Nitrative Modification of Caveolin-3: A Novel Mechanism of Cardiac Insulin Resistance and a Potential Therapeutic Target Against Ischemic Heart Failure in Prediabetic Animals.

BACKGROUND: Myocardial insulin resistance is a hallmark of diabetic cardiac injury. However, the underlying molecular mechanisms remain unclear. Recent studies demonstrate that the diabetic heart is resistant to other cardioprotective interventions, including adiponectin and preconditioning. The "universal" resistance to multiple therapeutic interventions suggests impairment of the requisite molecule(s) involved in broad prosurvival signaling cascades. Cav (Caveolin) is a scaffolding protein coordinating transmembrane signaling transduction. However, the role of Cav3 in diabetic impairment of cardiac protective signaling and diabetic ischemic heart failure is unknown. METHODS: Wild-type and gene-manipulated mice were fed a normal diet or high-fat diet for 2 to 12 weeks and subjected to myocardial ischemia and reperfusion. Insulin cardioprotection was determined. RESULTS: Compared with the normal diet group, the cardioprotective effect of insulin was significantly blunted as early as 4 weeks of high-fat diet feeding (prediabetes), a time point where expression levels of insulin-signaling molecules remained unchanged. However, Cav3/insulin receptor-ß complex formation was significantly reduced. Among multiple posttranslational modifications altering protein/protein interaction, Cav3 (not insulin receptor-ß) tyrosine nitration is prominent in the prediabetic heart. Treatment of cardiomyocytes with 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride reduced the signalsome complex and blocked insulin transmembrane signaling. Mass spectrometry identified Tyr73 as the Cav3 nitration site. Phenylalanine substitution of Tyr73 (Cav3Y73F) abolished 5-amino-3-(4-morpholinyl)-1,2,3-oxadiazolium chloride-induced Cav3 nitration, restored Cav3/insulin receptor-ß complex, and rescued insulin transmembrane signaling. It is most important that adeno-associated virus 9-mediated cardiomyocyte-specific Cav3Y73F reexpression blocked high-fat diet-induced Cav3 nitration, preserved Cav3 signalsome integrity, restored transmembrane signaling, and rescued insulin-protective action against ischemic heart failure. Last, diabetic nitrative modification of Cav3 at Tyr73 also reduced Cav3/AdipoR1 complex formation and blocked adiponectin cardioprotective signaling. CONCLUSION: Nitration of Cav3 at Tyr73 and resultant signal complex dissociation results in cardiac insulin/adiponectin resistance in the prediabetic heart, contributing to ischemic heart failure progression. Early interventions preserving Cav3-centered signalsome integrity is an effective novel strategy against diabetic exacerbation of ischemic heart failure.

Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature.

Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of 15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including TGFBI, CHST6, SLC4A11, and ZEB1. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was TGFBI (1823/2902, 62.82% of families), followed by CHST6 (483/2902, 16.64%) and SLC4A11 (201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in TGFBI, is crucial in the era of genomic medicine.

Undersampled MRI reconstruction based on spectral graph wavelet transform.

Compressed sensing magnetic resonance imaging (CS-MRI) has exhibited great potential to accelerate magnetic resonance imaging if an image can be sparsely represented. How to sparsify the image significantly affects the reconstruction quality of images. In this paper, a spectral graph wavelet transform (SGWT) is introduced to sparsely represent magnetic resonance images in iterative image reconstructions. The SGWT is achieved by extending the traditional wavelets transform to the signal defined on the vertices of the weighted graph, i.e. the spectral graph domain. This SGWT uses only the connectivity information encoded in the edge weights, and does not rely on any other attributes of the vertices. Therefore, SGWT can be defined and calculated for any domain where the underlying relations between data locations can be represented by a weighted graph. Furthermore, we present a Chebyshev polynomial approximation algorithm for fast computing this SGWT transform. The l1 norm regularized CS-MRI reconstruction model is introduced and solved by the projected iterative soft-thresholding algorithm to verify its feasibility. Numerical experiment results demonstrate that our proposed method outperforms several state-of-the-art sparsify transforms in terms of suppressing artifacts and achieving lower reconstruction errors on the tested datasets.

Cooperative Action of Fulvic Acid and Bacillus paralicheniformis Ferment in Regulating Soil Microbiota and Improving Soil Fertility and Plant Resistance to Bacterial Wilt Disease.

Excessive continuous cropping and soil degradation, such as acidification, hardening, fertility decline, and the degradation of microbial community, lead to the epidemic of soilborne diseases and cause great loss in agriculture production. Application of fulvic acid can improve the growth and yield of various crops and effectively suppress soilborne plant diseases. Bacillus paralicheniformis strain 285-3 producing poly-gamma-glutamic acid is used to remove the organic acid that can cause soil acidification and increase the fertilizer effect of fulvic acid and the effect of improving soil quality and inhibiting soilborne disease. In field experiments, the application of fulvic acid and Bacillus paralicheniformis ferment effectively reduced the incidence of bacterial wilt disease and improved soil fertility. Both fulvic acid powder and B. paralicheniformis ferment improved soil microbial diversity and increased the complexity and stability of the microbial network. For B. paralicheniformis ferment, the molecular weight of poly-gamma-glutamic acid became smaller after heating, which could better improve the soil microbial community and network structure. In fulvic acid and B. paralicheniformis ferment-treated soils, the synergistic interaction between microorganisms increased and the number of keystone microorganisms increased, which included antagonistic bacteria and plant growth-promoting bacteria. Changes in the microbial community and network structure were the main reason for the reduced incidence of bacterial wilt disease. Application of fulvic acid and Bacillus paralicheniformis ferment improved soil physicochemical properties and effectively controlled bacterial wilt disease by changing microbial community and network structure and enriching antagonistic and beneficial bacteria. IMPORTANCE Continuous cropping tobacco has led to soil degradation and caused soilborne bacterial wilt disease. Fulvic acid as a biostimulator was applied to restore soil and control bacterial wilt disease. For improving its effect, fulvic acid was fermented with Bacillus paralicheniformis strain 285-3 producing poly-gamma-glutamic acid. Fulvic acid and B. paralicheniformis ferment inhibited bacterial wilt disease, improved soil quality, enriched beneficial bacteria, and increased microbial diversity and microbial network complexity. Some keystone microorganisms in fulvic acid and B. paralicheniformis ferment-treated soils had potential antimicrobial activity and plant growth-promoting attributes. Fulvic acid and B. paralicheniformis 285-3 ferment could be used to restore soil quality and microbiota and control bacterial wilt disease. This study found new biomaterial to control soilborne bacterial disease by combining fulvic acid and poly-gamma-glutamic acid application.

Effects of heavy metal pollution and soil physicochemical properties on the Sphagnum farmland soil microbial community structure in Southern Guizhou, China.

Farmland soil pollution is a serious problem worldwide threatening environment and human health. Microbial communities plays a key role in soil function. The purpose of this study was to analyze the relationship between microbial structure and soil physicochemical properties under different heavy metal pollution levels, find out heavy metal tolerant species under different environmental conditions, then provide useful reference for the bioremediation of contaminated farmland. In this study, 16s rRNA high-throughput sequencing technology was used, multiple comparisons and correlation analyses of the data were performed using R software. The results showed that study area A was contaminated by heavy metal Cd, and study area A, B and C were contaminated by heavy metal Hg. From the analysis of the community structure of the samples, it can be seen that the dominant bacterial phyla were Proteobacteria, Acidobacteriota, Chloroflexi, Actinobacteria, and 10 others. Correlation and RDA analysis of samples showed that the heavy metals Hg and As in peat were related to dominant bacteria phyla, and the physicochemical properties of soil potential of hydrogen (pH), total nitrogen (TN), available nitrogen (AN), available phosphorus (AP), available potassium (AK), and soil organic matter (SOM) were significantly positively correlated with the bacteria (Acidobacterta and Chloroflexi). Moreover, Chloroflexi was more tolerant to the heavy metals Hg and As. There was a significant correlation between bacterial community abundance and diversity in the four study areas. Soil heavy metal concentration and soil physicochemical properties affected the main phyla, bacterial community abundance and bacterial diversity of peat soil. These results indicate that some microorganisms have strong tolerance to heavy metal pollution and certain heavy metal digestion ability, which can create a good environment for farmland soil remediation.

This manuscript is the first study on a new crop­Sphagnum in China. It mainly discusses the reaction of soil bacteria and microorganisms of Sphagnum in farmland to heavy metals and soil physical-chemical properties.

FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia.

BACKGROUND: Selectively targeting leukemia stem cells (LSCs) is a promising approach in treating acute myeloid leukemia (AML), for which identification of such therapeutic targets is critical. Increasing lines of evidence indicate that FBXO22 plays a critical role in solid tumor development and therapy response. However, its potential roles in leukemogenesis remain largely unknown. METHODS: We established a mixed lineage leukemia (MLL)-AF9-induced AML model with hematopoietic cell-specific FBXO22 knockout mice to elucidate the role of FBXO22 in AML progression and LSCs regulation, including self-renewal, cell cycle, apoptosis and survival analysis. Immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis, Western blotting and rescue experiments were performed to study the mechanisms underlying the oncogenic role of FBXO22. RESULTS: FBXO22 was highly expressed in AML, especially in MLL-rearranged (MLLr) AML. Upon FBXO22 knockdown, human MLLr leukemia cells presented markedly increased apoptosis. Although conditional deletion of Fbxo22 in hematopoietic cells did not significantly affect the function of hematopoietic stem cells, MLL-AF9-induced leukemogenesis was dramatically abrogated upon Fbxo22 deletion, together with remarkably reduced LSCs after serial transplantations. Mechanistically, FBXO22 promoted degradation of BACH1 in MLLr AML cells, and overexpression of BACH1 suppressed MLLr AML progression. In line with this, heterozygous deletion of BACH1 significantly reversed delayed leukemogenesis in Fbxo22-deficient mice. CONCLUSIONS: FBXO22 promotes MLLr AML progression by targeting BACH1 and targeting FBXO22 might be an ideal strategy to eradicate LSCs without influencing normal hematopoiesis.

Domestic Cattle in a National Park Restricting the Sika Deer Due to Diet Overlap.

Managers need to know the extent of the conflict between livestock and wild animals. Although many studies have reported the conflict between livestock and wild animals, few have checked the extent of the conflict. Cattle raising in the Northeast Tiger and Leopard National Park is considered one of the main driving forces behind the restricted distribution of sika deer. To understand whether foraging competition is contributing to avoidance patterns between sika deer and cattle, we investigated their feeding habits using DNA barcoding and high-throughput sequencing. Our study shows that although cattle are grazers in the traditional division of herbivores, their diet shifted to a predominance of dicotyledonous woody plants, and this diet shift resulted in a high degree of dietary overlap between sika deer and cattle. Moreover, compared to sika deer, cattle diets are more diverse at the species level with a wider ecological niche. Our results confirm that overlapping dietary niches and the superior competitive abilities of cattle contribute to the restricted distribution of the sika deer, which has critical implications for the conservation of their predators. Our study suggests that cattle grazing should be prohibited in the Park and effective measures should be taken for the benefit of sika deer.

A deep learning based two-layer predictor to identify enhancers and their strength.

The enhancer is a DNA sequence that can increase the activity of promoters and thus speed up the frequency of gene transcription. The enhancer plays an essential role in activating gene expression. Currently, gene sequencing technology has been developed for 30 years from the first generation to the third generation, and a variety of biological sequence data have increased significantly every year. Due to the importance of enhancer functions, it is very expensive to identify enhancers through biochemical experiments. Therefore, we need to study new methods for the identification and classification of enhancers. Based on the K-mer principle this study proposed a feature extraction method that others have not used in convolutional neural networks. Then, we combined it with one-hot encoding to build an efficient one-dimensional convolutional neural network ensemble model for predicting enhancers and their strengths. Finally, we used five commonly used classification problem evaluation indicators to compare with the models proposed by other researchers. The model proposed in this paper has a better performance by using the same independent test dataset as other models.

Developing NiMoO4-based multifunctional cathode for hybrid zinc battery.

Herein, we developed a multifunctional cathode (Co-NiMoO4/NF) based on nickel molybdate nanowires grown on Ni foam (NiMoO4/NF) for a hybrid zinc-nickel (Zn-Ni) and zinc-air (Zn-Air) battery. NiMoO4/NF demonstrated a high capacity and good rate capability in the Zn-Ni battery. The subsequent coating of the Co-based oxygen catalyst resulted in the Co-NiMoO4/NF and enabled the battery to exhibit the advantages of both batteries.

The Effect of Air Turbulence on Vortex Beams in Nonlinear Propagation.

Vortex beams with orthogonality can be widely used in atmospheric applications. We numerically analyzed the statistical regularities of vortex beams propagating through a lens or an axicon with different series of turbulent air phase screens. The simulative results revealed that the distortion of the transverse intensity was sensitive to the location and the structure constant of the turbulence screen. In addition, the axicon can be regarded as a very useful optical device, since it can not only suppress the turbulence but also maintain a stable beam pattern. We further confirmed that a vortex beam with a large topological charge can suppress the influence of air turbulence. Our outcomes are valuable for many applications in the atmospheric air, especially for optical communication and remote sensing.

Sensing dynamic human activity zones using geo-tagged big data in Greater London, UK during the COVID-19 pandemic.

Exploration of dynamic human activity gives significant insights into understanding the urban environment and can help to reinforce scientific urban management strategies. Lots of studies are arising regarding the significant human activity changes in global metropolises and regions affected by COVID-19 containment policies. However, the variations of human activity dynamics amid different phases divided by the non-pharmaceutical intervention policies (e.g., stay-at-home, lockdown) have not been investigated across urban areas in space and time and discussed with the urban characteristic determinants. In this study, we aim to explore the influence of different restriction phases on dynamic human activity through sensing human activity zones (HAZs) and their dominated urban characteristics. Herein, we proposed an explainable analysis framework to explore the HAZ variations consisting of three parts, i.e., footfall detection, HAZs delineation and the identification of relationships between urban characteristics and HAZs. In our study area of Greater London, United Kingdom, we first utilised the footfall detection method to extract human activity metrics (footfalls) counted by visits/stays at space and time from the anonymous mobile phone GPS trajectories. Then, we characterised HAZs based on the homogeneity of daily human footfalls at census output areas (OAs) during the predefined restriction phases in the UK. Lastly, we examined the feature importance of explanatory variables as the metric of the relationship between human activity and urban characteristics using machine learning classifiers. The results show that dynamic human activity exhibits statistically significant differences in terms of the HAZ distributions across restriction phases and is strongly associated with urban characteristics (e.g., specific land use types) during the COVID-19 pandemic. These findings can improve the understanding of the variation of human activity patterns during the pandemic and offer insights into city management resource allocation in urban areas concerning dynamic human activity.

Water-Modulated Biomimetic Hyper-Attribute-Gel Electronic Skin for Robotics and Skin-Attachable Wearables.

Electronic skin (e-skin), mimicking the physical-chemical and sensory properties of human skin, is promising to be applied as robotic skins and skin-attachable wearables with multisensory functionalities. To date, most e-skins are dedicated to sensory function development to mimic human skins in one or several aspects, yet advanced e-skin covering all the hyper-attributes (including both the sensory and physical-chemical properties) of human skins is seldom reported. Herein, a water-modulated biomimetic hyper-attribute-gel (Hygel) e-skin with reversible gel-solid transition is proposed, which exhibits all the desired skin-like physical-chemical properties (stretchability, self-healing, biocompatibility, biodegradability, weak acidity, antibacterial activities, flame retardance, and temperature adaptivity), sensory properties (pressure, temperature, humidity, strain, and contact), function reconfigurability, and evolvability. Then the Hygel e-skin is applied as an on-robot e-skin and skin-attached wearable to demonstrate its highly skin-like attributes in capturing multiple sensory information, reconfiguring desired functions, and excellent skin compatibility for real-time gesture recognition via deep learning. This Hygel e-skin may find more applications in advanced robotics and even skin-replaceable artificial skin.

Design, synthesis and biological evaluation of quercetin derivatives as novel ß-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors.

The ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/ß-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on ß-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with ß-catenin and disrupted the ß-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/ß-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore ß-catenin-related biology and a drug-like quercetin derivative as novel ß-catenin/BCL9 PPI inhibitors for further drug development.

Sensing dynamic human activity zones using geo-tagged big data in Greater London, UK during the COVID-19 pandemic.

Exploration of dynamic human activity gives significant insights into understanding the urban environment and can help to reinforce scientific urban management strategies. Lots of studies are arising regarding the significant human activity changes in global metropolises and regions affected by COVID-19 containment policies. However, the variations of human activity dynamics amid different phases divided by the non-pharmaceutical intervention policies (e.g., stay-at-home, lockdown) have not been investigated across urban areas in space and time and discussed with the urban characteristic determinants. In this study, we aim to explore the influence of different restriction phases on dynamic human activity through sensing human activity zones (HAZs) and their dominated urban characteristics. Herein, we proposed an explainable analysis framework to explore the HAZ variations consisting of three parts, i.e., footfall detection, HAZs delineation and the identification of relationships between urban characteristics and HAZs. In our study area of Greater London, United Kingdom, we first utilised the footfall detection method to extract human activity metrics (footfalls) counted by visits/stays at space and time from the anonymous mobile phone GPS trajectories. Then, we characterised HAZs based on the homogeneity of daily human footfalls at census output areas (OAs) during the predefined restriction phases in the UK. Lastly, we examined the feature importance of explanatory variables as the metric of the relationship between human activity and urban characteristics using machine learning classifiers. The results show that dynamic human activity exhibits statistically significant differences in terms of the HAZ distributions across restriction phases and is strongly associated with urban characteristics (e.g., specific land use types) during the COVID-19 pandemic. These findings can improve the understanding of the variation of human activity patterns during the pandemic and offer insights into city management resource allocation in urban areas concerning dynamic human activity.

Discovery of Novel 3-Phenylpiperidine Derivatives Targeting the ß-Catenin/B-Cell Lymphoma 9 Interaction as a Single Agent and in Combination with the Anti-PD-1 Antibody for the Treatment of Colorectal Cancer.

Direct disruption of the ß-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential strategy for colorectal cancer (CRC) treatment through inhibiting oncogenic Wnt activity. Herein, a series of 3-phenylpiperidine derivatives were synthesized and evaluated as ß-catenin/BCL9 PPI inhibitors. Among them, compound 41 showed the best IC50 (0.72 µM) in a competitive fluorescence polarization assay and a KD value of 0.26 µM for the ß-catenin protein. This compound selectively inhibited the growth of CRC cells, suppressed Wnt signaling transactivation, and downregulated oncogenic Wnt target gene expression. In vivo, 41 showed potent anti-CRC activity and promoted the infiltration and function of cytotoxic T lymphocytes while decreasing the infiltration of regulatory T-cells (Tregs). Furthermore, the combination of 41 and the anti-PD-1 antibody (Ab) efficiently enhanced anti-CRC efficacy, first verifying the in vivo efficacy of the small-molecule ß-catenin/BCL9 PPI inhibitor and anti-PD-1 Ab in combination.

Hedyotis diffusa alleviate aflatoxin B1-induced liver injury in ducks by mediating Nrf2 signaling pathway.

Aflatoxin B1 (AFB1), the most harmful aflatoxins, is a frequent contamination in feed and food items, raising global concerns in animal production and human public health. Also, AFB1 induces oxidative stress, cytotoxicity, mutations, and DNA lesions through its metabolic transformation into aflatoxin B1-8,9-epoxide (AFBO) by cytochrome P450 (CYP450). Hedyotis diffusa (HD) is a traditional Chinese herbal medicine known for its multiple pharmacological activities, including antioxidant, anti-inflammatory, and immunomodulatory. Yet, the influence of HD on AFB1-induced liver injury in ducks is still unknown. Here, we investigated whether HD positively affects AFB1-induced liver injury in ducks. Results revealed that I) AFB1 caused significant changes in serum biochemical indices and decreased growth performance of ducks (such as ALT, AST, ALP, TP, ALB, final body weight, and body weight gain), whereas HD supplementation at 200 mg/kg mitigated these alterations. II) HD alleviated hepatic histopathological changes and liver index induced by AFB1 in ducks. III) HD significantly attenuated AFB1-induced oxidative stress, as measured by increased antioxidant enzyme activities such as SOD, GPx, and T-AOC and decreased MDA levels. Furthermore, HD reduced the level of AFB1-DNA adduct in duck liver. IV) HD significantly promoted the transcriptional expression of NF-E2-related nuclear factor 2 (Nrf2) and associated genes, including heme oxygenase 1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1), glutamate-cysteine ligase catalytic (GCLC). In conclusion, these results demonstrated that HD could activate the Nrf2 pathway in ducks to reduce the hepatotoxicity driven by AFB1. This finding also provides theoretical and data support for a deeper understanding of the toxic mechanisms of AFB1 and its prevention.

Inhibition of YAP by lenvatinib in endothelial cells increases blood pressure through ferroptosis.

Lenvatinib, a multitarget tyrosine kinase inhibitor (TKI), increases the incidence of severe hypertension and thus the incidence of cardiovascular complications. Inhibition of ferroptosis, a newly recognized type of cell death, alleviates endothelial dysfunction. Here, we report that lenvatinib-induced hypertension is associated with ferroptosis of endothelial cells. RNA sequencing (RNA-seq) showed that lenvatinib led to ferroptosis of endothelial cells and that administration of mouse with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, dramatically ameliorated lenvatinib-induced hypertension and reversed lenvatinib-induced impairment of endothelium-dependent relaxation (EDR). Furthermore, lenvatinib significantly reduced glutathione peroxidase 4 (GPX4) expressions in the mouse aorta and human umbilical vein endothelial cells (HUVECs) and increased lipid peroxidation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) levels in HUVECs. Immunofluorescence and Western blotting showed that lenvatinib significantly reduced Yes-associated protein (YAP) nuclear translocation but not cytoplasmic YAP expression in HUVECs. The data, generated from both in vivo and in vitro, showed that lenvatinib reduced total YAP (t-YAP) expression and increased the phosphorylation of YAP at both Ser127 and Ser397, without affecting YAP mRNA levels in HUVECs. XMU-MP-1 mediated YAP activation or YAP overexpression effectively attenuated the lenvatinib-induced decrease in GPX4 expression and increases in LDH release and MDA levels. In addition, overexpression of YAP in HUVECs ameliorated lenvatinib-induced decrease in the mRNA and protein levels of spermidine/spermine N (1)-acetyltransferase-1 (SAT1), heme oxygenase-1 (HO-1), and ferritin heavy chain 1 (FTH1). Taken together, our data suggest that lenvatinib-induced inhibition of YAP led to ferroptosis of endothelial cells and subsequently resulted in vascular dysfunction and hypertension.

Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting ß-Catenin's Interactions with Its Nuclear Partners.

Dysregulation of the Wnt/ß-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/ß-catenin signaling activation increases nuclear dephosphorylated ß-catenin levels, resulting in ß-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting ß-catenin's interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/ß-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt ß-catenin's interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of ß-catenin and its nuclear binding partner into therapeutic agents.

Influence Mechanism of Polycentric Spatial Structure on Urban Land Use Efficiency: A Moderated Mediation Model.

Under the background of green development, the spatial structure of urban agglomerations (UA) has an important impact on urban land use efficiency (ULUE), but few studies have explored the impact mechanism between the two. This research explores the impacts of polycentric development on ULUE of UA, using data for 140 cities in China's top ten key UA covering the period from 2004-2019. The linkage between polycentric development and ULUE is explored by estimating models of determinants of ULUE. This research also examines the mechanism of the polycentric spatial structure of UA on ULUE by using a moderated mediation model. The main findings of the research can be concluded as below. The eastern UAs show a mostly polycentric spatial structure, whereas the central and western UAs show a weak polycentric spatial structure. The polycentric spatial structure of UA has a positive impact on ULUE. An inverted U-shape curve depicts the relationship between the polycentric spatial structure of UA and ULUE. However, the mediating variables, integration of industrial structure and factor mobility have a positive and partially mediating effect between the polycentric spatial structure of UA and ULUE. The infrastructure level has a positive U-shaped regulation effect, in which the impact coefficient of transport infrastructure is more significant. These findings provide empirical evidence for the coordinated development of China's regional space planning and ULUE.