits, the osmotic pressure exerted by changes in the soluble proteome must be compensated. The mechanisms and consequences underlying compensation are not known. Here, we show in cultured mammalian cells and in vivo that compensation requires electroneutral active transport of Na+, K+, and Cl- through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes alter their electrical activity at different times of the day. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

cell biology↗

bioRxiv2020

Eukaryotic cell biology is temporally coordinated to support the energetic demands of protein homeostasis

Every aspect of yeast physiology is subject to robust temporal regulation, this becomes apparent under nutrient-limiting conditions 1-6 and results in biological oscillations whose function and mechanism is poorly resolved7. These yeast metabolic oscillations share features with circadian rhythms and typically interact with, but are independent of, the cell division cycle. Here we show that these cellular rhythms act to minimise energy expenditure by temporally restricting protein synthesis until sufficient cellular resources are present, whilst maintaining osmotic homeostasis and protein quality control. Although nutrient supply is constant, cells initially sequester and store metabolic resources such as carbohydrates, amino acids, K+ and other osmolytes; which accumulate via increased synthesis, transport, autophagy and biomolecular condensation that is stimulated by low glucose and cytosolic acidification. Replete stores trigger increased H+ export to elevate cytosolic pH, thereby stimulating TORC1 and liberating proteasomes, ribosomes, chaperones and metabolic enzymes from non-membrane bound compartments. This facilitates a burst of increased protein synthesis, the liquidation of storage carbohydrates to sustain higher respiration rates and increased ATP turnover, and the export of osmolytes to maintain osmotic potential. As the duration of translational bursting is determined by cell-intrinsic factors, the period of oscillation is determined by the time cells take to store sufficient resources to license passage through the pH-dependent metabolic checkpoint that initiates translational bursting. We propose that dynamic regulation of ion transport and metabolic plasticity are required to maintain osmotic and protein homeostasis during remodelling of eukaryotic proteomes, and that bioenergetic constraints have selected for temporal organisation that promotes oscillatory behaviour.

molecular biology↗

bioRxiv2020

CRYPTOCHROME suppresses the circadian proteome and promotes protein homeostasis

The daily organisation of most mammalian cellular functions is attributed to circadian regulation of clock-controlled protein expression, driven by daily cycles of CRYPTOCHROME-dependent transcriptional feedback repression. To test this, we compared the circadian proteome and phosphoproteome of wild type and CRY-deficient fibroblast cells. Strikingly, CRY-deficient cells showed a two-fold increase in circadian-regulated proteins, phosphopeptides, and K+ transport. This was accompanied by extensive remodelling of the cellular proteome overall, including reduced phosphatase and proteasome subunit expression. These adaptations rendered CRY-deficient cells more sensitive to stress, which may account for their reduced circadian robustness and contribute to the wide-ranging phenotypes of CRY-deficient mice. We suggest that CRY ultimately functions to suppress, rather than generate, daily rhythms in cellular protein abundance, thereby maintaining protein and osmotic homeostasis.

cell biology↗

bioRxiv2018

Toward a model-free feedback control synthesis for treating acute inflammation -- A mathematical perspective

An effective and patient-specific feedback control synthesis for inflammation resolution is still an ongoing research area. A strategy consisting of manipulating a pro and anti-inflammatory mediator is considered here as used in some promising model-based control studies. These earlier studies, unfortunately, suffer from the difficultly of calibration due to the heterogeneity of individual patient responses even under similar initial conditions. We exploit a new model-free control approach and its corresponding \"intelligent\" controllers for this biomedical problem. A crucial feature of the proposed control problem is as follows: the two most important outputs which must be driven to their respective desired states are sensorless. This difficulty is overcome by assigning suitable reference trajectories to the other two outputs that do have sensors. A mathematical model, via a system of ordinary differential equations, is nevertheless employed as a \"virtual\" patient for in silico testing. We display several simulation results with respect to the most varied situations, which highlight the effectiveness of our viewpoint.

immunology↗

bioRxiv2016

Vertically transmitted rhabdoviruses are found across three insect families and have dynamic interactions with their hosts

A small number of free-living viruses have been found to be obligately vertically transmitted, but it remains uncertain how widespread vertically transmitted viruses are and how quickly they can spread through host populations. Recent metagenomic studies have found several insects to be infected with sigma viruses (Rhabdoviridae). Here, we report that sigma viruses that infect Mediterranean fruit flies (Ceratitis capitata), Drosophila immigrans, and speckled wood butterflies (Pararge aegeria) are all vertically transmitted. We find patterns of vertical transmission that are consistent with those seen in Drosophila sigma viruses, with high rates of maternal transmission, and lower rates of paternal transmission. This mode of transmission allows them to spread rapidly in populations, and using viral sequence data we found the viruses in D. immigrans and C. capitata had both recently swept through host populations. The viruses were common in nature, with mean prevalences of 12% in C. capitata, 38% in D. immigrans and 74% in P. aegeria. We conclude that vertically transmitted rhabdoviruses may be widespread in insects, and that these viruses can have dynamic interactions with their hosts.

evolutionary biology↗