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"Morgan, Richard"
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The Epigenomic Landscape of Prokaryotes
DNA methylation acts in concert with restriction enzymes to protect the integrity of prokaryotic genomes. Studies in a limited number of organisms suggest that methylation also contributes to prokaryotic genome regulation, but the prevalence and properties of such non-restriction-associated methylation systems remain poorly understood. Here, we used single molecule, real-time sequencing to map DNA modifications including m6A, m4C, and m5C across the genomes of 230 diverse bacterial and archaeal species. We observed DNA methylation in nearly all (93%) organisms examined, and identified a total of 834 distinct reproducibly methylated motifs. This data enabled annotation of the DNA binding specificities of 620 DNA Methyltransferases (MTases), doubling known specificities for previously hard to study Type I, IIG and III MTases, and revealing their extraordinary diversity. Strikingly, 48% of organisms harbor active Type II MTases with no apparent cognate restriction enzyme. These active 'orphan' MTases are present in diverse bacterial and archaeal phyla and show motif specificities and methylation patterns consistent with functions in gene regulation and DNA replication. Our results reveal the pervasive presence of DNA methylation throughout the prokaryotic kingdoms, as well as the diversity of sequence specificities and potential functions of DNA methylation systems.
Journal Article
Altered carbon
'Altered Carbon' is a lightening fast, breathtakingly violent noir thriller set in the San Francisco of the 26th century. It is an awe-inspiring vision of a future living on stolen time.
Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or Refractory Multiple Myeloma
Chimeric antigen receptor autologous T cells that were directed against the B-cell maturation antigen induced responses in 85% of the 33 patients with relapsed or refractory myeloma in whom they were infused only once. The frequency and severity of cytokine release syndrome were less than have been seen with other CAR T cells.
Journal Article
Thin air
\"On a Mars where ruthless commercial interests violently collide with a homegrown independence movement, as Earth-based overlords battle for profits and power, Hakan Veil is an ex-corporate enforcer equipped with military-grade body tech that's made him a human killing machine. But he's had enough of the turbulent red planet, and all he wants is a ticket back home--which is just what he's offered by the Earth Oversight organization, in exchange for being the bodyguard for an EO investigator. It's a beyond-easy gig for a heavy hitter like Veil ... until it isn't. When Veil's charge, Madison Madekwe, starts looking into the mysterious disappearance of a lottery winner, she stirs up a hornets' nest of intrigue and murder. And the deeper Veil is drawn into the dangerous game being played, the more long-buried secrets claw their way to the Martian surface. Now it's the expert assassin on the wrong end of a lethal weapon--as Veil stands targeted by powerful enemies hellbent on taking him down, by any means necessary\"-- Provided by publisher.
BOOK
AnnoTALE: bioinformatics tools for identification, annotation and nomenclature of TALEs from Xanthomonas genomic sequences
Transcription activator-like effectors (TALEs) are virulence factors, produced by the bacterial plant-pathogen
Xanthomonas
, that function as gene activators inside plant cells. Although the contribution of individual TALEs to infectivity has been shown, the specific roles of most TALEs and the overall TALE diversity in
Xanthomonas
spp. is not known. TALEs possess a highly repetitive DNA-binding domain, which is notoriously difficult to sequence. Here, we describe an improved method for characterizing
TALE
genes by the use of PacBio sequencing. We present ‘AnnoTALE’, a suite of applications for the analysis and annotation of
TALE
genes from
Xanthomonas
genomes and for grouping similar TALEs into classes. Based on these classes, we propose a unified nomenclature for
Xanthomonas
TALEs that reveals similarities pointing to related functionalities. This new classification enables us to compare related TALEs and to identify base substitutions responsible for the evolution of TALE specificities.
Journal Article
Alan and the animals
Alan, who loves all sorts of animals, has everything from ten rats to ten wild dogs.
Book
Human Tumor Xenografts: The Good, the Bad, and the Ugly
There has been a robust discussion for many years now on the utility, or lack thereof, of mouse tumor xenograft models in the study of human cell and gene therapies.[1-4] Of course, the reality is that the value of a model depends on what the modeler is trying to accomplish. A good use of human tumor xenograft models would be to support an experimental hypothesis, a bad use would be to present animal data that add little to the value of in vitro data, and an ugly use of tumor xenografts would be to facilitate publication of a manuscript or give a false sense of safety or efficacy.
Journal Article
Protein L: a novel reagent for the detection of Chimeric Antigen Receptor (CAR) expression by flow cytometry
Background
There has been significant progress in the last two decades on the design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. Structurally CARs consist of a single chain antibody fragment directed against a tumor-associated antigen fused to an extracellular spacer and transmembrane domain followed by T cell cytoplasmic signaling moieties. Currently several clinical trials are underway using gene modified peripheral blood lymphocytes (PBL) with CARs directed against a variety of tumor associated antigens. Despite the improvements in the design of CARs and expansion of the number of target antigens, there is no universal flow cytometric method available to detect the expression of CARs on the surface of transduced lymphocytes.
Methods
Currently anti-fragment antigen binding (Fab) conjugates are most widely used to determine the expression of CARs on gene-modified lymphocytes by flow cytometry. The limitations of these reagents are that many of them are not commercially available, generally they are polyclonal antibodies and often the results are inconsistent. In an effort to develop a simple universal flow cytometric method to detect the expression of CARs, we employed protein L to determine the expression of CARs on transduced lymphocytes. Protein L is an immunoglobulin (Ig)-binding protein that binds to the variable light chains (kappa chain) of Ig without interfering with antigen binding site. Protein L binds to most classes of Ig and also binds to single-chain antibody fragments (scFv) and Fab fragments.
Results
We used CARs derived from both human and murine antibodies to validate this novel protein L based flow cytometric method and the results correlated well with other established methods. Activated human PBLs were transduced with retroviral vectors expressing two human antibody based CARs (anti-EGFRvIII, and anti-VEGFR2), two murine antibody derived CARs (anti-CSPG4, and anti-CD19), and two humanized mouse antibody based CARs (anti-ERBB2, and anti-PSCA). Transduced cells were stained first with biotin labeled protein L followed by phycoerythrin (PE)-conjugated streptavidin (SA) and analyzed by flow cytometry. For comparison, cells were stained in parallel with biotin conjugated goat-anti-mouse Fab or CAR specific fusion proteins. Using protein L, all CAR transduced lymphocytes exhibited specific staining pattern ranging from 40 to 80% of positive cells (compared to untransduced cells) and staining was comparable to the pattern observed with anti-Fab antibodies.
Conclusion
Our data demonstrate the feasibility of employing Protein L as a general reagent for the detection of CAR expression on transduced lymphocytes by flow cytometry.
Journal Article