The development of a database and bioinformatics applications for the investigation of immune genes

The extensive allelic variability observed in several genes related to the immune response and its significance in transplantation, disease association studies and diversity in human populations has led the scientific community to analyse these variants among individuals. This thesis is focussed on the development of a database and software applications for the investigation of several immune genes and the frequencies of their corresponding alleles in worldwide human populations. The approach presented in this thesis includes the design of a relational database, a web interface, the design of models for data exchange and the development of online searching mechanisms for the analysis of allele, haplotype and genotype frequencies. At present, the database contains data from more than 1000 populations covering more than four million unrelated individuals. The repertory of datasets available in the database encompasses different polymorphic regions such as Human Leukocyte Antigens (HLA), Killer-cell Immunoglobulin-like Receptors (KIR), Major histocompatibility complex Class I chain-related (MIC) genes and a number of cytokine gene polymorphisms. The work presented in this document has been shown to be a valuable resource for the medical and scientific societies. Acting as a primary source for the consultation of immune gene frequencies in worldwide populations, the database has been widely used in a variety of contexts by scientists, including histocompatibility, immunology, epidemiology, pharmacogenetics and population genetics among many others. In the last year (August 2010 to August 2011), the website was accessed by 15,784 distinct users from 2,758 cities in 136 countries and has been cited in 168 peer-reviewed publications demonstrating its wide international use

Library of Apicomplexan Metabolic Pathways: a manually curated database for metabolic pathways of apicomplexan parasites.

The Library of Apicomplexan Metabolic Pathways (LAMP, http://www.llamp.net) is a web database that provides near complete mapping from genes to the central metabolic functions for some of the prominent intracellular parasites of the phylum Apicomplexa. This phylum includes the causative agents of malaria, toxoplasmosis and theileriosis-diseases with a huge economic and social impact. A number of apicomplexan genomes have been sequenced, but the accurate annotation of gene function remains challenging. We have adopted an approach called metabolic reconstruction, in which genes are systematically assigned to functions within pathways/networks for Toxoplasma gondii, Neospora caninum, Cryptosporidium and Theileria species, and Babesia bovis. Several functions missing from pathways have been identified, where the corresponding gene for an essential process appears to be absent from the current genome annotation. For each species, LAMP contains interactive diagrams of each pathway, hyperlinked to external resources and annotated with detailed information, including the sources of evidence used. We have also developed a section to highlight the overall metabolic capabilities of each species, such as the ability to synthesize or the dependence on the host for a particular metabolite. We expect this new database will become a valuable resource for fundamental and applied research on the Apicomplexa

New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy

[EN] Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obtained systems.The authors want to thank the Spanish Government (project RTI2018-100910-B-C41 (MCUI/AEI/FEDER, UE)) and the Generalitat Valenciana (project PROMETEO/2018/024) for support. This work was also supported by the project "MODELOS IN VITRO DE EVALUACION BIOFARMACEUTICA" SAF2016-78756(AEI/FEDER, EU) funded by Agencia Estatal Investigacion and European Union, through FEDER (Fondo Europeo de Desarrollo Regional).Hernández Teruel, A.; Gonzalez-Alvarez, I.; Bermejo, M.; Merino Sanjuán, V.; Marcos Martínez, MD.; Sancenón Galarza, F.; Gonzalez-Alvarez, M.... (2020). New Insights of Oral Colonic Drug Delivery Systems for Inflammatory Bowel Disease Therapy. International Journal of Molecular Sciences. 21(18):1-30. https://doi.org/10.3390/ijms21186502S1302118Lautenschläger, C., Schmidt, C., Fischer, D., & Stallmach, A. (2014). Drug delivery strategies in the therapy of inflammatory bowel disease. Advanced Drug Delivery Reviews, 71, 58-76. doi:10.1016/j.addr.2013.10.001Nakai, D., Miyake, M., & Hashimoto, A. (2020). Comparison of the Intestinal Drug Permeation and Accumulation Between Normal Human Intestinal Tissues and Human Intestinal Tissues With Ulcerative Colitis. Journal of Pharmaceutical Sciences, 109(4), 1623-1626. doi:10.1016/j.xphs.2019.12.015Kaser, A., Zeissig, S., & Blumberg, R. S. (2010). Inflammatory Bowel Disease. Annual Review of Immunology, 28(1), 573-621. doi:10.1146/annurev-immunol-030409-101225Xu, X.-M., & Zhang, H.-J. (2016). miRNAs as new molecular insights into inflammatory bowel disease: Crucial regulators in autoimmunity and inflammation. World Journal of Gastroenterology, 22(7), 2206-2218. doi:10.3748/wjg.v22.i7.2206Kim, D. H., & Cheon, J. H. (2017). Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. Immune Network, 17(1), 25. doi:10.4110/in.2017.17.1.25Inflammatory Bowel Disease | British Society for Immunology https://www.immunology.org/es/public-information/bitesized-immunology/immune-dysfunction/enfermedad-inflamatoria-intestinalJay, M., Beihn, R. M., Digenis, G. A., Deland, F. H., Caldwell, L., & Mlodozeniec, A. R. (1985). Disposition of radiolabelled suppositories in humans. Journal of Pharmacy and Pharmacology, 37(4), 266-268. doi:10.1111/j.2042-7158.1985.tb05058.xNewton, A. M. J., & Lakshmanan, P. (2014). Effect of HPMC - E15 LV premium Polymer on Release Profile and Compression Characteristics of Chitosan/ Pectin Colon Targeted Mesalamine Matrix Tablets and in vitro Study on Effect of pH Impact on the Drug Release Profile. Recent Patents on Drug Delivery & Formulation, 8(1), 46-62. doi:10.2174/1872211308666140225143926DeFilippis, E. M., Longman, R., Harbus, M., Dannenberg, K., & Scherl, E. J. (2016). Crohn’s Disease: Evolution, Epigenetics, and the Emerging Role of Microbiome-Targeted Therapies. Current Gastroenterology Reports, 18(3). doi:10.1007/s11894-016-0487-zNeurath, M. F., & Travis, S. P. L. (2012). Mucosal healing in inflammatory bowel diseases: a systematic review. Gut, 61(11), 1619-1635. doi:10.1136/gutjnl-2012-302830Hua, S., Marks, E., Schneider, J. J., & Keely, S. (2015). Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue. Nanomedicine: Nanotechnology, Biology and Medicine, 11(5), 1117-1132. doi:10.1016/j.nano.2015.02.018Hu, Z., Mawatari, S., Shibata, N., Takada, K., Yoshikawa, H., Arakawa, A., & Yosida, Y. (2000). Pharmaceutical Research, 17(2), 160-167. doi:10.1023/a:1007561129221Rana, S. V., Sharma, S., Malik, A., Kaur, J., Prasad, K. K., Sinha, S. K., & Singh, K. (2013). Small Intestinal Bacterial Overgrowth and Orocecal Transit Time in Patients of Inflammatory Bowel Disease. Digestive Diseases and Sciences, 58(9), 2594-2598. doi:10.1007/s10620-013-2694-xPhilip, A., & Philip, B. (2010). Colon Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches. Oman Medical Journal, 25(2), 70-78. doi:10.5001/omj.2010.24Rao, K. A. (2004). Objective evaluation of small bowel and colonic transit time using pH telemetry in athletes with gastrointestinal symptoms. British Journal of Sports Medicine, 38(4), 482-487. doi:10.1136/bjsm.2003.006825Podolsky, D. K. (2002). Inflammatory Bowel Disease. New England Journal of Medicine, 347(6), 417-429. doi:10.1056/nejmra020831Hebden, Blackshaw, Perkins, Wilson, & Spiller. (2000). Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis. Alimentary Pharmacology & Therapeutics, 14(2), 155-161. doi:10.1046/j.1365-2036.2000.00697.xFallingborg, J., Christensen, L. A., Jacobsen, B. A., & Rasmussen, S. N. (1993). Very low intraluminal colonic pH in patients with active ulcerative colitis. Digestive Diseases and Sciences, 38(11), 1989-1993. doi:10.1007/bf01297074Bratten, J., & Jones, M. P. (2006). New Directions in the Assessment of Gastric Function: Clinical Applications of Physiologic Measurements. Digestive Diseases, 24(3-4), 252-259. doi:10.1159/000092878NUGENT, S. G. (2001). Intestinal luminal pH in inflammatory bowel disease: possible determinants and implications for therapy with aminosalicylates and other drugs. Gut, 48(4), 571-577. doi:10.1136/gut.48.4.571Collnot, E.-M., Ali, H., & Lehr, C.-M. (2012). Nano- and microparticulate drug carriers for targeting of the inflamed intestinal mucosa. Journal of Controlled Release, 161(2), 235-246. doi:10.1016/j.jconrel.2012.01.028Sinha, V. R., & Kumria, R. (2001). Pharmaceutical Research, 18(5), 557-564. doi:10.1023/a:1011033121528Gorbach, S. L. (1971). Intestinal Microflora. Gastroenterology, 60(6), 1110-1129. doi:10.1016/s0016-5085(71)80039-2Simon, G. L., & Gorbach, S. L. (1986). The human intestinal microflora. Digestive Diseases and Sciences, 31(S9), 147-162. doi:10.1007/bf01295996Rubinstein, A. (1990). Microbially controlled drug delivery to the colon. Biopharmaceutics & Drug Disposition, 11(6), 465-475. doi:10.1002/bdd.2510110602Sartor, R. B. (2008). Therapeutic correction of bacterial dysbiosis discovered by molecular techniques. Proceedings of the National Academy of Sciences, 105(43), 16413-16414. doi:10.1073/pnas.0809363105Liu, T.-C., & Stappenbeck, T. S. (2016). Genetics and Pathogenesis of Inflammatory Bowel Disease. Annual Review of Pathology: Mechanisms of Disease, 11(1), 127-148. doi:10.1146/annurev-pathol-012615-044152Xiao, B., & Merlin, D. (2012). Oral colon-specific therapeutic approaches toward treatment of inflammatory bowel disease. Expert Opinion on Drug Delivery, 9(11), 1393-1407. doi:10.1517/17425247.2012.730517Lamprecht, A., Yamamoto, H., Takeuchi, H., & Kawashima, Y. (2005). Nanoparticles Enhance Therapeutic Efficiency by Selectively Increased Local Drug Dose in Experimental Colitis in Rats. Journal of Pharmacology and Experimental Therapeutics, 315(1), 196-202. doi:10.1124/jpet.105.088146Beloqui, A., Coco, R., Alhouayek, M., Solinís, M. Á., Rodríguez-Gascón, A., Muccioli, G. G., & Préat, V. (2013). Budesonide-loaded nanostructured lipid carriers reduce inflammation in murine DSS-induced colitis. International Journal of Pharmaceutics, 454(2), 775-783. doi:10.1016/j.ijpharm.2013.05.017Desai, M. P., Labhasetwar, V., Amidon, G. L., & Levy, R. J. (1996). Pharmaceutical Research, 13(12), 1838-1845. doi:10.1023/a:1016085108889Naeem, M., Bae, J., A. Oshi, M., Kim, M.-S., Moon, H. R., Lee, B. L., … Yoo, J.-W. (2018). Colon-targeted delivery of cyclosporine A using dual-functional Eudragit® FS30D/PLGA nanoparticles ameliorates murine experimental colitis. International Journal of Nanomedicine, Volume 13, 1225-1240. doi:10.2147/ijn.s157566Oshi, M. A., Naeem, M., Bae, J., Kim, J., Lee, J., Hasan, N., … Yoo, J.-W. (2018). Colon-targeted dexamethasone microcrystals with pH-sensitive chitosan/alginate/Eudragit S multilayers for the treatment of inflammatory bowel disease. Carbohydrate Polymers, 198, 434-442. doi:10.1016/j.carbpol.2018.06.107Date, A. A., Hanes, J., & Ensign, L. M. (2016). Nanoparticles for oral delivery: Design, evaluation and state-of-the-art. Journal of Controlled Release, 240, 504-526. doi:10.1016/j.jconrel.2016.06.016Vass, P., Démuth, B., Hirsch, E., Nagy, B., Andersen, S. K., Vigh, T., … Marosi, G. (2019). Drying technology strategies for colon-targeted oral delivery of biopharmaceuticals. Journal of Controlled Release, 296, 162-178. doi:10.1016/j.jconrel.2019.01.023Taghipour, Y. D., Bahramsoltani, R., Marques, A. M., Naseri, R., Rahimi, R., Haratipour, P., … Abdollahi, M. (2018). A systematic review of nano formulation of natural products for the treatment of inflammatory bowel disease: drug delivery and pharmacological targets. DARU Journal of Pharmaceutical Sciences, 26(2), 229-239. doi:10.1007/s40199-018-0222-4Zhang, M., & Merlin, D. (2018). Nanoparticle-Based Oral Drug Delivery Systems Targeting the Colon for Treatment of Ulcerative Colitis. Inflammatory Bowel Diseases, 24(7), 1401-1415. doi:10.1093/ibd/izy123Varum, F., Freire, A. C., Bravo, R., & Basit, A. W. (2020). OPTICORE™, an innovative and accurate colonic targeting technology. International Journal of Pharmaceutics, 583, 119372. doi:10.1016/j.ijpharm.2020.119372Lee, S. H., Bajracharya, R., Min, J. Y., Han, J.-W., Park, B. J., & Han, H.-K. (2020). Strategic Approaches for Colon Targeted Drug Delivery: An Overview of Recent Advancements. Pharmaceutics, 12(1), 68. doi:10.3390/pharmaceutics12010068Nidhi, Rashid, M., Kaur, V., Hallan, S. S., Sharma, S., & Mishra, N. (2016). Microparticles as controlled drug delivery carrier for the treatment of ulcerative colitis: A brief review. Saudi Pharmaceutical Journal, 24(4), 458-472. doi:10.1016/j.jsps.2014.10.001Yoon, S.-W., Shin, D. H., & Kim, J.-S. (2019). Liposomal itraconazole formulation for the treatment of glioblastoma using inclusion complex with HP-β-CD. Journal of Pharmaceutical Investigation, 49(4), 477-483. doi:10.1007/s40005-019-00432-4Bazan, L., Bendas, E. R., El Gazayerly, O. N., & Badawy, S. S. (2016). Comparative pharmaceutical study on colon targeted micro-particles of celecoxib: in-vitro–in-vivo evaluation. Drug Delivery, 23(9), 3339-3349. doi:10.1080/10717544.2016.1178824Goyanes, A., Hatton, G. B., Merchant, H. A., & Basit, A. W. (2015). Gastrointestinal release behaviour of modified-release drug products: Dynamic dissolution testing of mesalazine formulations. International Journal of Pharmaceutics, 484(1-2), 103-108. doi:10.1016/j.ijpharm.2015.02.051Ma, C., Battat, R., Dulai, P. S., Parker, C. E., Sandborn, W. J., Feagan, B. G., & Jairath, V. (2019). Innovations in Oral Therapies for Inflammatory Bowel Disease. Drugs, 79(12), 1321-1335. doi:10.1007/s40265-019-01169-yBak, A., Ashford, M., & Brayden, D. J. (2018). Local delivery of macromolecules to treat diseases associated with the colon. Advanced Drug Delivery Reviews, 136-137, 2-27. doi:10.1016/j.addr.2018.10.009Yu, A., Baker, J. R., Fioritto, A. F., Wang, Y., Luo, R., Li, S., … Sun, D. (2016). Measurement of in vivo Gastrointestinal Release and Dissolution of Three Locally Acting Mesalamine Formulations in Regions of the Human Gastrointestinal Tract. Molecular Pharmaceutics, 14(2), 345-358. doi:10.1021/acs.molpharmaceut.6b00641Ibekwe, V. C., Fadda, H. M., McConnell, E. L., Khela, M. K., Evans, D. F., & Basit, A. W. (2008). Interplay Between Intestinal pH, Transit Time and Feed Status on the In Vivo Performance of pH Responsive Ileo-Colonic Release Systems. Pharmaceutical Research, 25(8), 1828-1835. doi:10.1007/s11095-008-9580-9Mansuri, S., Kesharwani, P., Jain, K., Tekade, R. K., & Jain, N. K. (2016). Mucoadhesion: A promising approach in drug delivery system. Reactive and Functional Polymers, 100, 151-172. doi:10.1016/j.reactfunctpolym.2016.01.011Agüero, L., Zaldivar-Silva, D., Peña, L., & Dias, M. L. (2017). Alginate microparticles as oral colon drug delivery device: A review. Carbohydrate Polymers, 168, 32-43. doi:10.1016/j.carbpol.2017.03.033Duan, H., Lü, S., Gao, C., Bai, X., Qin, H., Wei, Y., … Liu, M. (2016). Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon. Colloids and Surfaces B: Biointerfaces, 145, 510-519. doi:10.1016/j.colsurfb.2016.05.038Cong, Z., Shi, Y., Wang, Y., Wang, Y., Niu, J., Chen, N., & Xue, H. (2018). A novel controlled drug delivery system based on alginate hydrogel/chitosan micelle composites. International Journal of Biological Macromolecules, 107, 855-864. doi:10.1016/j.ijbiomac.2017.09.065Gareb, B., Dijkstra, G., Kosterink, J. G. W., & Frijlink, H. W. (2019). Development of novel zero-order release budesonide tablets for the treatment of ileo-colonic inflammatory bowel disease and comparison with formulations currently used in clinical practice. International Journal of Pharmaceutics, 554, 366-375. doi:10.1016/j.ijpharm.2018.11.019Gareb, B., Posthumus, S., Beugeling, M., Koopmans, P., Touw, D. J., Dijkstra, G., … Frijlink, H. W. (2019). Towards the Oral Treatment of Ileo-Colonic Inflammatory Bowel Disease with Infliximab Tablets: Development and Validation of the Production Process. Pharmaceutics, 11(9), 428. doi:10.3390/pharmaceutics11090428González-Alvarez, M., Coll, C., Gonzalez-Alvarez, I., Giménez, C., Aznar, E., Martínez-Bisbal, M. C., … Sancenón, F. (2017). Gated Mesoporous Silica Nanocarriers for a «Two-Step» Targeted System to Colonic Tissue. Molecular Pharmaceutics, 14(12), 4442-4453. doi:10.1021/acs.molpharmaceut.7b00565Deng, X.-Q., Zhang, H.-B., Wang, G.-F., Xu, D., Zhang, W.-Y., Wang, Q.-S., & Cui, Y.-L. (2019). Colon-specific microspheres loaded with puerarin reduce tumorigenesis and metastasis in colitis-associated colorectal cancer. International Journal of Pharmaceutics, 570, 118644. doi:10.1016/j.ijpharm.2019.118644Shi, X., Yan, Y., Wang, P., Sun, Y., Zhang, D., Zou, Y., … Dong, Y. (2018). In vitro and in vivo study of pH-sensitive and colon-targeting P(LE-IA-MEG) hydrogel microspheres used for ulcerative colitis therapy. European Journal of Pharmaceutics and Biopharmaceutics, 122, 70-77. doi:10.1016/j.ejpb.2017.10.003Malviya, T., Joshi, S., Dwivedi, L. M., Baranwal, K., Shehala, Pandey, A. K., & Singh, V. (2018). Synthesis of Aloevera/Acrylonitrile based Nanoparticles for targeted drug delivery of 5-Aminosalicylic acid. International Journal of Biological Macromolecules, 106, 930-939. doi:10.1016/j.ijbiomac.2017.08.085Chen, J., Li, X., Chen, L., & Xie, F. (2018). Starch film-coated microparticles for oral colon-specific drug delivery. Carbohydrate Polymers, 191, 242-254. doi:10.1016/j.carbpol.2018.03.025Günter, E. A., & Popeyko, O. V. (2016). Calcium pectinate gel beads obtained from callus cultures pectins as promising systems for colon-targeted drug delivery. Carbohydrate Polymers, 147, 490-499. doi:10.1016/j.carbpol.2016.04.026Qiao, H., Fang, D., Chen, J., Sun, Y., Kang, C., Di, L., … Gao, Y. (2017). Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease. Drug Delivery, 24(1), 233-242. doi:10.1080/10717544.2016.1245367Morales‐Burgos, A. M., Carvajal‐Millan, E., Rascón‐Chu, A., Martínez‐López, A. L., Lizardi‐Mendoza, J., López‐Franco, Y. L., & Brown‐Bojorquez, F. (2019). Tailoring reversible insulin aggregates loaded in electrosprayed arabinoxylan microspheres intended for colon‐targeted delivery. Journal of Applied Polymer Science, 136(38), 47960. doi:10.1002/app.47960Miramontes-Corona, C., Escalante, A., Delgado, E., Corona-González, R. I., Vázquez-Torres, H., & Toriz, G. (2020). Hydrophobic agave fructans for sustained drug delivery to the human colon. Reactive and Functional Polymers, 146, 104396. doi:10.1016/j.reactfunctpolym.2019.104396Zhu, A. Z. X., Ho, M.-C. D., Gemski, C. K., Chuang, B.-C., Liao, M., & Xia, C. Q. (2016). Utilizing In Vitro Dissolution-Permeation Chamber for the Quantitative Prediction of pH-Dependent Drug-Drug Interactions with Acid-Reducing Agents: a Comparison with Physiologically Based Pharmacokinetic Modeling. The AAPS Journal, 18(6), 1512-1523. doi:10.1208/s12248-016-9972-4Barclay, T. G., Day, C. M., Petrovsky, N., & Garg, S. (2019). Review of polysaccharide particle-based functional drug delivery. Carbohydrate Polymers, 221, 94-112. doi:10.1016/j.carbpol.2019.05.067Naeem, M., Kim, W., Cao, J., Jung, Y., & Yoo, J.-W. (2014). Enzyme/pH dual sensitive polymeric nanoparticles for targeted drug delivery to the inflamed colon. Colloids and Surfaces B: Biointerfaces, 123, 271-278. doi:10.1016/j.colsurfb.2014.09.026Teruel, A., Coll, C., Costero, A., Ferri, D., Parra, M., Gaviña, P., … Sancenón, F. (2018). Functional Magnetic Mesoporous Silica Microparticles Capped with an Azo-Derivative: A Promising Colon Drug Delivery Device. Molecules, 23(2), 375. doi:10.3390/molecules23020375Teruel, A. H., Pérez-Esteve, É., González-Álvarez, I., González-Álvarez, M., Costero, A. M., Ferri, D., … Sancenón, F. (2019). Double Drug Delivery Using Capped Mesoporous Silica Microparticles for the Effective Treatment of Inflammatory Bowel Disease. Molecular Pharmaceutics, 16(6), 2418-2429. doi:10.1021/acs.molpharmaceut.9b00041Rafii, F., Franklin, W., & Cerniglia, C. E. (1990). Azoreductase activity of anaerobic bacteria isolated from human intestinal microflora. Applied and Environmental Microbiology, 56(7), 2146-2151. doi:10.1128/aem.56.7.2146-2151.1990Kaur, R., Gulati, M., & Singh, S. K. (2017). Role of synbiotics in polysaccharide assisted colon targeted microspheres of mesalamine for the treatment of ulcerative colitis. International Journal of Biological Macromolecules, 95, 438-450. doi:10.1016/j.ijbiomac.2016.11.066Ferri, D., Gaviña, P., Parra, M., Costero, A. M., El Haskouri, J., Amorós, P., … Martínez-Máñez, R. (2018). Mesoporous silica microparticles gated with a bulky azo derivative for the controlled release of dyes/drugs in colon. Royal Society Open Science, 5(8), 180873. doi:10.1098/rsos.180873Ma, Z.-G., Ma, R., Xiao, X.-L., Zhang, Y.-H., Zhang, X.-Z., Hu, N., … Sun, Z.-J. (2016). Azo polymeric micelles designed for colon-targeted dimethyl fumarate delivery for colon cancer therapy. Acta Biomaterialia, 44, 323-331. doi:10.1016/j.actbio.2016.08.021Karrout, Y., Dubuquoy, L., Piveteau, C., Siepmann, F., Moussa, E., Wils, D., … Siepmann, J. (2015). In vivo efficacy of microbiota-sensitive coatings for colon targeting: A promising tool for IBD therapy. Journal of Controlled Release, 197, 121-130. doi:10.1016/j.jconrel.2014.11.006Kumar, B., Kulanthaivel, S., Mondal, A., Mishra, S., Banerjee, B., Bhaumik, A., … Giri, S. (2017). Mesoporous silica nanoparticle based enzyme responsive system for colon specific drug delivery through guar gum capping. Colloids and Surfaces B: Biointerfaces, 150, 352-361. doi:10.1016/j.colsurfb.2016.10.049Yamada, K., Iwao, Y., Bani-Jaber, A., Noguchi, S., & Itai, S. (2015). Preparation and Evaluation of Newly Developed Chitosan Salt Coating Dispersions for Colon Delivery without Requiring Overcoating. CHEMICAL & PHARMACEUTICAL BULLETIN, 63(10), 799-806. doi:10.1248/cpb.c15-00308Amidon, S., Brown, J. E., & Dave, V. S. (2015). Colon-Targeted Oral Drug Delivery Systems: Design Trends and Approaches. AAPS PharmSciTech, 16(4), 731-741. doi:10.1208/s12249-015-0350-9Dagli, Ü., Balk, M., Yücel, D., Ülker, A., Över, H., Saydam, G., & Şahin, B. (1997). The Role of Reactive Oxygen Metabolites in Ulcerative Colitis. Inflammatory Bowel Diseases, 3(4), 260-264. doi:10.1097/00054725-199712000-00003Simmonds, N. J., & Rampton, D. S. (1993). Inflammatory bowel disease--a radical view. Gut, 34(7), 865-868. doi:10.1136/gut.34.7.865GRISHAM, M. (1994). Oxidants and free radicals in inflammatory bowel disease. The Lancet, 344(8926), 859-861. doi:10.1016/s0140-6736(94)92831-2Zhang, Q., Tao, H., Lin, Y., Hu, Y., An, H., Zhang, D., … Zhang, J. (2016). A superoxide dismutase/catalase mimetic nanomedicine for targeted therapy of inflammatory bowel disease. Biomaterials, 105, 206-221. doi:10.1016/j.biomaterials.2016.08.010Sedghi, S., Fields, J. Z., Klamut, M., Urban, G., Durkin, M., Winship, D., … Keshavarzian, A. (1993). Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis. Gut, 34(9), 1191-1197. doi:10.1136/gut.34.9.1191Simmonds, N. J., Allen, R. E., Stevens, T. R. J., Niall, R., Van Someren, M., Blake, D. R., & Rampton, D. S. (1992). Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterology, 103(1), 186-196. doi:10.1016/0016-5085(92)91112-hVong, L. B., Mo, J., Abrahamsson, B., & Nagasaki, Y. (2015). Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose–response efficacy. Journal of Controlled Release, 210, 19-25. doi:10.1016/j.jconrel.2015.05.275Vong, L. B., & Nagasaki, Y. (2

Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue

[EN] Colon targeted drug delivery is highly relevant not only to treat colonic local diseases but also for systemic therapies. Mesoporous silica nanoparticles (MSNs) have been demonstrated as useful systems for controlled drug release given their biocompatibility and the possibility of designing gated systems able to release cargo only upon the presence of certain stimuli. We report herein the preparation of three gated MSNs able to deliver their cargo triggered by different stimuli (redox ambient (S1), enzymatic hydrolysis (S2), and a surfactant or being in contact with cell membrane (S3)) and their performance in solution and in vitro with Caco-2 cells. Safranin O dye was used as a model drug to track cargo fate. Studies of cargo permeability in Caco-2 monolayers demonstrated that intracellular safranin O levels were significantly higher in Caco-2 monolayers when using MSNs compared to those of free dye. Internalization assays indicated that S2 nanoparticles were taken up by cells via endocytosis. S2 nanoparticles were selected for in vivo tests in rats. For in vivo assays, capsules were filled with S2 nanoparticles and coated with Eudragit FS 30 D to target colon. The enteric coated capsule containing the MSNs was able to deliver S2 nanoparticles in colon tissue (first step), and then nanoparticles were able to deliver safranin O inside the colonic cells after the enzymatic stimuli (second step). This resulted in high levels of safranin O in colonic tissue combined with low dye levels in plasma and body tissues. The results suggested that this combination of enzyme-responsive gated MSNs and enteric coated capsules may improve the absorption of drugs in colon to treat local diseases with a reduction of systemic effects.The authors acknowledge the financial support from the Spanish Government (Projects MAT2015-64139-C4-1-R, SAF2016-78756 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (Project GVA/2014/13).Gonzalez-Alvarez, M.; Coll Merino, MC.; Gonzalez-Alvarez, I.; Giménez Morales, C.; Aznar, E.; Martínez-Bisbal, M.; Lozoya Agulló, I.... (2017). Gated Mesoporous Silica Nanocarriers for a "two-Step" Targeted System to Colonic Tissue. Molecular Pharmaceutics. 14(12):4442-4453. https://doi.org/10.1021/acs.molpharmaceut.7b00565S44424453141

Dynamic risk control by human nucleus accumbens

Real-world decisions about reward often involve a complex counterbalance of risk and value. Although the nucleus accumbens has been implicated in the underlying neural substrate, its criticality to human behaviour remains an open question, best addressed with interventional methodology that probes the behavioural consequences of focal neural modulation. Combining a psychometric index of risky decision-making with transient electrical modulation of the nucleus accumbens, here we reveal profound, highly dynamic alteration of the relation between probability of reward and choice during therapeutic deep brain stimulation in four patients with treatment-resistant psychiatric disease. Short-lived phasic electrical stimulation of the region of the nucleus accumbens dynamically altered risk behaviour, transiently shifting the psychometric function towards more risky decisions only for the duration of stimulation. A critical, on-line role of human nucleus accumbens in dynamic risk control is thereby established

A New Catalog of HII Regions in M31

We present a new catalog of HII regions in M31. The full disk of the galaxy is covered in a 2.2 deg^2 mosaic of 10 fields observed with the Mosaic Camera as part of the Local Group Galaxies survey. We used HIIphot, a code for automated photometry of HII regions, to identify the regions and measure their fluxes and sizes. A 10 {\sigma} detection level was used to exclude diffuse gas fluctuations and star residuals after continuum subtraction. That selection limit may result in missing some faint HII regions, but our catalog of 3691 HII regions is still complete to a luminosity of LH{\alpha} = 10^34 erg/s. This is five times fainter than the only previous CCD-based study which contained 967 objects in the NE half of M31. We determined the H{\alpha} luminosity function (LF) by fitting a power law to luminosities larger than LH{\alpha} = 10^36.7 and determined a slope of 2.52\pm0.07. The in-arm and inter-arm LFs peak at different luminosities but they have similar bright-end slopes. The inter- arm regions are less populated (40% of total detected regions) and constitute only 14% of the total luminosity of LH{\alpha} = 5.6 /times 10^40 erg/s (after extinction correction and considering 65% contribution from diffused ionized gas). A star formation rate of 0.44 M\odot/yr was estimated from the H{\alpha} total luminosity; this value is consistent with the determination from the Spitzer 8 {\mu}m image. We removed all known and potential planetary nebulae, yet we found a double peaked luminosity function. The inter-arm older population suggests a starburst between 15 and 20 million years ago. This result is in agreement with UV studies of the star formation history in M31 which found a star formation rate decrease in the recent past. We found a fair spatial correlation between the HII regions and stellar clusters in selected star forming regions. Most of the matched regions lie within the arm regions.Comment: accepted to be published at A

Toxicological assessment of mesoporous silica particles in the nematode Caenorhabditis elegans

[EN] Here we report the toxicological evaluation of mesoporous silica particles (MSPs) in the nematode C. elegans. Specifically, we have investigated the effect of bare micro- (M0) and nano-sized (N0) MSPs, and their corresponding functionalized particles with a starch derivative (Glu-N) (M1 and N1, respectively) on C. elegans ageing parameters. The toxicity of MSPs, their impact on C. elegans lifespan, movement capacity, progeny and ability to survive upon exposure to acute oxidative stress were assessed. This study demonstrated that both size particles assayed (M0 and N0), labeled with rhodamine and monitored through fluorescence microscopy, are ingested by the nematode. Moreover, toxicity assays indicated that bare nano-sized particles (N0) have a negative impact on the C. elegans lifespan, reducing mobility and progeny production. By contrast, micro-sized particles (M0) proved innocuous for the nematodes. Furthermore, functionalization of nanoparticles with starch derivative reduced their toxicity in C. elegans. Thus, oral intake of N1 comparatively increased the mean lifespan and activity rates as well as resistance to oxidative stress. The overall findings presented here demonstrate the influence of MSP size and surface on their potential toxicity in vivo and indicate the silica-based mesoporous particles to be a potential support for encapsulation in oral delivery applications. Furthermore, the good correlation obtained between healthy aging variables and viability (mean lifespan) validates the use of C. elegans as a multicellular organism for nanotoxicology studies of MSPs.The authors wish to express their gratitude to the Spanish Government (MINECO Projects AGL2012-39597-C02-01, AGL2012-39597-C02-02, AGL2015-70235-C2-1, MAT2012-38429-C04-01 and MAT2015-64139-C4-1), the Generalitat Valenciana (Project PROMETEOII/2014/047) and Colombian Administrative Department of Science, Technology and Research which supported Ms. Acosta Scholarship. We would also like to thank the Institut de Ciencia dels Materials (ICMUV), the Microscopy Service of the Universitat Politecnica de Valencia and the microscopy service of IATA for technical support. We thank Roquette for the Glucidex samples.Acosta-Romero, C.; Barat Baviera, JM.; Martínez-Máñez, R.; Sancenón Galarza, F.; Llopis Llopis, S.; Gonzalez, N.; Genovés, S.... (2018). Toxicological assessment of mesoporous silica particles in the nematode Caenorhabditis elegans. Environmental Research. 166:61-70. https://doi.org/10.1016/j.envres.2018.05.018S617016

A database for curating the associations between killer cell immunoglobulin-like receptors and diseases in worldwide populations

The killer cell immunoglobulin-like receptors (KIR) play a fundamental role in the innate immune system, through their interactions with human leucocyte antigen (HLA) molecules, leading to the modulation of activity in natural killer (NK) cells, mainly related to killing pathogen-infected cells. KIR genes are hugely polymorphic both in the number of genes an individual carries and in the number of alleles identified. We have previously developed the Allele Frequency Net Database (AFND, http://www.allelefrequencies.net), which captures worldwide frequencies of alleles, genes and haplotypes for several immune genes, including KIR genes, in healthy populations, covering >4 million individuals. Here, we report the creation of a new database within AFND, named KIR and Diseases Database (KDDB), capturing a large quantity of data derived from publications in which KIR genes, alleles, genotypes and/or haplotypes have been associated with infectious diseases (e.g. hepatitis C, HIV, malaria), autoimmune disorders (e.g. type I diabetes, rheumatoid arthritis), cancer and pregnancy-related complications. KDDB has been created through an extensive manual curation effort, extracting data on more than a thousand KIR-disease records, comprising >50 000 individuals. KDDB thus provides a new community resource for understanding not only how KIR genes are associated with disease, but also, by working in tandem with the large data sets already present in AFND, where particular genes, genotypes or haplotypes are present in worldwide populations or different ethnic groups. We anticipate that KDDB will be an important resource for researchers working in immunogenetics. Database URL: http://www.allelefrequencies.net/diseases

The Solar Twin Planet Search. V. Close-in, low-mass planet candidates and evidence of planet accretion in the solar twin HIP 68468

[Methods]. We obtained high-precision radial velocities with HARPS on the ESO 3.6 m telescope and determined precise stellar elemental abundances (~0.01 dex) using MIKE spectra on the Magellan 6.5m telescope. [Results]. Our data indicate the presence of a planet with a minimum mass of 26 Earth masses around the solar twin HIP 68468. The planet is a super-Neptune, but unlike the distant Neptune in our solar system (30 AU), HIP 68468c is close-in, with a semi-major axis of 0.66 AU, similar to that of Venus. The data also suggest the presence of a super-Earth with a minimum mass of 2.9 Earth masses at 0.03 AU; if the planet is confirmed, it will be the fifth least massive radial velocity planet discovery to date and the first super-Earth around a solar twin. Both isochrones (5.9 Gyr) and the abundance ratio [Y/Mg] (6.4 Gyr) indicate an age of about 6 billion years. The star is enhanced in refractory elements when compared to the Sun, and the refractory enrichment is even stronger after corrections for Galactic chemical evolution. We determined a NLTE Li abundance of 1.52 dex, which is four times higher than what would be expected for the age of HIP 68468. The older age is also supported by the low log(R'HK) (-5.05) and low jitter. Engulfment of a rocky planet of 6 Earth masses can explain the enhancement in both lithium and the refractory elements. [Conclusions]. The super-Neptune planet candidate is too massive for in situ formation, and therefore its current location is most likely the result of planet migration that could also have driven other planets towards its host star, enhancing thus the abundance of lithium and refractory elements in HIP 68468. The intriguing evidence of planet accretion warrants further observations to verify the existence of the planets that are indicated by our data and to better constrain the nature of the planetary system around this unique star.Comment: A&A, in pres