Prolonging disuse in aged mice amplifies cortical but not trabecular bones’ response to mechanical loading

Objective: Short-term neurectomy-induced disuse (SN) has been shown to restore load responses in aged mice. We examined whether this restoration was further enhanced in both cortical and trabecular bone by simply extending the SN. Methods: Following load: strain calibration, tibiae in female C57BL/J6 mice at 8, 14 and 20 weeks and 18 months (n=8/group) were loaded and bone changes measured. Effects of long-term SN examined in twenty-six 18 months-old mice, neurectomised for 5 or 100 days with/without subsequent loading. Cortical and trabecular responses were measured histomorphometrically or by micro-computed tomography. Results: Loading increased new cortical bone formation, elevating cross-sectional area in 8, 14 and 20 week-old (p <0.05), but not 18 month-old aged mice. Histomorphometry showed that short-term SN reinstated load-responses in aged mice, with significant 33% and 117% increases in bone accrual at 47% and 37%, but not 27% of tibia length. Cortical responses to loading was heightened and widespread, now evident at all locations, following prolonged SN (108, 167 and 98% at 47, 37 and 27% of tibial length, respectively). In contrast, loading failed to modify trabecular bone mass or architecture. Conclusions: Mechanoadaptation become deficient with ageing and prolonging disuse amplifies this response in cortical but not trabecular bone

Predicting cortical bone adaptation to axial loading in the mouse tibia

The development of predictive mathematical models can contribute to a deeper understanding of the specific stages of bone mechanobiology and the process by which bone adapts to mechanical forces. The objective of this work was to predict, with spatial accuracy, cortical bone adaptation to mechanical load, in order to better understand the mechanical cues that might be driving adaptation. The axial tibial loading model was used to trigger cortical bone adaptation in C57BL/6 mice and provide relevant biological and biomechanical information. A method for mapping cortical thickness in the mouse tibia diaphysis was developed, allowing for a thorough spatial description of where bone adaptation occurs. Poroelastic finite-element (FE) models were used to determine the structural response of the tibia upon axial loading and interstitial fluid velocity as the mechanical stimulus. FE models were coupled with mechanobiological governing equations, which accounted for non-static loads and assumed that bone responds instantly to local mechanical cues in an on–off manner. The presented formulation was able to simulate the areas of adaptation and accurately reproduce the distributions of cortical thickening observed in the experimental data with a statistically significant positive correlation (Kendall's τ rank coefficient τ = 0.51, p < 0.001). This work demonstrates that computational models can spatially predict cortical bone mechanoadaptation to a time variant stimulus. Such models could be used in the design of more efficient loading protocols and drug therapies that target the relevant physiological mechanisms

Phospho1 deficiency transiently modifies bone architecture yet produces consistent modification in osteocyte differentiation and vascular porosity with ageing

PHOSPHO1 is one of principal proteins involved in initiating bone matrix mineralisation. Recent studies have found that Phospho1 KO mice (Phospho1-R74X) display multiple skeletal abnormalities with spontaneous fractures, bowed long bones, osteomalacia and scoliosis. These analyses have however been limited to young mice and it remains unclear whether the role of PHOSPHO1 is conserved in the mature murine skeleton where bone turnover is limited. In this study, we have used ex-vivo computerised tomography to examine the effect of Phospho1 deletion on tibial bone architecture in mice at a range of ages (5, 7, 16 and 34 weeks of age) to establish whether its role is conserved during skeletal growth and maturation. Matrix mineralisation has also been reported to influence terminal osteoblast differentiation into osteocytes and we have also explored whether hypomineralised bones in Phospho1 KO mice exhibit modified osteocyte lacunar and vascular porosity. Our data reveal that Phospho1 deficiency generates age-related defects in trabecular architecture and compromised cortical microarchitecture with greater porosity accompanied by marked alterations in osteocyte shape, significant increases in osteocytic lacuna and vessel number. Our in vitro studies examining the behaviour of osteoblast derived from Phospho1 KO and wild-type mice reveal reduced levels of matrix mineralisation and modified osteocytogenic programming in cells deficient in PHOSPHO1. Together our data suggest that deficiency in PHOSPHO1 exerts modifications in bone architecture that are transient and depend upon age, yet produces consistent modification in lacunar and vascular porosity. It is possible that the inhibitory role of PHOSPHO1 on osteocyte differentiation leads to these age-related changes in bone architecture. It is also intriguing to note that this apparent acceleration in osteocyte differentiation evident in the hypomineralised bones of Phospho1 KO mice suggests an uncoupling of the interplay between osteocytogenesis and biomineralisation. Further studies are required to dissect the molecular processes underlying the regulatory influences exerted by PHOSPHO1 on the skeleton with ageing

Development of a stochastic computational fluid dynamics approach for offshore wind farms

In this paper, a method for stochastic analysis of an offshore wind farm using computational fluid dynamics (CFD) is proposed. An existing offshore wind farm is modelled using a steady-state CFD solver at several deterministic input ranges and an approximation model is trained on the CFD results. The approximation model is then used in a Monte-Carlo analysis to build joint probability distributions for values of interest within the wind farm. The results are compared with real measurements obtained from the existing wind farm to quantify the accuracy of the predictions. It is shown that this method works well for the relatively simple problem considered in this study and has potential to be used in more complex situations where an existing analytical method is either insufficient or unable to make a good prediction

Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis

Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy-lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy-lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy-lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease

Breathing disorders in congestive heart failure: gender, etiology and mortality

We investigated the relationship between sleep-disordered breathing (SDB) and Cheyne-Stokes respiration (CSR) while awake as well as mortality. Eighty-nine consecutive outpatients (29 females) with congestive heart failure (CHF; left ventricular ejection fraction, LVEF <45%) were prospectively evaluated. The presence of SDB and of CSR while awake before sleep onset was investigated by polysomnography. SDB prevalence was 81 and 56%, using apnea-hypopnea index cutoffs >5 and >15, respectively. CHF etiologies were similar according to the prevalence of SDB and sleep pattern. Males and females were similar in age, body mass index, and LVEF. Males presented more SDB (P = 0.01), higher apnea-hypopnea index (P = 0.04), more light sleep (stages 1 and 2; P < 0.05), and less deep sleep (P < 0.001) than females. During follow-up (25 ± 10 months), 27% of the population died. Non-survivors had lower LVEF (P = 0.01), worse New York Heart Association (NYHA) functional classification (P = 0.03), and higher CSR while awake (P < 0.001) than survivors. As determined by Cox proportional model, NYHA class IV (RR = 3.95, 95%CI = 1.37-11.38, P = 0.011) and CSR while awake with a marginal significance (RR = 2.96, 95%CI = 0.94-9.33, P = 0.064) were associated with mortality. In conclusion, the prevalence of SDB and sleep pattern of patients with Chagas' disease were similar to that of patients with CHF due to other etiologies. Males presented more frequent and more severe SDB and worse sleep quality than females. The presence of CSR while awake, but not during sleep, may be associated with a poor prognosis in patients with CHF

Reverse Engineering the Anthropocene: Can Human Consciousness Change Reality?

A greater awareness of the Anthropocene brings to the surface critical questions about the nature of human reality or, more specifically, the role human consciousness plays in the formation of the physical world, its construction, functionality, and interactivity. This paper uses a dialogical correlation of Aristotle, Max Planck and Dean Radin in order to first, formulate parameters of reality formation and the active role of consciousness as part of this process; and, second, consider the possibility that humanity’s consciousness can be trained to effect deliberate change in the material world. This paper argues that one of the ways to understand the Anthropocene is through the idea that reality is “running away” from us because we are not aware of the role our consciousness plays in the process of reality formation.&nbsp

Research Notes : Zambia : Development of promiscuous soybean varieties

Zambia was perhaps the first country to initiate research on the development of promiscuous soybean varieties. Promiscuous soybean varieties have the capability of producing effective nodules with the indigenous rhizobia found in the Zambian soils. Two such varieties, \u27Magoye\u27 and \u27Hernon 147\u27, have already been released in Zambia