skip to content

Research Information

 
Subscribe to Recently added to Apollo feed
Apollo captures, stores, indexes, preserves, and distributes digital research material.
Updated: 20 min 57 sec ago

Relaxing non-photochemical quenching (NPQ) to improve photosynthesis in crops

Tue, 27/12/2022 - 00:00
Relaxing non-photochemical quenching (NPQ) to improve photosynthesis in crops Kromdijk, Johannes; Walter, Julia Sunlight intercepted by crop plants drives photosynthesis and growth. However, the light-harvesting antenna complexes that capture light energy for photosynthesis can also absorb too much light, which enhances the formation for reactive oxygen species and can result in damage to photosynthetic reaction centres. In order to prevent excessive damage, light-harvesting efficiency is reduced under high light, via upregulation of non-photochemical quenching (NPQ) processes involved in thermal dissipation of excitation energy in the photosystem II antennae. Relaxation of NPQ following high light exposure is not instantaneous and the response time increases with severity and longevity of the high light exposure. Due to slow NPQ relaxation, photosynthetic light use efficiency can be decreased for prolonged periods after high light exposure. In this chapter we review mechanistic understanding of light harvesting and NPQ, how NPQ can be measured and results from recent attempts to accelerate NPQ responses to light.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights.

Thu, 01/12/2022 - 00:00
Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights. Eldehna, Wagdy M; Maklad, Raed M; Almahli, Hadia; Al-Warhi, Tarfah; Elkaeed, Eslam B; Abourehab, Mohammed AS; Abdel-Aziz, Hatem A; El Kerdawy, Ahmed M In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

Sharing and reuse of human volunteer data

Thu, 24/11/2022 - 00:00
Sharing and reuse of human volunteer data Henson, Rik Presentation as part of the Open Research at Cambridge conference: Open data sharing and reuse session

Author Correction: Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data

Tue, 27/09/2022 - 01:00
Author Correction: Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data Wright, C. F.; Prigmore, E.; Rajan, D.; Handsaker, J.; McRae, J.; Kaplanis, J.; Fitzgerald, T. W.; FitzPatrick, D. R.; Firth, H. V.; Hurles, M. E.

Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis

Mon, 26/09/2022 - 01:00
Single-cell multi-omics profiling links dynamic DNA methylation to cell fate decisions during mouse early organogenesis Clark, Stephen J.; Argelaguet, Ricard; Lohoff, Tim; Krueger, Felix; Drage, Deborah; Göttgens, Berthold; Marioni, John C.; Nichols, Jennifer; Reik, Wolf Abstract: Background: Perturbation of DNA methyltransferases (DNMTs) and of the active DNA demethylation pathway via ten-eleven translocation (TET) methylcytosine dioxygenases results in severe developmental defects and embryonic lethality. Dynamic control of DNA methylation is therefore vital for embryogenesis, yet the underlying mechanisms remain poorly understood. Results: Here we report a single-cell transcriptomic atlas from Dnmt and Tet mutant mouse embryos during early organogenesis. We show that both the maintenance and de novo methyltransferase enzymes are dispensable for the formation of all major cell types at E8.5. However, DNA methyltransferases are required for silencing of prior or alternative cell fates such as pluripotency and extraembryonic programmes. Deletion of all three TET enzymes produces substantial lineage biases, in particular, a failure to generate primitive erythrocytes. Single-cell multi-omics profiling moreover reveals that this is linked to a failure to demethylate distal regulatory elements in Tet triple-knockout embryos. Conclusions: This study provides a detailed analysis of the effects of perturbing DNA methylation on mouse organogenesis at a whole organism scale and affords new insights into the regulatory mechanisms of cell fate decisions.

Environmental and maternal factors shaping tonsillar microbiota development in piglets

Mon, 26/09/2022 - 01:00
Environmental and maternal factors shaping tonsillar microbiota development in piglets Fredriksen, Simen; Guan, Xiaonan; Boekhorst, Jos; Molist, Francesc; van Baarlen, Peter; Wells, Jerry M. Abstract: Background: The palatine tonsils are part of the mucosal immune system and stimulate immune responses through M cell uptake sampling of antigens and bacteria in the tonsillar crypts. Little is known about the development of the tonsillar microbiota and the factors determining the establishment and proliferation of disease-associated bacteria such as Streptococcus suis. In this study, we assessed tonsillar microbiota development in piglets during the first 5 weeks of life and identified the relative importance of maternal and environmental farm parameters influencing the tonsillar microbiota at different ages. Additionally, we studied the effect sow vaccination with a bacterin against S. suis on microbiota development and S. suis colonisation in their offspring. Results: Amplicon sequencing of the 16S rRNA gene V3-V4 region revealed that a diverse tonsillar microbiota is established shortly after birth, which then gradually changes during the first 5 weeks of life without a large impact of weaning on composition or diversity. We found a strong litter effect, with siblings sharing a more similar microbiota compared to non-sibling piglets. Co-housing in rooms, within which litters were housed in separate pens, also had a large impact on microbiota composition. Sow parity and prepartum S. suis bacterin vaccination of sows had weaker but significant associations with microbiota composition, impacting on the abundance of Streptococcus species before and after weaning. Sex and birthweight had limited impact on the tonsillar microbiota, and none of the measured factors had consistent associations with microbiota diversity. Conclusions: The piglet tonsillar microbiota is established shortly after birth. While microbiota development is associated with both environmental and maternal parameters, weaning has limited impact on microbiota composition. Intramuscular vaccination of sows pre-partum had a significant effect on the tonsillar microbiota composition of their piglets. These findings provide new insights into the mechanisms shaping the tonsillar microbiota.

Targeting non-coding RNA family members with artificial endonuclease XNAzymes

Sat, 24/09/2022 - 01:00
Targeting non-coding RNA family members with artificial endonuclease XNAzymes Donde, Maria J.; Rochussen, Adam M.; Kapoor, Saksham; Taylor, Alexander I. Abstract: Non-coding RNAs (ncRNAs) offer a wealth of therapeutic targets for a range of diseases. However, secondary structures and high similarity within sequence families make specific knockdown challenging. Here, we engineer a series of artificial oligonucleotide enzymes (XNAzymes) composed of 2’-deoxy-2’-fluoro-β-D-arabino nucleic acid (FANA) that specifically or preferentially cleave individual ncRNA family members under quasi-physiological conditions, including members of the classic microRNA cluster miR-17~92 (oncomiR-1) and the Y RNA hY5. We demonstrate self-assembly of three anti-miR XNAzymes into a biostable catalytic XNA nanostructure, which targets the cancer-associated microRNAs miR-17, miR-20a and miR-21. Our results provide a starting point for the development of XNAzymes as a platform technology for precision knockdown of specific non-coding RNAs, with the potential to reduce off-target effects compared with other nucleic acid technologies.

Organization of the corticotropin‐releasing hormone and corticotropin‐releasing hormone‐binding protein systems in the central nervous system of the sea lamprey <i>Petromyzon marinus</i>

Fri, 23/09/2022 - 01:00
Organization of the corticotropin‐releasing hormone and corticotropin‐releasing hormone‐binding protein systems in the central nervous system of the sea lamprey Petromyzon marinus Sobrido‐Cameán, Daniel; González‐Llera, Laura; Anadón, Ramón; Barreiro‐Iglesias, Antón Abstract: The expression of the corticotropin‐releasing hormone (PmCRH) and the CRH‐binding protein (PmCRHBP) mRNAs was studied by in situ hybridization in the brain of prolarvae, larvae, and adults of the sea lamprey Petromyzon marinus. We also generated an antibody against the PmCRH mature peptide to study the distribution of PmCRH‐immunoreactive cells and fibers. PmCRH immunohistochemistry was combined with antityrosine hydroxylase immunohistochemistry, PmCRHBP in situ hybridization, or neurobiotin transport from the spinal cord. The most numerous PmCRH‐expressing cells were observed in the magnocellular preoptic nucleus‐paraventricular nucleus and in the superior and medial rhombencephalic reticular formation. PmCRH expression was more extended in adults than in larvae, and some cell populations were mainly (olfactory bulb) or only (striatum, ventral hypothalamus, prethalamus) observed in adults. The preopto‐paraventricular fibers form conspicuous tracts coursing toward the neurohypophysis, but many immunoreactive fibers were also observed coursing in many other brain regions. Brain descending fibers in the spinal cord mainly come from cells located in the isthmus and in the medial rhombencephalic reticular nucleus. The distribution of PmCRHBP‐expressing neurons was different from that of PmCRH cells, with cells mainly present in the septum, striatum, preoptic region, tuberal hypothalamus, pretectum, pineal complex, isthmus, reticular formation, and spinal cord. Again, expression in adults was more extended than in larvae. PmCRH‐ and PmCRHBP‐expressing cells are different, excluding colocalization of these substances in the same neuron. Present findings reveal a complex CRH/CRHBP system in the brain of the oldest extant vertebrate group, the agnathans, which shows similarities but important divergences with that of mammals.

Research data supporting "Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity"

Thu, 22/09/2022 - 16:38
Research data supporting "Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity" Barker, Katie; Higham, James; Pattison, Luke; Taylor, Toni; Chessell, Iain; Welsh, Fraser; Smith, Ewan; Bulmer, David To calculate Ca2+ imaging data, individual cells were circled on a brightfield image and outlines overlaid onto fluorescent images using ImageJ (NIH, MA, USA). Pixel intensity was measured and analysed with custom-written scripts in RStudio (RStudio, MA, USA). Background fluorescence was subtracted from each cell, and fluorescence intensity (F) baseline corrected and normalized to the maximum fluorescence elicited during 50 mM KCl stimulation (Fpos). Maximum KCl fluorescence was denoted as 1 F/Fpos. Further analysis was confined to cells with a fluorescence increase ≥5 standard deviations above the mean baseline before 50 mM KCl application. Neurons were deemed responsive to a drug challenge if a fluorescence increase of 0.1 F/Fpos was seen in response to drug perfusion. The proportion of responsive neurons and magnitude of the fluorescence response was measured for each experiment, with peak responses calculated from averaging fluorescence values of individual neurons at each time point. Immunocytochemistry data was obtained by first using an automatic ‘minimum error’ threshold algorithm on 8-bit images of βIII-tubulin or DAPI staining to distinguish background from objects. Binary and raw images were manually compared, and the threshold manually adjusted to ensure all regions of interest were captured. The threshold was placed at the first minimum after the major peak of the image histogram. Binary images then underwent watershed segmentation to separate distinct objects in proximity. Identified particles, positive for either βIII-tubulin or DAPI, were automatically counted using ImageJ and a ratio of βIII-tubulin-positive cells (neurons) to DAPI-positive cells (neurons and satellite cells) calculated. In electrophysiological recordings, nerve discharge was determined by measuring the number of spikes passing a manually determined threshold twice the level of background noise (typically 60−80 μV) and binned to determine average firing frequency every 10 s. Changes in neuronal firing rates were calculated by subtracting baseline firing (averaged 3 min prior to distension or drug perfusion) from increases in nerve activity following ramp distension or capsaicin application. Peak firing to noxious mechanical distension and capsaicin application was determined respectively as the highest neuronal activity during ramp distension 5 and during the 10 min post-capsaicin application. Changes to neuronal activity were recorded with each 5 mmHg increase in pressure and used to visualize ramp profiles. Capsaicin response profiles were plotted from binned data at 30 s increments. The area under the curve (AUC) was calculated for the duration of each ramp distension (0–80 mmHg) and for the 10 min following initial capsaicin application from response profiles using GraphPad Prism 9 software.

Modern Languages Research: Towards a Challenge-Based Interdisciplinary Model

Thu, 22/09/2022 - 11:08
Modern Languages Research: Towards a Challenge-Based Interdisciplinary Model Bennett, Wendy This article draws on the experience of the multi-institution, multi-disciplinary research programme, Multilingualism: Empowering Individuals, Transforming Societies, funded by the AHRC under its Open World Research Initiative, to argue that research in modern languages has important things to say about key issues of our time. This implies a challenge-based model for research conducted in an interdisciplinary framework. As Klein and Newell (1983) argue, interdisciplinary studies address topics that are too broad or complex to be dealt with by a single discipline but, drawing on disciplinary perspectives, seek to integrate their insights into a more comprehensive perspective. The approach is illustrated through four case studies relating to conflict and peace-building, linguistic rights and inequalities, health and wellbeing, and social cohesion.

The changing weight of expectation: how shifting priors underpin variability in hallucination frequency

Thu, 22/09/2022 - 11:08
The changing weight of expectation: how shifting priors underpin variability in hallucination frequency Fletcher, Paul; Christoph, Teufel The predictive processing framework encourages us to consider perception as arising from the integration of pre-existing knowledge with current sensory input (1). It formulates hallucinations - percepts without accompanying stimuli - in terms of increased weighting of predicted over actual input and thereby suggests an explanation of the computational mechanisms underlying such experiences. Several studies of individuals with, or prone to, hallucinations have exploited this framework and have suggested ways in which the balance between prediction and input may be altered. In this issue, Kafadar and colleagues (2) elegantly extend this work in three ways: first, they replicate a previous observation (3) that individuals experiencing auditory-verbal hallucinations show a greater influence of prediction on auditory experience; second, they show that this tendency reflects individuals’ current levels of auditory hallucinations rather than a persisting trait. Third, they validate an online version of their task, which may prove convenient in its future use.

Morning chronotype and digestive tract cancers: Mendelian randomization study

Thu, 22/09/2022 - 01:00
Morning chronotype and digestive tract cancers: Mendelian randomization study Yuan, Shuai; Mason, Amy M.; Titova, Olga E.; Vithayathil, Mathew; Kar, Siddhartha; Chen, Jie; Li, Xue; Burgess, Stephen; Larsson, Susanna C. Abstract: Morning chronotype has been associated with a reduced risk of prostate and breast cancer. However, few studies have examined whether chronotype is associated with digestive tract cancer risk. We conducted a Mendelian randomization (MR) study to assess the associations of chronotype with major digestive tract cancers. A total of 317 independent genetic variants associated with chronotype at the genome‐wide significance level (P < 5 × 10−8) were used as instrumental variables from a genome‐wide meta‐analysis of 449 734 individuals. Summary‐level data on overall and six digestive tract cancers, including esophageal, stomach, liver, biliary tract, pancreatic and colorectal cancers, were obtained from the UK Biobank (11 952 cases) and FinnGen (7638 cases) study. Genetic liability to morning chronotype was associated with reduced risk of overall digestive tract cancer and cancers of stomach, biliary tract and colorectum in UK Biobank. The associations for the overall digestive tract, stomach and colorectal cancers were directionally replicated in FinnGen. In the meta‐analysis of the two sources, genetic liability to morning chronotype was associated with a decreased risk of overall digestive tract cancer (odds ratio [OR] 0.94, 95% confidence interval [CI]: 0.90‐0.98), stomach cancer (OR 0.84, 95% CI: 0.73‐0.97) and colorectal cancer (OR 0.92, 95% CI: 0.87‐0.98), but not with the other studied cancers. The associations were consistent in multivariable MR analysis with adjustment for genetically predicted sleep duration, short sleep, insomnia and body mass index. The study provided MR evidence of inverse associations of morning chronotype with digestive tract cancer, particularly stomach and colorectal cancers. Funder: Swedish Cancer Society (Cancerfonden); Id: http://dx.doi.org/10.13039/501100002794

Author Correction: Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis

Wed, 21/09/2022 - 01:00
Author Correction: Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis Gallagher, C. S.; Mäkinen, N.; Harris, H. R.; Rahmioglu, N.; Uimari, O.; Cook, J. P.; Shigesi, N.; Ferreira, T.; Velez-Edwards, D. R.; Edwards, T. L.; Mortlock, S.; Ruhioglu, Z.; Day, F.; Becker, C. M.; Karhunen, V.; Martikainen, H.; Järvelin, M.-R.; Cantor, R. M.; Ridker, P. M.; Terry, K. L.; Buring, J. E.; Gordon, S. D.; Medland, S. E.; Montgomery, G. W.; Nyholt, D. R.; Hinds, D. A.; Tung, J. Y.; Perry, J. R. B.; Lind, P. A.; Painter, J. N.; Martin, N. G.; Morris, A. P.; Chasman, D. I.; Missmer, S. A.; Zondervan, K. T.; Morton, C. C.

Neurotrauma clinicians’ perspectives on the contextual challenges associated with traumatic brain injury follow up in low-income and middle-income countries: A reflexive thematic analysis

Mon, 19/09/2022 - 01:00
Neurotrauma clinicians’ perspectives on the contextual challenges associated with traumatic brain injury follow up in low-income and middle-income countries: A reflexive thematic analysis Smith, Brandon G.; Whiffin, Charlotte J.; Esene, Ignatius N.; Karekezi, Claire; Bashford, Tom; Mukhtar Khan, Muhammad; Fontoura Solla, Davi J.; Indira Devi, Bhagavatula; Paiva, Wellingson S.; Servadei, Franco; Hutchinson, Peter J.; Kolias, Angelos G.; Figaji, Anthony; Rubiano, Andres M. Background: Traumatic brain injury (TBI) is a major global health issue, but low- and middle-income countries (LMICs) face the greatest burden. Significant differences in neurotrauma outcomes are recognised between LMICs and high-income countries. However, outcome data is not consistently nor reliably recorded in either setting, thus the true burden of TBI cannot be accurately quantified. Objective: To explore the specific contextual challenges of, and possible solutions to improve, long-term follow-up following TBI in low-resource settings. Methods: A cross-sectional, pragmatic qualitative study, that considered knowledge subjective and reality multiple (i.e. situated within the naturalistic paradigm). Data collection utilised semi-structured interviews, by videoconference and asynchronous e-mail. Data were analysed using Braun and Clarke’s six-stage Reflexive Thematic Analysis. Results: 18 neurosurgeons from 13 countries participated in this study, and data analysis gave rise to five themes: Clinical Context: What must we understand?; Perspectives and Definitions: What are we talking about?; Ownership and Beneficiaries: Why do we do it?; Lost to Follow-up: Who misses out and why?; Processes and Procedures: What do we do, or what might we do? Conclusion: The collection of long-term outcome data plays an imperative role in reducing the global burden of neurotrauma. Therefore, this was an exploratory study that examined the contextual challenges associated with long-term follow-up in LMICs. Where technology can contribute to improved neurotrauma surveillance and remote assessment, these must be implemented in a manner that improves patient outcomes, reduces clinical burden on physicians, and does not surpass the comprehension, capabilities, or financial means of the end user. Future research is recommended to investigate patient and family perspectives, the impact on clinical care teams, and the full economic implications of new technologies for follow-up. Acknowledgements: Abenezer Tirsit Aklilu, Amos O. Adeleye, Bhagavatula Indira Devi, Anthony Figaji, Ankur Bajaj, Muhammad Tariq, Pritam Gurung, Tsegazeab Lake, Andres Mariano Rubiano, Ehanga Idi Marcel, Claire Karekezi, Nourou Dine Adeniran Bankole, Liew Boon Seng, Olufemi Emmanuel Idowu, Gustavo Sousa Noleto, Noor-ul-Huda Maŕia, Mohammad A Azab.

Secularization and its ethical consequences: orthodox Israeli Jews sanctifying ‘mundane’ Buddhist meditation

Sun, 18/09/2022 - 01:00
Secularization and its ethical consequences: orthodox Israeli Jews sanctifying ‘mundane’ Buddhist meditation Mautner, Ori Abstract: ‘Insight’ or vipassanā meditation refers to meditative practices employed within Buddhist traditions. But following the secularization of vipassanā in recent decades – that is, its differentiation from Buddhism – orthodox Jewish Israeli meditators frame it as a religiously neutral, therapeutic technique centred on the mundane human body. They thus consider it as involving no forbidden ‘Eastern’ religious contents. Nevertheless, these ‘Jewish Vipassanā’ meditators also utilize insight meditation for improving their Jewish practice, characters, and ability to experience closeness to God; and some situate it within a national‐religious historical narrative culminating in redemption. The secularization of vipassanā enables orthodox Jewish practitioners to engage with it in ways that are significant for them as observant Jews, and without continually being concerned over ‘idolatry’. Secularization therefore has important implications for people's ethical projects, or attempts to foster what they consider good. Examining these implications can both stimulate secular studies and contribute to anthropological research on ethics.

Characterization of missing data patterns and mechanisms in longitudinal composite outcome trial in rheumatoid arthritis

Sat, 17/09/2022 - 01:00
Characterization of missing data patterns and mechanisms in longitudinal composite outcome trial in rheumatoid arthritis Ibrahim, Fowzia; Tom, Brian D.M.; Scott, David L.; Prevost, Andrew Toby Background:: Composite measures, like the Disease Activity Score for 28 joints (DAS28), are key primary outcomes in rheumatoid arthritis (RA) trials. DAS28 combines four different components in a continuous measure. When one or more of these components are missing the overall composite score is also missing at intermediate or trial endpoint assessments. Objectives:: This study examined missing data patterns and mechanisms in a longitudinal RA trial to evaluate how best to handle missingness when analysing composite outcomes. Design:: The Tumour-Necrosis-Factor Inhibitors against Combination Intensive Therapy (TACIT) trial was an open label, pragmatic randomized multicentre two arm non-inferiority study. Patients were followed up for 12 months, with monthly measurement of the composite outcome and its components. Active RA patients were randomized to conventional disease modifying drugs (cDMARDs) or Tumour Necrosis Factor-α inhibitors (TNFis). Methods:: The TACIT trial was used to explore the extent of missing data in the composite outcome, DAS28. Patterns of missing data in components and the composite outcome were examined graphically. Longitudinal multivariable logistic regression analysis assessed missing data mechanisms during follow-up. Results:: Two hundred and five patients were randomized: at 12 months 59/205 (29%) had unobserved composite outcome and 146/205 (71%) had an observed DAS28 outcome; however, 34/146 had one or more intermediate assessments missing. We observed mixed missing data patterns, especially for the missing composite outcome due to one component missing rather than patient not attending thier visit. Age and gender predicted missingness components, providing strong evidence the missing observations were unlikely to be Missing Completely at Random (MCAR). Conclusion:: Researchers should undertake detailed evaluations of missing data patterns and mechanisms at the final and intermediate time points, whether or not the outcome variable is a composite outcome. In addition, the impact on treatment estimates in patients who only provide data at milestone assessments need to be assessed. Trial Registration ISRCTN Number:: 37438295 Peer reviewed: True

Remyelination varies between and within lesions in multiple sclerosis following bexarotene

Sat, 17/09/2022 - 01:00
Remyelination varies between and within lesions in multiple sclerosis following bexarotene Brown, J. William L.; Prados, Ferran; Altmann, Daniel R.; Kanber, Baris; Stutters, Jonathan; Cunniffe, Nick G.; Jones, Joanne L.; Georgieva, Zoya G.; Needham, Edward J.; Daruwalla, Cyrus; Wheeler‐Kingshott, Claudia Gandini; Connick, Peter; Chandran, Siddharthan; Franklin, Robin; MacManus, David; Samson, Rebecca; Coles, Alasdair; Chard, Declan Abstract: Objective: In multiple sclerosis chronic demyelination is associated with axonal loss, and ultimately contributes to irreversible progressive disability. Enhancing remyelination may slow, or even reverse, disability. We recently trialled bexarotene versus placebo in 49 people with multiple sclerosis. While the primary MRI outcome was negative, there was converging neurophysiological and MRI evidence of efficacy. Multiple factors influence lesion remyelination. In this study we undertook a systematic exploratory analysis to determine whether treatment response – measured by change in magnetisation transfer ratio – is influenced by location (tissue type and proximity to CSF) or the degree of abnormality (using baseline magnetisation transfer ratio and T1 values). Methods: We examined treatment effects at the whole lesion level, the lesion component level (core, rim and perilesional tissues) and at the individual lesion voxel level. Results: At the whole lesion level, significant treatment effects were seen in GM but not WM lesions. Voxel‐level analyses detected significant treatment effects in WM lesion voxels with the lowest baseline MTR, and uncovered gradients of treatment effect in both WM and CGM lesional voxels, suggesting that treatment effects were lower near CSF spaces. Finally, larger treatment effects were seen in the outer and surrounding components of GM lesions compared to inner cores. Interpretation: Remyelination varies markedly within and between lesions. The greater remyelinating effect in GM lesions is congruent with neuropathological observations. For future remyelination trials, whole GM lesion measures require less complex post‐processing compared to WM lesions (which require voxel level analyses) and markedly reduce sample sizes. Funder: Adeslon Medical Research Foundation; Funder: MS Society of the United Kingdom; Funder: NIHR; Id: http://dx.doi.org/10.13039/100006662; Funder: NIHR UCLH Biomedical Research Centre; Funder: Thorne Family Foundation; Funder: UCL; Id: http://dx.doi.org/10.13039/501100000765

Onset potential for electrolyte oxidation and Ni-rich cathode degradation in lithium-ion batteries

Thu, 15/09/2022 - 09:33
Onset potential for electrolyte oxidation and Ni-rich cathode degradation in lithium-ion batteries Grey, Clare; Dose, Wesley; Li, Weiqun; Temprano, Israel; O'Keefe, Christopher; Mehdi, B Layla; De Volder, Michael FL High-capacity Ni-rich layered metal oxide cathodes are highly desirable to increase the energy density of lithium-ion batteries. However, these materials suffer from poor cycling performance, which is exacerbated by increased cell voltage. We demonstrate here the detrimental effect of ethylene carbonate (EC), a core component in conventional electrolytes, when NMC811 (LiNi0.8Mn0.1Co0.1O2) is charged above 4.4 V vs. Li/Li+ – the onset potential for lattice oxygen release. Oxygen loss is enhanced by EC-containing electrolytes – compared to EC-free – and correlates with more electrolyte oxidation/breakdown and cathode surface degradation, which increase concurrently above 4.4 V. In contrast, NMC111 (LiNi0.33Mn0.33Co0.33O2), which does not release oxygen up to 4.6 V, shows similar extents of degradation irrespective of the electrolyte. This work highlights the incompatibility between conventional EC-based electrolytes and Ni-rich cathodes (more generally, cathodes that release lattice oxygen such as Li-/Mn-rich and disordered rocksalt cathodes), and motivates further work on wider classes of electrolytes and additives.

Effects of N-terminal acetylation on the aggregation of disease-related α-synuclein variants

Thu, 15/09/2022 - 09:33
Effects of N-terminal acetylation on the aggregation of disease-related α-synuclein variants Bell, Rosie; Castellana Cruz, Marta; Nene, Aishwarya; Thrush, Rebecca; Xu, Catherine; Kumita, Janet; Vendruscolo, Michele Mutations in the SCNA gene, which encodes the protein α-synuclein, have been linked with early onset Parkinson’s disease. The nature of this association, however, is still poorly understood. To investigate this problem, we started from the observation that α-synuclein is constitutively N-terminally acetylated, a post-translational modification that alters the charge and structure of α-synuclein molecules and affects their interaction with lipid membranes and their aggregation process. We thus studied five N-terminal acetylated familial variants (A30P, E46K, H50Q, G51D and A53T) of α-synuclein through a wide range of biophysical assays to probe the microscopic steps in their aggregation process and the structures of the resulting aggregates. Our results reveal a great complexity in the combined effects of the disease-related mutations with N-terminal acetylation on the aggregation of α-synuclein, which underscores the high sensitivity to chemical modifications in the behaviour of this protein.

Visualizing maturation factor extraction from the nascent ribosome by the AAA-ATPase Drg1

Thu, 15/09/2022 - 09:33
Visualizing maturation factor extraction from the nascent ribosome by the AAA-ATPase Drg1 Prattes, Michael; Grishkovskaya, Irina; Hodirnau, Victor-Valentin; Hetzmannseder, Christina; Zisser, Gertrude; Sailer, Carolin; Kargas, Vasileios; Loibl, Mathias; Gerhalter, Magdalena; Kofler, Lisa; Warren, Alan J; Stengel, Florian; Haselbach, David; Bergler, Helmut AbstractThe AAA-ATPase Drg1 is a key factor in eukaryotic ribosome biogenesis that initiates cytoplasmic maturation of the large ribosomal subunit. Drg1 releases the shuttling maturation factor Rlp24 from pre-60S particles shortly after nuclear export, a strict requirement for downstream maturation. The molecular mechanism of release remained elusive. Here, we report a series of cryo-EM structures that captured the extraction of Rlp24 from pre-60S particles by Saccharomyces cerevisiae Drg1. These structures reveal that Arx1 and the eukaryote-specific rRNA expansion segment ES27 form a joint docking platform that positions Drg1 for efficient extraction of Rlp24 from the pre-ribosome. The tips of the Drg1 N domains thereby guide the Rlp24 C terminus into the central pore of the Drg1 hexamer, enabling extraction by a hand-over-hand translocation mechanism. Our results uncover substrate recognition and processing by Drg1 step by step and provide a comprehensive mechanistic picture of the conserved modus operandi of AAA-ATPases.