The deregulation of BCL2 family proteins plays a crucial role in leukemia development. Therefore, pharmacological inhibition of this family of proteins is becoming a prevalent treatment method. ...However, due to the emergence of primary and acquired resistance, efficacy is compromised in clinical or preclinical settings. We developed a drug sensitivity prediction model utilizing a deep tabular learning algorithm for the assessment of venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL) patient samples. Through analysis of predicted venetoclax-sensitive and resistant samples, PLK1 was identified as a cooperating partner for the BCL2-mediated antiapoptotic program. This finding was substantiated by additional data obtained through phosphoproteomics and high-throughput kinase screening. Concurrent treatment using venetoclax with PLK1-specific inhibitors and PLK1 knockdown demonstrated a greater therapeutic effect on T-ALL cell lines, patient-derived xenografts, and engrafted mice compared with using each treatment separately. Mechanistically, the attenuation of PLK1 enhanced BCL2 inhibitor sensitivity through upregulation of BCL2L13 and PMAIP1 expression. Collectively, these findings underscore the dependency of T-ALL on PLK1 and postulate a plausible regulatory mechanism.
The oomycete Phytophthora infestans is the causal agent of late blight in potato and tomato. Since the underlying processes that govern pathogenicity and development in P. infestans are largely ...unknown, we have performed a large-scale phosphoproteomics study of six different P. infestans life stages. We have obtained quantitative data for 2922 phosphopeptides and compared their abundance. Life-stage-specific phosphopeptides include ATP-binding cassette transporters and a kinase that only occurs in appressoria. In an extended data set, we identified 2179 phosphorylation sites and deduced 22 phosphomotifs. Several of the phosphomotifs matched consensus sequences of kinases that occur in P. infestans but not Arabidopsis. In addition, we detected tyrosine phosphopeptides that are potential targets of kinases resembling mammalian tyrosine kinases. Among the phosphorylated proteins are members of the RXLR and Crinkler effector families. The latter are phosphorylated in several life stages and at multiple positions, in sites that are conserved between different members of the Crinkler family. This indicates that proteins in the Crinkler family have functions beyond their putative role as (necrosis-inducing) effectors. This phosphoproteomics data will be instrumental for studies on oomycetes and host-oomycete interactions. The data sets have been deposited to ProteomeXchange (identifier PXD000433).
Aims: To compare galactose‐negative strains of Streptococcus thermophilus and Lactobacillus delbrueckii subspecies bulgaricus isolated from fermented milk products and known to produce ...exopolysaccharides (EPSs).
Methods and Results: The structures of the EPSs were determined using nuclear magnetic resonance (NMR) and their genetic relationships determined using restriction endonuclease analysis (REA) and random amplification of polymorphic DNA (RAPD). Similar groupings were apparent by REA and RAPD, and each group produced an EPS with a particular subunit structure.
Conclusions: Although none of the strains assimilated galactose, all inserted a high proportion of galactose into their EPS when grown in skimmed milk, and fell into three distinct groups.
Significance and Impact of the Study: This information should help in an understanding of genetic exchanges in lactic acid bacteria.
Interdisciplinary work across the humanities and social sciences is moving beyond analysis of any one nation in isolation and instead placing urgent questions in the larger matrix of the Americas as ...a hemisphere. But little attention has been given to the overarching methodological, institutional, and pedagogical issues resulting from the growth of inter-American, or American hemispheric studies. "Teaching and Studying the Americas" is designed to give close consideration to the range of fundamental challenges and questions that a hemispheric studies perspective raises. It is unique in its primary concern with questions of institutional practice, pedagogic transformation, and research perspectives. This book contains three parts and an introduction by Alexander Byrd, Michael Emerson, Caroline Levander, and Anthony B. Pinn. Part I: Locating and Dislocating the Americas, contains: (1) Good Neighbor/Bad Neighbor: Boltonian Americanism and Hemispheric Studies (Antonio Barrenechea); (2) Bad Neighbor/Good Neighbor: Across the Disciplines Toward a Hemispheric Studies (Caroline Levander); and (3) Coloniality At Large: The Western Hemisphere and the Colonial Horizon of Modernity (Walter Mignolo). Part II: Disciplining Hemispheric Studies, contains: (4) A Major Motion Picture: Studying and Teaching the Americas (Michael O. Emerson); (5) Embodied Meaning: The "Look" and "Location" of Religion in the American Hemisphere (Anthony B. Pinn); (6) Primeval Whiteness: White Supremacies, (Latin) American History, and the Transamerican Challenge to Critical Race Studies (Ruth Hill); (7) The Making of "Americans": Old Boundaries, New Realities (Karen Manges Douglas and Rogelio Saenz); and (8) Interdisciplinary Approaches to Teaching the History of the Western Hemisphere (Moramay Lopez-Alonso). Part III: Programs and Pedagogy, contains: (9) Beyond National Borders: Researching and Teaching Jovita Gonzalez (Heather Miner and Robin Sager); (10) Migrant Archives: New Routes In and Out of American Studies (Rodrigo Lazo); (11) Partnering Across the Americas: Crossing National and Disciplinary Borders in Archival Development (Melissa Bailar); and (12) Ghosts of the American Century: The Intellectual, Programmatic and Institutional Challenges for Transnational/Hemispheric American Studies (Matthew Guterl and Deborah Cohn).
A set of new algorithms and software tools for automatic protein identification using peptide mass fingerprinting is presented. The software is automatic, fast and modular to suit different ...laboratory needs, and it can be operated either via a Java user interface or called from within scripts. The software modules do peak extraction, peak filtering and protein database matching, and communicate via XML. Individual modules can therefore easily be replaced with other software if desired, and all intermediate results are available to the user. The algorithms are designed to operate without human intervention and contain several novel approaches. The performance and capabilities of the software is illustrated on spectra from different mass spectrometer manufacturers, and the factors influencing successful identification are discussed and quantified. Motivation: Protein identification with mass spectrometric methods is a key step in modern proteomics studies. Some tools are available today for doing different steps in the analysis. Only a few commercial systems integrate all the steps in the analysis, often for only one vendor's hardware, and the details of these systems are not public. Results: A complete system for doing protein identification with peptide mass fingerprints is presented, including everything from peak picking to matching the database protein. The details of the different algorithms are disclosed so that academic researchers can have full control of their tools. Availability: The described software tools are available from the Halmstad University website www.hh.se/staff/bioinf/ Supplementary information: Details of the algorithms are described in supporting information available from the Halmstad University website www.hh.se/staff/bioinf/
Throughout American literature, the figure of the child is often represented in opposition to the adult. In Cradle of Liberty Caroline F. Levander proposes that this opposition is crucial to American ...political thought and the literary cultures that surround and help produce it. Levander argues that from the late eighteenth century through the early twentieth, American literary and political texts did more than include child subjects: they depended on them to represent, naturalize, and, at times, attempt to reconfigure the ground rules of U.S. national belonging. She demonstrates how, as the modern nation-state and the modern concept of the child (as someone fundamentally different from the adult) emerged in tandem from the late eighteenth century forward, the child and the nation-state became intertwined. The child came to represent nationalism, nation-building, and the intrinsic connection between nationalism and race that was instrumental in creating a culture of white supremacy in the United States. Reading texts by John Adams, Thomas Paine, Harriet Beecher Stowe, Augusta J. Evans, Mark Twain, Pauline Hopkins, William James, José Martí, W. E. B. Du Bois, and others, Levander traces the child as it figures in writing about several defining events for the United States. Among these are the Revolutionary War, the U.S.-Mexican War, the Civil War, and the U.S. expulsion of Spain from the Caribbean and Cuba. She charts how the child crystallized the concept of self-a self who could affiliate with the nation-in the early national period, and then follows the child through the rise of a school of American psychology and the period of imperialism. Demonstrating that textual representations of the child have been a potent force in shaping public opinion about race, slavery, exceptionalism, and imperialism, Cradle of Liberty shows how a powerful racial logic pervades structures of liberal democracy in the United States.
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