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Yue Pan - Top 30 Publications

Berberine inhibits the chemotherapy-induced repopulation by suppressing the arachidonic acid metabolic pathway and phosphorylation of FAK in ovarian cancer.

Cytotoxic chemotherapy is an effective and traditional treatment of ovarian cancer. However, chemotherapy-induced apoptosis may also trigger and ultimately accelerate the repopulation of the small number of adjacent surviving cells. This study mainly focused on the tumour cell repopulation caused by chemotherapy in ovarian cancer and the adjunctive/synergistic effect of Berberine on the prevention of tumour repopulation.

A NMDA-receptor calcium influx assay sensitive to stimulation by glutamate and glycine/D-serine.

N-methyl-D-aspartate-receptors (NMDARs) are ionotropic glutamate receptors that function in synaptic transmission, plasticity and cognition. Malfunction of NMDARs has been implicated in a variety of nervous system disorders, making them attractive therapeutic targets. Overexpression of functional NMDAR in non-neuronal cells results in cell death by excitotoxicity, hindering the development of cell-based assays for NMDAR drug discovery. Here we report a plate-based, high-throughput approach to study NMDAR function. Our assay enables the functional study of NMDARs with different subunit composition after activation by glycine/D-serine or glutamate and hence presents the first plate-based, high throughput assay that allows for the measurement of NMDAR function in glycine/D-serine and/or glutamate sensitive modes. This allows to investigate the effect of small molecule modulators on the activation of NMDARs at different concentrations or combinations of the co-ligands. The reported assay system faithfully replicates the pharmacology of the receptor in response to known agonists, antagonists, positive and negative allosteric modulators, as well as the receptor's sensitivity to magnesium and zinc. We believe that the ability to study the biology of NMDARs rapidly and in large scale screens will enable the identification of novel therapeutics whose discovery has otherwise been hindered by the limitations of existing cell based approaches.

Detecting cm-scale hot spot over 24-km-long single-mode fiber by using differential pulse pair BOTDA based on double-peak spectrum.

In distributed Brillouin optical fiber sensor when the length of the perturbation to be detected is much smaller than the spatial resolution that is defined by the pulse width, the measured Brillouin gain spectrum (BGS) experiences two or multiple peaks. In this work, we propose and demonstrate a technique using differential pulse pair Brillouin optical time-domain analysis (DPP-BOTDA) based on double-peak BGS to enhance small-scale events detection capability, where two types of single mode fiber (main fiber and secondary fiber) with 116 MHz Brillouin frequency shift (BFS) difference have been used. We have realized detection of a 5-cm hot spot at the far end of 24-km single mode fiber by employing a 50-cm spatial resolution DPP-BOTDA with only 1GS/s sampling rate (corresponding to 10 cm/point). The BFS at the far end of 24-km sensing fiber has been measured with 0.54 MHz standard deviation which corresponds to a 0.5°C temperature accuracy. This technique is simple and cost effective because it is implemented using the similar experimental setup of the standard BOTDA, however, it should be noted that the consecutive small-scale events have to be separated by a minimum length corresponding to the spatial resolution defined by the pulse width difference.

Influence of the Oil on the Structure and Electrochemical Performance of Emulsion-Templated Tin/Carbon Anodes for Lithium Ion Batteries.

Tin (Sn) is a useful anode material for lithium ion batteries (LIBs) because of its high theoretical capacity. We fabricated oil-in-water emulsion-templated tin nanoparticle/carbon black (SnNP/CB) anodes with octane, hexadecane, 1-chlorohexadecane, and 1-bromohexadecane as the oil phases. Emulsion creaming, the oil vapor pressure, and the emulsion droplet size distribution all affect drying and thus the morphology of the dried emulsion. This morphology has a direct impact on the electrochemical performance of the anode. SnNP/CB anodes prepared with hexadecane showed very few cracks and had the highest capacities and capacity retention. The combination of low vapor pressure, creaming, which forced the emulsion droplets into a close-packed arrangement on the surface of the continuous water phase, and the small droplets allowed for gentle evaporation of the liquids during drying. This led to lower differential stresses on the sample and reduced cracking. For octane, the vapor pressure was high, the droplet sizes were large for 1-cholorohexadecane, and there was no creaming for 1-bromohexadecane. All of these factors contributed to cracking of the anode surface during drying and reduced the electrochemical performance. Choosing an oil with balanced properties is important for obtaining the best cell performance for emulsion-templated anodes for LIBs.

Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer.

Breast cancer is the most common malignancy in women. Although personalized or targeting molecular cancer therapy is more popular up to now, the cytotoxicity chemotherapy for patients with advanced breast cancer is considered as the alternative option. However, chemoresistance is still the common and critical limitation for breast cancer treatment. Berberine, known as AMPK activator, has shown multiple activities including antitumor effect. In this study, we investigate the chemosensitive effect of different dosages berberine on drug-resistant human breast cancer MCF-7/MDR cell in vitro and in vivo, and the mechanisms underlying AMPK activation on Doxorubicin (DOX) chemosensitivity. Our results showed that berberine could overcome DOX resistance in dose-orchestrated manner: On one hand, low-dose berberine can enhance DOX sensitivity in drug-resistance breast cancer cells through AMPK-HIF-1α-P-gp pathway. On the other hand, high-dose berberine alone directly induces apoptosis through the AMPK-p53 pathway with the independence of HIF-1α expression. Taken together, our findings demonstrate that berberine sensitizes drug-resistant breast cancer to DOX chemotherapy and directly induces apoptosis through the dose-orchestrated AMPK signaling pathway in vitro and in vivo. Berberine appears to be a promising chemosensitizer and chemotherapeutic drug for breast cancer treatment.

Genetic variability and functional implication of the long control region in HPV-16 variants in Southwest China.

HPV-16 long control region (LCR) has been shown to be the most variable region of the HPV-16 genome and may play important roles in viral persistence and the development of cervical cancer. This study aimed to assess the risk of HPV-16 LCR variants for cervical cancer in women of Southwest China. 2146 cervical scrapings of volunteer outpatients and 74 cervical cancer tissues were screened.14 entire HPV-16 LCRs from asymptomatic carriers and 34 entire HPV-16 LCRs from cervical cancer patients were successfully amplified and sequenced to align to others described. 58 different point mutations were detected in 54 nucleotide sites of HPV-16 LCR. G7193T and G7521A variants, accounting for 100% of the infections, were predicted to locate at the binding site for FOXA1 and SOX9, respectively. A7730C variant which showed a high mutation frequency in cervical cancer was predicted to be a binding site for the cellular transcription factor PHOX2A. In addition, phylogenetic analysis displayed a high prevalence of A lineage in HPV-16 LCR in this Southwest China population. This study may help understanding of the intrinsic geographical relatedness and the correlations between LCR mutations and the development of carcinogenic lesions in Southwest China population. And it provides useful data for the further study of the biological function of HPV-16 LCR variants.

Upregulation of microRNA-135b and microRNA-182 promotes chemoresistance of colorectal cancer by targeting ST6GALNAC2 via PI3K/AKT pathway.

MicroRNAs (miRNAs) are increasingly involved in the development of drug resistance, including 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC). Aberrant sialylation is correlated with human CRC. The study was to explore whether miR-135b and miR-182 modulated 5-FU chemoresistance of CRC by targeting ST6GALNAC2 via PI3K/AKT pathway. MiR-135b and miR-182 were found to be up-regulated in CRC tissues and 5-FU resistant CRC cell lines. Forced miR-135b and miR-182 expression also affected ST6GALNAC2 levels. Using reporter-gene assay, ST6GALNAC2 was identified as direct target of miR-135b and miR-182, while ST6GALNAC2 expression exhibited patterns opposite to that of miR-135b and miR-182 in CRC samples and cell lines. Interestingly, up-regulation of miR-135b or miR-182 increased drug resistance and proliferation, but decreased apoptosis in 5-FU resistant CRC cell lines. Suppression of these miRNAs implicated an inverse function, while altered expression of ST6GALNAC2 mediated CRC progression upon transfection with miR-135b/-182 mimic or inhibitor. Furthermore, miR-135b and miR-182 were clarified to regulate the activity of phosphoinositide-3 kinase (PI3K)/AKT pathway. Inhibition of the PI3K/AKT pathway enhanced the chemosensitivity to 5-FU in HCT-8/5-FU and LoVo/5-FU. Taken together, miR-135b and miR-182 may reverse the resistance to 5-FU in CRC cells by targeting ST6GALNAC2 via PI3K/AKT pathway, which render potential chemotherapy targets for the treatment of CRC.

Intracellular adenosine regulates epigenetic programming in endothelial cells to promote angiogenesis.

The nucleoside adenosine is a potent regulator of vascular homeostasis, but it remains unclear how expression or function of the adenosine-metabolizing enzyme adenosine kinase (ADK) and the intracellular adenosine levels influence angiogenesis. We show here that hypoxia lowered the expression of ADK and increased the levels of intracellular adenosine in human endothelial cells. Knockdown (KD) of ADK elevated intracellular adenosine, promoted proliferation, migration, and angiogenic sprouting in human endothelial cells. Additionally, mice deficient in endothelial ADK displayed increased angiogenesis as evidenced by the rapid development of the retinal and hindbrain vasculature, increased healing of skin wounds, and prompt recovery of arterial blood flow in the ischemic hindlimb. Mechanistically, hypomethylation of the promoters of a series of pro-angiogenic genes, especially for VEGFR2 in ADK KD cells, was demonstrated by the Infinium methylation assay. Methylation-specific PCR, bisulfite sequencing, and methylated DNA immunoprecipitation further confirmed hypomethylation in the promoter region of VEGFR2 in ADK-deficient endothelial cells. Accordingly, loss or inactivation of ADK increased VEGFR2 expression and signaling in endothelial cells. Based on these findings, we propose that ADK downregulation-induced elevation of intracellular adenosine levels in endothelial cells in the setting of hypoxia is one of the crucial intrinsic mechanisms that promote angiogenesis.

Near infrared quantum dots in biomedical applications: current status and future perspective.

To address the requirements of biomedical applications including biosensing, bioimaging, and drug delivery, fluorescent nanomaterials served as efficient tools in many cases. Among them, near-infrared quantum dots (NIR QDs) have been used as novel fluorescent labels for their binary advantages of both QDs and NIR light. In this review, through collecting references in recent 10 years, we have introduced basic structures and properties of NIR QDs and summarized the classification and the related synthetic methods. This review also highlights the functionalization and surface bioconjugation of NIR QDs, and their biomedical applications in biosensing, bioimaging, and drug delivery. For further resources related to this article, please visit the WIREs website.

Long noncoding RNA linc00346 promotes the malignant phenotypes of bladder cancer.

More and more reports have demonstrated that long noncoding RNAs (lncRNAs) play an important role in the development of a variety of carcinomas, including bladder cancer. However, only a small fraction of them have been characterized. Linc00346 have been found to be upregulated in bladder cancer tissues compared to normal tissues in a microarray-based lncRNA profiling study. In this study, we would like to explore the expression pattern and functional role of linc00346 in bladder cancer.

Highly Water-Stable Lanthanide-Oxalate MOFs with Remarkable Proton Conductivity and Tunable Luminescence.

Although proton conductors derived from metal-organic frameworks (MOFs) are highly anticipated for various applications including solid-state electrolytes, H2 sensors, and ammonia synthesis, they are facing serious challenges such as poor water stability, fastidious working conditions, and low proton conductivity. Herein, we report two lanthanide-oxalate MOFs that are highly water stable, with so far the highest room-temperature proton conductivity (3.42 × 10(-3) S cm(-1) ) under 100% relative humidity (RH) among lanthanide-based MOFs and, most importantly, luminescent. Moreover, the simultaneous response of both the proton conductivity and luminescence intensity to RH allows the linkage of proton conductivity with luminescence intensity. This way, the electric signal of proton conductivity variation versus RH will be readily translated to optical signal of luminescence intensity, which can be directly visualized by the naked eye. If proper lanthanide ions or even transition-metal ions are used, the working wavelengths of luminescence emissions can be further extended from visible to near infrared light for even wider-range applications.

Carbon dots for tracking and promoting the osteogenic differentiation of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) hold great potential for tissue engineering and regeneration medicine. However, for clinical use, MSCs may be detrimental due to their uncertain fate during the transplantation. It is therefore highly desirable to develop biocompatible nanomaterials to integrate cell fate regulation with monitoring for MSC-based therapy. Herein, we employ recently developed citric acid-based carbon dots (CDs) and their derivatives (Et-IPCA) for labeling and tracking of rat bone marrow mesenchymal stem cells (rBMSCs). We further investigate their biocompatibility and effects on the osteogenic differentiation of rBMSCs. These highly fluorescent probes provide labeling of rBMSCs by internalization without affecting cell viability or inducing apoptosis when the concentration is lower than 50 μg mL(-1). Importantly, the presence of the CDs and Et-IPCA facilitates high-efficiency osteogenic differentiation of rBMSCs by promoting osteogenic transcription and enhancing matrix mineralization. Compared to Et-IPCA, CDs considerably provide long-term tracking and promote the differentiation of rBMSCs toward osteoblasts through the ROS-mediated MAPK pathway. Taken together, our results consistently demonstrate that carbon dots are capable of both tracking and enhancing the osteogenic differentiation of MSCs. This study sheds new light on the potential of carbon dots as a bifunctional tool in the thriving field of MSC-based therapy.

Berberine Reverses Hypoxia-induced Chemoresistance in Breast Cancer through the Inhibition of AMPK- HIF-1α.

Breast cancer is the most common type of cancer and the second leading cause of cancer death in American women. Chemoresistance is common and inevitable after a variable period of time. Therefore, chemosensitization is a necessary strategy on drug-resistant breast cancer. In this study, MCF-7 breast cancer cell was cultured under hypoxia for a week to induce the resistance to doxorubincin (DOX). The effect of different doses of berberine, a traditional Chinese medicine, on DOX sensitivity to MFC-7/hypoxia cells was observed. We found that hypoxia increased DOX resistance on breast cancer cells with the AMPK activation. Low-dose berberine could resensitize DOX chemosensitivity in MCF-7/hypoxia cell, however, high-dose berberine directly induced apoptosis. The intriguing fact was that the protein expressions of AMPK and HIF-1α were down-regulated by berberine, either low dose or high dose. But the downstream of HIF-1α occurred the bifurcation dependent on the dosage of berberine: AMPK-HIF-1α-P-gp inactivation played a crucial role on the DOX chemosensitivity of low-dose berberine, while AMPK-HIF-1α downregulaton inducing p53 activation led to apoptosis in high-dose berberine. These results were consistent to the transplanted mice model bearing MCF-7 drug-resistance tumor treated by berberine combined with DOX or high-dose berberine alone. This work shed light on a potentially therapeutic attempt to overcome drug-resistant breast cancer.

Complete genome analysis of dengue virus type 3 isolated from the 2013 dengue outbreak in Yunnan, China.

In the past few decades, dengue has spread rapidly and is an emerging disease in China. An unexpected dengue outbreak occurred in Xishuangbanna, Yunnan, China, resulting in 1331 patients in 2013. In order to obtain the complete genome information and perform mutation and evolutionary analysis of causative agent related to this largest outbreak of dengue fever. The viruses were isolated by cell culture and evaluated by genome sequence analysis. Phylogenetic trees were then constructed by Neighbor-Joining methods (MEGA6.0), followed by analysis of nucleotide mutation and amino acid substitution. The analysis of the diversity of secondary structure for E and NS1 protein were also performed. Then selection pressures acting on the coding sequences were estimated by PAML software. The complete genome sequences of two isolated strains (YNSW1, YNSW2) were 10,710 and 10,702 nucleotides in length, respectively. Phylogenetic analysis revealed both strain were classified as genotype II of DENV-3. The results indicated that both isolated strains of Xishuangbanna in 2013 and Laos 2013 stains (KF816161.1, KF816158.1, LC147061.1, LC147059.1, KF816162.1) were most similar to Bangladesh (AY496873.2) in 2002. After comparing with the DENV-3SS (H87) 62 amino acid substitutions were identified in translated regions, and 38 amino acid substitutions were identified in translated regions compared with DENV-3 genotype II stains Bangladesh (AY496873.2). 27(YNSW1) or 28(YNSW2) single nucleotide changes were observed in structural protein sequences with 7(YNSW1) or 8(YNSW2) non-synonymous mutations compared with AY496873.2. Of them, 4 non-synonymous mutations were identified in E protein sequences with (2 in the β-sheet, 2 in the coil). Meanwhile, 117(YNSW1) or 115 (YNSW2) single nucleotide changes were observed in non-structural protein sequences with 31(YNSW1) or 30 (YNSW2) non-synonymous mutations. Particularly, 14 single nucleotide changes were observed in NS1 sequences with 4/14 non-synonymous substitutions (4 in the coil). Selection pressure analysis revealed no positive selection in the amino acid sites of the genes encoding for structural and non-structural proteins. This study may help understand the intrinsic geographical relatedness of dengue virus 3 and contributes further to research on their infectivity, pathogenicity and vaccine development.

Inhibition of microRNA-500 has anti-cancer effect through its conditional downstream target of TFPI in human prostate cancer.

We investigated the prognostic potential and regulatory mechanism of microRNA-500 (miR-500), and human gene of tissue factor pathway inhibitor (TFPI) in prostate cancer.

An Essential Regulatory System Originating from Polygenic Transcriptional Rewiring of PhoP-PhoQ of Xanthomonas campestris.

How essential, regulatory genes originate and evolve is intriguing because mutations of these genes not only lead to lethality in organisms, but also have pleiotropic effects since they control the expression of multiple downstream genes. Therefore, the evolution of essential, regulatory genes is not only determined by genetic variations of their own sequences, but also by the biological function of downstream genes and molecular mechanisms of regulation. To understand the origin of essential, regulatory genes, experimental dissection of the complete regulatory cascade is needed. Here, we provide genetic evidences to reveal that PhoP-PhoQ is an essential two-component signal transduction system in the gram-negative bacterium Xanthomonas campestris, but that its orthologs in other bacteria belonging to Proteobacteria are nonessential. Mutational, biochemical, and chromatin immunoprecipitation together with high-throughput sequencing analyses revealed that phoP and phoQ of X. campestris and its close relative Pseudomonas aeruginosa are replaceable, and that the consensus binding motifs of the transcription factor PhoP are also highly conserved. PhoP Xcc in X. campestris regulates the transcription of a number of essential, structural genes by directly binding to cis-regulatory elements (CREs); however, these CREs are lacking in the orthologous essential, structural genes in P. aeruginosa, and thus the regulatory relationships between PhoP Pae and these downstream essential genes are disassociated. Our findings suggested that the recruitment of regulatory proteins by critical structural genes via transcription factor-CRE rewiring is a driving force in the origin and functional divergence of essential, regulatory genes.

Functional magnetic hybrid nanomaterials for biomedical diagnosis and treatment.

Magnetic nanomaterials integrating supplemental functional materials are called magnetic hybrid nanomaterials (MHNs). Such MHNs have drawn increasing attention due to their biocompatibility and the potential applications either as alternative contrast enhancing agents or effective heat nanomediators in hyperthermia therapy. The joint function comes from the hybrid nanostructures. Hybrid nanostructures of different modification can be easily achieved owing to the large surface-area-to-volume ratio and sophisticated surface characteristic. In this focus article, we mainly discussed the design and synthesis of MHNs and their applications as multimodal imaging probes and therapy agents in biomedicine. These MHNs consisting magnetic nanomaterials with functional nanocomponents such as noble metal or isotopes could perform not only superparamagnetism but also features that can be adapted in, for example, enhancing computed tomography contrast modalities, positron emission tomography, and single-photon emission computed tomography. The combination of several techniques provides more comprehensive information by both synergizing the advantages, such as quantitative evaluation, higher sensitivity and spatial resolution, and mitigating the disadvantages. Such hybrid nanostructures could also provide a unique nanoplatform for enhanced medical tracing, magnetic field, and light-triggered hyperthermia. Moreover, potential advantages and opportunities will be achieved via a combination of diagnostic and therapeutic agents within a single platform, which is so-called 'theranostics.' We expect the combination of unique structural characteristics and integrated functions of multicomponent magnetic hybrid nanomaterials will attract increasing research interest and could lead to new opportunities in nanomedicine and nanobiotechnology. For further resources related to this article, please visit the WIREs website.

Upconversion Modulation through Pulsed Laser Excitation for Anti-counterfeiting.

Lanthanide-doped upconversion nanomaterials are emerging as promising candidates in optoelectronics, volumetric display, anti-counterfeiting as well as biological imaging and therapy. Typical modulations of upconversion through chemical methods, such as controlling phase, composition, morphology and size enable us to rationally manipulate emission profiles and lifetimes of lanthanide ions by using continuous-wave laser excitation. Here we demonstrate that under pulsed laser excitation the emission color of NaYF4:Er/Tm (2/0.5%)@NaYF4 core-shell nanoparticles has an obvious transformation from green to red colors. Moreover, both pulse duration and repetition frequency are responsible for manipulating the upconversion emission color. The mechanism of the phenomena may be that the pulsed laser sequence triggers the emission levels to non-steady upconversion states first, and then cuts off the unfinished population process within the pulse duration. This pump source dependent and resultant tunable fluorescence emission enables NaYF4:Er/Tm (2/0.5%)@NaYF4 nanoparticles as a promising fluorophore in the transparent anti-fake printing.

Rationally Designed PI3Kα Mutants to Mimic ATR and Their Use to Understand Binding Specificity of ATR Inhibitors.

ATR, a protein kinase in the PIKK family, plays a critical role in the cell DNA-damage response and is an attractive anticancer drug target. Several potent and selective inhibitors of ATR have been reported showing significant antitumor efficacy, with most advanced ones entering clinical trials. However, due to the absence of an experimental ATR structure, the determinants contributing to ATR inhibitors' potency and specificity are not well understood. Here we present the mutations in the ATP-binding site of PI3Kα to progressively transform the pocket to mimic that of ATR. The generated PI3Kα mutants exhibit significantly improved affinity for selective ATR inhibitors in multiple chemical classes. Furthermore, we obtained the X-ray structures of the PI3Kα mutants in complex with the ATR inhibitors. The crystal structures together with the analysis on the inhibitor affinity profile elucidate the roles of individual amino acid residues in the binding of ATR inhibitors, offering key insights for the binding mechanism and revealing the structure features important for the specificity of ATR inhibitors. The ability to obtain structural and binding data for these PI3Kα mutants, together with their ATR-like inhibitor binding profiles, makes these chimeric PI3Kα proteins valuable model systems for structure-based inhibitor design.

Fatty acid DSF binds and allosterically activates histidine kinase RpfC of phytopathogenic bacterium Xanthomonas campestris pv. campestris to regulate quorum-sensing and virulence.

As well as their importance to nutrition, fatty acids (FA) represent a unique group of quorum sensing chemicals that modulate the behavior of bacterial population in virulence. However, the way in which full-length, membrane-bound receptors biochemically detect FA remains unclear. Here, we provide genetic, enzymological and biophysical evidences to demonstrate that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, a medium-chain FA diffusible signal factor (DSF) binds directly to the N-terminal, 22 amino acid-length sensor region of a receptor histidine kinase (HK), RpfC. The binding event remarkably activates RpfC autokinase activity by causing an allosteric change associated with the dimerization and histidine phosphotransfer (DHp) and catalytic ATP-binding (CA) domains. Six residues were found essential for sensing DSF, especially those located in the region adjoining to the inner membrane of cells. Disrupting direct DSF-RpfC interaction caused deficiency in bacterial virulence and biofilm development. In addition, two amino acids within the juxtamembrane domain of RpfC, Leu172 and Ala178, are involved in the autoinhibition of the RpfC kinase activity. Replacements of them caused constitutive activation of RpfC-mediated signaling regardless of DSF stimulation. Therefore, our results revealed a biochemical mechanism whereby FA activates bacterial HK in an allosteric manner, which will assist in future studies on the specificity of FA-HK recognition during bacterial virulence regulation and cell-cell communication.

Detection of Ketones by a Novel Technology: Dipolar Proton Transfer Reaction Mass Spectrometry (DP-PTR-MS).

Proton transfer reaction mass spectrometry (PTR-MS) has played an important role in the field of real-time monitoring of trace volatile organic compounds (VOCs) due to its advantages such as low limit of detection (LOD) and fast time response. Recently, a new technology of proton extraction reaction mass spectrometry (PER-MS) with negative ions OH(-) as the reagent ions has also been presented, which can be applied to the detection of VOCs and even inorganic compounds. In this work, we combined the functions of PTR-MS and PER-MS in one instrument, thereby developing a novel technology called dipolar proton transfer reaction mass spectrometry (DP-PTR-MS). The selection of PTR-MS mode and PER-MS mode was achieved in DP-PTR-MS using only water vapor in the ion source and switching the polarity. In this experiment, ketones (denoted by M) were selected as analytes. The ketone (molecular weight denoted by m) was ionized as protonated ketone [M + H](+) [mass-to-charge ratio (m/z) m + 1] in PTR-MS mode and deprotonated ketone [M - H](-) (m/z m - 1) in PER-MS mode. By comparing the m/z value of the product ions in the two modes, the molecular weight of the ketone can be positively identified as m. Results showed that whether it is a single ketone sample or a mixed sample of eight kinds of ketones, the molecular weights can be detected with DP-PTR-MS. The newly developed DP-PTR-MS not only maintains the original advantages of PTR-MS and PER-MS in sensitive and rapid detection of ketones, but also can estimate molecular weight of ketones. Graphical Abstract ᅟ.

From Graphite to Graphene Oxide and Graphene Oxide Quantum Dots.

Many methods have been reported for synthesizing graphene oxide (GO) and graphene oxide quantum dots (GOQDs) where a tedious operational procedure and long reaction time are generally required. Herein, a facile one-pot solvothermal method that allows selective synthesis of pure GO and pure GOQDs, respectively is demonstrated. What is more, the final product of either GO or differently sized GOQDs can be easily controlled by adjusting the reaction temperatures or reactant ratios, which is also feasible when enlarged to gram scale. The 2.5 nm GOQDs show excellent photoluminescence that can be utilized for bioimaging or distinctive detection of Eu(3+) and Tb(3+) from their respective mixtures with other rare earth and/or transition metal ions, at sub-ppm level.

Selective Carbonyl-C(sp(3) ) Bond Cleavage To Construct Ynamides, Ynoates, and Ynones by Photoredox Catalysis.

Carbon-carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl-C(sp(3) ) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl-radical-enabled carbonyl-C(sp(3) ) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β-carbonyl alkoxyl radical generation from β-carbonyl alcohols, including alcohols with high redox potential (Epox >2.2 V vs. SCE in MeCN). β-Amide, β-ester, and β-ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio- and chemoselectivity under mild reaction conditions.

Two-Component Signaling System VgrRS Directly Senses Extracytoplasmic and Intracellular Iron to Control Bacterial Adaptation under Iron Depleted Stress.

Both iron starvation and excess are detrimental to cellular life, especially for animal and plant pathogens since they always live in iron-limited environments produced by host immune responses. However, how organisms sense and respond to iron is incompletely understood. Herein, we reveal that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, VgrS (also named ColS) is a membrane-bound receptor histidine kinase that senses extracytoplasmic iron limitation in the periplasm, while its cognate response regulator, VgrR (ColR), detects intracellular iron excess. Under iron-depleted conditions, dissociation of Fe3+ from the periplasmic sensor region of VgrS activates the VgrS autophosphorylation and subsequent phosphotransfer to VgrR, an OmpR-family transcription factor that regulates bacterial responses to take up iron. VgrR-VgrS regulon and the consensus DNA binding motif of the transcription factor VgrR were dissected by comparative proteomic and ChIP-seq analyses, which revealed that in reacting to iron-depleted environments, VgrR directly or indirectly controls the expressions of hundreds of genes that are involved in various physiological cascades, especially those associated with iron-uptake. Among them, we demonstrated that the phosphorylated VgrR tightly represses the transcription of a special TonB-dependent receptor gene, tdvA. This regulation is a critical prerequisite for efficient iron uptake and bacterial virulence since activation of tdvA transcription is detrimental to these processes. When the intracellular iron accumulates, the VgrR-Fe2+ interaction dissociates not only the binding between VgrR and the tdvA promoter, but also the interaction between VgrR and VgrS. This relieves the repression in tdvA transcription to impede continuous iron uptake and avoids possible toxic effects of excessive iron accumulation. Our results revealed a signaling system that directly senses both extracytoplasmic and intracellular iron to modulate bacterial iron homeostasis.

Selective Visualization of the Endogenous Peroxynitrite in an Inflamed Mouse Model by a Mitochondria-Targetable Two-Photon Ratiometric Fluorescent Probe.

Peroxynitrite (ONOO(-)) is a kind of reactive oxygen species (ROS) with super activity of oxidization and nitration, and overproduction of ONOO(-) is associated with pathogenesis of many diseases. Thus, accurate detection of ONOO(-) with high sensitivity and selectivity is imperative for elucidating its functions in health or disease states. Herein we for the first time present a new two-photon ratiometric fluorescent ONOO(-) probe (MITO-CC) based on FRET mechanism by combining rational design strategy and dye-screening approach. MITO-CC, with fast response rate (within 20 s), excellent sensitivity (detection limit = 11.30 nM) and outstanding selectivity toward ONOO(-), was successfully applied to ratiometric detection of endogenous ONOO(-) produced by HepG2/RAW264.7 cells and further employed for imaging oxidative stress in an inflamed mouse model. Therefore, probe MITO-CC could be a potential biological tool to explore the roles of ONOO(-) under different physiological and pathological settings.

PEGylated [email protected] Nanodendrites as Novel Theranostic Agents for Computed Tomography Imaging and Photothermal/Radiation Synergistic Therapy.

The integration of photothermal therapy (PTT) with radiation therapy (RT) in a single nanoscale platform is believed to have considerable potential for cancer therapy. In this work, the rationally designed PEGylated [email protected] nanodendrites (NDs) have been developed as a novel X-ray computed tomography (CT) and PTT/RT enhanced theranostic agent for cancer therapy. The absorption of [email protected] NDs was turned to the near-infrared region with the growth of Pt nanobranches and thus enhances the efficacy of PTT. Furthermore, because of the high atomic number (high Z) of Au as well as Pt, [email protected] NDs significantly enhanced lethal effects of RT by inducing a highly localized radiation dose within cancer cells. More importantly, the combination of [email protected] ND-enhanced RT with PTT suppressed cancer cell growth more efficiently than that RT or PTT alone did, indicating a synergistic effect. Meanwhile, the [email protected] NDs also possess significant CT imaging signal enhancement that has the potential to guide PTT/RT for cancers. The integrated strategy significantly improved CT and PTT/RT of cancer cells with mild laser and radiation. Because of these advantages, [email protected] NDs have become appealing and effective agents for cancer theranostic.

Factors Associated with HIV Testing Among Participants from Substance Use Disorder Treatment Programs in the US: A Machine Learning Approach.

HIV testing is the foundation for consolidated HIV treatment and prevention. In this study, we aim to discover the most relevant variables for predicting HIV testing uptake among substance users in substance use disorder treatment programs by applying random forest (RF), a robust multivariate statistical learning method. We also provide a descriptive introduction to this method for those who are unfamiliar with it. We used data from the National Institute on Drug Abuse Clinical Trials Network HIV testing and counseling study (CTN-0032). A total of 1281 HIV-negative or status unknown participants from 12 US community-based substance use disorder treatment programs were included and were randomized into three HIV testing and counseling treatment groups. The a priori primary outcome was self-reported receipt of HIV test results. Classification accuracy of RF was compared to logistic regression, a standard statistical approach for binary outcomes. Variable importance measures for the RF model were used to select the most relevant variables. RF based models produced much higher classification accuracy than those based on logistic regression. Treatment group is the most important predictor among all covariates, with a variable importance index of 12.9%. RF variable importance revealed that several types of condomless sex behaviors, condom use self-efficacy and attitudes towards condom use, and level of depression are the most important predictors of receipt of HIV testing results. There is a non-linear negative relationship between count of condomless sex acts and the receipt of HIV testing. In conclusion, RF seems promising in discovering important factors related to HIV testing uptake among large numbers of predictors and should be encouraged in future HIV prevention and treatment research and intervention program evaluations.

siRNA-mediated suppression of collagen type iv alpha 2 (COL4A2) mRNA inhibits triple-negative breast cancer cell proliferation and migration.

Triple-negative breast cancer (TNBC) is more aggressive than other breast cancer subtypes. Collagen type IV alpha 2 (COL4A2), a major component of the basement membrane, dynamically influences a wide range of biological processes, including cancer pathogenesis and progression. This study evaluated the effects of COL4A2 siRNA delivered by lentiviral vector to TNBC cells. COL4A2 siRNA lenti-viral vector was constructed and transfected into MDA-MB-231 and MDA-MB-468 cells. The COL4A2 mRNA levels were quantified by RT-PCR. CCK8 assay was performed to evaluate cell proliferation and migration. Cell migration and invasion assays were carried out using Transwell. Cell apoptosis and cell cycle analyses were conducted using flow cytometric approach. We found that COL4A2 mRNA levels were significantly down-regulated in MDA-MB-231 and MDA-MB-468 cells after transfection with COL4A2 siRNA. Furthermore, cell migration and proliferation were significantly decreased and the cell cycle was arrested. Our results indicated that COL4A2 siRNA significantly suppresses the migration and proliferation of TNBC cells. Inhibition of COL4A2 may be a new target for the prevention and treatment of TNBC.

Substance use and STI acquisition: Secondary analysis from the AWARE study.

Sexually transmitted infections (STIs) are significant public health and financial burdens in the United States. This manuscript examines the relationship between substance use and prevalent and incident STIs in HIV-negative adult patients at STI clinics.

The shape effect of magnetic mesoporous silica nanoparticles on endocytosis, biocompatibility and biodistribution.

Although the aspect ratio (AR) play a crucial role in determining biological effects of homogeneous nanomaterials, studies available concerning how the shape contributes to biological effect of heterogeneous nanomaterials is limited. To systematically clarify the shape influence on the endocytosis, biocompatibility and biodistribution of magnetic mesoporous silica nanoparticles (M-MSNPs), three FITC-labeled M-MSNPs with different aspect ratio (AR=1, 2, and 4) were specifically designed and constructed through altering the ratios of CTAB/TEOS in a modified so-gel method. We have demonstrated that long-rod M-MSNP2 possessed higher intracellular internalization amount than the short-rod M-MSNP1 and the sphere-like M-MSNP0 in both cancer cells and normal cells due to the difference in the endocytosis pathways. However, there are no significant shape effects on biocompatibility including cytotoxicity and hemolytic rate. Moreover, biodistribution in HepG2 tumor-bearing mice showed that M-MSNPs administrated intravenously were mainly presented in reticuloendothelial system (RES) organs including liver, spleen and kidney. In particular, sphere-like M-MSNP0 were easily trapped in the liver, while long-rod M-MSP2 exhibited more retention in the spleen. It is worth noting that rod-like M-MSNPs are preferentially accumulated in tumor sites than sphere-like M-MSNPs, indicating an improved drug delivery efficacy in cancer therapy. Our findings may provide useful data for deeply understanding the interaction between the different shapes and biological behavior of M-MSNPs, which is expected to give rise to a new generation of heterogeneous M-MSNPs with significantly enhanced efficacy and safety for the cancer theranostics.