• Keto-on-the-Clock: A Survey of Dietetic Care Contact Time Taken to Provide Ketogenic Diets for Drug-Resistant Epilepsy in the UK

      Lambert, Bridget; email: bridgetlambert@vitaflo.co.uk; Lightfoot, Kathryn; email: kathryn.lightfoot@nhs.net; Meskell, Rachel; email: r.meskell@nhs.net; Whiteley, Victoria J.; email: victoria.whiteley@mft.nhs.uk; Martin-McGill, Kirsty J.; email: k.martinmcgill@chester.ac.uk; Schoeler, Natasha E.; orcid: 0000-0001-6202-1497; email: n.schoeler@ucl.ac.uk (MDPI, 2021-07-21)
      Medical ketogenic diets (KDs) are effective yet resource-intensive treatment options for drug-resistant epilepsy (DRE). We investigated dietetic care contact time, as no recent data exist. An online survey was circulated to ketogenic dietitians in the UK and Ireland. Data were collected considering feeding route, KD variant and type of ketogenic enteral feed (KEF), and the estimated number of hours spent on patient-related activities during the patient journey. Fifteen dietitians representing nine KD centres responded. Of 335 patients, 267 (80%) were 18 years old or under. Dietitians spent a median of 162 h (IQR 54) of care contact time per patient of which a median of 48% (IQR 6) was direct contact. Most time was required for the classical KD taken orally (median 193 h; IQR 213) as a combined tube and oral intake (median 211 h; IQR 172) or a blended food KEF (median 189 h; IQR 148). Care contact time per month was higher for all KDs during the three-month initial trial compared to the two-year follow-up stage. Patients and caregivers with characteristics such as learning or language difficulties were identified as taking longer. Twelve out of fifteen (80%) respondents managed patients following the KD for more than two years, requiring an estimated median contact care time of 2 h (IQR 2) per patient per month. Ten out of fifteen (67%) reported insufficient official hours for dietetic activities. Our small survey gives insight into estimated dietetic care contact time, with potential application for KD provision and service delivery
    • Keto-on-the-Clock: A Survey of Dietetic Care Contact Time Taken to Provide Ketogenic Diets for Drug-Resistant Epilepsy in the UK.

      Lambert, Bridget; Lightfoot, Kathryn; Meskell, Rachel; Whiteley, Victoria J; Martin-McGill, Kirsty J; Schoeler, Natasha E; orcid: 0000-0001-6202-1497 (2021-07-21)
      Medical ketogenic diets (KDs) are effective yet resource-intensive treatment options for drug-resistant epilepsy (DRE). We investigated dietetic care contact time, as no recent data exist. An online survey was circulated to ketogenic dietitians in the UK and Ireland. Data were collected considering feeding route, KD variant and type of ketogenic enteral feed (KEF), and the estimated number of hours spent on patient-related activities during the patient journey. Fifteen dietitians representing nine KD centres responded. Of 335 patients, 267 (80%) were 18 years old or under. Dietitians spent a median of 162 h (IQR 54) of care contact time per patient of which a median of 48% (IQR 6) was direct contact. Most time was required for the classical KD taken orally (median 193 h; IQR 213) as a combined tube and oral intake (median 211 h; IQR 172) or a blended food KEF (median 189 h; IQR 148). Care contact time per month was higher for all KDs during the three-month initial trial compared to the two-year follow-up stage. Patients and caregivers with characteristics such as learning or language difficulties were identified as taking longer. Twelve out of fifteen (80%) respondents managed patients following the KD for more than two years, requiring an estimated median contact care time of 2 h (IQR 2) per patient per month. Ten out of fifteen (67%) reported insufficient official hours for dietetic activities. Our small survey gives insight into estimated dietetic care contact time, with potential application for KD provision and service delivery.
    • Kindle project at the University of Chester

      McLean, Fiona; Shepherd, Joanna; University of Chester (SCONUL, 2012)
      Towards the end of 2010, Learning and Information Services (LIS) at the University of Chester decided to undertake a pilot project which explored how useful e-readers are in a university setting and if they could help to resolve issues about resource availability.
    • Knowledge and the Fall in American Neo-Calvinism: Toward a Van Til–Plantinga Synthesis

      Békefi, Bálint (Brill, 2021-09-17)
      Abstract Cornelius Van Til and Alvin Plantinga represent two strands of American Protestant philosophical thought influenced by Dutch neo-Calvinism. This paper compares and synthetizes their models of knowledge in non-Christians given the noetic effects of sin and non-Christian worldview commitments. The paper argues that Van Til’s distinction between the partial realization of the antithesis in practice and its absolute nature in principle correlates with Plantinga’s insistence on prima facie–warranted common-sense beliefs and their ultimate defeasibility given certain metaphysical commitments. Van Til endorsed more radical claims than Plantinga on epistemic defeat in non-Christian worldviews, the status of the sensus divinitatis, and conceptual accuracy in knowledge of the world. Finally, an approach to the use of evidence in apologetics is developed based on the proposed synthesis. This approach seeks to make more room for evidence than is generally recognized in Van Tilianism, while remaining consistent with the founder’s principles.
    • Labels and object categorization in six- and nine-month-olds: tracking labels across varying carrier phrases.

      Ferry, Alissa; email: alissa.ferry@manchester.ac.uk; Guellai, Bahia (2021-07-29)
      Language shapes object categorization in infants. This starts as a general enhanced attentional effect of language, which narrows to a specific link between labels and categories by twelve months. The current experiments examined this narrowing effect by investigating when infants track a consistent label across varied input. Six-month-old infants (N = 48) were familiarized to category exemplars, each presented with the exact same labeling phrase or the same label in different phrases. Evidence of object categorization at test was only found with the same phrase, suggesting that infants were not tracking the label's consistency, but rather that of the entire input. Nine-month-olds (N = 24) did show evidence of categorization across the varied phrases, suggesting that they were tracking the consistent label across the varied input. [Abstract copyright: Copyright © 2021 Elsevier Inc. All rights reserved.]
    • Lack of racial diversity within the palliative medicine workforce: does it affect our patients?

      Khiroya, Heena; orcid: 0000-0001-7613-1881; email: heenakhiroya@doctors.org.uk; Willis, Derek (2021-09-17)
    • Landslides in the Upper Submarine Slopes of Volcanic Islands: The Central Azores

      Chang, Yu‐Chun; orcid: 0000-0003-4941-5437; email: yu-chun.chang@manchester.ac.uk; Mitchell, Neil C.; orcid: 0000-0002-6483-2450; Quartau, Rui; orcid: 0000-0003-3148-7520 (2021-09-28)
      Abstract: Small landslides in the upper submarine slopes of volcanic islands present potential hazards locally because of their high frequency. We examine evidence for landsliding in high‐resolution bathymetric data from Faial, Pico, São Jorge, and Terceira islands of the Azores. Because the rugged morphology of the upper slopes makes landslides difficult to interpret, we develop two classification schemes for the 1,227 identified slope valleys. One scheme addresses how recognizable the valleys were as originating from landslides (whether scarps are prominent or indefinite), whereas the other scheme addresses valley types (whether apparently produced by single or multiple failures). Size distributions are used to assess the relative occurrence of large versus small landslides. Thirteen landslides are predicted to have generated tsunami heights at source of >1 m and one with height of >7 m. Some slopes have gradients far above 30°, the angle of repose of incohesive clastic sediment, so the seabed in those areas is strengthened perhaps by carbonate cementation, by seismic shaking or by the presence of coherent lava or lava talus. Using all types of slope valleys, Faial and Pico have smaller affected volumes per unit slope area than those of São Jorge and Terceira. These differences could be associated with varied seismic activity, with more frequent earthquakes beneath Faial and Pico preventing the build‐up of sediments on their slopes. Submarine landslide statistics are therefore potentially useful for assessing long‐term earthquake hazards of volcanic islands in seismically active environments such as the Azores.
    • Laser capture microdissection coupled mass spectrometry (LCM-MS) for spatially resolved analysis of formalin-fixed and stained human lung tissues

      Herrera, Jeremy A.; orcid: 0000-0003-4845-8494; email: Jeremy.Herrera@manchester.ac.uk; Mallikarjun, Venkatesh; Rosini, Silvia; Montero, Maria Angeles; Lawless, Craig; Warwood, Stacey; O’Cualain, Ronan; Knight, David; Schwartz, Martin A.; Swift, Joe; orcid: 0000-0002-5039-9094; email: Joe.Swift@manchester.ac.uk (BioMed Central, 2020-06-17)
      Abstract: Background: Haematoxylin and eosin (H&E)—which respectively stain nuclei blue and other cellular and stromal material pink—are routinely used for clinical diagnosis based on the identification of morphological features. A richer characterization can be achieved by laser capture microdissection coupled to mass spectrometry (LCM-MS), giving an unbiased assay of the proteins that make up the tissue. However, the process of fixing and H&E staining of tissues provides challenges with standard sample preparation methods for mass spectrometry, resulting in low protein yield. Here we describe a microproteomics technique to analyse H&E-stained, formalin-fixed paraffin-embedded (FFPE) tissues. Methods: Herein, we utilize heat extraction, physical disruption, and in column digestion for the analysis of H&E stained FFPE tissues. Micro-dissected morphologically normal human lung alveoli (0.082 mm3) and human lung blood vessels (0.094 mm3) from FFPE-fixed H&E-stained sections from Idiopathic Pulmonary Fibrosis (IPF) specimens (n = 3 IPF specimens) were then subject to a qualitative and then quantitative proteomics approach using BayesENproteomics. In addition, we tested the sensitivity of this method by processing and analysing a range of micro-dissected human lung blood vessel tissue volumes. Results: This approach yields 1252 uniquely expressed proteins (at a protein identification threshold of 3 unique peptides) with 892 differentially expressed proteins between these regions. In accord with prior knowledge, our methodology approach confirms that human lung blood vessels are enriched with smoothelin, CNN1, ITGA7, MYH11, TAGLN, and PTGIS; whereas morphologically normal human lung alveoli are enriched with cytokeratin-7, -8, -18, -19, 14, and -17. In addition, we identify a total of 137 extracellular matrix (ECM) proteins and immunohistologically validate that laminin subunit beta-1 localizes to morphologically normal human lung alveoli and tenascin localizes to human lung blood vessels. Lastly, we show that this micro-proteomics technique can be applied to tissue volumes as low as 0.0125 mm3. Conclusion: Herein we show that our multistep sample preparation methodology of LCM-MS can identify distinct, characteristic proteomic compositions of anatomical features within complex fixed and stained tissues.
    • Laser solid-phase synthesis of single-atom catalysts

      Peng, Yudong; Cao, Jianyun; Sha, Yang; Yang, Wenji; Li, Lin; Liu, Zhu; email: zhu.liu@manchester.ac.uk (Nature Publishing Group UK, 2021-08-18)
      Abstract: Single-atom catalysts (SACs) with atomically dispersed catalytic sites have shown outstanding catalytic performance in a variety of reactions. However, the development of facile and high-yield techniques for the fabrication of SACs remains challenging. In this paper, we report a laser-induced solid-phase strategy for the synthesis of Pt SACs on graphene support. Simply by rapid laser scanning/irradiation of a freeze-dried electrochemical graphene oxide (EGO) film loaded with chloroplatinic acid (H2PtCl6), we enabled simultaneous pyrolysis of H2PtCl6 into SACs and reduction/graphitization of EGO into graphene. The rapid freezing of EGO hydrogel film infused with H2PtCl6 solution in liquid nitrogen and the subsequent ice sublimation by freeze-drying were essential to achieve the atomically dispersed Pt. Nanosecond pulsed infrared (IR; 1064 nm) and picosecond pulsed ultraviolet (UV; 355 nm) lasers were used to investigate the effects of laser wavelength and pulse duration on the SACs formation mechanism. The atomically dispersed Pt on graphene support exhibited a small overpotential of −42.3 mV at −10 mA cm−2 for hydrogen evolution reaction and a mass activity tenfold higher than that of the commercial Pt/C catalyst. This method is simple, fast and potentially versatile, and scalable for the mass production of SACs.
    • Late diagnosis of isolated central diabetes insipidus secondary to congenital toxoplasmosis-case report.

      Omer, Tahir; orcid: 0000-0003-1832-6204; Khan, Mustafa; Western, Thomas (2020-11-24)
      Congenital toxoplasmosis is an uncommon infection. Hypothalamic/pituitary involvement leading to isolated central diabetes insipidus is extremely rare. Making a correct diagnosis of this condition, albeit challenging, is crucial for adequate management. We present a 54-year-old female who developed central diabetes insipidus as a complication of congenital toxoplasmosis. She had polydipsia and hypernatraemia on presentation and responded to intranasal desmopressin with normalization of above-mentioned findings. Magnetic resonance imaging and cranial X-ray's showed pronounced intracranial calcifications in both choroid plexuses. Thyroid function tests, serum cortisol level and anterior pituitary function were all normal. To the best of our knowledge, this is the first reported case of isolated diabetes insipidus due to congenital toxoplasmosis in literature diagnosed late in adulthood and gives an insight into the challenges of diagnosing central diabetes insipidus and the hypothalamic/pituitary involvement in cases of congenital toxoplasmosis. [Abstract copyright: © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.]
    • Late diagnosis of isolated central diabetes insipidus secondary to congenital toxoplasmosis—case report

      Omer, Tahir; orcid: 0000-0003-1832-6204; Khan, Mustafa; Western, Thomas (Oxford University Press (OUP), 2020-11-24)
      ABSTRACT Congenital toxoplasmosis is an uncommon infection. Hypothalamic/pituitary involvement leading to isolated central diabetes insipidus is extremely rare. Making a correct diagnosis of this condition, albeit challenging, is crucial for adequate management. We present a 54-year-old female who developed central diabetes insipidus as a complication of congenital toxoplasmosis. She had polydipsia and hypernatraemia on presentation and responded to intranasal desmopressin with normalization of above-mentioned findings. Magnetic resonance imaging and cranial X-ray’s showed pronounced intracranial calcifications in both choroid plexuses. Thyroid function tests, serum cortisol level and anterior pituitary function were all normal. To the best of our knowledge, this is the first reported case of isolated diabetes insipidus due to congenital toxoplasmosis in literature diagnosed late in adulthood and gives an insight into the challenges of diagnosing central diabetes insipidus and the hypothalamic/pituitary involvement in cases of congenital toxoplasmosis.
    • Latent Class Analysis of Mental Health in Middle Childhood: Evidence for the Dual-Factor Model

      Petersen, Kimberly J.; orcid: 0000-0002-4941-6897; email: kimberly.petersen@manchester.ac.uk; Humphrey, Neil; orcid: 0000-0002-8148-9500; Qualter, Pamela; orcid: 0000-0001-6114-3820 (Springer US, 2020-07-25)
      Abstract: Mental health is complex, comprising both mental distress and well-being. This study used latent class analysis to identify common combinations of mental distress and well-being (‘mental health classes’) among schoolchildren aged 8–9 years (N = 3340). Thirteen items, measuring a range of conduct problems, emotional symptoms, and subjective well-being, were included in the analysis. Four mental health classes were identified: (1) complete mental health (n = 1895, 57%), (2) vulnerable (n = 434, 13%), (3) emotional symptoms but content (n = 606, 18%), and (4) conduct problems but content (n = 404, 12%). The classes were reliably identified across different datasets, and for males and females. Differential relations with covariates indicated that mental health classes were distinct and externally valid. The results supported the dual-factor model of mental health, suggesting that mental distress and subjective well-being are separate continua. Three of the four possible combinations of high and low distress and subjective well-being posited by the dual-factor model were found using this inductive statistical method. Importantly, our analysis also revealed two ‘symptomatic but content’ groups, differentiated by symptom domain (internalising/externalising). The covariate analyses between mental health classes and sociodemographic factors, prior academic attainment, school connectedness, and peer support, indicated that there are nuanced relations between those variables and particular constellations of mental distress and well-being. As one of the few dual-factor studies to focus on middle childhood, the current study adds important new evidence that contributes to our understanding of the complexities of mental health among schoolchildren.
    • Laughing with, Laughing at

      Lionis, Chrisoula; email: chrisoula.lionis@manchester.ac.uk; Efthymiou, Alkisti; email: alkisefth@gmail.com (Berghahn Books, 2021-09-01)
      The autumn of 2019 was characterised by an eruption of global protests, including Lebanon, Iraq, Ecuador, Chile, and Egypt. The velocity with which these protests emerged nurtured a sense that the Global South ‘was on the march’. At the same time as these events were rapidly unfolding, the world’s premier mass art exhibition, the Venice Biennale, was in its final weeks. Harnessing discourse analysis, participant observation, and collaborative auto-ethnography, the authors draw together a comparative study of the Chilean and Egyptian pavilions and assess the impact of ongoing and suspended revolutionary histories of both nations. Approaching art as a form of ‘practical aesthetics’ (Bennett 2012) and focusing on humour as an aesthetic quality enmeshed in complex political temporalities, this article analyses the relationship between humour, contemporary art, and revolution, demonstrating how the laughter facilitated by these two pavilions negotiates understandings of national pasts, and uprisings in the present.
    • Learning Actions From Natural Language Instructions Using an ON-World Embodied Cognitive Architecture

      Giorgi, Ioanna; email: ioanna.giorgi@manchester.ac.uk; Cangelosi, Angelo; Masala, Giovanni L. (Frontiers Media S.A., 2021-05-13)
      Endowing robots with the ability to view the world the way humans do, to understand natural language and to learn novel semantic meanings when they are deployed in the physical world, is a compelling problem. Another significant aspect is linking language to action, in particular, utterances involving abstract words, in artificial agents. In this work, we propose a novel methodology, using a brain-inspired architecture, to model an appropriate mapping of language with the percept and internal motor representation in humanoid robots. This research presents the first robotic instantiation of a complex architecture based on the Baddeley's Working Memory (WM) model. Our proposed method grants a scalable knowledge representation of verbal and non-verbal signals in the cognitive architecture, which supports incremental open-ended learning. Human spoken utterances about the workspace and the task are combined with the internal knowledge map of the robot to achieve task accomplishment goals. We train the robot to understand instructions involving higher-order (abstract) linguistic concepts of developmental complexity, which cannot be directly hooked in the physical world and are not pre-defined in the robot's static self-representation. Our proposed interactive learning method grants flexible run-time acquisition of novel linguistic forms and real-world information, without training the cognitive model anew. Hence, the robot can adapt to new workspaces that include novel objects and task outcomes. We assess the potential of the proposed methodology in verification experiments with a humanoid robot. The obtained results suggest robust capabilities of the model to link language bi-directionally with the physical environment and solve a variety of manipulation tasks, starting with limited knowledge and gradually learning from the run-time interaction with the tutor, past the pre-trained stage.
    • Like Father Like Son: Cultural and Genetic Contributions to Song Inheritance in an Estrildid Finch

      Lewis, Rebecca N.; email: rebecca.lewis-3@manchester.ac.uk; Soma, Masayo; de Kort, Selvino R.; Gilman, R. Tucker (Frontiers Media S.A., 2021-06-04)
      Social learning of vocalizations is integral to song inheritance in oscine passerines. However, other factors, such as genetic inheritance and the developmental environment, can also influence song phenotype. The relative contributions of these factors can have a strong influence on song evolution and may affect important evolutionary processes such as speciation. However, relative contributions are well-described only for a few species and are likely to vary with taxonomy. Using archived song data, we examined patterns of song inheritance in a domestic population of Java sparrows (Lonchura oryzivora), some of which had been cross-fostered. Six-hundred and seventy-six songs from 73 birds were segmented and classified into notes and note subtypes (N = 22,972), for which a range of acoustic features were measured. Overall, we found strong evidence for cultural inheritance of song structure and of the acoustic characteristics of notes; sons’ song syntax and note composition were similar to that of their social fathers and were not influenced by genetic relatedness. For vocal consistency of note subtypes, a measure of vocal performance, there was no apparent evidence of social or genetic inheritance, but both age and developmental environment influenced consistency. These findings suggest that high learning fidelity of song material, i.e., song structure and note characteristics, could allow novel variants to be preserved and accumulate over generations, with implications for evolution and conservation. However, differences in vocal performance do not show strong links to cultural inheritance, instead potentially serving as condition dependent signals.
    • Line blot immunoassays in idiopathic inflammatory myopathies: retrospective review of diagnostic accuracy and factors predicting true positive results

      To, Fergus; orcid: 0000-0001-8860-3209; Ventín-Rodríguez, Clara; Elkhalifa, Shuayb; orcid: 0000-0002-6292-6795; Lilleker, James B.; orcid: 0000-0002-9230-4137; Chinoy, Hector; orcid: 0000-0001-6492-1288; email: hector.chinoy@manchester.ac.uk (BioMed Central, 2020-07-20)
      Abstract: Background: Line blot immunoassays (LIA) for myositis-specific (MSA) and myositis-associated (MAA) autoantibodies have become commercially available. In the largest study of this kind, we evaluated the clinical performance of a widely used LIA for MSAs and MAAs. Methods: Adults tested for MSA/MAA by LIA at a tertiary myositis centre (January 2016–July 2018) were identified. According to expert-defined diagnoses, true and false positive rates were calculated for strongly and weakly positive autoantibody results within three cohorts: idiopathic inflammatory myopathy (IIM), connective tissue disease (CTD) without myositis, and non-CTD/IIM. Factors associated with true positivity were determined. Results: We analysed 342 cases. 67 (19.6%) had IIM, in whom 71 autoantibodies were detected (50 strong positives [70.4%], 21 weak positives [29.6%]). Of the strong positives, 48/50 (96.0%; 19 MSAs, 29 MAAs) were deemed true positives. Of the weak positives, 15/21 (71.4%; 3 MSAs, 12 MAAs) were deemed true positives. In CTD without myositis cases (n = 120), 31/61 (51.0%; 5 MSAs, 26 MAAs) autoantibodies were strongly positive, with 24/31 (77.4%; 0 MSAs, 24 MAAs) true positives. 30/61 (49.2%; 13 MSAs, 17 MAAs) were weakly positive, with 16/30 (53.3%; 0 MSAs, 16 MAAs) true positives. In non-CTD/IIM cases (n = 155), all 24 MSAs and 22 MAAs were false positives; these results included 17 (37.0%; 7 MSAs, 10 MAAs) strong positives. Individual autoantibody specificities were > 98.2 and > 97.5% for weakly and strongly positive results, respectively. True positivity was associated with high pre-test for IIM (odds ratio 50.8, 95% CI 13.7–189.2, p < 0.001) and strong positive (versus weak positive) results (4.4, 2.3–8.3, p < 0.001). Conclusions: We demonstrated the high specificity of a myositis LIA in a clinical setting. However, a significant burden of false positive results was evident in those with a low pre-test likelihood of IIM and for weakly positive autoantibodies.
    • Liothyronine and levothyroxine prescribing in England: A comprehensive survey and evaluation

      Stedman, Mike; orcid: 0000-0002-0491-7823; Taylor, Peter; Premawardhana, Lakdasa; Okosieme, Onyebuchi; Dayan, Colin; Heald, Adrian H.; orcid: 0000-0002-9537-4050; email: adrian.heald@manchester.ac.uk (2021-07-06)
      Abstract: Introduction: The approach to thyroid hormone replacement varies across centres, but the extent and determinants of variation is unclear. We evaluated geographical variation in levothyroxine (LT4) and liothyronine (LT3) prescribing across General Practices in England and analysed the relationship of prescribing patterns to clinical and socioeconomic factors. Methods: Data was downloaded from the NHS monthly General Practice Prescribing Data in England for the period 2011‐2020. Results: The study covered a population of 19.4 million women over 30 years of age, attending 6,660 GP practices and being provided with 33.7 million prescriptions of LT4 and LT3 at a total cost of £90million/year. Overall, 0.5% of levothyroxine treated patients continue to receive liothyronine. All Clinical Commission Groups (CCGs) in England continue to have at least one liothyronine prescribing practice and 48.5% of English general practices prescribed liothyronine in 2019‐2020. Factors strongly influencing more levothyroxine prescribing (model accounted for 62% of variance) were the CCG to which the practice belonged and the proportion of people with diabetes registered on the practice list plus antidepressant prescribing, with socioeconomic disadvantage associated with less levothyroxine prescribing. Whereas factors that were associated with increased levels of liothyronine prescribing (model accounted for 17% of variance), were antidepressant prescribing and % of type 2 diabetes mellitus individuals achieving HbA1c control of 58 mmol/mol or less. Factors that were associated with reduced levels of liothyronine prescribing included smoking and higher obesity rates. Conclusion: In spite of strenuous attempts to limit prescribing of liothyronine in general practice a significant number of patients continue to receive this therapy, although there is significant geographical variation in the prescribing of this as for levothyroxine, with specific general practice and CCG‐related factors influencing prescribing of both levothyroxine and liothyronine across England.
    • Loss of mRNA surveillance pathways results in widespread protein aggregation

      Jamar, Nur Hidayah; Kritsiligkou, Paraskevi; orcid: 0000-0003-2452-141X; Grant, Chris M.; orcid: 0000-0002-0616-6576; email: chris.grant@manchester.ac.uk (Nature Publishing Group UK, 2018-03-01)
      Abstract: Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways. The proteins that aggregate in mRNA surveillance mutants tend to be more highly expressed, more abundant and more stable proteins compared with the wider proteome. There is also a strong correlation with the proteins that aggregate in response to nascent protein misfolding and an enrichment for proteins that are substrates of ribosome-associated Hsp70 chaperones, consistent with susceptibility for aggregation primarily occurring during translation/folding. We also identified a significant overlap between the aggregated proteins in mRNA surveillance mutants and ageing yeast cells suggesting that translation-dependent protein aggregation may be a feature of the loss of proteostasis that occurs in aged cell populations.
    • Loss of mRNA surveillance pathways results in widespread protein aggregation

      Jamar, Nur Hidayah; Kritsiligkou, Paraskevi; orcid: 0000-0003-2452-141X; Grant, Chris M.; orcid: 0000-0002-0616-6576; email: chris.grant@manchester.ac.uk (Nature Publishing Group UK, 2018-03-01)
      Abstract: Eukaryotic cells contain translation-associated mRNA surveillance pathways which prevent the production of potentially toxic proteins from aberrant mRNA translation events. We found that loss of mRNA surveillance pathways in mutants deficient in nonsense-mediated decay (NMD), no-go decay (NGD) and nonstop decay (NSD) results in increased protein aggregation. We have isolated and identified the proteins that aggregate and our bioinformatic analyses indicates that increased aggregation of aggregation-prone proteins is a general occurrence in mRNA surveillance mutants, rather than being attributable to specific pathways. The proteins that aggregate in mRNA surveillance mutants tend to be more highly expressed, more abundant and more stable proteins compared with the wider proteome. There is also a strong correlation with the proteins that aggregate in response to nascent protein misfolding and an enrichment for proteins that are substrates of ribosome-associated Hsp70 chaperones, consistent with susceptibility for aggregation primarily occurring during translation/folding. We also identified a significant overlap between the aggregated proteins in mRNA surveillance mutants and ageing yeast cells suggesting that translation-dependent protein aggregation may be a feature of the loss of proteostasis that occurs in aged cell populations.