An optical metamaterial is a composite in which subwavelength features, rather than the constituent materials, control the macroscopic electromagnetic properties of the material. Recently, properly designed metamaterials have garnered much interest because of their unusual interaction with electromagnetic waves. Whereas nature seems to have limits on the type of materials that exist, newly invented metamaterials are not bound by such constraints. These newly accessible electromagnetic properties make these materials an excellent platform for demonstrating unusual optical phenomena and unique applications such as subwavelength imaging and planar lens design. 'Negative-index materials', as first proposed, required the permittivity, epsilon, and permeability, mu, to be simultaneously less than zero, but such materials face limitations. Here, we demonstrate a comparatively low-loss, three-dimensional, all-semiconductor metamaterial that exhibits negative refraction for all incidence angles in the long-wave infrared region and requires only an anisotropic dielectric function with a single resonance. Using reflection and transmission measurements and a comprehensive model of the material, we demonstrate that our material exhibits negative refraction. This is furthermore confirmed through a straightforward beam optics experiment. This work will influence future metamaterial designs and their incorporation into optical semiconductor devices.

The functions of the paralogous transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in bone are controversial. Each has been observed to promote or inhibit osteogenesis in vitro, with reports of both equivalent and divergent functions. Their combinatorial roles in bone physiology are unknown. We report that combinatorial YAP/TAZ deletion from skeletal lineage cells, using Osterix-Cre, caused an osteogenesis imperfecta-like phenotype with severity dependent on allele dose and greater phenotypic expressivity with homozygous TAZ vs. YAP ablation. YAP/TAZ deletion decreased bone accrual and reduced intrinsic bone material properties through impaired collagen content and organization. These structural and material defects produced spontaneous fractures, particularly in mice with homozygous TAZ deletion and caused neonatal lethality in dual homozygous knockouts. At the cellular level in vivo, YAP/TAZ ablation reduced osteoblast activity and increased osteoclast activity, in an allele dose-dependent manner, impairing bone accrual and remodeling. Transcriptionally, YAP/TAZ deletion and small-molecule inhibition of YAP/TAZ interaction with the transcriptional coeffector TEAD reduced osteogenic and collagen-related gene expression, both in vivo and in vitro. These data demonstrate that YAP and TAZ combinatorially promote bone development through regulation of osteoblast activity, matrix quality, and osteoclastic remodeling.-Kegelman, C. D., Mason, D. E., Dawahare, J. H., Horan, D. J., Vigil, G. D., Howard, S. S., Robling, A. G., Bellido, T. M., Boerckel, J. D. Skeletal cell YAP and TAZ combinatorially promote bone development.

Fluorescence microscopy has enabled a dramatic development in modern biology. Due to its inherently weak signal, fluorescence microscopy is not only much noisier than photography, but also presented with Poisson-Gaussian noise where Poisson noise, or shot noise, is the dominating noise source. To get clean fluorescence microscopy images, it is highly desirable to have effective denoising algorithms and datasets that are specifically designed to denoise fluorescence microscopy images. While such algorithms exist, no such datasets are available. In this paper, we fill this gap by constructing a dataset -the Fluorescence Microscopy Denoising (FMD) dataset -that is dedicated to Poisson-Gaussian denoising. The dataset consists of 12,000 real fluorescence microscopy images obtained with commercial confocal, two-photon, and wide-field microscopes and representative biological samples such as cells, zebrafish, and mouse brain tissues. We use image averaging to effectively obtain ground truth images and 60,000 noisy images with different noise levels. We use this dataset to benchmark 10 representative denoising algorithms and find that deep learning methods have the best performance. To our knowledge, this is the first real microscopy image dataset for Poisson-Gaussian denoising purposes and it could be an important tool for high-quality, real-time denoising applications in biomedical research.

We characterize long (up to 285 mm) gradient index (GRIN) lens endoscope systems for multiphoton imaging. We fabricate a portable, rigid endoscope system suitable for imaging unstained tissues, potentially deep within the body, using a GRIN lens system of 1 mm diameter and 8 cm length. The portable device is capable of imaging a ~200 µm diameter field of view at 4 frames/s. The lateral and axial resolution in water is 0.85 µm and 7.4 µm respectively. In vivo images of unstained tissues in live, anesthetized rats using the portable device are presented. These results show great promise for GRIN endoscopy to be used clinically.

Multiphoton microscopy (MPM) is widely used for optical sectioning deep in scattering tissue, in vivo [1][2]. Phosphorescence lifetime imaging microscopy (PLIM) [3] is a powerful technique for obtaining biologically relevant chemical information through Förster resonance energy transfer and phosphorescence quenching [4][5]. Point-measurement PLIM [6] of phosphorescence quenching probes has recently provided oxygen partial pressure measurements in small rodent brain vasculature identified by high-resolution MPM [7,8]. However, the maximum fluorescence generation rate, which is inversely proportional to the phosphorescence lifetime, fundamentally limits PLIM pixel rates. Here we experimentally demonstrate a parallel-excitation/parallel collection MPM-PLIM system that increases pixel rate by a factor of 100 compared with conventional configurations while simultaneously acquiring lifetime and intensity images at depth in vivo. Full-frame three-dimensional in vivo PLIM imaging of phosphorescent quenching dye is presented for the first time and defines a new platform for biological and medical imaging.Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms * Corresponding Authors: Scott Howard < showard@nd.edu>, Chris Xu < cx10@cornell.edu>. AUTHOR CONTRIBUTIONS S.H. coordinated the project, designed and built the microscope, designed and fabricated the linear spatial light modulator, wrote control and image processing software, performed simulations, wrote analysis algorithms, analyzed data, preformed animal preparation and surgery, prepared dye and calibrations, and wrote the paper. A.S. greatly assisted with microscope design and assembly, performed simulations and analysis, wrote analysis algorithms, significantly contributed to the content of the paper, and performed experiments verifying pixel rate increase. N.H. and D.K. assisted in animal preparation and surgery for imaging. C.X. initiated the project, significantly contributed to the design of M4 and experimental design, and greatly contributed to the theoretical and experimental discussions. All authors contributed to manuscript editing. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptCurrent technologies for overcoming the fundamental pixel rate limitation of serialacquisition MPM require parallel excitation and imaging a sample onto multi-element detectors (typically CCD) [9][10]. While satisfactory for thin tissue slices or non-scattering samples, thick scattering samples typically encountered in in vivo applications cause crosstalk between excited pixels when imaged onto a detector array, resulting in smeared images [11]. State-of-the-art fast fluorescence lifetime imaging microscopy systems utilize parallel excitation (e.g. LED arrays or pulsed diode excitation) or collection (e.g. gated CCD, single photon avalanche dio...