Insights into molecular mechanisms of disease in Neurodegeneration with Brain Iron Accumulation; unifying theories.

Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterised by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and Ferritin Light Chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C19orf12, WDR45 and DCAF17 (C2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA-related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis and speculate potential overlap between NBIA subtypes

Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2β). Here we show that genetic ablation of PLA2G6 in mice (iPLA2β-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced up-regulation of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Moreover, glial cell activation and the elevation in TNF-α and IL-1β expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2β-/- mice are a valuable model for cerebellar atrophy in INAD and that early anti-inflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease

The Gaia-ESO Survey:Reevaluation of the parameters of the open cluster Trumpler 20 using photometry and spectroscopy

International audienceTrumpler 20 is an old open cluster (OC) located toward the Galactic centre, at about 3 kpc from the Sun and $\sim$7 kpc from the Galactic centre. Its position makes this cluster particularly interesting in the framework of the chemical properties of the Galactic disc because very few old OCs reside in the inner part of the disc. For this reason it has been selected as a cluster target of the Gaia-ESO Survey, and spectra of many stars in the main sequence and red clump phases are now available. Moreover, although it has been studied by several authors in the past, no consensus on the evolutionary status of Tr 20 has been reached. The heavy contamination of field stars (the line of sight of Tr 20 crosses the Carina spiral arm) complicates a correct interpretation. Another interesting aspect of the cluster is that it shows a broadened main-sequence turn-off and a prominent and extended red-clump, characteristics that are not easily explained by classical evolutionary models. Exploiting both spectroscopic information from the Gaia-ESO Survey (and the ESO archive) and literature photometry, we obtain a detailed and accurate analysis of the properties of the cluster. We make use of the first accurate metallicity measurement ever obtained from several spectra of red clump stars, and of cluster membership determination using radial velocities. According to the evolutionary models adopted, we find that Tr 20 has an age in the range 1.35-1.66 Gyr, an average reddening $E(B-V)$ in the range 0.31-0.35 mag, and a distance modulus $(m-M)_0$ between 12.64 and 12.72 mag. The spectroscopic metallicity is [Fe/H]=+0.17 dex. We discuss the structural properties of the object and constrain possible hypotheses for its broadened upper main sequence by estimating the effect of differential reddening and its extended red clump

Empowering standardization of cancer vaccines through ontology: enhanced modeling and data analysis

Abstract Background The exploration of cancer vaccines has yielded a multitude of studies, resulting in a diverse collection of information. The heterogeneity of cancer vaccine data significantly impedes effective integration and analysis. While CanVaxKB serves as a pioneering database for over 670 manually annotated cancer vaccines, it is important to distinguish that a database, on its own, does not offer the structured relationships and standardized definitions found in an ontology. Recognizing this, we expanded the Vaccine Ontology (VO) to include those cancer vaccines present in CanVaxKB that were not initially covered, enhancing VO’s capacity to systematically define and interrelate cancer vaccines. Results An ontology design pattern (ODP) was first developed and applied to semantically represent various cancer vaccines, capturing their associated entities and relations. By applying the ODP, we generated a cancer vaccine template in a tabular format and converted it into the RDF/OWL format for generation of cancer vaccine terms in the VO. ‘12MP vaccine’ was used as an example of cancer vaccines to demonstrate the application of the ODP. VO also reuses reference ontology terms to represent entities such as cancer diseases and vaccine hosts. Description Logic (DL) and SPARQL query scripts were developed and used to query for cancer vaccines based on different vaccine’s features and to demonstrate the versatility of the VO representation. Additionally, ontological modeling was applied to illustrate cancer vaccine related concepts and studies for in-depth cancer vaccine analysis. A cancer vaccine-specific VO view, referred to as “CVO,” was generated, and it contains 928 classes including 704 cancer vaccines. The CVO OWL file is publicly available on: http://purl.obolibrary.org/obo/vo/cvo.owl , for sharing and applications. Conclusion To facilitate the standardization, integration, and analysis of cancer vaccine data, we expanded the Vaccine Ontology (VO) to systematically model and represent cancer vaccines. We also developed a pipeline to automate the inclusion of cancer vaccines and associated terms in the VO. This not only enriches the data’s standardization and integration, but also leverages ontological modeling to deepen the analysis of cancer vaccine information, maximizing benefits for researchers and clinicians. Availability The VO-cancer GitHub website is: https://github.com/vaccineontology/VO/tree/master/CVO