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Full list of authors: Price-Whelan, Adrian M.; Lim, Pey Lian; Earl, Nicholas; Starkman, Nathaniel; Bradley, Larry; Shupe, David L.; Patil, Aarya A.; Corrales, Lia; Brasseur, C. E.; Noethe, Maximilian; Donath, Axel; Tollerud, Erik; Morris, Brett M.; Ginsburg, Adam; Vaher, Eero; Weaver, Benjamin A.; Tocknell, James; Jamieson, William; van Kerkwijk, Marten H.; Robitaille, Thomas P.; Merry, Bruce; Bachetti, Matteo; Gunther, H. Moritz; Aldcroft, Thomas L.; Alvarado-Montes, Jaime A.; Archibald, Anne M.; Bodi, Attila; Bapat, Shreyas; Barentsen, Geert; Bazan, Juanjo; Biswas, Manish; Boquien, Mederic; Burke, D. J.; Cara, Daria; Cara, Mihai; Conroy, Kyle E.; Conseil, Simon; Craig, Matthew W.; Cross, Robert M.; Cruz, Kelle L.; D'Eugenio, Francesco; Dencheva, Nadia; Devillepoix, Hadrien A. R.; Dietrich, Jorg P.; Eigenbrot, Arthur Davis; Erben, Thomas; Ferreira, Leonardo; Foreman-Mackey, Daniel; Fox, Ryan; Freij, Nabil; Garg, Suyog; Geda, Robel; Glattly, Lauren; Gondhalekar, Yash; Gordon, Karl D.; Grant, David; Greenfield, Perry; Groener, Austen M.; Guest, Steve; Gurovich, Sebastian; Handberg, Rasmus; Hart, Akeem; Hatfield-Dodds, Zac; Homeier, Derek; Hosseinzadeh, Griffin; Jenness, Tim; Jones, Craig K.; Joseph, Prajwel; Kalmbach, J. Bryce; Karamehmetoglu, Emir; Kaluszynski, Mikolaj; Kelley, Michael S. P.; Kern, Nicholas; Kerzendorf, Wolfgang E.; Koch, Eric W.; Kulumani, Shankar; Lee, Antony; Ly, Chun; Ma, Zhiyuan; MacBride, Conor; Maljaars, Jakob M.; Muna, Demitri; Murphy, N. A.; Norman, Henrik; O'Steen, Richard; Oman, Kyle A.; Pacifici, Camilla; Pascual, Sergio; Pascual-Granado, J.; Patil, Rohit R.; Perren, Gabriel, I; Pickering, Timothy E.; Rastogi, Tanuj; Roulston, Benjamin R.; Ryan, Daniel F.; Rykoff, Eli S.; Sabater, Jose; Sakurikar, Parikshit; Salgado, Jesus; Sanghi, Aniket; Saunders, Nicholas; Savchenko, Volodymyr; Schwardt, Ludwig; Seifert-Eckert, Michael; Shih, Albert Y.; Jain, Anany Shrey; Shukla, Gyanendra; Sick, Jonathan; Simpson, Chris; Singanamalla, Sudheesh; Singer, Leo P.; Singhal, Jaladh; Sinha, Manodeep; Sipocz, Brigitta M.; Spitler, Lee R.; Stansby, David; Streicher, Ole; Sumak, Jani; Swinbank, John D.; Taranu, Dan S.; Tewary, Nikita; Tremblay, Grant R.; De Val-Borro, Miguel; Vasovic, Zlatan; Van Kooten, Samuel J.; Verma, Shresth; Cardoso, Jose Vinicius de Miranda; Williams, Peter K. G.; Wilson, Tom J.; Winkel, Benjamin; Wood-Vasey, W. M.; Xue, Rui; Yoachim, Peter; Zhang, Chen; Zonca, Andrea; Astropy Project Contributors; TARDIS Collaboration; Astropy Coordination Comm.--This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited., The Astropy Project supports and fosters the development of open-source and openly developed Python packages that provide commonly needed functionality to the astronomical community. A key element of the Astropy Project is the core package astropy, which serves as the foundation for more specialized projects and packages. In this article, we summarize key features in the core package as of the recent major release, version 5.0, and provide major updates on the Project. We then discuss supporting a broader ecosystem of interoperable packages, including connections with several astronomical observatories and missions. We also revisit the future outlook of the Astropy Project and the current status of Learn Astropy. We conclude by raising and discussing the current and future challenges facing the Project. © 2022. The Author(s). Published by the American Astronomical Society., We acknowledge the Gordon and Betty Moore Foundation for their continued financial support. This work is partially supported by NASA under grant No. 80NSSC22K0347 issued through the NASA ROSES program. This work is partially supported by the international Gemini Observatory, a program of NSF’s NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation, on behalf of the Gemini partnership of Argentina, Brazil, Canada, Chile, the Republic of Korea, and the United States of America. We also thank NumFOCUS and the Python Software Foundation for financial support. J.A.A.-M. acknowledges funding support from Macquarie University through the International Macquarie University Research Excellence Scholarship (“iMQRES”). A.B. was supported by the Lendület Program of the Hungarian Academy of Sciences, project No. LP2018-7, and the KKP-137523 “SeismoLab” Élvonal grant of the Hungarian Research, Development and Innovation Office (NKFIH). M.B. gratefully acknowledges support from the ANID BASAL project FB210003 and the FONDECYT regular grant 1211000. F.D.E. acknowledges funding through the H2020 ERC Consolidator grant 683184, the ERC Advanced grant 695671 “QUENCH” and support from the Science and Technology Facilities Council (STFC). S.G. made contributions to Astropy as part of the Google Summer of Code 2021. S.G. acknowledges some intellectual support from the CCAD-UNC-NOVA. Funding for the Stellar Astrophysics Centre is provided by The Danish National Research Foundation (grant agreement No.: DNRF106). N.K. acknowledges support from the MIT Pappalardo fellowship. K.A.O. acknowledges support from the European Research Council (ERC) through Advanced Investigator grant to C.S. Frenk, DMIDAS (GA 786910). C.P. is supported by the Canadian Space Agency under a contract with NRC Herzberg Astronomy and Astrophysics. S.P. has been supported by Spanish MINECO-FEDER grant RTI2018-096188-B-I00 J.P.G. acknowledges funding support from Spanish public funds for research from project PID2019-107061GB-C63 from the “Programas Estatales de Generación de Conocimiento y Fortalecimiento Científico y Tecnológico del Sistema de I+D+i y de I+D+i Orientada a los Retos de la Sociedad,” as well as from the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award to the Instituto de Astrofísica de Andalucía (SEV-2017-0709). N.S. acknowledges support from the National Science Foundation through the Graduate Research Fellowship Program under grant 1842402. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the National Science Foundation. Supported by the international Gemini Observatory, a program of NSF’s NOIRLab, which is managed by the Association of Universities for Research in Astronomy (AURA) under a cooperative agreement with the National Science Foundation, on behalf of the Gemini Observatory partnership: the National Science Foundation (United States), National Research Council (Canada), Agencia Nacional de Investigación y Desarrollo (Chile), Ministerio de Ciencia, Tecnología e Innovación (Argentina), Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brazil), and Korea Astronomy and Space Science Institute (Republic of Korea). Parts of this research were supported by the Australian Research Council Centre of Excellence for All-Sky Astro-physics in 3 Dimensions (ASTRO 3D), through project number CE170100013. D.S. is supported by STFC grant ST/S000240/1. N.S. acknowledges the support of the Science and Engineering Research Council of Canada (NSERC) Canadian Graduate Scholarship—Doctoral Program, [funding reference numbers CGSD547212020].

[Image: see text] GSK2798745, a clinical candidate, was identified as an inhibitor of the transient receptor potential vanilloid 4 (TRPV4) ion channel for the treatment of pulmonary edema associated with congestive heart failure. We discuss the lead optimization of this novel spirocarbamate series and specifically focus on our strategies and solutions for achieving desirable potency, rat pharmacokinetics, and physicochemical properties. We highlight the use of conformational bias to deliver potency and optimization of volume of distribution and unbound clearance to enable desirable in vivo mean residence times.

High-performance polymers, most notably all-aromatic polyamides (aramids), enable the convergence of the disparate material properties, such as low density, high strength, high stiffness, and thermal stability. Sulfonated derivatives of aramids (sulfo-aramids) represent a unique class of materials that are a nexus between stiff and strong engineering materials and soft and dynamic biological matter. Specifically, sulfo-aramids are water soluble and often self-assemble into rodlike supramolecular structures in solution, similar to rodlike viruses or polypeptide helical assemblies. Such rodlike systems undergo spontaneous self-organization into a liquid crystalline (nematic) phase above a critical concentration, resulting in a high degree of local orientational order. Application of an external field, such as shear flow, can either increase or decrease the global orientational order of the nematic phase. Thus, understanding the solution structure and rheology of such phases has important implications for the fabrication of high-performance, sulfo-aramid nanocomposites. In this Dissertation, we investigate aspects of the solution structure, rheology, and nanocomposites fabricated from helical, rodlike assemblies of the sulfo-aramid, poly(2,2’- benzidine-4,4’-disulfonyl terephthalamide) (PBDT). PBDT forms a fully nematic phase at low concentrations in water, evidencing its high aspect ratio, enabling environmentally-benign fabrication of advanced nanocomposites with liquid crystalline graphene oxide or ionic liquids. Moreover, the low concentrations required for formation of a fully nematic phase enables direct interrogation of the rheological responses of the liquid crystalline rodlike assemblies. In contrast, the rheology of previously studied model LCPs are dominated by the nematic defect texture. In addition, the dynamic self-assembled nature of PBDT rodlike assemblies result in an unusual rheological behavior, known as irreversible shear-activated gelation, at high concentrations. Overall, our new insights on the solution structure and rheology of sulfo-aramids not only inform the design of advanced nanocomposites, but also provide a new platform for elucidating the flow behavior of high-aspect-ratio, charged rods.

Breast cancer cell-response to inflammatory cytokines such as interleukin-6 (IL-6) and oncostatin M (OSM) may affect the course of clinical disease in a cancer subtype-dependent manner. Furthermore, vascular endothelial growth factor A (VEGF) secretion induced by IL-6 and OSM may also be subtype-dependent. Utilizing datasets from Oncomine, we show that poor survival of invasive ductal carcinoma (IDC) breast cancer patients is correlated with both high VEGF expression and high cytokine or cytokine receptor expression in tumors. Importantly, epidermal growth factor receptor-negative (HER2-), but not HER2-positive (HER2+), patient survival is significantly lower with high tumor co-expression of VEGF and OSM, OSMRβ, IL-6, or IL-6Rα compared to low co-expression. Furthermore, assessment of HER2- breast cancer cells in vitro identified unique signaling differences regulating cytokine-induced VEGF secretion. The levels of VEGF secretion were analyzed by ELISA with siRNAs for hypoxia inducible factor 1 α (HIF1α) and signal transducer and activator of transcription 3 (STAT3). Specifically, we found that estrogen receptor-negative (ER-) MDA-MB-231 cells respond only to OSM through STAT3 signaling, while ER+ T47D cells respond to both OSM and IL-6, though to IL-6 to a lesser extent. Additionally, in the ER+ T47D cells, OSM signals through both STAT3 and HIF1α. These results highlight that the survival of breast cancer patients with high co-expression of VEGF and IL-6 family cytokines is dependent on breast cancer subtype. Thus, the heterogeneity of human breast cancer in relation to IL-6 family cytokines and VEGF may have important implications in clinical treatment options, disease progression, and ultimately patient prognosis.

[Image: see text] Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral in vivo tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug–drug interactions was managed by optimizing the series for subcutaneous injection.

Transient Receptor Potential Vanilloid 4 (TRPV4) is a member of the Transient Receptor Potential (TRP) superfamily of cation channels. TRPV4 is expressed in the vascular endothelium in the lung and regulates the integrity of the alveolar septal barrier. Increased pulmonary vascular pressure evokes TRPV4-dependent pulmonary edema, and therefore, inhibition of TRPV4 represents a novel approach for the treatment of pulmonary edema associated with conditions such as congestive heart failure. Herein we report the discovery of an orally active, potent, and selective TRPV4 blocker, 3-(1,4′-bipiperidin-1′-ylmethyl)-7-bromo-N-(1-phenylcyclopropyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxamide (GSK2193874, 28) after addressing an unexpected off-target cardiovascular liability observed from in vivo studies. GSK2193874 is a selective tool for elucidating TRPV4 biology both in vitro and in vivo.