Incretin-based therapy for the treatment of bone fragility in diabetes mellitus

Bone fractures are common comorbidities of type 2 diabetes mellitus (T2DM). Bone fracture incidence seems to develop due to increased risk of falls, poor bone quality and/or anti-diabetic medications. Previously, a relation between gut hormones and bone has been suspected. Most recent evidences suggest indeed that two gut hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may control bone remodeling and quality. The GIP receptor is expressed in bone cells and knockout of either GIP or its receptor induces severe bone quality alterations. Similar alterations are also encountered in GLP-1 receptor knock-out animals associated with abnormal osteoclast resorption. Some GLP-1 receptor agonist (GLP-1RA) have been approved for the treatment of type 2 diabetes mellitus and although clinical trials may not have been designed to investigate bone fracture, first results suggest that GLP-1RA may not exacerbate abnormal bone quality observed in T2DM. The recent design of double and triple gut hormone agonists may also represent a suitable alternative for restoring compromised bone quality observed in T2DM. However, although most of these new molecules demonstrated weight loss action, little is known on their bone safety. The present review summarizes the most recent findings on peptide-based incretin therapy and bone physiology

Efficacy of targeting bone-specific GIP receptor in ovariectomy-induced bone loss

Glucose-dependent insulinotropic polypeptide (GIP) has been recognized in the last decade as an important contributor of bone remodeling and is necessary for optimal bone quality. However, GIP receptors are expressed in several tissues in the body and little is known about the direct versus indirect effects of GIP on bone remodeling and quality. The aims of the present study were to validate two new GIP analogues, called [D-Ala2]-GIP-Tag and [D-Ala2]-GIP1-30, that specifically target either bone or whole body GIP receptors, respectively; and to ascertain the beneficial effects of GIP therapy on bone in a mouse model of ovariectomy-induced bone loss. Both GIP analogues exhibited similar binding capacities at the GIP receptor and intracellular responses as full-length GIP1-42. Furthermore, only [D-Ala2]-GIP-Tag, but not [D-Ala2]-GIP1-30, was undoubtedly found exclusively in the bone matrix and released at acidic pH. In ovariectomized animals, [D-Ala2]-GIP1-30 but not [D-Ala2]-GIP-Tag ameliorated bone stiffness at the same magnitude than alendronate treatment. Only [D-Ala2]-GIP1-30 treatment led to significant ameliorations in cortical microarchitecture. Although alendronate treatment increased the hardness of the bone matrix and the type B carbonate substitution in the hydroxyapatite crystals, none of the GIP analogues modified bone matrix composition. Interestingly, in ovariectomy-induced bone loss, [D-Ala²]-GIP-Tag failed to alter bone strength, microarchitecture and bone matrix composition. Overall, this study shows that the use of a GIP analogue that target whole body GIP receptors might be useful to improve bone strength in ovariectomized animals

Consistent retrieval of land surface radiation products from EO, including traceable uncertainty estimates

Earth observation (EO) land surface products have been demonstrated to provide a constraint on the terrestrial carbon cycle that is complementary to the record of atmospheric carbon dioxide. We present the Joint Research Centre Two-stream Inversion Package (JRC-TIP) for retrieval of variables characterising the state of the vegetation–soil system. The system provides a set of land surface variables that satisfy all requirements for assimilation into the land component of climate and numerical weather prediction models. Being based on a 1-D representation of the radiative transfer within the canopy–soil system, such as those used in the land surface components of advanced global models, the JRC-TIP products are not only physically consistent internally, but they also achieve a high degree of consistency with these global models. Furthermore, the products are provided with full uncertainty information. We describe how these uncertainties are derived in a fully traceable manner without any hidden assumptions from the input observations, which are typically broadband white sky albedo products. Our discussion of the product uncertainty ranges, including the uncertainty reduction, highlights the central role of the leaf area index, which describes the density of the canopy. We explain the generation of products aggregated to coarser spatial resolution than that of the native albedo input and describe various approaches to the validation of JRC-TIP products, including the comparison against in situ observations. We present a JRC-TIP processing system that satisfies all operational requirements and explain how it delivers stable climate data records. Since many aspects of JRC-TIP are generic, the package can serve as an example of a state-of-the-art system for retrieval of EO products, and this contribution can help the user to understand advantages and limitations of such products

Enteroendocrine K-cells exert complementary effects to control bone quality and mass in mice

International audienceThe involvement of a gut-bone axis in controlling bone physiology has been long suspected, although the exact mechanisms are unclear. We explored whether glucose-dependent insulinotropic polypeptide (GIP)-producing enteroendocrine K-cells were involved in this process. The bone phenotype of transgenic mouse models lacking GIP secretion (GIP-GFP-KI) or enteroendocrine K-cells (GIP-DT) was investigated. Mice deficient in GIP secretion exhibited lower bone strength, trabecular bone mass, trabecula number and cortical thickness, notably due to higher bone resorption. Alterations of microstructure, modifications of bone compositional parameters, represented by lower collagen cross-linking were also apparent. None of these alterations were observed in GIP-DT mice lacking enteroendocrine K-cells, suggesting that other K-cell secretory product acts to counteract GIP action. To assess this, stable analogues of the known K-cell peptide hormones, xenin and GIP, were administered to mature NIH Swiss male mice. Both were capable of modulating bone strength mostly by altering bone microstructure, bone gene expression and bone compositional parameters. However, the two molecules exhibited opposite actions on bone physiology, with evidence that xenin effects are mediated indirectly, possibly via neural networks. Our data highlight a previously unknown interaction between GIP and xenin, which both moderate gut-bone connectivity

Collective emotions online and their influence on community life

E-communities, social groups interacting online, have recently become an object of interdisciplinary research. As with face-to-face meetings, Internet exchanges may not only include factual information but also emotional information - how participants feel about the subject discussed or other group members. Emotions are known to be important in affecting interaction partners in offline communication in many ways. Could emotions in Internet exchanges affect others and systematically influence quantitative and qualitative aspects of the trajectory of e-communities? The development of automatic sentiment analysis has made large scale emotion detection and analysis possible using text messages collected from the web. It is not clear if emotions in e-communities primarily derive from individual group members' personalities or if they result from intra-group interactions, and whether they influence group activities. We show the collective character of affective phenomena on a large scale as observed in 4 million posts downloaded from Blogs, Digg and BBC forums. To test whether the emotions of a community member may influence the emotions of others, posts were grouped into clusters of messages with similar emotional valences. The frequency of long clusters was much higher than it would be if emotions occurred at random. Distributions for cluster lengths can be explained by preferential processes because conditional probabilities for consecutive messages grow as a power law with cluster length. For BBC forum threads, average discussion lengths were higher for larger values of absolute average emotional valence in the first ten comments and the average amount of emotion in messages fell during discussions. Our results prove that collective emotional states can be created and modulated via Internet communication and that emotional expressiveness is the fuel that sustains some e-communities.Comment: 23 pages including Supporting Information, accepted to PLoS ON

Influence of Spring and Autumn Phenological Transitions on Forest Ecosystem Productivity

We use eddy covariance measurements of net ecosystem productivity (NEP) from 21 FLUXNET sites (153 site-years of data) to investigate relationships between phenology and productivity (in terms of both NEP and gross ecosystem photosynthesis, GEP) in temperate and boreal forests. Results are used to evaluate the plausibility of four different conceptual models. Phenological indicators were derived from the eddy covariance time series, and from remote sensing and models. We examine spatial patterns (across sites) and temporal patterns (across years); an important conclusion is that it is likely that neither of these accurately represents how productivity will respond to future phenological shifts resulting from ongoing climate change. In spring and autumn, increased GEP resulting from an ¿extra¿ day tends to be offset by concurrent, but smaller, increases in ecosystem respiration, and thus the effect on NEP is still positive. Spring productivity anomalies appear to have carry-over effects that translate to productivity anomalies in the following autumn, but it is not clear that these result directly from phenological anomalies. Finally, the productivity of evergreen needleleaf forests is less sensitive to phenology than is productivity of deciduous broadleaf forests. This has implications for how climate change may drive shifts in competition within mixed-species stands.JRC.H.5-Land Resources Managemen

Optimal designs for rational function regression

We consider optimal non-sequential designs for a large class of (linear and nonlinear) regression models involving polynomials and rational functions with heteroscedastic noise also given by a polynomial or rational weight function. The proposed method treats D-, E-, A-, and $\Phi_p$-optimal designs in a unified manner, and generates a polynomial whose zeros are the support points of the optimal approximate design, generalizing a number of previously known results of the same flavor. The method is based on a mathematical optimization model that can incorporate various criteria of optimality and can be solved efficiently by well established numerical optimization methods. In contrast to previous optimization-based methods proposed for similar design problems, it also has theoretical guarantee of its algorithmic efficiency; in fact, the running times of all numerical examples considered in the paper are negligible. The stability of the method is demonstrated in an example involving high degree polynomials. After discussing linear models, applications for finding locally optimal designs for nonlinear regression models involving rational functions are presented, then extensions to robust regression designs, and trigonometric regression are shown. As a corollary, an upper bound on the size of the support set of the minimally-supported optimal designs is also found. The method is of considerable practical importance, with the potential for instance to impact design software development. Further study of the optimality conditions of the main optimization model might also yield new theoretical insights.Comment: 25 pages. Previous version updated with more details in the theory and additional example

Can We Use Satellite-Based FAPAR to Detect Drought?

Drought in Australia has widespread impacts on agriculture and ecosystems. Satellite-based Fraction of Absorbed Photosynthetically Active Radiation (FAPAR) has great potential to monitor and assess drought impacts on vegetation greenness and health. Various FAPAR products based on satellite observations have been generated and made available to the public. However, differences remain among these datasets due to different retrieval methodologies and assumptions. The Quality Assurance for Essential Climate Variables (QA4ECV) project recently developed a quality assurance framework to provide understandable and traceable quality information for Essential Climate Variables (ECVs). The QA4ECV FAPAR is one of these ECVs. The aim of this study is to investigate the capability of QA4ECV FAPAR for drought monitoring in Australia. Through spatial and temporal comparison and correlation analysis with widely used Moderate Resolution Imaging Spectroradiometer (MODIS), Satellite Pour l'Observation de la Terre (SPOT)/PROBA-V FAPAR generated by Copernicus Global Land Service (CGLS), and the Standardized Precipitation Evapotranspiration Index (SPEI) drought index, as well as the European Space Agency's Climate Change Initiative (ESA CCI) soil moisture, the study shows that the QA4ECV FAPAR can support agricultural drought monitoring and assessment in Australia. The traceable and reliable uncertainties associated with the QA4ECV FAPAR provide valuable information for applications that use the QA4ECV FAPAR dataset in the future

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes