Asthenosphere rheology inferred from observations of the 2012 Indian Ocean earthquake.

The concept of a weak asthenospheric layer underlying Earth's mobile tectonic plates is fundamental to our understanding of mantle convection and plate tectonics. However, little is known about the mechanical properties of the asthenosphere (the part of the upper mantle below the lithosphere) underlying the oceanic crust, which covers about 60 per cent of Earth's surface. Great earthquakes cause large coseismic crustal deformation in areas hundreds of kilometres away from and below the rupture area. Subsequent relaxation of the earthquake-induced stresses in the viscoelastic upper mantle leads to prolonged postseismic crustal deformation that may last several decades and can be recorded with geodetic methods. The observed postseismic deformation helps us to understand the rheological properties of the upper mantle, but so far such measurements have been limited to continental-plate boundary zones. Here we consider the postseismic deformation of the very large (moment magnitude 8.6) 2012 Indian Ocean earthquake to provide by far the most direct constraint on the structure of oceanic mantle rheology. In the first three years after the Indian Ocean earthquake, 37 continuous Global Navigation Satellite Systems stations in the region underwent horizontal northeastward displacements of up to 17 centimetres in a direction similar to that of the coseismic offsets. However, a few stations close to the rupture area that had experienced subsidence of up to about 4 centimetres during the earthquake rose by nearly 7 centimetres after the earthquake. Our three-dimensional viscoelastic finite-element models of the post-earthquake deformation show that a thin (30-200 kilometres), low-viscosity (having a steady-state Maxwell viscosity of (0.5-10) × 1018 pascal seconds) asthenospheric layer beneath the elastic oceanic lithosphere is required to produce the observed postseismic uplift.

Confined Singlet Oxygen in Mesoporous Silica Nanoparticles: Selective Photochemical Oxidation of Small Molecules in Living Cells.

Chemical conversion of specific bioactive molecules by external stimuli in living cells is a powerful noninvasive tool for clarification of biomolecular interactions and to control cellular functions. However, in chaotic biological environments, it has been difficult to induce arbitrary photochemical reactions on specific molecules because of their poor molecular selectivity. Here we report a selective and nontoxic photochemical reaction system utilizing photoactivated mesoporous silica nanoparticles to control biological functions. Methylene blue modification within nanoparticle pores for photosensitization produced singlet oxygen confined to the pore that could mediate selective oxidation of small molecules without any damage to living cells. This intracellular photochemical system produced bioactive molecules in situ and remotely controlled the cell cycle phase. We also confirmed that this photoreaction could be applied to control cell cycle phase in tumor tissue transplanted in mice. The cell cycle phase in the cells in mice, to which our system was administered, was arrested at the G2/M phase upon photoirradiation. We demonstrate a simple and promising method for the exogenous conversion of an intracellular biomolecule to another functional compound.

Phosphorescent ruthenium complexes with a nitroimidazole unit that image oxygen fluctuation in tumor tissue.

Understanding oxygen fluctuation in a cancerous tumor is important for effective treatment, especially during radiotherapy. In this paper, ruthenium complexes bearing a nitroimidazole group are shown to report the oxygen status in tumor tissue directly. The nitroimidazole group was known to be accumulated in hypoxic tumor tissues. On the other hand, the ruthenium complex showed strong phosphorescence around 600 nm. The emission of ruthenium is quenched instantaneously by molecular oxygen due to energy transfer between triplet states of oxygen and ruthenium complex, but the emission is then recovered by the removal of oxygen. Thus, we could observe oxygen fluctuation in tumor tissue in a real-time manner by monitoring the phosphorescence of the ruthenium complex. The versatility of the probe is demonstrated by monitoring oxygen fluctuation in living cells and tumor tissue planted in mice. The ruthenium complex promptly penetrated plasma membrane and accumulated in cells to emit its oxygen-dependent phosphorescence. In vivo experiments revealed that the oxygen level in tumor tissue seems to fluctuate at the sub-minute timescale.

Hypoxic X-irradiation as an external stimulus for conformational change of oligodeoxynucleotides that possess disulfide bond and regulation of DNAzyme function.

We achieved a conformational change of oligodeoxynucleotides and the regulation of DNAzyme function by means of a radiolytic strand exchange reaction of disulfide bond. We designed a system in which the DNAzyme function of RNA cleavage was suppressed by the hybridization of an inhibitor strand that possessed disulfide bond with an active DNAzyme. Hypoxic X-irradiation led to the recovery of RNA cleavage because the strand exchange reaction at the disulfide bond in inhibitor strand resulted in a release of inhibitor strand. This strategy may be applicable to gene regulation by hypoxic X-irradiation.

Synthesis and identification of α-cyano bis(indolyl)chalcones as novel anticancer agents.

Microwave-assisted synthesis of 23 α-cyano bis(indolyl)chalcones (6a-w) and their in vitro anticancer activity against three human cancer cell lines have been discussed. Among the synthesized chalcones, compound 6n was found to be the most potent and selective against A549 lung cancer cell line (IC50 = 0.8 µM). In a preliminary mechanism of action studies some α-cyano bis(indolyl)chalcones were found to enhance tubulin polymerization suggesting these compounds could act as microtubule stabilizing agents.

Enzyme-catalyzed conversion of chemical structures on the surface of gold nanorods.

For developing metal nanoparticles of which surface chemical structures could be altered by enzymes in the cells, functional linkers caged by coumaric acids have been synthesized. Synthesized gold nanorod (GNR) conjugates possessing coumaric acid precursors underwent (porcine liver) esterase-catalyzed hydrolysis on their surface to afford GNRs coated with amino-functionalized polyethylene glycol and fluorescent coumarins as reporter molecules for monitoring the conversion. The chemical structural conversion on the GNR surfaces was successfully observed inside cells by fluorescence microscopy when GNR conjugates were incubated with tumor cells.

Probing DNA mismatched and bulged structures by using 19F NMR spectroscopy and oligodeoxynucleotides with an 19F-labeled nucleobase.

In this study, DNA local structures with bulged bases and mismatched base pairs as well as ordinary full-matched base pairs by using (19)F NMR spectroscopy with (19)F-labeled oligodeoxynucleotides (ODNs) were monitored. The chemical shift change in the (19) F NMR spectra allowed discrimination of the DNA structures. Two types of ODNs possessing the bis(trifluoromethyl)benzene unit (F-unit) at specified uridines were prepared and hybridized with their complementary or noncomplementary strands to form matched, mismatched, or bulged duplexes. By using ODN F1, in which an F-unit was connected directly to a propargyl amine-substituted uridine, three local structures, that is, full-matched, G-U mismatch, and A-bulge could be analyzed, whereas other structures could not be discriminated. A molecular modeling study revealed that the F-unit in ODN F1 interacted little with the nucleobases and sugar backbone of the opposite strand because the linker length between the F-unit and the uridine base was too short. Therefore, the capacity of ODN F1 to discriminate the DNA local structures was limited. Thus, ODN F2 was designed to improve this system; aminobenzoic acid was inserted between the F-unit and uridine base so the F-unit could interact more closely with the opposite strand. Eventually, the G-bulge and T-U mismatch and the three aforementioned local structures could be discriminated by using ODN F2. In addition, the dissociation processes of these duplexes could be monitored concurrently by (19)F NMR spectroscopy.

Cationic porphyrin-quinoxaline conjugate as a photochemically triggered novel cytotoxic agent.

A novel cationic porphyrin-quinoxaline conjugate 8 was prepared in good yield by the coupling of activated quinoxaline carboxylic acid 5 with an appropriate aminoporphyrin. The UV-vis spectra of conjugate 8 with the addition of ctDNA shows substantial hypochromicity (39%) and a red shift (12 nm) in the Soret band indicating intercalation and self stacking along the surface. The binding constant of conjugate 8 with ctDNA was determined to be 1.26×10(6) M(-1). The porphyrin-quinoxaline conjugate 8 displayed enhanced photocytotoxicity (IC50=0.06 µM) when compared to TMPyP against A549 cancer cells.

Novel porphyrin-psoralen conjugates: synthesis, DNA interaction and cytotoxicity studies.

A Cu(i)-catalyzed azide-alkyne cycloaddition reaction (CuAAC) has been utilized to prepare novel triazole-linked cationic porphyrin-psoralen conjugates that exhibited significant photocytotoxicity against A549 cancer cells (IC50 = 84 nM).

Radiolytic reduction characteristics of drug-encapsulating DNA aggregates possessing disulfide bond.

Radiation-responsive aggregates consisting of artificial DNA were demonstrated. We prepared DNA amphiphiles (DAMs) consisting of oligodeoxynucleotides (ODNs) as the hydrophilic part and an alkyl chain as the hydrophobic part, which were linked by a radiation-sensitive disulfide bond. DAMs assembled to form nanosized aggregates in aqueous solution that encapsulated hydrophobic dyes and drugs. X-irradiation, which triggered selective reduction at the disulfide bond in the DAMs, induced an exchange reaction, resulting in dissociation of the aggregates and release of encapsulated dyes and drugs. Among the DAMs synthesized in this study, DAM 1 possessing 5 mer ODNs showed favorable properties as a nanocarrier; for example, the large amount of drug was encapsulated in the aggregates consisting of DAM 1, and the aggregates showed the high sensitivity to radiolytic reduction. Biological experiments using living A549 cells revealed that the aggregates smoothly penetrated into the cells without the need for transfection reagents, while the drugs inside the aggregates were inert because of the encapsulation. X-irradiation enhanced the cytotoxicity because of dissociation of the aggregates and concomitant release of drugs.

Reductive activation of 5-fluorodeoxyuridine prodrug possessing azide methyl group by hypoxic X-irradiation.

We prepared a 5-fluorodeoxyuridine (5-FdUrd) derivative possessing azide methyl group (N(3)-FdUrd) as a novel radiation-activated prodrug. The parent antitumor agent, 5-FdUrd, was released efficiently from N(3)-FdUrd by hypoxic X-irradiation. On the other hand, the activation of N(3)-FdUrd was suppressed upon X-irradiation under aerobic conditions. A biological assay using A549 cells revealed that the cytotoxicity of N(3)-FdUrd was significantly enhanced by hypoxic X-irradiation.

Synthesis and photooxidation of oligodeoxynucleotides containing 5-dimethylaminocytosine as an efficient hole-trapping site in the positive-charge transfer through DNA duplexes.

We have designed and synthesized DNA duplexes containing 5-dimethylaminocytosine ((DMA)C) to investigate the effects of C(5)-substituted cytosine bases on the transfer and trapping of positive charge (holes) in DNA duplexes. Fluorescence quenching experiments revealed that a (DMA)C base is more readily one-electron oxidized into a radical cation intermediate as compared with other natural nucleobases. Upon photoirradiation of the duplexes containing (DMA)C, the photosensitizer-injected hole migrated through the DNA bases and was trapped efficiently at the (DMA)C sites, where an enhanced oxidative strand cleavage occurred by hot piperidine treatment. The (DMA)C radical cation formed by hole transfer may undergo specific hydration and subsequent addition of molecular oxygen, thereby leading to its decomposition followed by a predominant strand cleavage at the (DMA)C site. This remarkable property suggests that the modified cytosine (DMA)C can function as an efficient hole-trapping site in the positive-charge transfer in DNA duplexes.

Synthesis and one-electron reduction characteristics of radiation-activated prodrugs possessing two 5-fluorodeoxyuridine units.

Two molecules of an antitumor agent, 5-fluorodeoxyuridine (5-FdUrd), were connected by a 2-oxoalkyl linker (Oxo-linker) at the N(3) position to obtain radiation-activated prodrugs, FdUrd(2) A and FdUrd(2) B. The prodrugs in this study released 5-FdUrd via one-electron reduction initiated by hypoxic X-irradiation. The release of 5-FdUrd from FdUrd(2) A and FdUrd(2) B proceeded more efficiently than that of previous prodrug, Oxo-FdUrd, which possessed one molecule of 5-FdUrd. FdUrd(2) A exhibited increased cytotoxicity against A549 cells when the FdUrd(2) A solution had been irradiated with a large dose of X-rays before administration to the cells. However, we observed no effect on cytotoxicity when the cells were X-irradiated under hypoxic conditions in the presence of FdUrd(2) A because the amount of 5-FdUrd released in the cells seemed to be too low to induce cytotoxic activity.

A case of posterior cerebral artery dissection presenting with migraine-like headache and visual field defect: usefulness of fast imaging employing steady-state acquisition (FIESTA) for diagnosis.

We report a 34-year-old woman with sudden onset of unilateral migraine-like headache and right homonymous hemianopsia. Fast imaging employing steady-state acquisition (FIESTA) of the posterior cerebral artery captured an intimal flap and a pseudolumen, leading to a diagnosis of posterior cerebral artery dissection. This case was considered a spontaneous posterior cerebral artery dissection causing migraine-like headache. The treatment of migraine-like headache hinges on correct diagnosis. In this case, FIESTA was very useful in diagnosing an intracranial artery dissection.

Physics-informed deep learning approach for modeling crustal deformation.

The movement and deformation of the Earth's crust and upper mantle provide critical insights into the evolution of earthquake processes and future earthquake potentials. Crustal deformation can be modeled by dislocation models that represent earthquake faults in the crust as defects in a continuum medium. In this study, we propose a physics-informed deep learning approach to model crustal deformation due to earthquakes. Neural networks can represent continuous displacement fields in arbitrary geometrical structures and mechanical properties of rocks by incorporating governing equations and boundary conditions into a loss function. The polar coordinate system is introduced to accurately model the displacement discontinuity on a fault as a boundary condition. We illustrate the validity and usefulness of this approach through example problems with strike-slip faults. This approach has a potential advantage over conventional approaches in that it could be straightforwardly extended to high dimensional, anelastic, nonlinear, and inverse problems.

Anthraquinone-sensitized photooxidation of 5-methylcytosine in DNA leading to piperidine-induced efficient strand cleavage.

One-electron photooxidations of 5-methyl-2'-deoxycytidine (d(m)C) and 5-trideuteriomethyl-2'-deoxycytidine ([D(3)]d(m)C) by sensitization with anthraquinone (AQ) derivatives were investigated. Photoirradiation of an aerated aqueous solution containing d(m)C and anthraquinone 2-sulfonate (AQS) afforded 5-formyl-2'-deoxycytidine (d(f)C) and 5-hydroxymethyl-2'-deoxycytidine (d(hm)C) in good yield through an initial one-electron oxidation process. The deuterium isotope effect on the AQS-sensitized photooxidation of d(m)C suggests that the rate-determining step in the photosensitized oxidation of d(m)C involves internal transfer of the C5-hydrogen atom of a d(m)C-tetroxide intermediate to produce d(f)C and d(hm)C. In the case of a 5-methylcytosine ((m)C)-containing duplex DNA with an AQ chromophore that is incorporated into the backbone of the DNA strand so as to be immobilized at a specific position, (m)C underwent efficient direct one-electron oxidation by the photoexcited AQ, which resulted in an exclusive DNA strand cleavage at the target (m)C site upon hot piperidine treatment. In accordance with the suppression of the strand cleavage at 5-trideuterio-methylcytosine observed in a similar AQ photosensitization, it is suggested that deprotonation at the C5-methyl group of an intermediate (m)C radical cation may occur as a key elementary reaction in the photooxidative strand cleavage at the (m)C site. Incorporation of an AQ sensitizer into the interior of a strand of the duplex enhanced the one-electron photooxidation of (m)C, presumably because of an increased intersystem crossing efficiency that may lead to efficient piperidine-induced strand cleavage at an (m)C site in a DNA duplex.

αvß3-Integrin-targeting lanthanide complex: synthesis and evaluation as a tumor-homing luminescent probe.

The application of lanthanide complexes in the time-resolved fluorescence imaging of living cells has emerged in the last few decades, providing high-contrast images of cells through detection of the delayed emission. In the present study, we synthesized novel trivalent lanthanide complexes containing the cyclic peptide c(RGDfK) to visualize the α(v)ß(3)-integrin-expressing tumor cells. Conjugation of c(RGDfK) with the macrocyclic bipyridine ligand had little effect on the fluorescence properties of the complex, indicating that the coordinated lanthanide ion was well isolated from the peptide. Bright luminescence images of α(v)ß(3)-integrin-expressing U87-MG cells were successfully obtained by employing the probes.

Synthesis and biological evaluation of indolyl chalcones as antitumor agents.

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b-d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC(50) values 0.03 and 0.09 microM, against PaCa-2 cell line, respectively.

Radiolytic cyclization of stem-and-loop structured oligodeoxynucleotide with neighboring arrangement of α,ω-bis-disulfides.

Upon X-ray irradiation of hypoxic aqueous solution, modified oligodeoxynucleotides (ODNs) bearing a pair of disulfides at both ends of the strand that forms a stem-and-loop structure with a neighboring arrangement of α,ω-bis-disulfides underwent efficient cyclization via an intramolecular exchange reaction at the disulfide moieties with a multiple turnover process. Mechanistic studies revealed that hydrogen atoms generated in the radiolysis of water are key active species initiating a chain reaction to produce cyclic ODN disulfides, in which addition of hydrogen atom results in dissociation of the original disulfide bond to generate a thiyl radical intermediate as the chain carrier for the succeeding disulfide exchange into cyclization. The properties were also assessed for the resultant cyclic ODN disulfide that has several favorable features for use in the transcriptional decoy strategy. The cyclic ODN disulfides produced by the present radiolytic method showed high thermal stability, resistance to nuclease, and high binding activity to a representative transcriptional factor of nuclear factor κB.

Significance of serum vascular endothelial growth factor level in patients with idiopathic pulmonary fibrosis.

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis, which has been implicated in the pathogenesis of fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF). The aim of this study was to examine the clinical significance of the serum VEGF level for evaluating disease severity and progression. The levels of VEGF in serum were measured in 41 patients with IPF, 14 patients with lung cancer, and 43 healthy volunteers. We measured the serum levels of CRP, LDH, KL-6, SP-D, and the parameters obtained from arterial blood gas analysis and pulmonary function tests. High-resolution computed tomography (HRCT) was performed to determine the extent of the interstitial and the alveolar opacities. The ability of each biomarker to predict disease severity was estimated by measuring the area under the receiver operating characteristic curve (AUC). The VEGF levels of IPF patients with high alveolar-arterial difference of oxygen (AaDO(2)) levels were significantly elevated than those with low AaDO(2) levels and those of healthy volunteers. When examined within the IPF group, a significant positive correlation was found between the VEGF levels and the HRCT interstitial score (p = 0.027) and the KL-6 levels (p = 0.037). Among several serum biomarkers, VEGF showed the largest AUC for predicting disease severity as defined by a high AaDO(2) value. There was an inverse correlation between the baseline VEGF level and the monthly change in percent predicted vital capacity. The serum VEGF level may reflect the severity of IPF and offer clinical benefits to predict the disease's progression.