Sclerostin's role in bone's adaptive response to mechanical loading

Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis

Dickkopf-3 is upregulated in osteoarthritis and has a chondroprotective role

Objective Dickkopf-3 (Dkk3) is a non-canonical member of the Dkk family of Wnt antagonists and its upregulation has been reported in microarray analysis of cartilage from mouse models of osteoarthritis (OA). In this study we assessed Dkk3 expression in human OA cartilage to ascertain its potential role in chondrocyte signaling and cartilage maintenance. Methods Dkk3 expression was analysed in human adult OA cartilage and synovial tissues and during chondrogenesis of ATDC5 and human mesenchymal stem cells. The role of Dkk3 in cartilage maintenance was analysed by incubation of bovine and human cartilage explants with interleukin-1 (IL1) and oncostatin-M (OSM). Dkk3 expression was measured in cartilage following murine hip avulsion. Whether Dkk3 influenced Wnt, TGF and activin cell signaling was assessed in primary human chondrocytes and SW1353 chondrosarcoma cells using RT-qPCR and luminescence assays. Results Increased gene and protein levels of Dkk3 were detected in human OA cartilage, synovial tissue and synovial fluid. DKK3 expression was decreased during chondrogenesis of both ATDC5 cells and humans MSCs. Dkk3 inhibited IL1 and OSM-mediated proteoglycan loss from human and bovine cartilage explants and collagen loss from bovine cartilage explans. Cartilage DKK3 expression was decreased following hip avulsion injury. TGF signaling was enhanced by Dkk3 and Wnt3a and activin signaling were inhibited. Conclusions We provide evidence that Dkk3 is upregulated in OA and may have a protective effect on cartilage integrity by preventing proteoglycan loss and helping to restore OA-relevant signaling pathway activity. Targeting Dkk3 may be a novel approach in the treatment of OA

Individual correlates of podoconiosis in areas of varying endemicity: a case-control study

BACKGROUND Podoconiosis is a non-filarial form of elephantiasis resulting in lymphedema of the lower legs. Previous studies have suggested that podoconiosis arises from the interplay of individual and environmental factors. Here, our aim was to understand the individual-level correlates of podoconiosis by comparing 460 podoconiosis-affected individuals and 707 unaffected controls. METHODS/PRINCIPAL FINDINGS This was a case-control study carried out in six kebeles (the lowest governmental administrative unit) in northern Ethiopia. Each kebele was classified into one of three endemicity levels: 'low' (prevalence 5%). A total of 142 (30.7%) households had two or more cases of podoconiosis. Compared to controls, the majority of the cases, especially women, were less educated (OR = 1.7, 95% CI = 1.3 to 2.2), were unmarried (OR = 3.4, 95% CI = 2.6-4.6) and had lower income (t = -4.4, p<0.0001). On average, cases started wearing shoes ten years later than controls. Among cases, age of first wearing shoes was positively correlated with age of onset of podoconiosis (r = 0.6, t = 12.5, p<0.0001). Among all study participants average duration of shoe wearing was less than 30 years. Between both cases and controls, people in 'high' and 'medium' endemicity kebeles were less likely than people in 'low' endemicity areas to 'ever' have owned shoes (OR = 0.5, 95% CI = 0.4-0.7). CONCLUSIONS Late use of shoes, usually after the onset of podoconiosis, and inequalities in education, income and marriage were found among cases, particularly among females. There were clustering of cases within households, thus interventions against podoconiosis will benefit from household-targeted case tracing. Most importantly, we identified a secular increase in shoe-wearing over recent years, which may give opportunities to promote shoe-wearing without increasing stigma among those at high risk of podoconiosis

Bones' adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition.

There is a widely held view that the relationship between mechanical loading history and adult bone mass/strength includes an adapted state or "lazy zone" where the bone mass/strength remains constant over a wide range of strain magnitudes. Evidence to support this theory is circumstantial. We investigated the possibility that the "lazy zone" is an artifact and that, across the range of normal strain experience, features of bone architecture associated with strength are linearly related in size to their strain experience. Skeletally mature female C57BL/6 mice were right sciatic neurectomized to minimize natural loading in their right tibiae. From the fifth day, these tibiae were subjected to a single period of external axial loading (40, 10-second rest interrupted cycles) on alternate days for 2 weeks, with a peak dynamic load magnitude ranging from 0 to 14 N (peak strain magnitude: 0-5000 µε) and a constant loading rate of 500 N/s (maximum strain rate: 75,000 µε/s). The left tibiae were used as internal controls. Multilevel regression analyses suggest no evidence of any discontinuity in the progression of the relationships between peak dynamic load and three-dimensional measures of bone mass/strength in both cortical and cancellous regions. These are essentially linear between the low-peak locomotor strains associated with disuse (∼300 µε) and the high-peak strains derived from artificial loading and associated with the lamellar/woven bone transition (∼5000 µε). The strain:response relationship and minimum effective strain are site-specific, probably related to differences in the mismatch in strain distribution between normal and artificial loading at the locations investigated

Effects of turbulent diffusion on the chemistry of diffuse clouds

Aims. We probe the effect of turbulent diffusion on the chemistry at the interface between a cold neutral medium (CNM) cloudlet and the warm neutral medium (WNM). Methods. We perform moving grid, multifluid, 1D, hydrodynamical simulations with chemistry including thermal and chemical diffusion. The diffusion coefficients are enhanced to account for turbulent diffusion. We post-process the steady-states of our simulations with a crude model of radiative transfer to compute line profiles. Results. Turbulent diffusion spreads out the transition region between the CNM and the WNM. We find that the CNM slightly expands and heats up: its CH and H$_2$ content decreases due to the lower density. The change of physical conditions and diffusive transport increase the H$^+$ content in the CNM which results in increased OH and H$_2$O. Diffusion transports some CO out of the CNM. It also brings H$_2$ into contact with the warm gas with enhanced production of CH$^+$, H$_3^+$, OH and H$_2$O at the interface. O lines are sensitive to the spread of the thermal profile in the intermediate region between the CNM and the WNM. Enhanced molecular content at the interface of the cloud broadens the molecular line profiles and helps exciting transitions of intermediate energy. The relative molecular yield are found higher for bigger clouds. Conclusions. Turbulent diffusion can be the source of additional molecular production and should be included in chemical models of the interstellar medium (ISM). It also is a good candidate for the interpretation of observational problems such as warm H$_2$, CH$^+$ formation and presence of H$_3^+$.Comment: 13 pages, 23 figures, A&A accepte

Causation, Measurement Relevance and No-conspiracy in EPR

In this paper I assess the adequacy of no-conspiracy conditions employed in the usual derivations of the Bell inequality in the context of EPR correlations. First, I look at the EPR correlations from a purely phenomenological point of view and claim that common cause explanations of these cannot be ruled out. I argue that an appropriate common cause explanation requires that no-conspiracy conditions are re-interpreted as mere common cause-measurement independence conditions. In the right circumstances then, violations of measurement independence need not entail any kind of conspiracy (nor backwards in time causation). To the contrary, if measurement operations in the EPR context are taken to be causally relevant in a specific way to the experiment outcomes, their explicit causal role provides the grounds for a common cause explanation of the corresponding correlations.Comment: 20 pages, 1 figur

Meal Patterns and Food Choices of Female Rats Fed a Cafeteria-Style Diet Are Altered by Gastric Bypass Surgery

After Roux-en-Y gastric bypass surgery (RYGB), rats tend to reduce consumption of high-sugar and/or high-fat foods over time. Here, we sought to investigate the behavioral mechanisms underlying these intake outcomes. Adult female rats were provided a cafeteria diet comprised of five palatable foodstuffs varying in sugar and fat content and intake was monitored continuously. Rats were then assigned to either RYGB, or one of two control (CTL) groups: sham surgery or a nonsurgical control group receiving the same prophylactic iron treatments as RYGB rats. Post-sur-gically, all rats consumed a large first meal of the cafeteria diet. After the first meal, RYGB rats reduced intake primarily by decreasing the meal sizes relative to CTL rats, ate meals more slowly, and displayed altered nycthemeral timing of intake yielding more daytime meals and fewer nighttime meals. Collectively, these meal patterns indicate that despite being motivated to consume a cafeteria diet after RYGB, rats rapidly learn to modify eating behaviors to consume foods more slowly across the entire day. RYGB rats also altered food preferences, but more slowly than the changes in meal patterns, and ate proportionally more energy from complex carbohydrates and protein and proportionally less fat. Overall, the pattern of results suggests that after RYGB rats quickly learn to adjust their size, eating rate, and distribution of meals without altering meal number and to shift their macronutrient intake away from fat; these changes appear to be more related to postingestive events than to a fundamental decline in the palatability of food choices

The COBE DIRBE Point Source Catalog

We present the COBE DIRBE Point Source Catalog, an all-sky catalog containing infrared photometry in 10 bands from 1.25 microns to 240 microns for 11,788 of the brightest near and mid-infrared point sources in the sky. Since DIRBE had excellent temporal coverage (100 - 1900 independent measurements per object during the 10 month cryogenic mission), the Catalog also contains information about variability at each wavelength, including amplitudes of variation observed during the mission. Since the DIRBE spatial resolution is relatively poor (0.7 degrees), we have carefully investigated the question of confusion, and have flagged sources with infrared-bright companions within the DIRBE beam. In addition, we filtered the DIRBE light curves for data points affected by companions outside of the main DIRBE beam but within the `sky' portion of the scan. At high Galactic latitudes (|b| > 5 degrees), the Catalog contains essentially all of the unconfused sources with flux densities greater than 90, 60, 60, 50, 90, and 165 Jy at 1.25, 2.2, 3.5, 4.9, 12, and 25 microns, respectively, corresponding to magnitude limits of approximately 3.1, 2.6, 1.7, 1.3, -1.3, and -3.5. At longer wavelengths and in the Galactic Plane, the completeness is less certain because of the large DIRBE beam and possible contributions from extended emission. The Catalog also contains the names of the sources in other catalogs, their spectral types, variability types, and whether or not the sources are known OH/IR stars. We discuss a few remarkable objects in the Catalog. [abridged]Comment: Accepted for publication in the Astrophysical Journal Supplement. The full tables are available at http://www.etsu.edu/physics/bsmith/dirbe