Genetic randomization reveals functional relationships among morphologic and tissue-quality traits that contribute to bone strength and fragility

We examined femora from adult AXB/BXA recombinant inbred (RI) mouse strains to identify skeletal traits that are functionally related and to determine how functional interactions among these traits contribute to genetic variability in whole-bone stiffness, strength, and toughness. Randomization of A/J and C57BL/6J genomic regions resulted in each adult male and female RI strain building mechanically functional femora by assembling unique sets of morphologic and tissue-quality traits. A correlation analysis was conducted using the mean trait values for each RI strain. A third of the 66 correlations examined were significant, indicating that many bone traits covaried or were functionally related. Path analysis revealed important functional interactions among bone slenderness, cortical thickness, and tissue mineral density. The path coefficients describing these functional relations were similar for both sexes. The causal relationship among these three traits suggested that cellular processes during growth simultaneously regulate bone slenderness, cortical thickness, and tissue mineral density so that the combination of traits is sufficiently stiff and strong to satisfy daily loading demands. A disadvantage of these functional interactions was that increases in tissue mineral density also deleteriously affected tissue ductility. Consequently, slender bones with high mineral density may be stiff and strong but they are also brittle. Thus, genetically randomized mouse strains revealed a basic biological paradigm that allows for flexibility in building bones that are functional for daily activities but that creates preferred sets of traits under extreme loading conditions. Genetic or environmental perturbations that alter these functional interactions during growth would be expected to lead to loss of function and suboptimal adult bone quality

Advanced Technologies for Oral Controlled Release: Cyclodextrins for oral controlled release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug-drug or drug-additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g. as osmotic pumps) and/ or hydrophobic CDs. New controlled delivery systems based on nanotechonology carriers (nanoparticles and conjugates) have also been reviewed

Enhancement of Naringenin Bioavailability by Complexation with Hydroxypropoyl-β-Cyclodextrin

The abundant flavonoid aglycone, naringenin, which is responsible for the bitter taste in grapefruits, has been shown to possess hypolipidemic and anti-inflammatory effects both in vitro and in vivo. Recently, our group demonstrated that naringenin inhibits hepatitis C virus (HCV) production, while others demonstrated its potential in the treatment of hyperlipidemia and diabetes. However, naringenin suffers from low oral bioavailability critically limiting its clinical potential. In this study, we demonstrate that the solubility of naringenin is enhanced by complexation with β-cyclodextrin, an FDA approved excipient. Hydroxypropoyl-β-cyclodextrin (HPβCD), specifically, increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Complexation of naringenin with HPβCD increased its plasma concentrations when fed to rats, with AUC values increasing by 7.4-fold and Cmax increasing 14.6-fold. Moreover, when the complex was administered just prior to a meal it decreased VLDL levels by 42% and increased the rate of glucose clearance by 64% compared to naringenin alone. These effects correlated with increased expression of the PPAR co-activator, PGC1α in both liver and skeletal muscle. Histology and blood chemistry analysis indicated this route of administration was not associated with damage to the intestine, kidney, or liver. These results suggest that the complexation of naringenin with HPβCD is a viable option for the oral delivery of naringenin as a therapeutic entity with applications in the treatment of dyslipidemia, diabetes, and HCV infection.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (K01DK080241)Harvard Clinical Nutrition Research Center (P30-DK040561)European Research Council (Starting Grant (TMIHCV 242699))Massachusetts General Hospital (BioMEMS Resource Center (P41 EB-002503))Alexander Silberman Institute of Life Science

Explicit expressions for the estimation of the elastic constants of lamellar bone as a function of the volumetric mineral content using a multi-scale approach

[EN] In this work, explicit expressions to estimate all the transversely isotropic elastic constants of lamellar bone as a function of the volumetric bone mineral density (BMD) are provided. The methodology presented is based on the direct homogenization procedure using the finite element method, the continuum approach based on the Hill bounds, the least-square method and the mean field technique. Firstly, a detailed description of the volumetric content of the different components of bone is provided. The parameters defined in this step are related to the volumetric BMD considering that bone mineralization process occurs at the smallest scale length of the bone tissue. Then, a thorough description provides the details of the numerical models and the assumptions adopted to estimate the elastic behaviour of the forward scale lengths. The results highlight the noticeable influence of the BMD on the elastic modulus of lamellar bone. Power law regressions fit the Young's moduli, shear stiffness moduli and Poisson ratios. In addition, the explicit expressions obtained are applied to the estimation of the elastic constants of cortical bone. At this scale length, a representative unit cell of cortical bone is analysed including the fibril orientation pattern given by Wagermaier et al. (Biointerphases 1:1-5, 2006) and the BMD distributions observed by Granke et al. (PLoS One 8:e58043, 2012) for the osteon. Results confirm that fibril orientation arrangement governs the anisotropic behaviour of cortical bone instead of the BMD distribution. The novel explicit expressions obtained in this work can be used for improving the accuracy of bone fracture risk assessment.The authors acknowledge the Ministerio de Economia y Competitividad for the financial support received through the project DPI2013-46641-R and to the Generalitat Valenciana for Programme PROMETEO 2016/007. The authors declare that they have no conflict of interestVercher Martínez, A.; Giner Maravilla, E.; Belda, R.; Aigoun, A.; Fuenmayor Fernández, F. (2018). Explicit expressions for the estimation of the elastic constants of lamellar bone as a function of the volumetric mineral content using a multi-scale approach. Biomechanics and Modeling in Mechanobiology. 17(2):449-464. https://doi.org/10.1007/s10237-017-0971-xS449464172Akiva U, Wagner HD, Weiner S (1998) Modelling the three-dimensional elastic constants of parallel-fibred and lamellar bone. J Mater Sci 33:1497–1509Ascenzi A, Bonucci E (1967) The tensile properties of single osteons. Ana Rec 158:375–386Barbour KE, Zmuda JM, Strotmeyer ES, Horwitz MJ, Boudreau R, Evans RW, Ensrud K, Petit MA, Gordon CL, Cauley JA (2013) Correlates of trabecular and cortical volumetric bone mineral density of the radius and tibia older men: the osteoporotic fractures in men study. J Bone Miner Res 25(5):1017–1028Bar-On B, Wagner HD (2013) Structural motifs and elastic properties of hierarchical biological tissues—a review. J Struct Biol 183:149–164Cowin SC (2000) How is a tissue built? J Biomech Eng 122:553–569Cowin SC (2001) Bone mechanics handbook, 2nd edn. CRC Press, Boca RatonCurrey JD (1986) Power law models for the mechanical properties of cancellous bone. Eng Med 15(3):153–154Currey JD (1988) The effect of porosity and mineral content on the Young’s modulus of elasticity of compact bone. J Biomech 21:131–139Daszkiewicz K, Maquer G, Zysset PK (2017) The effective elastic properties of human trabecular bone may be approximated using micro-finite element analyses of embedded volume elements. Biomech Model Mechanobiol 16:731–742Faingold A, Sidney RC, Wagner HD (2012) Nanoindentation of osteonal bone lamellae. J Mech Biomech Materials 9:198–206Fratzl P, Fratzl-Zelman N, Klaushofer K, Vogl G, Koller K (1991) Nucleation and growth of mineral crystals in bone studied by small-angle X-ray scattering. Calcif Tissue Int 48:407–413Fritsch A, Hellmich C (2007) ’Universal’ microstructural patterns in cortical and trabecular, extracellular and extravascular bone materials: micromechanics-based prediction of anisotropic elasticity. J Theo Biol 24:597–620Grampp S, Genant HK, Mathur A, Lang P, Jergas M, Takada M, Glüer CC, Lu Y, Chavez M (1997) Comparisons of noninvasive bone mineral measurements in assessing age-related loss, fracture discrimination and diagnostic classification. J Bone Miner Res 12:697–711Grant CA, Langton C, Schuetz MA, Epari DR (2011) Determination of the material properties of ovine cortical bone. Poster No. 2226, 57th Orthopaedic Research Society (ORS) Annual meeting, Long Beach, CaliforniaGranke M, Gourrier A, Rupin F, Raum K, Peyrin F, Burghammer M, Saïd A, Laugier P (2012) Microfibril orientation dominates the microelastic properties of human bone tissue at the lamellar length scale. PLoS One 8:e58043Gurtin ME (1972) The linear theory of elasticity. Handbuch del Physik VIa 2:1–296Hamed E, Jasiuk I (2012) Elastic modeling of bone at nanostructural level. Mat Sci Eng R73:27–49Hernández CJ, Beaupré GS, Keller TS, Carter DR (2001a) The influence of bone volume fraction and ash fraction on bone strength and modulus. Bone 29:74–78Hill R (1952) The elastic behaviour of a crystalline aggregate. Proc Phys Soc Sec A 65:349–354Hodge AJ, Petruska JA (1963) Recent studies with the electron microscope on ordered aggregates of the tropocollagen macromolecule. In: Ramachandran GN (ed) Aspects of protein structure. Academic Press, New York, pp 289–300Jäger I, Fratzl P (2000) Mineralized collagen: a mechanical model with a staggered arrangement of mineral particles. Biophys J 78:1737–1746Kuhn JL, Goldstein SA, Choi K, London M, Feldkamp LA, Matthews LS (1989) Comparison of the trabecular and cortical tissue moduli from human iliac crests. J Orthop Res 7:876–884Landis WJ, Song MJ, Leith A, McEwen L, McEwen BF (1993) Mineral and organic matrix interaction in normally calcifying tendon visualized in three dimensions by high-voltage electron microscopic tomography and graphic image reconstruction. J Struct Biol 110:39–54Lees S, Heeley JD, Cleary PF (1979) A study of some properties of a sample of bovine cortical bone using ultrasound. Calcif Tissue Int 29:107–117Lekhnitskii SG (1963) Theory of elasticity of anisotropic elastic body. Holden-Day, San Francisco, pp 1–73Lempriere BM (1968) Poisson’s ratio in orthotropic materials. Am Inst Aeronaut Astronaut J J6:2226–2227Liu Y, Kim YK, Dai L, Li N, Khan SO, Pashley DH, Tay FR (2011) Hierarchical and non-hierarchical mineralization of collagen. Biomater 32:1291–1300Majumdar S, Kothari M, Augat P, Newitt DC, Link TM, Lin JC, Lang T, Lu Y, Genant HK (1998) High-resolution magnetic resonance imaging: three-dimensional trabecular bone architecture and biomechanical properties. Bone 22(5):445–454Martínez-Reina J, Domínguez J, García-Aznar JM (2011) Effect of porosity and mineral content on the elastic constants of cortical bone: a multiscale approach. Biomech Model Mechanobiol 10:309–322Nobakhti S, Limbert G, Thurner PJ (2014) Cement lines and interlamellar areas in compact bone as strain amplifiers—Contributors to elasticity, fracture toughness and mechanotransduction. J Mech Behav Biomed Mater 29:235–251Orgel JPRO, Irving TC, Miller A, Wess TJ (2006) Microfibrillar structure of type I collagen in situ. PNAS USA 103:9001–9005Reisinger AG, Pahr DH, Zysset PK (2010) Sensitivity analysis and parametric study of elastic properties of unidirectional mineralized bone fibril-array using mean field methods. Biomech Model Mechanobiol 9:499–510Reisinger AG, Pahr DH, Zysset PK (2011) Elastic anisotropy of bone lamellae as a function of fibril orientation pattern. Biomech Model Mechanobiol 10:67–77Rho JY, Kuhn-Spearing L, Zioupos P (1998) Mechanical properties and the hierarchical structure of bone. Med Eng Phys 20:92–102Robinson RA, Rochester MD (1952) An electron-microscopic study of the crystalline inorganic component of bone and its relationship to the organic matrix. J Bone Joint Surg 34–a:389–435Roque WL, Arcaro K, Alberich-Bayarri A (2013) Mechanical competence of bone: a new parameter to grade trabecular bone fragility from tortuosity and elasticity. IEEE Trans Bio Eng 60:1363–1370Rubin MA, Jasiuk I, Taylor J, Rubin J, Ganey T, Apkarian RP (2003) TEM analysis of the nanostructure of normal and osteoporotic human trabecular bone. Bone 33:270–282Sasaki N, Tagami A, Goto T, Taniguchi M, Nakata M, Hikichi K (2002) Atomic force microscopic studies on the structure of bovine femoral cortical bone at the collagen fibril-mineral level. J Mater Sci Mater Med 13(3):333–337Schaffler MB, Burr DB (1988) Stiffness of compact bone: effects of porosity and density. J Biomech 21:13–16Silver FH, Landis WJ (2011) Deposition of apatite in mineralizing vertebrate extracellular matrices: a model of possible nucleation sites on type I collagen. Connect Tissue Res 52:242–254Tommasini SM, Nasser P, Hu B, Jepsen KJ (2008) Biological co-adaptation of morphological and composition traits contributes to mechanical functionality and skeletal fragility. J Bone Miner Res 23:236–246Ulrich D, Rietbergen B, Weinans H, Rüegsegger P (1998) Finite element analysis of trabecular bone structure: a comparison of image-based meshing techniques. J Biomech 31:1187–1192Ulrich D, Rietbergen B, Laib A, Rüegsegger P (1999) The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone. Bone 25:55–60Vercher A, Giner E, Arango C, Tarancón JE, Fuenmayor FJ (2014) Homogenized stiffness matrices for mineralized collagen fibrils and lamellar bone using unit cell finite element models. Biomech Model Mechanobiol 13:437–449Vercher-Martínez A, Giner E, Arango C, Fuenmayor FJ (2015) Influence of the mineral staggering on the elastic properties of the mineralized collagen fibril in lamellar bone. J Mech Behav Biomed Mater 42:243–256Wagermaier W, Gupta HS, Gourrier A, Burghammer M, Roschger P, Fratzl P (2006) Spiral twisting of fiber orientation inside bone lamellae. Biointerphases 1:1–5Weiner S, Traub W (1986) Organization of hydroxiapatite within collagen fibrils. FEBS Lett 206:262–266Weiner S, Wagner HD (1998) The material bone: structure-mechanical function relations. Annu Rev Mater Sci 28:271–298Yang L, Palermo L, Black DM, Eastell R (2014) Prediction of incident hip fracture with the estimated femoral strength by finite element analysis of DXA scans in the study of osteoporotic fractures. JBMR 29:2594–2600Yuan YJ, Cowin SC (2008a) The estimated elastic constants for a single bone osteonal lamella. Biomech Model Mechanobiol 7:1–11Yu W, Glüer CC, Grampp S, Jergas M, Fuerst T, Wu CY, Lu Y, Fan B, Genant HK (1995) Spinal bone mineral assessment in postmenopausal women: a comparison between dual X-ray absorptiometry and quantitative computed tomography. Osteoporos Int 5:433–439Yang L, Palermo L, Black DM, Eastell R (2014) Prediction of incident hip fracture with the estimated femoral strength by finite element analysis of DXS Scans in the study of osteoporotic fractures. J Bone Miner Res 29(12):2594–2600Yuan F, Stock SR, Haeffner DR, Almer JD, Dunand DC, Brinson LC (2011) A new model to simulate the elastic properties of mineralized collagen fibril. Biomech Model Mechanobiol 10:147–16

Transcriptional responses of winter barley to cold indicate nucleosome remodelling as a specific feature of crown tissues

We report a series of microarray-based comparisons of gene expression in the leaf and crown of the winter barley cultivar Luxor, following the exposure of young plants to various periods of low (above and below zero) temperatures. A transcriptomic analysis identified genes which were either expressed in both the leaf and crown, or specifically in one or the other. Among the former were genes responsible for calcium and abscisic acid signalling, polyamine synthesis, late embryogenesis abundant proteins and dehydrins. In the crown, the key organ for cereal overwintering, cold treatment induced transient changes in the transcription of nucleosome assembly genes, and especially H2A and HTA11, which have been implicated in cold sensing in Arabidopsis thaliana. In the leaf, various heat-shock proteins were induced. Differences in expression pattern between the crown and leaf were frequent for genes involved in certain pathways responsible for osmolyte production (sucrose and starch, raffinose, γ-aminobutyric acid metabolism), sugar signalling (trehalose metabolism) and secondary metabolism (lignin synthesis). The action of proteins with antifreeze activity, which were markedly induced during hardening, was demonstrated by a depression in the ice nucleation temperature

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2

In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today’s technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics

FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1

We review the physics opportunities of the Future Circular Collider, covering its e+e-, pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics