Extracellular Matrix Mineralization Promotes E11/gp38 Glycoprotein Expression and Drives Osteocytic Differentiation

Osteocytes are terminally differentiated osteoblasts which reside in a mineralized extracellular matrix (ECM). The factors that regulate this differentiation process are unknown. We have investigated whether ECM mineralization could promote osteocyte formation. To do this we have utilised MLO-A5 pre-osteocyte-like cells and western blotting and comparative RT-PCR to examine whether the expression of osteocyte-selective markers is elevated concurrently with the onset of ECM mineralization. Secondly, if mineralization of the ECM is indeed a driver of osteocyte formation, we reasoned that impairment of ECM mineralization would result in a reversible inhibition of osteocyte formation. Supplementation of MLO-A5 cell cultures with ascorbic acid and phosphate promoted progressive ECM mineralization as well as temporally associated increases in expression of the osteocyte-selective markers, E11/gp38 glycoprotein and sclerostin. Consistent with a primary role for ECM mineralization in osteocyte formation, we also found that inhibition of ECM mineralization, by omitting phosphate or adding sodium pyrophosphate, a recognized inhibitor of hydroxyapatite formation, resulted in a 15-fold decrease in mineral deposition that was closely accompanied by lower expression of E11 and other osteocyte markers such as Dmp1, Cd44 and Sost whilst expression of osteoblast markers Ocn and Col1a increased. To rule out the possibility that such restriction of ECM mineralization may produce an irreversible modification in osteoblast behaviour to limit E11 expression and osteocytogenesis, we also measured the capacity of MLO-A5 cells to re-enter the osteocyte differentiation programme. We found that the mineralisation process was re-initiated and closely allied to increased expression of E11 protein after re-administration of phosphate or omission of sodium pyrophosphate, indicating an ECM mineralization-induced restoration in osteocyte formation. These results emphasise the importance of cell-ECM interactions in regulating osteoblast behaviour and, more importantly, suggest that ECM mineralization exerts pivotal control during terminal osteoblast differentiation and acquisition of the osteocyte phenotype

(e,2e) measurements on xeon: reexamination of the fine-structure effect

The process of electron scattering from heavy target atoms is of considerable interest due to the enhanced role of relativistic effects and distortion of the electron trajectories resulting from the large value of nuclear charge. Here we present (e,2e) ionization measurements and distorted-wave Born approximation calculations for the scattering of spin-polarized electrons from xenon atoms in which the fine-structure levels of the residual ion are resolved. Comparison of measurements performed using a high-sensitivity toroidal analyzer spectrometer with the predictions of sophisticated calculations provide an improved understanding of the ionization dynamics of heavy target atoms and the treatment of electron exchange processes

(e,2e) Measurements on Xenon: Reexamination of the Fine-Structure Effect

The process of electron scattering from heavy target atoms is of considerable interest due to the enhanced role of relativistic effects and distortion of the electron trajectories resulting from the large value of nuclear charge. Here we present (e,2e) ionization measurements and distorted-wave Born approximation calculations for the scattering of spin-polarized electrons from xenon atoms in which the fine-structure levels of the residual ion are resolved. Comparison of measurements performed using a high-sensitivity toroidal analyzer spectrometer with the predictions of sophisticated calculations provide an improved understanding of the ionization dynamics of heavy target atoms and the treatment of electron exchange processes

Morphological and molecular evidence supports specific recognition of the recently extinct Bettongia anhydra (Marsupialia: Macropodidae)

In 1933, geologist and explorer Michael Terry collected the skull of a small macropodid captured by members of his party near Lake Mackay, western Northern Territory. In 1957, this skull was described as the sole exemplar of a distinct subspecies, Bettongia penicillata anhydra, but was later synonymized with B. lesueur and thereafter all but forgotten. We use a combination of craniodental morphology and ancient mitochondrial DNA to confirm that the Lake Mackay specimen is taxonomically distinct from all other species of Bettongia and recognize an additional specimen from a Western Australian Holocene fossil accumulation. B. anhydra is morphologically and genetically most similar to B. lesueur but differs in premolar shape, rostrum length, dentary proportions, and molar size gradient. In addition, it has a substantial mitochondrial cytochrome b pairwise distance of 9.6–12% relative to all other bettongs. The elevation of this recently extinct bettong to species status indicates that Australia’s mammal extinction record over the past 2 centuries is even worse than currently accepted. Like other bettongs, B. anhydra probably excavated much of its food and may have performed valuable ecological services that improved soil structure and water infiltration and retention, as well as playing an important role in the dispersal of seeds and mycorrhizal fungal spores. All extant species of Bettongia have experienced extensive range contractions since European colonization and some now persist only on island refugia. The near total loss of these ecosystem engineers from the Australian landscape has far-reaching ecological implications

Evaluation of a learner-designed course for teaching health research skills in Ghana

<p>Abstract</p> <p>Background</p> <p>In developing countries the ability to conduct locally-relevant health research and high quality education are key tools in the fight against poverty. The objective of our study was to evaluate the effectiveness of a novel UK accredited, learner-designed research skills course delivered in a teaching hospital in Ghana.</p> <p>Methods</p> <p>Study participants were 15 mixed speciality health professionals from Komfo Anokye Teaching Hospital, Kumasi, Ghana. Effectiveness measures included process, content and outcome indicators to evaluate changes in learners' confidence and competence in research, and assessment of the impact of the course on changing research-related thinking and behaviour. Results were verified using two independent methods.</p> <p>Results</p> <p>14/15 learners gained research competence assessed against UK Quality Assurance Agency criteria. After the course there was a 36% increase in the groups' positive responses to statements concerning confidence in research-related attitudes, intentions and actions. The greatest improvement (45% increase) was in learners' actions, which focused on strengthening institutional research capacity. 79% of paired before/after responses indicated positive changes in individual learners' research-related attitudes (n = 53), 81% in intention (n = 52) and 85% in action (n = 52). The course had increased learners' confidence to start and manage research, and enhanced life-long skills such as reflective practice and self-confidence. Doing their own research within the work environment, reflecting on personal research experiences and utilising peer support and pooled knowledge were critical elements that promoted learning.</p> <p>Conclusion</p> <p>Learners in Ghana were able to design and undertake a novel course that developed individual and institutional research capacity and met international standards. Learning by doing and a supportive peer community at work were critical elements in promoting learning in this environment where tutors were scarce. Our study provides a model for delivering and evaluating innovative educational interventions in developing countries to assess whether they meet external quality criteria and achieve their objectives.</p

A comprehensive database of quality-rated fossil ages for Sahul’s Quaternary vertebrates

Published: 19 July 2016The study of palaeo-chronologies using fossil data provides evidence for past ecological and evolutionary processes, and is therefore useful for predicting patterns and impacts of future environmental change. However, the robustness of inferences made from fossil ages relies heavily on both the quantity and quality of available data. We compiled Quaternary non-human vertebrate fossil ages from Sahul published up to 2013. This, the FosSahul database, includes 9,302 fossil records from 363 deposits, for a total of 478 species within 215 genera, of which 27 are from extinct and extant megafaunal species (2,559 records). We also provide a rating of reliability of individual absolute age based on the dating protocols and association between the dated materials and the fossil remains. Our proposed rating system identified 2,422 records with high-quality ages (i.e., a reduction of 74%). There are many applications of the database, including disentangling the confounding influences of hypothetical extinction drivers, better spatial distribution estimates of species relative to palaeo-climates, and potentially identifying new areas for fossil discovery.Marta Rodríguez-Rey, y, Salvador Herrando-Pérez, Barry W. Brook, Frédérik Saltré, John Alroy, Nicholas Beeton, Michael I. Bird, Alan Cooper, Richard Gillespie, Zenobia Jacobs, Christopher N. Johnson, Gifford H. Miller, Gavin J. Prideaux, Richard G. Roberts, Chris S.M. Turney and Corey J.A. Bradsha

A comprehensive database of quality-rated fossil ages for Sahul's Quaternary vertebrates.

The study of palaeo-chronologies using fossil data provides evidence for past ecological and evolutionary processes, and is therefore useful for predicting patterns and impacts of future environmental change. However, the robustness of inferences made from fossil ages relies heavily on both the quantity and quality of available data. We compiled Quaternary non-human vertebrate fossil ages from Sahul published up to 2013. This, the FosSahul database, includes 9,302 fossil records from 363 deposits, for a total of 478 species within 215 genera, of which 27 are from extinct and extant megafaunal species (2,559 records). We also provide a rating of reliability of individual absolute age based on the dating protocols and association between the dated materials and the fossil remains. Our proposed rating system identified 2,422 records with high-quality ages (i.e., a reduction of 74%). There are many applications of the database, including disentangling the confounding influences of hypothetical extinction drivers, better spatial distribution estimates of species relative to palaeo-climates, and potentially identifying new areas for fossil discovery

Differential iron requirements for osteoblast and adipocyte differentiation

Bone marrow mesenchymal progenitor cells are precursors for various cell types including osteoblasts, adipocytes, and chondrocytes. The external environment and signals act to direct the pathway of differentiation. Importantly, situations such as aging and chronic kidney disease display alterations in the balance of osteoblast and adipocyte differentiation, adversely affecting bone integrity. Iron deficiency, which can often occur during aging and chronic kidney disease, is associated with reduced bone density. The purpose of this study was to assess the effects of iron deficiency on the capacity of progenitor cell differentiation pathways. Mouse and human progenitor cells, differentiated under standard osteoblast and adipocyte protocols in the presence of the iron chelator deferoxamine (DFO), were used. Under osteogenic conditions, 5μM DFO significantly impaired expression of critical osteoblast genes, including osteocalcin, type 1 collagen, and dentin matrix protein 1. This led to a reduction in alkaline phosphatase activity and impaired mineralization. Despite prolonged exposure to chronic iron deficiency, cells retained viability as well as normal hypoxic responses with significant increases in transferrin receptor and protein accumulation of hypoxia inducible factor 1α. Similar concentrations of DFO were used when cells were maintained in adipogenic conditions. In contrast to osteoblast differentiation, DFO modestly suppressed adipocyte gene expression of peroxisome-proliferating activated receptor gamma, lipoprotein lipase, and adiponectin at earlier time points with normalization at later stages. Lipid accumulation was also similar in all conditions. These data suggest the critical importance of iron in osteoblast differentiation, and as long as the external stimuli are present, iron deficiency does not impede adipogenesis. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Daniel F. Edwards III, Christopher J. Miller, Arelis Quintana-Martinez, Christian S. Wright, Matthew Prideaux, Gerald J. Atkins, William R. Thompson, and Erica L. Clinkenbear

Use of rheumatoid arthritis impact of disease (RAID) in routine care; identification of DAS28 remission and unmet patient-reported outcomes.

Objective: The aim was to assess how the patient-reported outcome RA impact of disease (RAID) relates to DAS28 categories in routine care, its utility in identifying patients in DAS28 remission (RDAS) or low disease activity (LDAS) and the burden of unmet patient-reported needs in those achieving RDAS/LDAS. Methods: DAS28 and RAID scores were collected from patients with established RA attending for routine review. The relationship between RAID and DAS28 was assessed with univariate pairwise correlation and mixed-effects linear regression analyses. RAID <2 was defined as a patient-acceptable state. Results: One hundred and ninety-eight patients were assessed, with 220 observations, using DAS28-CRP categories: 47.5% RDAS, 14.1% LDAS, 31.8% moderate DAS (MDAS) and 6.6% high DAS (HDAS). Both patient visual analog scale score and tender joint count exhibited a high statistical association with RAID using linear regression (P < 0.0001). The mean RAID score per DAS28-CRP category was RDAS 1.84, LDAS 4.78, MDAS 5.60 and HDAS 7.68, with a statistically significant increase in RAID per unit increase in DAS-CRP or DAS28-ESR on linear regression (P  < 0.001). Of 66 patients with RAID <2, 64 (97%) were in RDAS and 65 (98.5%) in RDAS/LDAS. Of 134 patients in RDAS/LDAS, RAID was ≥2 in 69 (51.5%), with fatigue and sleep being the worst-scoring domains. Conclusion: RAID functions well as a patient-reported outcome in routine care. Patients with RAID <2 have a high likelihood of being in RDAS/LDAS and, if pre-screened, could avoid a clinic visit. Analysis of RAID domains provides individualized targets for holistic care in RA management, with fatigue and sleep problems dominating unmet needs in those in RDAS/LDAS

Search for Doubly-Charged Higgs Boson Production at HERA

A search for the single production of doubly-charged Higgs bosons H^{\pm \pm} in ep collisions is presented. The signal is searched for via the Higgs decays into a high mass pair of same charge leptons, one of them being an electron. The analysis uses up to 118 pb^{-1} of ep data collected by the H1 experiment at HERA. No evidence for doubly-charged Higgs production is observed and mass dependent upper limits are derived on the Yukawa couplings h_{el} of the Higgs boson to an electron-lepton pair. Assuming that the doubly-charged Higgs only decays into an electron and a muon via a coupling of electromagnetic strength h_{e \mu} = \sqrt{4 \pi \alpha_{em}} = 0.3, a lower limit of 141 GeV on the H^{\pm\pm} mass is obtained at the 95% confidence level. For a doubly-charged Higgs decaying only into an electron and a tau and a coupling h_{e\tau} = 0.3, masses below 112 GeV are ruled out.Comment: 15 pages, 3 figures, 1 tabl