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Liver cancer is one of the most common malignancies that is difficult to treat due to late diagnosis and chemo-resistance. In the present study, we developed and validated a cell based split nanoLuc biosensor to monitor the Apaf1-Apaf1 interactions in response to apoptosis-inducing drugs such as cisplatin. We showed that the activity of split nanoLuc is reconstituted only in response to apoptotic inducer, cisplatin and in a dose-dependent manner. Apaf1 mutants which were unable to oligomerize failed to recover nanoLuc activity while constitutively active variant increased the nanoLuc activity. Generation of Apaf1 knockout HepG2 and treatment with cisplatin showed dramatic reduction in cell death suggesting that cisplatin mainly targets liver cancer cells through apoptosis. As the natural products are potent sources of compounds for adjuvant therapy, we screened a collection of natural products and identified lentinan as an inducer of apoptosome formation, a key step for induction of apoptosis. Lentinan is a polysaccharide with antitumor, pro-apoptotic properties that functions with poorly understood mechanisms. Lentinan was shown to have cytotoxic effects with the IC50 of 650 μM. Sub-lethal lentinan concentration doubled the nanoLuc activity when co-treated with cisplatin. We also showed that lentinan hugely reduced the dose of cisplatin to induce certain amount of death and that lentinan co-treatment with cisplatin enhanced the Apaf1 transcription in HepG2 cells while lentinan or cisplatin alone failed to alter the transcription. In addition, lentinan and cisplatin co-treatment induced mitochondrial depolarization. This suggested that lentinan combinatorial therapy with cisplatin engaged a different signalling pathway to kill the liver cancer cells and that adjuvant therapy with lentinan can reduce the dose of cisplatin and thus reduce the possibility of chemo-resistance.

The fundamental structure-biofunction relationship of calcium phosphates (CaPs) remains unclear despite their clinical successes as important biomaterials. Herein, a series of CaP coatings with gradual change of topography and crystallinity is constructed by electrochemical deposition, and the roles of the two basic physicochemical properties are scrutinized for further understanding the mechanism behind the superior bioactivities of octacalcium phosphate (OCP). We observe a distinct modulation on cell proliferation on the prepared CaP coatings for different cells. The magnitude of the modulation seems to depend on the cellular size, and the effect is attributed mainly to the microstructure of the coatings. On the other hand, the crystallinity manifests its significance for the osteogenic property of the OCP coatings. Further transmission electron microscopy analysis and density functional theory calculations reveal a surface rich in HPO42- for the high-crystalline OCP nanocrystals. The results highlight that the nanocrystal surface properties of the OCP coatings, including the periodic structure and the HPO42- composition, may play significant roles surpassing the ion release effect in determining its osteogenic property, probably via surface spatial and/or chemical recognitions. The present findings shed light on the fundamental understanding of the structure-biofunction relationship for CaP biomaterials.

Biomass-based carbon aerogels have attracted significant research attention due to the wide range of raw material, low cost, and environmental friendliness. In this study, green and sustainable carbon aerogels have been prepared using starch as raw material. Potassium chloride and potassium carbonate have been selected as template and activator. Due to the joint action of potassium chloride and potassium carbonate, the starch-based carbon aerogels exhibit a specific surface area of 2367 m2 g-1 with ant-hole-like 3D network pore structure. The starch-based carbon aerogels have been further employed as the electrode material for supercapacitors. The specific capacitance of the carbon aerogels is 292.3 and 245 F g-1 at current densities of 1.0 and 10 A g-1, respectively. In addition, the starch-based carbon aerogels demonstrate excellent sorption ability for oil and organics as well as insignificant sorption ability for H2O, thus, indicating their potential use as optimal oil-water separation material.

Background: Current understanding of amyloid-β protein (Aβ) aggregation and toxicity provides an extensive list of drugs for treating Alzheimer’s disease (AD); however, one of the most promising strategies for its treatment has been tri-peptides. Objective: The aim of this study is to examine those tri-peptides, such as Arg-Arg-Try (RRY), which have the potential of Aβ1–42 aggregating inhibition and Aβ clearance. Methods: In the present study, in silico, in vitro, and in vivo studies were integrated for screening tri-peptides binding to Aβ, then evaluating its inhibition of aggregation of Aβ, and finally its rescuing cognitive deficit. Results: In the in silico simulations, molecular docking and molecular dynamics determined that seven top-ranking tri-peptides could bind to Aβ1–42 and form stable complexes. Circular dichroism, ThT assay, and transmission electron microscope indicated the seven tri-peptides might inhibit the aggregation of Aβ1–42 in vitro. In the in vivo studies, Morris water maze, ELISA, and Diolistic staining were used, and data showed that RRY was capable of rescuing the Aβ1–42-induced cognitive deficit, reducing the Aβ1–42 load and increasing the dendritic spines in the transgenic mouse model. Conclusion: Such converging outcomes from three consecutive studies lead us to conclude that RRY is a preferred inhibitor of Aβ1–42 aggregation and treatment for Aβ-induced cognitive deficit.

Developing the catalytic activity and selectivity of palladium (Pd) catalysts for acetylene hydrogenation is key importance in the chemical industry and remains a challenge to this day. Here, the catalytic performance of Pd catalysts are influenced by the Pd electronic structure, in turn, controlled by different heteroatom doped support. Different catalysts are prepared by ionic liquids (ILs) with different precursors, and catalytic activity of selective hydrogenation of acetylene was investigated. The Pd/NC catalyst exhibits extraordinary conversion, selectivity and stable for the hydrogenation of acetylene (94.6% acetylene conversion with 91.3% selectivity to ethylene). This remarkable catalytic performance of Pd/NC is mainly linked to nitrogen-doped (N-doped) changes the electronic structure of Pd nanoparticles, ensures the rapid desorption of ethylene and prevents the formation of unnecessary ethane by over hydrogenation (demonstrated by XPS and DFT). Our strategy of controlling the electronic structure of Pd can be widely used in the reactions that change the micro electrochemical properties of active metals. The selective hydrogenation of acetylene to ethylene over Pd/NC with excellent conversion and selectivity is investigated. The doping of nitrogen leads to the unique electronic structure of Pd on the Pd/NC catalyst, which influences the adsorption of ethylene and acetylene, thus promoting its catalytic activity.

Supercapacitors are promising for high power application in the recent years. In particular, the conversion of simple and available carbon materials into economic and high performance electrical devices receives excellent scientific and technological interest. This paper reports a one-step strategy for synthesizing hierarchical porous carbon derived from phenolic resin (PR), which is then used to configure electric double-layer capacitors (EDLCs). Here, a carbon material with a flexible porous structure, large specific surface area, and high graphitization degree is prepared using potassium ferrate (K2FeO4) to catalytically activate PR and to realize synchronous carbonization and graphitization. This method overcomes the disadvantage of time-consuming, high-cost, and environmentally unfriendly. In addition, the as-prepared carbon material has a high specific surface area (1086 m2 g−1) and a large pore size (3.07 nm), which can increase the transfer rate of electrolyte ions. The specific capacitance of the obtained electrode material is 315 F g−1 at 1.0 A g−1, and the optimized electrode material has an ultra-long cycle lifetime (capacitance retention rate is 96.3% after 10,000 cycles). Thus, the hierarchically Fe-doped porous carbon material derived from PR material is expected to realize high rate capacitance for supercapacitor applications.

12 páginas, 5 figuras, 2 tablas, Purpose: A diet high in fat and ethanol often results in chronic metabolic disorder, hepatic steatosis, and liver inflammation. Constitutive hepatic cyclooxygenase-2 (COX-2) expression could protect from high fat-induced metabolism disturbance in a murine model. In this study, we explored the influence of hCOX-2 transgenic [TG] to high fat with ethanol-induced metabolic disorder and liver injury using a mouse animal model. Methods: 12-week-old male hepatic hCOX-2 transgenic (TG) or wild type mice (WT) were fed either a high fat and ethanol liquid diet (HF+Eth) or a regular control diet (RCD) for 5 weeks (four groups: RCD/WT, RCD/TG; HF+Eth/TG, HF+Eth/WT). We assessed metabolic biomarkers, cytokine profiles, histomorphology, and gene expression to study the impact of persistent hepatic COX-2 expression on diet-induced liver injury. Results: In the HF+Eth diet, constitutively hepatic human COX-2 expression protects mice from body weight gain and white adipose tissue accumulation, accompanied by improved IPGTT response, serum triglyceride/cholesterol levels, and lower levels of serum and liver inflammatory cytokines. Histologically, hCOX-2 mice showed decreased hepatic lipid droplets accumulation, decreased hepatocyte ballooning, and improved steatosis scores. Hepatic hCOX-2 overexpression enhanced AKT insulin signaling and increased fatty acid synthesis in both RCD and HF+Eth diet groups. The anti-lipogenic effect of hCOX-2 TG in the HF+Eth diet animals was mediated by increasing lipid disposal through enhanced β-oxidation via elevations in the expression of PPARα and PPARγ, and increased hepatic autophagy as assessed by the ratio of autophagy markers LC3 II/I in hepatic tissue. Various protein acetylation pathway components, including HAT, HDAC1, SIRT1, and SNAIL1, were modulated in hCOX-2 TG mice in either RCD or HF+Eth diet. Conclusions: Hepatic human COX-2 expression protected mice from the metabolic disorder and liver injury induced by a high fat and ethanol diet by enhancing hepatic lipid expenditure. Epigenetic reprogramming of diverse metabolic genes might be involved in the anti-lipogenic effect of COX-2., This work was supported by NIH grant (K08AA024895 to Q.C), Department Chair Research Fund of UMB (Q.C), GE Healthcare/ RSNA Research Resident Grant (#RR1250 to Q.C), Innovation Seed Grant of UMB (Q.C), Ministry of Economy and Competitiveness (MINECO, Spain. SAF2016-75004-R to P.M.S. and M.C) and NIH grant (1R01AA028035-01 to L.P).

With the advances in instrumentation and sampling techniques, there is an explosive growth of data from molecular and cellular samples. The call to extract more information from the large data sets has greatly challenged the conventional chemometrics method. Deep learning, which utilizes very large data sets for finding hidden features therein and for making accurate predictions for a wide range of applications, has been applied in an unbelievable pace in biospectroscopy and biospectral imaging in the recent 3 years. In this Feature, we first introduce the background and basic knowledge of deep learning. We then focus on the emerging applications of deep learning in the data preprocessing, feature detection, and modeling of the biological samples for spectral analysis and spectroscopic imaging. Finally, we highlight the challenges and limitations in deep learning and the outlook for future directions.

Traditional electrochemical measurements based on either current or potential responses only present the average contribution of an entire electrode's surface. Here, we present an electrochemical photothermal reflectance microscope (EPRM) in which a potential-dependent nonlinear photothermal signal is exploited to map an electrochemical process with sub-micron spatial resolution. By using EPRM, we are able to monitor the photothermal signal of a Pt electrode during the electrochemical reaction at an imaging speed of 0.3 s per frame. The potential-dependent photothermal signal, which is sensitive to the free electron density, clearly revealed the evolution of surface species on the Pt surface. Our results agreed well with the reported spectroelectrochemical techniques under similar conditions but with a much faster imaging speed. We further mapped the potential oscillation during the oxidation of formic acid on the Pt surface. The photothermal images from the Pt electrode well matched the potential change. This technique opens new prospects for real-time imaging of surface chemical reaction to reveal the heterogeneity of electrochemical reactivity, which enables broad applications to the study of catalysis, energy storage, and light harvest systems., The potential-dependent photothermal signal, which is sensitive to the free electron density, map the evolution of surface species on the electrode in real time.

Molybdenum disulfide (MoS2) has been regarded as a promising anode material in the field of sodium-ion batteries (SIBs), with the advantages of high theoretical capacity and large interlayer spacings. Unfortunately, its intrinsic poor electrical conductivity and large volume changes during the sodiation/desodiation reactions still limit its practical application. To deal with this shortcoming, we built MoS2 nanosheet/multiwalled carbon nanotube (denoted as MoS2-MSs/MWCNTs) composites with a three-dimensional (3D) micro-spherical structure, assembled in situ from MoS2 nanosheets. These nanosheets are connected to each other by the MWCNTs network, which provides a highly conductive pathway for electrons/ions through interparticle and intraparticle interfaces, accelerating charge transfer and ion diffusion capabilities. More importantly, the carbon network can boost electrical conductivity and relieve structural strain. Consequently, the as-prepared MoS2-MSs/MWCNTs composite presents a high reversible specific capacity of 519 mA h g−1 at 0.1 A g−1 after 100 cycles with a capacity retention of 94.4% and excellent rate performance (227 mA h g−1 at 10 A g−1). Outstanding cycling stability was also achieved (327.1 mA h g−1 over 1000 cycles at 2 A g−1) and was characterized by scanning electron microscopy (SEM) analysis. Our findings provide a simple and effective strategy to explore anode materials with advanced sodium storage properties.

Phytochemical investigation on the ethanol extract of green walnut husks (Juglans mandshurica Maxim.) led to the isolation of two previously unknown compounds, including a macrolide compound (13S)-8-oxo-(9E, 11E)-8-oxo-octadeca-9,11-dien-13-olide (1) and a diarylheptanoid compound 1-(3'-methoxy-4'-hydroxyphenyl)-7-(3″,4″-dimethoxyphenyl)heptan-3-one (2), together with 19 known compounds. The structures of these 21 compounds were elucidated by extensive analyses of NMR and HR-MS data, and the basis of spectroscopic analysis.

Surface-enhanced Raman spectroscopy (SERS) is a powerful tool to monitor various interfacial behaviors providing molecular level information with high spatial and temporal resolutions. However, it is a challenge to obtain SERS spectra with high quality for analytes having a weak binding affinity with plasmonic nanostructures due to the short dwell time of the analyte on the surface. Here, we employed dynamic SERS, an acquisition method consisting of the rapid acquisition of a series of consecutive SERS spectra, to study the adsorption/desorption behavior of R6G on Ag surfaces. We demonstrated that the signal-noise ratio of SERS spectra of mobile molecules can be improved by dynamic SERS even when the acquisition time cannot catch up with the diffusion time of the molecule. More interestingly, we captured the neutral R6G0 state (spectroscopically different from the dominated positive R6G+ state) of R6G at the single-molecule level, which is a rare molecule event hardly detectable by traditional SERS. Dynamic SERS provides near real-time molecular vibrational information with an improved signal-noise ratio, which opens a new avenue to capture metastable or rare molecule events for the comprehensive understanding of interfacial processes related to catalysis and life science.

Mutations of the CYP17A1 gene could cause complete or partial and combined or isolated 17α-hydroxylase/17,20-lyase deficiency (17OHD), which is characterized by hypertension, hypokalemia, and abnormal development of the genitalia. Most of the mutations are located in the coding sequence, and very few are located in the intronic region. The aim of this study is to investigate the novel intronic CYP17A1 mutation and its possible influence on phenotype. A 30-year-old Chinese female patient (46, XY) was referred to our Urology Department for severe hypertension, hypokalemia and a right adrenal mass. Physical examination revealed a hypertrophic clitoris and blind-ending vagina. Hormone analysis exhibited increased concentrations of ACTH and low levels of cortisol and sexual steroids. Mutation analysis revealed compound heterozygous CYP17A1 mutations, with c.1072C T (p.Arg358*) in one allele and a novel intronic splicing mutation (c.970-1G A) in another allele. Bioinformatics software predicted that the novel mutation may activate a cryptic splice site, shifting the reading frame and introducing a premature stop codon. In conclusion, we discovered a novel splicing mutation of the CYP17A1 gene in a Chinese patient with 17OHD. Our study extended the CYP17A1 mutation spectrum and provided valuable information for patient management and genetic counseling.

In surface-enhanced Raman spectra, vibrational peaks are superimposed on a background continuum, which is known as one major experimental anomaly. This is problematic in assessing vibrational information especially in the low Raman-shift region below 200 cm−1, where the background signals dominate. Herein, we present a rigorous comparison of normal Raman and surface-enhanced Raman spectra for atomically defined surfaces of Au(111) or Au(100) with and without molecular adsorbates. It is clearly shown that the origin of the background continuum is well explained by a local field enhancement of electronic Raman scattering in the conduction band of Au. In the low Raman-shift region, electronic Raman scattering gains additional intensity, probably due to a relaxation in the conservation of momentum rule through momentum transfer from surface roughness. Based on the mechanism for generation of the spectral background, we also present a practical method to extract electronic and vibrational information at the metal/dielectric interface from the measured raw spectra by reducing the thermal factor, the scattering efficiency factor and the Purcell factor over wide ranges in both the Stokes and the anti-Stokes branches. This method enables us not only to analyse concealed vibrational features in the low Raman-shift region but also to estimate more reliable local temperatures from surface-enhanced Raman spectra., Both electronic and vibrational information at the metal/dielectric interface were explicitly extracted from surface-enhanced Raman spectra.

Plasmonic sensors are promising for ultrasensitive chemical and biological analysis. However, there are increasing experimental findings that cannot be well addressed by theoretical calculations, including the nonlinear dependence of the plasmonic peak wavelength on the refractive index (RI) and the ultrahigh sensitivity beyond the theoretical limit. The gap between experiments and theoretical calculations is that the bulk RI (BRI) used for calculation could be different from the interfacial RI (IRI) determining the electromagnetic response as a result of the interaction of molecules with the surface. But there is still no method to determine the IRI. Herein, we quantitatively determine the IRI by disentangling the surface RI (SRI) from the BRI. The obtained IRI can be directly applied in theoretical calculations to reliably reflect the experimental response and rigorously guide the design of plasmonic sensors. Moreover, it can be a fundamental dimensionless number to describe the light-matter interaction at the interface.

The rational design and applications of plasmon-mediated chemical reactions (PMCRs) are fundamentally determined by an understanding of photon-electron-molecule interactions. However, the current understanding of the PMCR of plasmon-decayed hot electron-mediated reactions remains implicit, since there has not been a single measurement of both hot-electron transfer and molecular transformation following photon excitation. Therefore, we invented a method called microphotoelectrochemical surface-enhanced Raman spectroscopy (μPEC-SERS) that uses an ultramicroelectrode (UME) whose dimensions match those of the focused laser spot. This system can simultaneously record the photocurrent (∼picoamps) of hot-electron transfer with a high signal-to-noise ratio and the SERS spectra of a molecular reaction in the same electrode area. The responses of the photocurrent and SERS spectra to laser illumination can correlate the surface reaction activated by hot electrons with the SERS spectral changes. A typical PMCR of

It is widely accepted that the sensitivity of surface-enhanced Raman spectroscopy (SERS) is mainly manipulated by the electromagnetic enhancement mechanism (EM). Herein, we determined that the direct adsorption of the target on the SERS active surface is vital as well, through the systematic investigation of the SERS behavior of three positively charged molecules on negatively charged gold (Au) or silver nanoparticles (Ag NPs). Facilitated by the synergistic effect among the molecule, the surface, and the specific adsorbed halide ions (Cl-, Br-, and I-), high SERS sensitivity for trace target was realized, which was mainly from the directly adsorbed molecules. Noteworthy, little contribution from the nondirectly adsorbed molecules was discernible, although the EM enhancement was at the same level for these two surface species dwelling within a distance significantly less than 1 nm from the surface. Further, the related strategy for trace detection sheds light on how to realize sensitive SERS detection of new targets.

The construction of a donor–acceptor (D–A) organic photocatalyst is a facile approach to improve photocatalytic performances because of the efficient separation of light-generated electrons and holes. The rational design of molecular skeletons and the selection of functional groups are of great importance to an organic photocatalyst with a high photocatalytic activity. Herein, we designed two D–A conjugated microporous polymers (CMPs) with different substituent groups of fluorine atoms and methyl groups on the acceptor unit of dibenzothiophene-dioxide (DBTDO). This study reveals that the introduction of fluorine atoms with strong electron-withdrawing ability onto the acceptor unit can further enhance the electron acceptability of the DBTDO unit, leading to the efficient separation of light-generated electrons and holes, while the introduction of methyl with electron-pushing ability decreases the electron acceptability of the acceptor unit, suppressing the separation of light-generated charge carriers. As a result, the polymer PyDF with fluorine atoms shows an excellent photocatalytic activity compared to PyDM with methyl groups. Under UV/Vis light irradiation, PyDF shows an attractive photocatalytic hydrogen generation rate of 18.93 mmol h−1 g−1, which is much higher than that of PyDM (3.96 mmol h−1 g−1), implying that the functional group acts as a vital role in the catalytic activity of polymer semiconducting photocatalysts.

Surface-enhanced Raman spectroscopy (SERS) is a vibrational spectroscopy technique with sensitivity down to the single molecule level that provides fine molecular fingerprints, allowing for direct identification of target analytes. Extensive theoretical and experimental research, together with continuous development of nanotechnology, has significantly broadened the scope of SERS and made it a hot research field in chemistry, physics, materials, biomedicine, and so on. However, SERS has not been developed into a routine analytical technique, and continuous efforts have been made to address the problems preventing its real-world application. The present minireview focuses on analyzing current and potential strategies to tackle problems and realize the SERS performance necessary for translation to practical applications., Surface-enhanced Raman spectroscopy (SERS) is a vibrational spectroscopy technique with sensitivity down to the single molecule level that provides fine molecular fingerprints, allowing for direct identification of target analytes.

Phytochemical investigation on the concentrate of Huangjing wine, resulted in the isolation of three new tyrosol derivatives 4′′′-hydroxyphenethyl 2-(R)-hydroxy-3-phenylpropionate (1), 4′′′-hydroxyphenethyl(4′-hydroxy-3′-methoxyphenyl)propionate (2) and 4′′-hydroxyphenethyl ethyl succinate (3), together with 5 known compounds, ferulic acid (4), L-phenyllactic acid (5), hydroxytyrosol (6), dihydroferulic acid (7), cyclo(L-Pro-D-Tyr) (8). Their structures were elucidated using spectroscopic analysis and by comparison with the literature data. All compounds displayed antioxidant effect in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical. Among them, the new compound 2 exhibited obvious antioxidant effect, and new compounds 1 and 3 exhibited medium antioxidant effect.

Fast acquisition of Raman images is essential for accurately characterizing the analytes' information. In this paper, we developed a collaborative low-rank matrix approximation method for fast hyperspectral Raman imaging as well as tip-enhanced Raman spectroscopy (TERS) imaging. This method combines high signal-to-noise ratio (SNR) data with the target data to perform collaborative singular value decomposition. The high-quality reference data can impose constraints on factorization, which will force its components to approximate the true signal or noise components. The simulation demonstrated that this method offers state-of-the-art signal extraction performance and, thus, can be used to accelerate data acquisition. Specifically, the results indicate that the CLRMA can largely decrease the root-mean-square error by 20.92-54.12% compared with the baseline method of our previous study. We then applied this method to the fast TERS imaging of a Au/Pd bimetallic surface and significantly decreased the integration time down to 0.1 s/pixel, which is about 10 times faster than that of conventional experiments. High-SNR TERS spectra and clear TERS images that are well consistent with scanning tunneling microscopy (STM) images can be obtained even under such a weak signal condition. We further applied this method to the fast Raman imaging of HeLa cells and obtained clear Raman images at a short integration time of 2 s/line, which is about 5 times faster than that of conventional experiments. This method offers a promising tool for TERS imaging as well as conventional Raman imaging where fast data acquisition is required.

Bin Ren,1,2,* Zhong-Chao Cai,1,* Xue-Jie Zhao,1 Lin-Song Li,1 Mei-Xia Zhao1 1Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan, 475004, People’s Republic of China; 2School of Mathematics and Statistics, Henan University, Jinming Campus, Kaifeng, 475004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mei-Xia ZhaoKey Laboratory of Natural Medicine and Immune Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan, 475004, People’s Republic of ChinaEmail zhaomeixia2011@henu.edu.cnPurpose: Gold nanoparticles (AuNPs) with good physical and biological properties are often used in medicine, diagnostics, food, and similar industries. This paper explored an AuNPs drug delivery system that had good target selectivity for folate-receptor overexpressing cells to induce apoptosis.Methods: A novel drug delivery system, Au@MPA-PEG-FA-PTX, was developed carrying paclitaxel (PTX) on folic acid (FA) and polyethylene glycol (PEG)-modified AuNPs. The nanomaterial was characterized by transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and ultraviolet-visible spectroscopy (UV-Vis). Also, the biological activity of the AuNPs drug delivery system was examined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in HL-7702, Hela, SMMC-7721, and HCT-116 cells. Furthermore, apoptotic activity using annexin V-FITC, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels was estimated by flow cytometry and fluorescence microscopy.Results: Au@MPA-PEG-FA-PTX exhibited a distinct core-shell structure with a controllable size of 28± 1 nm. Also, the AuNPs maintained good dispersion and spherical shape uniformity before and after modification. The MTT assay revealed good antitumor activity of the Au@MPA-PEG-FA-PTX against the Hela, SMMC-7721, and HCT-116 cells, while Au@MPA-PEG-FA-PTX produced better pharmacological effects than PTX in isolation. Further mechanistic investigation revealed that effective internalization of AuNPs by folate-receptor overexpressing cancer cells induced cell apoptosis through excessive production of intracellular ROS.Conclusion: The AuNPs drug delivery system showed good target selectivity for folate-receptor overexpressing cancer cells to induce target cell-specific apoptosis. These AuNPs may have great potential as theranostic agents such as in cancer.Keywords: gold nanoparticles, folic acid, paclitaxel, drug delivery system, apoptosis

To study the influences of curing period and sulfate concentration on the dynamic mechanical properties of cement soil, this study used a split Hopkinson pressure bar device. Impact tests were conducted on cement soil specimens with different curing periods and different sulfate concentrations. The relationships between the dynamic stress–strain, dynamic compressive strength, and absorption energy of these cement soil specimens were analyzed. The test results show that with continuous loading, cement soil specimens mainly experience an elastic stage, plastic stage, and failure stage, with increasing curing period and sulfate concentration, the dynamic compressive strength and absorption energy of cement soil specimens follow a trend of first increasing and then decreasing. The dynamic compressive strength and absorption energy of cement soil specimens reached maximum values at a curing period of 14 d and a Na2SO4 solution concentration of 9.0 g/L. Increasing the dynamic compressive strength and absorption energy can effectively improve the ability of cement soil specimens to resist damage. This paper provides a practical reference for the application of cement soil in dynamic environments.

Metallic nanostructures exhibit superior catalytic performance for diverse chemical reactions and the in-depth understanding of reaction mechanisms requires versatile characterization methods. Plasmon-enhanced Raman spectroscopy (PERS), including surface-enhanced Raman spectroscopy (SERS), shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS), and tip-enhanced Raman spectroscopy (TERS), appears as a powerful technique to characterize the Raman fingerprint information of surface species with high chemical sensitivity and spatial resolution. To expand the range of catalytic reactions studied by PERS, catalytically active metals are integrated with plasmonic metals to produce bifunctional metallic nanostructures. In this minireview, we discuss the recent advances in PERS techniques to probe the chemical reactions catalysed by bifunctional metallic nanostructures. First, we introduce different architectures of these dual-functionality nanostructures. We then highlight the recent works using PERS to investigate important catalytic reactions as well as the electronic and catalytic properties of these nanostructures. Finally, we provide some perspectives for future PERS studies in this field.

This article seeks to encourage the adoption of modern methods of surface analysis in teaching contexts by introducing the use of attenuated total reflection infrared spectroscopy (ATRIRS) in analysis of adsorption reactions at hydrous metal oxide thin films. The first experiment shows how outer-sphere adsorption of perchlorate ion is distinguished from inner-sphere adsorption of ethanedioate (oxalate) ion at TiO2 surfaces. The second experiment shows how the nature of adsorption of sulfate ion to iron oxide surfaces changes with pH. In the third experiment, the variation of the amount of benzene-1,2-diol (catechol) adsorbed to TiO2 with solution concentration enables an adsorption constant to be derived from the adsorption isotherm.

Two new 1, 8-naphthalimide-based fluorophore compounds, 4-piperazinyl-N-(4-Pyr-idinyl)-1, 8-naphthalimide (RB1) and 4-phenyl-N-(3-hydroxyphenyl)-1, 8-naphth- alimide (RB2) were synthesized via two-steps nucleophilic substitution reactions and Suzuki coupling reaction. The chemical structures of the title compounds were characterized by 1H NMR, 13C NMR, HRMS and FT-IR spectral analysis. Thermogravimetric analysis results show that the degradation temperatures of two compounds were about 300 °C. The single-crystal XRD analysis revealed that both RB1 and RB2 crystallize in the monoclinic P21/c (No. 14) space group, with lattice parameters of RB1 a = 15.3016(10), b = 15.4468(9), c = 7.1919(4) A, β = 95.384(2)°, V = 1692.38(18) A3, Z = 4 and RB2 a = 16.1990(3), b = 15.9460(3), c = 7.5870(15) A, β = 98.718(5)°, V = 1937.2(7) A3, Z = 4 respectively. Both crystals of two compounds have parallel offset stacking with extensive intermolecular interactions (hydrogen bond, C–H⋅⋅⋅π interaction), which are correspondence with the molecular packing of J-aggregation. The UV–vis and fluorescence properties of two compounds in different solvents were investigated, indicated that ICT characteristics of RB1 in organic solvents. Moreover, RB1 crystal can excite the strong green fluorescence with good thermal and optical stability qualifying it as a potential application in the fields of crystal luminescent functional materials.

Improving time resolution of Raman imaging is essential for the observation of dynamic processes involved in interfacial catalysis and biological systems. The crucial step is how to recognize and extract weak Raman signals overwhelmed in the strong noise under the low signal-to-noise ratio (SNR) condition. Here, by exploring the relationship between the SNR of a single Raman spectrum and the structural similarity (SSIM; the key parameter evaluating the image quality) of the whole image, we determined a semiempirical threshold with SNR = 0 dB for clear imaging for the first time. Therefore, we proposed one signal processing algorithm for fast Raman imaging by reconstructing the Raman spectrum with the aid of weak signal processing: extracting the reliable Raman signal of the target under the low SNR and then determining the suitable scanning time to obtain the Raman image with a trustworthy image quality. In the first step, fast Fourier transform (FFT), least squares, and 2-D median filter are sequentially applied to improve the SNR of each raw Raman spectrum. In the second step, a local SNR evaluation strategy is developed to predict image quality as well as the determination of clear imaging. The proposed method was successfully applied to the fast imaging of the cell under the low SNR condition.

Electrochemical tip-enhanced Raman spectroscopy (EC-TERS) appears as a promising in situ nanospectroscopic tool for characterization and understanding of the electrochemical interfacial processes at the nanometer scale and molecular level. However, the wide application of EC-TERS is hampered by its low sensitivity as a result of the optical path distortion due to the refractive index mismatch of the multilayer media (air, glass, and electrolyte). Here, we propose a new side-illumination EC-TERS setup by coupling a water immersion objective with a high numerical aperture to a scanning tunneling microscope scanning head customized with a large open space and a compact spectroelectrochemical cell. It not only effectively eliminates the optical distortion but also increases the sensitivity remarkably, which allows sensitive monitoring of the electrochemical redox processes of anthraquinone molecules. More importantly, EC-TERS is able to independently control the tip position and laser illumination position. By utilizing this feature, we reveal that the irreversible reduction reaction of anthraquinone observed in EC-TERS is induced by the synergistic effect of the negative potential and laser illumination rather than the localized surface plasmon. The highly improved sensitivity and the flexibility to control the tip and laser illumination position on the nanometer scale endows EC-TERS as an important tool for the fundamental understanding of the photo- or plasmon electrochemistry and the interfacial structure-activity relationship of important electrochemical systems.

Metal-organic frameworks (MOFs) derived porous carbons are promising electrode materials in electrochemical energy conversion and storage systems. However, the typical synthetic route of MOFs involving high temperature, organic solvent, massive energy consuming, and laboratory-scale production, hinders the realistic applications of MOFs serving as sacrificial templates for porous carbon. Herein, we demonstrate that highly crystalline MIL-100 (Fe) nanoparticles (MIL: Materials of Institute Lavoisier) can be synthesized in large scale with low cost under mild and green conditions. High-temperature pyrolysis of MIL-100(Fe) under argon atmosphere results in hollow carbon polyhedra (HCPs) featuring high degree of graphitization and hierarchical pore structures. The obtained HCPs are excellent electrode materials for electric double-layer capacitors (EDLCs), and show a specific capacitance of 214 F g−1 at current density 50 mA g−1. Moreover, the HCP-based supercapacitors can endure more than 5000 cycles without significant degradation of capacitance. The unique structure of HCPs, including hollow polyhedral shape, hierarchical micro/mesopore structures, and ultrathin layer of highly graphitized carbon shells, endows the superior performance of HCPs based EDLCs with specific capacitance and high rate capability.

Traditional carbon aerogels are made of resorcinol and formaldehyde. The synthesis process is cumbersome and the electrochemical performance is poor. Therefore, designing carbon aerogels with environmentally friendly raw materials, simple synthesis steps and good electrochemical performance is of great important. In this article, Cu-doped carbon aerogels (Cu-CA) were synthesized by one-step carbonization using sodium alginate (SA) as the carbon precursor. The specific surface area of the Cu-CA was 230.4 m2 g−1. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to obtained the microstructure of the Cu-CA. Cu nanoparticles (Cu NPs) were found to be embedded in the carbon aerogels homogeneously. The performances of the Cu-CA as supercapacitor electrode materials were investigated via cyclic voltammetry test (CV), galvanostatic charge-discharge test (GCD) and electrochemical impedance spectroscopy (EIS) using three-electrode system and the reference electrode was Hg/HgO electrode. Due to the metal-doped and unique hierarchical porous structure, the specific capacitance of the Cu-CA was up to 414.4 F g−1 with GCD (scan rate: 0.3 mV s−1), and the Cu-CA electrode showed good cycling stability. The excellent electrochemical performances of the Cu-CA indicate their great potential applications in the energy storage field.

Raman imaging is a promising technique that allows the spatial distribution of different components in the sample to be obtained using the molecular fingerprint information on individual species. However, the imaging speed is the bottleneck for the current Raman imaging methods to monitor the dynamic process of living cells. In this paper, we developed an artificial intelligence assisted fast Raman imaging method over the already fast line scan Raman imaging method. The reduced imaging time is realized by widening the slit and laser beam, and scanning the sample with a large scan step. The imaging quality is improved by a data-driven approach to train a deep convolutional neural network, which statistically learns to transform low-resolution images acquired at a high speed into high-resolution ones that previously were only possible with a low imaging speed. Accompanied with the improvement of the image resolution, the deteriorated spectral resolution as a consequence of a wide slit is also restored, thereby the fidelity of the spectral information is retained. The imaging time can be reduced to within 1 min, which is about five times faster than the state-of-the-art line scan Raman imaging techniques without sacrificing spectral and spatial resolution. We then demonstrated the reliability of the current method using fixed cells. We finally used the method to monitor the dynamic evolution process of living cells. Such an imaging speed opens a door to the label-free observation of cellular events with conventional Raman microscopy.

Speeding up antibiotic susceptibility testing (AST) is urgently needed in clincial settings to guide fast and tailored antibiotic prescription before treatment. It remains a big challenge to achieve a sample-to-AST answer within a half working day directly from a clinical sample. Here we develop single-cell Raman spectroscopy coupled with heavy water labeling (Raman-D

Cancer invasion and metastasis depend on accurate and rapid modulation of both chemical and mechanical activities. The S-nitrosylation (SNO) of membrane cytoskeletal cross-linker protein ezrin may regulate the malignant process in a tension-dependent manner. Methods: The level of nitrosylated ezrin in non-small cell lung cancer (NSCLC) tissues and A549 cell line were evaluated by biotin-switch assay. A few cysteine mutated plasmids of ezrin were used to identify active site for SNO. Newly designed ezrin or mutated-ezrin tension probes based on Forster resonance energy transfer (FRET) theory were applied to visually observe real-time tension changes. Cytoskeleton depolymerizing and motor molecular inhibiting experiments were performed to reveal the alternation of the mechanical property of ezrin after SNO. Transwell assays and xenograft mouse model were used to assess aggressiveness of A549 cells in different groups. Fluorescent staining was also applied to examine cellular location and structures. Results: High inducible nitric oxide synthase (iNOS) levels were observed to induce ezrin-SNO, and then promote malignant behaviors of NSCLC cells both in vitro and in vivo. Cys117 was identified as the only active site for ezrin-SNO. Meanwhile, an increased level of ezrin tension was observed after iNOS-induced SNO. Enhanced ezrin tension was positively correlated with aggressiveness of NSCLC. Moreover, Microfilament (MF) forces instead of microtubule (MT) forces played dominant roles in modulating ezrin tension, especially after ezrin nitrosylation. Conclusion: This study revealed a SNO-associated mechanism underlying the mechanical tension of ezrin. Ezrin-SNO promotes NSCLC cells invasion and metastasis through facilitating mechanical transduction from the cytoskeleton to the membrane. These studies implicate the therapeutic potential by targeting ezrin in the inhibition NSCLC invasion and metastasis.

Novel octahedron-like hybrids of highly graphitized carbon dopants and Fe2O3 (C-Fe2O3-2) were prepared via a simple one-pot annealing method. The morphology and level of graphitization of the carbon dopant in the Fe-based materials could be controlled by poly(vinyl pyrrolidone) (PVP). When using C-Fe2O3-2 as the catalyst in the heterogeneous Fenton-like reaction of methylene blue (MB) degradation, 96% of MB was removed within 420 min in the presence of H2O2. Furthermore, the activity of the carbon-doped Fe2O3 remained nearly constant over five cycles, indicating the long-term catalytic durability and recyclability of the catalyst. The large surface area and the synergistic effect between Fe2O3 and the highly graphitized carbon dopant in C-Fe2O3-2 are considered to be responsible for the enhanced Fenton-like performance.

Boron and nitrogen co-doped reduced graphene oxide (BN-rGO) materials were prepared via a facile dielectric barrier discharge plasma treatment method. X-ray photoelectron spectroscopy results demonstrated that the boron content in the boron-doped rGO (B-rGO) and BN-rGO is 1.21 at.% and 1.41 at.%, while the nitrogen content in the nitrogen-doped rGO (N-rGO) and BN-rGO is 2.12 at.% and 2.69 at.%, respectively. The doping of heteroatoms significantly improves the capacitance of the as-synthesized materials, giving BN-rGO a highly enhanced capacitance of 350 F g−1 at a current density of 0.5 A g−1, which is 2.36, 1.46 and 1.21 times higher than that of rGO, B-rGO or N-rGO, respectively.

Carbon aerogels with excellent conductive characteristics and high specific capacitance have attracted more and more interests for next-generation energy storage applications. Three-dimensional interconnected Mn2O3/carbon aerogel supercapacitor electrodes are prepared by a novel doping method using MnO2 coordinated by N, N-dimethylmethanamide (DMF). The coordinative MnO2 (DMF/MnO2) plays a key role in the sol-gel process of resorcinol and formaldehyde. The doped carbon aerogels exhibits a high specific surface area of 859 m2 g−1 and a good pore-size distribution of 10–15 nm. All of the doped carbon aerogels exhibit higher specific capacitance than pure carbon aerogels, and the highest specific capacitance (170 F g−1), at current density of 1.0 A g−1, is obtained in Mn–CA–5% when 5 mol% DMF/MnO2 is added to the precursor solution. The specific capacitance is as high as 100 F g−1, at current density of 10.0 A g−1, and 97% of initial capacitance is retained over 1000 cycles at a current density of 5.0 A g−1. The doped carbon aerogels exhibits a high coulombic efficiency (up to 99.8%) and a good rate capability. The corresponding result is due to the novel doping method of DMF/MnO2 addition.

Electrochemical interfaces determine the performance of electrochemical devices, including energy-related systems. An in-depth understanding of the heterogeneous interfaces requires in situ techniques with high sensitivity and high temporal and spatial resolution. We develop here an electrochemical reflective absorption microscope (EC-RAM) by using the absorption signals of reacting species with a reasonably good spatial resolution and high sensitivity. We systematically study the response of absorbance ( A) and its derivative, i.e. d A/d t, at different positions of the electrode surface and at electrodes with different sizes (50 μm, 500 μm, and 2 mm) both experimentally and theoretically. We find that the derivative cyclic voltabsorptometry (DCVA) frequently used to obtain the local current response in conventional electrochemical optical microscopy techniques is only applicable to reactions of surface species or solution species under linear diffusion control. For processes when the radial diffusion cannot be ignored, as in the case of a microelectrode or the edge of a large electrode, the DCVA curves show distinct diffusion behaviors for the electroactive species in different regions of the electrode, which cannot be directly related to the CV curves. When the radial diffusion dominates the reaction, CVA curves follow the same shape as the CV curves. The developed EC-RAM technique can be applied to extract in situ the local response of an electrochemical system during the dynamic reaction processes.

Breast cancer stem cells (BCSCs) are essential for cancer growth, metastasis and recurrence. The regulatory mechanisms of BCSC interactions with the vascular niche within the tumor microenvironment (TME) and their self-renewal are currently under extensive investigation. We have demonstrated the existence of an arteriolar niche in the TME of human BC tissues. Intriguingly, BCSCs tend to be enriched within the arteriolar niche in human estrogen receptor positive (ER+) BC and bi-directionally interact with arteriolar endothelial cells (ECs). Mechanistically, this interaction is driven by the lysophosphatidic acid (LPA)/protein kinase D (PKD-1) signaling pathway, which promotes both arteriolar differentiation of ECs and self-renewal of CSCs likely via differential regulation of CD36 transcription. This study indicates that CSCs may enjoy blood perfusion to maintain their stemness features. Targeting the LPA/PKD-1 -CD36 signaling pathway may have therapeutic potential to curb tumor progression by disrupting the arteriolar niche and effectively eliminating CSCs., Jiang, Guo, Hao et al. investigate the role of the tumour microenvironment in breast cancer stem cell regulation and identify an arteriolar niche in which BCSCs tended to be enriched in human estrogen receptor positive breast cancer. Here, BCSCs are found to interact with arteriolar endothelial cells through LPA/PKD-1 signalling-mediated arteriolar differentiation of ECs and self-renewal of BCSCs.

Juvenile hormone (JH) plays vital roles in insect reproduction, development, and in many aspects of physiology. JH primarily acts at the gene-regulatory level through interaction with an intracellular receptor (JHR), a ligand-activated complex of transcription factors consisting of the JH-binding protein Methoprene-tolerant (MET) and its partner Taiman (TAI). Initial studies indicated significance of post-transcriptional phosphorylation, subunit assembly, and nucleocytoplasmic transport of JHR in JH signaling. However, our knowledge of JHR regulation at the protein level remains rudimentary, partly due to the difficulty of obtaining purified, functional JHR proteins. Here we present a method for high-yield expression and purification of JHR complexes from two insect species, the beetle Tribolium castaneum and the mosquito Aedes aegypti. Recombinant JHR subunits from each species were co-expressed in an insect cell line using a baculovirus system. MET-TAI complexes were purified through affinity chromatography and anion exchange columns to yield proteins capable of binding both the hormonal ligand (JH III) and DNA bearing cognate JH-response elements. We further examined the beetle JHR complex (TcJHR) in greater detail. Biochemical analyses and mass spectrometry confirmed that TcJHR was a 1:1 heterodimer consisting of TcMET and TcTAI proteins, stabilized by the JHR agonist ligand methoprene. Phosphoproteomics uncovered multiple phosphorylation sites in the TcMET protein, some of which were induced by methoprene treatment. Finally, we report a functional bipartite nuclear localization signal, straddled by phosphorylated residues, within the disordered C-terminal region of TcMET. Our present characterization of the recombinant JHR is an initial step towards understanding JHR structure and function.

In spectroscopic analysis, push-to-the-limit sensitivity is one of the important topics, particularly when facing the qualitative and quantitative analyses of the trace target. Normally, the effective recognition and extraction of weak signals are the first key steps, for which there has been considerable effort in developing various denoising algorithms for decades. Nevertheless, the lower the signal-to-noise ratio (SNR), the greater the deviation of the peak height and shape during the denoising process. Therefore, we propose a denoising algorithm along with peak extraction and retention (PEER). First, both the first and second derivatives of the Raman spectrum are used to determine Raman peaks with a high SNR whose peak information is kept away from the denoising process. Second, an optimized window smoothing algorithm is applied to the left part of the Raman spectrum, which is combined with the untreated Raman peaks to obtain the denoised Raman spectrum. The PEER algorithm is demonstrated with much better signal extraction and retention and successfully improves the temporal resolution of Raman imaging of a living cell by at least 1 order of magnitude higher than those by traditional algorithms.

Tip-enhanced Raman spectroscopy (TERS) is a nano-optical approach to extract spatially resolved chemical information with nanometer precision. However, in the case of direct-illumination TERS, which is often employed in commercial TERS instruments, strong fluorescence or far-field Raman signals from the illuminated areas may be excited as a background. They may overwhelm the near-field TERS signal and dramatically decrease the near-field to far-field signal contrast of TERS spectra. It is still challenging for TERS to study the surface of fluorescent materials or a bulk sample that cannot be placed on an Au/Ag substrate. In this study, we developed an indirect-illumination TERS probe that allows a laser to be focused on a flat interface of a thin-film waveguide located far away from the region generating the TERS signal. Surface plasmon polaritons are generated stably on the waveguide and eventually accumulated at the tip apex, thereby producing a spatially and energetically confined hotspot to ensure stable and high-resolution TERS measurements with a low background. With this thin-film waveguide probe, TERS spectra with obvious contrast from a diamond plate can be acquired. Furthermore, the TERS technique based on this probe exhibits excellent TERS signal stability, a long lifetime, and good spatial resolution. This technique is expected to have commercial potential and enable further popularization and development of TERS technology as a powerful analytical method.

Background Fragments of subcutaneous adipose tissue that have been genetically modified to express bone morphogenetic protein‐2 (BMP‐2) regenerate large segmental osseous lesions in rodents. Gene‐activated adipose tissue can be implanted into osseous defects without prior cell extraction and cell culture. The present study aimed to explore whether the heterodimers BMP‐2/6 or BMP‐2/7 exceed the osteoinductive effect of BMP‐2 on adipose tissue. Methods In an in vitro tissue culture system, freshly harvested rat subcutaneous adipose tissue was cultivated in the presence of either BMP‐2 or BMP‐2/6 or BMP‐2/7 at a high (200 ng/ml) and low (50 ng/ml) concentration. Gene expression analysis as well as histological and immunohistochemical methods were applied to test for osteoinduction. Results A concentration of 200 ng/ml of homodimeric BMP‐2 induced osteogenic differentiation most potently, showing more calcification and a higher expression level of bone markers than both concentrations of BMP‐2/6 or ‐2/7. A concentration of 50 ng/ml of BMP‐2 was a significantly stronger osteogenic inducer than both concentrations of BMP‐2/6 and the low concentration of BMP‐2/7. The most potent heterodimeric driver of osteoinduction was BMP‐2/7 at a high concentration, demonstrating effects similar to those of BMP‐2 at a low concentration. Conclusions Homodimeric BMP‐2 evoked osteoinduction within adipose tissue more potently and at a lower concentration than heterodimeric BMP‐2/6 or BMP‐2/7. This result agrees well with the fact that it might be easier to translate adipose grafts activated by homodimeric BMP‐2 clinically. Preclinical in vivo gene transfer studies are necessary to confirm the results of the present study.

Functionalized gold nanoparticles (AuNPs) have been successfully used in many fields as a result of having low cytotoxicity, good biocompatibility, excellent optical properties, and their ability to target cancer cells. Here, we synthesized AuNP carriers that were modified by hyaluronic acid (HA), polyethylene glycol (PEG), and adipic dihydrazide (ADH). The antitumor drug doxorubicin (Dox) was loaded into AuNP carriers and attached chemically. The Au nanocomposite AuNPs@MPA-PEG-HA-ADH-Dox was able to disperse uniformly in aqueous solution, with a diameter of 15 nm. The results of a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that AuNP carriers displayed very little toxicity toward cells in high doses, although the antitumor properties of Au nanocomposites were significantly enhanced. Cellular uptake experiments demonstrated that AuNPs modified with hyaluronic acid were more readily ingested by HepG2 and HCT-116 cells, as they have a large number of CD44 receptors. A series of experiments measuring apoptosis such as Rh123 and annexin V-FITC staining, and analysis of mitochondrial membrane potential (MMP) analysis, indicated that apoptosis played a role in the inhibition of cell proliferation by AuNPs@MPA-PEG-HA-ADH-Dox. Excessive production of reactive oxygen species (ROS) was the principal mechanism by which the Au nanocomposites inhibited cell proliferation, leading to apoptosis. Thus, the Au nanocomposites, which allowed cell imaging in real-time and induced apoptosis in specific cell types, represent theragnostic agents with potential for future clinical applications in bowel cancer.