Meningeal lymphatic vessel crosstalk with central nervous system immune cells in aging and neurodegenerative diseases.

Meningeal lymphatic vessels form a relationship between the nervous system and periphery, which is relevant in both health and disease. Meningeal lymphatic vessels not only play a key role in the drainage of brain metabolites but also contribute to antigen delivery and immune cell activation. The advent of novel genomic technologies has enabled rapid progress in the characterization of myeloid and lymphoid cells and their interactions with meningeal lymphatic vessels within the central nervous system. In this review, we provide an overview of the multifaceted roles of meningeal lymphatic vessels within the context of the central nervous system immune network, highlighting recent discoveries on the immunological niche provided by meningeal lymphatic vessels. Furthermore, we delve into the mechanisms of crosstalk between meningeal lymphatic vessels and immune cells in the central nervous system under both homeostatic conditions and neurodegenerative diseases, discussing how these interactions shape the pathological outcomes. Regulation of meningeal lymphatic vessel function and structure can influence lymphatic drainage, cerebrospinal fluid-borne immune modulators, and immune cell populations in aging and neurodegenerative disorders, thereby playing a key role in shaping meningeal and brain parenchyma immunity.

Exploring the therapeutic implications of natural compounds modulating apoptosis in vascular dementia.

Vascular dementia (VaD) is a prevalent form of dementia stemming from cerebrovascular disease, manifesting in memory impairment and executive dysfunction, thereby imposing a substantial societal burden. Unfortunately, no drugs have been approved for the treatment of VaD due to its intricate pathogenesis, and the development of innovative and efficacious medications is urgently needed. Apoptosis, a programmed cell death process crucial for eliminating damaged or unwanted cells within an organism, assumes pivotal roles in embryonic development and tissue homeostasis maintenance. An increasing body of evidence indicates that apoptosis may significantly influence the onset and progression of VaD, and numerous natural compounds have demonstrated significant therapeutic potential. Here, we discuss the molecular mechanisms underlying apoptosis and its correlation with VaD. We also provide a crucial reference for developing innovative pharmaceuticals by systematically reviewing the latest research progress concerning the neuroprotective effects of natural compounds on VaD by regulating apoptosis. Further high-quality clinical studies are imperative to firmly ascertain these natural compounds' clinical efficacy and safety profiles in the treatment of VaD.

Periodic protein-restricted diets extend the lifespan of high-fat diet-induced Drosophila melanogaster males.

Research has shown that sustained protein restriction can improve the effects of a high-fat diet on health and extend lifespan. However, long-term adherence to a protein-restricted diet is challenging. Therefore, we used a fly model to investigate whether periodic protein restriction (PPR) could also mitigate the potential adverse effects of a high-fat diet and extend healthy lifespan. Our study results showed that PPR reduced body weight, lipid levels, and oxidative stress induced by a high-fat diet in flies and significantly extended the healthy lifespan of male flies. Lipid metabolism and transcriptome results revealed that the common differences between the PPR group and the control group and high-fat group showed a significant decrease in palmitic acid in the PPR group; the enriched common differential pathways Toll and Imd were significantly inhibited in the PPR group. Further analysis indicated a significant positive correlation between palmitic acid levels and gene expression in the Toll and Imd pathways. This suggests that PPR effectively improves fruit fly lipid metabolism, reduces palmitic acid levels, and thereby suppresses the Toll and Imd pathways to extend the healthy lifespan of flies. Our study provides a theoretical basis for the long-term effects of PPR on health and offers a new dietary adjustment option for maintaining health in the long term.

Risk Factors for Early Recurrence After Radical Resection of Hepatocellular Carcinoma Based on Preoperative Contrast-Enhanced Ultrasound and Clinical Features.

OBJECTIVES: To investigate risk factors for the early recurrence (ER) of hepatocellular carcinoma (HCC) after radical resection based on preoperative contrast-enhanced ultrasound (CEUS) and clinical features to provide guidance for clinical treatment. METHODS: The retrospective analysis selected 130 HCC patients who underwent radical tumor resection from October 2019 to November 2021. All patients underwent preoperative routine ultrasound examination and CEUS, and the pathology was confirmed as HCC after surgery. The patients were divided into two groups based on whether there is an ER, namely the ER group and the non-ER group. The general clinical, routine and CEUS data of patients were collected, and the factors were selected by using the least absolute shrinkage and selection operator (LASSO) regression. Multivariate logistic regression was used to screen the independent influencing factors of ER. Then a nomogram model was established to predict the risk of ER, and the application value of nomogram through internal validation was evaluated. RESULTS: Multivariate logistic regression identified several independent factors influencing ER after radical HCC resection. Significant factors included early wash-out phase (95%CI = 0.003-0.206, P = 0.001), liver cirrhosis (95%CI = 2.835-221.224, P = 0.004), incomplete envelope (95%CI = 5.247-1056.130,P = 0.001), multiple lesions (95%CI = 1.110-135.424,P = 0.041), Albumin <40 g/L (95%CI = 2.496-127.223,P = 0.004), and Golgi Protein 73 (GP73) ≥ 85 ng/mL (95%CI = 1.594-30.002, P = 0.010), with all P-values <0.05. The nomogram prediction model constructed based on the results of multivariate logistic regression, demonstrated a ROC curve AUC of 0.879, a sensitivity of 93.5%, a specificity of 66.7%, and a C-index of 0.602, indicating superior diagnostic efficiency compared to independent influencing factors. The ER nomogram prediction model confirmed good discrimination and calibration in internal validation. CONCLUSION: The CEUS-Clinical combined model effectively monitors the risk of ER in high-risk populations following radical resection of HCC, timely interventions to improve patient prognosis.

Oral Microto-Nano Genome-Editing System Enabling Targeted Delivery and Conditional Activation of CRISPR-Cas9 for Gene Therapy of Inflammatory Bowel Disease.

The potent CRISPR-Cas9 technology can correct genes in human mutated cells to achieve the treatment of multiple diseases, but it lacks safe and effective delivery systems. Herein, we proposed an oral microto-nano genome-editing system aiming at the enteric excessive level of TNF-α for specific gene therapy of inflammatory bowel disease (IBD). This editing system facilitated the assembly of Cas9/sgRNA ribonucleoprotein (RNP) into nanoclusters (NCs) through the bridging of disulfide bonds. RNP-NCs were subsequently encapsulated within inflammatory cell-targeted lipopolysaccharide-deleted outer membrane vesicles (dOMVs) sourced from Escherichia coli Nissle 1917, which were further shielded by an outer layer of calcium alginate microspheres (CAMs). By leveraging the protection effect of CAMs, the oral administration system withstood gastric acid degradation upon entry into the stomach, achieving targeted delivery to the intestines with high efficiency. As the pH gradually rose, the microscale CAMs swelled and disintegrated, releasing nanoscale RNP-NCs encapsulated in dOMVs into the intestines. These RNP-NCs@dOMVs could traverse the mucosal barrier and target inflammatory macrophages where conditionally activated Cas9/sgRNA RNPs effectively perform genomic editing of TNF-α within the nucleus. Such oral microto-nano genome-editing systems represent a promising translational platform for the treatment of IBD.

Competitive dynamics and balance between Streptococcus mutans and commensal streptococci in oral microecology.

Dental caries, as a biofilm-related disease, is closely linked to dysbiosis in microbial ecology within dental biofilms. Beyond its impact on oral health, bacteria within the oral cavity pose systemic health risks by potentially entering the bloodstream, thereby increasing susceptibility to bacterial endocarditis, among other related diseases. Streptococcus mutans, a principal cariogenic bacterium, possesses virulence factors crucial to the pathogenesis of dental caries. Its ability to adhere to tooth surfaces, produce glucans for biofilm formation, and metabolize sugars into lactic acid contributes to enamel demineralization and the initiation of carious lesions. Its aciduricity and ability to produce bacteriocins enable a competitive advantage, allowing it to thrive in acidic environments and dominate in changing oral microenvironments. In contrast, commensal streptococci, such as Streptococcus sanguinis, Streptococcus gordonii, and Streptococcus salivarius, act as primary colonizers and compete with S. mutans for adherence sites and nutrients during biofilm formation. This competition involves the production of alkali, peroxides, and antibacterial substances, thereby inhibiting S. mutans growth and maintaining microbial balance. This dynamic interaction influences the balance of oral microbiota, with disruptions leading to shifts in microbial composition that are marked by rapid increases in S. mutans abundance, contributing to the onset of dental caries. Thus, understanding the dynamic interactions between commensal and pathogenic bacteria in oral microecology is important for developing effective strategies to promote oral health and prevent dental caries. This review highlights the roles and competitive interactions of commensal bacteria and S. mutans in oral microecology, emphasizing the importance of maintaining oral microbial balance for health, and discusses the pathological implications of perturbations in this balance.

Lipids, Apolipoproteins, Lipid-Lowering Drugs, and the Risk of Cerebral Small Vessel Disease: A Mendelian Randomization Study.

BACKGROUND: Serum lipids are causally involved in the occurrence of atherosclerosis, but their roles in cerebral small vessel disease remain unclear. This study aimed to investigate the causal roles of lipid or apolipoprotein traits in cerebral small vessel disease and to determine the effects of lipid-lowering interventions on this disease. METHODS AND RESULTS: Data on genetic instruments of lipids/apolipoproteins, as well as characteristic cerebral small vessel disease manifestations, including small vessel stroke (SVS) and white matter hyperintensity (WMH), were obtained from publicly genome-wide association studies. Through 2-sample Mendelian randomization analyses, it was found that decreased levels of high-density lipoprotein cholesterol (odds ratio [OR], 0.85, P=0.007) and apolipoprotein A-I (OR, 0.83, P=0.005), as well as increased level of triglycerides (OR, 1.16, P=0.025) were associated with a higher risk of SVS. A low level of high-density lipoprotein cholesterol (OR, 0.93, P=0.032) was associated with larger WMH volume. Specifically, the genetically determined expressions of lipid fractions in various size-defined lipoprotein particles were more closely related to the risk of SVS than WMH. Moreover, it was found that the hypertension trait ranked at the top in mediating the causal effect of hyperlipidemia on SVS and WMH by using Mendelian randomization-based mediation analysis. For drug-target Mendelian randomization, the low-density lipoprotein cholesterol-reducing genetic variation alleles at HMGCR and NL1CL1 genes and the high-density lipoprotein cholesterol-raising genetic variation alleles at the CETP gene were predicted to decrease the risk of SVS. CONCLUSIONS: The present Mendelian randomization study indicates that genetically determined hyperlipidemia is closely associated with a higher risk of cerebral small vessel disease, especially SVS. Lipid-lowering drugs could be potentially considered for the therapies and preventions of SVS rather than WMH.

Nuclear reassembly defects after mitosis trigger apoptotic and p53-dependent safeguard mechanisms in Drosophila.

In animals, mitosis involves the breakdown of the nuclear envelope and the sorting of individualized, condensed chromosomes. During mitotic exit, emerging nuclei reassemble a nuclear envelope around a single mass of interconnecting chromosomes. The molecular mechanisms of nuclear reassembly are incompletely understood. Moreover, the cellular and physiological consequences of defects in this process are largely unexplored. Here, we have characterized a mechanism essential for nuclear reassembly in Drosophila. We show that Ankle2 promotes the PP2A-dependent recruitment of BAF and Lamin at reassembling nuclei, and that failures in this mechanism result in severe nuclear defects after mitosis. We then took advantage of perturbations in this mechanism to investigate the physiological responses to nuclear reassembly defects during tissue development in vivo. Partial depletion of Ankle2, BAF, or Lamin in imaginal wing discs results in wing development defects accompanied by apoptosis. We found that blocking apoptosis strongly enhances developmental defects. Blocking p53 does not prevent apoptosis but enhances defects due to the loss of a cell cycle checkpoint. Our results suggest that apoptotic and p53-dependent responses play a crucial role in safeguarding tissue development in response to sporadic nuclear reassembly defects.

Bioactivity and in vitro immunological studies of xenogeneic decellularized extracellular matrix scaffolds for implantable applications.

Decellularized scaffolds retain the main bioactive substances of the extracellular matrix, which can better promote cell proliferation and matrix reconstruction at the defect site, and have great potential for morphological and functional restoration in patients with tissue defects. Due to the safety of the material source of allogeneic decellularized scaffolds, there is a great limitation in their clinical application, so the preparation and evaluation of xenodermal acellular scaffolds have attracted much attention. In terms of skin tissue structure and function, porcine skin has a high degree of similarity to human skin and has the advantages of sufficient quantity and no ethical issues. However, there is a risk of immune rejection after xenodermal acellular scaffold transplantation. To address the above problems, this paper focuses on porcine dermal decellularized scaffolds prepared using two common decellularization preparation methods and compares the decellularization efficiency, retention of active components of the extracellular matrix, structural characterization of the decellularized scaffolds, and the effect of porcine dermal decellularized scaffolds on mouse Raw264.7 macrophages, so as to make a functional evaluation of the active components and immune effects of porcine dermal decellularized scaffolds, and to provide a reference for filling trauma-induced defects in humans.

Dynamic control of His-hemin coordination and catalysis by reversible host-guest inclusion in peptide assemblies.

Dynamic self-assembly has significant implications in the regulation of the enzyme activities. In this study, we present a histidine-based enzyme-mimicking catalyst, formed by the self-assembly of carefully-engineered FH-based short peptides with hemin, showcasing switchable catalytic activity of hemin due to externally induced reversible inclusion of a cucurbit[7]uril-peptide hybrid. 1H NMR, ITC and theoretical simulation are employed to examine the binding affinity between the guest and host components, and UV-vis spectra are used to investigate changes in the hemin coordination environment. The histidine segment of the short peptide can be partially shielded by the cucurbituril and released following addition of the azo compound, leading to a decrease and subsequent restoration of the histidine-hemin coordination affinity and hemin activity. The photoisomeriziable nature of the azo compound enabled the activation of FHH/hemin activity to be switched on and off by exposure to different wavelengths of light. During the operation, the Phe residue remained within the cucurbituril, allowing reversible inclusion and exposure of the histidine residues. The hemin stayed connected to FHH/cucurbit[7]uril hybrid, preventing the severe aggregation of hemin and irreversible deactivation. This work may provide insights into engineering the dynamic behaviors of the cofactor-dependent catalytic assemblies.

Decellularized Matrices for the Treatment of Tissue Defects: from Matrix Origin to Immunological Mechanisms.

Decellularized matrix transplantation has emerged as a promising therapeutic approach for repairing tissue defects, with numerous studies assessing its safety and efficacy in both animal models and clinical settings. The host immune response elicited by decellularized matrix grafts of natural biological origin plays a crucial role in determining the success of tissue repair, influenced by matrix heterogeneity and the inflammatory microenvironment of the wound. However, the specific immunologic mechanisms underlying the interaction between decellularized matrix grafts and the host immune system remain elusive. This article reviews the sources of decellularized matrices, available decellularization techniques, and residual immunogenic components. It focuses on the host immune response following decellularized matrix transplantation, with emphasis on the key mechanisms of Toll-like receptor, T-cell receptor, and TGF-ß/SMAD signaling in the stages of post-transplantation immunorecognition, immunomodulation, and tissue repair, respectively. Furthermore, it highlights the innovative roles of TLR10 and miR-29a-3p in improving transplantation outcomes. An in-depth understanding of the molecular mechanisms underlying the host immune response after decellularized matrix transplantation provides new directions for the repair of tissue defects.

Cytochrome P450 F3 promotes colorectal cancer via inhibiting NRF2-mediated ferroptosis.

Cytochrome P450 F3 (CYP4F3) is recognized as a disease-associated immune response initiator that is involved in the synthesis of cholesterol, steroids, and lipids. This study identified the upregulation of CYP4F3 expression in colorectal cancer (CRC) and its association with poor patient prognosis through a comparative analysis between CRC tumor tissues with normal tissues from public databases. The overexpression of CYP4F3 in CT26.wt and SW620, promoted cell proliferation and migration, a reduction of cellular oxidative stress, an up-regulation of the oxidative stress-related pathway NRF2, and an inhibition of cellular ferroptosis. Additionally, inhibition of NRF2 activity stimulated cellular ferroptosis when CYP4F3 was overexpressed. Ferroptosis, characterized by iron-dependent lipid peroxidation, is a non-apoptotic way of cell death with a critical role in cancer development. When given a ferroptosis agonist to CYP4F3-overexpression CRC cells, NRF2 was activated, and cell proliferation and migration were reduced. Furthermore, the mice subcutaneously injected with CYP4F3-overexpression CT26.wt cells formed significantly larger tumors compared to the CYP4F3-vector CT26.wt cell group. This study systematically identified an important role of CYP4F3 in CRC development as a regulator of CRC cells to escape ferroptosis via NRF2, highlighting the significance of CYP4F3 as a potential therapeutic target for CRC.

Imaging Single Prussian Blue Nanoparticles with Extraordinary Low-Spin Iron Capacity.

In attempts to obtain high-capacity Prussian blue nanomaterials, current efforts are predominantly focused on the particle-ensemble-level understanding of their structure-activity relationships. Complementarily, it would be insightful to screen out extraordinary individuals from the nanoparticle population. Using a simple and efficient technique of bright-field microscopy, this work enables, for the first time, quantitative characterization of the overall two-redox-center electrochemistry of single Prussian blue nanoparticles many at a time. Quantitative optical voltammograms with little interference from solvent breakdown and non-Faradaic electrode charging/discharging are extracted for each single nanoparticle, revealing clear heterogeneity among them. On this basis, the microscopic method allows a detailed comparative analysis between the two redox-active sites. It is found that while the synthesized nanoparticles show a similar specific capacity of the high-spin (HS-Fe) sites with STD/mean = 30%, most individual nanoparticles exhibit monodispersedly small capacities of the low-spin iron (LS-Fe) sites, only about 17±1 of the HS-Fe capacity. Most importantly, it is discovered that there is always a small fraction (∼8%) of the single nanoparticles showing an impressively tripled LS-Fe capacity. Facilitated by optical imaging, the discovery of this easily overlooked extraordinary subpopulation confers alternative opportunities for targeted efforts for material chemists to improve synthesis and material design based on these unusual individuals, which in turn implies the general significance of nanoparticle screening.

Correlation of Vanillin-Induced Cytotoxicity with CYP3A-Mediated Metabolic Activation.

Vanillin (VAN) is a common flavoring agent that can cause liver damage when ingested in large amounts. Nevertheless, the precise processes responsible for its toxicity remain obscure. The present research aimed to examine the metabolic activation of VAN and establish a potential correlation between its reactive metabolites and its cytotoxicity. In rat liver microsomes incubated with VAN, reduced glutathione/N-acetylcysteine (GSH/NAC), and nicotinamide adenine dinucleotide phosphate (NADPH), two conjugates formed from GSH and one conjugate derived from NAC were identified. We also discovered one GSH conjugate in both the bile obtained from rats and the rat primary hepatocytes that were subjected to VAN exposure. Additionally, the NAC conjugate exerted in the urine of VAN-treated rats was observed. These results indicate that a quinone intermediate was produced from VAN both in vitro and in vivo. Next, we identified CYP3A as the main enzyme that initiated the bioactive pathway of VAN. After the activity of CYP3A was selectively inhibited by ketoconazole (KTZ), the generation of the GSH conjugate declined in hepatocytes exposed to VAN. Furthermore, the vulnerability to VAN-induced toxicity was alleviated by KTZ in hepatocytes. Thus, we propose that the cytotoxicity of VAN may derive from metabolic activation triggered by CYP3A.

Prohibitin 2 confers NADPH oxidase 1-mediated cytosolic oxidative signaling to promote gastric cancer progression by ERK activation.

Oxidative signaling plays a dual role in tumor initiation and progression to malignancy; however, the regulatory mechanisms of oxidative stress in gastric cancer remain to be explored. In this study, we discovered that Prohibitin 2 (PHB2) specifically regulates cytosolic reactive oxygen species production in gastric cancer and facilitates its malignant progression. Previously, we found that PHB2 is upregulated in gastric cancer, correlating with increased tumorigenicity of gastric cancer cells and poor patient prognosis. Here, we discovered that PHB2 expression correlates with the activation of the ERK/MAPK cascade, positively regulating the top gene NADPH oxidase 1 (NOX1) within this pathway. Further mechanistic investigation reveals that PHB2 enhances NOX1 transcription by interacting with the transcription factor C/EBP-beta and promoting its translocation into the nucleus, resulting in elevated intracellular oxidative signaling driven by NOX1, which subsequently activates ERK. Therefore, we propose that targeting PHB2-C/EBP-beta-NOX1-mediated cytosolic oxidative stress could offer a promising therapeutic avenue for combating gastric cancer malignant progression.

Therapeutic Potential of Natural Resources Against Endometriosis: Current Advances and Future Perspectives.

Endometriosis (EMS) is defined as the appearance, growth, infiltration, and repeated bleeding of endometrioid tissue (glands and stroma) outside the uterus cavity, which can form nodules and masses. Endometriosis is a chronic inflammatory estrogen-dependent disease and occurs in women of reproductive age. This disorder may significantly affect the quality of life of patients. The pathogenic processes involved in the development and maintenance of endometriosis remain unclear. Current treatment options for endometriosis mainly include drug therapy and surgery. Drug therapy mainly ties to the use of non-steroidal anti-inflammatory drugs (NSAIDs) and hormonal drugs. However, these drugs may produce adverse effects when used for long-term treatment of endometriosis, such as nausea, vomiting gastrointestinal reactions, abnormal liver and kidney function, gastric ulcers, and thrombosis. Although endometriosis lesions can be surgically removed, the disease has a high recurrence rate after surgical resection, with a recurrence rate of 21.5% within 2 years and 40% to 50% within 5 years. Thus, there is an urgent need to develop alternative or additional therapies for the treatment of endometriosis. In this review, we give a systematic summary of therapeutic multiple component prescriptions (including traditional Chinese medicine and so on), bioactive crude extracts of plants/herbs and purified compounds and their newly found mechanisms reported in literature in recent years against endometriosis.

Immunogen characterization reveals an intrinsic hindrance in eliciting neutralizing antibodies against JN.1 variant.

The immune evasion of emerging SARS-CoV-2 variants significantly undermines current vaccination efforts, calling for an updated vaccine composition. To identify optimal booster candidates against circulating JN.1, a panel of variant spikes were characterized. The omicron spikes exhibited reduced plasma membrane expression, accompanied by lower cell-cell fusion but increased viral entry. Regimens with DNA prime-DNA boost or DNA prime-adenoviral vectored vaccine boost by intramuscular immunization elicited neutralizing antibody (NAbs) and T cell responses against all variants except BA.2.86 and JN.1. Intranasal immunization induced high IgA and NAb titers in bronchoalveolar lavage against all variants except BA.2.86 and JN.1. T cell responses were generally comparable for all immunogens tested. JN.1 completely escaped NAbs in one immunized cohort, and breakthrough infections marginally boosted antibody titers. Overall, this study indicates intrinsic difficulty in eliciting NAbs against the JN.1 strain, whereas vaccines based on XBB and EG.5.1 are relatively superior in generating cross-reactive NAbs.

The relationship between serum 1,5-anhydroglucitol and adverse outcomes in acute coronary syndrome with and without chronic kidney disease patients.

Purpose: Individuals with chronic kidney disease (CKD) face an elevated residual risk of cardiovascular events, but the relationship between this residual risk and 1,5-anhydroglucitol (1,5-AG) is uncertain. Our study aimed to examine the effect of 1,5-AG on major adverse cardiovascular events (MACEs) and all-cause mortality in acute coronary syndrome (ACS) individuals. Methods: 1253 ACS participants hospitalized were enrolled at Beijing Hospital between March 2017 and March 2020. All participants were classified into 2 groups based on their eGFR (60 ml/min/1.73 m2). The link between 1,5-AG and adverse outcome was investigated in non-CKD and CKD participants. Results: CKD patients had reduced concentrations of 1,5-AG than those without CKD. Throughout a median follow-up duration of 43 months, 1,5-AG was an autonomous hazard factor for MACEs and all-cause mortality. 1,5-AG<14 µg/ml participants had greater MACEs and all-cause mortality risk than those with 1,5-AG≥14 µg/ml, regardless of renal function. Furthermore, concomitant reduced concentrations of 1,5-AG and CKD portended a dismal prognosis in ACS patients. Conclusions: 1,5-AG was autonomously linked to MACEs and all-cause mortality in ACS participants with both non-CKD and CKD. Co-presence of reduced concentrations of 1,5-AG and CKD may portend adverse clinical outcomes.

Trimethylamine N-oxide predicts cardiovascular events in coronary artery disease patients with diabetes mellitus: a prospective cohort study.

Background: Gut microbiota has significant impact on the cardio-metabolism and inflammation, and is implicated in the pathogenesis and progression of atherosclerosis. However, the long-term prospective association between trimethylamine N-oxide (TMAO) level and major adverse clinical events (MACEs) in patients with coronary artery disease (CAD) with or without diabetes mellitus (DM) habitus remains to be investigated. Methods: This prospective, single-center cohort study enrolled 2090 hospitalized CAD patients confirmed by angiography at Beijing Hospital from 2017-2020. TMAO levels were performed using liquid chromatography-tandem mass spectrometry. The composite outcome of MACEs was identified by clinic visits or interviews annually. Multivariate Cox regression analysis, Kaplan-Meier analysis, and restricted cubic splines were mainly used to explore the relationship between TMAO levels and MACEs based on diabetes mellitus (DM) habitus. Results: During the median follow-up period of 54 (41, 68) months, 266 (12.7%) developed MACEs. Higher TMAO levels, using the tertile cut-off value of 318.28 ng/mL, were significantly found to be positive dose-independent for developing MACEs, especially in patients with DM (HR 1.744, 95%CI 1.084-2.808, p = 0.022). Conclusions: Higher levels of TMAO are significantly associated with long-term MACEs among CAD patients with DM. The combination of TMAO in patients with CAD and DM is beneficial for risk stratification and prognosis.

Controlled interconversion of macrocyclic atropisomers via defined intermediates.

Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C2v and C4v symmetry denoted as C2v-OC-4 and C4v-OC-4, respectively. Heating induces the efficient stepwise conversion of C2v- to C4v-OC-4 via a Cs-symmetric intermediate (Cs-OC-4). It differs from the typical transition state-mediated processes of simple C-C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C2v- and Cs-OC-4 from C4v-OC-4. In contrast to C2v-OC-4, C4v-OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.