Determining anion-quadrupole interactions among protein, DNA, and ligand molecules

Background An extensive search through the Protein Databank (about 4500 nonredundant structures) was previously completed within our lab to analyze the energetic and geometric characteristics of an understudied molecular interaction known as an anion-quadrupole (AQ) interaction. Such an interaction occurs when the positively charged edge of an aromatic ring, resulting from a quadruple moment (i.e., a dual dipole moment), renders the aromatic molecule noncovalently bound to a nearby anionic molecule. The study considered a very limited scenario of molecules that can participate in AQ interactions, consisting of the phenyl group of a phenylalanine (phe) amino acid as the aromatic participant and the carboxylate group of an aspartate (asp) or glutamate (glu) amino acid as the anionic participant. The results revealed anion-quadrupole pairs to be prevalent within most of the protein structures. It was also observed that the interaction energy for AQ pairs was heavily dependent on the angle between the anion and plane of the aromatic ring, favoring a more planar interaction. In light of these critical observations being made from such a limited scenario, only phe-glu and phe-asp pairs and in a reduced sample set of the PDB, we are now continuing this work of identifying AQ interactions using a greatly expanded strategy. We are following these four aims: 1. Optimizing the AQ-search program to run in a semi-parallel fashion and on a large cluster of processors in order to handle larger analyses, 2. Adding to our search additional anionic participants which will include non-protein structures such as DNA and small ligands, 3. Studying a subset of the AQ pairs with molecular dynamics simulations in buried and solvent exposed environments to observe non-static behavioral traits as well as the reproducibility of AQ interactions by force field parameters. 4. Building an online database for public access to our data and search program. Acknowledgments We would like to acknowledge the NSF-IGERT traineeship, Scalable Computing and Leading Edge Innovative Technologies (SCALE-IT), for providing the resources for this project

Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial

<p>Abstract</p> <p>Background</p> <p>Stereotactic ablative radiotherapy (SABR) has emerged as a new treatment option for patients with oligometastatic disease. SABR delivers precise, high-dose, hypofractionated radiotherapy, and achieves excellent rates of local control. Survival outcomes for patients with oligometastatic disease treated with SABR appear promising, but conclusions are limited by patient selection, and the lack of adequate controls in most studies. The goal of this multicenter randomized phase II trial is to assess the impact of a comprehensive oligometastatic SABR treatment program on overall survival and quality of life in patients with up to 5 metastatic cancer lesions, compared to patients who receive standard of care treatment alone.</p> <p>Methods</p> <p>After stratification by the number of metastases (1-3 vs. 4-5), patients will be randomized between Arm 1: current standard of care treatment, and Arm 2: standard of care treatment + SABR to all sites of known disease. Patients will be randomized in a 1:2 ratio to Arm 1:Arm 2, respectively. For patients receiving SABR, radiotherapy dose and fractionation depends on the site of metastasis and the proximity to critical normal structures. This study aims to accrue a total of 99 patients within four years. The primary endpoint is overall survival, and secondary endpoints include quality of life, toxicity, progression-free survival, lesion control rate, and number of cycles of further chemotherapy/systemic therapy.</p> <p>Discussion</p> <p>This study will provide an assessment of the impact of SABR on clinical outcomes and quality of life, to determine if long-term survival can be achieved for selected patients with oligometastatic disease, and will inform the design of a possible phase III study.</p> <p>Trial registration</p> <p>Clinicaltrials.gov identifier: NCT01446744</p

Interaction of HP1 and Brg1/Brm with the Globular Domain of Histone H3 Is Required for HP1-Mediated Repression

The heterochromatin-enriched HP1 proteins play a critical role in regulation of transcription. These proteins contain two related domains known as the chromo- and the chromoshadow-domain. The chromo-domain binds histone H3 tails methylated on lysine 9. However, in vivo and in vitro experiments have shown that the affinity of HP1 proteins to native methylated chromatin is relatively poor and that the opening of chromatin occurring during DNA replication facilitates their binding to nucleosomes. These observations prompted us to investigate whether HP1 proteins have additional histone binding activities, envisioning also affinity for regions potentially occluded by the nucleosome structure. We find that the chromoshadow-domain interacts with histone H3 in a region located partially inside the nucleosomal barrel at the entry/exit point of the nucleosome. Interestingly, this region is also contacted by the catalytic subunits of the human SWI/SNF complex. In vitro, efficient SWI/SNF remodeling requires this contact and is inhibited in the presence of HP1 proteins. The antagonism between SWI/SNF and HP1 proteins is also observed in vivo on a series of interferon-regulated genes. Finally, we show that SWI/SNF activity favors loading of HP1 proteins to chromatin both in vivo and in vitro. Altogether, our data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling

The First Nakba Novel? on Standing with Palestine

I wish to take this opportunity to respond to Bart Moore-Gilbert's essay “Palestine, Postcolonialism and Pessoptimism” by suggesting how its concerns might be amplified through a consideration of Ethel Mannin's nakba novel The Road to Beersheba (1963b). I offer my reading of Mannin's novel in the spirit of an unfinished dialogue with Bart Moore-Gilbert's work and as a tribute to his commitment to justice

Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells

Genomic instability is a common feature of cancer etiology. This provides an avenue for therapeutic intervention, since cancer cells are more susceptible than normal cells to DNA damaging agents. However, there is growing evidence that the epigenetic mechanisms that impact DNA methylation and histone status also contribute to genomic instability. The DNA damage response, for example, is modulated by the acetylation status of histone and non-histone proteins, and by the opposing activities of histone acetyltransferase and histone deacetylase (HDAC) enzymes. Many HDACs overexpressed in cancer cells have been implicated in protecting such cells from genotoxic insults. Thus, HDAC inhibitors, in addition to unsilencing tumor suppressor genes, also can silence DNA repair pathways, inactivate non-histone proteins that are required for DNA stability, and induce reactive oxygen species and DNA double-strand breaks. This review summarizes how dietary phytochemicals that affect the epigenome also can trigger DNA damage and repair mechanisms. Where such data is available, examples are cited from studies in vitro and in vivo of polyphenols, organosulfur/organoselenium compounds, indoles, sesquiterpene lactones, and miscellaneous agents such as anacardic acid. Finally, by virtue of their genetic and epigenetic mechanisms, cancer chemopreventive agents are being redefined as chemo- or radio-sensitizers. A sustained DNA damage response coupled with insufficient repair may be a pivotal mechanism for apoptosis induction in cancer cells exposed to dietary phytochemicals. Future research, including appropriate clinical investigation, should clarify these emerging concepts in the context of both genetic and epigenetic mechanisms dysregulated in cancer, and the pros and cons of specific dietary intervention strategies

Review of \u3ci\u3eArmy Letters from an Officer\u27s Wife\u3c/i\u3e By Frances M. A. Roe

Reminiscences of army wives constitute a distinct genre of the literature of the American West. About a dozen-among them Mrs. Custer, Mrs. Carrington, Mrs. Lane, Mrs. Summerhayes, Mrs. Viele, and Mrs. Boyd-offer perceptive, literate, and often graphic firsthand commentary on frontier army life and the people and conditions of the nineteenth-century American West. Near the top of the list-indeed, at the very top, in the opinion of this reviewer-stands Frances M. A. Roe\u27s Army Letters from an Officer\u27s Wife. In 1871 Frances Mack married Fayette W. Roe, an infantry lieutenant newly graduated from West Point. During the next two decades she accompanied him to rude frontier outposts such as Fort Lyon in Colorado, Camp Supply in Indian Territory, and various stations in Montana. Her letters (to whom is not stated, possibly her mother) are among the richest in detail and insight that we have from any of the army women. Because they are contemporary, they are all the more fresh and valuable. They tell of soldiers, Indians, badmen, and settlers, of life at remote army posts, of the land and its flora and fauna, and of the personalities she knew. These last she thinly disguised with altered names, but readers familiar with the frontier army will have no trouble recognizing Phillips as Penrose, Dickinson as Davidson, or Bourke as Brooke. Mrs. Roe thus becomes a major source for characterizations of particular frontier military ftgures. For flavor and detail alike, her letters are not excelled. This Bison Book reprint of the 1909 edition makes more generally available a work long treasured by the few but deserving a much wider audience. The introduction by Sandra Myres, a leading authority on frontier army women, ably sets the letters in their historical context