Brain organoids derived from human pluripotent stem cells provide a highly valuable in vitro model to recapitulate human brain development and neurological diseases. However, the current systems for ...brain organoid culture require further improvement for the reliable production of high-quality organoids. Here, we demonstrate two engineering elements to improve human brain organoid culture, (1) a human brain extracellular matrix to provide brain-specific cues and (2) a microfluidic device with periodic flow to improve the survival and reduce the variability of organoids. A three-dimensional culture modified with brain extracellular matrix significantly enhanced neurogenesis in developing brain organoids from human induced pluripotent stem cells. Cortical layer development, volumetric augmentation, and electrophysiological function of human brain organoids were further improved in a reproducible manner by dynamic culture in microfluidic chamber devices. Our engineering concept of reconstituting brain-mimetic microenvironments facilitates the development of a reliable culture platform for brain organoids, enabling effective modeling and drug development for human brain diseases.
The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and ...chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.
Gene expression data from a TCGA cohort (
= 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (
= 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.
EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (
= 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor HR, 1.5; 95% confidence interval (CI), 1.2-1.9;
= 0.001. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16-0.94;
= 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36-1.89;
= 0.65).
Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted.
Matrigel, a mouse tumor extracellular matrix protein mixture, is an indispensable component of most organoid tissue culture. However, it has limited the utility of organoids for drug development and ...regenerative medicine due to its tumor-derived origin, batch-to-batch variation, high cost, and safety issues. Here, we demonstrate that gastrointestinal tissue-derived extracellular matrix hydrogels are suitable substitutes for Matrigel in gastrointestinal organoid culture. We found that the development and function of gastric or intestinal organoids grown in tissue extracellular matrix hydrogels are comparable or often superior to those in Matrigel. In addition, gastrointestinal extracellular matrix hydrogels enabled long-term subculture and transplantation of organoids by providing gastrointestinal tissue-mimetic microenvironments. Tissue-specific and age-related extracellular matrix profiles that affect organoid development were also elucidated through proteomic analysis. Together, our results suggest that extracellular matrix hydrogels derived from decellularized gastrointestinal tissues are effective alternatives to the current gold standard, Matrigel, and produce organoids suitable for gastrointestinal disease modeling, drug development, and tissue regeneration.
Inflammation caused by the excessive secretion of inflammatory mediators in abnormally activated macrophages promotes many diseases along with oxidative stress. Loganin, a major iridoid glycoside ...isolated from Cornus officinalis, has recently been reported to exhibit anti-inflammatory and antioxidant effects, whereas the underlying mechanism has not yet been fully clarified. Therefore, the aim of the present study is to investigate the effect of loganin on inflammation and oxidative stress in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Our results indicated that loganin treatment markedly attenuated the LPS-mediated phagocytic activity and release of nitric oxide (NO) and prostaglandin E2, which was associated with decreased the expression of inducible NO synthase and cyclooxygenase-2. In addition, loganin suppressed the expression and their extracellular secretion of LPS-induced pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β. Furthermore, loganin abolished reactive oxygen species (ROS) generation, and promoted the activation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated macrophages. However, zinc protoporphyrin, a selective HO-1 inhibitor, reversed the loganin-mediated suppression of pro-inflammatory cytokines in LPS-treated macrophages. In conclusion, our findings suggest that the upregulation of the Nrf2/HO-1 signaling pathway is concerned at least in the protective effect of loganin against LPS-mediated inflammatory and oxidative stress, and that loganin can be a potential functional agent to prevent inflammatory and oxidative damage.
Controlling the crystallinity and surface morphology of perovskite layers by methods such as solvent engineering
and methylammonium chloride addition
is an effective strategy for achieving ...high-efficiency perovskite solar cells. In particular, it is essential to deposit α-formamidinium lead iodide (FAPbI
) perovskite thin films with few defects due to their excellent crystallinity and large grain size. Here we report the controlled crystallization of perovskite thin films with the combination of alkylammonium chlorides (RACl) added to FAPbI
. The δ-phase to α-phase transition of FAPbI
and the crystallization process and surface morphology of the perovskite thin films coated with RACl under various conditions were investigated through in situ grazing-incidence wide-angle X-ray diffraction and scanning electron microscopy. RACl added to the precursor solution was believed to be easily volatilized during coating and annealing owing to dissociation into RA
and HCl with deprotonation of RA
induced by RA⋯H
-Cl
binding to PbI
in FAPbI
. Thus, the type and amount of RACl determined the δ-phase to α-phase transition rate, crystallinity, preferred orientation and surface morphology of the final α-FAPbI
. The resulting perovskite thin layers facilitated the fabrication of perovskite solar cells with a power-conversion efficiency of 26.08% (certified 25.73%) under standard illumination.
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The aim of the Korean Imatinib Discontinuation Study was to identify predictors for safe and successful imatinib discontinuation. A total of 90 patients with a follow-up of ≥12 months were analyzed. ...After a median follow-up of 26.6 months after imatinib discontinuation, 37 patients lost the major molecular response. The probability of sustained major molecular response at 12 months and 24 months was 62.2% and 58.5%, respectively. All 37 patients who lost major molecular response were retreated with imatinib therapy for a median of 16.9 months, and all achieved major molecular response again at a median of 3.9 months after resuming imatinib therapy. We observed newly developed or worsened musculoskeletal pain and pruritus in 27 (30%) patients after imatinib discontinuation. Imatinib withdrawal syndrome was associated with a higher probability of sustained major molecular response (P=0.003) and showed a trend for a longer time to major molecular response loss (P=0.098). Positivity (defined as ≥ 17 positive chambers) of digital polymerase chain reaction at screening and longer imatinib duration before imatinib discontinuation were associated with a higher probability of sustained major molecular response. Our data demonstrated that the occurrence of imatinib withdrawal syndrome after imatinib discontinuation and longer duration of imatinib were associated with a lower rate of molecular relapse. In addition, minimal residual leukemia measured by digital polymerase chain reaction had a trend for a higher molecular relapse. (Trial registered at ClinicalTrials.gov: NCT01564836).
Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial ...phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response.
With the increasing demands of indoor air quality monitoring, highly sensitive and selective gas sensor arrays consisting of metal oxide semiconductors have been increasingly studied. As an effective ...strategy to obtain the desired performance, noble metal functionalization is frequently chosen owing to its target-specific sensing mechanisms. However, the lack of a comprehensive analysis on the sensing mechanisms of different combinations of metal oxides and noble metals limit the versatility of these sensor arrays for use in selective gas sensor arrays. In this study, we fabricate a 3 × 3 gas sensor array to obtain a reliable comparison of the sensing mechanism through the use of three metal oxides—WO3, SnO2 and NiO—in three different nanostructure forms: a thin film and dome-like nanostructures with and without Au nanoparticle (NP) decoration. The responses of the sensor arrays to four target gases (CH3COCH3, C6H5CH3, NH3, and H2S) are generally enhanced by the dome-like nanostructure and show distinctively enhanced responses when the sensors are decorated with Au NPs. Moreover, the dome-like SnO2 with Au NPs shows an increase of up to 121 times for C6H5CH3 compared with the pristine SnO2 thin film. Additionally, the sensitization effects of Au NPs depend on the types of metal oxides and gases, which improve the gas discrimination capability by diversifying the gas selectivity of the sensor units in the array. The prepared sensor array can distinguish four target gases by principal component analysis (PCA). The contributions of different enhancement mechanisms, which are dependent on the gases and metal oxides, are investigated by comparing the activation energy of each gas response with and without Au. The comparison among the chosen gases reveals that the decoration of Au NPs is effective for C6H5CH3 and NH3 regardless of the type of metal oxide. Among the metal oxides, the effects of Au NPs on gas responses are in the order of SnO2, NiO, and WO3, in which the energy level difference between the Au NPs and metal oxide are 0.2, 0.1, and −0.6 eV, respectively. These results confirm that the dominant enhancement mechanism of Au NPs for each combination of gases and metal oxide is a decrease in activation energy. Therefore, this study provides a systematic understanding of the sensitization mechanism of Au NPs on metal oxides toward gases for the fabrication of selective gas sensor arrays.
Biocatalytic cyclization is highly desirable for efficient synthesis of biologically derived chemical substances, such as the commodity chemicals ε-caprolactam and δ-valerolactam. To identify ...biocatalysts in lactam biosynthesis, we develop a caprolactam-detecting genetic enzyme screening system (CL-GESS). The Alcaligenes faecalis regulatory protein NitR is adopted for the highly specific detection of lactam compounds against lactam biosynthetic intermediates. We further systematically optimize the genetic components of the CL-GESS to enhance sensitivity, achieving 10-fold improvement. Using this highly sensitive GESS, we screen marine metagenomes and find an enzyme that cyclizes ω-amino fatty acids to lactam. Moreover, we determine the X-ray crystal structure and catalytic residues based on mutational analysis of the cyclase. The cyclase is also used as a helper enzyme to sense intracellular ω-amino fatty acids. We expect this simple and accurate biosensor to have wide-ranging applications in rapid screening of new lactam-synthesizing enzymes and metabolic engineering for lactam bio-production.
This article reviews recent fabrication methods for surface‐enhanced Raman spectroscopy (SERS) substrates with a focus on advanced nanoarchitecture based on noble metals with special nanospaces ...(round tips, gaps, and porous spaces), nanolayered 2D materials, including hybridization with metallic nanostructures (NSs), and the contemporary repertoire of nanoarchitecturing with organic molecules. The use of SERS for multidisciplinary applications has been extensively investigated because the considerably enhanced signal intensity enables the detection of a very small number of molecules with molecular fingerprints. Nanoarchitecture strategies for the design of new NSs play a vital role in developing SERS substrates. In this review, recent achievements with respect to the special morphology of metallic NSs are discussed, and future directions are outlined for the development of available NSs with reproducible preparation and well‐controlled nanoarchitecture. Nanolayered 2D materials are proposed for SERS applications as an alternative to the noble metals. The modern solutions to existing limitations for their applications are described together with the state‐of‐the‐art in bio/environmental SERS sensing using 2D materials‐based composites. To complement the existing toolbox of plasmonic inorganic NSs, hybridization with organic molecules is proposed to improve the stability of NSs and selectivity of SERS sensing by hybridizing with small or large organic molecules.
A summary of advances in developing surface‐enhanced Raman spectroscopy (SERS)‐active substrates via fabrication methods of nanostructured metals and 2D materials is provided. Approaches for controlling metal tips/gaps/pores including advantages and disadvantages are discussed. Moreover, recent advances and challenges of novel 2D‐layered SERS‐active substrates are presented. Functionalization strategies for SERS surfaces include use of small or large molecules to complement the preparation procedures.
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