Modulation Instability of Ultrashort Pulses in Quadratic Nonlinear Media beyond the Slowly Varying Envelope Approximation

We report a modulational instability (MI) analysis of a mathematical model appropriate for ultrashort pulses in cascaded quadratic-cubic nonlinear media beyond the so-called slowly varying envelope approximation. Theoretically predicted MI properties are found to be in good agreement with numerical simulation. The study shows the possibility of controlling the generation of MI and formation of solitons in a cascaded quadratic-cubic media in the few cycle regimes. We also find that stable propagation of soliton-like few-cycle pulses in the medium is subject to the fulfilment of the modulation instability criteria

Optimizing anti-gene oligonucleotide ‘Zorro-LNA’ for improved strand invasion into duplex DNA

Zorro-LNA (Zorro) is a newly developed, oligonucleotide (ON)-based, Z-shaped construct with the potential of specific binding to each strand of duplex DNA. The first-generation Zorros are formed by two hybridized LNA/DNA mixmers (2-ON Zorros) and was hypothesized to strand invade. We have now established a method, which conclusively demonstrates that an LNA ON can strand invade into duplex DNA. To make Zorros smaller in size and easier to design, we synthesized 3′–5′–5′–3′ single-stranded Zorro-LNA (ssZorro) by using both 3′- and 5′-phosphoramidites. With ssZorro, a significantly greater extent and rate of double-strand invasion (DSI) was obtained than with conventional 2-ON Zorros. Introducing hydrophilic PEG-linkers connecting the two strands did not significantly change the rate or extent of DSI as compared to ssZorro with a nucleotide-based linker, while the longest alkyl-chain linker tested (36 carbons) resulted in a very slow DSI. The shortest alkyl-chain linker (3 carbons) did not reduce the extent of DSI of ssZorro, but significantly decreased the DSI rate. Collectively, ssZorro is smaller in size, easier to design and more efficient than conventional 2-ON Zorro in inducing DSI. Analysis of the chemical composition of the linker suggests that it could be of importance for future therapeutic considerations

15-Deoxy-Δ12,14 Prostaglandin J2 Reduces the Formation of Atherosclerotic Lesions in Apolipoprotein E Knockout Mice

AIM: 15-deoxy-Δ¹²,¹⁴ prostaglandin J₂ (15d-PGJ₂) is a ligand of peroxisome proliferator-activated receptor γ (PPARγ) having diverse effects such as the differentiation of adipocytes and atherosclerotic lesion formation. 15d-PGJ₂ can also regulate the expression of inflammatory mediators on immune cells independent of PPARγ. We investigated the antiatherogenic effect of 15d-PGJ₂. METHODS: We fed apolipoprotein (apo) E-deficient female mice a Western-type diet from 8 to 16 wk of age and administered 1 mg/kg/day 15d-PGJ₂ intraperitoneally. We measured atherosclerotic lesions at the aortic root, and examined the expression of macrophage and inflammatory atherosclerotic molecules by immunohistochemical and real-time PCR in the lesion. RESULTS: Atherosclerotic lesion formation was reduced in apo E-null mice treated with 15d-PGJ₂, as compared to in the controls. Immunohistochemical and real-time PCR analyses showed that the expression of MCP-1, TNF-α, and MMP-9 in atherosclerotic lesions was significantly decreased in 15d-PGJ₂ treated mice. The 15d-PGJ₂ also reduced the expression of macrophages and RelA mRNA in atherosclerotic lesions. CONCLUSION: This is the first report 15d-PGJ₂, a natural PPARγ agonist, can improve atherosclerotic lesions in vivo. 15d-PGJ₂ may be a beneficial therapeutic agent for atherosclerosis

AV-65, a novel Wnt/β-catenin signal inhibitor, successfully suppresses progression of multiple myeloma in a mouse model

Multiple myeloma (MM) is a malignant neoplasm of plasma cells. Although new molecular targeting agents against MM have been developed based on the better understanding of the underlying pathogenesis, MM still remains an incurable disease. We previously demonstrated that β-catenin, a downstream effector in the Wnt pathway, is a potential target in MM using RNA interference in an in vivo experimental mouse model. In this study, we have screened a library of more than 100 000 small-molecule chemical compounds for novel Wnt/β-catenin signaling inhibitors using a high-throughput transcriptional screening technology. We identified AV-65, which diminished β-catenin protein levels and T-cell factor transcriptional activity. AV-65 then decreased c-myc, cyclin D1 and survivin expression, resulting in the inhibition of MM cell proliferation through the apoptotic pathway. AV-65 treatment prolonged the survival of MM-bearing mice. These findings indicate that this compound represents a novel and attractive therapeutic agent against MM. This study also illustrates the potential of high-throughput transcriptional screening to identify candidates for anticancer drug discovery

Transcriptional Silencing of the Wnt-Antagonist DKK1 by Promoter Methylation Is Associated with Enhanced Wnt Signaling in Advanced Multiple Myeloma

The Wnt/β-catenin pathway plays a crucial role in the pathogenesis of various human cancers. In multiple myeloma (MM), aberrant auto-and/or paracrine activation of canonical Wnt signaling promotes proliferation and dissemination, while overexpression of the Wnt inhibitor Dickkopf1 (DKK1) by MM cells contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggest that DKK1 is part of a negative feedback loop in MM and may act as a tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is low or undetectable in a subset of patients with advanced MM as well as in MM cell lines. This absence of DKK1 is correlated with enhanced Wnt pathway activation, evidenced by nuclear accumulation of β-catenin, which in turn can be antagonized by restoring DKK1 expression. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling

Role of Wnt canonical pathway in hematological malignancies

Wnt canonical signaling pathway plays a diverse role in embryonic development and maintenance of organs and tissues in adults. It has been observed that Wnt/β-catenin signaling pathway is involved in the pathogenesis of many carcinomas. Moreover, Wnt/β-catenin pathway has been revealed to be associated with angiogenesis. Wnt canonical pathway signaling has great potential as a therapeutic target. It has been disclosed that some hematological malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, may occur partly due to the constitutive activation of Wnt canonical signaling pathway. This review will summarize the latest development in Wnt canonical signaling pathway and its roles in tumorigenesis and angiogenesis

Noncovalent Interactions of Hydrated DNA and RNA Mapped by 2D-IR Spectroscopy

Biomolecules couple to their aqueous environment through a variety of noncovalent interactions. Local structures at the surface of DNA and RNA are frequently determined by hydrogen bonds with water molecules, complemented by non-specific electrostatic and many-body interactions. Structural fluctuations of the water shell result in fluctuating Coulomb forces on polar and/or ionic groups of the biomolecular structure and in a breaking and reformation of hydrogen bonds. Two-dimensional infrared (2D-IR) spectroscopy of vibrational modes of DNA and RNA gives insight into local hydration geometries, elementary molecular dynamics, and the mechanisms behind them. In this chapter, recent results from 2D-IR spectroscopy of native and artificial DNA and RNA are presented, together with theoretical calculations of molecular couplings and molecular dynamics simulations. Backbone vibrations of DNA and RNA are established as sensitive noninvasive probes of the complex behavior of hydrated helices. The results reveal the femtosecond fluctuation dynamics of the water shell, the short-range character of Coulomb interactions, and the strength and fluctuation amplitudes of interfacial electric fields.Comment: To appear as Chapter 8 of Springer Series in Optical Sciences: Coherent Multidimensional Spectroscopy -- Editors: Cho, Minhaeng (Ed.), 201