Cell Death Response to DNA Damage.

The cell death response to DNA damage is discussed in this Perspectives piece with cancer as the backdrop because DNA damaging agents (DDA) are widely used to treat cancer. From decades of clinical results, we learn that DDA have cured some cancers but their toxicity is temporary in most cancers due to emergence of DDA-resistant cancer cells. Investigation of DDA-activated genes, proteins, and pathways, known collectively as the DNA damage response (DDR), has uncovered the inner workings of DDR that protect the genome to sustain life. Paradoxically, however, DDR can also activate death. Current knowledge on DDA-activated death and hypotheses for how DDR may determine when and where to execute death are discussed. Given that cancer cells suffer from DDR defects, which account for their initial sensitivity to DDA, future therapeutic development may exploit those cancer-specific DDR defects to selectively create death-inducing DNA lesions, without using DDA, to kill DDA-resistant cancers

Extracellular vesicles transfer nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander effects.

Ionizing radiation (IR) not only activates DNA damage response (DDR) in irradiated cells but also induces bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways activated in irradiated cells stimulate BE is not well understood. We show here that extracellular vesicles secreted by irradiated cells (EV-IR), but not those from unirradiated controls (EV-C), inhibit colony formation in unirradiated cells by inducing reactive oxygen species (ROS). We found that µEV-IR from Abl nuclear localization signal-mutated ( Abl-µNLS) cells could not induce ROS, but expression of wild-type Abl restored that activity. Because nuclear Abl stimulates miR-34c biogenesis, we measured miR-34c in EV and found that its levels correlated with the ROS-inducing activity of EV. We then showed that EV from miR-34c minigene-transfected, but unirradiated cells induced ROS; and transfection with miR-34c-mimic, without radiation or EV addition, also induced ROS. Furthermore, EV-IR from miR34-family triple-knockout cells could not induce ROS, whereas EV-IR from wild-type cells could cause miR-34c increase and ROS induction in the miR-34 triple-knockout cells. These results establish a novel role for extracellular vesicles in transferring nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander oxidative stress

The preparation, characterization, and pharmacokinetic studies of chitosan nanoparticles loaded with paclitaxel/dimethyl-β-cyclodextrin inclusion complexes.

A novel biocompatible and biodegradable drug-delivery nanoparticle (NP) has been developed to minimize the severe side effects of the poorly water-soluble anticancer drug paclitaxel (PTX) for clinical use. PTX was loaded into the hydrophobic cavity of a hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), using an aqueous solution-stirring method followed by lyophilization. The resulting PTX/DM-β-CD inclusion complex dramatically enhanced the solubility of PTX in water and was directly incorporated into chitosan (CS) to form NPs (with a size of 323.9–407.8 nm in diameter) using an ionic gelation method. The formed NPs had a zeta potential of +15.9–23.3 mV and showed high colloidal stability. With the same weight ratio of PTX to CS of 0.7, the loading efficiency of the PTX/DM-β-CD inclusion complex-loaded CS NPs was 30.3-fold higher than that of the PTX-loaded CS NPs. Moreover, it is notable that PTX was released from the DM-β-CD/CS NPs in a sustained-release manner. The pharmacokinetic studies revealed that, compared with reference formulation (Taxol(®)), the PTX/DM-β-CD inclusion complex-loaded CS NPs exhibited a significant increase in AUC(0→24h) (the area under the plasma drug concentration–time curve over the period of 24 hours) and mean residence time by 2.7-fold and 1.4-fold, respectively. Therefore, the novel drug/DM-β-CD inclusion complex-loaded CS NPs have promising applications for the significantly improved delivery and controlled release of the poorly water-soluble drug PTX or its derivatives, thus possibly leading to enhanced therapeutic efficacy and less severe side effects

Resonance states of open quantum dots

We have computed the spectra of resonance states for several open quantum dot systems. These states are identified using the electron dwell time. The statistics of the spectra are exactly the same as that of the corresponding closed system, even when the level widths are comparable with the average spacing. In particular, for a regular structure, e.g., an open rectangular quantum dot, the resonance state level spacing satisfies the Poisson distribution. For an irregular structure, e.g., an open Sinai billiard, we found that the spacings satisfy the GOE or GUE statistics depending on whether an external magnetic field is applied. Thus in this regime of ballistic transport, the statistics of resonance transmission contains characteristics of the corresponding intrinsic quantum level distribution. © 1996 The American Physical Society.published_or_final_versio

Confirmatory factor analysis of the stagnation scale-a traditional chinese medicine construct operationalized for mental health practice

Background Traditional Chinese medicine stagnation ("yu") syndrome is characterized by a cluster of mind/body obstruction-like symptoms. Previous studies have operationalized the concept as a psychological construct through scale development, producing a three-factor 16-item inventory with good psychometric properties. Purpose The study aimed to further validate the Stagnation Scale by confirmatory factor analysis (CFA) and examine self-appraisal of stagnation as an illness. Method A cross-sectional questionnaire survey was conducted on a random community sample of 755 adults recruited by cluster sampling in Hong Kong. Results CFA revealed a good fit of the three-factor model (CFI=.95; RMSEA=.077; SRMR=.043). ROC analysis suggested a cutoff score at 50 on stagnation total score for predicting self-appraisal of an illness condition, with false positive and negative rates at 25.8% and 23.3%, respectively. Overall, 6.2% participants self-appraised to suffer stagnation symptoms to a degree of an illness, and for it, 1.9% participants intended to seek treatment. Stagnation showed positive correlations with physical distress, depression, and anxiety (r=.59-.76, p<.01) and negative correlation with age (r=?.22, p<.01). Conclusion The Stagnation Scale appeared to be robust in factorial and construct validity. With prevalence of illness by self-appraisal at 6.2% and intention for treatment at 1.9%, stagnation is a fairly common condition associated with treatment-seeking behaviors. © International Society of Behavioral Medicine 2011.published_or_final_versionSpringer Open Choice, 21 Feb 201

Patterned growth of InGaN/GaN quantum wells on freestanding GaN grating by molecular beam epitaxy

We report here the epitaxial growth of InGaN/GaN quantum wells on freestanding GaN gratings by molecular beam epitaxy (MBE). Various GaN gratings are defined by electron beam lithography and realized on GaN-on-silicon substrate by fast atom beam etching. Silicon substrate beneath GaN grating region is removed from the backside to form freestanding GaN gratings, and the patterned growth is subsequently performed on the prepared GaN template by MBE. The selective growth takes place with the assistance of nanoscale GaN gratings and depends on the grating period P and the grating width W. Importantly, coalescences between two side facets are realized to generate epitaxial gratings with triangular section. Thin epitaxial gratings produce the promising photoluminescence performance. This work provides a feasible way for further GaN-based integrated optics devices by a combination of GaN micromachining and epitaxial growth on a GaN-on-silicon substrate

Exploiting the promiscuity of imatinib

The protein kinase inhibitor imatinib, also known as Gleevec, has been a notable success in treating chronic myelogenous leukemia. A recent paper in BMC Structural Biology reports a 1.75 Å crystal structure of imatinib bound to the oxidoreductase NQO2 and reveals insights into the binding specificity and the off-target effects of the inhibitor

Nanoimaging of Organic Charge Retention Effects: Implications for Nonvolatile Memory, Neuromorphic Computing, and High Dielectric Breakdown Devices

While a large variety of organic and molecular materials have been found to exhibit charge memory effects, the underlying mechanism is not well-understood, which hinders rational device design. Here, we study the charge retention mechanism of a nanoscale memory system, an organic monolayer on a silicon substrate, with Au nanoparticles on top serving as the electrical contact. Combining scanning probe imaging/manipulation and density functional simulations, we observe stable charge retention effects in the system and attributed it to polaron effects at the amine functional groups. Our findings can pave the way for applications in nonvolatile memory, neuromorphic computing, and high dielectric breakdown devices