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Imidazole aldoximes effective in assisting butyrylcholinesterase catalysis of organophosphate detoxification.
Intoxication by organophosphate (OP) nerve agents and pesticides should be addressed by efficient, quickly deployable countermeasures such as antidotes reactivating acetylcholinesterase or scavenging the parent OP. We present here synthesis and initial in vitro characterization of 14 imidazole aldoximes and their structural refinement into three efficient reactivators of human butyrylcholinesterase (hBChE) inhibited covalently by nerve agent OPs, sarin, cyclosarin, VX, and the OP pesticide metabolite, paraoxon. Rapid reactivation of OP-hBChE conjugates by uncharged and nonprotonated tertiary imidazole aldoximes allows the design of a new OP countermeasure by conversion of hBChE from a stoichiometric to catalytic OP bioscavenger with the prospect of oral bioavailability and central nervous system penetration. The enhanced in vitro reactivation efficacy determined for tertiary imidazole aldoximes compared to that of their quaternary N-methyl imidazolium analogues is attributed to ion pairing of the cationic imidazolium with Asp 70, altering a reactive alignment of the aldoxime with the phosphorus in the OP-hBChE conjugate
Iterative in Situ Click Chemistry Assembles a Branched Capture Agent and Allosteric Inhibitor for Akt1
We describe the use of iterative in situ click chemistry to design an Akt-specific branched peptide triligand that is a drop-in replacement for monoclonal antibodies in multiple biochemical assays. Each peptide module in the branched structure makes unique contributions to affinity and/or specificity resulting in a 200 nM affinity ligand that efficiently immunoprecipitates Akt from cancer cell lysates and labels Akt in fixed cells. Our use of a small molecule to preinhibit Akt prior to screening resulted in low micromolar inhibitory potency and an allosteric mode of inhibition, which is evidenced through a series of competitive enzyme kinetic assays. To demonstrate the efficiency and selectivity of the protein-templated in situ click reaction, we developed a novel QPCR-based methodology that enabled a quantitative assessment of its yield. These results point to the potential for iterative in situ click chemistry to generate potent, synthetically accessible antibody replacements with novel inhibitory properties
Enzymic transformation of an acyclic sesterterpene terminal epoxide into a lanosterol analogue
V4332 Sagittarii revisited
The eruption of V4332 Sgr discovered in February 1994 shows striking
similarities to that of V838 Mon started in January 2002. The nature of these
eruptions is, however, enigmatic and unclear. We present new photometric and
spectroscopic data on V4332 Sgr obtained in April-May 2003 at the SAAO. The
obtained spectrum shows an unusual emission-line component superimposed on an
early M-type stellar spectrum. The emission-line spectrum is of very low
excitation and is dominated by lines from neutral elemets (NaI, FeI, CaI) and
molecular bands (TiO, ScO, AlO). We also analyse all the observational data,
mainly photometric measurements, available for V4332 Sgr. This allows us to
follow the evolution of the effective temperature, radius and luminosity of the
object since February 1994 till 2003. We show that the observed decline of
V4332 Sgr can be accounted for by a gravitational contraction of an inflated
stellar envelope. The combined optical and infrared photometry in 2003 shows
that apart from the M-type stellar component there is a strong infrared excess
in the KLM bands. This excess was absent in the 2MASS measurements done in 1998
but was probably starting to appear in K in 1999 when the object was observed
in the DENIS survey. We interpret the results in terms of a stellar merger
scenario proposed by Soker & Tylenda. The infrared excess is likely to be due
to a disc-like structure which is either of protostellar nature or has been
produced during the 1994 eruption and stores angular momentum from the merger
event.Comment: 11 pages, 5 figures, accepted in Astronomy & Astrophysic
Defining the toxicology of aging
Mammalian aging is complex and incompletely understood. While significant effort has been spent addressing the genetics or, more recently, the pharmacology of aging, the toxicology of aging has been relatively understudied. Just as an understanding of `carcinogens' has proven critical to modern cancer biology, an understanding of environmental toxicants that accelerate aging (`gerontogens') will inform gerontology. In this review, we discuss the evidence for the existence of mammalian gerontogens, as well as describe biomarkers needed to measure the age-promoting activity of a given toxicant. We focus on the effects of putative gerontogens on the in vivo accumulation of senescent cells, a characteristic feature of aging that plays a causal role in some age-associated phenotypes
Far infrared mapping of three Galactic star forming regions : W3(OH), S 209 & S 187
Three Galactic star forming regions associated with W3(OH), S209 and S187
have been simultaneously mapped in two trans-IRAS far infrared (FIR) bands
centered at ~ 140 and 200 micron using the TIFR 100 cm balloon borne FIR
telescope. These maps show extended FIR emission with structures. The HIRES
processed IRAS maps of these regions at 12, 25, 60 & 100 micron have also been
presented for comparison. Point-like sources have been extracted from the
longest waveband TIFR maps and searched for associations in the other five
bands. The diffuse emission from these regions have been quantified, which
turns out to be a significant fraction of the total emission. The spatial
distribution of cold dust (T < 30 K) for two of these sources (W3(OH) & S209),
has been determined reliably from the maps in TIFR bands. The dust temperature
and optical depth maps show complex morphology. In general the dust around S209
has been found to be warmer than that in W3(OH) region.Comment: Accepted for publication in Journal of Astrophysics and Astronomy (20
pages including 8 figures & 3 tables
INK4/ARF Transcript Expression Is Associated with Chromosome 9p21 Variants Linked to Atherosclerosis
Genome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a), p15(INK4b), ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs.We analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15(INK4b), p16(INK4a), ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs.Genotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging
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