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  • ItemOpen Access
    Macrophages in Nonalcoholic Steatohepatitis: Friend or Foe?
    (EMJ Hepatology) Grunhut, Joel; Wang, Wei; Aykut, Berk; Gakhal, Inderdeep; Torres-Hernandez, Alejandro; Miller, George
    Nonalcoholic steatohepatitis (NASH) is a subtype of nonalcoholic fatty liver disease that is characterised by steatosis, chronic inflammation, and hepatocellular injury with or without fibrosis. The role and activation of macrophages in the pathogenesis of NASH is complex and is being studied for possible therapeutic options to help the millions of people diagnosed with the disease. The purpose of this review is to discuss the pathogenesis of NASH through the activation and role of Kupffer cells and other macrophages in causing inflammation and progression of NASH. Furthermore, this review aims to outline some of the current therapeutic options targeting the pathogenesis of NASH.
  • ItemOpen Access
    The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
    (Cancer Discovery, 2018-04-01) Pushalkar, Smruti; Hundeyin, Mautin; Daley, Donnele; Zambirinis, Constantinos P; Kurz, Emma; Mishra, Ankita; Mohan, Navyatha; Aykut, Berk; Usyk, Mykhaylo; Torres, Luisana E; Werba, Gregor; Zhang, Kevin; Guo, Yuqi; Li, Qianhao; Akkad, Neha; Lall, Sarah; Wadowski, Benjamin; Gutierrez, Johana; Kochen Rossi, Juan Andres; Herzog, Jeremy W; Diskin, Brian; Torres-Hernandez, Alejandro; Leinwand, Josh; Wang, Wei; Taunk, Pardeep S; Savadkar, Shivraj; Janal, Malvin; Saxena, Anjana; Li, Xin; Cohen, Deirdre; Sartor, R Balfour; Saxena, Deepak; Miller, George
    Abstract We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression. Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403–16. ©2018 AACR. See related commentary by Riquelme et al., p. 386. This article is highlighted in the In This Issue feature, p. 371
  • ItemOpen Access
    EMX2 gene expression predicts liver metastasis and survival in colorectal cancer
    (BMC Cancer, 2017-12) Aykut, Berk; Ochs, Markus; Radhakrishnan, Praveen; Brill, Adrian; Höcker, Hermine; Schwarz, Sandra; Weissinger, Daniel; Kehm, Roland; Kulu, Yakup; Ulrich, Alexis; Schneider, Martin
  • ItemOpen Access
    Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma
    (Nature Communications) Barilla, Rocky M; Diskin, Brian; Caso, Raul Caso; Lee, Ki Buom; Mohan, Navyatha; Buttar, Chandan; Adam, Salma; Sekendiz, Zennur; Wang, Junjie; Salas, Ruben D; Cassini, Marcelo F; Karlen, Jason; Sundberg, Belen; Akbar, Hashem; Levchenko, Dmitry; Gakhal, Inderdeep; Gutierrez, Johana; Wang, Wei; Hundeyin, Mautin; Torres-Hernandez, Alejandro; Leinwand, Joshua; Kurz, Emma; Rossi, Juan A Kochen; Mishra, Ankita; Liria, Miguel; Sanchez, Gustavo; Panta, Jyoti; Loke, P’ng; Aykut, Berk; Miller, George
    AbstractThe drivers and the specification of CD4+ T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique TH-program. Specifically, CD11b+CD103− DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b+CD103− DC promote CD4+ T cell tolerance in PDA which may underscore its resistance to immunotherapy.
  • ItemOpen Access
    CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma
    (Cell Death & Differentiation, 2015-07) Teodorczyk, M; Kleber, S; Wollny, D; Sefrin, JP; Aykut, B; Mateos, A; Herhaus, P; Sancho-Martinez, I; Hill, O; Gieffers, C; Sykora, J; Weichert, W; Eisen, C; Trumpp, A; Sprick, MR; Bergmann, F; Welsch, T; Martin-Villalba, A
  • ItemOpen Access
    A rare case of recurrent malignant triton tumor in a male with NF1: Case report and mini-review
    (International Journal of Surgery Case Reports, 2016) Aykut, B; Wieczorek, K; Schirmacher, P; Büchler, MW; Hoffmann, K
  • ItemOpen Access
    BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer
    (Oncogene, 2022-09-16) Diskin, Brian; Adam, Salma; Soto, Gustavo Sanchez; Liria, Miguel; Aykut, Berk; Sundberg, Belen; Li, Eric; Leinwand, Joshua; Chen, Ruonan; Kim, Mirhee; Salas, Ruben D; Cassini, Marcelo F; Buttar, Chandan; Wang, Wei; Farooq, Mohammad Saad; Shadaloey, Sorin AA; Werba, Gregor; Fnu, Amreek; Yang, Fan; Hirsch, Carolina; Glinski, John; Panjwani, Angilee; Weitzner, Yael; Cohen, Deirdre; Asghar, Usman; Miller, George
  • ItemOpen Access
    Comparing Survival After Resection, Ablation, and Radiation in Small Intrahepatic Cholangiocarcinoma.
    (Annals of surgical oncology, 2023-10) Masoud, Sabran J; Rhodin, Kristen E; Kanu, Elishama; Bao, Jiayin; Eckhoff, Austin M; Bartholomew, Alex J; Howell, Thomas C; Aykut, Berk; Kosovec, Juliann E; Palta, Manisha; Befera, Nicholas T; Kim, Charles Y; Herbert, Garth; Shah, Kevin N; Nussbaum, Daniel P; Blazer, Dan G; Zani, Sabino; Allen, Peter J; Lidsky, Michael E

    Background

    Hepatectomy is the cornerstone of curative-intent treatment for intrahepatic cholangiocarcinoma (ICC). However, in patients unable to be resected, data comparing efficacy of alternatives including thermal ablation and radiation therapy (RT) remain limited. Herein, we compared survival between resection and other liver-directed therapies for small ICC within a national cancer registry.

    Patients and methods

    Patients with clinical stage I-III ICC < 3 cm diagnosed 2010-2018 who underwent resection, ablation, or RT were identified in the National Cancer Database. Overall survival (OS) was compared using Kaplan-Meier and multivariable Cox proportional hazards methods.

    Results

    Of 545 patients, 297 (54.5%) underwent resection, 114 (20.9%) ablation, and 134 (24.6%) RT. Median OS was similar between resection and ablation [50.5 months, 95% confidence interval (CI) 37.5-73.9; 39.5 months, 95% CI 28.7-58.4, p = 0.14], both exceeding that of RT (20.9 months, 95% CI 14.1-28.3). RT patients had high rates of stage III disease (10.4% RT vs. 1.8% ablation vs. 11.8% resection, p < 0.001), but the lowest rates of chemotherapy utilization (9.0% RT vs. 15.8% ablation vs. 38.7% resection, p < 0.001). In multivariable analysis, resection and ablation were associated with reduced mortality compared with RT [hazard ratio (HR) 0.44, 95% CI 0.33-0.58 and HR 0.53, 95% CI 0.38-0.75, p < 0.001, respectively].

    Conclusion

    Resection and ablation were associated with improved survival in patients with ICC < 3 cm compared with RT. Acknowledging confounders, anatomic constraints of ablation, limitations of available data, and need for prospective study, these results favor ablation in small ICC where resection is not feasible.
  • ItemOpen Access
    γδ T Cells Promote Steatohepatitis by Orchestrating Innate and Adaptive Immune Programming
    (Hepatology, 2020-02) Torres‐Hernandez, Alejandro; Wang, Wei; Nikiforov, Yuri; Tejada, Karla; Torres, Luisana; Kalabin, Aleksandr; Adam, Salma; Wu, Jingjing; Lu, Lu; Chen, Ruonan; Lemmer, Aaron; Camargo, Jimmy; Hundeyin, Mautin; Diskin, Brian; Aykut, Berk; Kurz, Emma; Kochen Rossi, Juan A; Khan, Mohammed; Liria, Miguel; Sanchez, Gustavo; Wu, Nan; Su, Wenyu; Adams, Steven; Haq, Muhammad Israr Ul; Farooq, Mohammad Saad; Vasudevaraja, Varshini; Leinwand, Joshua; Miller, George
    Background and Aims The recruitment and activation of inflammatory cells in the liver delineates the transition from hepatic steatosis to steatohepatitis (SH). Approach and Results We found that in SH, γδT cells are recruited to the liver by C‐C chemokine receptor (CCR) 2, CCR5, and nucleotide‐binding oligomerization domain‐containing protein 2 signaling and are skewed toward an interleukin (IL)‐17A+ phenotype in an inducible costimulator (ICOS)/ICOS ligand–dependent manner. γδT cells exhibit a distinct Vγ4+, PD1+, Ly6C+CD44+ phenotype in SH. Moreover, γδT cells up‐regulate both CD1d, which is necessary for lipid‐based antigens presentation, and the free fatty acid receptor, CD36. γδT cells are stimulated to express IL‐17A by palmitic acid and CD1d ligation. Deletion, depletion, and targeted interruption of γδT cell recruitment protects against diet‐induced SH and accelerates disease resolution. Conclusions We demonstrate that hepatic γδT cells exacerbate SH, independent of IL‐17 expression, by mitigating conventional CD4+ T‐cell expansion and modulating their inflammatory program by CD1d‐dependent vascular endothelial growth factor expression.
  • ItemOpen Access
    Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance.
    (Nature medicine, 2017-05) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Ochi, Atsuo; Heindel, Daniel W; Lee, Ki Buom; Zambirinis, Constantinos P; Pandian, Gautam Sd Balasubramania; Savadkar, Shivraj; Torres-Hernandez, Alejandro; Nayak, Shruti; Wang, Ding; Hundeyin, Mautin; Diskin, Brian; Aykut, Berk; Werba, Gregor; Barilla, Rocky M; Rodriguez, Robert; Chang, Steven; Gardner, Lawrence; Mahal, Lara K; Ueberheide, Beatrix; Miller, George
    The progression of pancreatic oncogenesis requires immune-suppressive inflammation in cooperation with oncogenic mutations. However, the drivers of intratumoral immune tolerance are uncertain. Dectin 1 is an innate immune receptor crucial for anti-fungal immunity, but its role in sterile inflammation and oncogenesis has not been well defined. Furthermore, non-pathogen-derived ligands for dectin 1 have not been characterized. We found that dectin 1 is highly expressed on macrophages in pancreatic ductal adenocarcinoma (PDA). Dectin 1 ligation accelerated the progression of PDA in mice, whereas deletion of Clec7a-the gene encoding dectin 1-or blockade of dectin 1 downstream signaling was protective. We found that dectin 1 can ligate the lectin galectin 9 in mouse and human PDA, which results in tolerogenic macrophage programming and adaptive immune suppression. Upon disruption of the dectin 1-galectin 9 axis, CD4+ and CD8+ T cells, which are dispensable for PDA progression in hosts with an intact signaling axis, become reprogrammed into indispensable mediators of anti-tumor immunity. These data suggest that targeting dectin 1 signaling is an attractive strategy for developing an immunotherapy for PDA.
  • ItemOpen Access
    Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming
    (Cancer Discovery, 2019-09-01) Hundeyin, Mautin; Kurz, Emma; Mishra, Ankita; Rossi, Juan Andres Kochen; Liudahl, Shannon M; Leis, Kenna R; Mehrotra, Harshita; Kim, Mirhee; Torres, Luisana E; Ogunsakin, Adesola; Link, Jason; Sears, Rosalie C; Sivagnanam, Shamilene; Goecks, Jeremy; Islam, KM Sadeq; Dolgalev, Igor; Savadkar, Shivraj; Wang, Wei; Aykut, Berk; Leinwand, Joshua; Diskin, Brian; Adam, Salma; Israr, Muhammad; Gelas, Maeliss; Lish, Justin; Chin, Kathryn; Farooq, Mohammad Saad; Wadowski, Benjamin; Wu, Jingjing; Shah, Suhagi; Adeegbe, Dennis O; Pushalkar, Smruti; Vasudevaraja, Varshini; Saxena, Deepak; Wong, Kwok-Kin; Coussens, Lisa M; Miller, George
    Abstract Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4−CD8−NK1.1− innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. Significance: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy. See related commentary by Banerjee et al., p. 1164. This article is highlighted in the In This Issue feature, p. 1143
  • ItemOpen Access
    Intrahepatic microbes govern liver immunity by programming NKT cells
    (Journal of Clinical Investigation, 2022-04-15) Leinwand, Joshua C; Paul, Bidisha; Chen, Ruonan; Xu, Fangxi; Sierra, Maria A; Paluru, Madan M; Nanduri, Sumant; Alcantara, Carolina G; Shadaloey, Sorin AA; Yang, Fan; Adam, Salma A; Li, Qianhao; Bandel, Michelle; Gakhal, Inderdeep; Appiah, Lara; Guo, Yuqi; Vardhan, Mridula; Flaminio, Zia; Grodman, Emilie R; Mermelstein, Ari; Wang, Wei; Diskin, Brian; Aykut, Berk; Khan, Mohammad; Werba, Gregor; Pushalkar, Smruti; McKinstry, Mia; Kluger, Zachary; Park, Jaimie J; Hsieh, Brandon; Dancel-Manning, Kristen; Liang, Feng-Xia; Park, James S; Saxena, Anjana; Li, Xin; Theise, Neil D; Saxena, Deepak; Miller, George
  • ItemOpen Access
    NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma.
    (The Journal of experimental medicine, 2017-06) Daley, Donnele; Mani, Vishnu R; Mohan, Navyatha; Akkad, Neha; Pandian, Gautam SD Balasubramania; Savadkar, Shivraj; Lee, Ki Buom; Torres-Hernandez, Alejandro; Aykut, Berk; Diskin, Brian; Wang, Wei; Farooq, Mohammad S; Mahmud, Arif I; Werba, Gregor; Morales, Eduardo J; Lall, Sarah; Wadowski, Benjamin J; Rubin, Amanda G; Berman, Matthew E; Narayanan, Rajkishen; Hundeyin, Mautin; Miller, George
    The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
  • ItemOpen Access
    PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer
    (Nature Immunology, 2020-04) Diskin, Brian; Adam, Salma; Cassini, Marcelo F; Sanchez, Gustavo; Liria, Miguel; Aykut, Berk; Buttar, Chandan; Li, Eric; Sundberg, Belen; Salas, Ruben D; Chen, Ruonan; Wang, Junjie; Kim, Mirhee; Farooq, Mohammad Saad; Nguy, Susanna; Fedele, Carmine; Tang, Kwan Ho; Chen, Ting; Wang, Wei; Hundeyin, Mautin; Rossi, Juan A Kochen; Kurz, Emma; Haq, Muhammad Israr Ul; Karlen, Jason; Kruger, Emma; Sekendiz, Zennur; Wu, Dongling; Shadaloey, Sorin AA; Baptiste, Gillian; Werba, Gregor; Selvaraj, Shanmugapriya; Loomis, Cynthia; Wong, Kwok-Kin; Leinwand, Joshua; Miller, George
  • ItemOpen Access
    RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer
    (Cancer Cell, 2018-11) Wang, Wei; Marinis, Jill M; Beal, Allison M; Savadkar, Shivraj; Wu, Yue; Khan, Mohammed; Taunk, Pardeep S; Wu, Nan; Su, Wenyu; Wu, Jingjing; Ahsan, Aarif; Kurz, Emma; Chen, Ting; Yaboh, Inedouye; Li, Fei; Gutierrez, Johana; Diskin, Brian; Hundeyin, Mautin; Reilly, Michael; Lich, John D; Harris, Philip A; Mahajan, Mukesh K; Thorpe, James H; Nassau, Pamela; Mosley, Julie E; Leinwand, Joshua; Kochen Rossi, Juan A; Mishra, Ankita; Aykut, Berk; Glacken, Michael; Ochi, Atsuo; Verma, Narendra; Kim, Jacqueline I; Vasudevaraja, Varshini; Adeegbe, Dennis; Almonte, Christina; Bagdatlioglu, Ece; Cohen, Deirdre J; Wong, Kwok-Kin; Bertin, John; Miller, George
  • ItemOpen Access
    Salinomycin inhibits growth of pancreatic cancer and cancer cell migration by disruption of actin stress fiber integrity
    (Cancer Letters, 2015-03) Schenk, Miriam; Aykut, Berk; Teske, Christian; Giese, Nathalia A; Weitz, Juergen; Welsch, Thilo
  • ItemOpen Access
    Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis
    (Oncogene, 2019-06) Torres-Hernandez, Alejandro; Wang, Wei; Nikiforov, Yuri; Tejada, Karla; Torres, Luisana; Kalabin, Aleksandr; Wu, Yue; Haq, Muhammad Israr Ul; Khan, Mohammed Y; Zhao, Zhen; Su, Wenyu; Camargo, Jimmy; Hundeyin, Mautin; Diskin, Brian; Adam, Salma; Rossi, Juan A Kochen; Kurz, Emma; Aykut, Berk; Shadaloey, Sorin AA; Leinwand, Joshua; Miller, George
  • ItemOpen Access
    Regulatory T Cells Keep Pancreatic Cancer at Bay
    (Cancer Discovery, 2020-03-01) Aykut, Berk; Chen, Ruonan; Miller, George
    Abstract Summary: Although CD4+ FOXP3+ T regulatory (Treg) cells are well-known mediators of immunologic tolerance, their influences in the tumor microenviroment are incompletely understood. Writing in this issue of Cancer Discovery, Zhang and colleagues demonstrate that in pancreatic cancer, Treg cells promote the differentiation of tumor-restraining myofibroblastic cancer-associated fibroblasts, challenging the existing notion that Treg cells enable tumor progression. See related article by Zhang et al., p. 422.
  • ItemOpen Access
    Colorectal Cancer Liver Metastases: Multimodal Therapy.
    (Surgical oncology clinics of North America, 2023-01) Aykut, Berk; Lidsky, Michael E
    Despite a steady decline in incidence and mortality rates, colorectal cancer (CRC) remains the second most common cancer diagnosis in women and the third most common in men worldwide. Notably, the liver is recognized as the most common site of CRC metastasis, and metastases to the liver remain the primary driver of disease-specific mortality for patients with CRC. Although hepatic resection is the backbone of curative-intent treatment, management of CRLM has become increasingly multimodal during the last decade and includes the use of downstaging chemotherapy, ablation techniques, and locoregional therapy, each of which are reviewed herein.
  • ItemOpen Access
    The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL
    (Nature, 2019-10-10) Aykut, Berk; Pushalkar, Smruti; Chen, Ruonan; Li, Qianhao; Abengozar, Raquel; Kim, Jacqueline I; Shadaloey, Sorin A; Wu, Dongling; Preiss, Pamela; Verma, Narendra; Guo, Yuqi; Saxena, Anjana; Vardhan, Mridula; Diskin, Brian; Wang, Wei; Leinwand, Joshua; Kurz, Emma; Kochen Rossi, Juan A; Hundeyin, Mautin; Zambrinis, Constantinos; Li, Xin; Saxena, Deepak; Miller, George

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