Biochemistry and Cell Biology - Journal Articles

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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.
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    Vanadium isotope fractionation of alkali basalts during mantle melting
    (Elsevier B.V., 2023-02-22) Chen, Zhenwu; Ding, Xin; Kiseeva, Ekaterina S.; Lin, Xiaobao; Huang, Jian; National Key Research and Development Program of China; Chinese Academy of Sciences; Natural Environment Research Council; Irish Research Council; Youth Innovation Promotion Association of the Chinese Academy of Sciences
    It is well known that vanadium (V) is redox-sensitive during magmatism, but whether V isotopes can be used as a mantle oxygen fugacity (fO2) sensor remains controversial. Before using V isotopes as a redox proxy, it is crucial to understand the fractionation behavior and controlling factors of V isotopes during mantle melting. This study reports high-precision V isotopic data for alkali basalts with high fO2 in eastern China, which were derived from carbonated mantle by a low degree of partial melting. Our results show that their δ51V values (−0.85‰ to −0.61‰) are higher than those of bulk silicate Earth (BSE) and mid-ocean ridge basalts (MORBs). Chemical alteration, crustal contamination or fractional crystallization negligibly affect the δ51V values of alkali basalts. Although subducted carbonates are involved in the mantle source region under eastern China, mass balance calculations show that the incorporation of carbonates did not significantly increase the δ51V values of alkali basalts. In contrast, the observed high δ51V values probably reflect that mantle melting controls the V isotopic compositions of mantle-derived melts. The relative abundances of V5+, V4+ and V3+ in silicate melt are influenced by the variation of fO2 and/or the degree of partial melting. Basaltic melts tend to be enriched in V with high valence at the condition of high fO2 during mantle melting, which contributes to the enrichment of 51V in alkali basalts because of the affinity of high valence V and 51V. Because mantle minerals are overall more compatible of V with low valence, the valence states of V in silicate melt tend to be higher at low degree of partial melting, resulting in more significant fractionation of V isotopes. Therefore, this study validates discernable V isotope fractionation during partial melting of the mantle and examines the potential of using V isotopes to trace the redox state of magmatic systems.
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    Investigation of the gut microbiome, bile acid composition and host immunoinflammatory response in a model of azoxymethane-induced colon cancer at discrete timepoints
    (Springer Nature, 2022-11-23) Keane, Jonathan M.; Walsh, Calum J.; Cronin, P.; Baker, Kevin J.; Melgar, Silvia; Cotter, Paul D.; Joyce, Susan A.; Gahan, Cormac G. M.; Houston, Aileen M.; Hyland, Niall P.; Science Foundation Ireland
    Background: Distinct sets of microbes contribute to colorectal cancer (CRC) initiation and progression. Some occur due to the evolving intestinal environment but may not contribute to disease. In contrast, others may play an important role at particular times during the tumorigenic process. Here, we describe changes in the microbiota and host over the course of azoxymethane (AOM)-induced tumorigenesis. Methods: Mice were administered AOM or PBS and were euthanised 8, 12, 24 and 48 weeks later. Samples were analysed using 16S rRNA gene sequencing, UPLC-MS and qRT-PCR. Results: The microbiota and bile acid profile showed distinct changes at each timepoint. The inflammatory response became apparent at weeks 12 and 24. Moreover, significant correlations between individual taxa, cytokines and bile acids were detected. One co-abundance group (CAG) differed significantly between PBS- and AOM-treated mice at week 24. Correlation analysis also revealed significant associations between CAGs, bile acids and the bile acid transporter, ASBT. Aberrant crypt foci and adenomas were first detectable at weeks 24 and 48, respectively. Conclusion: The observed changes precede host hyperplastic transformation and may represent early therapeutic targets for the prevention or management of CRC at specific timepoints in the tumorigenic process.