Endocrine therapies for prostate cancer inhibit the androgen receptor (AR) transcription factor. In most cases, AR activity resumes during therapy and drives progression to castration-resistant ...prostate cancer (CRPC). However, therapy can also promote lineage plasticity and select for AR-independent phenotypes that are uniformly lethal. Here, we demonstrate the stem cell transcription factor Krüppel-like factor 5 (KLF5) is low or absent in prostate cancers prior to endocrine therapy, but induced in a subset of CRPC, including CRPC displaying lineage plasticity. KLF5 and AR physically interact on chromatin and drive opposing transcriptional programs, with KLF5 promoting cellular migration, anchorage-independent growth, and basal epithelial cell phenotypes. We identify ERBB2 as a point of transcriptional convergence displaying activation by KLF5 and repression by AR. ERBB2 inhibitors preferentially block KLF5-driven oncogenic phenotypes. These findings implicate KLF5 as an oncogene that can be upregulated in CRPC to oppose AR activities and promote lineage plasticity.
This learned volume offers a close reading of chapters 3 to 6 of the book of Amos, and attempts to locate biblical study and theological reflection within the complex cultural context of Latin ...America. The author prefaces his study with a wide-ranging survey of the continuing debate over the proper use of the Bible as a model for the structures of society. The author's particular focus is Latin America, and through sociological and textual analysis, he seeks to define the role of the prophetic biblical voice in this society and presses for a recognition of moral complexities and a constant questioning and self-evaluation from those who would claim to speak for God in society.
The Bible in Human Society Mark Daniel Carroll R., David J. A. Clines, Philip R. Davies / Mark Daniel Carroll R., David J. A. Clines, Philip R. Davies
1995, 1995-10-01, Letnik:
200
eBook
This collection of essays written by biblical scholars from around the world attempts to probe the relationship between the Bible and the world. It reflects modern social, political and hermeneutical ...issues, including liberation concerns. These themes echo John Rogerson's commitment to relate his research and the Bible to contemporary issues - a commitment visible both in his publications and in his religious and political activities. This book is an expression of appreciation of John Rogerson by former and current colleagues, former students, and other biblical scholars.
Contexts for Amos Carroll R., Mark Daniel; R, M Daniel Carroll
2009
eBook
This learned volume offers a close reading of chapters 3 to 6 of the book of Amos, and attempts to locate biblical study and theological reflection within the complex cultural context of Latin ...America. The author prefaces his study with a wide-ranging survey of the continuing debate over the proper use of the Bible as a model for the structures of society. The author's particular focus is Latin America, and through sociological and textual analysis, he seeks to define the role of the prophetic biblical voice in this society and presses for a recognition of moral complexities and a constant questioning and self-evaluation from those who would claim to speak for God in society.
In the last two decades, there has been a resurgence of interest in the value of the Old Testament for modern ethical questions. John Rogerson is a scholar who has dedicated much of his academic life ...to probing the possibility of the abiding significance of the Old Testament for moral issues today. This volume brings together for the first time many of his contributions - both published and unpublished - to Old Testament social ethics. Rogerson's essays cover a wide range of modern social issues including: using the Bible in the debate about abortion; the Old Testament and nuclear disarmament; and the use of the Old Testament with reference to work and unemployment. Several essays examine the contribution of philosophical ethics to the study of Old Testament. Rogerson also offers a brief account of his pilgrimage in Old Testament ethics and outlines the basic framework of his perspective. The introduction by the editor provides a summary and survey of Rogerson's work. This is volume 405 in the Journal for the Study of the Old Testament Supplement series.
This volume brings together ten essays on the various contexts for texts that social-scientific approaches invoke. These contexts are: the cultural values that inform the writers of texts, the ...relationship between the text and the reader or community of readers, and the production of texts themselves as social artifacts. In the first, predominantly theoretical, section of the book, John Rogerson applies the perspective of Adorno to the reading of biblical texts; Mark Brett advocates methodological pluralism and deconstructs ethnicity in Genesis; and Gerald West explores the 'graininess' of texts. The second part contains both theory and application: Jonathan Dyck draws a 'map of ideology' for biblical critics and then applies an ideological critical analysis to Ezra 2. M. Daniel Carroll R. reexamines 'popular religion' and uses Amos as a test case; Stanley Porter considers dialect and register in the Greek of the New Testament, then applies it to Mark's Gospel. This is an original as well as wide-ranging exploration of important social-scientific issues and their application to a range of biblical materials.
The Bible in Ethics John W. Rogerson, Mark Daniel Carroll R., Margaret Davies
1995, 1995-12-01, Letnik:
207
eBook
The Bible has influenced contemporary culture both positively and negatively. The present volume is a collection of papers that were discussed at an international colloquium on the use of the Bible ...in Ethics in the Department of Biblical Studies at the University of Sheffield in April 1995. Participants came from many parts of the world and from different backgrounds, and the papers reflect their varied interests and the contexts in which they work. The contributors, in addition to the three editors, are John Barton, Bruce Birch, Mark Brett, Mark Chapman, David Clines, Philip Davies, Cheryl Exum, Stephen Fowl, Norman Gottwald, John Haldane, Walter Houston, Sharon Ringe, Chrisopher Rowland, Lisa Sowle Cahill and Gerald West.
The endogenous metabolite itaconate has recently emerged as a regulator of macrophage function, but its precise mechanism of action remains poorly understood. Here we show that itaconate is required ...for the activation of the anti-inflammatory transcription factor Nrf2 (also known as NFE2L2) by lipopolysaccharide in mouse and human macrophages. We find that itaconate directly modifies proteins via alkylation of cysteine residues. Itaconate alkylates cysteine residues 151, 257, 288, 273 and 297 on the protein KEAP1, enabling Nrf2 to increase the expression of downstream genes with anti-oxidant and anti-inflammatory capacities. The activation of Nrf2 is required for the anti-inflammatory action of itaconate. We describe the use of a new cell-permeable itaconate derivative, 4-octyl itaconate, which is protective against lipopolysaccharide-induced lethality in vivo and decreases cytokine production. We show that type I interferons boost the expression of Irg1 (also known as Acod1) and itaconate production. Furthermore, we find that itaconate production limits the type I interferon response, indicating a negative feedback loop that involves interferons and itaconate. Our findings demonstrate that itaconate is a crucial anti-inflammatory metabolite that acts via Nrf2 to limit inflammation and modulate type I interferons.
Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and ...focus mainly on 80 that bind the receptor binding domain (RBD). We devise a competition data-driven method to map RBD binding sites. We find that although antibody binding sites are widely dispersed, neutralizing antibody binding is focused, with nearly all highly inhibitory mAbs (IC50 < 0.1 μg/mL) blocking receptor interaction, except for one that binds a unique epitope in the N-terminal domain. Many of these neutralizing mAbs use public V-genes and are close to germline. We dissect the structural basis of recognition for this large panel of antibodies through X-ray crystallography and cryoelectron microscopy of 19 Fab-antigen structures. We find novel binding modes for some potently inhibitory antibodies and demonstrate that strongly neutralizing mAbs protect, prophylactically or therapeutically, in animal models.
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•Map 377 mAbs: 19 of 80 recognizing the RBD are potent neutralizers; 1 potent NTD binder•19 Fab-antigen complex structures; 80 mAbs mapped on RBD and clustered into 5 epitopes•Most potent mAbs are ACE2 blockers, neutralize with few ACE2s, some Fabs glycosylated•mAbs reveal unique examples of NTD binding, RBD binding mode, and LC optimization
Dejnirattisai et al. present an in-depth study of the human antibody response to SARS-CoV-2 infection. By characterizing 377 human mAbs from recovered COVID-19 patients, and determining 19 protein structures, they construct a map of antibody footprints on the RBD that describes in great detail its antigenic anatomy.
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