Observation of stacking engineered magnetic phase transitions within moiré supercells of twisted van der Waals magnets.

Recent demonstrations of moiré magnetism, featuring exotic phases with noncollinear spin order in the twisted van der Waals (vdW) magnet chromium triiodide CrI3, have highlighted the potential of twist engineering of magnetic (vdW) materials. However, the local magnetic interactions, spin dynamics, and magnetic phase transitions within and across individual moiré supercells remain elusive. Taking advantage of a scanning single-spin magnetometry platform, here we report observation of two distinct magnetic phase transitions with separate critical temperatures within a moiré supercell of small-angle twisted double trilayer CrI3. By measuring temperature-dependent spin fluctuations at the coexisting ferromagnetic and antiferromagnetic regions in twisted CrI3, we explicitly show that the Curie temperature of the ferromagnetic state is higher than the Néel temperature of the antiferromagnetic one by ~10 K. Our mean-field calculations attribute such a spatial and thermodynamic phase separation to the stacking order modulated interlayer exchange coupling at the twisted interface of moiré superlattices.

Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncovers Skp2 function in metastasis, genomic instability and immune activation and reveals additional target pathways.

Osteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target is SKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout of Skp2 in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout of Rb1 and Trp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption of Skp2: one with Skp2 knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in the Skp2 disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in the Skp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in the Skp2 knockout mice. Finally, we report several potential mechanisms of escape from targeting Skp2 in OS, including upregulation of Myc targets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology and Skp2 function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.

New anti-adipogenic triterpenoid saponins from the aerial parts of Glinus oppositifolius.

Glinus oppositifolius L., a member of the Molluginaceae family, has a long-standing history of utilization as both a vegetable and a medicinal agent across numerous countries. This plant possesses a diverse range of pharmacological activities and attracts scientific interest in studying its chemical profile. The present phytochemical investigation of the plant resulted in the isolation of eleven new triterpenoid saponins, accompanied by three known compounds. Their structures were elucidated by intensive spectroscopic analysis, DFT calculations, and comparison with previously reported data. The isolates were evaluated for their anti-adipogenic effect and cytotoxicity against human cancer cell lines, namely, colorectal carcinoma HCT116, hepatoblastoma cell HepG2, breast cancer cell MDA-MB-231, and human lung adenocarcinoma cell A549. Compounds 5, 7, and 13 exhibited a potent inhibitory effect against the differentiation of preadipocyte 3T3-L1. In addition, compound 13 displayed inhibitory effects against the growth of A549 cancer cells.

MiR-29 and MiR-140 regulate TRAIL-induced drug tolerance in lung cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has chemotherapeutic potential as a regulator of an extrinsic apoptotic ligand, but its effect as a drug is limited by innate and acquired resistance. Recent findings suggest that an intermediate drug tolerance could mediate acquired resistance, which has made the main obstacle for limited utility of TRAIL as an anti-cancer therapeutics. We propose miRNA-dependent epigenetic modification drives the drug tolerant state in TRAIL-induced drug tolerant (TDT). Transcriptomic analysis revealed miR-29 target gene activation in TDT cells, showing oncogenic signature in lung cancer. Also, the restored TRAIL-sensitivity was associated with miR-29ac and 140-5p expressions, which is known as tumor suppressor by suppressing oncogenic protein RSK2 (p90 ribosomal S6 kinase), further confirmed in patient samples. Moreover, we extended this finding into 119 lung cancer cell lines from public data set, suggesting a significant correlation between TRAIL-sensitivity and RSK2 mRNA expression. Finally, we found that increased RSK2 mRNA is responsible for NF-κB activation, which we previously showed as a key determinant in both innate and acquired TRAIL-resistance. Our findings support further investigation of miR-29ac and -140-5p inhibition to maintain TRAIL-sensitivity and improve the durability of response to TRAIL in lung cancer.

Methanol extract of Elsholtzia fruticosa promotes 3T3-L1 preadipocyte differentiation.

Elsholtzia fruticosa (EF) is present in tropical regions throughout South Asian countries as well as the Himalayas. Although it has been used as a traditional medicine to treat digestive, respiratory, and inflammatory issues, its effect on preadipocyte differentiation is unknown. In this study, we examined the effects of a methanol extract prepared from EF on the differentiation of 3T3-L1 preadipocytes. Cell differentiation was assessed by microscopic observation and oil-red O staining. The expression of adipogenic and lipogenic genes, including PPARγ and C/EBPα, was measured by western blot analysis and quantitative real-time polymerase chain reaction (qRT-PCR), to provide insight into adipogenesis and lipogenesis mechanisms. The results indicated that EF promotes the differentiation of 3T3-L1 preadipocytes, with elevated lipid accumulation occurring in a concentration-dependent manner without apparent cytotoxicity. EF enhances the expression of adipogenic and lipogenic genes, including PPARγ, FABP4, adiponectin, and FAS, at the mRNA and protein levels. The effect of EF was more pronounced during the early and middle stages of 3T3-L1 cell differentiation. Treatment with EF decreased C/EBP homologous protein (CHOP) mRNA and protein levels, while increasing C/EBPα and PPARγ expression. Treatment with EF resulted in the upregulation of cyclin E and CDK2 gene expression within 24 h, followed by a decrease at 48 h, demonstrating the early-stage impact of EF. A concomitant increase in cyclin-D1 levels was observed compared with untreated cells, indicating that EF modulates lipogenic and adipogenic genes through intricate mechanisms involving CHOP and cell cycle pathways. In summary, EF induces the differentiation of 3T3-L1 preadipocytes by increasing the expression of adipogenic and lipogenic genes, possibly through CHOP and cell cycle-dependent mechanisms.

Stellera chamaejasme L. extract inhibits adipocyte differentiation through activation of the extracellular signal-regulated kinase pathway.

Stellera chamaejasme L. (SCL) is a perennial herb with demonstrated bioactivities against inflammation and metabolic dysfunction. Adipocyte differentiation is a critical regulator of metabolic homeostasis and a promising target for the treatment of metabolic diseases, so we examined the effects of SCL on adipogenesis. A methanol extract of SCL dose-dependently suppressed intracellular lipid accumulation in adipocyte precursors cultured under differentiation induction conditions and reduced expression of the adipogenic transcription factors PPARγ and C/EBPα as well as the downstream lipogenic genes fatty acid binding protein 4, adiponectin, fatty acid synthase, and stearoyl-CoA desaturase. The extract also promoted precursor cell proliferation and altered expression of the cell cycle regulators cyclin-dependent kinase 4, cyclin E, and cyclin D1. In addition, SCL extract stimulated extracellular signal-regulated kinase (ERK) phosphorylation, while pharmacological inhibition of ERK effectively blocked the inhibitory effects of SCL extract on preadipocyte differentiation. These results suggest that SCL extract contains bioactive compounds that can suppress adipogenesis through modulation of the ERK pathway.

CREB5 promotes the proliferation and self-renewal ability of glioma stem cells.

Glioblastoma multiforme (GBM) is the most fatal form of brain cancer in humans, with a dismal prognosis and a median overall survival rate of less than 15 months upon diagnosis. Glioma stem cells (GSCs), have recently been identified as key contributors in both tumor initiation and therapeutic resistance in GBM. Both public dataset analysis and direct differentiation experiments on GSCs have demonstrated that CREB5 is more highly expressed in undifferentiated GSCs than in differentiated GSCs. Additionally, gene silencing by short hairpin RNA (shRNA) of CREB5 has prevented the proliferation and self-renewal ability of GSCs in vitro and decreased their tumor forming ability in vivo. Meanwhile, RNA-sequencing, luciferase reporter assay, and ChIP assay have all demonstrated the closely association between CREB5 and OLIG2. These findings suggest that targeting CREB5 could be an effective approach to overcoming GSCs.

Automated Quantification of Total Cerebral Blood Flow from Phase-Contrast MRI and Deep Learning.

Knowledge of input blood to the brain, which is represented as total cerebral blood flow (tCBF), is important in evaluating brain health. Phase-contrast (PC) magnetic resonance imaging (MRI) enables blood velocity mapping, allowing for noninvasive measurements of tCBF. In the procedure, manual selection of brain-feeding arteries is an essential step, but is time-consuming and often subjective. Thus, the purpose of this work was to develop and validate a deep learning (DL)-based technique for automated tCBF quantifications. To enhance the DL segmentation performance on arterial blood vessels, in the preprocessing step magnitude and phase images of PC MRI were multiplied several times. Thereafter, a U-Net was trained on 218 images for three-class segmentation. Network performance was evaluated in terms of the Dice coefficient and the intersection-over-union (IoU) on 40 test images, and additionally, on externally acquired 20 datasets. Finally, tCBF was calculated from the DL-predicted vessel segmentation maps, and its accuracy was statistically assessed with the correlation of determination (R2), the intraclass correlation coefficient (ICC), paired t-tests, and Bland-Altman analysis, in comparison to manually derived values. Overall, the DL segmentation network provided accurate labeling of arterial blood vessels for both internal (Dice=0.92, IoU=0.86) and external (Dice=0.90, IoU=0.82) tests. Furthermore, statistical analyses for tCBF estimates revealed good agreement between automated versus manual quantifications in both internal (R2=0.85, ICC=0.91, p=0.52) and external (R2=0.88, ICC=0.93, p=0.88) test groups. The results suggest feasibility of a simple and automated protocol for quantifying tCBF from neck PC MRI and deep learning.

Endotaxial stabilization of 2D charge density waves with long-range order.

Charge density waves are emergent quantum states that spontaneously reduce crystal symmetry, drive metal-insulator transitions, and precede superconductivity. In low-dimensions, distinct quantum states arise, however, thermal fluctuations and external disorder destroy long-range order. Here we stabilize ordered two-dimensional (2D) charge density waves through endotaxial synthesis of confined monolayers of 1T-TaS2. Specifically, an ordered incommensurate charge density wave (oIC-CDW) is realized in 2D with dramatically enhanced amplitude and resistivity. By enhancing CDW order, the hexatic nature of charge density waves becomes observable. Upon heating via in-situ TEM, the CDW continuously melts in a reversible hexatic process wherein topological defects form in the charge density wave. From these results, new regimes of the CDW phase diagram for 1T-TaS2 are derived and consistent with the predicted emergence of vestigial quantum order.

Osteochondral Repair with Autologous Cartilage Transplantation with or without Bone Grafting: A Short Pilot Study in Mini-Pigs.

OBJECTIVE: Treatment strategies for osteochondral defects, for which particulated autologous cartilage transplantation (PACT) is an emerging treatment strategy, aim to restore the structure and function of the hyaline cartilage. Herein, we compared the efficacy of PACT with control or human transforming growth factor-ß (rhTGF-ß), and clarified the necessity of bone graft (BG) with PACT to treat shallow osteochondral defects in a porcine model. DESIGN: Two skeletally mature male micropigs received 4 osteochondral defects in each knee. The 16 defects were randomized to (1) empty control, (2) PACT, (3) PACT with BG, or (4) rhTGF-ß. Animals were euthanized after 2 months and histomorphometry, immunofluorescence analysis, semiquantitative evaluation (O'Driscoll score), and magnetic resonance observation of cartilage repair tissue (MOCART) score were performed. RESULTS: Hyaline cartilages, glycosaminoglycan synthesis, and collagen type II staining were more abundant in the PACT than in the control and rhTGF-ß groups. The O'Driscoll score was significantly different between groups (P < 0.001), with both PACT groups showing superiority (P = 0.002). PACT had the highest score (P = 0.002), with improved restoration of subchondral bone compared with PACT with BG. The MOCART score showed significant differences between groups (P = 0.021); MOCART and O'Driscoll scores showed high correlation (r = 0.847, P < 0.001). CONCLUSION: Treatment of osteochondral defects with PACT improved tissue quality compared with that with control or rhTGF-ß in a porcine model. BG, in addition to PACT, may be unnecessary for shallow osteochondral defects. Clinical Relevance. BG may not be necessary while performing PACT.

Development and evaluation of simulation-based scenario education program for professional oral hygiene care in intubated patient.

PURPOSE: This study was conducted to develop a professional oral hygiene care (POHC) simulation education program for intubated patients and to evaluate the suitability of education by evaluating the performance confidence (PC), critical thinking disposition (CT), and learning satisfaction (LS) of dental hygiene students. METHODS: This study developed a POHC simulation education program (theory, skill training, scenario education, and debriefing) for intubated patients through expert validation and consisted of a single-group pre- and postexperiment design. The subjects were 3rd and 4th year students at the Department of Dental Hygiene in Wonju City, and a total of 30 people were enrolled. The collected data were analyzed using the PASW Statistics version 23.0. The content validity test was measured by the CVI (Content validity index) value, and the PC, CT, and LS of the subjects before and after participating in the program were analyzed using a paired t-test. The significance level (α) was based on .05. RESULTS: After the program, the PC improved from 4.29 ± 0.43 to 4.54 ± 0.44, and there was a significant difference (p = .004). CT improved from 3.73 ± 0.36 to 3.84 ± 0.36, but there was no significant difference (p = .062), and prudence improved from 4.21 ± 0.33 to 4.43 ± 0.27, and there was significant difference. (p = .001). LS increased from 4.66 ± 0.36 to 4.90 ± 0.16 after education, and there was a significant difference (p = .002). CONCLUSION(S): Simulation education program improved dental hygiene students' POHC performance confidence. Various scenarios will need to be developed in the future, and it is necessary to evaluate simulation education within the dental hygiene curriculum and identify areas for improvement.

Revealing intrinsic domains and fluctuations of moiré magnetism by a wide-field quantum microscope.

Moiré magnetism featured by stacking engineered atomic registry and lattice interactions has recently emerged as an appealing quantum state of matter at the forefront of condensed matter physics research. Nanoscale imaging of moiré magnets is highly desirable and serves as a prerequisite to investigate a broad range of intriguing physics underlying the interplay between topology, electronic correlations, and unconventional nanomagnetism. Here we report spin defect-based wide-field imaging of magnetic domains and spin fluctuations in twisted double trilayer (tDT) chromium triiodide CrI3. We explicitly show that intrinsic moiré domains of opposite magnetizations appear over arrays of moiré supercells in low-twist-angle tDT CrI3. In contrast, spin fluctuations measured in tDT CrI3 manifest little spatial variations on the same mesoscopic length scale due to the dominant driving force of intralayer exchange interaction. Our results enrich the current understanding of exotic magnetic phases sustained by moiré magnetism and highlight the opportunities provided by quantum spin sensors in probing microscopic spin related phenomena on two-dimensional flatland.