Real-Time and Low-Cost Sensing Technique Based on Photonic Bandgap Structures

This paper was published in OPTICS LETTERS and is made available as an electronic reprint with the permission of OSA. The paper can be found at the following URL on the OSA website: http://dx.doi.org/10.1364/OL.36.002707. Systematic or multiple reproduction or distribution to multiple locations via electronic or other means is prohibited and is subject to penalties under law[EN] A technique for the development of low-cost and high-sensitivity photonic biosensing devices is proposed and experimentally demonstrated. In this technique, a photonic bandgap structure is used as transducer, but its readout is performed by simply using a broadband source, an optical filter, and a power meter, without the need of obtaining the transmission spectrum of the structure; thus, a really low-cost system and real-time results are achieved. Experimental results show that it is possible to detect very low refractive index variations, achieving a detection limit below 2 x 10(-6) refractive index units using this low-cost measuring technique. (C) 2011 Optical Society of America[This work was funded by the Spanish Ministerio de Ciencia e Innovacion (MICINN) under contracts TEC2008-06333, JCI-009-5805, and TEC2008-05490. Support by the Universidad Politecnica de Valencia through program PAID-06-09 and the Conselleria d'Educacio through program GV-2010-031 is acknowledged.García Castelló, J.; Toccafondo, V.; Pérez Millán, P.; Sánchez Losilla, N.; Cruz, JL.; Andres, MV.; García-Rupérez, J. (2011). Real-Time and Low-Cost Sensing Technique Based on Photonic Bandgap Structures. Optics Letters. 36(14):2707-2709. https://doi.org/10.1364/OL.36.002707S270727093614Fan, X., White, I. M., Shopova, S. I., Zhu, H., Suter, J. D., & Sun, Y. (2008). Sensitive optical biosensors for unlabeled targets: A review. Analytica Chimica Acta, 620(1-2), 8-26. doi:10.1016/j.aca.2008.05.022Homola, J., Yee, S. S., & Gauglitz, G. (1999). Surface plasmon resonance sensors: review. Sensors and Actuators B: Chemical, 54(1-2), 3-15. doi:10.1016/s0925-4005(98)00321-9Kersey, A. D., Davis, M. A., Patrick, H. J., LeBlanc, M., Koo, K. P., Askins, C. G., … Friebele, E. J. (1997). Fiber grating sensors. Journal of Lightwave Technology, 15(8), 1442-1463. doi:10.1109/50.618377De Vos, K., Bartolozzi, I., Schacht, E., Bienstman, P., & Baets, R. (2007). Silicon-on-Insulator microring resonator for sensitive and label-free biosensing. Optics Express, 15(12), 7610. doi:10.1364/oe.15.007610Iqbal, M., Gleeson, M. A., Spaugh, B., Tybor, F., Gunn, W. G., Hochberg, M., … Gunn, L. C. (2010). Label-Free Biosensor Arrays Based on Silicon Ring Resonators and High-Speed Optical Scanning Instrumentation. IEEE Journal of Selected Topics in Quantum Electronics, 16(3), 654-661. doi:10.1109/jstqe.2009.2032510Xu, D.-X., Vachon, M., Densmore, A., Ma, R., Delâge, A., Janz, S., … Schmid, J. H. (2010). Label-free biosensor array based on silicon-on-insulator ring resonators addressed using a WDM approach. Optics Letters, 35(16), 2771. doi:10.1364/ol.35.002771Skivesen, N., Têtu, A., Kristensen, M., Kjems, J., Frandsen, L. H., & Borel, P. I. (2007). Photonic-crystal waveguide biosensor. Optics Express, 15(6), 3169. doi:10.1364/oe.15.003169Lee, M. R., & Fauchet, P. M. (2007). Nanoscale microcavity sensor for single particle detection. Optics Letters, 32(22), 3284. doi:10.1364/ol.32.003284García-Rupérez, J., Toccafondo, V., Bañuls, M. J., Castelló, J. G., Griol, A., Peransi-Llopis, S., & Maquieira, Á. (2010). Label-free antibody detection using band edge fringes in SOI planar photonic crystal waveguides in the slow-light regime. Optics Express, 18(23), 24276. doi:10.1364/oe.18.024276Toccafondo, V., García-Rupérez, J., Bañuls, M. J., Griol, A., Castelló, J. G., Peransi-Llopis, S., & Maquieira, A. (2010). Single-strand DNA detection using a planar photonic-crystal-waveguide-based sensor. Optics Letters, 35(21), 3673. doi:10.1364/ol.35.003673Luff, B. J., Wilson, R., Schiffrin, D. J., Harris, R. D., & Wilkinson, J. S. (1996). Integrated-optical directional coupler biosensor. Optics Letters, 21(8), 618. doi:10.1364/ol.21.000618Sepúlveda, B., Río, J. S. del, Moreno, M., Blanco, F. J., Mayora, K., Domínguez, C., & Lechuga, L. M. (2006). Optical biosensor microsystems based on the integration of highly sensitive Mach–Zehnder interferometer devices. Journal of Optics A: Pure and Applied Optics, 8(7), S561-S566. doi:10.1088/1464-4258/8/7/s41Densmore, A., Vachon, M., Xu, D.-X., Janz, S., Ma, R., Li, Y.-H., … Schmid, J. H. (2009). Silicon photonic wire biosensor array for multiplexed real-time and label-free molecular detection. Optics Letters, 34(23), 3598. doi:10.1364/ol.34.003598Povinelli, M. L., Johnson, S. G., & Joannopoulos, J. D. (2005). Slow-light, band-edge waveguides for tunable time delays. Optics Express, 13(18), 7145. doi:10.1364/opex.13.007145Garcia, J., Sanchis, P., Martinez, A., & Marti, J. (2008). 1D periodic structures for slow-wave induced non-linearity enhancement. Optics Express, 16(5), 3146. doi:10.1364/oe.16.003146Pérez-Millán, P., Torres-Peiró, S., Cruz, J. L., & Andrés, M. V. (2008). Fabrication of chirped fiber Bragg gratings by simple combination of stretching movements. Optical Fiber Technology, 14(1), 49-53. doi:10.1016/j.yofte.2007.07.00

Integrated optical bimodal waveguide biosensors : principles and applications

Altres ajuts: the ICN2 is funded by the CERCA program/Generalitat de Catalunya.Integrated optical biosensors have become one of the most compelling technologies for the achievement of highly sensitive, multianalyte, portable and easy to use point-of-care (POC) devices with tremendous impact in healthcare and environmental protection, among other application fields. In this context, bimodal waveguide (BiMW) interferometers have emerged over the last years as a powerful biosensor technology providing the benefits of extreme sensitivity under a label-free scheme, reliability and robustness within a highly compact footprint that can be integrated and multiplexed in lab-on-a-chip (LOC) platforms. In this review, we provide an overview of the state-of-the-art about integrated optical BiMW biosensors from the theoretical fundamentals to their practical implementation. Furthermore, we explore recent advances such as novel designs, integration in specific LOC systems and its application in real biosensing scenarios. Final remarks and perspectives on the potential impact of these biosensor interferometric structures are also provided, as well as some limitations that must be addressed in next steps

Real-time observation of antigen¿antibody association using a low-cost biosensing system based on photonic bandgap structures

This paper was published in OPTICS LETTERS and is made available as an electronic reprint with the permission of OSA. The paper can be found at the following URL on the OSA website: http://dx.doi.org/10.1364/OL.37.003684. Systematic or multiple reproduction or distribution to multiple locations via electronic or other means is prohibited and is subject to penalties under law[EN] In this letter, we present experimental results of antibody detection using a biosensor based on photonic bandgap structures, which are interrogated using a power-based readout technique. This interrogation method allows a realtime monitoring of the association process between the antigen probes and the target antibodies, allowing the instantaneous observation of any interaction event between molecules. because etunable lasers and optical spectrum analyzers are avoided for the readout, a drastic reduction of the final cost of the platform is obtained. Furthermore, the performance of the biosensing system is significantly enhanced due to the large number of data values obtained per second.This work was partially funded by the European Commission under contract FP7-295043-BELERA, from the Spanish Ministerio de Ciencia e Innovacion (MICINN) under contracts TEC2008-06333 and CTQ2010-15943 (subprogram BQU), and from Generalitat Valenciana through the PROMETEO grants 2010-008 and 2012-087.García Castelló, J.; Toccafondo, V.; Escorihuela Fuentes, J.; Bañuls Polo, MJ.; Maquieira Catala, Á.; García-Rupérez, J. (2012). Real-time observation of antigen¿antibody association using a low-cost biosensing system based on photonic bandgap structures. Optics Letters. 37(17):3684-3686. https://doi.org/10.1364/OL.37.003684S368436863717Luchansky, M. S., & Bailey, R. C. (2011). High-Q Optical Sensors for Chemical and Biological Analysis. Analytical Chemistry, 84(2), 793-821. doi:10.1021/ac2029024Qavi, A. J., & Bailey, R. C. (2010). Multiplexed Detection and Label-Free Quantitation of MicroRNAs Using Arrays of Silicon Photonic Microring Resonators. Angewandte Chemie International Edition, 49(27), 4608-4611. doi:10.1002/anie.201001712García-Rupérez, J., Toccafondo, V., Bañuls, M. J., Castelló, J. G., Griol, A., Peransi-Llopis, S., & Maquieira, Á. (2010). Label-free antibody detection using band edge fringes in SOI planar photonic crystal waveguides in the slow-light regime. Optics Express, 18(23), 24276. doi:10.1364/oe.18.024276Toccafondo, V., García-Rupérez, J., Bañuls, M. J., Griol, A., Castelló, J. G., Peransi-Llopis, S., & Maquieira, A. (2010). Single-strand DNA detection using a planar photonic-crystal-waveguide-based sensor. Optics Letters, 35(21), 3673. doi:10.1364/ol.35.003673Claes, T., Molera, J. G., De Vos, K., Schacht, E., Baets, R., & Bienstman, P. (2009). Label-Free Biosensing With a Slot-Waveguide-Based Ring Resonator in Silicon on Insulator. IEEE Photonics Journal, 1(3), 197-204. doi:10.1109/jphot.2009.2031596Scullion, M. G., Di Falco, A., & Krauss, T. F. (2011). Slotted photonic crystal cavities with integrated microfluidics for biosensing applications. Biosensors and Bioelectronics, 27(1), 101-105. doi:10.1016/j.bios.2011.06.023Zlatanovic, S., Mirkarimi, L. W., Sigalas, M. M., Bynum, M. A., Chow, E., Robotti, K. M., … Grot, A. (2009). Photonic crystal microcavity sensor for ultracompact monitoring of reaction kinetics and protein concentration. Sensors and Actuators B: Chemical, 141(1), 13-19. doi:10.1016/j.snb.2009.06.007Sepúlveda, B., Río, J. S. del, Moreno, M., Blanco, F. J., Mayora, K., Domínguez, C., & Lechuga, L. M. (2006). Optical biosensor microsystems based on the integration of highly sensitive Mach–Zehnder interferometer devices. Journal of Optics A: Pure and Applied Optics, 8(7), S561-S566. doi:10.1088/1464-4258/8/7/s41Claes, T., Bogaerts, W., & Bienstman, P. (2011). Vernier-cascade label-free biosensor with integrated arrayed waveguide grating for wavelength interrogation with low-cost broadband source. Optics Letters, 36(17), 3320. doi:10.1364/ol.36.003320Zinoviev, K. E., Gonzalez-Guerrero, A. B., Dominguez, C., & Lechuga, L. M. (2011). Integrated Bimodal Waveguide Interferometric Biosensor for Label-Free Analysis. Journal of Lightwave Technology, 29(13), 1926-1930. doi:10.1109/jlt.2011.2150734Densmore, A., Vachon, M., Xu, D.-X., Janz, S., Ma, R., Li, Y.-H., … Schmid, J. H. (2009). Silicon photonic wire biosensor array for multiplexed real-time and label-free molecular detection. Optics Letters, 34(23), 3598. doi:10.1364/ol.34.003598Castelló, J. G., Toccafondo, V., Pérez-Millán, P., Losilla, N. S., Cruz, J. L., Andrés, M. V., & García-Rupérez, J. (2011). Real-time and low-cost sensing technique based on photonic bandgap structures. Optics Letters, 36(14), 2707. doi:10.1364/ol.36.002707Krishnamoorthy, G., Bianca Beusink, J., & Schasfoort, R. B. M. (2010). High-throughput surface plasmon resonance imaging-based biomolecular kinetic screening analysis. Analytical Methods, 2(8), 1020. doi:10.1039/c0ay00112

Experimental study of subwavelength grating bimodal waveguides as ultrasensitive interferometric sensors

[EN] Over the recent years, subwavelength grating (SWG) structures have increasingly attracted attention in the area of evanescent-field photonic sensors. In this Letter, for the first time to the best of our knowledge, we demonstrate experimentally the real-time refractive index (RI) sensing using the SWG bimodal interferometric structures. Two different configurations are considered to compare the effect of the nonlinear phase shift, obtained between the two first transverse electromagnetic propagating modes, in the measured bulk sensitivity. Very high experimental values up to 2270 nm/RIU are reached, which perfectly match the numerical simulations and significantly enhance other existing SWG and spectralbased sensors. By measuring the spectral shift, the obtained experimental sensitivity does not depend on the sensor length. As a result, a highly sensitive and compact singlechannel interferometer is experimentally validated for refractive index sensing, thus opening new paths in the field of optical integrated sensors.European Commission (PHC-634013 PHOCNOSIS project); Spanish Government (TEC2015-63838-C3-1-R-OPTONANOSENS project); Universitat Politecnica de Valencia (grant PAID 01-18).Torrijos-Morán, L.; Griol Barres, A.; García-Rupérez, J. (2019). Experimental study of subwavelength grating bimodal waveguides as ultrasensitive interferometric sensors. Optics Letters. 44(19):4702-4705. https://doi.org/10.1364/OL.44.004702S470247054419Cheben, P., Xu, D.-X., Janz, S., & Densmore, A. (2006). Subwavelength waveguide grating for mode conversion and light coupling in integrated optics. Optics Express, 14(11), 4695. doi:10.1364/oe.14.004695Schmid, J. H., Cheben, P., Janz, S., Lapointe, J., Post, E., & Xu, D.-X. (2007). Gradient-index antireflective subwavelength structures for planar waveguide facets. Optics Letters, 32(13), 1794. doi:10.1364/ol.32.001794Bock, P. J., Cheben, P., Schmid, J. H., Lapointe, J., Delâge, A., Janz, S., … Hall, T. J. (2010). Subwavelength grating periodic structures in silicon-on-insulator: a new type of microphotonic waveguide. Optics Express, 18(19), 20251. doi:10.1364/oe.18.020251Halir, R., Bock, P. J., Cheben, P., Ortega‐Moñux, A., Alonso‐Ramos, C., Schmid, J. H., … Janz, S. (2014). Waveguide sub‐wavelength structures: a review of principles and applications. Laser & Photonics Reviews, 9(1), 25-49. doi:10.1002/lpor.201400083Cheben, P., Halir, R., Schmid, J. H., Atwater, H. A., & Smith, D. R. (2018). Subwavelength integrated photonics. Nature, 560(7720), 565-572. doi:10.1038/s41586-018-0421-7Gonzalo Wangüemert-Pérez, J., Cheben, P., Ortega-Moñux, A., Alonso-Ramos, C., Pérez-Galacho, D., Halir, R., … Schmid, J. H. (2014). Evanescent field waveguide sensing with subwavelength grating structures in silicon-on-insulator. Optics Letters, 39(15), 4442. doi:10.1364/ol.39.004442Donzella, V., Sherwali, A., Flueckiger, J., Grist, S. M., Fard, S. T., & Chrostowski, L. (2015). Design and fabrication of SOI micro-ring resonators based on sub-wavelength grating waveguides. Optics Express, 23(4), 4791. doi:10.1364/oe.23.004791Flueckiger, J., Schmidt, S., Donzella, V., Sherwali, A., Ratner, D. M., Chrostowski, L., & Cheung, K. C. (2016). Sub-wavelength grating for enhanced ring resonator biosensor. Optics Express, 24(14), 15672. doi:10.1364/oe.24.015672Yan, H., Huang, L., Xu, X., Chakravarty, S., Tang, N., Tian, H., & Chen, R. T. (2016). Unique surface sensing property and enhanced sensitivity in microring resonator biosensors based on subwavelength grating waveguides. Optics Express, 24(26), 29724. doi:10.1364/oe.24.029724Huang, L., Yan, H., Xu, X., Chakravarty, S., Tang, N., Tian, H., & Chen, R. T. (2017). Improving the detection limit for on-chip photonic sensors based on subwavelength grating racetrack resonators. Optics Express, 25(9), 10527. doi:10.1364/oe.25.010527Benedikovic, D., Berciano, M., Alonso-Ramos, C., Le Roux, X., Cassan, E., Marris-Morini, D., & Vivien, L. (2017). Dispersion control of silicon nanophotonic waveguides using sub-wavelength grating metamaterials in near- and mid-IR wavelengths. Optics Express, 25(16), 19468. doi:10.1364/oe.25.019468Halir, R., Cheben, P., Luque‐González, J. M., Sarmiento‐Merenguel, J. D., Schmid, J. H., Wangüemert‐Pérez, G., … Molina‐Fernández, Í. (2016). Ultra‐broadband nanophotonic beamsplitter using an anisotropic sub‐wavelength metamaterial. Laser & Photonics Reviews, 10(6), 1039-1046. doi:10.1002/lpor.201600213Luque-González, J. M., Herrero-Bermello, A., Ortega-Moñux, A., Molina-Fernández, Í., Velasco, A. V., Cheben, P., … Halir, R. (2018). Tilted subwavelength gratings: controlling anisotropy in metamaterial nanophotonic waveguides. Optics Letters, 43(19), 4691. doi:10.1364/ol.43.004691Jahani, S., Kim, S., Atkinson, J., Wirth, J. C., Kalhor, F., Noman, A. A., … Jacob, Z. (2018). Controlling evanescent waves using silicon photonic all-dielectric metamaterials for dense integration. Nature Communications, 9(1). doi:10.1038/s41467-018-04276-8Torrijos-Morán, L., & García-Rupérez, J. (2019). Single-channel bimodal interferometric sensor using subwavelength structures. Optics Express, 27(6), 8168. doi:10.1364/oe.27.008168Levy, R., & Ruschin, S. (2009). Design of a Single-Channel Modal Interferometer Waveguide Sensor. IEEE Sensors Journal, 9(2), 146-1. doi:10.1109/jsen.2008.2011075Zinoviev, K. E., Gonzalez-Guerrero, A. B., Dominguez, C., & Lechuga, L. M. (2011). Integrated Bimodal Waveguide Interferometric Biosensor for Label-Free Analysis. Journal of Lightwave Technology, 29(13), 1926-1930. doi:10.1109/jlt.2011.2150734Kozma, P., Kehl, F., Ehrentreich-Förster, E., Stamm, C., & Bier, F. F. (2014). Integrated planar optical waveguide interferometer biosensors: A comparative review. Biosensors and Bioelectronics, 58, 287-307. doi:10.1016/j.bios.2014.02.049Levy, R., & Ruschin, S. (2008). Critical sensitivity in hetero-modal interferometric sensor using spectral interrogation. Optics Express, 16(25), 20516. doi:10.1364/oe.16.020516García-Rupérez, J., Toccafondo, V., Bañuls, M. J., Castelló, J. G., Griol, A., Peransi-Llopis, S., & Maquieira, Á. (2010). Label-free antibody detection using band edge fringes in SOI planar photonic crystal waveguides in the slow-light regime. Optics Express, 18(23), 24276. doi:10.1364/oe.18.024276Zhang, W., Serna, S., Le Roux, X., Vivien, L., & Cassan, E. (2016). Highly sensitive refractive index sensing by fast detuning the critical coupling condition of slot waveguide ring resonators. Optics Letters, 41(3), 532. doi:10.1364/ol.41.000532Di Falco, A., O’Faolain, L., & Krauss, T. F. (2009). Chemical sensing in slotted photonic crystal heterostructure cavities. Applied Physics Letters, 94(6), 063503. doi:10.1063/1.3079671Molina-Fernández, Í., Leuermann, J., Ortega-Moñux, A., Wangüemert-Pérez, J. G., & Halir, R. (2019). Fundamental limit of detection of photonic biosensors with coherent phase read-out. Optics Express, 27(9), 12616. doi:10.1364/oe.27.01261

Implications of zoonotic and vector-borne parasites to free-roaming cats in central Spain

Cats are definitive hosts and reservoirs for several parasites, some of which are responsible for serious zoonotic diseases. We conducted a case-control study of data from a trap-neuter-return (TNR) programme (years 2014-2017) designed to examine the prevalence of zoonotic parasites in free-roaming cats living in urban areas of central Spain. In the animal population tested (n = 263), we detected a 29.2% prevalence of endoparasites, including high rates of cestodes (12.9%) and Toxocara cati (11.7%). While faecal samples showed no Toxoplasma gondii oocysts, the seroprevalence of T. gondii infection was 24.2%. Antibodies to Leishmania infantum were detected in 4.8% of the animals, though all skin and blood samples analyzed were PCR negative for this parasite. Ectoparasites (ticks and fleas) were found in 4.6% of the cat population, and 10.6% of the cats were detected with Otodectes cynotis. Finally, 6.3% and 7.9% cats tested positive for feline leukaemia virus and feline immunodeficiency virus, respectively. Our study provides useful information for animal-welfare and public-health, as the parasites detected can affect native wild animals through predation, competition and disease transmission. Our detection of zoonotic parasites such as L. infantum, T. gondii, T. cati, Giardia duodenalis and several ectoparasites prompts an urgent need for health control measures in stray cats.S

Robust Resolution-Enhanced Prostate Segmentation in Magnetic Resonance and Ultrasound Images through Convolutional Neural Networks

[EN] Prostate segmentations are required for an ever-increasing number of medical applications, such as image-based lesion detection, fusion-guided biopsy and focal therapies. However, obtaining accurate segmentations is laborious, requires expertise and, even then, the inter-observer variability remains high. In this paper, a robust, accurate and generalizable model for Magnetic Resonance (MR) and three-dimensional (3D) Ultrasound (US) prostate image segmentation is proposed. It uses a densenet-resnet-based Convolutional Neural Network (CNN) combined with techniques such as deep supervision, checkpoint ensembling and Neural Resolution Enhancement. The MR prostate segmentation model was trained with five challenging and heterogeneous MR prostate datasets (and two US datasets), with segmentations from many different experts with varying segmentation criteria. The model achieves a consistently strong performance in all datasets independently (mean Dice Similarity Coefficient -DSC- above 0.91 for all datasets except for one), outperforming the inter-expert variability significantly in MR (mean DSC of 0.9099 vs. 0.8794). When evaluated on the publicly available Promise12 challenge dataset, it attains a similar performance to the best entries. In summary, the model has the potential of having a significant impact on current prostate procedures, undercutting, and even eliminating, the need of manual segmentations through improvements in terms of robustness, generalizability and output resolutionThis work has been partially supported by a doctoral grant of the Spanish Ministry of Innovation and Science, with reference FPU17/01993Pellicer-Valero, OJ.; González-Pérez, V.; Casanova Ramón-Borja, JL.; Martín García, I.; Barrios Benito, M.; Pelechano Gómez, P.; Rubio-Briones, J.... (2021). Robust Resolution-Enhanced Prostate Segmentation in Magnetic Resonance and Ultrasound Images through Convolutional Neural Networks. Applied Sciences. 11(2):1-17. https://doi.org/10.3390/app11020844S117112Marra, G., Ploussard, G., Futterer, J., & Valerio, M. (2019). Controversies in MR targeted biopsy: alone or combined, cognitive versus software-based fusion, transrectal versus transperineal approach? World Journal of Urology, 37(2), 277-287. doi:10.1007/s00345-018-02622-5Ahdoot, M., Lebastchi, A. H., Turkbey, B., Wood, B., & Pinto, P. A. (2019). Contemporary treatments in prostate cancer focal therapy. Current Opinion in Oncology, 31(3), 200-206. doi:10.1097/cco.0000000000000515Krizhevsky, A., Sutskever, I., & Hinton, G. E. (2017). ImageNet classification with deep convolutional neural networks. Communications of the ACM, 60(6), 84-90. doi:10.1145/3065386Allen, P. D., Graham, J., Williamson, D. C., & Hutchinson, C. E. (s. f.). Differential Segmentation of the Prostate in MR Images Using Combined 3D Shape Modelling and Voxel Classification. 3rd IEEE International Symposium on Biomedical Imaging: Macro to Nano, 2006. doi:10.1109/isbi.2006.1624940Freedman, D., Radke, R. J., Tao Zhang, Yongwon Jeong, Lovelock, D. M., & Chen, G. T. Y. (2005). Model-based segmentation of medical imagery by matching distributions. IEEE Transactions on Medical Imaging, 24(3), 281-292. doi:10.1109/tmi.2004.841228Klein, S., van der Heide, U. A., Lips, I. M., van Vulpen, M., Staring, M., & Pluim, J. P. W. (2008). Automatic segmentation of the prostate in 3D MR images by atlas matching using localized mutual information. Medical Physics, 35(4), 1407-1417. doi:10.1118/1.2842076Ronneberger, O., Fischer, P., & Brox, T. (2015). U-Net: Convolutional Networks for Biomedical Image Segmentation. 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Moderate SIRT1 overexpression protects against brown adipose tissue inflammation

Objective: Metainflammation is a chronic low-grade inflammatory state induced by obesity and associated comorbidities, including peripheral insulin resistance. Brown adipose tissue (BAT), a therapeutic target against obesity, is an insulin target tissue sensitive to inflammation. Therefore, it is demanding to find strategies to protect BAT against the effects of inflammation in energy balance. In this study we have explored the impact of moderate Sirtuin 1 (SIRT1) overexpression in insulin sensitivity and β-adrenergic responses in BAT and brown adipocytes (BA) under pro-inflammatory conditions. Methods: The effect of inflammation in BAT functionality was studied in obese db/db mice and lean wild-type (WT) mice or mice with moderate overexpression of SIRT1 (SIRT1Tg+) injected a low dose of bacterial lipopolysaccharide (LPS) to mimic endotoxemia. We also conducted studies in differentiated BA (BA-WT and BA-SIRT1Tg+) exposed to a macrophagederived pro-inflammatory conditioned medium (CM) to evaluate the protection of SIRT1 overexpression in insulin signaling and glucose uptake, mitochondrial respiration, fatty acid oxidation (FAO), as well as norepinephrine (NE)-mediated-modulation of uncoupling protein-1 (UCP-1) expression. Results: BAT from db/db mice was susceptible to metabolic inflammation manifested by activation of pro-inflammatory signaling cascades, increased pro-inflammatory gene expression, tissue-specific insulin resistance and reduced UCP-1 expression. Impairment of insulin and noradrenergic responses were also found in lean WT mice upon LPS injection. By contrast, BAT from mice with moderate overexpression of SIRT1 (SIRT1Tg+) was protected against LPSinduced activation of pro-inflammatory signaling, insulin resistance and defective thermogenicrelated responses upon cold exposure. Importantly, the drop of triiodothyronine (T3) levels both in circulation and intra-BAT after exposure of WT mice to LPS and cold was markedly attenuated in SIRT1Tg+ mice. In vitro experiments in BA from the two genotypes revealed that upon differentiation with a T3-enriched medium and subsequent exposure to a macrophagederived pro-inflammatory CM, only BA-SIRT1Tg+ fully recovered insulin and noradrenergic responses. Conclusion: This study has unraveled the benefit of moderate overexpression of SIRT1 to confer protection against defective insulin and β-adrenergic responses caused by inflammation in BAT. Our results have potential therapeutic value proposing combinatorial therapies of BATspecific thyromimetics and SIRT1 activators to combat metainflammation in this tissue