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Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD
Bilson J, Oquendo CJ, Read J, Scorletti E, Afolabi PR, Lord J, Bindels LB, Targher G, Mahajan S, Baralle D, Calder PC, Byrne CD and Sethi JK
Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD
Bilson J, Oquendo CJ, Read J, Scorletti E, Afolabi PR, Lord J, Bindels LB, Targher G, Mahajan S, Baralle D, Calder PC, Byrne CD and Sethi JK
Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome.
Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation
Devitt G, Johnson PB, Hanrahan N, Lane SIR, Vidale MC, Sheth B, Allen JD, Humbert MV, Spalluto CM, Hervé RC, Staples K, West JJ, Forster R, Divecha N, McCormick CJ, Crispin M, Hempler N, Malcolm GPA and Mahajan S
Mechanisms of SARS-CoV-2 Inactivation Using UVC Laser Radiation
Devitt G, Johnson PB, Hanrahan N, Lane SIR, Vidale MC, Sheth B, Allen JD, Humbert MV, Spalluto CM, Hervé RC, Staples K, West JJ, Forster R, Divecha N, McCormick CJ, Crispin M, Hempler N, Malcolm GPA and Mahajan S
Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) has had a tremendous impact on humanity. Prevention of transmission by disinfection of surfaces and aerosols through a chemical-free method is highly desirable. Ultraviolet C (UVC) light is uniquely positioned to achieve inactivation of pathogens. We report the inactivation of SARS-CoV-2 virus by UVC radiation and explore its mechanisms. A dose of 50 mJ/cm using a UVC laser at 266 nm achieved an inactivation efficiency of 99.89%, while infectious virions were undetectable at 75 mJ/cm indicating >99.99% inactivation. Infection by SARS-CoV-2 involves viral entry mediated by the spike glycoprotein (S), and viral reproduction, reliant on translation of its genome. We demonstrate that UVC radiation damages ribonucleic acid (RNA) and provide in-depth characterization of UVC-induced damage of the S protein. We find that UVC severely impacts SARS-CoV- 2 spike protein's ability to bind human angiotensin-converting enzyme 2 (hACE2) and this correlates with loss of native protein conformation and aromatic amino acid integrity. This report has important implications for the design and development of rapid and effective disinfection systems against the SARS-CoV-2 virus and other pathogens.
Development of hydrogel-based standards and phantoms for non-linear imaging at depth
Haseeb F, Bourdakos KN, Forsyth E, Setchfield K, Gorman A, Venkateswaran S, Wright AJ, Mahajan S and Bradley M
Development of hydrogel-based standards and phantoms for non-linear imaging at depth
Haseeb F, Bourdakos KN, Forsyth E, Setchfield K, Gorman A, Venkateswaran S, Wright AJ, Mahajan S and Bradley M
Rapid advances in medical imaging technology, particularly the development of optical systems with non-linear imaging modalities, are boosting deep tissue imaging. The development of reliable standards and phantoms is critical for validation and optimization of these cutting-edge imaging techniques.
All-fiberized 1840-nm femtosecond thulium fiber laser for label-free nonlinear microscopy
Xu D, Bourdakos KN, Crisford A, Johnson P, Abughazaleh I, Srisamran P, Oreffo ROC, Mahajan S, Richardson DJ and Xu L
All-fiberized 1840-nm femtosecond thulium fiber laser for label-free nonlinear microscopy
Xu D, Bourdakos KN, Crisford A, Johnson P, Abughazaleh I, Srisamran P, Oreffo ROC, Mahajan S, Richardson DJ and Xu L
We report an all-fiberized 1840-nm thulium-fiber-laser source, comprising a dissipative-soliton mode-locked seed laser and a chirped-pulse-amplification system for label-free biological imaging through nonlinear microscopy. The mode-locked thulium fiber laser generated dissipative-soliton pulses with a pre-chirped duration of 7 ps and pulse energy of 1 nJ. A chirped-pulse fiber-amplification system employing an in-house-fabricated, short-length, single-mode, high-absorption, thulium fiber delivered pulses with energies up to 105 nJ. The pulses were capable of being compressed to 416 fs by passing through a grating pair. Imaging of mouse tissue and human bone samples was demonstrated using this source via third-harmonic generation microscopy.
Leveraging real-world data to improve cochlear implant outcomes: Is the data available?
Findlay C, Edwards M, Hough K, Grasmeder M and Newman TA
Leveraging real-world data to improve cochlear implant outcomes: Is the data available?
Findlay C, Edwards M, Hough K, Grasmeder M and Newman TA
A small but persistent proportion of individuals do not gain the expected benefit from cochlear implants(CI). A step-change in the understanding of factors affecting outcomes could come through data science. This study evaluates clinical data capture to assess the quality and utility of CI user's health records for data science, by assessing the recording of otitis media. Otitis media was selected as it is associated with the development of sensorineural hearing loss and may affect cochlear implant outcomes.
Human Tau Aggregates Are Permissive to Protein Synthesis-Dependent Memory in Tauopathy Models
Vourkou E, Rouiz Ortega ED, Mahajan S, Mudher A and Skoulakis EMC
Human Tau Aggregates Are Permissive to Protein Synthesis-Dependent Memory in Tauopathy Models
Vourkou E, Rouiz Ortega ED, Mahajan S, Mudher A and Skoulakis EMC
Tauopathies including Alzheimer's disease, are characterized by progressive cognitive decline, neurodegeneration, and intraneuronal aggregates comprised largely of the axonal protein Tau. It has been unclear whether cognitive deficits are a consequence of aggregate accumulation thought to compromise neuronal health and eventually lead to neurodegeneration. We use the tauopathy model and mixed-sex populations to reveal an adult onset pan-neuronal Tau accumulation-dependent decline in learning efficacy and a specific defect in protein synthesis-dependent memory (PSD-M), but not in its protein synthesis-independent variant. We demonstrate that these neuroplasticity defects are reversible on suppression of new transgenic human Tau expression and surprisingly correlate with an increase in Tau aggregates. Inhibition of aggregate formation via acute oral administration of methylene blue results in re-emergence of deficient memory in animals with suppressed human Tau (hTau) expression. Significantly, aggregate inhibition results in PSD-M deficits in hTau-expressing animals, which present elevated aggregates and normal memory if untreated with methylene blue. Moreover, methylene blue-dependent hTau aggregate suppression within adult mushroom body neurons also resulted in emergence of memory deficits. Therefore, deficient PSD-M on human Tau expression in the CNS is not a consequence of toxicity and neuronal loss because it is reversible. Furthermore, PSD-M deficits do not result from aggregate accumulation, which appears permissive, if not protective of processes underlying this memory variant. Intraneuronal Tau aggregate accumulation has been proposed to underlie the cognitive decline and eventual neurotoxicity that characterizes the neurodegenerative dementias known as tauopathies. However, we show in three experimental settings that Tau aggregates in the CNS do not impair but rather appear to facilitate processes underlying protein synthesis-dependent memory within affected neurons.
A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy
Khan AH, Soundara Pandi SP, Scott JA, Sánchez-Bretaño A, Lynn SA, Ratnayaka JA, Teeling JL and Lotery AJ
A laser-induced mouse model of progressive retinal degeneration with central sparing displays features of parafoveal geographic atrophy
Khan AH, Soundara Pandi SP, Scott JA, Sánchez-Bretaño A, Lynn SA, Ratnayaka JA, Teeling JL and Lotery AJ
There are no disease-modifying treatments available for geographic atrophy (GA), the advanced form of dry age-related macular degeneration. Current murine models fail to fully recapitulate the features of GA and thus hinder drug discovery. Here we describe a novel mouse model of retinal degeneration with hallmark features of GA. We used an 810 nm laser to create a retinal lesion with central sparing (RLCS), simulating parafoveal atrophy observed in patients with progressive GA. Laser-induced RLCS resulted in progressive GA-like pathology with the development of a confluent atrophic lesion. We demonstrate significant changes to the retinal structure and thickness in the central unaffected retina over a 24-week post-laser period, confirmed by longitudinal optical coherence tomography scans. We further show characteristic features of progressive GA, including a gradual reduction in the thickness of the central, unaffected retina and of total retinal thickness. Histological changes observed in the RLCS correspond to GA pathology, which includes the collapse of the outer nuclear layer, increased numbers of GFAP + , CD11b + and FcγRI + cells, and damage to cone and rod photoreceptors. We demonstrate a laser-induced mouse model of parafoveal GA progression, starting at 2 weeks post-laser and reaching confluence at 24 weeks post-laser. This 24-week time-frame in which GA pathology develops, provides an extended window of opportunity for proof-of-concept evaluation of drugs targeting GA. This time period is an added advantage compared to several existing models of geographic atrophy.
An Exploratory Study Provides Insights into MMP9 and Aβ Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients
Lynn SA, Soubigou F, Dewing JM, Smith A, Ballingall J, Sass T, Nica I, Watkins C, Gupta B, Almuhtaseb H, Lash SC, Yuen HM, Cree A, Newman TA, Lotery AJ and Ratnayaka JA
An Exploratory Study Provides Insights into MMP9 and Aβ Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients
Lynn SA, Soubigou F, Dewing JM, Smith A, Ballingall J, Sass T, Nica I, Watkins C, Gupta B, Almuhtaseb H, Lash SC, Yuen HM, Cree A, Newman TA, Lotery AJ and Ratnayaka JA
Matrix metalloproteinase-9 (MMP9) and total amyloid-beta (Aβ) are prospective biomarkers of ocular ageing and retinopathy. These were quantified by ELISA in the vitreous and blood from controls ( = 55) and in a subset of age-related macular degeneration (AMD) patients ( = 12) for insights and possible additional links between the ocular and systemic compartments. Vitreous MMP9 levels in control and AMD groups were 932.5 ± 240.9 pg/mL and 813.7 ± 157.6 pg/mL, whilst serum levels were 2228 ± 193 pg/mL and 2386.8 ± 449.4 pg/mL, respectively. Vitreous Aβ in control and AMD groups were 1173.5 ± 117.1 pg/mL and 1275.6 ± 332.9 pg/mL, whilst plasma Aβ were 574.3 ± 104.8 pg/mL and 542.2 ± 139.9 pg/mL, respectively. MMP9 and Aβ showed variable levels across the lifecourse, indicating no correlation to each other or with age nor AMD status, though the smaller AMD cohort was a limiting factor. Aβ and MMP9 levels in the vitreous and blood were unrelated to mean arterial pressure. Smoking, another modifiable risk, showed no association with vitreous Aβ. However, smoking may be linked with vitreous ( = 0.004) and serum ( = 0.005) MMP9 levels in control and AMD groups, though this did not reach our elevated ( = 0.001) significance. A bioinformatics analysis revealed promising MMP9 and APP/Aβ partners for further scrutiny, many of which are already linked with retinopathy.
Inflammation in dementia with Lewy bodies
Amin J, Erskine D, Donaghy PC, Surendranathan A, Swann P, Kunicki AP, Boche D, Holmes C, McKeith IG, O'Brien JT, Teeling JL and Thomas AJ
Inflammation in dementia with Lewy bodies
Amin J, Erskine D, Donaghy PC, Surendranathan A, Swann P, Kunicki AP, Boche D, Holmes C, McKeith IG, O'Brien JT, Teeling JL and Thomas AJ
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative cause of dementia, behind Alzheimer's disease (AD). The profile of inflammation in AD has been extensively researched in recent years, with evidence that chronic peripheral inflammation in midlife increases the risk of late-onset AD, and data supporting inflammation being associated with disease progression. In contrast, our understanding of the role of inflammation in DLB is less developed. Most research to date has examined inflammation in related disorders, such as Parkinson's disease, but there is now a growing range of literature examining inflammation in DLB itself. We present a review of the literature in this field, exploring a range of research methodologies including those quantifying markers of inflammation in cerebrospinal fluid, peripheral blood, post-mortem brain tissue, and using neuroimaging and preclinical data. Our review reveals evidence from PET imaging and peripheral blood analysis to support an increase in cerebral and peripheral inflammation in mild or prodromal DLB, that dissipates with disease progression. We present evidence from post-mortem brain tissue and pre-clinical studies that indicate α-synuclein directly promotes inflammation, but that also support the presence of AD co-pathology as an important factor in the profile of neuroinflammation in DLB. We propose that specific markers of inflammation may play a sentinel role in the mild stage of the disease, particularly when combined with AD pathology. We advocate further examination of the profile of inflammation in DLB through robust longitudinal studies, to enhance our understanding of the pathogenesis of the disease. The goal should be to utilise future results to develop a composite biomarker to aid diagnosis of DLB, and to potentially identify novel therapeutic targets.
Repeated short-term exposure to diesel exhaust reduces honey bee colony fitness
Reitmayer CM, Girling RD, Jackson CW and Newman TA
Repeated short-term exposure to diesel exhaust reduces honey bee colony fitness
Reitmayer CM, Girling RD, Jackson CW and Newman TA
Production of insect-pollinated crops is often reliant on honey bee (Apis mellifera) pollination services. Colonies can be managed and moved to meet the demands of modern intensified monoculture farming systems. Increased colony mortalities have been observed, which are thought be caused by interacting factors including exposure to pesticides, parasites, viruses, agricultural intensification, and changes in global and regional climate. However, whilst common tropospheric air pollutants (e.g. NO, particulate matter etc) are known to cause a range of negative effects on human health, there is little evidence of their impact on the health of A. mellifera. This study investigates the effects of exposure to diesel exhaust on A. mellifera, both at the level of individual foragers and on the whole colony. We exposed a series of colonies to diesel exhaust fumes for 2Â h a day over the course of three weeks and contrasted their performance to a series of paired control colonies located at the same field site. We investigated markers of neuronal health in the brains of individual foragers and measured the prevalence of common viruses. Electronic counters monitored daily colony activity patterns and pollen samples from returning foragers were analysed to investigate plant species richness and diversity. The amounts of honey, brood and pollen in each colony were measured regularly. We demonstrated an upregulation of the synapse protein Neurexin 1 in forager brains repeatedly exposed to diesel exhaust. Furthermore, we found that colonies exposed to diesel exhaust lost colony weight after the exposure period until the end of the summer season, whereas control colonies gained weight towards the end of the season. Further investigations are required, but we hypothesise that such effects on both individual foragers and whole colony fitness parameters could ultimately contribute to winter losses of honey bee colonies, particularly in the presence of additional stressors.
Antibiotic-Loaded Polymersomes for Clearance of Intracellular
Porges E, Jenner D, Taylor AW, Harrison JSP, De Grazia A, Hailes AR, Wright KM, Whelan AO, Norville IH, Prior JL, Mahajan S, Rowland CA, Newman TA and Evans ND
Antibiotic-Loaded Polymersomes for Clearance of Intracellular
Porges E, Jenner D, Taylor AW, Harrison JSP, De Grazia A, Hailes AR, Wright KM, Whelan AO, Norville IH, Prior JL, Mahajan S, Rowland CA, Newman TA and Evans ND
Melioidosis caused by the facultative intracellular pathogen is difficult to treat due to poor intracellular bioavailability of antibiotics and antibiotic resistance. In the absence of novel compounds, polymersome (PM) encapsulation may increase the efficacy of existing antibiotics and reduce antibiotic resistance by promoting targeted, infection-specific intracellular uptake. In this study, we developed PMs composed of widely available poly(ethylene oxide)-polycaprolactone block copolymers and demonstrated their delivery to intracellular infection using multispectral imaging flow cytometry (IFC) and coherent anti-Stokes Raman scattering microscopy. Antibiotics were tightly sequestered in PMs and did not inhibit the growth of free-living . However, on uptake of antibiotic-loaded PMs by infected macrophages, IFC demonstrated PM colocalization with intracellular and a significant inhibition of their growth. We conclude that PMs are a viable approach for the targeted antibiotic treatment of persistent intracellular infection.
Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration
Chouhan JK, Püntener U, Booth SG and Teeling JL
Systemic Inflammation Accelerates Changes in Microglial and Synaptic Markers in an Experimental Model of Chronic Neurodegeneration
Chouhan JK, Püntener U, Booth SG and Teeling JL
Bacterial infections are a common cause of morbidity and mortality in the elderly, and particularly in individuals with a neurodegenerative disease. Experimental models of neurodegeneration have shown that LPS-induced systemic inflammation increases neuronal damage, a process thought to be mediated by activation of "primed" microglia. The effects of a real systemic bacterial infection on the innate immune cells in the brain and neuronal networks are less well described, and therefore, in this study we use the ME7 prion model to investigate the alterations in microglia activation and phenotype and synaptic markers in response to a low grade, live bacterial infection. Mice with or without a pre-existing ME7 prion-induced neurodegenerative disease were given a single systemic injection of live at early or mid-stage of disease progression. Immune activation markers CD11b and MHCII and pro-inflammatory cytokines were analyzed 4 weeks post-infection. Systemic infection with resulted in an exaggerated inflammatory response when compared to ME7 prion mice treated with saline. These changes to inflammatory markers were most pronounced at mid-stage disease. Analysis of synaptic markers in ME7 prion mice revealed a significant reduction of genes that are associated with early response in synaptic plasticity, extracellular matrix structure and post-synaptic density, but no further reduction following systemic infection. In contrast, analysis of activity-related neuronal receptors involved in development of learning and memory, such as and , showed a significant decrease in response to systemic bacterial challenge. These changes were observed early in the disease progression and associated with reduced burrowing activity. The exaggerated innate immune activation and altered expression of genes linked to synaptic plasticity may contribute to the onset and/or progression of neurodegeneration.
Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort
Michopoulou S, Prosser A, Kipps C, Dickson J, Guy M and Teeling J
Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort
Michopoulou S, Prosser A, Kipps C, Dickson J, Guy M and Teeling J
Neuroinflammation is an integral part of Alzheimer's disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-β (Aβ), the propagation of tau pathology and neuronal loss.
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease
Michopoulou S, Prosser A, Dickson J, Guy M, Teeling JL and Kipps C
Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease
Michopoulou S, Prosser A, Dickson J, Guy M, Teeling JL and Kipps C
Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis.
Tau-mediated axonal degeneration is prevented by activation of the Wld pathway
Stubbs K, Batchelor B, Sivanantharajah L, Sealey M, Ramirez-Moreno M, Ruiz E, Richardson B, Perry VH, Newman TA and Mudher A
Tau-mediated axonal degeneration is prevented by activation of the Wld pathway
Stubbs K, Batchelor B, Sivanantharajah L, Sealey M, Ramirez-Moreno M, Ruiz E, Richardson B, Perry VH, Newman TA and Mudher A
Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (Wld) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of Wld. In a model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, Wld was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of Wld completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of Wld was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, Wld expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of Wld intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.