Lysine demethylase KDM3A alleviates hyperoxia-induced bronchopulmonary dysplasia in mice by promoting ETS1 expression.

Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease among neonates, with increasing morbidity and mortality. This study aims to investigate the effect and mechanism of lysine demethylase 3A (KDM3A) on hyperoxia-induced BPD. Hyperoxia-induced BPD mouse and alveolar epithelial cell models were constructed. The effects of hyperoxia on lung development were evaluated by histological and morphological analysis. The levels of KDM3A, E26 transformation specific-1 (ETS1), H3 lysine 9 dimethylation (H3K9me2), and endoplasmic reticulum (ER) stress-related indexes were quantified by RT-qPCR, Western blot, and IF staining. Cell apoptosis was assessed by flow cytometry and TUNEL staining. Transfection of oe-ETS1, oe-KDM3A, and sh-ETS1 was applied in hyperoxia-induced alveolar epithelial cells to explore the mechanism of the KDM3A/ETS1 axis in hyperoxia-induced apoptosis. KDM3A inhibitor IOX1 was applied to validate the in vivo effect of KDM3A in hyperoxia-induced BPD mice. The results displayed that hyperoxia-induced BPD mice showed reduced body weight, severe destruction of alveolar structure, decreased radial alveolar count (RAC), and increased mean linear intercept (MLI) and mean alveolar diameter (MAD). Further, hyperoxia induction down-regulated ETS1 expression, raised ER stress levels, and increased apoptosis rate in BPD mice and alveolar epithelial cells. However, transfection of oe-ETS1 improved the above changes in hyperoxia-induced alveolar epithelial cells. Moreover, transfection of oe-KDM3A up-regulated ETS1 expression, down-regulated H3K9me2 expression, inhibited ER stress, and reduced apoptosis rate in hyperoxia-induced alveolar epithelial cells. In addition, transfection of sh-ETS1 reversed the inhibitory effect of KDM3A on hyperoxia-induced apoptosis by regulating ER stress. In vivo experiments, KDM3A inhibitor IOX1 intervention further aggravated BPD in newborn mice. In a word, KDM3A alleviated hyperoxia-induced BPD in mice by promoting ETS1 expression.

Bioinformatics analysis of the prognosis and biological significance of N6 methyladenine regulators in oral squamous cell carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a common type of cancer. We performed the present study to explore the function and specific regulatory mechanism of m6A in OSCC and to find a new diagnosis and treatment strategy for OSCC. METHODS: Using bioinformatics, we examined the associations between 20 genes associated with methylation and the epidemiological data about OSCC tumor samples. RESULTS: We created two subgroup curves based on the gene expression levels related to m6A methylation. In total, 14 genes were found to be differentially expressed. Significant differences in terms of survival rates, Grade and gender were found among subgroups with different m6A expression levels. Nine genes had areas under the curves greater than 0.7. Therefore, these genes may be utilized for the clinical diagnosis and prognosis of OSCC. Because of their high individual predictive value, HNRNPC and IGF2BP2 were chosen as the two potential predictors. The two regulatory elements were used to create the prognostic signals for OSCC. The developed prognostic signals made it possible to discern between the samples with good and poor prognoses without potential confounding factors. Four genes (HNRNPC, METTL14, YTHDF2 and ALKBH5) combined well with compounds, which had an anti-cancer effect. CONCLUSIONS: Our findings suggested that OSCC-related genes with m6A methylation could be beneficial treatment targets or prognostic indicators.

Sirtuin-6 knockout causes exacerbated stalled healing of diabetic ulcers in mice.

BACKGROUND: Diabetic ulcers (DUs) are characterized by chronic inflammation and delayed re-epithelialization, with a high incidence and weighty economic burden. The primary therapeutic strategies for refractory wounds include surgery, non-invasive wound therapy, and drugs, while the optimum regimen remains controversial. Sirtuin-6 (SIRT6) is a histone deacetylase and a key epigenetic factor that exerts anti-inflammatory and pro-proliferatory effects in wound healing. However, the exact function of SIRT6 in DUs remains unclear. METHODS: We generated tamoxifen-inducible SIRT6 knockout mice by crossing SIRT6flox/flox homozygous mice with UBC-creERT2+ transgenic mice. Systemic SIRT6 null mice, under either normal or diabetic conditions, were utilized to assess the effects of SIRT6 in DUs treatment. Gene and protein expressions of SIRT6 and inflammatory cytokines were measured by Western blotting and RT-qPCR. Histopathological examination confirmed the altered re-epithelialization (PCNA), inflammation (NF-κB p50 and F4/80), and angiogenesis (CD31) markers during DUs restoration. RESULTS: Knockout of SIRT6 inhibited the healing ability of DUs, presenting attenuated re-epithelialization (PCNA), exacerbated inflammation responses (NF-κB p50, F4/80, Il-1ß, Tnf-α, Il-6, Il-10, and Il-4), and hyperplasia vascular (CD31) compared with control mice. CONCLUSIONS: SIRT6 could boost impaired wound healing through improving epidermal proliferation, inflammation, and angiogenesis. Our study highlighted the therapeutic potential of the SIRT6 agonist for DUs treatment.

Mediating Triple Ions Migration Behavior via a Fluorinated Separator Interface toward Highly Reversible Aqueous Zn Batteries.

Rampant dendrite growth, electrode passivation and severe corrosion originate from the uncontrolled ions migration behavior of Zn2+ , SO4 2- , and H+ , which are largely compromising the aqueous zinc ion batteries (AZIBs) performance. Exploring the ultimate strategy to eliminate all the Zn anode issues is challenging but urgent at present. Herein, a fluorinated separator interface (PVDF@GF) is constructed simply by grafting the polyvinylidene difluoride (PVDF) on the GF surface to realize high-performance AZIBs. Experimental and theoretical studies reveal that the strong interaction between C─F bonds in the PVDF and Zn2+ ions enables evenly redistributed Zn2+ ions concentration at the electrode interface and accelerates the Zn transportation kinetics, leading to homogeneous and fast Zn deposition. Furthermore, the electronegative separator interface can spontaneously repel the SO4 2- and anchor H+ ions to alleviate the passivation and corrosion. Accordingly, the Zn|Zn symmetric cell with PVDF@GF harvests a superior cycling stability of 500 h at 10 mAh cm-2 , and the Zn|VOX full cell delivers 76.8% capacity retention after 1000 cycles at 2 A g-1 . This work offers an all-round solution and provides new insights for the design of advanced separators with ionic sieve function toward stable and reversible Zn metal anode chemistry.

Separator Design Strategies to Advance Rechargeable Aqueous Zinc Ion Batteries.

With the increasing demand for low-cost and high-safety portable batteries, aqueous zinc-ion batteries (ZIBs) have been regarded as a potential alternative to the lithium-ion batteries, bringing about extensive research dedicated in the exploration of high-performance and highly reversible ZIBs. Although separators are generally considered as non-active components in conventional research on ZIBs, advanced separators designs seem to offer effective solutions to the majority of issues within ZIBs system. These issues encompass concerns related to the zinc anode, cathode, and electrolyte. Initially, we delve into the origins and implications of various inherent problems within the ZIBs system. Subsequently, we present the latest research advancements in addressing these challenges through separators engineering. This includes a comprehensive, detailed exploration of various strategies, coupled with instances of advanced characterizations to provide a more profound insight into the mechanisms that influence the separators. Finally, we undertake a multi-criteria evaluation, based on application standards for diverse substrate separators, while proposing guiding principles for the optimal design of separators in zinc batteries. This review aims to furnish valuable guidance for the future development of advanced separators, thereby nurturing progress in the field of ZIBs.

Gender differences in symptom burden among people living with HIV/AIDS receiving antiretroviral therapy in Yunnan, China.

ABSTRACTLittle is known about gender differences in the symptom burden of people living with HIV/AIDS (PLWHA) on antiretroviral therapy in China. This study was conducted based on a biopsychosocial-medical model to describe gender differences in symptom burden among 1035 PLWHA in Yunnan Province, China. After propensity score matching, 798 PLWHA were included in this analysis. Feeling stressed, poor sleep, and memory loss were the most burdensome symptoms among men, while feeling stressed, memory loss, and dizziness were the most burdensome symptoms among women. Among men PLWHA, factors associated with symptom burden were being of the ethnic minority, CD4 count ≥ 500 cells/mm3, physical functioning, and social support. Among women PLWHA, factors associated with symptom burden were being an inpatient, physical functioning, psychological functioning, and social support. Our findings suggest that healthcare providers need to take into account gender differences when developing optimal prevention, treatment, and care programs that provide individualized care to reduce patients' symptom burden.

Visceral adiposity index as a predictor of type 2 diabetes mellitus risk: A systematic review and dose-response meta-analysis.

AIMS: Considering the positive association between visceral adiposity index (VAI) and type 2 diabetes mellitus (T2DM), no comprehensive assessment on the summarized and dose-response relationship between VAI and T2DM has yet been reported. Therefore, we performed a meta-analysis, including dose-response analysis, to quantitively elucidate this association. DATA SYNTHESIS: MEDLINE via PubMed and Embase databases were searched for relevant articles up to December 14, 2021. Random-effects generalized least squares regression models were used to assess the quantitative association between VAI and T2DM risk across studies. Restricted cubic splines were used to model the dose-response association. A total of 9 prospective cohort studies and 5 cross sectional studies were included in our review. Based on the meta-analysis, the pooled RR of T2DM was 2.05 (95% CI 1.74-2.41) for the highest versus reference VAI category. We found that the risk of T2DM was increased by 44% (RR, 1.44; 95% CI, 1.23-1.68) with each 1-unit increment of VAI. While, we found no evidence of a nonlinear dose-response association of VAI and T2DM (Pnon-linearity = 0.428). With the linear cubic spline model, when compared to population with VAI at 0.6, for those with VAI at 2.0, the risk of T2DM was increased by 81% (RR, 1.81; 95% CI 1.55-2.12). CONCLUSIONS: Our meta-analysis provides quantitative data suggesting that VAI is associated with an increased risk of T2DM. Public health strategies focusing on weight loss among obesity, especially the people characterized by the thin-on-the-outside--fat-on-the-inside phenotype could possibly reduce a substantial risk of T2DM. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022372666.

The effect of PAP on UACR and metabolic indexes in patients with MS and OSAHS.

PURPOSE: To investigate the effects of positive airway pressure (PAP) device on urinary albumin to creatinine ratio (UACR) and metabolic indexes in patients with metabolic syndrome (MS) and obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: This study is a retrospective cohort study. Grouped according to whether to use PAP treatment, there were 25 cases in the PAP group and 44 cases in the no OSAHS treatment group. The PAP group received positive airway pressure device and routine treatment of MS. The no OSAHS treatment group received routine treatment of OSAHS and MS. The treatment period is 3 months. RESULTS: 1. The PAP group demonstrated significant reductions in Body Mass Index (BMI), Waist circumference (WC), Neck circumference (NC), Visceral fat area (VFA), Fasting C peptide (FCP), high-sensitivity C-reactive protein (hs-CRP), and UACR compared to the no OSAHS treatment group, with significant differences (P all <0.05). Among them, the UACR in the PAP group decreased significantly (from 86.05(52.55,131.61)mg/g to 16.76(8.70,25.12)mg/g, P<0.001). 2. Linear regression analysis using the decrease in UACR values as the dependent variable demonstrated a positive linear relationship with the decrease in BMI, VFA, fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR). Furthermore, multiple linear regression analysis indicated that the decrease in VFA (B=0.537 [95% confidence interval, 0.084 to 0.989]; P = 0.021) and HOMA-IR (B=1.000 [95% confidence interval, 0.082 to 1.917]; P = 0.033) values independently correlated with decrease in UACR values. CONCLUSIONS: PAP treatment can reduce UACR in patients with MS and OSAHS, and has the effect of improving metabolic disorders. The decrease of UACR in patients may be related to the decrease of visceral fat and the improvement of insulin resistance.

A rare case report of infratentorial cisternal angiolipoma with review of literature.

Angiolipomas are slow-growing benign mesenchymal-derived tumors consisting of mature adipocytes and thin-walled blood vessels. While the majority of angiolipomas are found in subcutaneous tissues, rarely there are case reports of intracranial lesions. We present a case of cisternal angiolipoma in a 10-year-old female. She presented with vague symptoms like dizziness without neurological deficits and radiological evaluation confirmed a left-sided infratentorial cisternal partially enhancing mass. She underwent craniotomy and had complete resection of the mass, which was histologically composed of mature adipocytes and blood vessels, consistent with angiolipoma. A review of the literature found only 18 cases of intracranial angiolipoma ever reported with our case representing the first case of infratentorial cisternal region.

Novel Loss of Function (G15D) Mutation on RAC2 in a Family with Combined Immunodeficiency and Increased Levels of Immunoglobulin G, A, and E.

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secretion, and phagocytosis. It also performs a suppressing function in immunoglobulin (Ig) switching in Rac2-/- animals or cells. Several RAC2 natural mutations have been described in patients with primary immunodeficiency. RAC2 mutations can be classified into loss-of-function inactivating (LoF-I) and gain-of-function activating mutations according to their functional effects. Only two LoF-I mutations on RAC2 have been reported, including a dominant D57N mutation in several cases that exhibit granulocyte function defects and a recessive D56X mutation in cases with common variable immunodeficiency. Regardless of the type of mutation, most of the reported RAC2 mutant cases have shown reduced IgG, IgA, and IgM levels. Herein, we report on a family with three members that suffer from persistent HPV infection, recurrent respiratory infections, bronchiectasis, and autoimmune disease. The immunologic profile suggests that the family was affected by combined immunodeficiency (CID) with increased serum levels of IgG, IgA, and IgE. Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family. Gene functional experiments identified that such mutation results in reduced guanosine triphosphate binding activity and RAC2 protein expression. In patients' lymphocytes, impaired aggregation and proliferation effects, decreased mitochondrial membrane potential, and increased levels of cell apoptosis were observed, although no functional abnormalities were detected in neutrophils. To our knowledge, this study was the first to identify a LoF-I mutation of RAC2 affecting lymphocyte function that consequently led to CID and increased levels of serum IgG, IgE, and IgA. This study presents a novel subtype of RAC2-related immune disorder.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Chronic social comparison elicits depression- and anxiety-like behaviors and alterations in brain-derived neurotrophic factor expression in male rats.

Social comparison is a fundamental human characteristic; however, long-term social comparison may induce psychological stress and can lead to depression and anxiety. Recent studies have shown that nonhuman primates compare themselves with others; however, no studies have investigated whether social comparisons exist among rodents. In the present study, we established a rat model of social comparison. This model was subsequently used to examine the effects of the differential environment of a partner on depression- and anxiety-like behaviors in male rats, as well as to assess the changes in serum, medial prefrontal cortex (mPFC), and dorsal hippocampus brain-derived neurotrophic factor (BDNF) levels induced by long-term social comparison. Compared to rats whose partners were exposed to the same environment, rats whose partners were exposed to two combined enriched environmental stimuli for 14 days showed significantly decreased social novelty preference and sucrose consumption. No anxiety-like behaviors were observed. Rats whose partners were exposed to one enriched environment for 31 days showed significantly increased immobility time in the forced swimming test, and significantly decreased time spent in the center area in the open-field test. Further, rats whose partners were exposed to one enriched environment for 31 days showed lower BDNF levels in the mPFC and dorsal hippocampus, but not following partner exposure for 14 days. These results suggest that social comparisons exist in rats and can induce psychosocial stress and other negative affect. This model will not only provide the possibility to reveal the neurobiological basis of the emotional impact of social comparison, but could also be used to confirm the conservative evolutionary characteristics of social comparison as a behavioral attribute.

Imaging mismatch between Alberta Stroke Program Early CT Score and perfusion imaging may be a good variable for endovascular treatment.

OBJECTIVE: Some patients with acute large vessel occlusion (LVO) presented imaging mismatch, low Alberta Stroke Program Early CT Score (ASPECTS) with small ischemic core, or high ASPECTS with large ischemic core. The study was designed to explore whether patients with imaging mismatch could benefit from endovascular treatment (EVT). METHODS: We retrospectively reviewed patients with LVO treated with EVT in our center from March 2018 to Jul 2020. Patients were divided into three groups, imaging mismatch, small ischemic core, and large ischemic core groups. Pooled analyses based on stroke onset to treatment time were done. Multivariate regression analysis was performed to explore the factors for good outcomes. RESULTS: Sixty-eight of 419 patients with LVO presented with imaging mismatch, and 35 of those (51%) achieved good outcomes after EVT at 90-day. No significant differences were noted in good outcomes and symptomatic intracranial hemorrhage (sICH) between patients with imaging mismatch and small ischemic core. Compared with large ischemic core, patients with imaging mismatch presented lower risk of sICH (95% confidence interval (CI) 0.04-0.75, p = 0.011) within 6 h and higher proportion of good outcomes (95% CI 0.37-0.82, p = 0.002) at 6 to 24 h. Baseline NIHSS (odds ratio (OR) = 0.91, 95% CI 0.88-0.95)), ASPECTS (OR = 1.14, 95% CI 1.01-1.29), ischemic core (OR = 0.99, 95% CI 0.98-1.00), and sICH (OR = 61.61, 95% CI 8.09-461.32) were associated with good outcomes. CONCLUSIONS: Patients with imaging mismatch treated within 24 h could benefit from EVT and without increasing the risk of sICH. KEY POINTS: • Patients with imaging mismatch between ASPECTS and ischemic core could achieve good outcomes after endovascular treatment. • Compared with large ischemic core, patients with imaging mismatch presented lower risk of symptomatic hemorrhage within 6 h and higher proportion of good outcomes within 6-24 h. • Baseline NIHSS score, ASPECTS, ischemic core, and symptomatic intracranial hemorrhage were associated with good outcomes.

ETS1 Ameliorates Hyperoxia-Induced Bronchopulmonary Dysplasia in Mice by Activating Nrf2/HO-1 Mediated Ferroptosis.

PURPOSE: Bronchopulmonary dysplasia (BPD) is associated with hyperoxia-induced oxidative stress-associated ferroptosis. This study examined the effect of E26 oncogene homolog 1 (ETS1) on oxidative stress-associated ferroptosis in BPD. METHODS: Hyperoxia-induced A549 cells and neonatal mice were used to establish BPD models. The effects of ETS1 on hyperoxia-induced ferroptosis-like changes in A549 cells were investigated by overexpression of ETS1 plasmid transfection and erastin treatment. Glucose consumption, lactate production, and NADPH levels were assessed by the glucose, lactate, and NADP+/NADPH assay kits, respectively. The potential regulatory relationship between ETS1 and Nrf2/HO-1 was examined by treating hyperoxia-induced A549 cells with the Nrf2 inhibitor ML385. ETS1 effect on the Nrf2 promoter was explored by dual-luciferase reporter and chromatin immunoprecipitation assay. The effect of ETS1 on the symptoms of BPD mice was examined by injecting an adenovirus overexpressing ETS1. RESULTS: ETS1 overexpression increased hyperoxia-induced cell viability, glucose consumption, lactate production, and NADPH levels and reduced inflammation and apoptosis in A549 cells. In animal experiments, ETS1 overexpression prevented weight loss, airway enlargement, and reductions in radial alveolar counts in BPD mice, while reducing the mean linear intercept, mean alveolar diameter and inflammation. ETS1 overexpression suppressed PTGS2 and CHAC1 expression, reduced ROS, MDA and ferrous iron (Fe2+) production and increased GSH levels in hyperoxia-induced A549 cells and BPD mice. In addition, ETS1 can bind to the Nrf2 promoter region and thus promote Nrf2 transcription. ETS1 overexpression increased the mRNA and protein levels of Nrf2, HO-1, xCT, and GPX4 in hyperoxia-induced A549 cells and BPD mice. In hyperoxia-induced A549 cells, erastin and ML385 treatment abolished the effect of ETS1 overexpression. CONCLUSION: ETS1 is important in oxidative stress-related ferroptosis in a hyperoxia-induced BPD model, and the effect is partially mediated by the Nrf2/HO-1 axis.

[Advances in mechanism of traditional Chinese medicine in inhibiting angiogenesis in ovarian cancer].

Ovarian cancer is one of the three major cancers in gynecology. Ovarian cancer has insidious symptoms in its early stages and mostly has progressed to advanced stages when detected. Surgical treatment combined with chemotherapy is currently the main treatment, but the 5-year survival rate is still less than 45%. Angiogenesis is a key step in the growth and metastasis of ovarian cancer. The inhibition of ovarian cancer angiogenesis has become a new hotspot in anti-tumor targeted therapy, which has many advantages such as less drug resistance, high specificity, few side effects, and broad anti-tumor spectrum. Modern research has confirmed that traditional Chinese medicine(TCM) can inhibit tumor angiogenesis by inhibiting the expression of pro-angiogenic factors, up-regulating the expression of anti-angiogenic factors, inhibiting the proliferation of vascular endothelial cells, reducing the density of tumor microvessels, and regulating related signaling pathways, with unique advantages in the treatment of ovarian cancer. This paper presented a review of the role of TCM in inhibiting ovarian cancer angiogenesis in order to provide references for the optimization of clinical ovarian cancer treatment strategies.

Cyclodextrin-Confined Supramolecular Lanthanide Photoswitch.

The utilization of azobenzene-based photoisomerization cannot only control the morphology of supramolecular assemblies, but can also regulate many biological processes. However, the design of azobenzene-involved nanoconstructs with switchable photoluminescence remains challenging because of the light-quenching ability of azobenzene. Herein, an azobenzene-derived multicomponent nanosystem is reported and its function as a supramolecular lanthanide photoswitch is explored. The metal chelation between lanthanide ions (Ln3+  = Eu3+ and Tb3+ ) and 2,6-pyridinedicarboxylic acid is utilized as the light-emitting center but its inherent fluorescence emission is completely suppressed via the disordered motion of the adjoining azophenyl unit. Interestingly, the hydrophobic cavity of α-cyclodextrin can provide a confined microenvironment to immobilize the molecular conformation of trans-azobenzene, thus leading to the recovery of characteristic lanthanide luminescence both in aqueous solution and the hydrogel state. Also, the luminescence can be reversibly turned off when the cis-azobenzene is expelled from the cavity of α-cyclodextrin upon alternating light irradiation. This mutual cooperation arising from host-guest complexation and metal-ligand coordination confers the desired photoswitchable luminescence abilities on the commonly used azobenzenes, which may hold great promise in the creation of more advanced light-responsive smart materials.

In Situ Atomic-Scale Observation of Monolayer MoS2 Devices under High-Voltage Biasing via Transmission Electron Microscopy.

2D materials have great potential for not only device scaling but also various applications. To prompt the development of 2D electronics and optoelectronics, a better understanding of the limitation of materials is essential. Material failure caused by bias can lead to variations in device behavior and even electrical breakdown. In this study, the structural evolution of monolayer MoS2 with high bias is revealed via in situ transmission electron microscopy at the atomic scale. The biasing process is recorded and studied with the aid of aberration-corrected scanning transmission electron microscopy. The effects of electron beam irradiation and biasing are also discussed through the combination of experiments and theory. It is found that the Mo nanoclusters result from disintegration of MoS2 and sulfur depletion, which are induced by Joule heating. The thermal stress can also damage the MoS2 layer and form long cracks in both in situ and ex situ biasing cases. Investigation of the results obtained with different applied voltages helps to further verify the mechanism of evolution and provide a comprehensive study of the function of biasing.

Revealing Resistive Switching Mechanism in CaFeOx Perovskite System with Electroforming-Free and Reset Voltage-Controlled Multilevel Resistance Characteristics.

Recently, perovskite (PV) oxides with ABO3 structures have attracted considerable interest from scientists owing to their functionality. In this study, CaFeOx is introduced to reveal the resistive switching properties and mechanism of oxygen vacancy transition in PV and brownmillerite (BM) structures. BM-CaFeO2.5 is grown on an Nb-STO conductive substrate epitaxially. CaFeOx exhibits excellent endurance and reliability. In addition, the CaFeOx also demonstrates an electroforming-free characteristic and multilevel resistance properties. To construct the switching mechanism, high-resolution transmission electron microscopy is used to observe the topotactic phase change in CaFeOx . In addition, scanning TEM and electron energy loss spectroscopy show the structural evolution and valence state variation of CaFeOx after the switching behavior. This study not only reveals the switching mechanism of CaFeOx , but also provides a PV oxide option for the dielectric material in resistive random-access memory (RRAM) devices.

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants.

PURPOSE: The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause. METHODS: Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest. RESULTS: We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341C>T), 2 families with R781H (c.2342G>A), and 1 family with R781L (c.2342G>T). Another 2 variants included I783T (c.2348T>C) in 1 family and Q777E (c.2329C>G) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-ß-mediated transcriptional responses. CONCLUSION: This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

Functional Comparison of Interferon-α Subtypes Reveals Potent Hepatitis B Virus Suppression by a Concerted Action of Interferon-α and Interferon-γ Signaling.

BACKGROUND AND AIMS: Interferon (IFN)-α, composed of numerous subtypes, plays a crucial role in immune defense. As the most studied subtype, IFN-α2 has been used for treating chronic hepatitis B virus (HBV) infection, with advantages of finite treatment duration and sustained virologic response, but its efficacy remains relatively low. This study aimed to screen for IFN-α subtypes with the highest anti-HBV potency and to characterize mechanisms of IFN-α-mediated HBV restriction. APPROACH AND RESULTS: Using cell culture-based HBV infection systems and a human-liver chimeric mouse model, IFN-α subtype-mediated antiviral response and signaling activation were comprehensively analyzed. IFN-α14 was identified as the most effective subtype in suppression of HBV covalently closed circular DNA transcription and HBV e antigen/HBV surface antigen production, with median inhibitory concentration values approximately 100-fold lower than those of the conventional IFN-α2. IFN-α14 alone elicited IFN-α and IFN-γ signaling crosstalk in a manner similar to the combined use of IFN-α2 and IFN-γ, inducing multiple potent antiviral effectors, which synergistically restricted HBV replication. Guanylate binding protein 5, one of the most differentially expressed genes between IFN-α14-treated and IFN-α2-treated liver cells, was identified as an HBV restriction factor. A strong IFN-α-IFN-α receptor subunit 1 interaction determines the anti-HBV activity of IFN-α. The in vivo anti-HBV activity of IFN-α14 and treatment-related transcriptional patterns were further confirmed, and few adverse effects were observed. CONCLUSIONS: A concerted IFN-α and IFN-γ response in liver, which could be efficiently elicited by IFN-α subtype 14, is associated with potent HBV suppression. These data deepen the understanding of the divergent activities of IFN-α subtypes and the mechanism underlying the synergism between IFN-α and IFN-γ signaling, with implications for improved IFN therapy and HBV curative strategies.