Now showing items 1-20 of 176

    • Right cardiac chambers echo-bubble contrast in a patient with decompression sickness: A case report and a literature review

      Harfoush, Allam; Ramadan, Mohammad; Hamdallah, Hanady; Tishreen University Hospital; University of Chester (Wiley Open Access, 2022-04-14)
      Background: so far there is no available modality to fully confirm the diagnosis, however, the application of echocardiography in suspected DCS cases has been more frequently used, in this case, transthoracic echocardiography (TTE) was used to detect micro-bubbles in the right cardiac chambers and monitor the patient after hyperbaric oxygen therapy (HBOT); which proposes the possible applicability of TTE in diagnosing and monitoring DCS patients. Case presentation: This report describes a 54-year-old fisherman who was referred to the emergency department with dyspnea and mild confusion after rapid ascend of a saturation diving of 50m sea depth. After the initial evaluation, he was assessed using TTE to exclude the presence of structural heart diseases, where it surprisingly showed spontaneous echo contrast inside the right cardiac chambers similar to agitated saline echo testing, the patient then was admitted for HBOT and follow-up; rapid improvement was noticed after the first HBOT session and the TTE findings were fully resolved. Conclusion: TTE could be considered in the initial workup when DCS is suspected, and it might have a role in monitoring DCS patients if echocardiographic findings of bubbles formation were documented in the pre-hyperbaric therapy settings.
    • The Effect of Exercise Training Intensity on VO2max in Healthy Adults: An Overview of Systematic Reviews and Meta-Analyses

      Crowley, Emmet; Powell, Cormac; Carson, Brian P.; Davies, Robert W.; University of Limerick; Sport Ireland National Sports Campus; University of Chester (Hindawi, 2022-02-24)
      This study aimed to evaluate systematic reviews and meta-analyses that have examined the effect of exercise training on VO2max in healthy individuals at different intensities. Five databases were searched: EBSCOhost, MEDLINE/PubMed, SPORTDiscus, Web of Science, and Google Scholar. Eligibility criteria for selecting reviews included systematic reviews and meta-analyses of healthy adults that examined the effect of lower intensity training (LIT) and/or high intensity training (HIT) on VO2max. Eleven reviews met the eligibility criteria. All reviews were of moderate-to-very strong methodological quality. The included reviews reported data from 179 primary studies with an average of 23 ± 10 studies per review. All reviews included in this overview showed that exercise training robustly increased VO2max at all intensities. Three meta-analyses that compared LIT versus HIT protocols on VO2max reported small/moderate beneficial effects for HIT over LIT; however, the beneficial effects of HIT on VO2max appear to be moderated by training variables other than intensity (e.g., training impulse, interval length, training volume, and duration) and participants’ baseline characteristics (e.g., age and fitness levels). Overall, evidence from this overview suggests that the apparent differences between LIT and HIT protocols on VO2max were either small, trivial, or inconclusive, with several methodological considerations required to standardise research designs and draw definitive conclusions.
    • Time to Load Up–Resistance Training Can Improve the Health of Women with Polycystic Ovary Syndrome (PCOS): A Scoping Review

      Kite, Chris; Parkes, Elizabeth; Taylor, Suzan R.; Davies, Robert W.; Lagojda, Lukasz; Brown, James E.; Broom, David R.; Kyrou, Ioannis; Randeva, Harpal S.; University of Wolverhampton; University Hospitals Coventry and Warwickshire NHS Trust; Coventry University; University of Chester; Aston University; University of Warwick; Agricultural University of Athens (MDPI, 2022-09-22)
      Background: Guidelines for the management of polycystic ovary syndrome (PCOS) focus on lifestyle changes, incorporating exercise. Whilst evidence suggests that aerobic exercise may be beneficial, less is known about the effectiveness of resistance training (RT), which may be more feasible for those that have low fitness levels and/or are unable to tolerate/participate in aerobic exercise. Objectives: To identify the available evidence on RT in women with PCOS and to summarise findings in the context of a scoping review. Eligibility criteria: Studies utilising pre-post designs to assess the effectiveness of RT in PCOS; all outcomes were included. Sources of evidence: Four databases (PubMed, CENTRAL, CINAHL and SportDiscus) were searched and supplemented by hand searching of relevant papers/reference lists. Charting methods: Extracted data were presented in tables and qualitatively synthesised. Results: Searches returned 42 papers; of those, 12 papers were included, relating to six studies/trials. Statistical changes were reported for multiple pertinent outcomes relating to metabolic (i.e., glycaemia and fat-free mass) and hormonal (i.e., testosterone and sex hormone-binding globulin) profiles. Conclusions: There is a striking lack of studies in this field and, despite the reported statistical significance for many outcomes, the documented magnitude of changes are small and the quality of the evidence questionable. This highlights an unmet need for rigorously designed/reported and sufficiently powered trials.
    • The Effect of Fava Bean (Vicia faba L.) Protein Ingestion on Myofibrillar Protein Synthesis at Rest and after Resistance Exercise in Healthy, Young Men and Women: A Randomised Control Trial

      Davies, Robert W.; Kozior, Marta; Lynch, Arthur E.; Bass, Joseph J.; Atherton, Philip J.; Smith, Ken; Jakeman, Philip M.; University of Chester (MDPI, 2022-09-06)
      The aim of the present study was to evaluate the effect of feeding fava bean (Vicia faba L.) protein (FBP) on resting and post-exercise myofibrillar fractional synthetic rate (myoFSR). In a parallel, double-blind, randomised control trial, sixteen young, healthy recreationally active adults (age = 25 (5) years, body mass = 70 (15) kg, stature = 1.72 (0.11) m, mean (SD)) ingested 0.33 g·kg−1 FBP (n = 8) or a negative control (CON, i.e., EAA-free mixture) (n = 8), immediately after a bout of unilateral knee-extensor resistance exercise. Plasma, saliva, and m. vastus lateralis muscle samples were obtained pre-ingestion and 3 h post-ingestion. MyoFSR was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography–pyrolysis–isotope ratio mass spectrometry (GC-Pyr-IRMS). Resistance exercise increased myoFSR (p = 0.012). However, ingestion of FBP did not evoke an increase in resting (FBP 29 [−5, 63] vs. CON 12 [−25, 49]%, p = 0.409, mean % change [95% CI]) or post-exercise (FBP 78 [33, 123]% vs. CON 58 [9, 107]%, p = 0.732) myoFSR. Ingestion of 0.33 g·kg−1 of FBP does not appear to enhance resting or post-exercise myoFSR in young, healthy, recreationally active adults.
    • Global prevalence of adaptive and prolonged infections’ muta-tions in the receptor-binding domain of the SARS-CoV-2 spike protein

      Lennerstrand, Johan; Palanisamy, Navaneethan; Uppsala University; University of Chester (MDPI, 2021-09-30)
      Several vaccines with varying efficacies have been developed and are currently administered globally to minimize the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite having an RNA-dependent RNA polymerase with a proofreading activity, new variants of SARS-CoV-2 are on the rise periodically. Some of the mutations in these variants, especially mutations on the spike protein, aids the virus in transmission, infectivity and host immune evasion. Further, these mutations also reduce the effectiveness of some of the current vaccines and monoclonal antibodies (mAbs). In the present study, using the available 984,769 SARS-CoV-2 nucleotide sequences on the NCBI database from the end of 2019 till 28 July 2021, we have estimated the global prevalence of so-called ‘adaptive mutations’ and ‘mutations identified in the prolonged infections’, in the receptor-binding domain (RBD) of the spike (S) protein. Irrespective of the geographical regions, in the case of the adaptive mutations, N501Y (48.38 %) was found to be the dominant mutation followed by L452R (17.52 %), T478K (14.31 %), E484K (4.69 %), S477N (3.29 %), K417T (1.64 %), N439K (0.7 %) and S494P (0.7 %). Other mutations were found to be less prevalent (less than 0.7 %). Since the last two months, there has been a massive increase of L452R and T478K mutations (delta variant) in certain areas. In the case of prolonged infections’ mutations (long-term SARS-CoV-2 infections), V483A (0.009 %) was found to be dominant followed by Q493R (0.009 %), while other mutations were found in less than 0.007 % of the studied sequences. The data obtained in this study will aid in the development of better infection control policies thereby curbing the spread of this virus.
    • SARS-CoV-2 variants of concern and Spike protein mutational dynamics in a Swedish cohort during 2021, studied by Nanopore sequencing

      Mannsverk, Steinar; Bergholm, Julia; Palanisamy, Navaneethan; Ellström, Patrik; Kaden, René; Lindh, Johan; Lennerstrand, Johan; Uppsala University; University of Chester (BMC, 2022-10-18)
      Background: Since the beginning of the COVID-19 pandemic, new variants of significance to public health have emerged. Consequently, early detection of new mutations and variants through whole-genome sequencing remains crucial to assist health officials in employing appropriate public health measures. Methods: We utilized the ARTIC Network SARS-CoV-2 tiled amplicon approach and Nanopore sequencing to sequence 4,674 COVID-19 positive patient samples from Uppsala County, Sweden, between week 15 and 52 in 2021. Using this data, we mapped the circulating variants of concern (VOC) in the county over time and analysed the Spike (S) protein mutational dynamics in the Delta variant throughout 2021. Results: The distribution of the SARS-CoV-2 VOC matched the national VOC distribution in Sweden, in 2021. In the S protein of the Delta variant, we detected mutations attributable to variants under monitoring and variants of interest (e.g., E484Q, Q613H, Q677H, A222V and Y145H) and future VOC (e.g., T95I and Y144 deletion, which are signature mutations in the Omicron variant). We also frequently detected some less well-described S protein mutations in our Delta sequences, that might play a role in shaping future emerging variants. These include A262S, Q675K, I850L, Q1201H, V1228L and M1237I. Lastly, we observed that some of the Delta variant’s signature mutations were underrepresented in our study due to artifacts of the used bioinformatics tools, approach and sequencing method. We therefore discuss some pitfalls and considerations when sequencing SARS-CoV-2 genomes. Conclusions: Our results suggest that genomic surveillance in a small, representative cohort can be used to make predictions about the circulating variants nationally. Moreover, we show that detection of transient mutations in currently circulating variants can give valuable clues to signature mutations of future VOC. Here we suggest six such mutations, that we detected frequently in the Delta variant during 2021. Lastly, we report multiple systematic errors that occurred when following the ARTIC Network SARS-CoV-2 tiled amplicon approach using the V3 primers and Nanopore sequencing, which led to the masking of some of the important signature mutations in the Delta sequences.
    • Screening for Mental Illness using GMHAT App of patients with Type 2 Diabetes Mellitus at a tertiary care hospital in India – A cross sectional study

      Majgi, Sumanth M.; Mal, Nihar M.; Krishna, Murali; Ebuenyi, Ikenna D.; Jones, Steven; Mysore Medical College and Research Institute; JSS Medical College, Mysore; University of Bangor; University College Dublin; University of Chester (Medknow Publications, 2022-10-31)
      People with diabetes will have some coexisting mental illness most of the time and its evaluation and management are essential for the well‑being of the person. With this background, the Global Mental Health Assessment Tool (GMHAT) app was used to screen for mental illness among type 2 diabetes mellitus patients in Mysore, India. Methods: A cross‑sectional study was conducted on 100 patients who were on treatment for type 2 diabetes for at least 6 months. Interviews were conducted using a structured GMHAT. Results: The mean age of the study participants was 48.8 ± 11.6 years. Among the 100 diabetic patients, 39% (n = 39) had mental illness and among the 39 subjects, 21% had depression, 14% had anxiety disorder and 4% suffered from organic disorder. Apart from diabetes, 29, 17, 13, 27, 23 and 20% had hypertension, chronic kidney disease, liver disease, retinopathy, neuropathy and nephropathy, respectively, as comorbid conditions. Conclusion: There is a higher prevalence of mental illness in patients with diabetes mellitus. The prevalence rate increases with an increase in the chronicity of diabetes. The use of the GMHAT app will help in rapid assessment and accurate diagnoses
    • Postnatal Protein Intake as a Determinant of Skeletal Muscle Structure and Function in Mice-A Pilot Study

      Giakoumaki, Ifigeneia; Pollock, Natalie; Aljuaid, Turki; Sannicandro, Anthony J.; Alameddine, Moussira; Owen, Euan; Myrtziou, Ioanna; Ozanne, Susan E.; Kanakis, Ioannis; Goljanek-Whysall, Katarzyna; et al. (MDPI, 2022-08-08)
      Sarcopenia is characterised by an age-related decrease in the number of muscle fibres and additional weakening of the remaining fibres, resulting in a reduction in muscle mass and function. Many studies associate poor maternal nutrition during gestation and/or lactation with altered skeletal muscle homeostasis in the offspring and the development of sarcopenia. The aim of this study was to determine whether the musculoskeletal physiology in offspring born to mouse dams fed a low-protein diet during pregnancy was altered and whether any physiological changes could be modulated by the nutritional protein content in early postnatal stages. Thy1-YFP female mice were fed ad libitum on either a normal (20%) or a low-protein (5%) diet. Newborn pups were cross-fostered to different lactating dams (maintained on a 20% or 5% diet) to generate three groups analysed at weaning (21 days): Normal-to-Normal (NN), Normal-to-Low (NL) and Low-to-Normal (LN). Further offspring were maintained ad libitum on the same diet as during lactation until 12 weeks of age, creating another three groups (NNN, NLL, LNN). Mice on a low protein diet postnatally (NL, NLL) exhibited a significant reduction in body and muscle weight persisting up to 12 weeks, unlike mice on a low protein diet only prenatally (LN, LNN). Muscle fibre size was reduced in mice from the NL but not LN group, showing recovery at 12 weeks of age. Muscle force was reduced in NLL mice, concomitant with changes in the NMJ site and changes in atrophy-related and myosin genes. In addition, μCT scans of mouse tibiae at 12 weeks of age revealed changes in bone mass and morphology, resulting in a higher bone mass in the NLL group than the control NNN group. Finally, changes in the expression of miR-133 in the muscle of NLL mice suggest a regulatory role for this microRNA in muscle development in response to postnatal diet changes. Overall, this data shows that a low maternal protein diet and early postnatal life low-protein intake in mice can impact skeletal muscle physiology and function in early life while postnatal low protein diet favours bone integrity in adulthood.
    • Small-RNA Sequencing Reveals Altered Skeletal Muscle microRNAs and snoRNAs Signatures in Weanling Male Offspring from Mouse Dams Fed a Low Protein Diet during Lactation

      Kanakis, Ioannis; Alameddine, Moussira; Folkes, Leighton; Moxon, Simon; Myrtziou, Ioanna; Ozanne, Susan E.; Peffers, Mandy J.; Goljanek-Whysall, Katarzyna; Vasilaki, Aphrodite; University of Liverpool; University of Chester; University of East Anglia; University of Cambridge; NUI Galway (MDPI, 2021-05-11)
      Maternal diet during gestation and lactation affects the development of skeletal muscles in offspring and determines muscle health in later life. In this paper, we describe the association between maternal low protein diet-induced changes in offspring skeletal muscle and the differential expression (DE) of small non-coding RNAs (sncRNAs). We used a mouse model of maternal protein restriction, where dams were fed either a normal (N, 20%) or a low protein (L, 8%) diet during gestation and newborns were cross-fostered to N or L lactating dams, resulting in the generation of NN, NL and LN offspring groups. Total body and tibialis anterior (TA) weights were decreased in weanling NL male offspring but were not different in the LN group, as compared to NN. However, histological evaluation of TA muscle revealed reduced muscle fibre size in both groups at weaning. Small RNA-sequencing demonstrated DE of multiple miRs, snoRNAs and snRNAs. Bioinformatic analyses of miRs-15a, -34a, -122 and -199a, in combination with known myomiRs, confirmed their implication in key muscle-specific biological processes. This is the first comprehensive report for the DE of sncRNAs in nutrition-associated programming of skeletal muscle development, highlighting the need for further research to unravel the detailed molecular mechanisms.
    • MicroRNAs as central regulators of adult myogenesis and proteostasis loss in skeletal muscle ageing

      Kanakis, Ioannis; Myrtziou, Ioanna; Goljanek-Whysall, Katarzyna; Vasilaki, Aphrodite; University of Liverpool; University of Chester; NUI Galway (CRC Press, 2021-11-23)
      Sarcopenia (from the Greek words sarca (σάρκα) = flesh and penia (πενία) = deficiency) is considered as an age-associated disease, characterized by dysregulation of the balance between muscle hypertrophy, atrophy and regeneration, which leads to advanced loss of skeletal muscle mass and function associated with a high risk of falls and fractures in the elderly. Numerous studies in humans and animals have explored the pathophysiology of musculoskeletal aging but the detailed mechanisms that contribute to skeletal muscle dysfunction have not been yet fully elucidated. Recently, several studies have focused on the role of microRNAs as a dynamic and promising epigenetic mechanism which may regulate post-transcriptional gene expression that modulate skeletal muscle homeostasis. In this chapter, we describe the crucial role of microRNAs in skeletal myogenesis during adulthood and their association with the pathogenesis of sarcopenia linked to proteostasis loss.
    • Age-related changes in microRNAs expression in cruciate ligaments of wild-stock house mice

      Nye, Gareth; Kharaz, Yalda; Goljanek‐Whysall, Katarzyna; Hurst, Jane; McArdle, Anne; Comerford, Eithne; University of Chester; University of Liverpool
      Cruciate ligaments (CL) of the knee joint are injured following trauma or aging. MicroRNAs (miRs) are potential therapeutic targets in musculoskeletal disorders, but there is little known about the role of miRs and their expression ligaments during aging. This study aimed to (1) identify if mice with normal physical activity, wild-stock house mice are an appropriate model to study age-related changes in the knee joint and (2) investigate the expression of miRs in aging murine cruciate ligaments. Knee joints were collected from 6 and 24 months old C57BL/6 and wild-stock house mice (Mus musculus domesticus) for ligament and cartilage (OARSI) histological analysis. Expression of miR targets in CLs was determined in 6-, 12-, 24-, and 30-month-old wild-stock house mice, followed by the analysis of predicted mRNA target genes and Ingenuity Pathway Analysis. Higher CL and knee OARSI histological scores were found in 24-month-old wild-stock house mice compared with 6- and 24-month-old C57BL/6 and 6-month-old wild-stock house mice (p < 0.05). miR-29a and miR-34a were upregulated in 30-month-old wild-stock house mice in comparison with 6-, 12-, and 24-month-old wild-stock house mice (p < 0.05). Ingenuity Pathway Analysis on miR-29a and 34a targets was associated with inflammation through interleukins, TGFβ and Notch genes, and p53 signaling. Collagen type I alpha 1 chain (COL1A1) correlated negatively with both miR-29a (r = −0.35) and miR-34a (r = −0.33). The findings of this study support wild-stock house mice as an appropriate aging model for the murine knee joint. This study also indicated that miR-29a and miR-34a may be potential regulators of COL1A1 gene expression in murine CLs.
    • Chapter 5: Applying Proteomics to Investigate Extracellular Matrix in Health and Disease

      Randles, Michael; Lennon, Rachel; University of Manchester; Manchester Academic Health Science Centre (Academic Press, 2015-11-23)
      The molecular composition of basement membranes (BMs) has traditionally been investigated by candidate-based approaches leading to the identification of key structural components as described in previous chapters. Laminins, collagen IV, nidogens, perlecan, and type XV/XVIII collagen are integral to BMs with isoforms showing tissue specificity. More recently the application of mass spectrometry (MS)-based proteomics has led to the discovery of many more structural and regulatory components of BMs and more broadly, extracellular matrix (ECM). These investigations have revealed tissue-specific signatures of between 100 and 150 ECM components, demonstrating the complexity of the extracellular niche. In addition to providing a structural scaffold for cells, ECM is a dynamic extracellular environment capable of regulating the physical properties of tissues. Global investigations of ECM with proteomics in turn enable systems level analyses and when applied to health and disease states these investigations provide insights into pathways regulating matrix dysregulation. This chapter focuses on the methods used to extract ECM and on the analysis of its composition using MS-based proteomics, and it provides examples of how these approaches have been used to investigate health and disease states.
    • Lrig2 and Hpse2, mutated in urofacial syndrome, pattern nerves in the urinary bladder

      Roberts, Neil A.; Hilton, Emma N.; Lopes, Filipa M.; Singh, Subir; Randles, Michael J.; Gardiner, Natalie J.; Chopra, Karl; Coletta, Riccardo; Bajwa, Zunera; Hall, Robert J.; et al. (Elsevier, 2019-03-08)
      Mutations in leucine-rich-repeats and immunoglobulin-like-domains 2 (LRIG2) or in heparanase 2 (HPSE2) cause urofacial syndrome, a devastating autosomal recessive disease of functional bladder outlet obstruction. It has been speculated that urofacial syndrome has a neural basis, but it is unknown whether defects in urinary bladder innervation are present. We hypothesized that urofacial syndrome features a peripheral neuropathy of the bladder. Mice with homozygous targeted Lrig2 mutations had urinary defects resembling those found in urofacial syndrome. There was no anatomical blockage of the outflow tract, consistent with a functional bladder outlet obstruction. Transcriptome analysis revealed differential expression of 12 known transcripts in addition to Lrig2, including 8 with established roles in neurobiology. Mice with homozygous mutations in either Lrig2 or Hpse2 had increased nerve density within the body of the urinary bladder and decreased nerve density around the urinary outflow tract. In a sample of 155 children with chronic kidney disease and urinary symptoms, we discovered novel homozygous missense LRIG2 variants that were predicted to be pathogenic in 2 individuals with non-syndromic bladder outlet obstruction. These observations provide evidence that a peripheral neuropathy is central to the pathobiology of functional bladder outlet obstruction in urofacial syndrome, and emphasize the importance of LRIG2 and heparanase 2 for nerve patterning in the urinary tract.
    • Identification of an Altered Matrix Signature in Kidney Aging and Disease

      Randles, Michael; Lausecker, Franziska; Kong, Qingyang; Suleiman, Hani; Reid, Graeme; Kolatsi-Joannou, Maria; Davenport, Bernard; Tian, Pinyuan; Falcone, Sara; Potter, Paul; et al. (American Society of Nephrology, 2021-06-30)
      Background: Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Although histologic and ultrastructural patterns of excess matrix form the basis of human disease classifications, a comprehensive molecular resolution of abnormal matrix is lacking. Methods: Using mass spectrometry–based proteomics, we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidney matrix during aging and to existing kidney disease datasets to identify common molecular features. Results: Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, and XV; fibrinogens; and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons, and the increase in interstitial matrix was also observed in human kidney disease datasets. Conclusions: This study provides deep molecular resolution of matrix accumulation in kidney aging and disease, and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.
    • Basement membrane ligands initiate distinct signalling networks to direct cell shape

      Randles, Michael; Lausecker, Franziska; Humphries, Jonathan D.; Byron, Adam; Clark, Simon J.; Miner, Jeffrey H.; Zent, Roy; Humphries, Martin J.; Lennon, Rachel; The University of Manchester; University of Edinburgh; Eberhard Karls University of Tübingen; Washington University School of Medicine; Vanderbilt University Medical Center; Royal Manchester Children's Hospital; Manchester Academic Health Science Centre; University of Chester (Elsevier, 2020-03-06)
      Cells have evolved mechanisms to sense the composition of their adhesive microenvironment. Although much is known about general mechanisms employed by adhesion receptors to relay signals between the extracellular environment and the cytoskeleton, the nuances of ligand-specific signalling remain undefined. Here, we investigated how glomerular podocytes, and four other basement membrane-associated cell types, respond morphologically to different basement membrane ligands. We defined the composition of the respective adhesion complexes using mass spectrometry-based proteomics. On type IV collagen, all epithelial cell types adopted a round morphology, with a single lamellipodium and large adhesion complexes rich in actin-binding proteins. On laminin (511 or 521), all cell types attached to a similar degree but were polygonal in shape with small adhesion complexes enriched in endocytic and microtubule-binding proteins. Consistent with their distinctive morphologies, cells on type IV collagen exhibited high Rac1 activity, while those on laminin had elevated PKCa. Perturbation of PKCa was able to interchange morphology consistent with a key role for this pathway in matrix ligand-specific signalling. Therefore, this study defines the switchable basement membrane adhesome and highlights two key signalling pathways within the systems that determine distinct cell morphologies. Proteomic data are available via ProteomeXchange with identifier PXD017913.
    • A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background

      Falcone, Sara; Nicol, Thomas; Blease, Andrew; Randles, Michael J.; Angus, Elizabeth; Page, Anton; Tam, Frederick W. K.; Pusey, Charles D.; Lennon, Rachel; Potter, Paul K.; et al. (Elsevier, 2021-11-10)
      Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminaemia, edema and hyperlipidaemia. Genetic studies of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signaling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is essential for embryonic development and, in association with laminin β2 and laminin γ1, is a major component of the glomerular basement membrane, a critical component of the glomerular filtration barrier. Mutations in LAMA5 were recently identified in children with nephrotic syndrome. Here, we have identified a novel missense mutation (E884G) in the uncharacterized L4a domain of LAMA5 where homozygous mice develop nephrotic syndrome with severe proteinuria with histological and ultrastructural changes in the glomerulus mimicking the progression seen in most patients. The levels of LAMA5 are reduced in vivo and the assembly of the laminin 521 heterotrimer significantly reduced in vitro. Proteomic analysis of the glomerular extracellular fraction revealed changes in the matrix composition. Importantly, the genetic background of the mice had a significant effect on aspects of disease progression from proteinuria to changes in podocyte morphology. Thus, our novel model will provide insights into pathologic mechanisms of nephrotic syndrome and pathways that influence the response to a dysfunctional glomerular basement membrane that may be important in a range of kidney diseases.
    • The kidney matrisome in health, aging and disease

      Lausecker, Franziska; Lennon, Rachel; Randles, Michael J.; The University of Manchester; University of Chester (Elsevier, 2022-07-20)
      Dysregulated extracellular matrix is the hallmark of fibrosis, and it has a profound impact on kidney function in disease. Furthermore, perturbation of matrix homeostasis is a feature of aging and is associated with declining kidney function. Understanding these dynamic processes, in the hope of developing therapies to combat matrix dysregulation, requires the integration of data acquired by both well-established and novel technologies. Owing to its complexity, the extracellular proteome, or matrisome, still holds many secrets and has great potential for the identification of clinical biomarkers and drug targets. The molecular resolution of matrix composition during aging and disease has been illuminated by cutting-edge mass spectrometry-based proteomics in recent years, but there remain key questions about the mechanisms that drive altered matrix composition. Basement membrane components are particularly important in the context of kidney function; and data from proteomic studies suggest that switches between basement membrane and interstitial matrix proteins are likely to contribute to organ dysfunction during aging and disease. Understanding the impact of such changes on physical properties of the matrix, and the subsequent cellular response to altered stiffness and viscoelasticity, is of critical importance. Likewise, the comparison of proteomic datasets from multiple organs is required to identify common matrix biomarkers and shared pathways for therapeutic intervention. Coupled with single cell transcriptomics there is the potential to identify the cellular origin of matrix changes, which could enable cell targeted therapy. This review provides a contemporary perspective of the complex kidney matrisome and draws comparison to altered matrix in heart and liver disease.
    • Intellectual disability and autism in adults influence psychological treatments for mental health conditions

      Mills, Rachel; Soper, Paul; Michelet, Felix; Stewart, Alex; Jaydeokar, Sujeet; University of Chester
      Mental health conditions are often underdiagnosed in adults with intellectual disability and do not always receive psychological interventions as recommended by the National Institute for Health and Care Excellent guidelines. To realise the national UK programme’s aim of stopping overuse of medications in people with intellectual disability, it is important that these individuals have access to appropriate non-pharmacological interventions. We examined the relationship between an individual’s level of intellectual disability and presence or absence of autism with access to relevant non-pharmacological interventions from specialist community intellectual disability services. A cross-sectional study of adults accessing four specialist intellectual disability services in North West England in 2019. There was high prevalence of mental health co-morbidity, even higher for autistic adults. However, a relatively small percentage of the study population were receiving psychological interventions. The most frequent non-pharmacological intervention was positive behaviour support plan, irrespective of comorbid mental illnesses. Not having access to psychological interventions for the treatment of mental illness could result in poor health outcomes and increasing health inequalities. The study highlights the need for developing psychological interventions particularly for those with moderate to severe intellectual disability and for those with associated autism. This large sample study examined the relationship between intellectual disability level and presence of autism with accessing psychological interventions.
    • Co-production of post-diagnostic psychosocial interventions with carers of people with intellectual disability and dementia

      Acton, Daniel; Duncan, Caroline; Jaydeokar, Sujeet; Cheshire and Wirral Partnership NHS Foundation Trust; University of Chester (Emerald, 2022-04-21)
      This paper aims to underline the importance of using a collaborative approach when designing and adapting a post diagnostic psychosocial intervention of cognitive stimulation therapy (CST) for people with intellectual disability and dementia. As part of a service improvement, a manual of CST was adapted, for delivery in clinical practice. A qualitative co-production method allowed participants with a lived experience to provide regular feedback relating to the development of the adapted CST manual and intervention programme. This feedback was used to make continual development changes to the CST manual. The study demonstrated co-production with those who provide care is valuable in adapting psychosocial therapies for people with an intellectual disability and dementia. Additional findings identified the need for carer education in ageing, dementia care, and the physical health needs for older people with intellectual disability. This is the first study that has used a co-production approach with families and carers in adapting a group therapy programme for people with an intellectual disability. This paper underlines the need for post diagnostic clinical interventions for people with dementia and those who provide care.
    • Baba Vefatından Sonra Çocukların İyi Oluşu: Anne Görüşlerine Dayalı Nitel Bir Analiz

      ÖZDEMİR, Münevver; ERUYAR, Şeyda; YAZICI, Hikmet; VOSTANIS, Panos (Ayna Klinik Psikoloji Dergisi, 2022-04-19)
      Death of a parent has well-established adverse effects on the child’s well-being. The surviving parent is often the most important source of support for the child and a close witness of the child bereavement process. The aim of this study was to understand the perceived effects of paternal bereavement on children’s mental health and coping strategies through their mothers’ narratives. Adopting qualitative research methods, semi-structured interviews were conducted with nine mothers who had lost their spouses. Thematic analysis revealed three themes: negative effects on mental health, posttraumatic growth, and coping strategies. The findings indicated that the consequences of paternal loss are not limited to negative effects on children’s functioning, as they may also experience positive changes following the loss. Mothers noticed that their children overcame paternal death successfully by using coping strategies such as discovering new activities, religion, and social support. Grief-response and resilience-enhancing strategies should be tailored to the emotional needs of each family.