Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer Cells.

Mammalian folate metabolism is comprised of cytosolic and mitochondrial pathways with nearly identical core reactions, yet the functional advantages of such an organization are not well understood. Using genome-editing and biochemical approaches, we find that ablating folate metabolism in the mitochondria of mammalian cell lines results in folate degradation in the cytosol. Mechanistically, we show that QDPR, an enzyme in tetrahydrobiopterin metabolism, moonlights to repair oxidative damage to tetrahydrofolate (THF). This repair capacity is overwhelmed when cytosolic THF hyperaccumulates in the absence of mitochondrially produced formate, leading to THF degradation. Unexpectedly, we also find that the classic antifolate methotrexate, by inhibiting its well-known target DHFR, causes even more extensive folate degradation in nearly all tested cancer cell lines. These findings shed light on design features of folate metabolism, provide a biochemical basis for clinically observed folate deficiency in QDPR-deficient patients, and reveal a hitherto unknown and unexplored cellular effect of methotrexate.

Exploring Present and Future Directions in Nano-Enhanced Optoelectronic Neuromodulation.

Electrical neuromodulation has achieved significant translational advancements, including the development of deep brain stimulators for managing neural disorders and vagus nerve stimulators for seizure treatment. Optoelectronics, in contrast to wired electrical systems, offers the leadless feature that guides multisite and high spatiotemporal neural system targeting, ensuring high specificity and precision in translational therapies known as "photoelectroceuticals". This Account provides a concise overview of developments in novel optoelectronic nanomaterials that are engineered through innovative molecular, chemical, and nanostructure designs to facilitate neural interfacing with high efficiency and minimally invasive implantation.This Account outlines the progress made both within our laboratory and across the broader scientific community, with particular attention to implications in materials innovation strategies, studying bioelectrical activation with spatiotemporal methods, and applications in regenerative medicine. In materials innovation, we highlight a nongenetic, biocompatible, and minimally invasive approach for neuromodulation that spans various length scales, from single neurons to nerve tissues using nanosized particles and monolithic membranes. Furthermore, our discussion exposes the critical unresolved questions in the field, including mechanisms of interaction at the nanobio interface, the precision of cellular or tissue targeting, and integration into existing neural networks with high spatiotemporal modulation. In addition, we present the challenges and pressing needs for long-term stability and biocompatibility, scalability for clinical applications, and the development of noninvasive monitoring and control systems.In addressing the existing challenges in the field of nanobio interfaces, particularly for neural applications, we envisage promising strategic directions that could significantly advance this burgeoning domain. This involves a deeper theoretical understanding of nanobiointerfaces, where simulations and experimental validations on how nanomaterials interact spatiotemporally with biological systems are crucial. The development of more durable materials is vital for prolonged applications in dynamic neural interfaces, and the ability to manipulate neural activity with high specificity and spatial resolution, paves the way for targeting individual neurons or specific neural circuits. Additionally, integrating these interfaces with advanced control systems, possibly leveraging artificial intelligence and machine learning algorithms and programming dynamically responsive materials designs, could significantly ease the implementation of stimulation and recording. These innovations hold the potential to introduce novel treatment modalities for a wide range of neurological and systemic disorders.

CCDC66 mutations are associated with high myopia through affected cell mitosis.

BACKGROUND: High myopia (HM) refers to an eye refractive error exceeding -5.00 D, significantly elevating blindness risk. The underlying mechanism of HM remains elusive. Given the extensive genetic heterogeneity and vast genetic base opacity, it is imperative to identify more causative genes and explore their pathogenic roles in HM. METHODS: We employed exome sequencing to pinpoint the causal gene in an HM family. Sanger sequencing was used to confirm and analyse the gene mutations in this family and 200 sporadic HM cases. Single-cell RNA sequencing was conducted to evaluate the gene's expression patterns in developing human and mouse retinas. The CRISPR/Cas9 system facilitated the gene knockout cells, aiding in the exploration of the gene's function and its mutations. Immunofluorescent staining and immunoblot techniques were applied to monitor the functional shifts of the gene mutations at the cellular level. RESULTS: A suspected nonsense mutation (c.C172T, p.Q58X) in CCDC66 was found to be co-segregated with the HM phenotype in the family. Additionally, six other rare variants were identified among the 200 sporadic patients. CCDC66 was consistently expressed in the embryonic retinas of both humans and mice. Notably, in CCDC66-deficient HEK293 cells, there was a decline in cell proliferation, microtube polymerisation rate and ace-tubulin level. Furthermore, the mutated CCDC66 failed to synchronise with the tubulin system during Hela cell mitosis, unlike its wild type counterpart. CONCLUSIONS: Our research indicates that the CCDC66 variant c.C172T is associated with HM. A deficiency in CCDC66 might disrupt cell proliferation by influencing the mitotic process during retinal growth, leading to HM.

High Thermal Stability and Low Thermal Resistance of Large Area GaN/3C-SiC/Diamond Junctions for Practical Device Processes.

Thermal management is critical in contemporary electronic systems, and integrating diamond with semiconductors offers the most promising solution to improve heat dissipation. However, developing a technique that can fully exploit the high thermal conductivity of diamond, withstand high-temperature annealing processes, and enable mass production is a significant challenge. In this study, the successful transfer of AlGaN/GaN/3C-SiC layers grown on Si to a large-size diamond substrate is demonstrated, followed by the fabrication of GaN high electron mobility transistors (HEMTs) on the diamond. Notably, no exfoliation of 3C-SiC/diamond bonding interfaces is observed even after annealing at 1100 °C, which is essential for high-quality GaN crystal growth on the diamond. The thermal boundary conductance of the 3C-SiC-diamond interface reaches ≈55 MW m-2 K-1, which is efficient for device cooling. GaN HEMTs fabricated on the diamond substrate exhibit the highest maximum drain current and the lowest surface temperature compared to those on Si and SiC substrates. Furthermore, the device thermal resistance of GaN HEMTs on the diamond substrate is significantly reduced compared to those on SiC substrates. These results indicate that the GaN/3C-SiC on diamond technique has the potential to revolutionize the development of power and radio-frequency electronics with improved thermal management capabilities.

Devastating the Supply Wagons: Multifaceted Liposomes Capable of Exhausting Tumor to Death via Triple Energy Depletion.

The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.

Ionic Peltier effect in Li-ion electrolytes.

The coupled transport of charge and heat provide fundamental insights into the microscopic thermodynamics and kinetics of materials. We describe a sensitive ac differential resistance bridge that enables measurements of the temperature difference on two sides of a coin cell with a resolution of better than 10 µK. We use this temperature difference metrology to determine the ionic Peltier coefficients of symmetric Li-ion electrochemical cells as a function of Li salt concentration, solvent composition, electrode material, and temperature. The Peltier coefficients Π are negative, i.e., heat flows in the direction opposite to the drift of Li ions in the applied electric field, large, -Π > 30 kJ mol-1, and increase with increasing temperature at T > 300 K. The Peltier coefficient is approximately constant on time scales that span the characteristic time for mass diffusion across the thickness of the electrolyte, suggesting that heat of transport plays a minor role in comparison to the changes in partial molar entropy of Li at the interface between the electrode and electrolyte. Our work demonstrates a new platform for studying the non-equilibrium thermodynamics of electrochemical cells and provides a window into the transport properties of electrochemical materials through measurements of temperature differences and heat currents that complement traditional measurements of voltages and charge currents.

Phosphorylation: new star of pathogenesis and treatment in steatotic liver disease.

Steatotic liver disease poses a serious threat to human health and has emerged as one of the most significant burdens of chronic liver disease worldwide. Currently, the research mechanism is not clear, and there is no specific targeted drug for direct treatment. Phosphorylation is widely regarded as the most common type of protein modification, closely linked to steatotic liver disease in previous studies. However, there is no systematic review to clarify the relationship and investigate from the perspective of phosphorylation. Phosphorylation has been found to mainly regulate molecule stability, affect localization, transform molecular function, and cooperate with other protein modifications. Among them, adenosine 5'-monophosphate-activated protein kinase (AMPK), serine/threonine kinase (AKT), and nuclear factor kappa-B (NF-kB) are considered the core mechanisms in steatotic liver disease. As to treatment, lifestyle changes, prescription drugs, and herbal ingredients can alleviate symptoms by influencing phosphorylation. It demonstrates the significant role of phosphorylation as a mechanism occurrence and a therapeutic target in steatotic liver disease, which could be a new star for future exploration.

Cutting-Edge HEK293T Protein-Integrated Lipid Nanostructures: Boosting Biocompatibility and Efficacy.

Recently, artificial exosomes have been developed to overcome the challenges of natural exosomes, such as production scalability and stability. In the production of artificial exosomes, the incorporation of membrane proteins into lipid nanostructures is emerging as a notable approach for enhancing biocompatibility and treatment efficacy. This study focuses on incorporating HEK293T cell-derived membrane proteins into liposomes to create membrane-protein-bound liposomes (MPLCs), with the goal of improving their effectiveness as anticancer therapeutics. MPLCs were generated by combining two key elements: lipid components that are identical to those in conventional liposomes (CLs) and membrane protein components uniquely derived from HEK293T cells. An extensive comparison of CLs and MPLCs was conducted across multiple in vitro and in vivo cancer models, employing advanced techniques such as cryo-TEM (tramsmission electron microscopy) imaging and FT-IR (fourier transform infrared spectroscopy). MPLCs displayed superior membrane fusion capabilities in cancer cell lines, with significantly higher cellular uptake. Additionally, MPLCs maintained their morphology and size better than CLs when exposed to FBS (fetal bovine serum), suggesting enhanced serum stability. In a xenograft mouse model using HeLa and ASPC cancer cells, intravenous administration of MPLCs MPLCs accumulated more in tumor tissues, highlighting their potential for targeted cancer therapy. Overall, these results indicate that MPLCs have superior tumor-targeting properties, possibly attributable to their membrane protein composition, offering promising prospects for enhancing drug delivery efficiency in cancer treatments. This research could offer new clinical application opportunities, as it uses MPLCs with membrane proteins from HEK293T cells, which are known for their efficient production and compatibility with GMP (good manufacturing practice) standards.

A Bioengineered Nanovesicle Vaccine Boosts T-B cell Interaction for Immunotherapy of Echinococcus multilocularis.

Alveolar echinococcosis (AE) is a zoonotic parasitic disease, resulting from being infected with the metacestode larvae of the tapeworm Echinococcus multilocularis (E. multilocularis). Novel prophylactic and therapeutic interventions are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. Bioengineered nano cellular membrane vesicles are widely used for displaying the native conformational epitope peptides because of their unique structure and biocompatibility. In this study, four T-cells and four B-cells dominant epitope peptides of E. multilocularis with high immunogenicity were engineered into the Vero cell surface to construct a membrane vesicle nanovaccine for the treatment of AE. The results showed that the nanovesicle vaccine can efficiently activate dendritic cells, induce specific T/B cells to form a mutually activated circuit, and inhibit E. multilocularis infection. This study presents for the first time a nanovaccine strategy that can completely eliminate the burden of E. multilocularis.

Solvation Structure Tuning Induces LiF/Li3 N-Rich CEI and SEI Interfaces for Superior Li/CFx Batteries.

The electrode/electrolyte interfaces play an important role in the electrochemical reaction kinetics to alleviate the severe polarization and voltage hysteresis in lithium primary batteries. Herein, C5 F5 N is proposed as an electrolyte additive to tune the characteristics of the electrode/electrolyte interfaces. The Li/CFx primary battery with C5 F5 N additive exhibits an excellent discharge-specific capacity of 981.4 mAh g-1 (0.1 C), a remarkable high-rate capability of 598 mAh g-1 (15 C), and an outstanding energy/power density of 1068.7 Wh kg-1 /24362.5 W kg-1 . It also shows remarkable storage performance with 717.2 mAh g-1 at 0.1 C after storage at 55 °C for 2 months. The excellent performance of the Li/CFx batteries is closely related to the improved and stable Li3 N/LiF-rich homogeneous interfaces induced by the C5 F5 N additive, which results in uniform distribution of Li+ flux, facilitated electrochemical kinetics, and increased rate capability of Li/CFx battery. Therefore, C5 F5 N is expected to be a promising electrolyte additive, and the related electrode/electrolyte interface engineering provides an effective and facile strategy to increase the performance of the lithium primary battery.

Efficacy and safety of tirzepatide for treatment of overweight or obesity. A systematic review and meta-analysis.

BACKGROUND: Recent studies suggest that tirzepatide, a dual glucose-dependent insulinotropic-peptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has significant weight loss effects. This systematic review and meta-analysis aims to assess the efficacy and safety of tirzepatide for weight loss in patients with overweight or obesity. METHODS: Medline, Embase and Cochrane CENTRAL were searched for randomized controlled trials (RCTs) on tirzepatide's weight loss efficacy for these patients. A single arm meta-analysis of proportions estimated primary outcomes, ≥5%, ≥10%, and ≥15% weight loss, and adverse events (AEs); while meta-analysis of means estimated secondary outcomes. Comparative meta-analysis was conducted between tirzepatide and control arms where mean differences and odds ratios were estimated for continuous and dichotomous outcomes respectively. RESULTS: RCTs included in this study revealed that among 5800 patients, 78.22% (95% CI: 72.15% to 83.73%), 55.60% (95% CI: 46.54% to 64.47%), 32.28% (95% CI: 23.17% to 42.12%) achieved ≥5%, ≥10%, and ≥15% weight loss, respectively. Tirzepatide 5 mg demonstrated weight loss superiority relative to placebo (MD: -12.47 kg, 95% CI: -13.94 kg to -11.00 kg) and semaglutide (n = 1409, MD: -1.90 kg, 95% CI: -2.97 kg to -0.83 kg) with dose-dependent increase for 10 mg and 15 mg doses. The comparison between tirzepatide and semaglutide was examined in the SURPASS-2 trial that was included in this systematic review. For AEs, there was increase odds of experiencing gastrointestinal AEs with tirzepatide compared to placebo, but no significant difference with semaglutide. CONCLUSION: Tirzepatide has significant potential as a weight loss drug in patients with overweight and obesity, with little increase in AEs compared to other weight loss drugs. With its ability to concurrently target multiple aspects of metabolic syndrome, it should be considered as the next helm of weight loss therapies.

Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice.

BACKGROUND: We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis. METHODS: Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic. RESULTS: S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs. CONCLUSION: The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.

Identifying the impacts of land use landscape pattern and climate changes on streamflow from past to future.

Identifying the individual and combined hydrological response of land use landscape pattern and climate changes is key to effectively managing the ecohydrological balance of regions. However, their nonlinearity, effect size, and multiple causalities limit causal investigations. Therefore, this study aimed to establish a comprehensive methodological framework to quantify changes in the landscape pattern and climate, evaluate trends in streamflow response, and analyze the attribution of streamflow events in five basins in Beijing from the past to the future. Future climate projections were based on three general circulation models (GCMs) under two shared socioeconomic pathways (SSPs). Additionally, the landscape pattern in 2035 under a natural development scenario was simulated by the patch-generating land use simulation (PLUS). The Soil and Water Assessment Tool (SWAT) was applied to evaluate the streamflow spatial and temporal dynamics over the period 2005-2035 with multiple scenarios. A bootstrapping nonlinear regression analysis and boosted regression tree (BRT) model were used to analyze the individual and combined attribution of landscape pattern and climate changes on streamflow, respectively. The results indicated that in the future, the overall streamflow in the Beijing basin would decrease, with a slightly reduced peak streamflow in most basins in the summer and a significant increase in the autumn and winter. The nonlinear quadratic regression more effectively explained the impact of landscape pattern and climate changes on streamflow. The trends in the streamflow change depended on where the relationship curve was in relation to the threshold. In addition, the impacts of landscape pattern and climate changes on streamflow were not isolated but were joint. They presented a nonlinear, non-uniform, and coupled relationship. Except for the YongDing River Basin, the annual streamflow change was influenced more by the landscape pattern. The dominant factors and the critical pair interactions varied from basin to basin. Our findings have implications for city planners and managers for optimizing ecohydrological functions and promoting sustainable development.

m6A Modification-mediated GRAP Regulates Vascular Remodeling in Hypoxic Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling induced by human pulmonary arterial smooth muscle cell (HPASMC) proliferation, migration, and apoptosis resistance. m6A (N6-methyladenosine) is the most prevalent RNA posttranscriptional modification in eukaryotic cells. However, its role in PAH remains elusive. We designed this study to investigate whether m6A modification and its effector proteins play a role in pulmonary vascular resistance. Lung samples were used to profile m6A concentrations in control subjects and patients with PAH. Bioinformatics analysis, real-time PCR, immunohistochemistry, and Western blotting were used to determine the role of m6A effectors in PAH. The biological effects of GRAP modified by m6A were investigated using in vitro and in vivo models. Furthermore, RIP-PCR was used to assess the writers and readers of GRAP. In this study, we revealed that m6A-modified GRAP mRNA was upregulated in PAH lung samples, cHx/Su-induced mouse models, and hypoxia-stimulated HPASMCs; however, GRAP mRNA and protein were abnormally downregulated. Functionally, overexpression of GRAP drastically alleviated the proliferative and invasive ability of PAH HPASMCs through inhibition of the Ras/ERK signaling pathway in vitro and in vivo. In addition, METTL14 (methyltransferase-like 14) and the m6A binding protein YTHDF2 were significantly increased in PAH. Moreover, we found that m6A-modified GRAP mRNA was recognized by YTHDF2 to mediate the degradation. GRAP expression was consistently negatively correlated with METTL14 and YTHDF2 in vivo and in vitro. Taken together, for the first time, our findings highlight the function and therapeutic target value of GRAP and extend our understanding of the importance of RNA epigenetics in PAH.

Long-Chain Poly-d-Lysines Interact with the Plasma Membrane and Induce Protective Autophagy and Intense Cell Necrosis.

Polylysines have been frequently used in drug delivery and antimicrobial and cell adhesion studies. Because of steric hindrance, chirality plays a major role in the functional difference between poly-l-lysine (PLL) and poly-d-lysine (PDL), especially when they interact with the plasma membranes of mammalian cells. Therefore, it is speculated that the interaction between chiral polylysines and the plasma membrane may cause different cellular behaviors. Here, we carefully investigated the interaction pattern of PLL and PDL with plasma membranes. We found that PDL could be anchored onto the plasma membrane and interact with the membrane lipids, leading to the rapid morphological change and death of A549 cells (a human lung cancer cell line) and HPAEpiCs (a human pulmonary alveolar epithelial cell line). In contrast, PLL exhibited good cytocompatibility and was not anchored onto the plasma membranes of these cells. Unlike PLL, PDL could trigger protective autophagy to prevent cells in a certain degree, and the PDL-caused cell death occurred via intense necrosis (featured by increased intracellular Ca2+ content and plasma membrane disruption). In addition, it was found that the short-chain PDL with a repeat unit number of 9 (termed DL9) could locate in lysosomes and induce autophagy at high concentrations, but it could not elicit drastic cell death, which proved that the repeat unit number of polylysine could affect its cellular action. This research confirms that the interaction between chiral polylysines and the plasma membrane can induce autophagy and intense necrosis, which provides guidance for the future studies of chiral molecules/drugs.

NLRP3 inflammasome contributes to endothelial dysfunction in angiotensin II-induced hypertension in mice.

AIMS: Inflammation is a key feature of endothelial dysfunction induced by angiotensin (Ang) II. The purpose of this study was to explore the role of Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in endothelial dysfunction in Ang II-induced hypertension. MATERIALS AND METHODS: We analyzed blood pressure and vascular function of wild-type (WT) and Nlrp3 knockout (Nlrp3-/-) mice, treated with Ang II. In vitro, we mainly tested the endothelial nitric oxide synthase (eNOS) phosphorylation expression of human umbilical vein endothelial cells (HUVECs). KEY FINDINGS: Here we showed that 14-day Ang II infusion into mice resulted in the elevation of blood pressure, NLRP3 expression, serum interleukin (IL)-1ß level, and the decline of endothelium-dependent relaxation function, p-eNOS-Ser1177 expression in aortas. Nlrp3 deficiency reduced Ang II-induced blood pressure elevation and endothelial dysfunction. In vitro, NLRP3 was involved in the effect of Ang II on reducing p-eNOS-Ser1177 expression. Moreover, the direct effect of IL-1ß on vascular endothelial injury could be observed in both vivo and vitro. SIGNIFICANCE: Our result demonstrates that the NLRP3 inflammasome is critically involved in the detrimental effects of Ang II on vascular endothelium in hypertension via the activation of IL-1ß, placing NLRP3 as a potential target for therapeutic interventions in conditions with endothelial dysfunction in hypertension.

Prediction of long-term mortality by using machine learning models in Chinese patients with connective tissue disease-associated interstitial lung disease.

BACKGROUND: The exact risk assessment is crucial for the management of connective tissue disease-associated interstitial lung disease (CTD-ILD) patients. In the present study, we develop a nomogram to predict 3­ and 5-year mortality by using machine learning approach and test the ILD-GAP model in Chinese CTD-ILD patients. METHODS: CTD-ILD patients who were diagnosed and treated at the First Affiliated Hospital of Zhengzhou University were enrolled based on a prior well-designed criterion between February 2011 and July 2018. Cox regression with the least absolute shrinkage and selection operator (LASSO) was used to screen out the predictors and generate a nomogram. Internal validation was performed using bootstrap resampling. Then, the nomogram and ILD-GAP model were assessed via likelihood ratio testing, Harrell's C index, integrated discrimination improvement (IDI), the net reclassification improvement (NRI) and decision curve analysis. RESULTS: A total of 675 consecutive CTD-ILD patients were enrolled in this study, during the median follow-up period of 50 (interquartile range, 38-65) months, 158 patients died (mortality rate 23.4%). After feature selection, 9 variables were identified: age, rheumatoid arthritis, lung diffusing capacity for carbon monoxide, right ventricular diameter, right atrial area, honeycombing, immunosuppressive agents, aspartate transaminase and albumin. A predictive nomogram was generated by integrating these variables, which provided better mortality estimates than ILD-GAP model based on the likelihood ratio testing, Harrell's C index (0.767 and 0.652 respectively) and calibration plots. Application of the nomogram resulted in an improved IDI (3- and 5-year, 0.137 and 0.136 respectively) and NRI (3- and 5-year, 0.294 and 0.325 respectively) compared with ILD-GAP model. In addition, the nomogram was more clinically useful revealed by decision curve analysis. CONCLUSIONS: The results from our study prove that the ILD-GAP model may exhibit an inapplicable role in predicting mortality risk in Chinese CTD-ILD patients. The nomogram we developed performed well in predicting 3­ and 5-year mortality risk of Chinese CTD-ILD patients, but further studies and external validation will be required to determine the clinical usefulness of the nomogram.

Prediction and prognosis of adverse maternal and foetal/neonatal outcomes in pulmonary hypertension: an observational study and nomogram construction.

BACKGROUND: Pregnant women with pulmonary hypertension (PH) have higher mortality rates and poor foetal/neonatal outcomes. Tools to assess these risk factors are not well established. METHODS: Predictive and prognostic nomograms were constructed using data from a "Development" cohort of 420 pregnant patients with PH, recorded between January 2009 and December 2018. Logistic regression analysis established models to predict the probability of adverse maternal and foetal/neonatal events and overall survival by Cox analysis. An independent "Validation" cohort comprised data of 273 consecutive patients assessed from January 2019 until May 2022. Nomogram performance was evaluated internally and implemented with online software to increase the ease of use. RESULTS: Type I respiratory failure, New York Heart Association functional class, N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L, arrhythmia, and eclampsia with pre-existing hypertension were independent risk factors for maternal mortality or heart failure. Type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, New York Heart Association functional class, and N-terminal pro-brain natriuretic peptide [Formula: see text] 1400 ng/L were independent predictors of pulmonary hypertension survival during pregnancy. For foetal/neonatal adverse clinical events, type I respiratory failure, arrhythmia, general anaesthesia for caesarean section, parity, platelet count, fibrinogen, and left ventricular systolic diameter were important predictors. Nomogram application for the Development and Validation cohorts showed good discrimination and calibration; decision curve analysis demonstrated their clinical utility. CONCLUSIONS: The nomogram and its online software can be used to analyse individual mortality, heart failure risk, overall survival prediction, and adverse foetal/neonatal clinical events, which may be useful to facilitate early intervention and better survival rates.

Coherent Coupling between Phonons, Magnons, and Photons.

Mechanical degrees of freedom, which have often been overlooked in various quantum systems, have been studied for applications ranging from quantum information processing to sensing. Here, we develop a hybrid platform consisting of a magnomechanical cavity and an optomechanical cavity, which are coherently coupled by the straightway physical contact. The phonons in the system can be manipulated either with the magnetostrictive interaction or optically through the radiation pressure. Together with mechanical state preparation and sensitive readout, we demonstrate the microwave-to-optical conversion with an ultrawide tuning range up to 3 GHz. In addition, we observe a mechanical motion interference effect, in which the optically driven mechanical motion is canceled by the microwave-driven coherent motion. Manipulating mechanical oscillators with equal facility through both magnonic and photonic channels enables new architectures for signal transduction between the optical, microwave, mechanical, and magnetic fields.

Palmitic acid promotes endothelial-to-mesenchymal transition via activation of the cytosolic DNA-sensing cGAS-STING pathway.

Elevated levels of plasma free fatty acids (FFAs) lead to endothelial dysfunction, a process that is involved in the pathogenesis of atherosclerosis. Endothelial-to-mesenchymal transformation (EndMT) has been reported to accelerate endothelial dysfunction during the process of atherosclerosis. However, the underlying mechanisms of EndMT remain poorly understood. The present study aimed to investigate the role of the cytosolic DNA-sensing cyclic GMP-AMP synthase-stimulator interferon gene (cGAS-STING) pathway in palmitic acid (PA)-induced EndMT. Human aortic endothelial cells (HAECs) were exposed to different concentrations of PA, and subsequently its effects on EndMT and the cGAS-STING pathway were assessed. To investigate the role of cGAS-STING pathway on PA-induced EndMT, RNA interference was used to knockdown the expression of cGAS in HAECs prior to their exposure to PA. First, it was observed that PA reduced cell viability and intracellular nitric oxide production, and increased migratory capacity of the HAECs as well as the cellular oxidative stress response, leading to EndMT. Moreover, it was observed that the cGAS-STING pathway was activated in PA-exposed primary HAECs. Activating cGAS-STING pathway via mtDNA directing lead to EndMT in HAECs. Interestingly, cGAS knockdown by RNA interference attenuated PA-induced inflammation, oxidative stress and EndMT in HAECs. Taken together, the results of the present study suggested that the cytosolic DNA-sensing cGAS-STING pathway may have important roles in PA-induced EndMT in endothelial cells.