Vesicle trafficking and pathways to neurodegeneration

Neurodegenerative diseases, encompassing a diverse range of inherited and sporadic disorders characterised by progressive loss of relatively discrete neuronal populations, are a significant and increasing challenge to human health and the global economy [1]. Despite significant advances in our understanding of the underlying ætiology of diseases such as Alzheimer’s, Parkinson’s and Huntington’s, and intense efforts targeting the development of disease-modifying therapies for these disorders, for the majority of people living with neurodegenerative conditions the prognosis remains poor [2,3,4]. Improving our knowledge of the underlying causes of neuronal loss in these disorders with the goal of developing novel disease-modifying therapies is thus a top priority for research, patient and care-giver communities

Subchondral chitosan/blood implant-guided bone plate resorption and woven bone repair is coupled to hyaline cartilage regeneration from microdrill holes in aged rabbit knees

SummaryObjectiveLittle is known of how to routinely elicit hyaline cartilage repair tissue in middle-aged patients. We tested the hypothesis that in skeletally aged rabbit knees, microdrill holes can be stimulated to remodel the bone plate and induce a more integrated, voluminous and hyaline cartilage repair tissue when treated by subchondral chitosan/blood implants.DesignNew Zealand White rabbits (13 or 32 months old, N = 7) received two 1.5 mm diameter, 2 mm depth drill holes in each knee, either left to bleed as surgical controls or press-fit with a 10 kDa (distal hole: 10K) or 40 kDa (proximal hole: 40K) chitosan/blood implant with fluorescent chitosan tracer. Post-operative knee effusion was documented. Repair tissues at day 0 (N = 1) and day 70 post-surgery (N = 6) were analyzed by micro-computed tomography, and by histological scoring and histomorphometry (SafO, Col-2, and Col-1) at day 70.ResultsAll chitosan implants were completely cleared after 70 days, without increasing transient post-operative knee effusion compared to controls. Proximal control holes had worse osteochondral repair than distal holes. Both implant formulations induced bone remodeling and improved lateral integration of the bone plate at the hole edge. The 40K implant inhibited further bone repair inside 50% of the proximal holes, while the 10K implant specifically induced a “wound bloom” reaction, characterized by decreased bone plate density in a limited zone beyond the initial hole edge, and increased woven bone (WB) plate repair inside the initial hole (P = 0.016), which was accompanied by a more voluminous and hyaline cartilage repair (P < 0.05 vs control defects).ConclusionIn a challenging aged rabbit model, bone marrow-derived hyaline cartilage repair can be promoted by treating acute drill holes with a biodegradable subchondral implant that elicits bone plate resorption followed by anabolic WB repair within a 70-day repair period

Exploring autophagy with Gene Ontology.

Autophagy is a fundamental cellular process that is well conserved among eukaryotes. It is one of the strategies that cells use to catabolize substances in a controlled way. Autophagy is used for recycling cellular components, responding to cellular stresses and ridding cells of foreign material. Perturbations in autophagy have been implicated in a number of pathological conditions such as neurodegeneration, cardiac disease and cancer. The growing knowledge about autophagic mechanisms needs to be collected in a computable and shareable format to allow its use in data representation and interpretation. The Gene Ontology (GO) is a freely available resource that describes how and where gene products function in biological systems. It consists of 3 interrelated structured vocabularies that outline what gene products do at the biochemical level, where they act in a cell and the overall biological objectives to which their actions contribute. It also consists of \u27annotations\u27 that associate gene products with the terms. Here we describe how we represent autophagy in GO, how we create and define terms relevant to autophagy researchers and how we interrelate those terms to generate a coherent view of the process, therefore allowing an interoperable description of its biological aspects. We also describe how annotation of gene products with GO terms improves data analysis and interpretation, hence bringing a significant benefit to this field of study. Autophagy 2018 Feb 17; 1-18

Exploring autophagy with Gene Ontology.

Autophagy is a fundamental cellular process that is well conserved among eukaryotes. It is one of the strategies that cells use to catabolize substances in a controlled way. Autophagy is used for recycling cellular components, responding to cellular stresses and ridding cells of foreign material. Perturbations in autophagy have been implicated in a number of pathological conditions such as neurodegeneration, cardiac disease and cancer. The growing knowledge about autophagic mechanisms needs to be collected in a computable and shareable format to allow its use in data representation and interpretation. The Gene Ontology (GO) is a freely available resource that describes how and where gene products function in biological systems. It consists of 3 interrelated structured vocabularies that outline what gene products do at the biochemical level, where they act in a cell and the overall biological objectives to which their actions contribute. It also consists of \u27annotations\u27 that associate gene products with the terms. Here we describe how we represent autophagy in GO, how we create and define terms relevant to autophagy researchers and how we interrelate those terms to generate a coherent view of the process, therefore allowing an interoperable description of its biological aspects. We also describe how annotation of gene products with GO terms improves data analysis and interpretation, hence bringing a significant benefit to this field of study. Autophagy 2018; 14(3):419-436

Hydroxyferroroméite, a new secondary weathering mineral from Oms, France

Hydroxyferroroméite, ideally (Fe2+ 1.5[]0.5)Sb5+ 2O6(OH), is a new secondary mineral from the Correc d'en Llinassos, Oms, Pyrénées-Orientales Department, France. Hydroxyferroroméite occurs as yellow to yellow-brown powdery boxwork replacements up to about 50μm across after tetrahedrite in a siderite–quartz matrix. No distinct crystals have been observed. The empirical formula (based on 7 (O + OH) per formula unit, pfu) is (Fe2+ 1.07Cu2+ 0.50Zn0.03Sr0.03Ca 0.01[]0.36)Σ2 (Sb5+ 1.88Si0.09Al0.02As0.01)Σ2 O6 ((OH)0.86 O0.14). X-ray photoelectron spectroscopy was used to determine the valence states of Sb, Fe and Cu. Hydroxyferroroméite crystallises in the space group Fd3 m with the pyrochlore structure and hence is a new Fe2+ -dominant member of the roméite group of the pyrochlore supergroup. It has the unit-cell parameters: a = 10.25(3) Å, V = 1077(6) Å3 and Z = 8. A model, based on bond-valence theory, for incorporation of the small Fe2+ cation into a displaced variant of the A site of the pyrochlore structure is proposed.The attached document is the author(’s’) final accepted/submitted version of the journal article. You are advised to consult the publisher’s version if you wish to cite from it

Zincalstibite-9R: the first nine-layer polytype with the layered double hydroxide structure-type

Zincalstibite-9R, a new polytype in the hydrotalcite supergroup is reported from the Monte Avanza mine, Italy. It occurs as pale blue curved disc-like tablets flattened on {001} intergrown to form rosettes typically less than 50 μm in diameter, with cyanophyllite and linarite in cavities in baryte. Zincalstibite-9R is uniaxial (−), with refractive indices ω = 1.647(2) and ε = 1.626(2) measured in white light. The empirical formula (based on 12 OH groups) is (Zn^(2+)_(1.09)Cu^(2+)_(0.87)Al_(0.04))_(Σ2.00)Al_(1.01) (Sb^(5+)_(0.97)Si_(0.02))Σ_(0.99)(OH)_(12), and the ideal formula is (Zn,Cu)_2Al(OH)_6[Sb(OH)_6]. Zincalstibite-9R crystallizes in space group R3İ, with ɑ = 5.340(2), c = 88.01(2) Å, V = 2173.70(15) Å^3 and Z = 9. The crystal structure was refined to R_1 = 0.0931 for 370 unique reflections [F_o > 4σ(F)] and R_1 = 0.0944 for all 381 unique reflections. It has the longest periodic layer stacking sequence for a layered double hydroxide compound reported to date

mTOR independent alteration in ULK1 Ser758 phosphorylation following chronic LRRK2 kinase inhibition

Unc-51 Like Kinase 1 (ULK1) is a critical regulator of the biogenesis of autophagosomes, the central component of the catabolic macroautophagy pathway. Regulation of ULK1 activity is dependent upon several phosphorylation events acting to repress or activate the enzymatic function of this protein. Phosphorylation of Ser758 ULK1 has been linked to repression of autophagosome biogenesis and was thought to be exclusively dependent upon mTOR complex 1 kinase activity. In this study, a novel regulation of Ser758 ULK1 phosphorylation is reported following prolonged inhibition of the Parkinson's disease linked protein Leucine Rich Repeat Kinase 2 (LRRK2). Here, modulation of Ser758 ULK1 phosphorylation following LRRK2 inhibition is decoupled from the repression of autophagosome biogenesis and independent of mTOR complex 1 activity