Rescuing Loading Induced Bone Formation at Senescence

The increasing incidence of osteoporosis worldwide requires anabolic treatments that are safe, effective, and, critically, inexpensive given the prevailing overburdened health care systems. While vigorous skeletal loading is anabolic and holds promise, deficits in mechanotransduction accrued with age markedly diminish the efficacy of readily complied, exercise-based strategies to combat osteoporosis in the elderly. Our approach to explore and counteract these age-related deficits was guided by cellular signaling patterns across hierarchical scales and by the insight that cell responses initiated during transient, rare events hold potential to exert high-fidelity control over temporally and spatially distant tissue adaptation. Here, we present an agent-based model of real-time Ca2+/NFAT signaling amongst bone cells that fully described periosteal bone formation induced by a wide variety of loading stimuli in young and aged animals. The model predicted age-related pathway alterations underlying the diminished bone formation at senescence, and hence identified critical deficits that were promising targets for therapy. Based upon model predictions, we implemented an in vivo intervention and show for the first time that supplementing mechanical stimuli with low-dose Cyclosporin A can completely rescue loading induced bone formation in the senescent skeleton. These pre-clinical data provide the rationale to consider this approved pharmaceutical alongside mild physical exercise as an inexpensive, yet potent therapy to augment bone mass in the elderly. Our analyses suggested that real-time cellular signaling strongly influences downstream bone adaptation to mechanical stimuli, and quantification of these otherwise inaccessible, transient events in silico yielded a novel intervention with clinical potential

Dispensing quails, mincemeat, leaven: Katherine Parr's patronage of the paraphrases of Erasmus

As a prominent patron of humanist scholarship and Reformed religion, and the author of several devotional works in her own right, Katherine Parr exerted a significant influence on the English Reformation – as several scholars have begun to explore. Yet to date, it is the texts that most legibly bear her authorial signature that have attracted critical attention. Parr’s patronage, by contrast, has long been widely celebrated as historical fact and at the same time surprisingly ignored as a social, literary and mechanical process. In the Acts and Monuments (1563), for instance, John Foxe paints a triumphal Protestant portrait of the queen as the period’s ‘only patroness of the professors of the truth’. And Parr’s recent biographer Susan James goes so far as to say that Katherine was ‘by conviction, by influence and by actions the first true queen of the English Reformation’. According to James Kelsey McConica’s 1965 portrayal of the period, Parr’s generation: "found appropriate patronage, not in a Machiavellian Secretary of State, but in a noble lady of irenic temperament and sincere attachment to humanist learning. ... It is in her circle, which revives the traditions of her royal predecessors Margaret Beaufort and Catherine of Aragon, that the Erasmian spirit finds new shelter and influential support.