Insight into the chemistry of TNT during shock compression through ultrafast absorption spectroscopies.

Thin films of trinitrotoluene (TNT) were shock compressed using the ultrafast laser shock apparatus at Los Alamos National Laboratory. Visible (VIS) and mid-infrared (MIR) transient absorption spectroscopies were simultaneously performed to probe for electronic and vibrational changes during shock compression of TNT. Three shock pressures (16 GPa, 33 GPa, and 45 GPa) were selected to observe no reaction, incipient reaction, and strongly developed reactions for TNT within the experimental time scale of <250 ps. Negligible absorption changes in MIR or VIS absorptions were observed at 16 GPa. At 33 GPa, MIR absorptions in the 3000 cm-1-4000 cm-1 range were observed to increase during the shock and continue to increase during the rarefaction, in contrast to the VIS absorption measurements, which increased during the shock and almost fully recovered during rarefaction. At 45 GPa, both VIS and MIR absorptions were strong and irreversible. The intense and spectrally broad MIR absorptions were attributed to short lived intermediates with strong, spectrally broad absorptions that dominate the spectral response. The MIR and VIS absorption changes observed at 33 GPa and 45 GPa were credited to shock induced chemistry, most likely including the formation of a very broad hydrogenic stretch feature. The results from these experiments are consistent with the chemical mechanisms that include O-H or N-H formation such as CH3 oxidation or C-N homolysis.

Insight into the Chemistry of PETN Under Shock Compression Through Ultrafast Broadband Mid-Infrared Absorption Spectroscopy.

Thin films of pentaerythritol tetranitrate (PETN) were shock compressed using the laser driven shock apparatus at Los Alamos National Laboratory (LANL). Two spectroscopic probes were available to this apparatus: visible white light transient absorption spectroscopy (VIS) from 400 to 700 nm and mid-infrared transient absorption spectroscopy (MIR) from 1150 to 3800 cm-1. Important PETN vibrational modes are the symmetric and antisymmetric NO2 stretches at 1280 and 1650 cm-1, respectively, as well as CH stretches at ∼2900 cm-1. Shock strength was varied from approximately 3 to 55 GPa to span from the chemically unreactive regime to the regime in which fast chemical reaction took place on the 250 ps time scale of the measurements. VIS and MIR results suggest irreversible chemistry was induced in PETN at pressures above 30 GPa. At lower shock pressures, the spectroscopy showed minimal changes attributable to pressure induced effects. Under the higher-pressure reactive conditions, the frequency region at the antisymmetric NO2 stretch mode had a significantly increased absorption while the region around the symmetric NO2 stretch did not. No observable increased absorption occurred in the higher frequency regions where CH-, NH-, and OH- bond absorptions would be observed. A broad absorption appeared on the shoulder at the red-edge of the CO2 vibrational band around 2200 cm-1. In addition to the experiments, reactive molecular dynamics were carried out under equivalent shock conditions to correlate the evolution of the infrared spectrum to molecular processes. The simulations show results consistent to experiments up to 30 GPa but suggest that NO and NO2 related features provided the strongest contributions to the shocked infrared changes. Proposed mechanisms for shocked PETN chemistry are analyzed as consistent or inconsistent with the data presented here. Our experimental data suggests C≡O or N2O bond formation, nitrite formation, and absence of significant hydroxyl or amine concentrations in the initial chemistry steps in PETN shocked above 30 GPa.

A benchtop shock physics laboratory: Ultrafast laser driven shock spectroscopy and interferometry methods.

Common Ti:sapphire chirped pulse amplified laser systems can be readily adapted to be both a generator of adjustable pressure shock waves and a source for multiple probes of the ensuing ultrafast shock dynamics. In this paper, we detail experimental considerations for optimizing the shock generation, interferometric characterization, and spectroscopic probing of shock dynamics with visible and mid-infrared transient absorption. While we have reported results using these techniques elsewhere, here we detail how the spectroscopies are integrated with the shock and interferometry experiment. The interferometric characterization uses information from beams at multiple polarizations and angles of incidence combined with thin film equations and shock dynamics to determine the shock velocity, particle velocity, and shocked refractive index. Visible transient absorption spectroscopy uses a white light supercontinuum in a reflection geometry, synchronized to the shock wave, to time resolve shock-induced changes in visible absorption such as changes to electronic structure or strongly absorbing products and intermediates due to reaction. Mid-infrared transient absorption spectroscopy uses two color filamentation supercontinuum generation combined with a simple thermal imaging microbolometer spectrometer to enable broadband single shot detection of changes in the vibrational spectra. These methods are demonstrated here in the study of shock dynamics at stresses from 5 to 30 GPa in organic materials and from a few GPa to >70 GPa in metals with spatial resolution of a few micrometers and temporal resolution of a few picoseconds. This experiment would be possible to replicate in any ultrafast laser laboratory containing a single bench top commercial chirped pulse amplification laser system.

Shock induced chemistry in liquids studied with ultrafast dynamic ellipsometry and visible transient absorption spectroscopy.

The response to ultrafast laser shock loading of nine liquids was monitored in an effort to reveal evidence of chemical changes occurring during the first 350 ps following the shock front. In an effort to compare molecular structures possessing a variety of common bonding patterns, data were acquired for the liquids: cyclohexane, cyclohexene, 1,3-cyclohexadiene, benzene, water, acetonitrile, acrylonitrile, tert-butylacetylene, and phenylacetylene. Transient absorption spectra were measured in the spectral region from 440 to 780 nm over shock stress states from 7 to 20 GPa. Ultrafast dynamic ellipsometry was used to measure the shock and particle velocity as well as the shocked refractive index. Significant transient absorption attributed to chemical reaction was observed for shocked phenylacetylene and acrylonitrile. Evidence of volume decreasing chemical reactions was also observed in the ultrafast dynamic ellipsometry data for phenylacetylene and acrylonitrile. The liquid 1,3-cyclohexadiene exhibited volume decreasing reaction in the ultrafast dynamic ellipsometry data but did not exhibit an increase in the transient absorption spectra. There was no evidence of chemical reaction in cyclohexane, cyclohexene, benzene, water, acetonitrile, or tert-butylacetylene in the first 350 ps, despite the application of shock stress that was in many cases well above the reaction threshold observed at microsecond time scales.

Pulsed quantum cascade laser-based CRDS substance detection: real-time detection of TNT.

This paper presents experimental results from a pulsed quantum cascade laser based cavity ringdown spectrometer used as a high-throughput detection system. The results were obtained from an optical cavity with 99.8% input and output coupling mirrors that was rapidly swept (0.2s to 7s sweep times) between 1582.25 cm(-1) (6.3201µm) and 1697.00 cm(-1) (5.8928µm). The spectrometer was able to monitor gas species over the pressure range 585 torr to 1µtorr, and the analysis involves a new digital data processing system that optimises the processing speed and minimises the data storage requirements. In this approach we show that is it not necessary to make direct measurements of the ringdown time of the cavity to obtain the system dynamics. Furthermore, we show that correct data processing is crucial for the ultimate implementation of a wideband IR spectrometer that covers a range similar to that of commercial Fourier transform infrared instruments.

Use of the Gerchberg-Saxton algorithm in optimal coherent anti-Stokes Raman spectroscopy.

We are utilizing recent advances in ultrafast laser technology and recent discoveries in optimal shaping of laser pulses to significantly enhance the stand-off detection of explosives via control of molecular processes at the quantum level. Optimal dynamic detection of explosives is a method whereby the selectivity and sensitivity of any of a number of nonlinear spectroscopic methods are enhanced using optimal shaping of ultrafast laser pulses. We have recently investigated the Gerchberg-Saxton algorithm as a method to very quickly estimate the optimal spectral phase for a given analyte from its spontaneous Raman spectrum and the ultrafast laser pulse spectrum. Results for obtaining selective coherent anti-Stokes Raman spectra (CARS) for an analyte in a mixture, while suppressing the CARS signals from the other mixture components, are compared for the Gerchberg-Saxton method versus previously obtained results from closed-loop machine-learning optimization using evolutionary strategies.

Femtosecond stimulated Raman scattering picosecond molecular thermometry in condensed phases.

We demonstrate the capability of femtosecond stimulated Raman scattering (FSRS) data to measure the temperature of condensed matter at the molecular vibrational level. We report the temperature dependence of Raman loss to Raman gain ratios for low frequency modes (<300 cm(-1)) in a CaCO3 single crystal from cryogenic to room temperature, which is shown to be in agreement with theoretical predictions. We also report the measurements of nonequilibrium time evolution of mode specific vibrational temperatures in the CaCO3 single crystal to demonstrate that FSRS can measure temperature on picosecond time scales. Finally, we point out the unique origin of this temperature dependent anti-Stokes to Stokes ratio in stimulated Raman, which is not present in other coherent Raman spectroscopies. These measurements require no material dependent parameters or prior calibration.

Inhibition of thromboxane A2-induced arrhythmias and intracellular calcium changes in cardiac myocytes by blockade of the inositol trisphosphate pathway.

We have recently reported that left atrial injections of the thromboxane A(2) (TXA(2)) mimetic, (5Z)-7-[(1R,4S,5S,6R)-6-[(1E,3S)-3-hydroxy-1-octenyl]-2 -oxabicyclo[2.2.1]hept-5-yl]-5-heptenoic acid (U46619), induced ventricular arrhythmias in the anesthetized rabbit. Data from this study led us to hypothesize that TXA(2) may be inducing direct actions on the myocardium to induce these arrhythmias. The aim of this study was to further elucidate the mechanism responsible for these arrhythmias. We report that TXA(2)R is expressed at both the gene and protein levels in atrial and ventricular samples of adult rabbits. In addition, TXA(2)R mRNA was identified in single, isolated ventricular cardiac myocytes. Furthermore, treatment of isolated cardiac myocytes with U46619 increased intracellular calcium in a dose-dependent manner and these increases were blocked by the specific TXA(2)R antagonist, 7-(3-((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ29548). Pretreatment of myocytes with an inhibitor of inositol trisphosphate (IP(3)) formation, gentamicin, or with an inhibitor of IP(3) receptors, 2-aminoethoxydiphenylborate (2-APB), blocked the increase in intracellular calcium. In vivo pretreatment of anesthetized rabbits with either gentamicin or 2-APB subsequently inhibited the formation of ventricular arrhythmias elicited by U46619. These data support the hypothesis that TXA(2) can induce arrhythmias via a direct action on cardiac myocytes. Furthermore, these arrhythmogenic actions were blocked by inhibitors of the IP(3) pathway. In summary, this study provides novel evidence for direct TXA(2)-induced cardiac arrhythmias and provides a rationale for IP(3) as a potential target for the treatment of TXA(2)-mediated arrhythmias.

Control of cis-stilbene photochemistry using shaped ultraviolet pulses.

We demonstrate product branching control of the photoisomerization and cyclization reactions of cis-stilbene dissolved in n-hexane. An acousto-optical modulator-based pulse shaper was used at 266 nm, in a shaped pump-supercontinuum probe technique, to enhance and suppress the relative yields of the cis- to trans-stilbene isomerization as well as the cis-stilbene to 4a,4b-dihydrophenanthrene cyclization. Global, local, and single variable optimization control schemes were all successful at controlling stilbene's excited-state intramolecular rearrangements. The presence of multiphoton transitions was determined to be crucial in changing the yield under the experimental conditions employed. We have mapped experimental conditions in which multiphoton absorption was successful in controlling photoproduct branching ratios in stilbene, illustrated that the intensity dependence of the product yields can provide details of reactive channel branching ratios of higher excited-states, and shown that under the experimental conditions employed (150 fs laser) intensity control was the only mechanism available to the optimal control methods employed that could affect reaction yields.

Infrared complex refractive index measurements and simulated reflection mode infrared absorption spectroscopy of shock-compressed polymer thin films.

Thin film interference effects complicate the interpretation of reflection-mode infrared absorption spectra obtained in shock-compressed thin film materials and must be carefully accounted for in any analysis attempting to unravel shock-induced energy transfer or reactivity. We have calculated such effects for spectrally simple model systems and also, to the extent possible, for real systems such as polymethylmethacrylate (PMMA) and nitrocellulose (NC). We have utilized angle-dependent infrared (IR) reflectometry to obtain the ambient spectral complex index for PMMA and NC for use in the calculations and to interpret experiments. A number of counter-intuitive spectral effects are observed versus film thickness and during uniaxial shock compression: absorption band shifts, changes of shape, and changes in both absolute and relative peak intensities. The film thickness effects can be predicted by thin film interference alone, while additional assumptions are required to predict the effects due to shock compression. Since it is very difficult to obtain the complex index in the shock state, we made very simple assumptions regarding the change in vibrational spectra upon shock load-ing. We illustrate general thin film interference effects that could be expected and compare them to experimental results for the antisymmetric NO2 stretch mode of NC.

Incidence of hip osteonecrosis among renal transplantation recipients: a prospective study.

AIM: To investigate whether a lessened glucocorticoid cumulative dose would lead to a decreased incidence of femoral head osteonecrosis. METHODS: Newly transplanted in-patients (n = 49) underwent hip radiographs and magnetic resonance imaging (MRI) a mean of 17.0+/-4.3 (range 8-29) days after renal transplantation. For the 48 patients without evidence of prevalent osteonecrosis, imaging at a mean of 5.9+/-0.8 (range 4.8-8.7) months after renal transplantation was graded for presence/absence of femoral head osteonecrosis by two blinded radiologists. Sociodemographic and disease characteristics of patients were compared to identify potential associations with incident osteonecrosis. RESULTS: At 6-month follow-up, only two patients (4%) had osteonecrosis of the femoral head (three hips). The two primary radiologists had excellent agreement between osteonecrosis diagnosis (kappa coefficient=0.78). Both cases of a definite MRI diagnosis of osteonecrosis occurred in patients who were in the highest tertile of glucocorticoid dosage. CONCLUSION: Osteonecrosis was uncommon among a prospective cohort of renal transplant recipients within 6 months after engraftment.

Relationship of p15 and p16 gene alterations to elevated dihydrofolate reductase in childhood acute lymphoblastic leukaemia.

The downstream effects of p15 and p16 gene deletions and loss of transcripts on dihydrofolate reductase (DHFR) were examined in 63 B-precursor (BP) acute lymphoblastic leukaemia (ALL) samples. p15 and/or p16 gene deletions were seen in 6% and 8%, respectively, of BP-ALL samples; however, losses of p15 and/or p16 transcripts were seen in 26 out of 63 (41%) samples. Loss of p15 transcripts (36.5%) exceeded that for p16 (17.5%). For the 26 BP-ALLs that lacked p15 and/or p16 transcripts, only six (23%) exhibited low levels of DHFR by flow cytometry assay with Pt430, a fluorescent anti-folate. Conversely, 18 out of 37 (49%) BP-ALL samples with intact p15 and/or p16 genes and transcripts showed low levels of DHFR (P = 0.04). In p15- and p16-null K562 cells transfected with a tetracycline-inducible p15 cDNA construct, induction of p15 transcripts and protein was accompanied by decreased growth rates, decreased S-phase fraction, decreased retinoblastoma protein phosphorylation, and markedly reduced levels of DHFR transcripts and protein. Collectively, our results suggest that losses of p15 and/or p16 gene expression result in elevated levels of DHFR in BP-ALL in children. However, additional downstream factors undoubtedly also contribute to elevated levels of this enzyme target.

Determination of energetic materials in soil using multivariate analysis of Raman spectra.

Contamination of soils by energetic materials (EMs) is an important issue in many locations (such as test mounds, ordnance depots, and manufacturing sites). Raman spectroscopy can be useful as a screening technique at the percent level (by mass) if interference from soil fluorescence can be overcome. Multivariate analysis is shown capable of both extracting the Raman signatures of EMs from spectra obscured by large fluorescence backgrounds caused by soil components, and generating calibration curves for the EMs at the percent level.

Measurement of shock wave rise times in metal thin films.

We have measured the rise time of laser-generated shock waves in vapor plated metal thin films using frequency-domain interferometry with subpicosecond time resolution. 10%- 90% rise times of <6.25 ps were found in targets ranging from 0.25 to 2.0 microm in thickness. Particle and average shock velocities were simultaneously determined. Shock velocities of approximately 5 nm/ps were inferred from the measured free surface velocity, corresponding to pressures of 30-50 kbar. Thus, the shock front extends only a few tens of lattice spacings.

1,2-Disubstituted indole, azaindole and benzimidazole derivatives possessing amine moiety: a novel series of thrombin inhibitors.

A novel series of 1,2-disubstituted indole, azaindole and benzimidazole derivatives possessing an amine moiety was identified as thrombin inhibitors. An indole with basic diamine moieties (12a) was the most potent thrombin inhibitor in the series with Kass= 197 x 10(6) L/mol.

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. Part 6: further focus on the contracted C4'-side chain analogues.

Novel benzo[b]thiophene diamine thrombin inhibitors were investigated, focusing on a contracted C4'-side chain series. SAR studies identified compounds with either a pyrrolidino or morpholino group as potent, active site directed thrombin inhibitors when the amino group was connected to the C3-phenyl ring with a methylene linker at the C4' position of the phenyl ring.

1,2-Dibenzamidobenzene inhibitors of human factor Xa.

High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K(ass) = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K(ass) = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.

Structure-based design of potent, amidine-derived inhibitors of factor Xa: evaluation of selectivity, anticoagulant activity, and antithrombotic activity.

To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of fXa to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in fXa affinity and a refined model of the new inhibitors in the fXa active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of fXa relative to other trypsin-like serine proteases. Furthermore, the fXa affinity of compounds in this series (K(ass) = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives.

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.