Biochemistry and Cell Biology - Journal Articles

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    Wild herbivores enhance resistance to invasion by exotic cacti in an African savanna
    (Wiley; British Ecology Society, 2022-10-11) Wells, Harry B. M.; Crego, Ramiro D.; Alston, Jesse M.; Ndung'u, S. Kimani; Khasoha, Leo M.; Reed, Courtney G.; Hassan, Abdikadir A.; Kurukura, Samson; Ekadeli, Jackson; Namoni, Mathew; Stewart, Peter S.; Kimuyu, Duncan M.; Wolf, Amelia A.; Young, Truman P.; Kartzinel, Tyler R.; Palmer, Todd M.; Goheen, Jacob R.; Pringle, Robert M.; Natural Sciences and Engineering Research Council of Canada; University of Florida; University of British Columbia; Government of the Republic of Kenya; National Science Foundation; National Geographic Society; University of Wyoming; High Meadows Environmental Institute, Princeton University; Nature Conservancy; Institute at Brown for Environment and Society, Brown University; Smithsonian Institution; Bundesministerium für Bildung und Forschung; Sächsisches Staatsministerium für Wissenschaft und Kunst; Natural Environment Research Council; Durham University
    1.Whether wild herbivores confer biotic resistance to invasion by exotic plants remains a key question in ecology. There is evidence that wild herbivores can impede invasion by exotic plants, but it is unclear whether and how this generalises across ecosystems with varying wild herbivore diversity and functional groups of plants, particularly over long-term (decadal) time frames. 2. Using data from three long-term (13- to 26-year) exclosure experiments in central Kenya, we tested the effects of wild herbivores on the density of exotic invasive cacti, Opuntia stricta and O. ficus-indica (collectively, Opuntia), which are among the worst invasive species globally. We also examined relationships between wild herbivore richness and elephant occurrence probability with the probability of O. stricta presence at the landscape level (6150 km2). 3. Opuntia densities were 74% to 99% lower in almost all plots accessible to wild herbivores compared to exclosure plots. Opuntia densities also increased more rapidly across time in plots excluding wild herbivores. These effects were largely driven by megaherbivores (≥1000 kg), particularly elephants. 4. At the landscape level, modelled Opuntia stricta occurrence probability was negatively correlated with estimated species richness of wild herbivores and elephant occurrence probability. On average, O. stricta occurrence probability fell from ~0.56 to ~0.45 as wild herbivore richness increased from 6 to 10 species and fell from ~0.57 to ~0.40 as elephant occurrence probability increased from ~0.41 to ~0.84. These multi-scale results suggest that any facilitative effects of Opuntia by wild herbivores (e.g. seed/vegetative dispersal) are overridden by suppression (e.g. consumption, uprooting, trampling). 5. Synthesis. Our experimental and observational findings that wild herbivores confer resistance to invasion by exotic cacti add to evidence that conserving and restoring native herbivore assemblages (particularly megaherbivores) can increase community resistance to plant invasions.
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    Alpha-synuclein alters the faecal viromes of rats in a gut-initiated model of Parkinson’s disease
    (Nature Research, 2021) Stockdale, Stephen R.; Draper, Lorraine A.; O'Donovan, Sarah; Barton, Wiley; O'Sullivan, Orla; Volpicelli-Daley, Laura A.; Sullivan, Aideen M.; O'Neill, Cora; Hill, Colin; Science Foundation Ireland
    Parkinson’s disease (PD) is a chronic neurological disorder associated with the misfolding of alpha-synuclein (α-syn) into aggregates within nerve cells that contribute to their neurodegeneration. Recent evidence suggests α-syn aggregation may begin in the gut and travel to the brain along the vagus nerve, with microbes potentially a trigger initiating α-syn misfolding. However, the effects α-syn alterations on the gut virome have not been investigated. In this study, we show longitudinal faecal virome changes in rats administered either monomeric or preformed fibrils (PFF) of α-syn directly into their enteric nervous system. Differential changes in rat viromes were observed when comparing monomeric and PFF α-syn, with alterations compounded by the addition of LPS. Changes in rat faecal viromes were observed after one month and did not resolve within the study’s five-month observational period. These results suggest that virome alterations may be reactive to host α-syn changes that are associated with PD development.
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    The impact of fingolimod on Treg function in brain ischaemia
    (John Wiley and Sons Inc, 2023) Malone, Kyle; Shearer, Jennifer A.; Waeber, Christian; Moore, Anne C.; Irish Research Council; Health Research Board; European Regional Development Fund
    Fingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T-cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10-days post-ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod-treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4+ IL-10+ , CD4+ IFN-γ+ and CD4+ IL-10+ IFN-γ+ cells in spleen and blood, and CD4+ IL-17+ cells in the spleen, with only minor effects on CD8+ T-cell cytokine production. Treg from post-ischaemic mice had reduced suppressive function compared to Treg from non-ischaemic mice. Fingolimod treatment rescued this function against saline-treated but not fingolimod-treated CD4+ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post-stroke while also increasing the resistance of CD4+ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.
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    Low adenovirus vaccine doses administered to skin using microneedle patches induce better functional antibody immunogenicity as compared to systemic injection
    (MDPI AG, 2021) Flynn, Olivia; Dillane, Kate; Lanza, Juliane S.; Marshall, Jennifer M.; Jin, Jing; Silk, Sarah E.; Draper, Simon J.; Moore, Anne C.; Health Research Board
    Adenovirus-based vaccines are demonstrating promising clinical potential for multiple infectious diseases, including COVID-19. However, the immunogenicity of the vector itself decreases its effectiveness as a boosting vaccine due to the induction of strong anti-vector neutralizing immunity. Here we determined how dissolvable microneedle patches (DMN) for skin immunization can overcome this issue, using a clinically-relevant adenovirus-based Plasmodium falciparum malaria vaccine, AdHu5–PfRH5, in mice. Incorporation of vaccine into patches significantly enhanced its thermostability compared to the liquid form. Conventional high dose repeated immunization by the intramuscular (IM) route induced low antigen-specific IgG titres and high anti-vector immunity. A low priming dose of vaccine, by the IM route, but more so using DMN patches, induced the most efficacious immune responses, assessed by parasite growth inhibitory activity (GIA) assays. Administration of low dose AdHu5–PfRH5 using patches to the skin, boosted by high dose IM, induced the highest antigen-specific serum IgG response after boosting, the greatest skewing of the antibody response towards the antigen and away from the vector, and the highest efficacy. This study therefore demonstrates that repeated use of the same adenovirus vaccine can be highly immunogenic towards the transgene if a low dose is used to prime the response. It also provides a method of stabilizing adenovirus vaccine, in easy-to-administer dissolvable microneedle patches, permitting storage and distribution out of cold chain.
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    eIF2α controls memory consolidation via excitatory and somatostatin neurons
    (Nature Research, 2020-10-07) Sharma, Vijendra; Sood, Rapita; Khlaifia, Abdessattar; Eslamizade, Mohammad Javad; Hung, Tzu-Yu; Lou, Danning; Asgarihafshejani, Azam; Lalzar, Maya; Kiniry, Stephen J.; Stokes, Matthew P.; Cohen, Noah; Nelson, Alissa J.; Abell, Kathryn; Possemato, Anthony P.; Gal-Ben-Ari, Shunit; Truong, Vinh T.; Wang, Peng; Yiannakas, Adonis; Saffarzadeh, Fatemeh; Cuello, A. Claudio; Nader, Karim; Kaufman, Randal J.; Costa-Mattioli, Mauro; Baranov, Pavel V.; Quintana, Albert; Sanz, Elisenda; Khoutorsky, Arkady; Lacaille, Jean-Claude; Rosenblum, Kobi; Sonenberg, Nahum; International Development Research Centre; Azrieli Foundation; Canadian Institutes of Health Research; Israel Science Foundation; National Institutes of Health; Ministerio de Ciencia, Innovación y Universidades; European Research Council; Ministerio de Economía y Competitividad; Agència de Gestió d’Ajuts Universitaris i de Recerca; National Institute of Neurological Disorders and Stroke; Richard and Edith Strauss Foundation
    An important tenet of learning and memory is the notion of a molecular switch that promotes the formation of long-term memory1,2,3,4. The regulation of proteostasis is a critical and rate-limiting step in the consolidation of new memories5,6,7,8,9,10. One of the most effective and prevalent ways to enhance memory is by regulating the synthesis of proteins controlled by the translation initiation factor eIF211. Phosphorylation of the α-subunit of eIF2 (p-eIF2α), the central component of the integrated stress response (ISR), impairs long-term memory formation in rodents and birds11,12,13. By contrast, inhibiting the ISR by mutating the eIF2α phosphorylation site, genetically11 and pharmacologically inhibiting the ISR kinases14,15,16,17, or mimicking reduced p-eIF2α with the ISR inhibitor ISRIB11, enhances long-term memory in health and disease18. Here we used molecular genetics to dissect the neuronal circuits by which the ISR gates cognitive processing. We found that learning reduces eIF2α phosphorylation in hippocampal excitatory neurons and a subset of hippocampal inhibitory neurons (those that express somatostatin, but not parvalbumin). Moreover, ablation of p-eIF2α in either excitatory or somatostatin-expressing (but not parvalbumin-expressing) inhibitory neurons increased general mRNA translation, bolstered synaptic plasticity and enhanced long-term memory. Thus, eIF2α-dependent mRNA translation controls memory consolidation via autonomous mechanisms in excitatory and somatostatin-expressing inhibitory neurons.