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Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1 +/- mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Surface-enhanced Raman scattering (SERS) has been extensively applied to detect complex analytes due to its ability to enhance the fingerprint signals of molecules around nanostructured metallic surfaces. Thus, it is essential to design SERS-active nanostructures with abundant electromagnetic hotspots in a probed volume according to the dimensions of the analytes, as the analytes must be located in their hotspots for maximum signal enhancement. Herein, we demonstrate a simple method for detecting robust SERS signals from multi-scaled bioanalytes, regardless of their dimensions in the liquid state, through a photothermally driven co-assembly with colloidal plasmonic nanoparticles as signal enhancers. Under resonant light illumination, plasmonic nanoparticles and analytes in the solution quickly assemble at the focused surface area by convective movements induced by the photothermal heating of the plasmonic nanoparticles without any surface modification. Such collective assemblies of plasmonic nanoparticles and analytes were optimized by varying the optical density and surface charge of the nanoparticles, the viscosity of the solvent, and the light illumination time to maximize the SERS signals. Using these light-induced co-assemblies, the intrinsic SERS signals of small biomolecules can be detected down to nanomolar concentrations based on their fingerprint spectra. Furthermore, large-sized biomarkers, such as viruses and exosomes, were successfully detected without labels, and the complexity of the collected spectra was statistically analyzed using t-distributed stochastic neighbor embedding combined with support vector machine (t-SNE + SVM). The proposed method is expected to provide a robust and convenient method to sensitively detect biologically and environmentally relevant analytes at multiple scales in liquid samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Despite growing ecological concerns, studies on microplastics and nanoplastics are still in their initial stages owing to technical hurdles in analytical techniques, especially for nanoplastics. We provide an overview of the general attributes of micro/nanoplastics in natural environments and analytical techniques commonly used for their analysis. After demonstrating the analytical challenges associated with the identification of nanoplastics due to their distinctive characteristics, we discuss recent technological advancements for detecting nanoplastics.

Ovarian cancer is the leading cause of gynecologic cancer death. Among the most innovative anti-cancer approaches, the genetic concept of synthetic lethality is that mutations in multiple genes work synergistically to effect cell death. Previous studies found that although vaccinia-related kinase-1 (VRK1) associates with DNA damage repair proteins, its underlying mechanisms remain unclear. Here, we found high VRK1 expression in ovarian tumors, and that VRK1 depletion can significantly promote apoptosis and cell cycle arrest. The effect of VRK1 knockdown on apoptosis was manifested by increased DNA damage, genomic instability, and apoptosis, and also blocked non-homologous end joining (NHEJ) by destabilizing DNA-PK. Further, we verified that VRK1 depletion enhanced sensitivity to a PARP inhibitor (PARPi), olaparib, promoting apoptosis through DNA damage, especially in ovarian cancer cell lines with high VRK1 expression. Proteins implicated in DNA damage responses are suitable targets for the development of new anti-cancer therapeutic strategies, and their combination could represent an alternative form of synthetic lethality. Therefore, normal protective DNA damage responses are impaired by combining olaparib with elimination of VRK1 and could be used to reduce drug dose and its associated toxicity. In summary, VRK1 represents both a potential biomarker for PARPi sensitivity, and a new DDR-associated therapeutic target, in ovarian cancer., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest. All the authors reviewed the data, read the manuscript, and consented for publication All the raw data and material is available with the corresponding author., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics., (©2024 American Association for Cancer Research.)

Alpha-2-Glycoprotein 1, Zinc-binding (AZGP1, ZAG) is a secreted protein that is synthesized by adipocytes and epithelial cells; it is downregulated in several malignancies such as breast, prostate, liver and lung cancers. However, its function remains unclear in cholangiocarcinoma (CCA). Here, we evaluated the impact AZGP1 in CCA using Gene Expression Omnibus (GEO) and GEPIA. In addition, we analysed AZGP1 expression using quantitative reverse transcription PCR and western blotting. Expression of AZGP1 was nearly deficient in CCA patients and cell lines and was associated with poor prognosis. AZGP1 overexpression upregulated apoptosis markers. Co-immunoprecipitation experiments showed that AZGP1 interacts with tripartite motif-containing protein 25 (TRIM25), and tissue microarray and bioinformatic analysis showed that AZGP1 is negatively correlated with TRIM25 expression in CCA. Thereafter, TRIM25 knockdown led to AZGP1 upregulation and induced cancer cell apoptosis. TRIM25 targets AZGP1 for degradation by catalysing its ubiquitination. AZGP1 overexpression significantly suppressed tumour growth in a xenograft mouse model. This study findings suggest that AZGP1 is a potential therapeutic target or a diagnostic biomarker for treating patients with CCA., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so the molecular mechanisms ensuring successful morphogen delivery remain unclear. To tackle this longstanding problem, we developed a mouse model for compromised sonic hedgehog (SHH) morphogen delivery and discovered that endocytic recycling promotes SHH loading into signaling filopodia called cytonemes. We optimized methods to preserve in vivo cytonemes for advanced microscopy and show endogenous SHH localized to cytonemes in developing mouse neural tubes. Depletion of SHH from neural tube cytonemes alters neuronal cell fates and compromises neurodevelopment. Mutation of the filopodial motor myosin 10 (MYO10) reduces cytoneme length and density, which corrupts neuronal signaling activity of both SHH and WNT. Combined, these results demonstrate that cytoneme-based signal transport provides essential contributions to morphogen dispersion during mammalian tissue development and suggest MYO10 is a key regulator of cytoneme function., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

With the advancements of nanotechnology, innovative photonic designs coupled with functional materials provide a unique way to acquire, share, and respond effectively to information. It is found that the simple deposition of a 30 nm-thick palladium nanofilm on a terahertz (THz) metasurface chip with a 14 nm-wide effective nanogap of asymmetric materials and geometries allows the tracking of both interatomic and interfacial gas-matter interactions, including gas adsorption, hydrogenation (or dehydrogenation), metal phase changes, and unique water-forming reactions. Combinatorial analyses by simulation and experimental measurements demonstrate the distinct nanostructures, which leads to significant light-matter interactions and corresponding THz absorption in a real-time, highly repeatable, and reliable manner. The complex lattice dynamics and intrinsic properties of metals influenced by hydrogen gas exposure are also thoroughly examined using systematically controlled ternary gas mixture devices that mimic normal temperature and pressure. Furthermore, the novel degrees of freedom are utilized to analyze various physical phenomena, and thus, analytical methods that enable the tracking of unknown hidden stages of water-forming reactions resulting in water growth are introduced. A single exposure of the wave spectrum emphasizes the robustness of the proposed THz nanoscopic probe, bridging the gap between fundamental laboratory research and industry., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant ( PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type ( PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.

Recepteur d'origine nantais (RON, MST1R) is a single-span transmembrane receptor tyrosine kinase (RTK) aberrantly expressed in numerous cancers, including various solid tumors. How naturally occurring splicing isoforms of RON, especially those which are constitutively activated, affect tumorigenesis and therapeutic response, is largely unknown. Here, we identified that presence of activated RON could be a possible factor for the development of resistance against anti-EGFR (cetuximab) therapy in colorectal cancer patient tissues. Also, we elucidated the roles of three splicing variants of RON, RON Δ155, Δ160, and Δ165 as tumor drivers in cancer cell lines. Subsequently, we designed an inhibitor of RON, WM-S1-030, to suppress phosphorylation thereby inhibiting the activation of the three RON variants as well as the wild type. Specifically, WM-S1-030 treatment led to potent regression of tumor growth in solid tumors expressing the RON variants Δ155, Δ160, and Δ165. Two mechanisms for the RON oncogenic activity depending on KRAS genotype was evaluated in our study which include activation of EGFR and Src, in a trimeric complex, and stabilization of the beta-catenin. In terms of the immunotherapy, WM-S1-030 elicited notable antitumor immunity in anti-PD-1 resistant cell derived mouse model, likely via repression of M1/M2 polarization of macrophages. These findings suggest that WM-S1-030 could be developed as a new treatment option for cancer patients expressing these three RON variants., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Colorectal cancer (CRC) is one of the highest mortality rates worldwide, and various studies reported to the occurrence of CRC. In particular, the Wnt/β-catenin pathway is known to be a major factor in the progression of CRC and β-catenin involved in the expression of its downstream target genes. We searched for TCOF1 through sliver staining to identify a new binding partner for β-catenin and to investigate the role of the gene involved in CRC. Treacle Ribosome Biogenesis Factor 1 (TCOF1) is a nucleolar protein that regulates the transcription of ribosomal DNA (rDNA). There are many reports of genetic studies on TCOF1 mutations and defects, but its function in CRC remains unknown. We demonstrated that TCOF1 and β-catenin expression in tissue microarray (TMA) containing 101 individual CRC and 17 adjacent normal samples. Additionally, the effects of TCOF1 knockdown or overexpression were examined proliferation, colony formation assay, western blot, and quantitative real-time PCR (qRT-PCR). TCOF1 knockdown or overexpression regulates cell proliferation about three-fold and the phosphorylation of β-catenin, cyclin D1 expression levels. Besides, we discovered the mechanism through which TCOF1 regulates the stability of β-catenin was involved in degradation through proteasome using ubiquitination assay. Finally, we confirmed the interaction of TCOF1 with the tankyrase inhibitor NVP-TNKS656, which destabilizes β-catenin through in vitro and in vivo. Collectively, this study shows that significantly correlation was observed that TCOF1 and β-catenin were risk factor for tumor progression. The stability of β-catenin via regulating TCOF1 expression could be a potential strategy for therapeutic with CRC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The Fabry-Perot (FP) resonator is an intuitive and versatile optical structure owing to its uniqueness in light-matter interactions, yielding resonance with a wide range of wavelengths as it couples with photonic materials encapsulated in a dielectric cavity. Leveraging the FP resonator for molecular detection, a simple geometry of the metal-dielectric-metal structure is demonstrated to allow tuning of the enhancement factors (EFs) of surface-enhanced Raman scattering (SERS). The optimum near-field EF from randomly dispersed gold nano-gaps and dynamic modulation of the far-field SERS EF by varying the optical resonance of the FP etalon are systematically investigated by performing computational and experimental analyses. The proposed strategy of combining plasmonic nanostructures with FP etalons clearly reveals wavelength matching of FP resonance to excitation and scattering wavelengths plays a key role in determining the magnitude of the SERS EF. Finally, the optimum near-field generating optical structure with controlled dielectric cavity is suggested for a tunable SERS platform, and its dynamic SERS switching performance is confirmed by demonstrating information encryption through liquid immersion., (© 2023 Wiley-VCH GmbH.)

Emerging as substantial concerns in the ecosystem, submicron plastics have attracted much attention for their considerable hazards. However, their effect and even amount in the environment remain unclear. Establishing a substantive analytic platform is essential to expand the understanding of nanoplastics. However, the issues of diffusion and detection limit that arise from ultradiluted concentration and extremely small scales of nanoplastics leave significant technical hurdles to analyze the nanoplastic pollutants. In this study, we obtain effective Raman signals in real time from underwater nanoplastics with ultralow concentrations via AC electro-osmotic flows and dielectrophoretic tweezing. This enables the field-induced active collection of nanoplastics toward the optical sensing area from remote areas in a rapid manner, integrating conventional technical skills of preconcentration, separation, and identification in a single process. A step further, synergetic combination with plasmonic nanorods, accomplishes the highest on-site detection performance so far.

Dysregulated Wnt signaling is associated with malignant oncogenic transformation, especially in colon cancer. Recently, numerous drugs have been developed based on tumorigenesis biomarkers, thus having high potential as drug targets. Likewise, WNT/β-catenin pathway members are attractive therapeutic targets for colon cancer and are currently in various stages of development. However, although inhibitors of proteins regulating the WNT/β-catenin signaling pathway have been extensively studied, they have yet to be clinically approved, and the underlying molecular mechanism(s) of their anticancer effects remain poorly understood. Herein, we show that a novel WNT/β-catenin inhibitor, DGG-300273, inhibits colon cancer cell growth in a Wnt-dependent manner due to upregulation of the BCL2-family protein Bim and caspase-dependent apoptotic cell death. Additionally, DGG-300273-mediated cell death occurs by increased reactive oxygen species (ROS), as shown by abrogation of apoptotic cell death and ROS production following pretreatment with the antioxidant N-acetylcysteine. These results suggest that DGG-300273 represents a promising investigational drug for the treatment of Wnt-associated cancer, thus warranting further characterization and study., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Passive water penetration across the cell membrane by osmotic diffusion is essential for the homeostasis of cell volume, in addition to the protein-assisted active transportation of water. Since membrane components can regulate water permeability, controlling compositional variation during the volume regulatory process is a prerequisite for investigating the underlying mechanisms of water permeation and related membrane dynamics. However, the lack of a viable in vitro membrane platform in hypertonic solutions impedes advanced knowledge of cell volume regulation processes, especially cholesterol-enriched lipid domains called lipid rafts. By reconstituting the liquid-ordered (L o ) domain as a likeness of lipid rafts, we verified suppressed water permeation across the L o domains, which had yet to be confirmed with experimental demonstrations despite a simulation approach. With the help of direct transfer of the L o domains from vesicles to supported lipid membranes, the biological roles of lipid composition in suppressed water translocation were experimentally confirmed. Additionally, the improvement in membrane stability under hypertonic conditions was demonstrated based on molecular dynamics simulations.

Background: Escherichia coli have both the Embden-Meyerhof-Parnas pathway (EMPP) and Entner-Doudoroff pathway (EDP) for glucose breakdown, while the EDP primarily remains inactive for glucose metabolism. However, EDP is a more favorable route than EMPP for the production of certain products., Results: EDP was activated by deleting the pfkAB genes in conjunction with subsequent adaptive laboratory evolution (ALE). The evolved strains acquired mutations in transcriptional regulatory genes for glycolytic process (crp, galR, and gntR) and in glycolysis-related genes (gnd, ptsG, and talB). The genotypic, transcriptomic and phenotypic analyses of those mutations deepen our understanding of their beneficial effects on cellulosic biomass bio-conversion. On top of these scientific understandings, we further engineered the strain to produce higher level of lycopene and 3-hydroxypropionic acid., Conclusions: These results indicate that the E. coli strain has innate capability to use EDP in lieu of EMPP for glucose metabolism, and this versatility can be harnessed to further engineer E. coli for specific biotechnological applications., (© 2022. The Author(s).)

Objectives: To analyse the effect of hypertension on the occurrence of out-of-hospital cardiac arrest, and to find out whether the effect is dependent on the use of anti-hypertensive drugs., Methods: The case-control study used secondary data from the Cardiac Arrest Pursuit Trial with Unique Registration and Epidemiologic Surveillance project and comprised patients with presumed cardiac aetiology adult out-of-hospital cardiac arrest assessed by emergency medical service from 27 participating emergency departments from January 2016 to December 2017. Controls matched for age, gender and county were recruited from the Korea National Health and Nutrition Examination Survey database in a 4:1 ratio. Multivariate logistic regression analysis was used to analyse the effects of hypertension and the administration of anti-hypertensive medication on out-of-hospital cardiac arrest incidence. Data was analysed using SAS 9.4., Results: Of the 7330 subjects, 1,466(20%) were patients and 5864(80%) were controls. Hypertension was found in 662(45.2%) patients and 3,190(54.4%) controls. Hypertension lowered the incidence of out-of-hospital cardiac arrest (adjusted odds ratio: 0.69 [95% confidence interval: 0.60-0.80]); in the medication group 0.64(0.55-0.75), and 1.12(0.83-1.49) in the non-medication group., Conclusions: Administration of anti-hypertensive medications in patients of hypertension may help reduce the incidence of out-of-hospital cardiac arrest. Active hypertension diagnosis and anti-hypertensive medications to reduce the incidence of out-of-hospital cardiac arrest is critical.

With narrow and dense nanoarchitectures increasingly adopted to improve optical functionality, achieving the complete wetting of photonic devices is required when aiming at underwater molecule detection over the water-repellent optical materials. Despite continuous advances in photonic applications, real-time monitoring of nanoscale wetting transitions across nanostructures with 10-nm gaps, the distance at which photonic performance is maximized, remains a chronic hurdle when attempting to quantify the water influx and molecules therein. For this reason, the present study develops a photonic switch that transforms the wetting transition into perceivable color changes using a liquid-permeable Fabry-Perot resonator. Electro-capillary-induced Cassie-to-Wenzel transitions produce an optical memory effect in the photonic switch, as confirmed by surface-energy analysis, simulations, and an experimental demonstration. The results show that controlling the wetting behavior using the proposed photonic switch is a promising strategy for the integration of aqueous media with photonic hotspots in plasmonic nanostructures such as biochemical sensors., (© 2022 Wiley-VCH GmbH.)

Background/aim: Colorectal cancer is reported to have the highest mortality rate among human malignancies. Although many research results for the treatment of colorectal cancer have been reported, there is no suitable treatment when resistance has developed. Therefore, it is necessary to develop new therapeutic agents. Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling plays an essential role in cell differentiation, proliferation, and survival. Abnormal activation of the JAK/STAT signaling pathway, by gene mutation or amplification, may induce cancer development, and sustained JAK/STAT activation is involved in chemoresistance. While many therapeutic agents have been developed to treat colon cancer, there remains no drug to overcome resistance to chemotherapies. The purpose of this study was to determine the potential of CJ14939 as a novel JAK inhibitor for the treatment of colorectal cancer., Materials and Methods: In this study, cell culture, cell death assay, 3- (4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, colony formation assay, immunoblot analysis and tumor xenograft were applied., Results: CJ14939 induced cell death, and inhibited phosphorylation of JAK1 and STAT3 in colorectal cancer cells. Furthermore, CJ14939 also promoted oxaliplatin-induced cell death, up-regulated expression of cleaved caspase-3, and down-regulated expression of phospho-JAK1 and phospho-STAT3. In vivo, co-treatment with CJ14939 and oxaliplatin notably reduced tumor growth when compared with CJ14939 or oxaliplatin treatment alone., Conclusion: This study identifies the important potential of CJ14939 in colorectal cancer treatment and suggests that combining CJ14939 with oxaliplatin might be a novel therapeutic strategy for patients with colorectal cancer., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

With strong demands of real-time monitoring of biomolecules or environmental pollutants, overcoming technical hurdles on control and detection of freely diffusive nanoscale objects become a question of issue to solve in a variety of research fields. Most existing optical techniques inevitably require labeling to the target material, which sometimes denature the measuring biomaterials. For highly efficient real-time monitoring without complicated pretreatment or labeling, many successes in development of label-free or non-destructive detection techniques via increased sensitivity were accomplished by the additional structures. Metasurface-based two-dimensional photonic/electric devices have recently represented extraordinary performances in both manipulation and sensing for various small particles and biochemical species, repeatedly overcoming the limit of detection achieved right before. In parallel, various metasurface-based devices were also introduced promoting transportation of targets into optical hotspot sites, overcoming diffusion limits. We noted this point, therefore, reviewed two major research fields such as metasurface-assisted material sensing and transportation technologies that have contributed to present prospective sensing technologies, then showed perspective views on how great synergy can be created when two technologies are cleverly integrated. Recently, a trend of conceptual merging of optical detection and transporting schemes beyond both diffraction limit and diffusion limit leads to a creation of exceptional performance in molecular detections. In this review, the trends of the latest technologies accomplishing this purpose by hybridization of various composite materials and functional metasurfaces will be introduced., (© 2022 Geon Lee et al., published by De Gruyter, Berlin/Boston.)

Methylorubrum extorquens AM1 is an efficient platform strain possessing biotechnological potential in formate- and methanol-based single carbon (C1) bioeconomy. Constitutive expression or costly chemical-inducible expression systems are not always desirable. Here, several glucose-, xylose-, and levulinic acid (LA)-inducible promoter systems were assessed for the induction of green fluorescent protein (GFP) as a reporter protein. Among them, the LA-inducible gene expression system (HpdR/P hpdH ) showed a strong expression of GFP (51-fold) compared to the control. The system was induced even at a low concentration of LA (0.1 mM). The fluorescence intensity increased with increasing concentrations of LA up to 20 mM. The system was tunable and tightly controlled with meager basal expression. The maximum GFP yield obtained using the system was 42 mg/g biomass, representing 10% of the total protein content. The efficiency of the proposed system was nearly equivalent (90%-100%) to that of the widely used strong promoters such as P mxaF and P L/O4 . The HpdR/P hpdH system worked equally efficiently in five different strains of M. extorquens . LA is a low-cost, renewable, and sustainable platform chemical that can be used to generate a wide range of products. Hence, the reported system in potent strains of M. extorquens is highly beneficial in the C1-biorefinery industry to produce value-added products and bulk chemicals ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sathesh-Prabu, Ryu and Lee.)

The sodium-dependent vitamin C transporter 2 (SVCT2) surface glycoprotein regulates ascorbate accumulation in the plasma, often resulting in the induction of cancer cell death. Therefore, high expression of this gene associates with increased overall survival in several cancers. However, in colorectal cancer (CRC), high (likely mutated) SVCT2 expression relates to poor overall survival, and its functional significance has not been studied. Thus, we hypothesize that mutant SVCT2 expression could affect CRC patient survival. According to biological databases, SVCT2 has been found to be mutated frequently, and SVCT2 E264K has a particularly high pathogenic score (0.98), compared to other SVCT2 mutant sites, in CRC patients. Interestingly, our results reveal expression of SVCT2 E264K in many CRC tissues and cells. Also, we found wild-type SVCT2 expression to be largely localized to the cytoplasm and membrane, while SVCT2 E264K was restricted to the cytoplasm. We further found that SVCT2 E264K overexpression increases cell growth. By contrast, SVCT2 E264K knockdown significantly reduced cell proliferation and promoted cell apoptosis, resulting in inhibition of cell invasion and migration. Taken together, SVCT2 E264K plays a critical role in proliferation in CRC. Our results suggest that SVCT2 E264K could be a promising novel therapeutic target in CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Despite technological advances in biomolecule detections, evaluation of molecular interactions via potentiometric devices under ion-enriched solutions has remained a long-standing problem. To avoid severe performance degradation of bioelectronics by ionic screening effects, we cover probe surfaces of field effect transistors with a single film of the supported lipid bilayer, and realize respectable potentiometric signals from receptor-ligand bindings irrespective of ionic strength of bulky solutions by placing an ion-free water layer underneath the supported lipid bilayer. High-energy X-ray reflectometry together with the circuit analysis and molecular dynamics simulation discovered biochemical findings that effective electrical signals dominantly originated from the sub-nanoscale conformational change of lipids in the course of receptor-ligand bindings. Beyond thorough analysis on the underlying mechanism at the molecular level, the proposed supported lipid bilayer-field effect transistor platform ensures the world-record level of sensitivity in molecular detection with excellent reproducibility regardless of molecular charges and environmental ionic conditions.

Probing the kinetic evolution of nanoparticle (NP) growth in liquids is essential for understanding complex nano-phases and their corresponding functions. Terahertz (THz) sensing, an emerging technology for next-generation laser photonics, has been developed with unique photonic features, including label-free, non-destructive, and molecular-specific spectral characteristics. Recently, metasurface-based sensing platforms have helped trace biomolecules by overcoming low THz absorption cross-sectional limits. However, the direct probing of THz signals in aqueous environments remains difficult. Here, the authors report that vertically aligned nanogap-hybridized metasurfaces can efficiently trap traveling NPs in the sensing region, thus enabling us to monitor the real-time kinetic evolution of NP assemblies in liquids. The THz photonics approach, together with an electric tweezing technique via spatially matching optical hotspots to particle trapping sites with a nanoscale spatial resolution, is highly promising for underwater THz analysis, forging a route toward unraveling the physicochemical events of nature within an ultra-broadband wavelength regime., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Stem cell-based therapies have recently emerged to treat various incurable diseases and disorders. Types of stem cell-derived cells and their functions should be intensively analyzed before therapy. However, current pre-treatment steps for biological analysis are mostly destructive. Here, we report a novel optical method that enables ultra-fast and label-free characterization of cells, eliminating invasive, destructive steps. The technique, referred to as "autofluorescence-Raman mapping integration (ARMI)" analysis uses cell autofluorescence (AF) to reveal cellular morphology and cytosolic microstructures, while Raman mapping allows site-specific intensive analysis of target molecules, which enables ultra-fast identification of cell types. We used human mesenchymal stem cells (MSCs) as a model and induced adipogenesis. Lipid droplets in cells appeared as "blanks" in three-dimensional AF images and site-specific Raman mapping guided by AF identified the structure and components of the CH 2 stretch. Adipogenesis could be rapidly and precisely analyzed, not only for the same batch but also for different batches. Therefore, the developed tool is highly useful for the accurate screening of stem cell differentiation and implementation in biomedical and clinical applications., (Copyright © 2021 Elsevier B.V. All rights reserved.)

SVCT2, Sodium-dependent Vitamin C Transporter 2, uniquely transports ascorbic acid (also known as vitamin C and ascorbate) into all types of cells. Vitamin C is an essential nutrient that must be obtained through the diet and plasma levels are tightly regulated by transporter activity. Vitamin C plays an important role in antioxidant defenses and is a cofactor for many enzymes that enable hormone synthesis, oxygen sensing, collagen synthesis and epigenetic pathways. Although SVCT2 has various functions, regulation of its expression/activity remains poorly understood. We found a p53-binding site, within the SVCT2 promoter, using a transcription factor binding-site prediction tool. In this study, we show that p53 can directly repress SVCT2 transcription by binding a proximal- (~-185 to -171 bp) and a distal- (~-1800 to -1787 bp) p53-responsive element (PRE), Chromatin immunoprecipitation assays showed that PRE-bound p53 interacts with the corepressor-histone deacetylase 3 (HDAC3), resulting in deacetylation of histones Ac-H4, at the proximal promoter, resulting in transcriptional silencing of SVCT2. Overall, our data suggests that p53 is a potent transcriptional repressor of SVCT2, a critical transporter of diet-derived ascorbic acid, across the plasma membranes of numerous essential tissue cell types.

Signal enhancement of spectroscopies including terahertz time-domain spectroscopy (THz-TDS) and surface-enhanced Raman scattering (SERS) is a critical issue for effective molecular detection and identification. In this study, the sensing performance between THz-TDS and SERS individually accompanied by the proper plasmonic subwavelength structures was compared. For the precisely quantitative study on the optical properties of rhodamine 6G (R6G) dyes, SERS incorporates with the non-linearly enhanced Raman emissions at the molecular characteristic peaks while THz-TDS refers to the transmittance change and the shift of the spectral resonance. The local molecular density-dependent trade-off relationship between limit-of-detection and quenching was observed from both measurements. The specificity for two samples, R6G and methylene blue, is determined by the discriminations in spectral features such as the intensity ratio of assigned peaks in SERS and transmittance difference in THz-TDS. The comprehension of field enhancement by the specific nanostructures was supported by the finite-element method-based numerical computations. As a result, both spectroscopic techniques with the well-tailored nanostructures show great potential for highly sensitive, reproducible, label-free, and cost-effective diagnosis tools in the biomedical fields.

Terahertz (THz) imaging technology has shown significant potential for use in biomedical imaging owing to its non-ionizing characteristics by its low photon energy and its ultrabroadband spectral comparability with many molecular vibrational resonances. However, despite the significant advantage of being able to identify bio-materials in label-free configurations, most meaningful signals are buried by huge water absorption, thus it is very difficult to distinguish them using the small differences in optical constants at THz regime, limiting the practical application of this technology. Here, we demonstrate advanced THz imaging with enhanced color contrast by the use of THz field that is localized and enhanced by a nanometer-scale slot array. THz images of a biological specimen, such as mouse brain tissue and fingerprint, on a nano-slot array-based metamaterial sensing chip, which is elaborately fabricated in large-area, show a higher contrast and clearer boundary information in reflectance without any labeling. A reliable numerical solution to find accurate optical constants using THz nano-slot resonance for the quantitative analysis of target bio-specimens is also introduced. Finally, the precise optical properties of real bio-samples and atlas information are provided for specific areas where amyloid beta proteins, known to cause dementia, have accumulated in a mouse brain., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Going beyond an improved colour gamut, an asymmetric colour contrast, which depends on the viewing direction, and its ability to readily deliver information could create opportunities for a wide range of applications, such as next-generation optical switches, colour displays, and security features in anti-counterfeiting devices. Here, we propose a simple Fabry-Perot etalon architecture capable of generating viewing-direction-sensitive colour contrasts and encrypting pre-inscribed information upon immersion in particular solvents (optical camouflage). Based on the experimental verification of the theoretical modelling, we have discovered a completely new and exotic optical phenomenon involving a tuneable colour switch for viewing-direction-dependent information delivery, which we define as asymmetric optical camouflage., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s) 2020.)

We report the surface-energy-dependent wetting transition characteristics of an evaporating water droplet on surface-energy-controlled microcavity structures with functional nanocoatings. The droplet wetting scenarios were categorized into four types depending on the synergistic effect of surface energy and pattern size. The silicon (Si) microcavity surfaces ( γ Si = 69.8 mJ/m 2 ) and the polytetrafluoroethylene (PTFE)-coated microcavity surfaces ( γ PTFE = 15.0 mJ/m 2 ) displayed stable Wenzel and Cassie wetting states, respectively, irrespective of time. In contrast, diamond-like carbon (DLC)-coated ( γ DLC = 55.5 mJ/m 2 ) and fluorinated diamond-like carbon (FDLC)-coated ( γ FDLC = 36.2 mJ/m 2 ) surfaces demonstrated a time-dependent transition of wetting states. In particular, the DLC-coated surface showed random filling of microcavities at the earlier time point, while the FDLC-coated surface displayed directional filling of microcavities at the late stage of drop evaporation. Such dynamic wetting scenarios based on surface energy, in particular, the random and directional wetting transitions related to surface energy of nanocoatings have not been explored previously. Furthermore, the microscopic role of nanocoating in the wetting scenarios was analyzed by monitoring the time-dependent deformation and movement of the air-water interface (AWI) at individual cavities using the fluorescence interference-contrast (FLIC) technique. A coating-dependent depinning mechanism of the AWI was responsible for variable filling of cavities leading to time-dependent wetting scenarios. A capillary wetting model was used to relate this depinning event to the evaporation-induced internal flow within the droplet. Interestingly, FLIC analysis revealed that a hydrophilic nanocoating can induce microscopic hydrophobicity near the cavity edges leading to delayed and variable cavity filling. The surface energy-dependent classification of the wetting scenarios may help the design of novel evaporation-assisted thermodynamic and mass-transfer processes.

Axl receptor tyrosine kinase has been implicated in cancer progression, invasion, and metastasis in various cancer types. Axl overexpression has been observed in many cancers, and selective inhibitors of Axl, including R428, may be promising therapeutic agents for several human cancers, such as breast, lung, and pancreatic cancers. Here, we examined the cell growth inhibition mediated by R428 and auranofin individually as well as in combination in the human breast cancer cell lines MCF-7 and MDAMB- 231 to identify new advanced combination treatments for human breast cancer. Our data showed that combination therapy with R428 and auranofin markedly inhibited cancer cell proliferation. Isobologram analyses of these cells indicated a clear synergism between R428 and auranofin with a combination index value of 0.73. The combination treatment promoted apoptosis as indicated by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. Cancer cell migration was also significantly inhibited by this combination treatment. Moreover, we found that combination therapy significantly increased the expression level of Bax, a mitochondrial proapoptotic factor, but decreased that of the X-linked inhibitor of apoptosis protein. Furthermore, the suppression of cell viability and induction of Bax expression by the combination treatment were recovered by treatment with N-acetylcysteine. In conclusion, our data demonstrated that combined treatment with R428 and auranofin synergistically induced apoptosis in human breast cancer cells and may thus serve as a novel and valuable approach for cancer therapy.

Non-small lung cancer (NSCLC) is the most common cancer in the world. The epidermal growth factor receptor (EGFR) gene is mutated in approximately 10% of lung cancer cases in the US and 50% of lung cancer in Asia. The representative target therapeutic agent, erlotinib (EGFR tyrosine kinase inhibitor; EGFR TKI), is effective in inactivating EGFR in lung cancer patients. However, approximately 50-60% of patients are resistant to EGFR TKI. These populations are associated with the EGFR mutation. To overcome resistance to EGFR TKI, we discovered a JAK1 inhibitor, CJ14939. We investigated the efficacy of CJ14939 in human NSCLC cell lines in vitro and in vivo. Our results showed that CJ14939 induced the inhibition of cell growth. Moreover, we demonstrated that combination treatment with erlotinib and CJ14939 induced cell death in vitro and inhibited tumor growth in vivo. In addition, we confirmed the suppression of phosphorylated EGFR, JAK1, and Stat3 expression in erlotinib and CJ14939-treated human NSCLC cell lines. Our results provide evidence that JAK inhibition overcomes resistance to EGFR TKI in human NSCLCs., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Toward the development of surface-sensitive analytical techniques for biosensors and diagnostic biochip assays, a local integration of low-concentration target materials into the sensing region of interest is essential to improve the sensitivity and reliability of the devices. As a result, the dynamic process of sorting and accurate positioning the nanoparticulate biomolecules within pre-defined micro/nanostructures is critical, however, it remains a huge hurdle for the realization of practical surface-sensitive biosensors and biochips. A scalable, massive, and non-destructive trapping methodology based on dielectrophoretic forces is highly demanded for assembling nanoparticles and biosensing tools. Herein, we propose a vertical nanogap architecture with an electrode-insulator-electrode stack structure, facilitating the generation of strong dielectrophoretic forces at low voltages, to precisely capture and spatiotemporally manipulate nanoparticles and molecular assemblies, including lipid vesicles and amyloid-beta protofibrils/oligomers. Our vertical nanogap platform, allowing low-voltage nanoparticle captures on optical metasurface designs, provides new opportunities for constructing advanced surface-sensitive optoelectronic sensors.

There are widespread concerns that low-calorie sweeteners (LCSs) cause metabolic derangement. These concerns stem in part from prior studies linking LCS consumption to impaired glucose tolerance in humans and rodents. Here, we examined this linkage in mice. In experiment 1 , we provided mice with chow, water, and an LCS-sweetened solution (saccharin, sucralose, or acesulfame K) for 28 days and measured glucose tolerance and body weight across the exposure period. Exposure to the LCS solutions did not impair glucose tolerance or alter weight gain. In experiment 2 , we provided mice with chow, water, and a solution containing saccharin, glucose, or a mixture of both for 28 days, and tested for metabolic changes. Exposure to the saccharin solution increased the insulinemic response of mice to the glucose challenge, and exposure to the saccharin + glucose solution increased the rate of glucose uptake during the glucose challenge. However, neither of these test solutions altered glucose tolerance, insulin sensitivity, plasma triglycerides, or percent body fat. In contrast, exposure to the glucose solution increased glucose tolerance, early insulin response, insulin sensitivity, and percent body fat. We conclude that whereas the LCS-containing solutions induced a few metabolic changes, they were modest compared with those induced by the glucose solution.

Screening target microorganisms from a mutated recombinant library plays a crucial role in advancing synthetic biology and metabolic engineering. However, conventional screening tools have several limitations regarding throughput, cost, and labor. Here, we used the fluid array platform to conduct high-throughput screening (HTS) that identified Escherichia coli 'TesA thioesterase mutants producing elevated yields of free fatty acids (FFAs) from a large (10 6 ) mutant library. A growth-based screening method using a TetA-RFP fusion sensing mechanism and a reporter-based screening method using high-level FFA producing mutants were employed to identify these mutants via HTS. The platform was able to cover >95% of the mutation library, and it screened target cells from many arrays of the fluid array platform so that a post-analysis could be conducted by gas chromatography. The 'TesA mutation of each isolated mutant showing improved FFA production in E. coli was characterized, and its enhanced FFA production capability was confirmed., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

A label-free, non-dispruptive, and real-time analytical device to monitor the dynamic features of biomolecules and their interactions with neighboring molecules is an essential prerequisite for biochip- and diagonostic assays. To explore one of the central questions on the lipid-lipid interactions in the course of the liquid-ordered (l o ) domain formation, called rafts, we developed a method of reconstituting continuous but spatially heterogeneous lipid membrane platforms with molayer-bilayer juntions (MBJs) that enable to form the l o domains in a spatiotemporally controlled manner. This allows us to detect the time-lapse dynamics of the lipid-lipid interactions during raft formation and resultant membrane phase changes together with the raft-associated receptor-ligand binding through the surface plasmon resonance (SPR). For cross-validation, using epifluorescence microscopy, we demonstrated the underlying mechanisms for raft formations that the infiltration of cholesterols into the sphingolipid-enriched domains plays a crucial roles in the membrane phase-separation. Our membrane platform, being capable of monitoring dynamic interactions among lipids and performing the systematic optical analysis, will unveil physiological roles of cholesterols in a variety of biological events., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ambient air particulate matter (PM) induces senescence in human skin cells. However, the underlying mechanisms remain largely unknown. We investigated how epigenetic regulatory mechanisms participate in cellular senescence induced by PM with a diameter <2.5 (PM 2.5 ) in human keratinocytes and mouse skin tissues. PM 2.5 -treated cells exhibited characteristics of cellular senescence. PM 2.5 induced a decrease in DNA methyltransferase (DNMT) expression and an increase in DNA demethylase (ten-eleven translocation; TET) expression, leading to hypomethylation of the p16 INK4A promoter region. In addition, PM 2.5 led to a decrease in polycomb EZH2 histone methyltransferase expression, whereas the expression of the epigenetic transcriptional activator MLL1 increased. Furthermore, binding of DNMT1, DNMT3B, and EZH2 to the promoter region of p16 INK4A decreased in PM 2.5 -treated keratinocytes, whereas TET1 and MLL1 binding increased, leading to decreased histone H3 lysine 27 trimethylation (H3K27Me3) and increased H3K4Me3 in the promoter of p16 INK4A . PM 2.5 -induced senescence involved aryl hydrocarbon receptor (AhR)-induced reactive oxygen species (ROS) production. ROS scavenging dampened PM 2.5 -induced cellular senescence through regulation of DNA and histone methylation. Altogether, our work shows that skin senescence induced by environmental PM 2.5 occurs through ROS-dependent the epigenetic modification of senescence-associated gene expression. Our findings provide information for the design of preventive and therapeutic strategies against skin senescence, particularly in light of the increasing problem of PM 2.5 exposure due to air pollution.

The Global Satellite Navigation System (GNSS) used in various location-based services is accurate and stable in outdoor environments. However, it cannot be utilized in an indoor environment because of low signal availability and degradation of accuracy due to the multipath distortion of satellite signals in urban areas. On the contrary, LTE signals are available almost everywhere in urban areas and are quite stable without much variation throughout the year. This is because of the fixed location of base stations and the well-maintained policy of mobile communication service providers. Its varied stability and reliability make LTE signals a more viable method for localization. However, there are some complexities in utilizing LTE signals including signal interference distortion phenomena during propagation multipath fading, and various types of noise. In this paper, we propose a surface correlation-based fingerprinting method to utilize LTE signals for localization in urban areas. The surface correlation converts timely measured signal strength into spatial pattern using the walking distance from a Pedestrian Dead-Reckoning (PDR). The surface correlation is carried out by comparing the spatial signal strength pattern of a pedestrian`s movement trajectory with a fingerprinting database to estimate the location. A reference trajectory of the moving pedestrian is chosen to have a greater correlation among the multiple trajectory candidates generated from a link-based fingerprinting database. By comparing spatial signal strength patterns, the proposed method can improve robustness in localization overcoming the accuracy degradation problem due to RF multipath and noise that are dominant in the conventional RSS measurement-based LTE localization scheme. The test results in urban areas demonstrate that the proposed surface correlation-based fingerprinting method has improved performance compared to the other conventional methods, thus proving to be a useful complementary method to the GNSS in urban areas.

A metasurface is a planar optical device that controls the phase, amplitude, and polarization of light through subwavelength-scale unit elements, called meta-atom. The tunability of plasmonic vortex lens (PVL) which generates surface plasmon polaritons (SPPs) carrying orbital angular momentum can be improved by using meta-atom. However, conventional PVLs exhibit nonuniform field profiles according to the incident polarization states owing to the spin-orbital interaction (SOI) effect observed during SPP excitation. This paper describes a method of compensating for SOI of PVL by using the geometric phase of distributed nanoslits in a gold film. By designing the orientation angles of slit pairs, the anti-phase of the SOI effect can be generated for compensatory effect. In addition, polarization-independent PVLs are designed by applying a detour phase based on the position of the slit pairs. PVLs for center-, off-center-, and multiple-focus cases are demonstrated and measured via a near-field scanning microscope.

Purpurogallin, a natural phenol obtained from oak nutgalls, has been shown to possess antioxidant, anticancer, and anti-inflammatory effects. Recently, in addition to ultraviolet B (UVB) radiation that induces cell apoptosis via oxidative stress, particulate matter 2.5 (PM 2.5 ) was shown to trigger excessive production of reactive oxygen species. In this study, we observed that UVB radiation and PM 2.5 severely damaged human HaCaT keratinocytes, disrupting cellular DNA, lipids, and proteins and causing mitochondrial depolarization. Purpurogallin protected HaCaT cells from apoptosis induced by UVB radiation and/or PM 2.5 . Furthermore, purpurogallin effectively modulates the pro-apoptotic and anti-apoptotic proteins under UVB irradiation via caspase signaling pathways. Additionally, purpurogallin reduced apoptosis via MAPK signaling pathways, as demonstrated using MAPK-p38, ERK, and JNK inhibitors. These results indicate that purpurogallin possesses antioxidant effects and protects cells from damage and apoptosis induced by UVB radiation and PM 2.5 .

In this study, we aimed to illustrate the potential bio-effects of 3-bromo-4,5-dihydroxybenzaldehyde (3-BDB) on the antioxidant/cytoprotective enzyme heme oxygenase-1 (HO-1) in keratinocytes. The antioxidant effects of 3-BDB were examined via reverse transcription PCR, Western blotting, HO-1 activity assay, and immunocytochemistry. Chromatin immunoprecipitation analysis was performed to test for nuclear factor erythroid 2-related factor 2 (Nrf2) binding to the antioxidant response element of the HO-1 promoter. Furthermore, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that the cytoprotective effects of 3-BDB were mediated by the activation of extracellular signal-regulated kinase (ERK) and protein kinase B (PKB, Akt) signaling. Moreover, 3-BDB induced the phosphorylation of ERK and Akt, while inhibitors of ERK and Akt abrogated the 3-BDB-enhanced levels of HO-1 and Nrf2. Finally, 3-BDB protected cells from H 2 O 2 - and UVB-induced oxidative damage. This 3-BDB-mediated cytoprotection was suppressed by inhibitors of HO-1, ERK, and Akt. The present results indicate that 3-BDB activated Nrf2 signaling cascades in keratinocytes, which was mediated by ERK and Akt, upregulated HO-1, and induced cytoprotective effects against oxidative stress.

Particulate matter (PM) increases levels of pro-inflammatory cytokines, but its effects on the skin remain largely unknown. We investigated the signal transduction pathway and epigenetic regulatory mechanisms underlying cellular inflammation induced by PM with a diameter of ≤ 2.5 (PM 2.5 ) in vitro and in vivo. PM 2.5 -treated skin keratinocytes produced various inflammatory cytokines, including IL-6. The binding of PM 2.5 to TLR5 initiated intracellular signaling through MyD88, and led to the translocation of NFκB to the nucleus, where it bound the NFκB site within IL-6 promoter. Furthermore, PM 2.5 induced a direct interaction between TLR5 and NOX4, and in turn induced the production of ROS and activated NFκB-IL-6 downstream, which was prevented by siRNA-mediated knockdown of NOX4 or antioxidant treatment. Furthermore, expression of TLR5, MyD88, NOX4, phospho-NFκB, and IL-6 was increased in skin tissue of PM 2.5 -treated flaky tail mice. PM 2.5 -induced increased transcription of IL-6 was regulated via DNA methylation and histone methylation by epigenetic modification; the binding of DNA demethylase and histone methyltransferase to the IL-6 promoter regions resulted in increased IL-6 mRNA expression. Our findings provide deep insight into the pathogenesis of PM 2.5 exposure and can be used as a therapeutic strategy to treat inflammatory skin diseases caused by PM 2.5 exposure., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The apoptotic effects of shikonin (5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methylpent-3-enyl]naphthalene-1,4-dione) on the human colon cancer cell line SNU-407 were investigated in this study. Shikonin showed dose-dependent cytotoxic activity against SNU-407 cells, with an estimated IC₅₀ value of 3 µM after 48 h of treatment. Shikonin induced apoptosis, as evidenced by apoptotic body formation, sub-G₁ phase cells, and DNA fragmentation. Shikonin induced apoptotic cell death by activating mitogen-activated protein kinase family members, and the apoptotic process was mediated by the activation of endoplasmic reticulum (ER) stress, leading to activation of the PERK/elF2α/CHOP apoptotic pathway, and mitochondrial Ca²⁺ accumulation. Shikonin increased mitochondrial membrane depolarization and altered the levels of apoptosis-related proteins, with a decrease in B cell lymphoma (Bcl)-2 and an increase in Bcl-2-associated X protein, and subsequently, increased expression of cleaved forms of caspase-9 and -3. Taken together, we suggest that these mechanisms, including MAPK signaling and the ER-and mitochondria-mediated pathways, may underlie shikonin-induced apoptosis related to its anticancer effect.

Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH-SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8-DHF may be developed into a promising candidate for the treatment of diabetic neuropathy.

A liquid-permeable concept in a metal-insulator-metal (MIM) structure is proposed to achieve highly sensitive color-tuning property through the change of the effective refractive index of the dielectric insulator layer. A semicontinuous top metal film with nanoapertures, adopted as a transreflective layer for MIM resonator, allows to tailor the nanomorphology of a dielectric layer through selective etching of the underneath insulator layer, resulting in nanopillars and hollow voids in the insulator layer. By allowing outer mediums to enter into the hollow voids of the dielectric layer, such liquid-permeable MIM architecture enables to achieve the wavelength shift as large as 323.5 nm/RIU in the visible range, which is the largest wavelength shift reported so far. Our liquid-permeable approaches indeed provide dramatic color tunablility, a real-time sensing scheme, long-term durability, and reproducibility in a simple and scalable manner.

The therapeutic benefits offered by 5-fluorouracil (5-FU) are limited because of the acquisition of drug resistance, the main cause of treatment failure and metastasis. The ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT) contributes significantly to cancer metastatic potential and chemo-resistance. However, the underlying molecular mechanisms of 5-FU-resistance have remained elusive. Here, we show that reactive oxygen species (ROS), produced by dual oxidase 2 (DUOX2), promote 5-FU-induced EMT. First, we showed that 5-FU-resistant SNUC5 colon cancer cells (SNUC5/FUR cells) undergo EMT by analyzing the expression of EMT markers such as N-cadherin, vimentin and E-cadherin. In addition, we found that the resistant cells expressed higher levels of Snail, Slug, Twist and Zeb1, which are all critical EMT regulators and had enhanced migratory and invasive capabilities. Furthermore, SNUC5/FUR cells had increased level of DUOX2, resulting in increased ROS level. This effect was due to the enhanced binding of the ten eleven translocation 1 (TET1) demethylase to the DUOX2 promoter in the SNUC5/FUR cells. Importantly, silencing of TET1 reversed the effects of 5-FU on the cells. Finally, the antioxidant N-acetylcysteine attenuated the effects of 5-FU on EMT and metastasis. Our study demonstrates the existence of a TET1/DUOX2/ROS/EMT axis that could play a role in colon cancer chemo-resistance and the aggressiveness of this cancer., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Photosensitive materials contain biologically engineered elements and are constructed using delicate techniques, with special attention devoted to efficiency, stability, and biocompatibility. However, to date, no photosensitive material has been developed to replace damaged visual-systems to detect light and transmit the signal to a neuron in the human body. In the current study, artificial nanovesicle-based photosensitive materials are observed to possess the characteristics of photoreceptors similar to the human eye. The materials exhibit considerably effective spectral characteristics according to each pigment. Four photoreceptors originating from the human eye with color-distinguishability are produced in human embryonic kidney (HEK)-293 cells and partially purified in the form of nanovesicles. Under various wavelengths of visible light, electrochemical measurements are performed to analyze the physiological behavior and kinetics of the photoreceptors, with graphene, performing as an electrode, playing an important role in the lipid bilayer deposition and oxygen reduction processes. Four nanovesicles with different photoreceptors, namely, rhodopsin (Rho), short-, medium-, and longwave sensitive opsin 1 (1SW, 1MW, 1LW), show remarkable color-dependent characteristics, consistent with those of natural human retina. With four different light-emitting diodes for functional verification, the photoreceptors embedded in nanovesicles show remarkably specific color sensitivity. This study demonstrates the potential applications of light-activated platforms in biological optoelectronic industries., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The skin is the largest organ of the human body and the one mostly exposed to outdoor contaminants. To evaluate the biological mechanisms underlying skin damage caused by fine particulate matter (PM 2.5 ), we analyzed the effects of PM 2.5 on cultured human keratinocytes and the skin of experimental animals. PM 2.5 was applied to human HaCaT keratinocytes at 50 µg/mL for 24 h and to mouse skin at 100 µg/mL for 7 days. The results indicate that PM 2.5 induced oxidative stress by generating reactive oxygen species both in vitro and in vivo, which led to DNA damage, lipid peroxidation, and protein carbonylation. As a result, PM 2.5 induced endoplasmic reticulum stress, mitochondrial swelling, and autophagy, and caused apoptosis in HaCaT cells and mouse skin tissue. The PM 2.5 -induced cell damage was attenuated by antioxidant N-acetyl cysteine, confirming that PM 2.5 cellular toxicity was due to oxidative stress. These findings contribute to understanding of the pathophysiological mechanisms triggered in the skin by PM 2.5 , among which oxidative stress may play a major role.

Cisplatin-based chemotherapy often results in the development of chemoresistance when used to treat ovarian cancer, which is difficult to overcome. The present study investigated the cytotoxic and anti-migratory effects of shikonin, a naphthoquinone compound, on cisplatin-resistant human ovarian cancer A2780 cells (A2780-CR). Shikonin had a potent dose-dependent cytotoxic effect on A2780-CR cells, with 9 µM shikonin treatment reducing A2780-CR cell viability by 50%, validate using an MTT assay. Shikonin induced apoptosis, as evidenced by the increased number of apoptotic bodies, following staining with Hoechst 33342, and terminal deoxynucleotidyl cell transferase dUTP nick end labeling-positive cells following treatment. Flow cytometry and fluorescent microscope imaging, following JC-1 staining, revealed that shikonin increased mitochondrial membrane depolarization. Also it altered the levels of apoptosis-associated proteins, leading to diminished expression of B cell lymphoma-2 (Bcl-2), enhanced expression of Bcl-associated X, and cleavage of caspase-9 and -3, as revealed using western blot analysis. Shikonin activated mitogen-activated protein kinases; while treatment with specific inhibitors of these kinases attenuated the decline in cell viability induced by shikonin treatment. In addition, the cell migration assay and western blot analysis indicated that shikonin decreased the migratory capacity of A2780-CR cells via the upregulation of epithelial-cadherin and downregulation of neural-cadherin. Taken together, the results of the present study indicated that shikonin induces mitochondria-mediated apoptosis and attenuates the epithelial-mesenchymal transition in A2780-CR cells.