Condensation of preformed charge density waves in kagome metals.

Charge density wave (CDW) is a spontaneous spatial modulation of charges in solids whose general microscopic descriptions are yet to be completed. Kagome metals of AV3Sb5 (A = K, Rb, Cs) provide a chance to realize CDW intertwined with dimensional effects as well as their special lattice. Here, based on a state-of-the-art molecular dynamics simulation, we propose that their phase transition to CDW is a condensation process of incoherently preformed charge orders. Owing to unavoidable degeneracy in stacking charge orders, phases of preformed orders on each layer are shown to fluctuate between a limited number of states with quite slower frequencies than typical phonon vibrations until reaching their freezing temperature. As the size of interfacial alkali atom increases, the fluctuations are shown to counterbalance the condensation of orderings, resulting in a maximized transition temperature for RbV3Sb5. Our results resolve controversial observations on their CDWs, highlighting a crucial role of their interlayer interactions.

Computational Analysis of miR-140 and miR-135 as Potential Targets to Develop Combinatorial Therapeutics for Degenerative Tendinopathy.

Background: Degenerative tendinopathy, a condition causing movement restriction due to high pain, highly impacts productivity and quality of life. The healing process is a complex phenomenon and involves a series of intra-cellular and inter-cellular processes. Proliferation and differentiation of the tenocyte is a major and essential process to heal degenerative tendinopathy. The recent development in microRNA (miRNA)-mediated reprogramming of the cellular function through specific pathways opened door for the development of new regenerative therapeutics. Based on information about gene expression and regulation of tendon injury and healing, we attempted to evaluate the combinatorial effect of selected miRNAs for better healing of degenerative tendinopathy. Methods: The present study was designed to evaluate the combinatorial effect of two miRNAs (has-miR-140 and has-miR-135) in the healing process of the tendon. Publicly available information/data were retrieved from appropriate platforms such as PubMed. Only molecular data, directly associated with tendinopathies, including genes/proteins and miRNAs, were used in this study. The miRNAs involved in tendinopathy were analyzed by a Bioinformatics tools (e.g., TargetScan, miRDB, and the RNA22v2). Interactive involvement of the miRNAs with key proteins involved in tendinopathy was predicted by the Insilco approach. Results: Based on information available in the public domain, tendon healing-associated miRNAs were predicted to explore their therapeutic potentials. Based on computation analysis, focusing on the potential regulatory effect on tendon healing, the miR-135 and miR-140 were selected for this study. These miRNAs were found as key players in tendon healing through Rho-associated coiled-coil containing protein kinase 1 (ROCK1), IGF-1/PI3K/Akt, PIN, and Wnt signaling pathways. It was also predicted that these miRNAs may reprogram the cells to induce proliferation and differentiation activity. Many miRNAs are likely to regulate genes important for the tendinopathy healing process, and the result of this study allows an approach for miRNA-mediated regeneration of the tenocyte for tendon healing. Based on computational analysis, the role of these miRNAs in different pathways was established, and the results provided insights into the combinatorial approach of miRNA-mediated cell reprogramming. Conclusions: In this study, the association between miRNAs and the disease was evaluated to correlate the tendinopathy genes and the relevant role of different miRNAs in their regulation. Through this study, it was established that the synergistic effect of more than one miRNA on directed reprogramming of the cell could be helpful in the regeneration of damaged tissue. It is anticipated that this study will be helpful for the design of miRNA cocktails for the orchestration of cellular reprogramming events.

Polycomb Group Protein CBX7 Represses Cardiomyocyte Proliferation Through Modulation of the TARDBP/RBM38 Axis.

BACKGROUND: Shortly after birth, cardiomyocytes exit the cell cycle and cease proliferation. At present, the regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7 (chromobox 7), a polycomb group (PcG) protein, regulates the cell cycle, but its role in cardiomyocyte proliferation is unknown. METHODS: We profiled CBX7 expression in the mouse hearts through quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse cardiomyocytes through adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (Tnnt2-Cre;Cbx7fl/+ and Myh6-MCM;Cbx7fl/fl, respectively). We measured cardiomyocyte proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. To examine the role of CBX7 in cardiac regeneration, we used neonatal cardiac apical resection and adult myocardial infarction models. We examined the mechanism of CBX7-mediated repression of cardiomyocyte proliferation through coimmunoprecipitation, mass spectrometry, and other molecular techniques. RESULTS: We explored Cbx7 expression in the heart and found that mRNA expression abruptly increased after birth and was sustained throughout adulthood. Overexpression of CBX7 through adenoviral transduction reduced proliferation of neonatal cardiomyocytes and promoted their multinucleation. On the other hand, genetic inactivation of Cbx7 increased proliferation of cardiomyocytes and impeded cardiac maturation during postnatal heart growth. Genetic ablation of Cbx7 promoted regeneration of neonatal and adult injured hearts. Mechanistically, CBX7 interacted with TARDBP (TAR DNA-binding protein 43) and positively regulated its downstream target, RBM38 (RNA Binding Motif Protein 38), in a TARDBP-dependent manner. Overexpression of RBM38 inhibited the proliferation of CBX7-depleted neonatal cardiomyocytes. CONCLUSIONS: Our results demonstrate that CBX7 directs the cell cycle exit of cardiomyocytes during the postnatal period by regulating its downstream targets TARDBP and RBM38. This is the first study to demonstrate the role of CBX7 in regulation of cardiomyocyte proliferation, and CBX7 could be an important target for cardiac regeneration.

ETV2/ER71, the key factor leading the paths to vascular regeneration and angiogenic reprogramming.

Extensive efforts have been made to achieve vascular regeneration accompanying tissue repair for treating vascular dysfunction-associated diseases. Recent advancements in stem cell biology and cell reprogramming have opened unforeseen opportunities to promote angiogenesis in vivo and generate autologous endothelial cells (ECs) for clinical use. We have, for the first time, identified a unique endothelial-specific transcription factor, ETV2/ER71, and revealed its essential role in regulating endothelial cell generation and function, along with vascular regeneration and tissue repair. Furthermore, we and other groups have demonstrated its ability to directly reprogram terminally differentiated non-ECs into functional ECs, proposing ETV2/ER71 as an effective therapeutic target for vascular diseases. In this review, we discuss the up-to-date status of studies on ETV2/ER71, spanning from its molecular mechanism to vasculo-angiogenic role and direct cell reprogramming toward ECs. Furthermore, we discuss future directions to deploy the clinical potential of ETV2/ER71 as a novel and potent target for vascular disorders such as cardiovascular disease, neurovascular impairment and cancer.

Protocol for the induction of hindlimb ischemia and isolation of muscle endothelial cells in mice.

A mouse model of hindlimb ischemia is an important tool for studying diverse therapeutic approaches for vascularization with high surgical success and low mortality rates. Here, we present a protocol for the induction of hindlimb ischemia in mice, including the surgery procedure and steps to analyze blood perfusion in the ischemic area using a laser speckle contrast analyzer. We also detail the isolation of endothelial cells from thigh muscles using flow cytometry after ischemic surgery. For complete details on the use and execution of this protocol, please refer to Park et al. (2016).1.

Comparison of Primary Versus Revision Lumbar Discectomy Using a Biportal Endoscopic Technique.

STUDY DESIGN: Retrospective study. OBJECTIVE: To compare the clinical outcomes of the biportal endoscopic technique for primary lumbar discectomy (BE-LD) and revision lumbar discectomy (BE-RLD). METHODS: Eighty-one consecutive patients who underwent BE-LD or BE-RLD, and could be followed up for at least 12 months were divided into two groups: Group A (BE-LD; n = 59) and Group B (BE-RLD; n = 22). Clinical outcomes included the visual analog scale (VAS), Oswestry Disability Index (ODI), and modified MacNab's criteria. Perioperative results included operation time (OT), length of hospital stay (LOS), amount of surgical drain, and kinetics of serum creatine phosphokinase (CPK) and C-reactive protein (CRP). Clinical and perioperative outcomes were assessed preoperatively and postoperatively at 2 days and at 3, 6, and 12 months. Postoperative complications were noted. RESULTS: Both groups showed significant improvement in pain (VAS) and disability (ODI) compared to baseline values at postoperative day 2, which lasted until the final follow-up. There were no significant differences in the improvement of the VAS and ODI scores between the groups. According to the modified MacNab's criteria, 88.1 and 90.9% of the patients were excellent or good in groups A and B, respectively. OT, LOS, amount of surgical drain, and kinetics in serum CRP and CPK levels were comparable. Complications in Group A included incidental durotomy (n = 2), epidural hematoma (n = 1), and local recurrence (n = 1) and in Group B incidental durotomy (n = 1) and epidural hematoma (n = 1). CONCLUSION: BE-RLD showed favorable clinical outcomes, less postoperative pain, and early laboratory recovery equivalent to BE-LD.

Comparison of Extracorporeal Shock Wave Therapy and Ultrasound-Guided Shoulder Injection Therapy in Patients with Supraspinatus Tendinitis.

Background: The present study compared the clinical effect of extracorporeal shock wave therapy (ESWT) with that of ultrasound (US)-guided shoulder steroid injection therapy in patients with supraspinatus tendinitis. We hypothesized that the two treatments would show comparable results. Methods: The inclusion criteria were age over 20 years and diagnosis of supraspinatus tendinitis using US. Ultimately, 26 patients were assigned using blocked randomization: 13 in the US-guided shoulder injection group and 13 in the ESWT group. Treatment outcomes were evaluated using the pain visual analog scale (pVAS), the American Shoulder and Elbow Society (ASES) score, and the Constant score at baseline and at 1 and 3 months after the procedure. Results: At 1 month after the intervention, pVAS, ASES, and constant score were significantly higher in the US-guided shoulder injection group than in the ESWT group, but not at 3 months after the intervention. Both groups showed clinically significant treatment effects at 3 months after the intervention compared to baseline. No significance was shown using equivalence testing. Conclusions: US-guided shoulder injection therapy was not superior to ESWT therapy. Considering the complications and rebound phenomenon of steroid injections, interventions using ESWT may be a good alternative to treat patients with supraspinatus tendinitis.

Role of Sr doping and external strain on relieving bottleneck of oxygen diffusion in La2-xSrxCuO4-δ.

In many complex oxides, the oxygen vacancy formation is a promising route to modify the material properties such as a superconductivity and an oxygen diffusivity. Cation substitutions and external strain have been utilized to control the concentration and diffusion of oxygen vacancies, but the mechanisms behind the controls are not fully understood. Using first-principles calculations, we find how Sr doping and external strain greatly enhances the diffusivity of oxygen vacancies in La2-xSrxCuO4-δ (LSCO) in the atomic level. In hole-doped case (2x > δ), the formation energy of an apical vacancy in the LaO layer is larger than its equatorial counterpart by 0.2 eV that the bottleneck of diffusion process is for oxygen vacancies to escape equatorial sites. Such an energy difference can be reduced and even reversed by either small strain (< 1.5%) or short-range attraction between Sr and oxygen vacancy, and in turn, the oxygen diffusivity is greatly enhanced. For fully compensated hole case (2x ≦ δ), the formation energy of an apical vacancy becomes too high that most oxygen vacancies cannot move but would be trapped at equatorial sites. From our electronic structure analysis, we found that the contrasting change in the formation energy by Sr doping and external strain is originated from the different localization natures of electron carrier from both types of oxygen vacancies.

Calculation of charge density wave phase diagram by interacting eigenmodes method.

Patterns and periods of charge density waves (CDWs) in transition metal dichalcogenides exhibit complex phase diagrams that depend on pressure, temperature, metal intercalation, or chalcogen alloying. The phase diagrams have been understood in the context of Landau free energy model which explains the lock-in behavior in the commensurate-incommensurate phase transition and rotational symmetry breaking (stripe phase) in CDW phase. Here, we present that our interatomic potential energy function has not only reproduced the above behaviors in the temperature-dependent phase diagram of monolayer H-TaSe2without adjustable parameters, but also predict a new commensurate-commensurate phase transition. For the calculation, eigenmodes of the lattice potential were used for variables in the interatomic potential and CDWs are obtained as ground states of interacting eigenmodes. Unlike Landau model, the parameters in our potential energy function are directly calculated from first-principles. Our work explicitly shows how the aforementioned behaviors in CDW phase transition are related with the lattice anharmonicity.

Topography inversion in scanning tunneling microscopy of single-atom-thick materials from penetrating substrate states.

Scanning tunneling microscopy (STM) is one of the indispensable tools to characterize surface structures, but the distinction between atomic geometry and electronic effects based on the measured tunneling current is not always straightforward. In particular, for single-atomic-thick materials (graphene or boron nitride) on metallic substrates, counterintuitive phenomena such as a larger tunneling current for insulators than for metal and a topography opposite to the atomic geometry are reported. Using first-principles density functional theory calculations combined with analytical modeling, we reveal the critical role of penetrating states of metallic substrates that surpass 2D material states, hindering the measurement of intrinsic 2D materials states and leading to topography inversion. Our finding should be instrumental in the interpretation of STM topographies of atomic-thick materials and in the development of 2D material for (opto)electronic and various quantum applications.

Evaluation of the efficacy and safety of conventional and biportal endoscopic decompressive laminectomy in patients with lumbar spinal stenosis (ENDO-B trial): a protocol for a prospective, randomized, assessor-blind, multicenter trial.

BACKGROUND: Recent studies on biportal endoscopic spine surgery in patients with lumbar spinal stenosis have reported good clinical results. However, these studies have been limited by the small sample sizes and use of a retrospective study design. Therefore, we aim to compare the efficacy and safety of biportal endoscopic decompressive laminectomy with those of conventional decompressive laminectomy in a multicenter, prospective, randomized controlled trial. METHODS: This study will include 120 patients (60 per group, aged 20-80 years) with 1- or 2-level lumbar spinal stenosis, who will be recruited from six hospitals. The study will be conducted from July 2021 to December 2024. The primary outcome (Oswestry Disability Index at 12 months after surgery) will be evaluated through a modified intention-to-treat method. The secondary outcomes will include the following: visual analog scale score for low back and lower extremity radiating pain, EuroQol 5-dimensions score, surgery satisfaction, walking time, postoperative return to daily life period, postoperative surgical scars, and some surgery-related variables. Radiographic outcomes will be analyzed using magnetic resonance imaging or computed tomography. All outcomes will be evaluated before the surgery and at 2 weeks, 3 months, 6 months, and 12 months postoperatively. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines for reporting of clinical trial protocols. DISCUSSION: It is hypothesized that the efficacy and safety of biportal endoscopic and conventional decompressive laminectomy will be comparable in patients with lumbar spinal stenosis. The results of this trial will provide a high level of evidence for the efficacy and safety of the biportal endoscopic technique in patients with lumbar spinal stenosis and facilitate the development of clinical practice guidelines. Furthermore, the results of this study may indicate the feasibility of the biportal endoscopic technique for other types of spinal surgery. TRIAL REGISTRATION: The ENDO-B trial is registered at Clinical Research Information Service (CRIS, cris.nih.go.kr ) (KCT0006057; April 52,021).

LRP5 Regulates HIF-1α Stability via Interaction with PHD2 in Ischemic Myocardium.

Low-density lipoprotein receptor-related protein 5 (LRP5) has been studied as a co-receptor for Wnt/ß-catenin signaling. However, its role in the ischemic myocardium is largely unknown. Here, we show that LRP5 may act as a negative regulator of ischemic heart injury via its interaction with prolyl hydroxylase 2 (PHD2), resulting in hypoxia-inducible factor-1α (HIF-1α) degradation. Overexpression of LRP5 in cardiomyocytes promoted hypoxia-induced apoptotic cell death, whereas LRP5-silenced cardiomyocytes were protected from hypoxic insult. Gene expression analysis (mRNA-seq) demonstrated that overexpression of LRP5 limited the expression of HIF-1α target genes. LRP5 promoted HIF-1α degradation, as evidenced by the increased hydroxylation and shorter stability of HIF-1α under hypoxic conditions through the interaction between LRP5 and PHD2. Moreover, the specific phosphorylation of LRP5 at T1492 and S1503 is responsible for enhancing the hydroxylation activity of PHD2, resulting in HIF-1α degradation, which is independent of Wnt/ß-catenin signaling. Importantly, direct myocardial delivery of adenoviral constructs, silencing LRP5 in vivo, significantly improved cardiac function in infarcted rat hearts, suggesting the potential value of LRP5 as a new target for ischemic injury treatment.

ER71/ETV2 Promotes Hair Regeneration from Chemotherapeutic Drug-Induced Hair Loss by Enhancing Angiogenesis.

Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.

Dual role of endothelial Myct1 in tumor angiogenesis and tumor immunity.

The cross-talk between angiogenesis and immunity within the tumor microenvironment (TME) is critical for tumor prognosis. While pro-angiogenic and immunosuppressive TME promote tumor growth, anti-angiogenic and immune stimulatory TME inhibit tumor progression. Therefore, there is a great interest in achieving vascular normalization to improve drug delivery and enhance antitumor immunity. However, anti-vascular endothelial growth factor (VEGF) mechanisms to normalize tumor vessels have offered limited therapeutic efficacies for patients with cancer. Here, we report that Myct1, a direct target of ETV2, was nearly exclusively expressed in endothelial cells. In preclinical mouse tumor models, Myct1 deficiency reduced angiogenesis, enhanced high endothelial venule formation, and promoted antitumor immunity, leading to restricted tumor progression. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed a significant (P < 0.05) correlation between MYCT1 expression, angiogenesis, and antitumor immunity in human cancers, as suggested by decreased FOXP3 expression and increased antitumor macrophages in patients with low MYCT1 expression. Mechanistically, MYCT1 interacted with tight junction protein Zona Occludens 1 and regulated Rho GTPase-mediated actin cytoskeleton dynamics, thereby promoting endothelial motility in the angiogenic environment. Myct1-deficient endothelial cells facilitated trans-endothelial migration of cytotoxic T lymphocytes and polarization of M1 macrophages. Myct1 targeting combined with anti-PD1 treatment significantly (P < 0.05) increased complete tumor regression and long-term survival in anti-PD1-responsive and -refractory tumor models in mice. Our data collectively support a critical role for Myct1 in controlling tumor angiogenesis and reprogramming tumor immunity. Myct1-targeted vascular control, in combination with immunotherapy, may become an exciting therapeutic strategy.

PPARγ increases HUWE1 to attenuate NF-κB/p65 and sickle cell disease with pulmonary hypertension.

Sickle cell disease (SCD)-associated pulmonary hypertension (PH) causes significant morbidity and mortality. Here, we defined the role of endothelial specific peroxisome proliferator-activated receptor γ (PPARγ) function and novel PPARγ/HUWE1/miR-98 signaling pathways in the pathogenesis of SCD-PH. PH and right ventricular hypertrophy (RVH) were increased in chimeric Townes humanized sickle cell (SS) mice with endothelial-targeted PPARγ knockout (SSePPARγKO) compared with chimeric littermate control (SSLitCon). Lung levels of PPARγ, HUWE1, and miR-98 were reduced in SSePPARγKO mice compared with SSLitCon mice, whereas SSePPARγKO lungs were characterized by increased levels of p65, ET-1, and VCAM1. Collectively, these findings indicate that loss of endothelial PPARγ is sufficient to increase ET-1 and VCAM1 that contribute to endothelial dysfunction and SCD-PH pathogenesis. Levels of HUWE1 and miR-98 were decreased, and p65 levels were increased in the lungs of SS mice in vivo and in hemin-treated human pulmonary artery endothelial cells (HPAECs) in vitro. Although silencing of p65 does not regulate HUWE1 levels, the loss of HUWE1 increased p65 levels in HPAECs. Overexpression of PPARγ attenuated hemin-induced reductions of HUWE1 and miR-98 and increases in p65 and endothelial dysfunction. Similarly, PPARγ activation attenuated baseline PH and RVH and increased HUWE1 and miR-98 in SS lungs. In vitro, hemin treatment reduced PPARγ, HUWE1, and miR-98 levels and increased p65 expression, HPAEC monocyte adhesion, and proliferation. These derangements were attenuated by pharmacological PPARγ activation. Targeting these signaling pathways can favorably modulate a spectrum of pathobiological responses in SCD-PH pathogenesis, highlighting novel therapeutic targets in SCD pulmonary vascular dysfunction and PH.

Author Correction: Solid-phase hetero epitaxial growth of α-phase formamidinium perovskite.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-020-19846-y .

Solid-phase hetero epitaxial growth of α-phase formamidinium perovskite.

Conventional epitaxy of semiconductor films requires a compatible single crystalline substrate and precisely controlled growth conditions, which limit the price competitiveness and versatility of the process. We demonstrate substrate-tolerant nano-heteroepitaxy (NHE) of high-quality formamidinium-lead-tri-iodide (FAPbI3) perovskite films. The layered perovskite templates the solid-state phase conversion of FAPbI3 from its hexagonal non-perovskite phase to the cubic perovskite polymorph, where the growth kinetics are controlled by a synergistic effect between strain and entropy. The slow heteroepitaxial crystal growth enlarged the perovskite crystals by 10-fold with a reduced defect density and strong preferred orientation. This NHE is readily applicable to various substrates used for devices. The proof-of-concept solar cell and light-emitting diode devices based on the NHE-FAPbI3 showed efficiencies and stabilities superior to those of devices fabricated without NHE.

MicroRNA-98 reduces nerve growth factor expression in nicotine-induced airway remodeling.

Evolving evidence suggests that nicotine may contribute to impaired asthma control by stimulating expression of nerve growth factor (NGF), a neurotrophin associated with airway remodeling and airway hyperresponsiveness. We explored the hypothesis that nicotine increases NGF by reducing lung fibroblast (LF) microRNA-98 (miR-98) and PPARγ levels, thus promoting airway remodeling. Levels of NGF, miR-98, PPARγ, fibronectin 1 (FN1), endothelin-1 (EDN1, herein referred to as ET-1), and collagen (COL1A1 and COL3A1) were measured in human LFs isolated from smoking donors, in mouse primary LFs exposed to nicotine (50 µg/ml), and in whole lung homogenates from mice chronically exposed to nicotine (100 µg/ml) in the drinking water. In selected studies, these pathways were manipulated in LFs with miR-98 inhibitor (anti-miR-98), miR-98 overexpression (miR-98 mimic), or the PPARγ agonist rosiglitazone. Compared with unexposed controls, nicotine increased NGF, FN1, ET-1, COL1A1, and COL3A1 expression in human and mouse LFs and mouse lung homogenates. In contrast, nicotine reduced miR-98 levels in LFs in vitro and in lung homogenates in vivo Treatment with anti-miR-98 alone was sufficient to recapitulate increases in NGF, FN1, and ET-1, whereas treatment with a miR-98 mimic significantly suppressed luciferase expression in cells transfected with a luciferase reporter linked to the putative seed sequence in the NGF 3'UTR and also abrogated nicotine-induced increases in NGF, FN1, and ET-1 in LFs. Similarly, rosiglitazone increased miR-98 and reversed nicotine-induced increases in NGF, FN1, and ET-1. Taken together, these findings demonstrate that nicotine-induced increases in NGF and other markers of airway remodeling are negatively regulated by miR-98.

Quantum Phase Engineering of Two-Dimensional Post-Transition Metals by Substrates: Toward a Room-Temperature Quantum Anomalous Hall Insulator.

We propose a new strategy to engineer topological and magnetic properties of two-dimensional (2D) hexagonal lattices consisting of post-transition metals. Our first-principles calculations demonstrate that substrates serve as templates to form 2D lattices with high thermodynamic stability, where their topological properties as well as magnetic properties sensitively change as a function of lattice constants, i.e., the system undergoes a first-order phase transition from nonmagnetic to ferromagnetic state above a critical lattice constant. Consequently, substrates can be used to explore versatile magnetic, electronic, and quantum topological properties. We establish phase diagrams of versatile quantum phases in terms of exchange coupling and spin-orbit coupling effectively tuned by the lattice constants. We further reveal the first room-temperature quantum anomalous Hall (QAH) effect, i.e., Sn on 2√3 × 2√3 graphane is a QAH insulator with a large spin-orbit coupling gap of ∼0.2 eV and a Curie temperature of ∼380 K by using the 2D anisotropic Heisenberg model.

Measures to Promote Rural Healthcare Tourism with a Scientific Evidence-Based Approach.

The present study aimed to evaluate the effects of physical activities on human health in forests in countryside and rural areas. The test experiment was conducted in a countryside forest, whereas the controlled experiment was conducted in an urban area where the study participants resided. A total of 22 participants (aged 20.9 ± 1.3 years) were evaluated in this study. Heart rate variability and salivary cortisol level were used as indices of physiological conditions, and semantic differential method, profile of mood states (POMS), and state-trait anxiety inventory (STAI) were used to evaluate the participants' emotional states. The participants were asked to walk around forest and urban areas for 15 min. The results were as follows. As compared to the urban area, in the forest area, (1) the power of the high-frequency (HF) component of the heart rate variability (HRV) was significantly higher; (2) low-frequency (LF)/(LF + HF) was significantly lower; (3) salivary cortisol level was significantly lower; (4) the participants felt more comfortable, natural, relaxed, and less anxious and showed higher levels of positive emotions and lower levels of negative emotions. Consequently, walking in the forest area induces relaxing short-term physiological and psychological effects on young people living in urban areas.