Deubiquitination of CIB1 by USP14 promotes lenvatinib resistance via the PAK1-ERK1/2 axis in hepatocellular carcinoma.

Background: Lenvatinib is the most common multitarget receptor tyrosine kinase inhibitor for the treatment of advanced hepatocellular carcinoma (HCC). Acquired resistance to lenvatinib is one of the major factors leading to the failure of HCC treatment, but the underlying mechanism has not been fully characterized. Methods: We established lenvatinib-resistant cell lines, cell-derived xenografts (CDXs) and patient-derived xenografts (PDXs) and obtained lenvatinib-resistant HCC tumor tissues for further study. Results: We found that ubiquitin-specific protease 14 (USP14) was significantly increased in lenvatinib-resistant HCC cells and tumors. Silencing USP14 significantly attenuated lenvatinib resistance in vitro and in vivo. Mechanistically, USP14 directly interacts with and stabilizes calcium- and integrin-binding protein 1 (CIB1) by reversing K48-linked proteolytic ubiquitination at K24, thus facilitating the P21-activated kinase 1 (PAK1)-ERK1/2 signaling axis. Moreover, in vivo adeno-associated virus 9 mediated transduction of CIB1 promoted lenvatinib resistance in PDXs, whereas CIB1 knockdown resensitized the response of PDXs to lenvatinib. Conclusions: These findings provide new insights into the role of CIB1/PAK1-ERK1/2 signaling in lenvatinib resistance in HCC. Targeting CIB1 and its pathways may be a novel pharmaceutical intervention for the treatment of lenvatinib-resistant HCC.

[Effects of " Air Pollution Prevention and Control Action Plan " on PM2.5 and Chemical Compositions in Zhengzhou in Polluted Winters].

The Air Pollution Prevention and Control Action Plan （APPCAP） was promulgated in China in 2013. To explore the effectiveness of APPCAP on PM2.5 in winter in Zhengzhou, PM2.5 samples were collected in Zhengzhou Monitoring Center during December 2013 and December 2018. The chemical composition of PM2.5 was analyzed, including EC, OC, water soluble ions, and metal elements. Pollution episodes under different stages were selected to investigate the changes in PM2.5 concentration and composition. The results showed that： ① The average concentration of PM2.5 in winter in Zhengzhou decreased from （215.38 ±107.28） µg·m-3 in 2013 to （77.45 ±49.81） µg·m-3 in 2018, with a decrease rate of 64%. ② The concentrations of EC, K+, SO42-, and Cl- decreased by 85%, 80%, 78%, and 72%, respectively, and the decrease rate in OC, NH4+, and NO3- was 50%, 41%, and 32%, respectively. ③ Compared with those in winter of 2013, the ratios of OC/EC in winter of 2018 increased by 2.6 times, and the proportion of secondary organic carbon in OC increased to 57%； meanwhile, values of sulfur oxidation rate and nitrogen oxidation rate increased by 1.5 and 1.0 times, respectively, indicating heavy secondary pollution in Zhengzhou. ④ The mass ratios of NO3-/SO42-increased from 0.8 ±0.2 in 2013 to 2.5 ±1.0 in 2018, indicating that the contribution of mobile sources increased and surpassed fixed sources as the main source in Zhengzhou. ⑤The comparison results of different stages of the heavy pollution process showed that ρ（PM2.5） decreased significantly in 2018 compared with that in 2013, with the peak concentration decreasing by 61%. The main chemical composition changed from OC, NO3-, SO42-, and NH4+ to OC, NO3-, and NH4+. The results indicated that the primary emission source control in Zhengzhou had achieved remarkable effects, but the contribution of secondary generation to PM2.5 showed an elevated trend； thus, the influence of secondary generation requires further attention in the future.

Exploring seasonal variations, assembly dynamics, and relationships of bacterial communities in different habitats of marine ranching.

Offshore coastal marine ranching ecosystems provide habitat for diverse and active bacterial communities. In this study, 16S rRNA gene sequencing and multiple bioinformatics methods were applied to investigate assembly dynamics and relationships in different habitats. The higher number of edges in the water network, more balanced ratio of positive and negative links, and more keystone species included in the co-occurrence network of water. Stochastic processes dominated in shaping gut and sediment community assembly (R2 < 0.5), while water bacterial community assembly were dominated by deterministic processes (R2 > 0.5). Dissimilarity-overlap curve model indicated that the communities in different habitats have general dynamics and interspecific interaction (P < 0.001). Bacterial source-tracking analysis revealed that the gut was more similar to the sediment than the water bacterial communities. In summary, this study provides basic data for the ecological study of marine ranching through the study of bacterial community dynamics.

The timing of pronuclear transfer critically affects the developmental competence and quality of embryos.

Pronuclear transfer has been successfully used in human assisted reproduction to suppress the adverse effects of a defective oocyte cytoplasm or to bypass an idiopathic developmental arrest. However, the effects of the initial parental genome remodelling in a defective cytoplasm on the subsequent development after pronucleus transfer have not been systematically studied. By performing pronuclear transfer in pre-replication and post-replication mouse embryos, we show that the timing of the procedure plays a critical role. Although apparently morphologically normal blastocysts were obtained in both pre- and post-replication pronuclear transfer groups, post-replication pronuclear transfer led to a decrease in developmental competence and profound changes in embryonic gene expression. By inhibiting the replication in the abnormal cytoplasm before pronuclear transfer into a healthy cytoplasm, the developmental potential of embryos could be largely be restored. This shows that the conditions under which the first embryonic replication occurs strongly influence developmental potential. Although pronuclear transfer is the method of choice for mitigating the impact of a faulty oocyte cytoplasm on early development, our results show that the timing of this intervention should be restricted to the pre-replication phase.

Promising G-Quadruplex-Targeted Dibenzoquinoxaline Type-1 Photosensitizer Triggers DNA Damage in Triple-Negative Breast Cancer Cells.

G-quadruplexes (G4s) are potential drug targets in cancer treatment. However, the G4-targeted ligands seem to lack sufficient selectivity between tumors and normal tissues, appealing for a new modified anticancer strategy on the basis of them. Type-1 photodynamic therapy (PDT) is a promising strategy possessing excellent spatiotemporal precision for solid tumors with a hypoxic microenvironment. However, type-1 photosensitizers that target G4s and induce in situ photodamage have never been previously reported. In this study, we reported a promising type-1 photosensitizer based on a G4-targeted, high-contrast fluorescent ligand (TR2). The subsequent studies demonstrated that TR2 could transfer from lysosomes to nuclei and induce elevated G4 formation as well as DNA damage upon irradiation. Notably, it was observed that TR2 may not activate DNA damage repair machinery upon irradiation, suggesting a durable, strong effect on inducing DNA damage. Consequently, light-irradiated TR2 exhibited excellent photocytotoxicity on triple-negative breast cancer cell proliferation (at nanomolar concentration) and showed obvious inhibition on the growth of three-dimensional (3D) tumor spheroids. Finally, RNA-seq analysis demonstrated that TR2-mediated PDT may have a negative impact on enhancing the DNA damage repair machinery and may activate the antitumor immunity pathways. Overall, this study provided a promising chemical tool for image-guided PDT.

Nrf2 mediated signaling axis in heart failure: Potential pharmacological receptor.

Heart failure (HF) has emerged as the most pressing health concerns globally, and extant clinical therapies are accompanied by side effects and patients have a high burden of financial. The protein products of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes have a variety of cardioprotective effects, including antioxidant, metabolic functions and anti-inflammatory. By evaluating established preclinical and clinical research in HF to date, we explored the potential of Nrf2 to exert unique cardioprotective functions as a novel therapeutic receptor for HF. In this review, we generalize the progression, structure, and function of Nrf2 research in the cardiovascular system. The mechanism of action of Nrf2 involved in HF as well as agonists of Nrf2 in natural compounds are summarized. Additionally, we discuss the challenges and implications for future clinical translation and application of pharmacology targeting Nrf2. It's critical to developing new drugs for HF.

Zwitterionic Thiolate-Protected Ag22(0/I) and Ag20(I) Clusters: Assembly, Structural Characterization, and Antibacterial Activity.

Zwitterionic thiolate ligands have the potential to introduce novel assembly modes and functions for noble metal clusters. However, their utilization in the synthesis of silver clusters remains understudied, particularly for the clusters containing reductive Ag(0) species. In this article, we report the first synthesis of a mixed-valence silver(0/I) cluster protected by zwitterionic Tab as thiolate ligands (Tab = 4-(trimethylammonio)benzenethiolate), denoted as [Ag22(Tab)24](PF6)20·16CH3OH·6Et2O (Ag22·16CH3OH·6Et2O), alongside an Ag(I) cluster [Ag20(Tab)12(PhCOO)10(MeCN)2(H2O)](PF6)10·11MeCN (Ag20·11MeCN). Ag22 has a distinct hierarchical supratetrahedral structure with a central {Ag6} kernel surrounded by four [Ag4(Tab)6]4+ units. High-resolution electrospray ionization mass spectra demonstrate that Ag22 has two free electrons, indicating a superatomic core. Ag20 has a drum-like [Ag12(Tab)6(PhCOO)6(H2O)]6+ inner core capped by two tetrahedral-like [Ag4(Tab)3(PhCOO)2(MeCN)]2+ units. Ag20 can be transformed into Ag22 after its reaction with NaBH4 in solution. Antibacterial measurements reveal that Ag22 has a significantly lower minimum inhibitory concentration than that of the Ag20 cluster. This work not only extends the stabilization of silver(0/I) clusters to neutral thiol ligands but also offers new materials for the development of novel antibacterial materials.

The effectiveness of dexmedetomidine for preventing acute kidney injury after surgery: a systematic review and meta-analysis.

Background: Postoperative acute kidney injury (AKI) is a serious and distressing complication connected to various adverse outcomes following the surgical operation. Controversy remains regarding the dexmedetomidine's preventive impact on postoperative AKI. Therefore, this investigation aims to explore the efficiency and safety of dexmedetomidine in preventing AKI after surgical operation. Methods: We systematically searched electronic databases such as PubMed, Embase, Web of Science, and the Cochrane Library to detect eligible randomized controlled studies that used dexmedetomidine for the prevention of AKI following operation up to April 30, 2023. The main outcome evaluated was AKI incidence. The evidence quality was assessed employing the Grading of Recommendations Assessment, Development, and Evaluation. Results: The meta-analysis included 25 trials, including 3,997 individuals. Of these, 2,028 were in the dexmedetomidine group, and 1,969 were in the control group. The result showed that patients administered dexmedetomidine significantly decreased the AKI incidence following surgical operation in contrast to the control group (risk ratio, 0.60; 95% confidence intervals, 0.45-0.78; p < 0.05; I 2 = 46%). In addition, dexmedetomidine decreased the period of hospitalization in both the intensive care unit (ICU) and the hospital while also reducing postoperative delirium (POD) occurrence. However, dexmedetomidine elevated the incidence of bradycardia but did not have a significant impact on other indicators. Conclusion: Our meta-analysis indicates that the dexmedetomidine treatment reduces the postoperative AKI and POD risk while also shortening the time of hospitalization in the ICU and hospital. However, it is connected to an increased bradycardia risk.

[Socio-ecological risk analysis framework coupled with ecosystem services]. / 耦合生态系统服务的社会生态风险分析框架.

The strong coupling between society and ecosystem makes socio-ecological risks become the main object of risk management. As the link between ecological and social processes, ecosystem services (ESs) are the core variable in deconstructing the social-ecological risks and the crucial point in resolving the risks. We explored the concept and the internal formation mechanisms of socio-ecological risk combining ESs, and further put the cascade logic and evolution process of "real risk-risk perception-risk behavior". Based on driver-pressure-state-impact-response framework (DPSIR), we proposed a framework for analyzing socio-ecological risk, and expanded the content and methodology system of research and management practices related to socio-ecological risks. We proposed that socio-ecological risk research coupled with ESs should focus on: 1) exploring the transmission mechanism between ecosystem processes, ecosystem services, and human well-being; 2) exploring the response mechanism of social subject behavior and its impacts on ecosystem services and human well-being; 3) construction of a multi-scale assessment model for social ecological risks coupled with ESs. The socio-ecological risk analysis framework for coupled ecosystem services was based on the mutual feedback between human and nature to explore the logic of risk formation, evolution, and governance, which could provide ideas for clarifying the deep meaning of ecological problems and selecting pathways to resolve socio-ecological risks.

Polyhedral {Ag12} and {Ag16} Clusters: Synthesis, Structural Characterization and Third-Order Nonlinear Optical Properties.

Two polyhedral silver-thiolate clusters, [S@Ag16(Tab)10(MeCN)8](PF6)14 (Ag16) and [Ag12(Tab)6(DMF)12](PF6)12 (Ag12), were synthesized by using electroneutral Tab species as protective ligands (Tab=4-(trimethylammonio)benzenethiolate, DMF=N,N-dimethylformamide, MeCN=acetonitrile). Ag16 has a decahedral shape composed of eight pentagon {Ag5} units and two square {Ag4} units. The structure of Ag12 is a cuboctahedron, a classical Archimedean structure composed of six triangular faces and eight square faces. The former configuration is discovered in silver-thiolate cluster for the first time, possibly benefited from the more flexible coordination between the Tab ligand and Ag+ facilitated by the electropositive -N(CH3)3 + substituent group. Third-order nonlinear optical studies show that both clusters in DMF exhibit reverse saturate absorption response under the irradiation of 532 nm laser.

Electron wave and quantum optics in graphene.

In the last decade, graphene has become an exciting platform for electron optical experiments, in some aspects superior to conventional two-dimensional electron gases (2DEGs). A major advantage, besides the ultra-large mobilities, is the fine control over the electrostatics, which gives the possibility of realising gap-less and compact p-n interfaces with high precision. The latter host non-trivial states,e.g., snake states in moderate magnetic fields, and serve as building blocks of complex electron interferometers. Thanks to the Dirac spectrum and its non-trivial Berry phase, the internal (valley and sublattice) degrees of freedom, and the possibility to tailor the band structure using proximity effects, such interferometers open up a completely new playground based on novel device architectures. In this review, we introduce the theoretical background of graphene electron optics, fabrication methods used to realise electron-optical devices, and techniques for corresponding numerical simulations. Based on this, we give a comprehensive review of ballistic transport experiments and simple building blocks of electron optical devices both in single and bilayer graphene, highlighting the novel physics that is brought in compared to conventional 2DEGs. After describing the different magnetic field regimes in graphene p-n junctions and nanostructures, we conclude by discussing the state of the art in graphene-based Mach-Zender and Fabry-Perot interferometers.

Impact of age and donor sites on bioactivities of tendon cells in autologous tenocyte implantation (OrthoATI™) for treatment of chronic tendinopathy.

OBJECTIVES: Autologous tenocyte implantation (OrthoATI™) therapy has demonstrated efficacy in treating patients with tendinopathy at various anatomical sites. This study evaluates the effect of patient age, gender, and tendon biopsy site on morphology, growth, and gene expression of autologous tendon cells used to treat chronic tendinopathy. METHODS: Patients undergoing OrthoATI™ for tendinopathies between 2020 and 2022 were initially treated by biopsies taken from patella tendon (PT) or palmaris longus tendon (PL). The biopsies were sent to a Good Manufacturing Practice (GMP) cell laboratory where tendon cells were isolated, cultured, and expanded for four to six weeks. Cell morphology was assessed using phase contrast microscopy. Droplet digital PCR (ddPCR) was utilized for gene expression analysis. Dichotomous results were compared between groups using x2 or Fisher's exact tests with no adjustment for multiple comparisons. The nonparametric Mann-Whitney U and Kruskal-Wallis tests were utilized for the sex and age (<35y, 35-44y, 45-54y, >55y) analyses, respectively. All analyses were performed using IBM SPSS v27, and a two-tailed P-value of <0.05 was considered statistically significant. RESULTS: 149 patients were included in the analysis. The PT was biopsied in 63 patients, and PL in 86 patients. There were no observer effects for age and gender between the PT and PL groups. There was no statistical significance between the PT and PL tendons for cell morphology, average cell population doubling time (PDT) (PT 83.9 vs PL 82.7 â€‹h, p â€‹= â€‹0.482), cellular yield (PT 16.2 vs PL 15.2 â€‹× â€‹106, p â€‹= â€‹0.099), and cell viability (PT 98.7 vs PL 99.0%, p â€‹= â€‹0.277). Additionally, ddPCR analyses showed no statistical significance found in tenogenic gene expression, including collagen type I (COL1, p â€‹= â€‹0.86), tenomodulin (TNMD, p â€‹= â€‹0.837) and scleraxis (SCX, p â€‹= â€‹0.331) between PT- and PL-derived tendon cells. An age stratification analysis found no effect on growth and gene expression. COL1 was found to be higher in males when compared to females (P â€‹< â€‹0.001), but otherwise no difference was seen in growth and gene expression in the gender analysis. No postbiopsy clinical complications were reported for either group. CONCLUSION: This study has shown that the growth and bioactivities of tendon cells from tendon biopsies for OrthoATI™ are not affected by tendon donor site and age. LEVEL OF EVIDENCE: IV.

Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti-B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8+ CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Novel quinoxaline analogs as telomeric G-quadruplex ligands exert antitumor effects related to enhanced immunomodulation.

G-quadruplexes (G4s) are commonly formed in the G-rich strand of telomeric DNA. Ligands targeting telomeric G4 induce DNA damage and telomere dysfunction, which makes them potential antitumor drugs. New telomeric G4 ligands with drug-likeness are still needed to be exploited, especially with their antitumor mechanisms thoroughly discussed. In this study, a novel series of quinoxaline analogs were rationally designed and synthesized. Among them, R1 was the most promising ligand for its cytotoxic effects on tumor cells and stabilizing ability with telomeric G4. Cellular assays illustrated that R1 stabilized G4 and induced R-loop accumulation in the telomeric regions, subsequently triggering DNA damage responses, cell cycle arrest in G2/M phase, apoptosis and antiproliferation. Moreover, R1 evoked immunogenic cell death (ICD) in tumor cells, which promoted the maturation of bone marrow derived dendritic cells (BMDCs). In breast cancer mouse model, R1 exhibited a significant decrease in tumor burden through the immunomodulatory effects, including the increase of CD4+ and CD8+ T cells in tumors and cytokine levels in sera. Our research provides a new idea that targeting telomeric G4 induces DNA damage responses, causing antitumor effects both in vitro and in vivo, partially due to the enhancement of immunomodulation.

CXCL9 Overexpression Predicts Better HCC Response to Anti-PD-1 Therapy and Promotes N1 Polarization of Neutrophils.

Background: Anti-programmed death-1 (PD1) antibodies have changed the treatment landscape for hepatocellular carcinoma (HCC) and exhibit promising treatment efficacy. However, the majority of HCCs still do not respond to anti-PD-1 therapy. Methods: We analyzed the expression of CXCL9 in blood samples from patients who received anti-PD-1 therapy and evaluated its correlation with clinicopathological characteristics and treatment outcomes. Based on the results of Cox regression analysis, a nomogram was established for predicting HCC response to anti-PD-1 therapy. qRT‒PCR and multiple immunofluorescence assays were utilized to analyze the proportions of N1-type neutrophils in vitro and in tumor samples, respectively. Results: The nomogram showed good predictive efficacy in the training and validation cohorts and may be useful for guiding clinical treatment of HCC patients. We also found that HCC cell-derived CXCL9 promoted N1 polarization of neutrophils in vitro and that AMG487, a specific CXCR3 inhibitor, significantly blocked this process. Moreover, multiple immunofluorescence (mIF) showed that patients with higher serum CXCL9 levels had greater infiltration of the N1 phenotype of tumor-associated neutrophils (TANs). Conclusion: Our study highlights the critical role of CXCL9 as an effective biomarker of immunotherapy efficacy and in promoting the polarization of N1-type neutrophils; thus, targeting the CXCL9-CXCR3 axis could represent a novel pharmaceutical strategy to enhance immunotherapy for HCC.

Case report: Rapidly progressive desmoid tumor after surgery for esophagogastric junction cancer and slowly progressive primary desmoid tumor: a report of two cases and literature review.

Background: Desmoid tumor (DT) is a rare locally aggressive but non-metastatic mesenchymal soft tissue neoplasm that predominantly occurs in the abdominal wall, abdominal cavity, and extremities. Its occurrence in the mesentery is relatively uncommon. Case reports: This article reports two cases of desmoid tumor treated at the Department of Gastrointestinal Surgery, Weifang People's Hospital. The first case was a 59-year-old male patient who had previously undergone surgery for esophagogastric junction cancer. Postoperatively, he developed an intra-abdominal mass that rapidly increased in size within three months. The second case was a 60-year-old male patient who incidentally discovered a mass in the left lower abdomen. Both patients underwent surgical treatment, and the postoperative pathological diagnosis was mesenteric desmoid tumor. Conclusion: The treatment of desmoid tumor remains challenging. Simple surgical resection often yields unsatisfactory outcomes, and the efficacy of adjuvant radiotherapy and chemotherapy is also limited. Further research and clinical practice are necessary to improve diagnostic and therapeutic strategies, aiming to enhance patient survival and quality of life.

Discovery of a mitochondrial G-quadruplex targeted fluorescent ligand via a slight variation on the near-infrared heptamethine cyanine scaffold.

The heptamethine cyanine dyes are one kind of promising near-infrared (NIR) compounds, holding great potential in both diagnostic and therapeutic regions. Remolding such structures to realize detection of unclarified biotargets or interfering with them seems to be important in the field of chemical biology. In this study, we developed a fluorescent ligand (IR1) targeting mitochondrial G-quadruplexes (mitoG4s) by a slight variation on the typical NIR scaffold (IR780). This ligand could be applied for sensing mitoG4s by fluorescence, making it different from the unmodified dye whose fluorescence was quenched by mitoG4s. Then, IR1 was demonstrated to accumulate in the mitochondria through a mitochondrial membrane potential (MMP) dependent manner. Some of IR1 then bound to mitoG4s, causing mtDNA loss and mitochondrial dysfunction, which thereby triggered PANoptosis, including apoptosis, autophagy and pyroptosis. To the best of our knowledge, IR1 was the first NIR fluorescent ligand with emission centered at above 800 nm for mitoG4s, and the first example causing PANoptosis among the reported mitoG4-targeted ligands.

Impact of nondiameter aortic indices on surgical eligibility: Results from the Treatment in Thoracic Aortic Aneurysm: Surgery Versus Surveillance (TITAN: SvS) randomized controlled trial.

OBJECTIVES: Traditional criterion for intervention on an asymptomatic ascending aortic aneurysm has been a maximal aortic diameter of 5.5 cm or more. The 2022 American College of Cardiology/American Heart Association aortic guidelines adopted cross-sectional aortic area/height ratio, aortic size index, and aortic height index as alternate parameters for surgical intervention. The objective of this study was to evaluate the impact of using these newer indices on patient eligibility for surgical intervention in a prospective, multicenter cohort with moderate-sized ascending aortic aneurysms between 5.0 and 5.4 cm. METHODS: Patients enrolled from 2018 to 2023 in the randomization or registry arms of the multicenter trial, Treatment In Thoracic Aortic aNeurysm: Surgery versus Surveillance, were included in the study. Clinical data were captured prospectively in an online database. Imaging data were derived from a core computed laboratory. RESULTS: Among the 329 included patients, 20% were female. Mean age was 65.0 ± 11.6 years, and mean maximal aortic diameter was 50.8 ± 3.9 mm. In the one-third of all patients (n = 109) who met any 1 of the 3 criteria (ie, aortic size index ≥3.08 cm/m2, aortic height index ≥3.21 cm/m, or cross-sectional aortic area/height ≥ 10 cm2/m), their mean maximal aortic diameter was 52.5 ± 0.52 mm. Alternate criteria were most commonly met in women compared with men: 20% versus 2% for aortic size index (P < .001), 39% versus 5% for aortic height index (P < .001), and 39% versus 21% for cross-sectional aortic area/height (P = .002), respectively. CONCLUSIONS: One-third of patients in Treatment In Thoracic Aortic aNeurysm: Surgery versus Surveillance would meet criteria for surgical intervention based on novel parameters versus the classic definition of diameter 5.5 cm or more. Surgical thresholds for aortic size index, aortic height index, or cross-sectional aortic area/height ratio are more likely to be met in female patients compared with male patients.

Ldl-stimulated microglial activation exacerbates ischemic white matter damage.

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

Development of a fluorescent ligand that can illuminate nuclear G-quadruplexes and modulate oncogene expression.

In this study, we developed a promising dual-function fluorescent ligand termed KS-1 by a slight structural modification on a reported carbazole-based scaffold. KS-1 was then found to mainly bind and illuminate the nuclear DNA G-quadruplexes (G4s) in a sandwich-like interacting mode, and also effectively modulate the oncogene expression through a G4-mediated manner. Furthermore, KS-1 was proved to inhibit cancer cell growth either in 2D monolayer cells or 3D multicellular tumor spheroids. To be noted, this ligand could overcome the shortcomings of other reported dual-function ligands that appeared to accumulate in the lysosomes or mitochondria, and may be used as a theranostic agent in the future.