High estrogen induces trans-differentiation of vascular smooth muscle cells to a macrophage-like phenotype resulting in aortic inflammation via inhibiting VHL/HIF1a/KLF4 axis.

Estrogen is thought to have a role in slowing down aging and protecting cardiovascular and cognitive function. However, high doses of estrogen are still positively associated with autoimmune diseases and tumors with systemic inflammation. First, we administered exogenous estrogen to female mice for three consecutive months and found that the aorta of mice on estrogen develops inflammatory manifestations similar to Takayasu arteritis (TAK). Then, in vitro estrogen intervention was performed on mouse aortic vascular smooth muscle cells (MOVAS cells). Stimulated by high concentrations of estradiol, MOVAS cells showed decreased expression of contractile phenotypic markers and increased expression of macrophage-like phenotypic markers. This shift was blocked by tamoxifen and Krüppel-like factor 4 (KLF4) inhibitors and enhanced by Von Hippel-Lindau (VHL)/hypoxia-inducible factor-1α (HIF-1α) interaction inhibitors. It suggests that estrogen-targeted regulation of the VHL/HIF-1α/KLF4 axis induces phenotypic transformation of vascular smooth muscle cells (VSMC). In addition, estrogen-regulated phenotypic conversion of VSMC to macrophages is a key mechanism of estrogen-induced vascular inflammation, which justifies the risk of clinical use of estrogen replacement therapy.

GhCLCc-1, a Chloride Channel Gene from Upland Cotton, Positively Regulates Salt Tolerance by Modulating the Accumulation of Chloride Ions.

The ionic toxicity induced by salinization has adverse effects on the growth and development of crops. However, researches on ionic toxicity and salt tolerance in plants have focused primarily on cations such as sodium ions (Na+), with very limited studies on chloride ions (Cl-). Here, we cloned the homologous genes of Arabidopsis thaliana AtCLCc, GhCLCc-1A/D, from upland cotton (Gossypium hirsutum), which were significantly induced by NaCl or KCl treatments. Subcellular localization showed that GhCLCc-1A/D were both localized to the tonoplast. Complementation of Arabidopsis atclcc mutant with GhCLCc-1 rescued its salt-sensitive phenotype. In addition, the silencing of the GhCLCc-1 gene led to an increased accumulation of Cl- in the roots, stems, and leaves of cotton seedlings under salt treatments, resulting in compromised salt tolerance. And ectopic expression of the GhCLCc-1 gene in Arabidopsis reduced the accumulation of Cl- in transgenic lines under salt treatments, thereby enhancing salt tolerance. These findings elucidate that GhCLCc-1 positively regulates salt tolerance by modulating Cl- accumulation and could be a potential target gene for improving salt tolerance in plants.

Low-abundance proteins-based label-free SERS approach for high precision detection of liver cancer with different stages.

BACKGROUND: Surface-enhanced Raman scattering (SERS) technology have unique advantages of rapid, simple, and highly sensitive in the detection of serum, it can be used for the detection of liver cancer. However, some protein biomarkers in body fluids are often present at ultra-low concentrations and severely interfered with by the high-abundance proteins (HAPs), which will affect the detection of specificity and accuracy in cancer screening based on the SERS immunoassay. Clearly, there is a need for an unlabeled SERS method based on low abundance proteins, which is rapid, noninvasive, and capable of high precision detection and screening of liver cancer. RESULTS: Serum samples were collected from 60 patients with liver cancer (27 patients with stage T1 and T2 liver cancer, 33 patients with stage T3 and T4 liver cancer) and 40 healthy volunteers. Herein, immunoglobulin and albumin were separated by immune sorption and Cohn ethanol fractionation. Then, the low abundance protein (LAPs) was enriched, and high-quality SERS spectral signals were detected and obtained. Finally, combined with the principal component analysis-linear discriminant analysis (PCA-LDA) algorithm, the SERS spectrum of early liver cancer (T1-T2) and advanced liver cancer (T3-T4) could be well distinguished from normal people, and the accuracy rate was 98.5% and 100%, respectively. Moreover, SERS technology based on serum LAPs extraction combined with the partial least square-support vector machine (PLS-SVM) successfully realized the classification and prediction of normal volunteers and liver cancer patients with different tumor (T) stages, and the diagnostic accuracy of PLS-SVM reached 87.5% in the unknown testing set. SIGNIFICANCE: The experimental results show that the serum LAPs SERS detection combined with multivariate statistical algorithms can be used for effectively distinguishing liver cancer patients from healthy volunteers, and even achieved the screening of early liver cancer with high accuracy (T1 and T2 stage). These results showed that serum LAPs SERS detection combined with a multivariate statistical diagnostic algorithm has certain application potential in early cancer screening.

Progress on H2B as a multifunctional protein related to pathogens.

Histone H2B is a member of the core histones, which together with other histones form the nucleosome, the basic structural unit of chromosomes. As scientists delve deeper into histones, researchers gradually realize that histone H2B is not only an important part of nucleosomes, but also plays a momentous role in regulating gene transcription, acting as a receptor and antimicrobial action outside the nucleus. There are a variety of epigenetically modified sites in the H2B tail rich in arginine and lysine, which can occur in ubiquitination, phosphorylation, methylation, acetylation, etc. When stimulated by foreign factors such as bacteria, viruses or parasites, histone H2B can act as a receptor for the recognition of these pathogens, and induce an intrinsic immune response to enhance host defense. In addition, the extrachromosomal histone H2B is also an important anti-microorganism agent, which may be the key to the development of antibiotics in the future. This review aims to summarize the interaction between histone H2B and etiological agents and explore the role of H2B in epigenetic modifications, receptors and antimicrobial activity.

Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

BACKGROUND: Atherosclerosis (AS) is a persistent inflammatory condition triggered and exacerbated by several factors including lipid accumulation, endothelial dysfunction and macrophages infiltration. Nobiletin (NOB) has been reported to alleviate atherosclerosis; however, the underlying mechanism remains incompletely understood. METHODS: This study involved comprehensive bioinformatic analysis, including multidatabase target prediction; GO and KEGG enrichment analyses for function and pathway exploration; DeepSite and AutoDock for drug binding site prediction; and CIBERSORT for immune cell involvement. In addition, target intervention was verified via cell scratch assays, oil red O staining, ELISA, flow cytometry, qRT‒PCR and Western blotting. In addition, by establishing a mouse model of AS, it was demonstrated that NOB attenuated lipid accumulation and the extent of atherosclerotic lesions. RESULTS: (1) Altogether, 141 potentially targetable genes were identified through which NOB could intervene in atherosclerosis. (2) Lipid and atherosclerosis, fluid shear stress and atherosclerosis may be the dominant pathways and potential mechanisms. (3) ALB, AKT1, CASP3 and 7 other genes were identified as the top 10 target genes. (4) Six genes, including PPARG, MMP9, SRC and 3 other genes, were related to the M0 fraction. (5) CD36 and PPARG were upregulated in atherosclerosis samples compared to the normal control. (6) By inhibiting lipid uptake in RAW264.7 cells, NOB prevents the formation of foam cell. (7) In RAW264.7 cells, the inhibitory effect of oxidized low-density lipoprotein on foam cells formation and lipid accumulation was closely associated with the PPARG signaling pathway. (8) In vivo validation showed that NOB significantly attenuated intra-arterial lipid accumulation and macrophage infiltration and reduced CD36 expression. CONCLUSIONS: Nobiletin alleviates atherosclerosis by inhibiting lipid uptake via the PPARG/CD36 pathway.

Experimental study on the impact of "IDS + JFCS" complex wetting agent on the characteristics of coal bodies.

As China's coal mines have transitioned to deep mining, the ground stress within the coal seams has progressively increased, resulting in reduced permeability and poor wetting ability of conventional wetting agents. Consequently, these agents have become inadequate in fulfilling the requirements for preventing washouts during deep mining operations. In response to the aforementioned challenges, a solution was proposed to address the issues by formulating a composite wetting agent. This composite wetting agent combines a conventional surfactant with a chelating agent called tetrasodium iminodisuccinate (IDS). By conducting a meticulous screening of surfactant monomer solutions, the ideal formulation for the composite wetting agent was determined by combining the monomer surfactant with IDS. Extensive testing, encompassing evaluations of the composite solution's apparent strain, contact angle measurements, and alterations in the oxygenated functional groups on the coal surface, led to the identification of the optimal composition. This composition consisted of IDS serving as the chelating agent and fatty alcohol polyoxyethylene ether (JFCS).Subsequent assessment of the physical and mechanical performance of the coal briquettes treated with the composite wetting agent revealed notable enhancements. These findings signify significant advancements in the field and hold promising implications. Following the application of the composite wetting agent, notable reductions were observed in the dry basis ash and dry basis full sulfur of coal. Additionally, the water content within the coal mass increased significantly, leading to a substantial enhancement in the wetting effect of the coal body. This enhanced wetting effect effectively mitigated the coal body's inclination towards impact, thereby offering technical support for optimizing water injection into coal seams and preventing as well as treating impact ground pressure.

The Down-Shifting Luminescence of Rare-Earth Nanoparticles for Multimodal Imaging and Photothermal Therapy of Breast Cancer.

Nanotheranostic agents capable of simultaneously enabling real-time tracking and precise treatment at tumor sites play an increasingly pivotal role in the field of medicine. In this article, we report a novel near-infrared-II window (NIR-II) emitting downconversion rare-earth nanoparticles (RENPs) to improve image-guided therapy for breast cancer. The developed α-NaErF4@NaYF4 nanoparticles (α-Er NPs) have a diameter of approximately 24.1 nm and exhibit superior biocompatibility and negligible toxicity. RENPs exhibit superior imaging quality and photothermal conversion efficiency in the NIR-II range compared to clinically approved indocyanine green (ICG). Under 808 nm laser irradiation, the α-Er NPs achieve significant tumor imaging performance and photothermal effects in vivo in a mouse model of breast cancer. Simultaneously, it combines X-ray computed tomography (CT) and ultrasound (US) tri-modal imaging to guide therapy for cancer. The integration of NIR-II imaging technology and RENPs establishes a promising foundation for future medical applications.

Association between SpO2 and the risk of death in elderly T2DM patients with cerebral infarction: a retrospective cohort study.

Objective: This study aimed to evaluate the SpO2 (transcutaneous oxygen saturation) -mortality link in elderly T2DM (diabetes mellitus type 2) patients with cerebral infarction and identify their optimal SpO2 range. Methods: In this investigation, we employed a comprehensive approach. Initially, we screened the MIMIC-IV database, identifying elderly T2DM patients with cerebral infarction, utilizing specific ICD-9 and ICD-10 codes. We then harnessed the power of restricted cubic splines to craft a visual representation of the correlation between SpO2 and 1-year mortality. To enhance our analysis, we harnessed Cox multivariate regression, allowing us to compute adjusted hazard ratios (HR) accompanied by 95% confidence intervals (CIs). Additionally, we crafted Cumulative Mortality Curve analyses, augmenting our study by engaging in rigorous subgroup analyses, stratifying our observations based on pertinent covariates. Results: In this study, 448 elderly T2DM patients with cerebral infarction were included. Within 1-year post-discharge, 161 patients (35.94%) succumbed. Employing Restricted Cubic Spline analysis, a statistically significant U-shaped non-linear relationship between admission ICU SpO2 levels and 1-year mortality was observed (P-value < 0.05). Further analysis indicated that both low and high SpO2 levels increased the mortality risk. Cox multivariate regression analysis, adjusting for potential confounding factors, confirmed the association of low (≤94.5%) and high SpO2 levels (96.5-98.5%) with elevated 1-year mortality risk, particularly notably high SpO2 levels (>98.5%) [HR = 2.06, 95% CI: 1.29-3.29, P-value = 0.002]. The cumulative mortality curves revealed the following SpO2 subgroups from high to low cumulative mortality at the 365th day: normal levels (94.5% < SpO2 ≤ 96.5%), low levels (SpO2 ≤ 94.5%), high levels (96.5% < SpO2 ≤ 98.5%), and notably high levels (>98.5%). Subgroup analysis demonstrated no significant interaction between SpO2 and grouping variables, including Sex, Age, Congestive heart failure, Temperature, and ICU length of stay (LOS-ICU; P-values for interaction were >0.05). Conclusions: Striking an optimal balance is paramount, as fixating solely on lower SpO2 limits or neglecting high SpO2 levels may contribute to increased mortality rates. To mitigate mortality risk in elderly T2DM patients with cerebral infarction, we recommend maintaining SpO2 levels within the range of 94.5-96.5%.

Analysis of the evolution of water culture and water security in the Weihe River Basin over a 100 year-period.

The significance of water culture in addressing water crises and ensuring water security has garnered considerable attention, emerging as a focal point in global change and water science research. Water culture is a societal adaptation to changes in hydrological systems. However, this needs to be acknowledged within contemporary discourse on water security governance. This study utilized historical policy document data from many sources, including local municipal records from Shaanxi and Gansu, and water conservancy records. It aimed to identify the significant nodes and stages of policy transformation in the Weihe River Basin (WRB) during the last century (1949-2020). This study employed a content analysis method to elucidate the evolutionary patterns of water culture in the study region during the previous century. Drawing on the co-evolution framework, our investigation delved into the reciprocal relationship between changes in water culture and the evolution of water security in the WRB. Our findings indicated that water culture transformation in the WRB has undergone four significant stages: the Disaster-Resistant Hydraulic (1949-1966), Irrigation Hydraulic (1967-1998), Resources Hydraulic (1999-2010), and Ecological Hydraulic (2011-2020) phases. Water security assessment showed that policy attention varied across the different stages. The disaster-resistant hydraulic phase primarily addressed water-related disaster concerns, whereas the irrigation hydraulic phase emphasized the scarcity of water resources. The resource hydraulic phase focused on ensuring the security of the water environment, while the ecological hydraulic phase placed emphasis on safeguarding water sustainability. Moreover, we found that prevailing water policies prioritize resolving isolated issues; however, water security is a multifaceted systemic matter that requires a comprehensive approach. This study has the potential to offer policy makers a more comprehensive and systematic perspective, enabling them to enhance their understanding of the underlying nature of the problems. Additionally, this study can assist in developing future water security policies.

Combining near infrared fluorescence and laser speckle imaging with optical tissue clearing for in vivo transcranial monitoring of cerebral blood vessels damaged by photodynamic nanoformulation.

In vivo near infrared (NIR) fluorescence imaging and laser speckle contrast imaging (LSCI) are emerging optical bioimaging modalities, which can provide information on blood vessels morphology, volume and the blood flow velocity. Optical tissue clearing (OTC) technique addresses a light scattering problem in optical bioimaging, which is imperative for the transcranial brain imaging. Herein, we report an approach combining NIR fluorescence and LSC microscopy imaging with OTC. A liposomal nanoformulation comprising NIR fluorescent dye ICG and photosensitizer BPD was synthesized and injected intravenously into mouse with OTC treated skull. Transcranial excitation of BPD in nanoliposomes resulted in the localized, irradiation dose dependent photodynamic damage of the brain blood vessels, which was manifested both in NIR fluorescence and LSC transcranial imaging, revealing changes in the vessels morphology, volume and the blood flow rate. The developed approach allows for bimodal imaging guided, localized vascular PDT of cancer and other diseases.

Salvianolic acid B attenuates liver fibrosis by targeting Ecm1 and inhibiting hepatocyte ferroptosis.

Hepatocyte ferroptosis promotes the pathogenesis and progression of liver fibrosis. Salvianolic acid B (Sal B) exerts antifibrotic effects. However, the pharmacological mechanism and target has not yet been fully elucidated. In this study, liver fibrosis was induced by CCl4 in wild-type mice and hepatocyte-specific extracellular matrix protein 1 (Ecm1)-deficient mice, which were separately treated with Sal B, ferrostatin-1, sorafenib or cilengitide. Erastin- or CCl4-induced hepatocyte ferroptosis models with or without Ecm1 gene knockdown were evaluated in vitro. Subsequently, the interaction between Ecm1 and xCT and the binding kinetics of Sal B and Ecm1 were determined. We found that Sal B significantly attenuated liver fibrosis in CCl4-induced mice. Ecm1 deletion in hepatocytes abolished the antifibrotic effect of Sal B. Mechanistically, Sal B protected against hepatocyte ferroptosis by upregulating Ecm1. Further research revealed that Ecm1 as a direct target for treating liver fibrosis with Sal B. Interestingly, Ecm1 interacted with xCT to regulate hepatocyte ferroptosis. Hepatocyte ferroptosis in vitro was significantly attenuated by Sal B treatment, which was abrogated after knockdown of Ecm1 in LO2 cells. Therefore, Sal B alleviates liver fibrosis in mice by targeting up-regulation of Ecm1 and inhibiting hepatocyte ferroptosis. The interaction between Ecm1 and xCT regulates hepatocyte ferroptosis.

Real-time visualization of skeletal muscle necrosis in mice and swine through NIR-II/I fluorescence imaging.

Avulsion often occurs in the limb due to heavy shearing forces which not only damage skeletal muscle but also main vessels, resulting in life-threatening muscle ischemia and necrosis. Defining muscle activity is vital for surgical repair. Currently, the color, capacity of blood, contractibility, and consistency (4C) are the primary principles for evaluating the activities of torn muscles. Based on clinical experiences, this standard turns out to be delayed diagnosis, which is not defined by specific parameters. Recently, near-infrared (NIR) fluorescence probes emitting within the second near-infrared window (NIR-II, 1000-1700 nm) have been widely used for non-invasive optical imaging because the tissue absorption and autofluorescence in the NIR-II region are negligible, thus allowing deeper penetration depths with micrometer-scale spatial resolution in vivo. As pathogenesis and development of muscle necrosis, necrosis-related protein may participate in this procedure. There is promising future for NIR-II to be used in evaluating muscle activity in avulsion. A new approach is developed based on experiments with mice and large animals (swine). Myoblasts were incubated with indocyanine green (ICG) to identify the necrosis muscles. The model of extremity damaged muscle was established for the real-time visualization and detection of developed necrosis muscle field under new equipment, both in balb/c mice (female) and long-haired swines. A visible NIR-II/I imaging system was first used in a large animal injured skeletal muscle-related model. Our NIR-II/I imaging system is suitable for evaluating the normal and injured skeletal muscle ICG cycle and pointing to the necrotic skeletal muscle tissue. NIR-II imaging is superior to NIR-I imaging in estimating skeletal muscle, best with 1100 nm filter. NIR-II fluorescence with 1100 nm filter is suitable for analyzing the progress of necrosis muscle tissue, leading to a new approach for intraoperative evaluation.

Phage-assisted evolution of compact Cas9 variants targeting a simple NNG PAM.

Compact Cas9 nucleases hold great promise for therapeutic applications. Although several compact Cas9 nucleases have been developed, many genomic loci still could not be edited due to a lack of protospacer adjacent motifs (PAMs). We previously developed a compact SlugCas9 recognizing an NNGG PAM. Here we demonstrate that SlugCas9 displays comparable activity to SpCas9. We developed a simple phage-assisted evolution to engineer SlugCas9 for unique PAM requirements. Interestingly, we generated a SlugCas9 variant (SlugCas9-NNG) that could recognize an NNG PAM, expanding the targeting scope. We further developed a SlugCas9-NNG-based adenine base editor and demonstrated that it could be delivered by a single adeno-associated virus to disrupt PCSK9 splice donor and splice acceptor. These genome editors greatly enhance our ability for in vivo genome editing.

Neutrophil Extracellular Traps Aggravate Contrast-Induced Acute Kidney Injury by Damaging Glomeruli and Peritubular Capillaries.

Background: Contrast-induced acute kidney injury (CI-AKI) is considered to be the third leading cause of hospital-acquired kidney injury. Current studies mostly suggest that contrast agents mainly harm renal tubular epithelial cells, but we hypothesized that the development of CI-AKI should be the result of the interaction of renal vascular and tubular injury. Methods: First we constructed a CI-AKI mouse model and verified the success of the model by pathological injury and serum creatinine level. Immunohistochemistry, protein quantification and qRT-PCR were used to detect the location and level of expression of neutrophil extracellular traps (NETs) in the kidney. Then, we blocked the in vivo accumulation of NETs using GSK484 and DNase I and detected the expression of NETs and the damage of glomerular and peritubular capillaries. Results: We first identified the presence of NETs in CI-AKI mice, and NETs were mainly accumulated in glomeruli and peritubular capillaries. The expression of NETs was positively correlated with the severity of CI-AKI kidney. After inhibition of NETs release or promotion of NETs degradation by drugs, renal vascular endothelial cell injury was reduced and renal pathological changes and creatinine levels were reversed in CI-AKI mice. In addition, inhibition of NETs reduced apoptosis and pyroptosis of renal cells and attenuated inflammation in vivo. Conclusion: These findings suggest that NETs are involved in the development of CI-AKI by damaging glomerular and peritubular capillary endothelial cells. This study will provide a new strategy for clinical prevention and treatment of CI-AKI.

A DNA methylation haplotype block landscape in human tissues and preimplantation embryos reveals regulatory elements defined by comethylation patterns.

DNA methylation and associated regulatory elements play a crucial role in gene expression regulation. Previous studies have focused primarily on the distribution of mean methylation levels. Advances in whole-genome bisulfite sequencing (WGBS) have enabled the characterization of DNA methylation haplotypes (MHAPs), representing CpG sites from the same read fragment on a single chromosome, and the subsequent identification of methylation haplotype blocks (MHBs), in which adjacent CpGs on the same fragment are comethylated. Using our expert-curated WGBS data sets, we report comprehensive landscapes of MHBs in 17 representative normal somatic human tissues and during early human embryonic development. Integrative analysis reveals MHBs as a distinctive type of regulatory element characterized by comethylation patterns rather than mean methylation levels. We show the enrichment of MHBs in open chromatin regions, tissue-specific histone marks, and enhancers, including super-enhancers. Moreover, we find that MHBs tend to localize near tissue-specific genes and show an association with differential gene expression that is independent of mean methylation. Similar findings are observed in the context of human embryonic development, highlighting the dynamic nature of MHBs during early development. Collectively, our comprehensive MHB landscapes provide valuable insights into the tissue specificity and developmental dynamics of DNA methylation.

Endothelial SARS-CoV-2 infection is not the underlying cause of COVID-19-associated vascular pathology in mice.

Endothelial damage and vascular pathology have been recognized as major features of COVID-19 since the beginning of the pandemic. Two main theories regarding how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages endothelial cells and causes vascular pathology have been proposed: direct viral infection of endothelial cells or indirect damage mediated by circulating inflammatory molecules and immune mechanisms. However, these proposed mechanisms remain largely untested in vivo. In the present study, we utilized a set of new mouse genetic tools developed in our lab to test both the necessity and sufficiency of endothelial human angiotensin-converting enzyme 2 (hACE2) in COVID-19 pathogenesis. Our results demonstrate that endothelial ACE2 and direct infection of vascular endothelial cells do not contribute significantly to the diverse vascular pathology associated with COVID-19.

Research on charge induction law and application of coal samples with different fissures.

Indoor testing are performed to explore the charge induction law during the uniaxial compression fracture process of coal samples, and the charge time and frequency domain signals of coal samples with different primary fissures are analyzed in the paper. On-site monitoring of charge in different fissures distribution areas of underground coal tunnels, and the charge signals of different drillingdepths in coal seams are analyzed. The results show that the uniaxial compressive strength and elastic modulus of multi-fissured coal samples are less than those of less fissured coal samples, and the Poisson's ratio is greater than those of less fissured coal samples. The charge induction signal intensity during the fracture process of multi-fissured coal samples is relatively low, but it is concentrated at the low frequency of 0-50 Hz in the compacting elasticity stage. The charge signal intensity during the fracture process of coal samples with less fissure is relatively high, and the charge frequency during the reinforcement damage stage is concentrated at a low frequency of 0-50 Hz. Therefore, the sudden appearance of low-frequency charge signals is more suitable as effective precursor information for the instability and failure of less fissured coal bodies. The average charge intensity is small in the multi-fissured area with a drilling depth of 1-4 m in the coal seam, and the average charge intensity of the coal body with less fissures is larger in the 5-12 m region. The on-site charge monitoring results have good consistency with the indoor test results. This study has guiding significance in setting up a charge monitoring warning index of instability failure in different coal body fissures regions.

mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

BACKGROUND: Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in PIK3CA (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. METHODS: We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and PIK3CA gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs. RESULTS: We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs. CONCLUSIONS: Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.

Tf2O/DMSO-mediated dual activation of aryl phosphinate to access various aryl phosphonates.

A metal-free method for the dual activation of aryl phosphinate has been developed; the P-H and P-O bonds are sequentially activated by the Tf2O/DMSO system. Without the requirement of metals and unstable P-reagents, this one-pot procedure provides a convenient and practical access to a variety of aryl phosphonates. A mechanism involving twice generation of electrophilic P-species and two SN-processes is proposed on the basis of the control experiments.