11 research outputs found
Transcriptional profile of immediate response to ionizing radiation exposure
Astronauts participating in long duration space missions are likely to be exposed to ionizing radiation associated with highly energetic and charged heavy particles. Previously proposed gene biomarkers for radiation exposure include phosphorylated H2A Histone Family, Member X (ÎłH2AX), Tumor Protein 53 (TP53), and Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A). However, transcripts of these genes may not be the most suitable biomarkers for radiation exposure due to a lack of sensitivity or specificity. As part of a larger effort to develop lab-on-a-chip methods for detecting radiation exposure events using blood samples, we designed a doseâcourse microarray study in order to determine coding and non-coding RNA transcripts undergoing differential expression immediately following radiation exposure. The main goal was to elicit a small set of sensitive and specific radiation exposure biomarkers at low, medium, and high levels of ionizing radiation exposure. Four separate levels of radiation were considered: 0Â Gray (Gy) control; 0.3Â Gy; 1.5Â Gy; and 3.0Â Gy with four replicates at each radiation level. This report includes raw gene expression data files from the resulting microarray experiments from all three radiation levels ranging from a lower, typical exposure than an astronaut might see (0.3Â Gy) to high, potentially lethal, levels of radiation (3.0Â Gy). The data described here is available in NCBI's Gene Expression Omnibus (GEO), accession GSE64375. Keywords: Ionizing radiation, Radiation exposure, Astronaut, Long duration space trave
Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: StructureâActivity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies
Rhodesain is a major
cysteine protease of Trypanosoma
brucei rhodesiense, a pathogen causing Human African
Trypanosomiasis, and a validated drug target. Recently, we reported
the development of α-halovinylsulfones as a new class of covalent
reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates
were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series,
shows a single-digit nanomolar affinity and high selectivity toward
mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments
indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorable metabolism and biodistribution by accumulation in
mice brain tissue after intraperitoneal and oral administration. The
highest antitrypanosomal activity was observed for inhibitors with
an N-terminal 2,3-dihydrobenzoÂ[b]Â[1,4]Âdioxine group
and a 4-Me-Phe residue in P2 (2e/4e) with
nanomolar EC50 values (0.14/0.80 ÎŒM). The different
mechanisms of reversible and irreversible inhibitors were explained
using QM/MM calculations and MD simulations