Ligand Effect in 1-Octanethiol Passivation of InP/ZnSe/ZnS Quantum Dots-Evidence of Incomplete Surface Passivation during Synthesis.

The lack of anionic carboxylate ligands on the surface of InP/ZnSe/ZnS quantum dots (QDs), where zinc carboxylate ligands can be converted to carboxylic acid or carboxylate ligands via proton transfer by 1-octanethiol, is demonstrated. The as-synthesized QDs initially have an under-coordinated vacancy surface, which is passivated by solvent ligands such as ethanol and acetone. Upon exposure of 1-octanethiol to the QD surface, 1-octanethiol effectively induces the surface binding of anionic carboxylate ligands (derived from zinc carboxylate ligands) by proton transfer, which consequently exchanges ethanol and acetone ligands that bind on the incomplete QD surface. These systematic chemical analyses, such as thermogravimetric analysis-mass spectrometry and proton nuclear magnetic resonance spectroscopy, directly show the interplay of surface ligands, and it associates with QD light-emitting diodes (QD-LEDs). It is believed that this better understanding can lead to industrially feasible QD-LEDs.

Activation of galactose utilization by the addition of glucose for the fermentation of agar hydrolysate using Lactobacillus brevis ATCC 14869.

OBJECTIVE: To investigate the application of carbon catabolite repression (CCR) relaxed Lactobacillus brevis ATCC 14869 in the utilization of agar hydrolysate to produce bioethanol and lactic acid through fermentation. RESULTS: As a single carbon source, galactose was not metabolized by L. brevis. However, L. brevis consumed galactose simultaneous to glucose and ceased cell growth after depletion of glucose. For complete use of galactose from agar hydrolysis, glucose need to be periodically replenished into the growth medium. Overall, L. brevis successfully used agar hydrolysate and produced 17.2 g/L of ethanol and 31.9 g/L of lactic acid. The maximum specific cell growth rate on galactose and glucose mixture was the same with the glucose-only medium at 0.12 h-1. The molar product yields from glucose for lactic acid and ethanol were 1.02 and 0.95 respectively, equal to values obtained from the simultaneous utilization of glucose and galactose. CONCLUSION: In contribution to the ongoing efforts to utilize marine biomass, the relaxed CCR in Lactobacillus brevis ATCC 14869 was herein exploited to produce bioethanol and lactic acid from red seaweed hydrolysates.

Enhanced Electroluminescence via a Nanohybrid Material Consisting of Aromatic Ligand-Modified InP Quantum Dots and an Electron-Blocking Polymer as the Single Active Layer in Quantum Dot-LEDs.

Electron overcharge causes rapid luminescence quenching in the quantum dot (QD) emission layer in QD light-emitting diodes (QD-LEDs), resulting in low device performance. In this paper we describe the application of different aromatic thiol ligands and their influence on device performance as well as their behavior in combination with an electron blocking material (EBM). The three different ligands, 1-octanethiol (OcSH), thiophenol (TP), and phenylbutan-1-thiol (PBSH), were introduced on to InP/ZnSe/ZnS QDs referred to as QD-OcSH, QD-TP, and QD-PBSH. PBSH is in particular applied as a ligand to improve QD solubility and to enhance the charge transport properties synergistically with EBM probably via π-π interaction. We synthesized poly-[N,N-bis[4-(carbazolyl)phenyl]-4-vinylaniline] (PBCTA) and utilized it as an EBM to alleviate excess electrons in the active layer in QD-LEDs. The comparison of the three QD systems in an inverted device structure without the application of PBCTA as an EBM shows the highest efficiency for QD-PBSH. Moreover, when PBCTA is introduced as an EBM in the active layer in combination with QD-PBSH in a conventional device structure, the current efficiency shows a twofold increase compared to the reference device without EBM. These results strongly confirm the role of PBCTA as an EBM that effectively alleviates excess electrons in the active layer, leading to higher device efficiency.

Maternal exposure to polystyrene nanoplastics causes brain abnormalities in progeny.

As global plastic production continues to grow, microplastics released from a massive quantity of plastic wastes have become a critical environmental concern. These microplastic particles are found in a wide range of living organisms in a diverse array of ecosystems. In this study, we investigated the biological effects of polystyrene nanoplastic (PSNP) on development of the central nervous system using cultured neural stem cells (NSCs) and mice exposed to PSNP during developmental stages. Our study demonstrates that maternal administration of PSNP during gestation and lactating periods altered the functioning of NSCs, neural cell compositions, and brain histology in progeny. Similarly, PSNP-induced molecular and functional defects were also observed in cultured NSCs in vitro. Finally, we show that the abnormal brain development caused by exposure to high concentrations of PSNP results in neurophysiological and cognitive deficits in a gender-specific manner. Our data demonstrate the possibility that exposure to high amounts of PSNP may increase the risk of neurodevelopmental defects.

Metal Sulfide Nanoparticle Synthesis with Ionic Liquids - State of the Art and Future Perspectives.

Metal sulfides are among the most promising materials for a wide variety of technologically relevant applications ranging from energy to environment and beyond. Incidentally, ionic liquids (ILs) have been among the top research subjects for the same applications and also for inorganic materials synthesis. As a result, the exploitation of the peculiar properties of ILs for metal sulfide synthesis could provide attractive new avenues for the generation of new, highly specific metal sulfides for numerous applications. This article therefore describes current developments in metal sulfide nanoparticle synthesis as exemplified by a number of highlight examples. Moreover, the article demonstrates how ILs have been used in metal sulfide synthesis and discusses the benefits of using ILs over more traditional approaches. Finally, the article demonstrates some technological challenges and how ILs could be used to further advance the production and specific property engineering of metal sulfide nanomaterials, again based on a number of selected examples.

Effects of Ultra-high doserate FLASH Irradiation on the Tumor Microenvironment in Lewis Lung Carcinoma: Role of Myosin Light Chain.

PURPOSE: To investigate whether the vascular collapse in tumors by conventional dose rate (CONV) irradiation (IR) would also occur by the ultra-high dose rate FLASH IR. METHODS AND MATERIALS: Lewis lung carcinoma (LLC) cells were subcutaneously implanted in mice. This was followed by CONV or FLASH IR at 15 Gy. Tumors were harvested at 6 or 48 hours after IR and stained for CD31, phosphorylated myosin light chain (p-MLC), γH2AX (a surrogate marker for DNA double strand break), intracellular reactive oxygen species (ROS), or immune cells such as myeloid and CD8α T cells. Cell lines were irradiated with CONV IR for Western blot analyses. ML-7 was intraperitoneally administered daily to LLC-bearing mice for 7 days before 15 Gy CONV IR. Tumors were similarly harvested and analyzed. RESULTS: By immunostaining, we observed that CONV IR at 6 hours resulted in constricted vessel morphology, increased expression of p-MLC, and much higher numbers of γH2AX-positive cells in tumors, which were not observed with FLASH IR. Mechanistically, MLC activation by ROS is unlikely, because FLASH IR produced significantly more ROS than CONV IR in tumors. In vitro studies demonstrated that ML-7, an inhibitor of MLC kinase, abrogated IR-induced γH2AX formation and disappearance kinetics. Lastly, we observed that CONV IR when combined with ML-7 produced some effects similar to FLASH IR, including reduction in the vasculature collapse, fewer γH2AX-positive cells, and increased immune cell influx to the tumors. CONCLUSIONS: FLASH IR produced novel changes in the tumor microenvironment that were not observed with CONV IR. We believe that MLC activation in tumors may be responsible for some of the microenvironmental changes differentially regulated between CONV and FLASH IR.

Variable Tumor Microenvironment-on-a-chip with Temporal Angiogenic Switching System by Diffusion Control.

Organ-on-a-chip has the potential to replace preclinical trials which have been problematic for decades due to unaffordable cost and time. The performance of in vitro tumor-on-a-chip depends on how accurately the system represents analogous tumor-microenvironment (TME) and TME associated phenomena. In this study, we have focused on angiogenesis, one of the most significant features of TME for tumor growth and metastasis. Angiogenesis in TME is triggered through cascaded interactions among TME associated neighboring cells including immune cells, tumor cells, and fibroblast cells [1]. Therefore, temporally-controlled TME-on-a-chip is desired for an accurate representation of angiogenesis. However, conventional microfluidic devices cannot temporarily manipulate the condition of interacting cells and secreted signal molecules. Here, we proposed a hydrogel-based variable TME-on-a-chip with diffusion switch channels. The channels between hydrogel walls enable temporal diffusion control by controlling inflow. The diffusion control was observed in diffusion experiment with a fluorescent dye. Furthermore, experiment of HUVEC's migration toward diffused VEGF also confirmed that TME-on-a-chip is capable of reproducing an angiogenic switch triggering through temporal diffusion control. Due to a simple fabrication procedure, the design of the microfluidic device can be easily modified to represent more complex variable TME models.

CD64-targeted HO-1 RNA interference enhances chemosensitivity in orthotopic model of acute myeloid leukemia and patient-derived bone marrow cells.

Acute myeloid leukemia is the most frequent and life-threatening blood cancer. The main treatment is chemotherapy, sometimes followed by stem cell transplant. Resistance to chemotherapy and hepatotoxicity of the CD33-targeted therapy require an alternative therapeutic strategy. Here, we report CD64-targeted RNA interference as a novel AML therapy, which was delivered by a recombinant fusion protein of CD64-binding antibody and nona-arginine (sR9). The sR9-mediated heme oxygenase-1 siRNA (siHO-1) delivery efficiently enhanced apoptotic response to daunorubicin of AML cells and AML-targeted HO-1 silencing improved chemotherapy and prolonged survival in orthotopic myeloid leukemia model. CD64 expression was verified and HO-1-silencing-mediated chemo-sensitization was also validated in leukemic blast cells originated from AML M4/M5 patient's bone marrow. Collectively, CD64-targeted RNA interference could be a promising strategy for AML therapy and AML-targeted HO-1 suppression is expected to improve the chemotherapeutic effect in future clinical trials.

Volatile profiles and involvement step of moisture in bulk oils during oxidation by action of deuterium oxide (D2O).

Volatile formation is an inevitable result of lipid oxidation, which impact the quality of lipid rich foods. In this study, moisture role on the formation of volatiles were evaluated using deuterium oxide (D2O) and possible steps of moisture involvement were suggested. Moisture content in corn oil with deuterium free water (H2O) was significantly (p < 0.05) higher than that in corn oil with D2O. The contents of some volatiles including pentane, hexanal, 2-hexenal, and t-2-heptenal in corn oil with D2O were higher than those in corn oil with H2O for the first 8 days. Volatiles containing deuterium appeared in the order of pentane, t-2-pentenal, and t-2-heptenal during oxidation. Deuterium incorporated volatiles could be formed after the ß-scission of lipid hydroperoxides. Therefore, moisture plays important roles in the formation of volatiles as well as the locations of oxidation in bulk oils.

Surfactant-free solubilization and systemic delivery of anti-cancer drug using low molecular weight methylcellulose.

Docetaxel, an advanced taxoid, has been widely used as an anti-mitotic agent, but further augmentation of its properties is still required, including improvement in low aqueous solubility. Herein, we report the development of bio-eliminable low molecular weight methylcellulose-based surfactant-free injectable formulation for the delivery of docetaxel. Crude methylcellulose, a hydrophobically modified cellulose derivative, was hydrolyzed by an enzymatic degradation method to obtain low molecular weight methylcellulose (LMwMC). Docetaxel was successfully loaded in micelles with small particle sizes high drug loading and sustained release profile. The in vivo anti-cancer effects of intravenously injected nanoparticle systems in B16F10 melanoma xenograft mice were evaluated and demonstrated a significantly enhanced therapeutic effect with the docetaxel-LMwMC micellar aggregates compared to a commercially available docetaxel, Taxotere®. Surfactant-free solubilization of docetaxel could be a promising delivery method for effective insoluble drug delivery for anti-tumor efficacy.

Radiation-induced immune responses: mechanisms and therapeutic perspectives.

Recent advancement in the radiotherapy technology has allowed conformal delivery of high doses of ionizing radiation precisely to the tumors while sparing large volume of the normal tissues, which have led to better clinical responses. Despite this technological advancement many advanced tumors often recur and they do so within the previously irradiated regions. How could tumors recur after receiving such high ablative doses of radiation? In this review, we outlined how radiation can elicit anti-tumor responses by introducing some of the cytokines that can be induced by ionizing radiation. We then discuss how tumor hypoxia, a major limiting factor responsible for failure of radiotherapy, may also negatively impact the anti-tumor responses. In addition, we highlight how there may be other populations of immune cells including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that can be recruited to tumors interfering with the anti-tumor immunity. Finally, the impact of irradiation on tumor hypoxia and the immune responses according to different radiotherapy regimen is also delineated. It is indeed an exciting time to see that radiotherapy is being combined with immunotherapy in the clinic and we hope that this review can add an excitement to the field.

Identification of Gene Networks with Time Delayed Regulation Based on Temporal Expression Profiles.

There are fundamental limitations in inferring the functional interaction structure of a gene (regulatory) network only from sequence information such as binding motifs. To overcome such limitations, various approaches have been developed to infer the functional interaction structure from expression profiles. However, most of them have not been so successful due to the experimental limitations and computational complexity. Hence, there is a pressing need to develop a simple but effective methodology that can systematically identify the functional interaction structure of a gene network from time-series expression profiles. In particular, we need to take into account the different time delay effects in gene regulation since they are ubiquitously present. We have considered a new experiment that measures the overall expression changes after a perturbation on a specific gene. Based on this experiment, we have proposed a new inference method that can take account of the time delay induced while the perturbation affects its primary target genes. Specifically, we have developed an algebraic equation from which we can identify the subnetwork structure around the perturbed gene. We have also analyzed the influence of time delay on the inferred network structure. The proposed method is particularly useful for identification of a gene network with small variations in the time delay of gene regulation.

Serum-stable quantum dot-protein hybrid nanocapsules for optical bio-imaging.

We introduce shell cross-linked protein/quantum dot (QD) hybrid nanocapsules as a serum-stable systemic delivery nanocarrier for tumor-targeted in vivo bio-imaging applications. Highly luminescent, heavy-metal-free Cu0.3InS2/ZnS (CIS/ZnS) core-shell QDs are synthesized and mixed with amine-reactive six-armed poly(ethylene glycol) (PEG) in dichloromethane. Emulsification in an aqueous solution containing human serum albumin (HSA) results in shell cross-linked nanocapsules incorporating CIS/ZnS QDs, exhibiting high luminescence and excellent dispersion stability in a serum-containing medium. Folic acid is introduced as a tumor-targeting ligand. The feasibility of tumor-targeted in vivo bio-imaging is demonstrated by measuring the fluorescence intensity of several major organs and tumor tissue after an intravenous tail vein injection of the nanocapsules into nude mice. The cytotoxicity of the QD-loaded HSA-PEG nanocapsules is also examined in several types of cells. Our results show that the cellular uptake of the QDs is critical for cytotoxicity. Moreover, a significantly lower level of cell death is observed in the CIS/ZnS QDs compared to nanocapsules loaded with cadmium-based QDs. This study suggests that the systemic tumor targeting of heavy-metal-free QDs using shell cross-linked HSA-PEG hybrid nanocapsules is a promising route for in vivo tumor diagnosis with reduced non-specific toxicity.

Integrative analysis of time course microarray data and DNA sequence data via log-linear models for identifying dynamic transcriptional regulatory networks.

Since eukaryotic transcription is regulated by sets of Transcription Factors (TFs) having various transcriptional time delays, identification of temporal combinations of activated TFs is important to reconstruct Transcriptional Regulatory Networks (TRNs). Our methods combine time course microarray data, information on physical binding between the TFs and their targets and the regulatory sequences of genes using a log-linear model to reconstruct dynamic functional TRNs of the yeast cell cycle and human apoptosis. In conclusion, our results suggest that the proposed dynamic motif search method is more effective in reconstructing TRNs than the static motif search method.

Transcriptome sequencing of the Antarctic vascular plant Deschampsia antarctica Desv. under abiotic stress.

Antarctic hairgrass (Deschampsia antarctica Desv.) is the only natural grass species in the maritime Antarctic. It has been studied as an extremophile that has successfully adapted to marginal land with the harshest environment for terrestrial plants. However, limited genetic research has focused on this species due to the lack of genomic resources. Here, we present the first de novo assembly of its transcriptome by massive parallel sequencing and its expression profile using D. antarctica grown under various stress conditions. Total sequence reads generated by pyrosequencing were assembled into 60,765 unigenes (28,177 contigs and 32,588 singletons). A total of 29,173 unique protein-coding genes were identified based on sequence similarities to known proteins. The combined results from all three stress conditions indicated differential expression of 3,110 genes. Quantitative reverse transcription polymerase chain reaction showed that several well-known stress-responsive genes encoding late embryogenesis abundant protein, dehydrin 1, and ice recrystallization inhibition protein were induced dramatically and that genes encoding U-box-domain-containing protein, electron transfer flavoprotein-ubiquinone, and F-box-containing protein were induced by abiotic stressors in a manner conserved with other plant species. We identified more than 2,000 simple sequence repeats that can be developed as functional molecular markers. This dataset is the most comprehensive transcriptome resource currently available for D. antarctica and is therefore expected to be an important foundation for future genetic studies of grasses and extremophiles.

A pathway-based classification of breast cancer integrating data on differentially expressed genes, copy number variations and microRNA target genes.

Breast cancer is a clinically heterogeneous disease characterized by distinct molecular aberrations. Understanding the heterogeneity and identifying subgroups of breast cancer are essential to improving diagnoses and predicting therapeutic responses. In this paper, we propose a classification scheme for breast cancer which integrates data on differentially expressed genes (DEGs), copy number variations (CNVs) and microRNAs (miRNAs)-regulated mRNAs. Pathway information based on the estimation of molecular pathway activity is also applied as a postprocessor to optimize the classifier. A total of 250 malignant breast tumors were analyzed by k-means clustering based on the patterns of the expression profiles of 215 intrinsic genes, and the classification performances were compared with existing breast cancer classifiers including the BluePrint and the 625-gene classifier. We show that a classification scheme which incorporates pathway information with various genetic variations achieves better performance than classifiers based on the expression levels of individual genes, and propose that the identified signature serves as a basic tool for identifying rational therapeutic opportunities for breast cancer patients.

p53 and microRNA-34 are suppressors of canonical Wnt signaling.

Although loss of p53 function and activation of canonical Wnt signaling cascades are frequently coupled in cancer, the links between these two pathways remain unclear. We report that p53 transactivated microRNA-34 (miR-34), which consequently suppressed the transcriptional activity of ß-catenin-T cell factor and lymphoid enhancer factor (TCF/LEF) complexes by targeting the untranslated regions (UTRs) of a set of conserved targets in a network of genes encoding elements of the Wnt pathway. Loss of p53 function increased canonical Wnt signaling by alleviating miR-34-specific interactions with target UTRs, and miR-34 depletion relieved p53-mediated Wnt repression. Gene expression signatures reflecting the status of ß-catenin-TCF/LEF transcriptional activity in breast cancer and pediatric neuroblastoma patients were correlated with p53 and miR-34 functional status. Loss of p53 or miR-34 contributed to neoplastic progression by triggering the Wnt-dependent, tissue-invasive activity of colorectal cancer cells. Further, during development, miR-34 interactions with the ß-catenin UTR affected Xenopus body axis polarity and the expression of Wnt-dependent patterning genes. These data provide insight into the mechanisms by which a p53-miR-34 network restrains canonical Wnt signaling cascades in developing organisms and human cancer.

A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition.

Snail1 is a zinc finger transcriptional repressor whose pathological expression has been linked to cancer cell epithelial-mesenchymal transition (EMT) programs and the induction of tissue-invasive activity, but pro-oncogenic events capable of regulating Snail1 activity remain largely uncharacterized. Herein, we demonstrate that p53 loss-of-function or mutation promotes cancer cell EMT by de-repressing Snail1 protein expression and activity. In the absence of wild-type p53 function, Snail1-dependent EMT is activated in colon, breast, and lung carcinoma cells as a consequence of a decrease in miRNA-34 levels, which suppress Snail1 activity by binding to highly conserved 3' untranslated regions in Snail1 itself as well as those of key Snail1 regulatory molecules, including ß-catenin, LEF1, and Axin2. Although p53 activity can impact cell cycle regulation, apoptosis, and DNA repair pathways, the EMT and invasion programs initiated by p53 loss of function or mutation are completely dependent on Snail1 expression. These results identify a new link between p53, miR-34, and Snail1 in the regulation of cancer cell EMT programs.

Clinical validation of colorectal cancer biomarkers identified from bioinformatics analysis of public expression data.

PURPOSE: Identification of novel biomarkers of cancer is important for improved diagnosis, prognosis, and therapeutic intervention. This study aimed to identify marker genes of colorectal cancer (CRC) by combining bioinformatics analysis of gene expression data and validation experiments using patient samples and to examine the potential connection between validated markers and the established oncogenes such as c-Myc and K-ras. EXPERIMENTAL DESIGN: Publicly available data from GenBank and Oncomine were meta-analyzed leading to 34 candidate marker genes of CRC. Multiple case-matched normal and tumor tissues were examined by RT-PCR for differential expression, and 9 genes were validated as CRC biomarkers. Statistical analyses for correlation with major clinical parameters were carried out, and RNA interference was used to examine connection with major oncogenes. RESULTS: We show with high confidence that 9 (ECT2, ETV4, DDX21, RAN, S100A11, RPS4X, HSPD1, CKS2, and C9orf140) of the 34 candidate genes are expressed at significantly elevated levels in CRC tissues compared to normal tissues. Furthermore, high-level expression of RPS4X was associated with nonmucinous cancer cell type and that of ECT2 with lack of lymphatic invasion while upregulation of CKS2 was correlated with early tumor stage and lack of family history of CRC. We also demonstrate that RPS4X and DDX21 are regulatory targets of c-Myc and ETV4 is downstream to K-ras signaling. CONCLUSIONS: We have identified multiple novel biomarkers of CRC. Further analyses of their function and connection to signaling pathways may reveal potential value of these biomarkers in diagnosis, prognosis, and treatment of CRC.

miRGator v2.0: an integrated system for functional investigation of microRNAs.

miRGator is an integrated database of microRNA (miRNA)-associated gene expression, target prediction, disease association and genomic annotation, which aims to facilitate functional investigation of miRNAs. The recent version of miRGator v2.0 contains information about (i) human miRNA expression profiles under various experimental conditions, (ii) paired expression profiles of both mRNAs and miRNAs, (iii) gene expression profiles under miRNA-perturbation (e.g. miRNA knockout and overexpression), (iv) known/predicted miRNA targets and (v) miRNA-disease associations. In total, >8000 miRNA expression profiles, ∼300 miRNA-perturbed gene expression profiles and ∼2000 mRNA expression profiles are compiled with manually curated annotations on disease, tissue type and perturbation. By integrating these data sets, a series of novel associations (miRNA-miRNA, miRNA-disease and miRNA-target) is extracted via shared features. For example, differentially expressed genes (DEGs) after miRNA knockout were systematically compared against miRNA targets. Likewise, differentially expressed miRNAs (DEmiRs) were compared with disease-associated miRNAs. Additionally, miRNA expression and disease-phenotype profiles revealed miRNA pairs whose expression was regulated in parallel in various experimental and disease conditions. Complex associations are readily accessible using an interactive network visualization interface. The miRGator v2.0 serves as a reference database to investigate miRNA expression and function (http://miRGator.kobic.re.kr).