On occurrence of spectral edges for periodic operators inside the Brillouin zone

The article discusses the following frequently arising question on the spectral structure of periodic operators of mathematical physics (e.g., Schroedinger, Maxwell, waveguide operators, etc.). Is it true that one can obtain the correct spectrum by using the values of the quasimomentum running over the boundary of the (reduced) Brillouin zone only, rather than the whole zone? Or, do the edges of the spectrum occur necessarily at the set of ``corner'' high symmetry points? This is known to be true in 1D, while no apparent reasons exist for this to be happening in higher dimensions. In many practical cases, though, this appears to be correct, which sometimes leads to the claims that this is always true. There seems to be no definite answer in the literature, and one encounters different opinions about this problem in the community. In this paper, starting with simple discrete graph operators, we construct a variety of convincing multiply-periodic examples showing that the spectral edges might occur deeply inside the Brillouin zone. On the other hand, it is also shown that in a ``generic'' case, the situation of spectral edges appearing at high symmetry points is stable under small perturbations. This explains to some degree why in many (maybe even most) practical cases the statement still holds.Comment: 25 pages, 10 EPS figures. Typos corrected and a reference added in the new versio

Effect of Harmonicity on the Detection of a Signal in a Complex Masker and on Spatial Release from Masking

The amount of masking of sounds from one source (signals) by sounds from a competing source (maskers) heavily depends on the sound characteristics of the masker and the signal and on their relative spatial location. Numerous studies investigated the ability to detect a signal in a speech or a noise masker or the effect of spatial separation of signal and masker on the amount of masking, but there is a lack of studies investigating the combined effects of many cues on the masking as is typical for natural listening situations. The current study using free-field listening systematically evaluates the combined effects of harmonicity and inharmonicity cues in multi-tone maskers and cues resulting from spatial separation of target signal and masker on the detection of a pure tone in a multi-tone or a noise masker. A linear binaural processing model was implemented to predict the masked thresholds in order to estimate whether the observed thresholds can be accounted for by energetic masking in the auditory periphery or whether other effects are involved. Thresholds were determined for combinations of two target frequencies (1 and 8 kHz), two spatial configurations (masker and target either co-located or spatially separated by 90 degrees azimuth), and five different masker types (four complex multi-tone stimuli, one noise masker). A spatial separation of target and masker resulted in a release from masking for all masker types. The amount of masking significantly depended on the masker type and frequency range. The various harmonic and inharmonic relations between target and masker or between components of the masker resulted in a complex pattern of increased or decreased masked thresholds in comparison to the predicted energetic masking. The results indicate that harmonicity cues affect the detectability of a tonal target in a complex masker

PF-05280014 (a trastuzumab biosimilar) plus paclitaxel compared with reference trastuzumab plus paclitaxel for HER2-positive metastatic breast cancer: a randomised, double-blind study

BACKGROUND: This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS: Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2 ) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS: The risk ratio for ORR was 0.940 (95% CI: 0.842–1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80–1.25. ORR was 62.5% (95% CI: 57.2–67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3–71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION: When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198967

Computational methodology to determine fluid related parameters on non regular three-dimensional scaffolds

The application of three-dimensional (3D) biomaterials to facilitate the adhesion, proliferation, and differentiation of cells has been widely studied for tissue engineering purposes. The fabrication methods used to improve the mechanical response of the scaffold produce complex and non regular structures. Apart from the mechanical aspect, the fluid behavior in the inner part of the scaffold should also be considered. Parameters such as permeability (k) or wall shear stress (WSS) are important aspects in the provision of nutrients, the removal of metabolic waste products or the mechanically-induced differentiation of cells attached in the trabecular network of the scaffolds. Experimental measurements of these parameters are not available in all labs. However, fluid parameters should be known prior to other types of experiments. The present work compares an experimental study with a computational fluid dynamics (CFD) methodology to determine the related fluid parameters (k and WSS) of complex non regular poly(L-lactic acid) scaffolds based only on the treatment of microphotographic images obtained with a microCT (lCT). The CFD analysis shows similar tendencies and results with low relative difference compared to those of the experimental study, for high flow rates. For low flow rates the accuracy of this prediction reduces. The correlation between the computational and experimental results validates the robustness of the proposed methodology.The authors gratefully acknowledge research support from the Spanish Ministry of Science and Innovation through research project DPI2010-20399-C04-01. The Instituto de Salud Carlos III (ISCIII) through the CIBER initiative and the Platform for Biological Tissue Characterization of the Centro de Investigacion Biomedica en Red en Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN) are also gratefully acknowledged.Acosta Santamaría, VA.; Malvé, M.; Duizabo, A.; Mena Tobar, A.; Gallego Ferrer, G.; García Aznar, J.; Doblare Castellano, M.... (2013). Computational methodology to determine fluid related parameters on non regular three-dimensional scaffolds. Annals of Biomedical Engineering. 41(11):2367-2380. https://doi.org/10.1007/s10439-013-0849-8S236723804111Acosta Santamaría, V., H. Deplaine, D. Mariggió, A. R. Villanueva-Molines, J. M. García-Aznar, J. L. Gómez Ribelles, M. Doblaré, G. Gallego Ferrer, and I. Ochoa. Influence of the macro and micro-porous structure on the mechanical behavior of poly(l-lactic acid) scaffolds. J. Non-Cryst. Solids 358(23):3141–3149, 2012.Adachi, T., Y. Osako, M. Tanaka, M. Hojo, and S. J. Hollister. Framework for optimal design of porous scaffold microstructure by computational simulation of bone regeneration. Biomaterials 27(21):3964–3972, 2006.Adamczyk, Z., and T. G. M. Vandeven. Deposition of particles under external forces in laminar-flow through parallel-plate and cylindrical channels. J. Colloid Interface Sci. 80(2):340–356, 1981.Alberich, B. A., D. Moratal, J. L. Escobar, J. C. Rodríguez, A. Vallés-Lluch, L. Martí-Bonmatí, et al. Microcomputed tomography and microfinite element modeling for evaluating polymer scaffolds architecture and their mechanical properties. J. Biomed. Mater. Res. B Appl. Biomater. 91B(1):191–202, 2009.Al-Munajjed, A., M. Hien, R. Kujat, J. P. Gleeson, and J. Hammer. Influence of pore size on tensile strength, permeability and porosity of hyaluronan-collagen scaffolds. J. Mater. Sci. Mater. Med. 19(8):2859–2864, 2008.Alves da Silva, M. L., A. Martins, A. R. Costa-Pinto, V. M. Correlo, P. Sol, M. Bhattacharya, S. Faria, R. L. Reis, and N. M. Neves. Chondrogenic differentiation of human bone marrow mesenchymal stem cells in chitosan-based scaffolds using a flow-perfusion bioreactor. J. Tissue Eng. Regen. Med. 5(9):722–732, 2011.Ansys (2010) CFX Theory User Manual. Canonsburg, PA: Ansys Software.Brígido, R. D., J. M. Estellés, J. A. Sanz, J. M. García-Aznar, and M. S. Sánchez. Polymer scaffolds with interconnected spherical pores and controlled architecture for tissue engineering: fabrication, mechanical properties, and finite element modeling. J. Biomed. Mater. Res. B Appl. Biomater. 81B(2):448–455, 2007.Byrne, P. D., D. Lacroix, J. A. Planell, D. J. Kelly, and P. J. Prendergast. Simulation of tissue differentiation in a scaffold as a function of porosity, Young’s modulus and dissolution rate: application of mechanobiological models in tissue engineering. Biomaterials 28:5544–5554, 2007.Chor, M. V., and W. Li. A permeability measurement system for tissue engineering scaffolds. Meas. Sci. Technol. 18(1):208–216, 2007.Cozensroberts, C., J. A. Quinn, and D. A. Lauffenburger. Receptor-mediated adhesion phenomena—model studies with the radial-flow detachment assay. Biophys. J. 58(1):107–125, 1990.Davisson, T., R. L. Sah, and A. Ratcliffe. Perfusion increases cell content and matrix synthesis in chondrocyte three-dimensional cultures. Tissue Eng. 8(5):807–816, 2002.Deplaine, H., M. Lebourg, P. Ripalda, A. Vidaurre, P. Sanz-Ramos, G. Mora, F. Prósper, I. Ochoa, M. Doblaré, J. L. Gómez Ribelles, I. Izal-Azcárate, and G. Gallego Ferrer. Biomimetic hydroxyapatite coating on pore walls improves osteointegration of poly(l-lactic acid) scaffolds. J. Biomed. Mater. Res. B Appl. Biomater. 101(1):173–186, 2013.Dias, M. R., P. R. Fernandes, J. M. Guedes, and S. J. Hollister. Permeability analysis of scaffolds for bone tissue engineering. J. Biomech. 45(6):938–944, 2012.Freyman, T. M., I. V. Yannas, and L. J. Gibson. Cellular materials as porous scaffolds for tissue engineering. Prog. Mater Sci. 46:273–282, 2001.Gong, S., H. Wang, Q. Sun, S. T. Xue, and J. Wang. Mechanical properties and in vitro biocompatibility of porous zein scaffolds. Biomaterials 27(20):3793–3799, 2006.Gutierrez, R. A., and E. T. Crumpler. Potential effect of geometry on wall shear stress distribution across scaffold surfaces. Ann. Biomed. Eng. 36(1):77–85, 2008.Hammer, D. A., and D. Lauffenburger. A dynamic-model for receptor-mediated cell adhesion to surfaces. Biophys. J. 52(3):475–487, 1987.Ho, S. T., and D. W. Hutmacher. A comparison of micro CT with other techniques used in the characterization of scaffolds. Biomaterials 27(8):1362–1376, 2006.Ho, M. H., P. Y. Kuo, H. J. Hsieh, T. Y. Hsien, L. T. Hou, J. Y. Lai, and D. M. Wang. Preparation of porous scaffolds by using freeze-extraction and freeze-gelation methods. Biomaterials 25(1):129–138, 2004.Hutmacher, D. W., J. T. Schantz, C. X. Lam, K. C. Tan, and T. C. Lim. State of the art and future directions of scaffold-based bone engineering from a biomaterials perspective. J. Tissue Eng. Regen. Med. 1(4):245–260, 2007.Izal, I., P. Aranda, P. Sanz-Ramos, P. Ripalda, G. Mora, F. Granero-Moltó, H. Deplaine, J. L. Gómez-Ribelles, G. G. Ferrer, V. Acosta, I. Ochoa, J. M. García-Aznar, E. J. Andreu, M. Monleón-Pradas, M. Doblaré, and F. Prósper. Culture of human bone marrow-derived mesenchymal stem cells on of poly(l-lactic acid) scaffolds: potential application for the tissue engineering of cartilage. Knee Surg. Sports Traumatol. Arthrosc., 2012.Kapur, S., D. J. Baylink, and K. H. Lau. Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways. Bone 32(3):241–251, 2003.Karande, T. S., J. L. Ong, and C. M. Agrawal. Diffusion in musculoskeletal tissue engineering scaffolds: design issues related to porosity, permeability, architecture, and nutrient mixing. Ann. Biomed. Eng. 32(12):1728–1743, 2004.Kelly, D. J., and P. J. Prendergast. Mechano-regulation of stem cell differentiation and tissue regeneration in osteochondral defects. J. Biomech. 38(7):1413–1422, 2005.Kreke, M. R., L. A. Sharp, Y. W. Lee, and A. S. Goldstein. Effect of intermittent shear stress on mechanotransductive signaling and osteoblastic differentiation of bone marrow stromal cells. Tissue Eng. Part A 14(4):529–537, 2008.Lacroix, D., A. Chateau, M. P. Ginebra, and J. A. Planell. Micro-finite element models of bone tissue-engineering scaffolds. Biomaterials 27(30):5326–5334, 2006.Lacroix, D., and P. J. Prendergast. A mechano-regulation model for tissue differentiation during fracture healing: analysis of gap size and loading. J. Biomech. 35(9):1163–1171, 2002.Li, S., J. R. De Wijn, J. Li, P. Layrolle, and K. De Groot. Macroporous biphasic calcium phosphate scaffold with high permeability/porosity ratio. Tissue Eng. 9:535–548, 2003.Melchels, F. P. W., B. Tonnarelli, A. L. Olivares, I. Martin, D. Lacroix, J. Feijen, et al. The influence of the scaffold design on the distribution of adhering cells after perfusion cell seeding. Biomaterials 32(11):2878–2884, 2011.O’Brien, F. J., B. A. Harley, M. A. Waller, I. Yannas, L. J. Gibson, and P. Prendergast. The effect of pore size on permeability and cell attachment in collagen scaffolds for tissue engineering. Technol. Health Care 15(1):3–17, 2007.Ochoa, I., J. A. Sanz, J. M. Garcia-Aznar, M. Doblare, D. M. Yunos, and A. R. Boccaccini. Permeability evaluation of 45S5 bioglass-based scaffolds for bone tissue engineering. J. Biomech. 42:257–260, 2009.Porter, B., R. Zauel, H. Stockman, R. Guldberg, and D. Fyhrie. 3-D computational modeling of media flow through scaffolds in a perfusion bioreactor. Mater. Res. 38:543–549, 2005.Sandino, C., S. Checa, P. J. Prendergast, and D. Lacroix. Simulation of angiogenesis and cell differentiation in a CaP scaffold subjected to compressive strains using a lattice modeling approach. Biomaterials 31(8):2446–2452, 2010.Sanz, J. A., J. M. García-Aznar, and M. Doblaré. On scaffold designing for bone regeneration: a computational multiscale approach. Acta Biomater. 5(1):219–229, 2009.Sanz, J. A., C. Kasper, M. van Griensven, J. M. Garcia-Aznar, I. Ochoa, and M. Doblare. Mechanical and flow characterization of Sponceram® carriers: evaluation by homogenization theory and experimental validation. J. Biomed. Mater. Res. B Appl. Biomater. 87B(1):42–48, 2008.Singh, H., S. H. Teoh, H. T. Low, and D. W. Hutmacher. Flow modelling within a scaffold under the influence of uni-axial and bi-axial bioreactor rotation. J. Biotechnol. 119:181–196, 2005.Sjollema, J., and H. J. Busscher. Deposition of polystyrene latex-particles toward polymethylmethacrylate in a parallel plate flow cell. J. Colloid Interface Sci. 132(2):382–394, 1989.Truscello, S., G. Kerckhofs, S. Van Bael, G. Pyka, J. Schrooten, and H. Van Oosterwyck. Prediction of permeability of regular scaffolds for skeletal tissue engineering: a combined computational and experimental study. Acta Biomater. 8(4):1648–1658, 2012.Woodfield, T. B., J. Malda, J. Wijn, F. Péters, J. Riesle, and C. A. van Blitterswijk. Design of porous scaffolds for cartilage tissue engineering using a three-dimensional fiber-deposition technique. Biomaterials 25(18):4149–4161, 2004

Non-Linear Elasticity of Extracellular Matrices Enables Contractile Cells to Communicate Local Position and Orientation

Most tissue cells grown in sparse cultures on linearly elastic substrates typically display a small, round phenotype on soft substrates and become increasingly spread as the modulus of the substrate increases until their spread area reaches a maximum value. As cell density increases, individual cells retain the same stiffness-dependent differences unless they are very close or in molecular contact. On nonlinear strain-stiffening fibrin gels, the same cell types become maximally spread even when the low strain elastic modulus would predict a round morphology, and cells are influenced by the presence of neighbors hundreds of microns away. Time lapse microscopy reveals that fibroblasts and human mesenchymal stem cells on fibrin deform the substrate by several microns up to five cell lengths away from their plasma membrane through a force limited mechanism. Atomic force microscopy and rheology confirm that these strains locally and globally stiffen the gel, depending on cell density, and this effect leads to long distance cell-cell communication and alignment. Thus cells are acutely responsive to the nonlinear elasticity of their substrates and can manipulate this rheological property to induce patterning

Genome-wide association study of REM sleep behavior disorder identifies polygenic risk and brain expression effects

Rapid-eye movement (REM) sleep behavior disorder (RBD), enactment of dreams during REM sleep, is an early clinical symptom of alpha-synucleinopathies and defines a more severe subtype. The genetic background of RBD and its underlying mechanisms are not well understood. Here, we perform a genome-wide association study of RBD, identifying five RBD risk loci near SNCA, GBA, TMEM175, INPP5F, and SCARB2. Expression analyses highlight SNCA-AS1 and potentially SCARB2 differential expression in different brain regions in RBD, with SNCA-AS1 further supported by colocalization analyses. Polygenic risk score, pathway analysis, and genetic correlations provide further insights into RBD genetics, highlighting RBD as a unique alpha-synucleinopathy subpopulation that will allow future early intervention