Transport composite fuselage technology: Impact dynamics and acoustic transmission

A program was performed to develop and demonstrate the impact dynamics and acoustic transmission technology for a composite fuselage which meets the design requirements of a 1990 large transport aircraft without substantial weight and cost penalties. The program developed the analytical methodology for the prediction of acoustic transmission behavior of advanced composite stiffened shell structures. The methodology predicted that the interior noise level in a composite fuselage due to turbulent boundary layer will be less than in a comparable aluminum fuselage. The verification of these analyses will be performed by NASA Langley Research Center using a composite fuselage shell fabricated by filament winding. The program also developed analytical methodology for the prediction of the impact dynamics behavior of lower fuselage structure constructed with composite materials. Development tests were performed to demonstrate that the composite structure designed to the same operating load requirement can have at least the same energy absorption capability as aluminum structure

Damping mechanism for the strongly renormalized cc-axis charge transport in high-TcT_c cuprate superconductors

We analyze the $c$-axis infrared reflectivity of La$_{1.85}$Sr$_{0.15}$CuO$_4$ single crystals. The plasma edge near 6 meV, observed below $T_c$, is due to Cooper-pair tunneling. This low value of the plasma edge is consistent with the $c$-axis plasma frequency ($\nu_p$) obtained from LDA calculations ($>0.1$ eV) if we take into account that the single-particle charge transport along the $c$ axis is strongly incoherent both above and below $T_c$. We find no evidence for a reduction of the $c$-axis scattering rate ($\gamma$) below $T_c$. Our investigation suggests $h\gamma>h\nu_{p}\gg 3.5k_BT_c$, which is exactly opposite to the clean limit. VSGD.94.6.1Comment: 4 pages, figures on request. Revtex, version 2, Materials Science Center Internal Report Number VSGD.94.6.

Anti-malarial ozonides OZ439 and OZ609 tested at clinically relevant compound exposure parameters in a novel ring-stage survival assay

BACKGROUND: Drug efficacy against kelch 13 mutant malaria parasites can be determined in vitro with the ring-stage survival assay (RSA). The conventional assay protocol reflects the exposure profile of dihydroartemisinin. METHODS: Taking into account that other anti-malarial peroxides, such as the synthetic ozonides OZ439 (artefenomel) and OZ609, have different pharmacokinetics, the RSA was adjusted to the concentration-time profile of these ozonides in humans and a novel, semi-automated readout was introduced. RESULTS: When tested at clinically relevant parameters, it was shown that OZ439 and OZ609 are active against the Plasmodium falciparum clinical isolate Cam3.I(R539T). CONCLUSION: If the in vitro RSA does indeed predict the potency of compounds against parasites with increased tolerance to artemisinin and its derivatives, then the herein presented data suggest that following drug-pulses of at least 48 h, OZ439 and OZ609 will be highly potent against kelch 13 mutant isolates, such as P. falciparum Cam3.I(R539T)

In vitro assessment of the pharmacodynamic properties and the partitioning of OZ277/RBx-11160 in cultures of Plasmodium falciparum

Objectives: Using synchronous cultures of Plasmodium falciparum malaria, the stage sensitivity of the parasite to OZ277 (RBx-11160), the first fully synthetic antimalarial peroxide that has entered Phase II clinical trials, was investigated in vitro over a concentration range of 1× to 100× the IC50. Secondly, partitioning of OZ277 into P. falciparum-infected red blood cells (RBCs) and uninfected RBCs was studied in vitro by measuring its distribution between RBCs and plasma (R/P). Methods: The effects of timed in vitro exposure (1, 6, 12 or 24 h) to OZ277 were monitored by incorporation of [3H]hypoxanthine into parasite nucleic acids and by light-microscopic analysis of parasite morphology. Partitioning studies were performed with radiolabelled [14C]OZ277. Results: After 1 h of exposure to OZ277 at the highest concentration (100× the IC50) followed by removal of the compound, the hypoxanthine assay showed that growth of mature stages of P. falciparum was reduced to below 20%. Young ring forms were slightly less sensitive (43% growth). Similar stage-specific profiles were found for the antimalarial reference compounds artemether and chloroquine. Strong inhibition (≤6% growth) of all parasite stages was observed when the parasites were exposed to each of the three compounds for 6 h or longer. After removal of the compounds, the parasites did not recover, indicating that the observed growth inhibitions were cytotoxic rather than cytostatic. Pyrimethamine was confirmed to be active exclusively against young schizonts. Light-microscopic analysis also demonstrated the specificity of pyrimethamine against the schizont forms and showed that OZ277, artemether and chloroquine attenuated parasite growth more rapidly than did pyrimethamine. The R/P for OZ277 was 1.5 for uninfected RBCs and up to 270 for infected RBCs. Conclusions: The present study indicates similar stage-specific profiles for OZ277 and for the more well-established antimalarial agents artemether and chloroquine. Secondly, the study describes a significant accumulation of radiolabelled OZ277 in P. falciparum-infected RBC

Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity.

yesAncient Chinese herbal texts as far back as the 4th Century Zhou hou bei ji fang describe methods for the use of Qing Hao (Artemisia annua) for the treatment of intermittent fevers. Today, the A. annua constituent artemisinin is an important antimalarial drug and the herb itself is being grown and used locally for malaria treatment although this practice is controversial. Here we show that the ancient Chinese methods that involved either soaking, (followed by wringing) or pounding, (followed by squeezing) the fresh herb are more effective in producing artemisinin-rich extracts than the usual current method of preparing herbal teas from the dried herb. The concentrations of artemisinin in the extracts was up to 20-fold higher than that in a herbal tea prepared from the dried herb, but the amount of total artemisinin extracted by the Chinese methods was much less than that removed in the herbal tea. While both extracts exhibited potent in vitro activities against Plasmodium falciparum, only the pounded juice contained sufficient artemisinin to suppress parasitaemia in P. berghei infected mice. The implications of these results are discussed in the context of malaria treatment using A. annua infusions

Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development

Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment

Complex microwave conductivity of Na-DNA powders

We report the complex microwave conductivity, $\sigma=\sigma_1-i\sigma_2$, of Na-DNA powders, which was measured from 80 K to 300 K by using a microwave cavity perturbation technique. We found that the magnitude of $\sigma_1$ near room temperature was much larger than the contribution of the surrounding water molecules, and that the decrease of $\sigma_1$ with decreasing temperature was sufficiently stronger than that of the conduction of counterions. These results clearly suggest that the electrical conduction of Na-DNA is intrinsically semiconductive.Comment: 16 pages, 7 figure

The anomaly of the oxygen bond-bending mode at 320 cm−1^{-1} and the additional absorption peak in the c-axis infrared conductivity of underdoped YBa2_{2}Cu3_{3}O7−δ_{7-\delta} single crystals revisited by ellipsometricmeasurements

We have performed ellipsometric measurements of the far-infrared c-axis dielectric response of underdoped YBa$_{2}$Cu$_{3}$O$_{7-\delta}$ single crystals. Here we report a detailed analysis of the temperature-dependent renormalization of the oxygen bending phonon mode at 320 cm$^{-1}$ and the formation of the additional absorption peak around 400-500 cm$^{-1}$. For a strongly underdoped YBa$_{2}$Cu$_{3}$O$_{6.5}$ crystal with T$_{c}$=52 K we find that, in agreement with previous reports based on conventional reflection measurements, the gradual onset of both features occurs well above T$_{c}$ at T*$\sim$150 K. Contrary to some of these reports, however, our data establish that the phonon anomaly and the formation of the additional peak exhibit very pronounced and steep changes right at T$_{c}$. For a less underdoped YBa$_{2}$Cu$_{3}$O$_{6.75}$ crystal with T$_{c}$=80 K, the onset temperature of the phonon anomaly almost coincides with T$_{c}$. Also in contrast to some previous reports, we find for both crystals that a sizeable fraction of the spectral weight of the additional absorption peak cannot be accounted for by the spectral-weight loss of the phonon modes but instead arises from a redistribution of the electronic continuum. Our ellipsometric data are consistent with a model where the bilayer cuprate compounds are treated as a superlattice of intra- and inter-bilayer Josephson-junctions

The 3-phosphoinositide-dependent protein kinase 1 is an essential upstream activator of protein kinase A in malaria parasites

Cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signalling is essential for the proliferation of Plasmodium falciparum malaria blood stage parasites. The mechanisms regulating the activity of the catalytic subunit PfPKAc, however, are only partially understood, and PfPKAc function has not been investigated in gametocytes, the sexual blood stage forms that are essential for malaria transmission. By studying a conditional PfPKAc knockdown (cKD) mutant, we confirm the essential role for PfPKAc in erythrocyte invasion by merozoites and show that PfPKAc is involved in regulating gametocyte deformability. We furthermore demonstrate that overexpression of PfPKAc is lethal and kills parasites at the early phase of schizogony. Strikingly, whole genome sequencing (WGS) of parasite mutants selected to tolerate increased PfPKAc expression levels identified missense mutations exclusively in the gene encoding the parasite orthologue of 3-phosphoinositide-dependent protein kinase-1 (PfPDK1). Using targeted mutagenesis, we demonstrate that PfPDK1 is required to activate PfPKAc and that T189 in the PfPKAc activation loop is the crucial target residue in this process. In summary, our results corroborate the importance of tight regulation of PfPKA signalling for parasite survival and imply that PfPDK1 acts as a crucial upstream regulator in this pathway and potential new drug target