Near-field focusing and magnification through self-assembled nanoscale spherical lenses

Lee, Ju Young,Hong, Byung Hee,Kim, Woo Youn,Min, Seung Kyu,Kim, Yukyung,Jouravlev, Mikhail V.,Bose, Ranojoy,Kim, Keun Soo,Hwang, In-Chul,Kaufman, Laura J.,Wong, Chee Wei,Kim, Philip,Kim, Kwang S. Macmillan Publishers Limited. All rights reserved 2009 Nature Vol.460 No.7254

It is well known that a lens-based far-field optical microscope cannot resolve two objects beyond Abbe’s diffraction limit. Recently, it has been demonstrated that this limit can be overcome by lensing effects driven by surface-plasmon excitation, and by fluorescence microscopy driven by molecular excitation. However, the resolution obtained using geometrical lens-based optics without such excitation schemes remains limited by Abbe’s law even when using the immersion technique, which enhances the resolution by increasing the refractive indices of immersion liquids. As for submicrometre-scale or nanoscale objects, standard geometrical optics fails for visible light because the interactions of such objects with light waves are described inevitably by near-field optics. Here we report near-field high resolution by nanoscale spherical lenses that are self-assembled by bottom-up integration of organic molecules. These nanolenses, in contrast to geometrical optics lenses, exhibit curvilinear trajectories of light, resulting in remarkably short near-field focal lengths. This in turn results in near-field magnification that is able to resolve features beyond the diffraction limit. Such spherical nanolenses provide new pathways for lens-based near-field focusing and high-resolution optical imaging at very low intensities, which are useful for bio-imaging, near-field lithography, optical memory storage, light harvesting, spectral signal enhancing, and optical nano-sensing.

Phospholipase D-mediated autophagic regulation is a potential target for cancer therapy

Jang, Y H,Choi, K Y,Min, D S Macmillan Publishers Limited 2014 Cell death and differentiation Vol.21 No.4

Autophagy is a catabolic process in which cell components are degraded to maintain cellular homeostasis by nutrient limitations. Defects of autophagy are involved in numerous diseases, including cancer. Here, we demonstrate a new role of phospholipase D (PLD) as a regulator of autophagy. PLD inhibition enhances autophagic flux via ATG1 (ULK1), ATG5 and ATG7, which are essential autophagy gene products critical for autophagosome formation. Moreover, PLD suppresses autophagy by differentially modulating phosphorylation of ULK1 mediated by mTOR and adenosine monophosphate-activated protein kinase (AMPK), and by suppressing the interaction of Beclin 1 with vacuolar-sorting protein 34 (Vps34), indicating that PLD coordinates major players of the autophagic pathway, AMPK-mTOR-ULK1 and Vps34/Beclin 1. Ultimately, PLD inhibition significantly sensitized in vitro and in vivo cancer regression via genetic and pharmacological inhibition of autophagy, providing rationale for a new therapeutic approach to enhancing the anticancer efficacy of PLD inhibition. Collectively, we show a novel role for PLD in the molecular machinery regulating autophagy.

Two-dimensional normal-state quantum oscillations in a superconducting heterostructure

Kozuka, Y.,Kim, M.,Bell, C.,Kim, B. G.,Hikita, Y.,Hwang, H. Y. Macmillan Publishers Limited. All rights reserved 2009 Nature Vol.462 No.7272

Semiconductor heterostructures provide an ideal platform for studying high-mobility, low-density electrons in reduced dimensions. The realization of superconductivity in heavily doped diamond, silicon, silicon carbide and germanium suggests that Cooper pairs eventually may be directly incorporated in semiconductor heterostructures, but these newly discovered superconductors are currently limited by their extremely large electronic disorder. Similarly, the electron mean free path in low-dimensional superconducting thin films is usually limited by interface scattering, in single-crystal or polycrystalline samples, or atomic-scale disorder, in amorphous materials, confining these examples to the extreme ‘dirty limit’. Here we report the fabrication of a high-quality superconducting layer within a thin-film heterostructure based on SrTiO<SUB>3</SUB> (the first known superconducting semiconductor). By selectively doping a narrow region of SrTiO<SUB>3</SUB> with the electron-donor niobium, we form a superconductor that is two-dimensional, as probed by the anisotropy of the upper critical magnetic field. Unlike in previous examples, however, the electron mobility is high enough that the normal-state resistance exhibits Shubnikov–de Haas oscillations that scale with the perpendicular field, indicating two-dimensional states. These results suggest that delta-doped SrTiO<SUB>3</SUB> provides a model system in which to explore the quantum transport and interplay of both superconducting and normal electrons. They also demonstrate that high-quality complex oxide heterostructures can maintain electron coherence on the macroscopic scales probed by transport, as well as on the microscopic scales demonstrated previously.

Novel anti-apoptotic mechanism of A20 through targeting ASK1 to suppress TNF-induced JNK activation

Won, M,Park, K A,Byun, H S,Sohn, K-C,Kim, Y-R,Jeon, J,Hong, J H,Park, J,Seok, J H,Kim, J M,Yoon, W-H,Jang, I-S,Shen, H M,Liu, Z G,Hur, G M Macmillan Publishers Limited 2010 CELL DEATH AND DIFFERENTIATION Vol.17 No.12

The zinc-finger protein A20 has crucial physiological functions as a dual inhibitor of nuclear factor-κB (NF-κB) activation and apoptosis in tumor necrosis factor (TNF) receptor 1 signaling pathway. Although the molecular basis for the anti-NF-κB function of A20 has been well elucidated, the anti-apoptotic function of A20 is largely unknown. Here, we report a novel mechanism underlying the anti-apoptotic function of A20: A20 blocks TNF-induced apoptosis through suppression of c-jun N-terminal kinase (JNK) by targeting apoptosis signal-regulating kinase1 (ASK1). First, the ectopic expression of A20 drastically inhibits TNF-induced JNK activation and apoptosis in multiple cell types including those deficient of NF-κB activation. Unexpectedly, the blunting effect of A20 on TNF-induced JNK activation is not mediated by affecting the TNFR1 signaling complex formation. Instead, A20 interacts with ASK1, an important MAPKK kinase in the JNK signaling cascade. More importantly, overexpression of wild-type A20, but not of mutant A20 (ZnF4; C624A, C627A), promotes degradation of the ASK1 through the ubiquitin-proteasome system. Taken together, the results from this study reveal a novel anti-apoptotic mechanism of A20 in TNF signaling pathway: A20 binds to ASK1 and mediates ASK1 degradation, leading to suppression of JNK activation and eventually blockage of apoptosis.

Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma

Lee, S H,Yoo, K H,Sung, K W,Kim, J Y,Cho, E J,Koo, H H,Chung, S E,Kang, S W,Oh, S Y,Ham, D-I,Kim, Y-D Macmillan Publishers Limited 2008 BONE MARROW TRANSPLANTATION -BASINGSTOKE- Vol.42 No.6

Although external-beam radiation therapy (EBRT) has been an effective treatment modality in patients with bilateral advanced retinoblastoma, it significantly increases the risk of second malignancies and facial deformities. This study aimed to evaluate the efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) for treatment, instead of EBRT, in children with bilateral advanced retinoblastoma. Fourteen patients with bilateral retinoblastoma received chemotherapy, and local therapy was provided whenever possible. When at least one functional eye could not be saved by chemoreduction and local therapy, tandem HDCT/ASCR was provided to avoid EBRT. As a result, nine patients received tandem HDCT/ASCR. The toxicities were tolerable and there was no TRM. All nine patients who received tandem HDCT/ASCR had at least one functional eye without EBRT, and in two patients, both eyes were saved. No second malignancy has developed to date. HDCT/ASCR might be an effective treatment for bilateral advanced retinoblastoma, especially in cases in which at least one functional eye could not be preserved with chemoreduction and local therapy alone, and where EBRT was unavoidable. Long-term follow-up and further studies are needed to evaluate the efficacy and toxicity of HDCT/ASCR as an alternative treatment to EBRT.Bone Marrow Transplantation (2008) 42, 385–391; doi:10.1038/bmt.2008.181; published online 23 June 2008

Relationship between paraoxonase-1 activity, carotid intima-media thickness and arterial stiffness in hypertensive patients

Yang, W-I,Lee, S-H,Ko, Y-G,Kang, S-M,Choi, D,Ha, J-W,Hong, M-K,Chung, N,Shim, W-H,Cho, S-Y,Jang, Y Macmillan Publishers Limited 2010 Journal of human hypertension Vol.24 No.7

Genetic variations in ATP2B1, CSK, ARSG and CSMD1 loci are related to blood pressure and/or hypertension in two Korean cohorts

Hong, K-W,Go, M J,Jin, H-S,Lim, J-E,Lee, J-Y,Han, B G,Hwang, S-Y,Lee, S-H,Park, H K,Cho, Y S,Oh, B Macmillan Publishers Limited 2010 Journal of human hypertension Vol.24 No.6

Blood pressure, one of the important vital signs, is affected by multiple genetic and environmental factors. Recently, several genome-wide association (GWA) studies have successfully identified genetic factors that influence blood pressure and hypertension risk. In this study, we report results of the Korean Association REsource (KARE, 8842 subjects) GWA study on blood pressure and hypertension risk. In all, 10 single-nucleotide polymorphisms (SNPs) that showed significant association with hypertension were further analysed for replication associations in the Health2 project (7861 subjects). Among these 10 SNPs, 3 were replicated in the Health2 cohort for an association with systolic or diastolic blood pressure. The most significant SNP (rs17249754 located in ATPase, Ca<SUP>++</SUP> transporting, plasma membrane 1 (ATP2B1)) has been previously reported, and the other two SNPs are rs1378942 in the c-src tyrosine kinase (CSK) gene and rs12945290 in the arylsulphatase G (ARSG) gene. An additional hypertension case–control study confirmed that rs17249754 (in ATP2B1) increases hypertension risk in both the KARE and Health2 (meta-analysis, P-value=4.25 × 10<SUP>−9</SUP>) cohorts. One more SNP, rs995322, located in the CUB and Sushi multiple domains 1 (CSMD1), is also associated with increased risk of hypertension (meta-analysis, P-value=1.00 × 10<SUP>−4</SUP>). Despite the difficulty of obtaining replication results for a complex trait genetic association between blood pressure and hypertension, we were able to identify consistent genetic factors in both the Korean cohorts in ATP2B1, CSK, ARSG and CSMD1 genes.

Non-synonymous single-nucleotide polymorphisms associated with blood pressure and hypertension

Hong, K-W,Jin, H-S,Lim, J-E,Cho, Y S,Go, M J,Jung, J,Lee, J-E,Choi, J,Shin, C,Hwang, S-Y,Lee, S-H,Park, H K,Oh, B Macmillan Publishers Limited 2010 Journal of human hypertension Vol.24 No.11

In this study, we determined the association of 1180 non-synonymous single-nucleotide polymorphisms (SNPs) with systolic blood pressure (SBP) and hypertensive status. A total of 8842 subjects were taken from two community-based cohorts—Ansung (n=4183) and Ansan (n=4659), South Korea—which had been established for genome-wide association studies (GWAS). Five SNPs (rs16835244, rs2286672, rs6265, rs17237198 and rs7312017) were significantly associated (P-values: 0.003–0.0001, not corrected for genome-wide significance) with SBP in both cohorts. Of these SNPs, rs16835244 and rs2286672 correlated with risk for hypertension. The rs16835244 SNP replaces Ala288 in arginine decarboxylase (ADC) with serine, and rs2286672 replaces Arg172 in phospholipase D2 (PLD2) with cysteine. A comparison of peptide sequences between vertebrate homologues revealed that the SNPs identified occur at conserved amino-acid residues. In silico analysis of the protein structure showed that the substitution of a polar residue, serine, for a non-polar alanine at amino-acid residue 288 affects a conformational change in ADC, and that Arg172 in PLD2 resides in the PX domain, which is important for membrane trafficking. These results provide insights into the function of these non-synonymous SNPs in the development of hypertension. The study investigating non-synonymous SNPs from GWAS not only by statistical association analysis but also by biological relevance through the protein structure might be a good approach for identifying genetic risk factors for hypertension, in addition to discovering causative variations.

Caspase-dependent generation of reactive oxygen species in human astrocytoma cells contributes to resistance to TRAIL-mediated apoptosis

Choi, K,Ryu, S-W,Song, S,Choi, H,Kang, S W,Choi, C Macmillan Publishers Limited 2010 CELL DEATH AND DIFFERENTIATION Vol.17 No.5

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family of cytokines, causes apoptosis by caspase activation in various cell types, particularly in transformed cells. Numerous types of tumors are relatively resistant to TRAIL-induced cytotoxicity; however, the reasons for this are not yet fully understood. We report here a new signal transduction pathway involving protein kinase Cδ (PKCδ), NADPH oxidase 4 (NOX4) and reactive oxygen species (ROS), that inhibits caspase-dependent cell death induced by TRAIL ligation in human malignant astrocytoma cells. In our experiments, TRAIL ligation-induced generation of intracellular ROS through caspase-dependent proteolytic activation of PKCδ and subsequent activation of the NOX4 complex. Suppression of intracellular ROS induction using various pharmacological inhibitors or PKCδ- or NOX4-specific RNA interference enhanced the enzymatic activity of caspase-3 by blocking the oxidative modification of its catalytic cysteine residue, resulting in marked augmentation of TRAIL-mediated cell death. These results collectively indicate that TRAIL-induced activation of PKCδ and NOX4 can modulate TRAIL-mediated apoptosis by promoting oxidative modification of active caspase-3 in a negative-feedback manner.

Generation of donor natural killer cells from CD34⁺ progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study

Yoon, S R,Lee, Y S,Yang, S H,Ahn, K H,Lee, Je-H,Lee, Ju-H,Kim, D Y,Kang, Y A,Jeon, M,Seol, M,Ryu, S G,Chung, J W,Choi, I,Lee, K H Macmillan Publishers Limited 2010 BONE MARROW TRANSPLANTATION -BASINGSTOKE- Vol.45 No.6

Post transplant infusion of donor-type natural killer (NK) cells has been shown to have an anti-leukemia-enhancing effect without evoking GVHD in murine hematopoietic cell transplantation (HCT) models. Here, we tested 14 patients (age, 23–65 years), 12 with acute leukemia and 2 with myelodysplastic syndrome, who underwent HLA-mismatched HCT and subsequently received donor NK cell infusions. Cell donors (age, 16–51 years), comprising seven siblings, five offspring, and two mothers of the patients, underwent growth factor-mobilized leukapheresis for 3–5 days. Cells collected on the first 2–4 days were used for HCT, whereas those collected on the last day were CD34 selected by magnetic-activated cell sorting (median, 2.22 × 10<SUP>6</SUP> cells/kg; range, 0.29–5.66). Donor NK cells were generated from the CD34<SUP>+</SUP> cells by ex vivo cell culture over a 6-week period (median, 9.28 × 10<SUP>6</SUP> cells/kg; range, 0.33–24.50; CD122/CD56<SUP>+</SUP> 64%; CD3<SUP>+</SUP> 1.0%; and viability 88%). There were no signs of acute toxicity in patients infused with these cells 6–7 weeks post transplant. Overall, one and five patients developed acute and chronic GVHD during post transplant period, respectively. These results showed that clinical-grade donor NK cell production from CD34<SUP>+</SUP> cells is feasible.