Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation.

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. METHODS: In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. RESULTS: Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. CONCLUSION: In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

Non-Hermitian chiral degeneracy of gated graphene metasurfaces.

Non-Hermitian degeneracies, also known as exceptional points (EPs), have been the focus of much attention due to their singular eigenvalue surface structure. Nevertheless, as pertaining to a non-Hermitian metasurface platform, the reduction of an eigenspace dimensionality at the EP has been investigated mostly in a passive repetitive manner. Here, we propose an electrical and spectral way of resolving chiral EPs and clarifying the consequences of chiral mode collapsing of a non-Hermitian gated graphene metasurface. More specifically, the measured non-Hermitian Jones matrix in parameter space enables the quantification of nonorthogonality of polarisation eigenstates and half-integer topological charges associated with a chiral EP. Interestingly, the output polarisation state can be made orthogonal to the coalesced polarisation eigenstate of the metasurface, revealing the missing dimension at the chiral EP. In addition, the maximal nonorthogonality at the chiral EP leads to a blocking of one of the cross-polarised transmission pathways and, consequently, the observation of enhanced asymmetric polarisation conversion. We anticipate that electrically controllable non-Hermitian metasurface platforms can serve as an interesting framework for the investigation of rich non-Hermitian polarisation dynamics around chiral EPs.

Diesel Exhaust Particles Impair Therapeutic Effect of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis through ROS/ERK/cFos Signaling Pathway.

Background and Objectives: Epidemiological investigations have shown positive correlations between increased diesel exhaust particles (DEP) in ambient air and adverse health outcomes. DEP are the major constituent of particulate atmospheric pollution and have been shown to induce proinflammatory responses both in the lung and systemically. Here, we report the effects of DEP exposure on the properties of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs), including stemness, regeneration, and immunomodulation. Methods and Results: Non-apoptotic concentrations of DEP (10 µg/ml) inhibited the migration and osteogenic differentiation capacity of WJ-MSCs. Gene expression profiling showed that DEP increased intracellular reactive oxygen species (ROS) and expression of pro-inflammatory and metabolic-process-related genes including cFos. Furthermore, WJ-MSCs cultured with DEP showed impaired suppression of T cell proliferation that was reversed by inhibition of ROS or knockdown of cFos. ERK inhibition assay revealed that DEP-induced ROS regulated cFos through activation of ERK but not NF-κB signaling. Overall, low concentrations of DEP (10 µg/ml) significantly suppressed the stemness and immunomodulatory properties of WJ-MSCs through ROS/ERK/cFos signaling pathways. Furthermore, WJ-MSCs cultured with DEP impaired the therapeutic effect of WJ-MSCs in experimental colitis mice, but was partly reversed by inhibition of ROS. Conclusions: Taken together, these results indicate that exposure to DEP enhances the expression of pro-inflammatory cytokines and immune responses through a mechanism involving the ROS/ERK/cFos pathway in WJ-MSCs, and that DEP-induced ROS damage impairs the therapeutic effect of WJ-MSCs in colitis. Our results suggest that modulation of ROS/ERK/cFos signaling pathways in WJ-MSCs might be a novel therapeutic strategy for DEP-induced diseases.

A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer.

BACKGROUND: Colorectal cancer is the second-leading cause of cancer-related mortality in the United States and a leading cause of cancer-related mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factor-beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA-based profile associated with SMAD4 expression could be used to better identify high-risk colorectal cancer patients. AIM: Identify a gene expression-based SMAD4-modulated profile and test its association with patient outcome. METHODS AND RESULTS: Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD-binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient-derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease-free survival was analyzed by the Kaplan-Meier method. In vitro analysis of three genes identified in the SMAD4-modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease-free survival (p = .02, log-rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease-free survival (p = .013, log-rank test). CONCLUSIONS: A SMAD4-modulated gene expression profile identified high-risk stage II and III colorectal cancer patients, can predict disease-free survival, and has prognostic potential for stage II and III colorectal cancer patients.

Bulk Metamaterials Exhibiting Chemically Tunable Hyperbolic Responses.

Extraordinary properties of traditional hyperbolic metamaterials, not found in nature, arise from their man-made subwavelength structures causing unique light-matter interactions. However, their preparation requiring nanofabrication processes is highly challenging and merely provides nanoscale two-dimensional structures. Stabilizing their bulk forms via scalable procedures has been a sought-goal for broad applications of this technology. Herein, we report a new strategy of designing and realizing bulk metamaterials with finely tunable hyperbolic responses. We develop a facile two-step process: (1) self-assembly to obtain heterostructured nanohybrids of building blocks and (2) consolidation to convert nanohybrid powders to dense bulk pellets. Our samples have centimeter-scale dimensions typically, readily further scalable. Importantly, the thickness of building blocks and their relative concentration in bulk materials serve as a delicate means of controlling hyperbolic responses. The resulting new bulk heterostructured material system consists of the alternating h-BN and graphite/graphene nanolayers and exhibits significant modulation in both type-I and type-II hyperbolic resonance modes. It is the first example of real bulk hyperbolic metamaterials, consequently displaying the capability of tuning their responses along both in-plane and out-of-plane directions of the materials for the first time. It also distinctly interacts with unpolarized and polarized transverse magnetic and electronic beams to give unique hyperbolic responses. Our achievement can be a new platform to create various bulk metamaterials without complicated nanofabrication techniques. Our facile synthesis method using common laboratory techniques can open doors to broad-range researchers for active interdisciplinary studies for this otherwise hardly accessible technology.

Extracellular Vesicles from Thapsigargin-Treated Mesenchymal Stem Cells Ameliorated Experimental Colitis via Enhanced Immunomodulatory Properties.

Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton's jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-ß1 (TGFß), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.

Xeno-Free Condition Enhances Therapeutic Functions of Human Wharton's Jelly-Derived Mesenchymal Stem Cells against Experimental Colitis by Upregulated Indoleamine 2,3-Dioxygenase Activity.

The therapeutic applications of mesenchymal stem cells (MSCs) have been actively explored due to their broad anti-inflammatory and immunomodulatory properties. However, the use of xenogeneic components, including fetal bovine serum (FBS), in the expansion media might pose a risk of xenoimmunization and zoonotic transmission to post-transplanted patients. Here, we extensively compared the physiological functions of human Wharton's jelly-derived MSCs (WJ-MSCs) in a xeno-free medium (XF-MSCs) and a medium containing 10% FBS (10%-MSCs). Both groups showed similar proliferation potential; however, the 10%-MSCs showed prolonged expression of CD146, with higher colony-forming unit-fibroblast (CFU-F) ability than the XF-MSCs. The XF-MSCs showed enhanced adipogenic differentiation potential and sufficient hematopoietic stem cell (HSC) niche activity, with elevated niche-related markers including CXCL12. Furthermore, we demonstrated that the XF-MSCs had a significantly higher suppressive effect on human peripheral blood-derived T cell proliferation, Th1 and Th17 differentiation, as well as naïve macrophage polarization toward an M1 phenotype. Among the anti-inflammatory molecules, the production of indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase 2 (NOS2) was profoundly increased, whereas cyclooxygenase-2 (COX-2) was decreased in the XF-MSCs. Finally, the XF-MSCs had an enhanced therapeutic effect against mouse experimental colitis. These findings indicate that xeno-free culture conditions improved the immunomodulatory properties of WJ-MSCs and ex vivo-expanded XF-MSCs might be an effective strategy for preventing the progression of colitis.

A pilot study using machine learning methods about factors influencing prognosis of dental implants.

PURPOSE: This study tried to find the most significant factors predicting implant prognosis using machine learning methods. MATERIALS AND METHODS: The data used in this study was based on a systematic search of chart files at Seoul National University Bundang Hospital for one year. In this period, oral and maxillofacial surgeons inserted 667 implants in 198 patients after consultation with a prosthodontist. The traditional statistical methods were inappropriate in this study, which analyzed the data of a small sample size to find a factor affecting the prognosis. The machine learning methods were used in this study, since these methods have analyzing power for a small sample size and are able to find a new factor that has been unknown to have an effect on the result. A decision tree model and a support vector machine were used for the analysis. RESULTS: The results identified mesio-distal position of the inserted implant as the most significant factor determining its prognosis. Both of the machine learning methods, the decision tree model and support vector machine, yielded the similar results. CONCLUSION: Dental clinicians should be careful in locating implants in the patient's mouths, especially mesio-distally, to minimize the negative complications against implant survival.

Electrical access to critical coupling of circularly polarized waves in graphene chiral metamaterials.

Active control of polarization states of electromagnetic waves is highly desirable because of its diverse applications in information processing, telecommunications, and spectroscopy. However, despite the recent advances using artificial materials, most active polarization control schemes require optical stimuli necessitating complex optical setups. We experimentally demonstrate an alternative-direct electrical tuning of the polarization state of terahertz waves. Combining a chiral metamaterial with a gated single-layer sheet of graphene, we show that transmission of a terahertz wave with one circular polarization can be electrically controlled without affecting that of the other circular polarization, leading to large-intensity modulation depths (>99%) with a low gate voltage. This effective control of polarization is made possible by the full accessibility of three coupling regimes, that is, underdamped, critically damped, and overdamped regimes by electrical control of the graphene properties.

Self-Assembly of Silver Nanowire Ring Structures Driven by the Compressive Force of a Liquid Droplet.

In a nanowire dispersed in liquid droplets, the interplay between the surface tension of the liquid and the elasticity of the nanowire determines the final morphology of the bent or buckled nanowire. Here, we investigate the fabrication of a silver nanowire ring generated as the nanowire encapsulated inside of fine droplets. We used a hybrid aerodynamic and electrostatic atomization method to ensure the generation of droplets with scalable size in the necessary regime for ring formation. We analytically calculate the compressive force of the droplet driven by surface tension as the key mechanism for the self-assembly of ring structures. Thus, for potential large-scale manufacturing, the droplet size provides a convenient parameter to control the realization of ring structures from nanowires.

Graphene-ferroelectric metadevices for nonvolatile memory and reconfigurable logic-gate operations.

Memory metamaterials are artificial media that sustain transformed electromagnetic properties without persistent external stimuli. Previous memory metamaterials were realized with phase-change materials, such as vanadium dioxide or chalcogenide glasses, which exhibit memory behaviour with respect to electrically/optically induced thermal stimuli. However, they require a thermally isolated environment for longer retention or strong optical pump for phase-change. Here we demonstrate electrically programmable nonvolatile memory metadevices realised by the hybridization of graphene, a ferroelectric and meta-atoms/meta-molecules, and extend the concept further to establish reconfigurable logic-gate metadevices. For a memory metadevice having a single electrical input, amplitude, phase and even the polarization multi-states were clearly distinguishable with a retention time of over 10 years at room temperature. Furthermore, logic-gate functionalities were demonstrated with reconfigurable logic-gate metadevices having two electrical inputs, with each connected to separate ferroelectric layers that act as the multi-level controller for the doping level of the sandwiched graphene layer.

THz near-field spectral encoding imaging using a rainbow metasurface.

We demonstrate a fast image acquisition technique in the terahertz range via spectral encoding using a metasurface. The metasurface is composed of spatially varying units of mesh filters that exhibit bandpass features. Each mesh filter is arranged such that the centre frequencies of the mesh filters are proportional to their position within the metasurface, similar to a rainbow. For imaging, the object is placed in front of the rainbow metasurface, and the image is reconstructed by measuring the transmitted broadband THz pulses through both the metasurface and the object. The 1D image information regarding the object is linearly mapped into the spectrum of the transmitted wave of the rainbow metasurface. Thus, 2D images can be successfully reconstructed using simple 1D data acquisition processes.

Rotationally reconfigurable metamaterials based on moiré phenomenon.

Exploiting moiré interference, we make a new type of reconfigurable metamaterials and study their transmission tunability for incident electromagnetic waves. The moiré pattern is formed by overlapping two transparent layers, each of which has a periodic metallic pattern, and the cluster size of the resulting moiré pattern can be varied by changing the relative superposition angle of the two layers. In our reconfigurable metamaterials, both the size and structural shape of the unit cell can be varied simultaneously through moiré interference. We show that the transmission of electromagnetic waves can be controlled from 90% to 10% at 11 GHz by experiments and numerical simulation. The reconfigurable metamaterial proposed here can be applied in bandpass filters and tunable modulation devices.

Nondispersive optical activity of meshed helical metamaterials.

Extreme optical properties can be realized by the strong resonant response of metamaterials consisting of subwavelength-scale metallic resonators. However, highly dispersive optical properties resulting from strong resonances have impeded the broadband operation required for frequency-independent optical components or devices. Here we demonstrate that strong, flat broadband optical activity with high transparency can be obtained with meshed helical metamaterials in which metallic helical structures are networked and arranged to have fourfold rotational symmetry around the propagation axis. This nondispersive optical activity originates from the Drude-like response as well as the fourfold rotational symmetry of the meshed helical metamaterials. The theoretical concept is validated in a microwave experiment in which flat broadband optical activity with a designed magnitude of 45° per layer of metamaterial is measured. The broadband capabilities of chiral metamaterials may provide opportunities in the design of various broadband optical systems and applications.

Optical activity enhanced by strong inter-molecular coupling in planar chiral metamaterials.

The polarization of light can be rotated in materials with an absence of molecular or structural mirror symmetry. While this rotating ability is normally rather weak in naturally occurring chiral materials, artificial chiral metamaterials have demonstrated extraordinary rotational ability by engineering intra-molecular couplings. However, while in general, chiral metamaterials can exhibit strong rotatory power at or around resonances, they convert linearly polarized waves into elliptically polarized ones. Here, we demonstrate that strong inter-molecular coupling through a small gap between adjacent chiral metamolecules can lead to a broadband enhanced rotating ability with pure rotation of linearly polarized electromagnetic waves. Strong inter-molecular coupling leads to nearly identical behaviour in magnitude, but engenders substantial difference in phase between transmitted left and right-handed waves.

A case of malignant granular cell tumor in the sigmoid colon.

Granular cell tumor (GCT) is an uncommon, usually benign neoplasm; however, a malignant potential has been described. Malignant GCT is an extremely rare neoplasm showing rapid growth and invasion into adjacent muscles, lymph nodes, or vessels, or even distant metastasis. We recently experienced a case of a histologically benign or atypical but clinically malignant GCT, with invasion of the lymph nodes and vessels in the sigmoid colon, diagnosed by segmental colon resection with lymph node dissection. We also performed a review of relevant medical literature.

Neuromuscular junction in a microfluidic device.

Malfunctions at the site of neuromuscular junction (NMJ) of post-injuries or diseases are major barriers to recovery of function. The ability to efficiently derive motor neurons (MN) from embryonic stem cells has indicated promise toward the development of new therapies in increasing functional outcomes post injury. Recent advances in micro-technologies have provided advanced culture platforms allowing compartmentalization of sub-cellular components of neurons. In this study, we combined these advances in science and technology to develop a compartmentalized in vitro NMJ model. The developed NMJ system is between mouse embryonic stem cell (mESC)-derived MNs and c2c12 myotubes cultured in a compartmentalized polydimethylsiloxane (PDMS) microfluidic device. While some functional in vitro NMJ systems have been reported, this system would further contribute to research in NMJ-related diseases by providing a system to study the site of action of NMJ aimed at improving promoting better functional recovery.

The role of Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans in arsenic bioleaching from soil.

Bioleaching of As from the soil in an abandoned Ag-Au mine was carried out using Acidithiobacillus ferrooxidans and Acidithiobacillus thiooxidans. A. ferrooxidans is an iron oxidizer and A. thiooxidans is a sulfur oxidizer. These two microbes are acidophilic and chemoautotrophic microbes. Soil samples were collected from the Myoungbong and Songcheon mines. The main contaminant of the soil was As, with an average concentration of 4,624 mg/kg at Myoungbong and 5,590 mg/kg at Songcheon. A. ferrooxidans and A. thiooxidans generated lower pH conditions during their metabolism process. The bioleaching of As from soil has a higher removal efficiency than chemical leaching. A. ferrooxidans could remove 70 % of the As from the Myoungbong and Songcheon soils; however, A. thiooxidans extracted only 40 % of the As from the Myoungbong soil. This study shows that bioleaching is an effective process for As removal from soil.

Immobilization of lysozyme-CLEA onto electrospun chitosan nanofiber for effective antibacterial applications.

Chitosan (CS) nanofibers with a diameter of 150-200nm were fabricated from a mixed chitosan/poly (vinyl alcohol) (PVA) solution by the electrospinning method. The nascent CS/PVA nanofibers were treated with 0.5M NaOH solution to make stable CS nanofibers by removing PVA under aqueous conditions. Hen egg-white lysozyme was immobilized on electrospun CS nanofibers via cross-linked enzyme aggregates (CLEAs) and used for effective and continuous antibacterial applications. The maximum amount of lysozyme immobilized on the CS nanofibers was determined to be 62.3mg/g of nanofibers under the optimum conditions. The immobilized lysozyme-CLEA retained more than 75.4% of its initial activity after 80 days of storage at room temperature, while the free lysozyme lost all of its activity under the same conditions. In addition, the immobilized lysozyme-CLEA retained more than 76% of its activity after 100 consecutive uses. Finally, the durability of the lysozyme-CLEA immobilized CS nanofibers showed bacteriostasis ratios of 82.4%, 79.8%, 83.4%, and 84.1% after 10 cycles against 4 pathogenic bacteria, viz. Staphylococcus aureus, Bacillus subtilis, Shigella flexneri, and Psedomonas aeruginosa, respectively. These results demonstrated that lysozyme-CLEA immobilized CS nanofibers could be used as a promising material for enhanced and continuous antibacterial applications.

[The prevalence of Barrett's esophagus and the comparison of Barrett's esophagus with cardiac intestinal metaplasia in the health screening at a secondary care hospital].

BACKGROUND/AIMS: The purpose of this study was to estimate the prevalence of Barrett's esophagus (BE) and its association with reflux esophagitis (RE) and peptic ulcer disease detected by free charge endoscopy which was covered by the National Health Insurance at a secondary care hospital, and to compare the results of the biopsy of BE with that of cardiac intestinal metaplasia (CIM). METHODS: A total of 4,002 patients underwent endoscopy from March 2010 to December 2012. BE was diagnosed if there was histologically proven specialized intestinal metaplasia, and CIM was diagnosed if intestinal metaplasia was accompanied with chronic gastritis. RESULTS: Four hundred twenty four patients underwent endoscopic biopsy, and the prevalence of BE was 1.0% (42/4,002). The mean age and the proportion of males in BE were significantly higher than those of the rest of study population, and BE had slight tendency related to RE than the rest of study population. CIM was observed in 34 patients and BE and CIM showed similar results, regarding age, sex and association with RE. The mean length of endoscopic Barrett's mucosa of BE group was 9.2±5.1 mm, and it was similar to that of CIM. CONCLUSIONS: The prevalence of BE in the secondary care hospital was not low, and old age and male sex were significantly associated with BE. Because BE was observed in about 10% of biopsied patients and CIM was observed in a similar percentage with BE, the precise targeted biopsy is warranted and the biopsy method should be reestablished through the large prospective study of multiple secondary care hospitals.