Developmental Origin of Oligodendrocyte Lineage Cells Determines Response to Demyelination and Susceptibility to Age-Associated Functional Decline.

Oligodendrocyte progenitors (OPs) arise from distinct ventral and dorsal domains within the ventricular germinal zones of the embryonic CNS. The functional significance, if any, of these different populations is not known. Using dual-color reporter mice to distinguish ventrally and dorsally derived OPs, we show that, in response to focal demyelination of the young adult spinal cord or corpus callosum, dorsally derived OPs undergo enhanced proliferation, recruitment, and differentiation as compared with their ventral counterparts, making a proportionally larger contribution to remyelination. However, with increasing age (up to 13 months), the dorsally derived OPs become less able to differentiate into mature oligodendrocytes. Comparison of dorsally and ventrally derived OPs in culture revealed inherent differences in their migration and differentiation capacities. Therefore, the responsiveness of OPs to demyelination, their contribution to remyelination, and their susceptibility to age-associated functional decline are markedly dependent on their developmental site of origin in the developing neural tube.A.H.C. was funded by a Wellcome Trust Integrated Training Fellowship (096384/Z/11/Z). Work in R.J.M.F.’s laboratory was funded by The UK Multiple Sclerosis Society (941) and by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute. Work in W.D.R.’s laboratory was funded by the Medical Research Council (G0800575), the Wellcome Trust (WT100269AIA), and the European Research Council (293544).This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.celrep.2016.03.06

Article Oligodendrocyte Dynamics in the Healthy Adult CNS: Evidence for Myelin Remodeling

SUMMARY Oligodendrocyte precursors (OPs) continue to proliferate and generate myelinating oligodendrocytes (OLs) well into adulthood. It is not known whether adult-born OLs ensheath previously unmyelinated axons or remodel existing myelin. We quantified OP division and OL production in different regions of the adult mouse CNS including the 4-month-old optic nerve, in which practically all axons are already myelinated. Even there, all OPs were dividing and generating new OLs and myelin at a rate higher than can be explained by first-time myelination of naked axons. We conclude that adult-born OLs in the optic nerve are engaged in myelin remodeling, either replacing OLs that die in service or intercalating among existing myelin sheaths. The latter would predict that average internode length should decrease with age. Consistent with that, we found that adult-born OLs elaborated much shorter but many more internodes than OLs generated during early postnatal life

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Remarkable Stability of Myelinating Oligodendrocytes in Mice

Summary: New myelin-forming oligodendrocytes (OLs) are generated in the mouse central nervous system during adulthood. These adult-born OLs might augment the existing population, contributing to neural plasticity, or else replace OLs that die in use (turnover). To distinguish between these alternatives, we induced genetic labeling of mature myelinating OLs in young adult mice and tracked their subsequent survival. OL survival rates were region dependent, being higher in corpus callosum (∼90% survival over 20 months) and motor cortex (∼70% survival) than in corticospinal tract or optic nerve (50%–60% survival). Survival rates over the first 8 months were 90%–100% in all regions except the optic nerve. In the corpus callosum, new OLs accumulate during young adulthood and are therefore likely to participate in adaptive myelination. We also found that the number of myelin internodes maintained by individual cortical OLs is stable for at least 8 months but declines ∼12% in the following year. : Tripathi et al. estimate the lifetime of myelinating oligodendrocytes (OLs) by fate-mapping in Opalin-CreERT2: Tau-mGFP mice. In the corpus callosum, >90% of OLs survived for >1.5 years and probably outlive the mouse. Therefore, adult-born OLs are not needed for myelin homeostasis but potentially contribute to experience-dependent, adaptive myelination. Keywords: myelin, internode, cell survival, cell turnover, transgenic mouse, Opalin-CreER, corpus callosum, cerebral cortex, spinal cord, optic nerv

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Not AvailableEquine influenza viruses (EIVs) of H3N8 subtype are culprits of severe acute respiratory infections in horses, and are still responsible for significant outbreaks worldwide. Adaptability of influenza viruses to a particular host is significantly influenced by their codon usage preference, due to an absolute dependence on the host cellular machinery for their replication. In the present study, we analyzed genome-wide codon usage patterns in 92 EIV strains, including both H3N8 and H7N7 subtypes by computing several codon usage indices and applying multivariate statistical methods. Relative synonymous codon usage (RSCU) analysis disclosed bias of preferred synonymous codons towards A/U-ended codons. The overall codon usage bias in EIVs was slightly lower, and mainly affected by the nucleotide compositional constraints as inferred from the RSCU and effective number of codon (ENc) analysis. Our data suggested that codon usage pattern in EIVs is governed by the interplay of mutation pressure, natural selection from its hosts and undefined factors. The H7N7 subtype was found less fit to its host (horse) in comparison to H3N8, by possessing higher codon bias, lower mutation pressure and much less adaptation to tRNA pool of equine cells. To the best of our knowledge, this is the first report describing the codon usage analysis of the complete genomes of EIVs. The outcome of our study is likely to enhance our understanding of factors involved in viral adaptation, evolution, and fitness towards their hosts.Not Availabl

Community perspective and healthcare assessment in malaria endemic states of India: a cross-sectional study protocol

Introduction India’s contribution to the malaria burden was highest in South-East Asia Region in 2021, accounting for 79% of the estimated malaria cases and 83% of malaria-related deaths. Intensified Malaria Control Programme supported by Global Funds to Fight against AIDS, Tuberculosis and Malaria has deployed crucial interventions to reduce the overall burden of malaria in India. Evaluation of utilisation of malaria elimination interventions by the community and assessment of the healthcare system is underway in eleven high malaria endemic states in India. Health system preparedness for malaria elimination, logistics, and supply chain management of diagnostic kits and anti-malarial drugs in addition to the knowledge, attitude and practice of the healthcare workers is also being assessed.Methods and analysis The study is being undertaken in 11 malaria endemic states with a variable annual parasite incidence of malaria. In total, 47 districts (administrative unit of malaria control operations) covering 37 976 households are to be interviewed and assessed. We present here the protocol following which the study is being undertaken at the behest and approval of Ministry of Health and Family Welfare in India.Ethics and dissemination No patients were involved in the study. Study findings will be shared with Institutional ethics board of National Institute for Malaria Research New Delhi (NIMR) in a timely, comprehensive, accurate, unbiased, unambiguous and transparent manner and to the National Vector-borne Disease (Malaria) Control Programme officers and the Community public who participated. Important findings will be communicated through community outreach meetings which are existing in the Health system. Results will be informed to study participants via local fieldwork supervised by District Malaria Officers. Also findings will be published in reputed journals based on Indian Council of Medical Research (ICMR) publication policy.The ICMR-NIMR ethics committee approved the study via letter No. NIMR/ECM/2023/Feb/14 dated 24 April 2023 for version 5. All standard ethical practices will be followed

Developmental origin of oligodendrocytes determines their function in the adult brain.

In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function.We thank Dr Daniel Morrison, Matthew Gratian and Mark Bowen for technical support. Funding: This work was supported by the UK Multiple Sclerosis Society (RJMF/CZ), and The Adelson Medical Research Foundation (RJMF/DHR/K-AN/MR/DEB); the Swedish Research Council (grant 2015-03558 and 2019-01360), the European Union (Horizon 2020 Research and Innovation Programme/European Research Council Consolidator Grant EPIScOPE, grant agreement number 681893), the Swedish Brain Foundation (FO2017-0075), Knut and Alice Wallenberg Foundation (grant 2019-0107 and 2019-0089), The Swedish Society for Medical Research (SSMF, grant JUB2019), the G.ran Gustafsson Foundation for Research in Natural Sciences and Medicine, Strategic Research Programme in Neuroscience (StratNeuro), Ming Wai Lau Centre for Reparative Medicine and Karolinska Institutet (GC-B); the Medical Research Council (G0800575) (NK and WDR); a Project Grant from the National Centre for the Replacement, Refinement, & Reduction of Animals in Research (NC/N001451/1) (CJH,LLC, TJB, LMS); the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2173) (EK, TJB, LMS); the NIH (AG072305) (DB); and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). SF was supported by a PhD studentship from the Wellcome Trust. TB is supported by a Junior Fellowship from the Loulou Foundation

Developmental origin of oligodendrocytes determines their function in the adult brain

Acknowledgements: We thank D. Morrison, M. Gratian and M. Bowen for technical support. This work was supported by the UK Multiple Sclerosis Society (RJMF/CZ); the Adelson Medical Research Foundation (RJMF/DHR/K-AN/MR/DEB); the Swedish Research Council (grants 2015-03558 and 2019-01360); the European Union (Horizon 2020 Research and Innovation Program/European Research Council Consolidator Grant EPIScOPE, grant agreement number 681893); the Swedish Brain Foundation (FO2017-0075); the Knut and Alice Wallenberg Foundation (grants 2019-0107 and 2019-0089); the Swedish Society for Medical Research (grant JUB2019); the Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, Strategic Research Programme in Neuroscience (StratNeuro); the Ming Wai Lau Centre for Reparative Medicine and Karolinska Institutet (GC-B); the Medical Research Council (G0800575) (N.K. and W.D.R.); a project grant from the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/N001451/1) (C.J.H., L.L.-C., T.J.B. and L.S.); the Korean Health Technology R&D Project; the Ministry of Health & Welfare, Republic of Korea (HI14C2173) (E.K., T.J.B. and L.S.); the National Institutes of Health (AG072305) (D.E.B.); and a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). S.F. was supported by a PhD studentship from the Wellcome Trust. T.B. is supported by a Junior Fellowship from the Loulou Foundation.In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile as well as subtle myelination abnormalities. The failure of eOLs to fully assume the role of the original dorsally derived cells results in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage and its importance for homeostatic brain function