The goal of this study is to evaluate the theoretically achievable accuracy in estimating photon cross sections at low energies (20-1000 keV) from idealized dual-energy x-ray computed tomography (CT) images. Cross-section estimation from dual-energy measurements requires a model that can accurately represent photon cross sections of any biological material as a function of energy by specifying only two characteristic parameters of the underlying material, e.g., effective atomic number and density. This paper evaluates the accuracy of two commonly used two-parameter cross-section models for postprocessing idealized measurements derived from dual-energy CT images. The parametric fit model (PFM) accounts for electron-binding effects and photoelectric absorption by power functions in atomic number and energy and scattering by the Klein-Nishina cross section. The basis-vector model (BVM) assumes that attenuation coefficients of any biological substance can be approximated by a linear combination of mass attenuation coefficients of two dissimilar basis substances. Both PFM and BVM were fit to a modern cross-section library for a range of elements and mixtures representative of naturally occurring biological materials (Z = 2-20). The PFM model, in conjunction with the effective atomic number approximation, yields estimated the total linear cross-section estimates with mean absolute and maximum error ranges of 0.6%-2.2% and 1%-6%, respectively. The corresponding error ranges for BVM estimates were 0.02%-0.15% and 0.1%-0.5%. However, for photoelectric absorption frequency, the PFM absolute mean and maximum errors were 10.8%-22.4% and 29%-50%, compared with corresponding BVM errors of 0.4%-11.3% and 0.5%-17.0%, respectively. Both models were found to exhibit similar sensitivities to image-intensity measurement uncertainties. Of the two models, BVM is the most promising approach for realizing dual-energy CT cross-section measurement.
Artemis and PALF (also called APLF) appear to be among the primary nucleases involved in NHEJ and responsible for most nucleolytic end processing in NHEJ. About 60% of NHEJ events show an alignment of the DNA ends that uses 1 or 2 bp of microhomology (MH) between the two DNA termini. Thus, MH is a common feature of NHEJ. For most naturally-occurring human chromosomal deletions (e.g., after oxidative damage or radiation) and translocations, such as those seen in human neoplasms and as well as inherited chromosomal structural variations, MH usage occurs at a frequency that is typical of NHEJ, and does not suggest major involvement of alternative pathways that require more extensive MH. Though we mainly focus on human NHEJ at DSBs, comparison on these points to other eukaryotes, primarily S. cerevisiae, is informative.
SignificanceAminoglycosides remain a vital clinical asset. Gentamicin C complex in particular is remarkably potent in treating systemic Gram-negative infections, and semisynthetic gentamicins that combat pathogen resistance or show reduced toxicity remain attractive goals. We report here the roles of clustered genes and enzymes that define a methylation network in gentamicin biosynthesis and also identify a remote gene on the chromosome encoding the essential methyltransferase GenL, which is decisive for the proportions of the five major components present in the gentamicin C complex. This is an important step toward engineered fermentation to produce single components as valuable starting materials for semisynthesis of next-generation aminoglycoside antibiotics.
Purpose MUC1, an oncogene overexpressed in multiple solid tumors including pancreatic cancer, reduces overall survival and imparts resistance to radiation and chemotherapies. We previously identified that MUC1 facilitates growth promoting metabolic alterations in pancreatic cancer cells. The present study investigates the role of MUC1-mediated metabolism in radiation resistance of pancreatic cancer by utilizing cell lines and in vivo models. Experimental design We used MUC1 knockdown and overexpressed cell line models for evaluating the role of MUC1-mediated metabolism in radiation resistance through in vitro cytotoxicity, clonogenicity, DNA damage response and metabolomic evaluations. We also investigated if inhibition of glycolysis could revert MUC1-mediated metabolic alterations and radiation resistance using in vitro and in vivo models. Results MUC1 expression diminished radiation-induced cytotoxicity and DNA damage in pancreatic cancer cells by enhancing glycolysis, pentose phosphate pathway, and nucleotide biosynthesis. Such metabolic reprogramming resulted in high nucleotide pools and radiation resistance in in vitro models. Pre-treatment with the glycolysis inhibitor, 3-bromopyruvate (BrPA) abrogated MUC1-mediated radiation resistance both in vitro and in vivo, by reducing glucose flux into nucleotide biosynthetic pathways and enhancing DNA damage, which could again be reversed by pre-treatment with nucleoside pools. Conclusions MUC1-mediated nucleotide metabolism plays a key role in facilitating radiation-resistance in pancreatic cancer and targeted effectively through glycolytic inhibition.
Human nuclease Artemis belongs to the metallo-beta-lactamase protein family. It acquires double-stranded DNA endonuclease activity in the presence of DNA-PKcs. This double-stranded DNA endonuclease activity is critical for opening DNA hairpins in V(D)J recombination and is thought to be important for processing overhangs during the nonhomologous DNA end joining (NHEJ) process. Here we show that purified human Artemis exhibits single-stranded DNA endonuclease activity. This activity is proportional to the amount of highly purified Artemis from a gel filtration column. The activity is stimulated by DNA-PKcs and modulated by purified antibodies raised against Artemis. Moreover, the divalent cation-dependence and sequence-dependence of this single-stranded endonuclease activity is the same as the double-stranded DNA endonuclease activity of Artemis:DNA-PKcs. These findings further expand the range of DNA substrates upon which Artemis and Artemis:DNA-PKcs can act. The findings are discussed in the context of NHEJ.
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