A mineral-based origin of Earth's initial hydrogen peroxide and molecular oxygen.

Terrestrial reactive oxygen species (ROS) may have played a central role in the formation of oxic environments and evolution of early life. The abiotic origin of ROS on the Archean Earth has been heavily studied, and ROS are conventionally thought to have originated from H2O/CO2 dissociation. Here, we report experiments that lead to a mineral-based source of oxygen, rather than water alone. The mechanism involves ROS generation at abraded mineral-water interfaces in various geodynamic processes (e.g., water currents and earthquakes) which are active where free electrons are created via open-shell electrons and point defects, high pressure, water/ice interactions, and combinations of these processes. The experiments reported here show that quartz or silicate minerals may produce reactive oxygen-containing sites (≡SiO•, ≡SiOO•) that initially emerge in cleaving Si-O bonds in silicates and generate ROS during contact with water. Experimental isotope-labeling experiments show that the hydroxylation of the peroxy radical (≡SiOO•) is the predominant pathway for H2O2 generation. This heterogeneous ROS production chemistry allows the transfer of oxygen atoms between water and rocks and alters their isotopic compositions. This process may be pervasive in the natural environment, and mineral-based production of H2O2 and accompanying O2 could occur on Earth and potentially on other terrestrial planets, providing initial oxidants and free oxygen, and be a component in the evolution of life and planetary habitability.

Efficacy and safety of immune checkpoint inhibitors in solid tumor patients combined with chronic coronary syndromes or its risk factor: a nationwide multicenter cohort study.

BACKGROUND: Although, immune checkpoint inhibitors (ICIs) have been widely applied in the therapy of malignant tumors, the efficacy and safety of ICIs in patients with tumors and pre-existing CAD, especially chronic coronary syndromes (CCS) or their risk factors (CRF), is not well identified. METHODS: This was a nationwide multicenter observational study that enrolled participants who diagnosed with solid tumors and received ICIs therapy. The main efficacy indicators were progression-free survival (PFS) and overall survival (OS), followed by objective response rate (ORR) and disease control rate (DCR). Safety was assessed by describing treatment-related adverse events (TRAEs) during ICIs therapy evaluated by the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). RESULTS: In the current research, we retrospectively analyzed the data of 551 patients diagnosed with solid tumors and received ICIs therapy, and these patients were divided into CCS/CRF group and non-CCS/CRF group. Patients with CCS/CRF had more favorable PFS and OS than patients without CCS/CRF (P < 0.001) and the pre-existing CCS/CRF was a protective factor for survival. The ORR (51.8% vs. 39.1%) and DCR (95.8% vs. 89.2%) were higher in CCS/CRF group than in non-CCS/CRF group (P = 0.003, P = 0.006). In this study, there was no significant difference in treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), between the two groups. CONCLUSIONS: We concluded that ICIs appear to have better efficacy in malignant solid tumor patients with pre-existing CCS/CRF and are not accompanied by more serious irAEs.

A Reversible MnO2 Deposition-Enabled Multicolor Electrochromic Device with Efficient Tunability of Ultraviolet-Visible Light.

Electrochromic technology offers exciting opportunities for smart applications such as energy-saving and interactive systems. However, achieving dual-band regulation together with the multicolor function is still an unmet challenge for electrochromic devices. Herein, an ingenious electrochromic strategy based on reversible manganese oxide (MnO2) electrodeposition, different from traditional ion intercalation/deintercalation-type electrochromic materials is proposed. Such a deposition/dissolution-based MnO2 brings an intriguing electrochromic feature of dual-band regulation for the ultraviolet (UV) and visible lights with high optical modulation (93.2% and 93.6% at 400 and 550 nm, respectively) and remarkable optical memory. Moreover, a demonstrative smart window assembled by MnO2 and Cu electrodes delivers the electrochromic properties of effective dual-band regulation accompanied by multicolor changes (transparent, yellow, and brown). The robust redox deposition/dissolution process endows the MnO2-based electrochromic device with excellent rate capability and an areal capacity of 570 mAh m-2 at 0.1 mA cm-2. It is believed that the metal oxide-based reversible electrodeposition strategy would be an attractive and promising electrochromic technology and provide a train of thought for the development of multifunctional electrochromic devices and applications.

Estrogen deficiency accelerates postmenopausal atherosclerosis by inducing endothelial cell ferroptosis through inhibiting NRF2/GPX4 pathway.

Oxidative stress and lipid metabolism disorder caused by estrogen deficiency are regarded as the main causes of postmenopausal atherosclerosis, but the underlying mechanisms remain still unclear. In this study, ovariectomized (OVX) female ApoE-/- mice fed with high-fat diet were used to imitate postmenopausal atherosclerosis. The atherosclerosis progression was significantly accelerated in OVX mice, accompanied by the upregulation of ferroptosis indicators, including increased lipid peroxidation and iron deposition in the plaque and the plasma. While both estradiol (E2) and ferroptosis inhibitor ferrostatin-1 alleviated atherosclerosis in OVX mice, with the inhibition of lipid peroxidation and iron deposition, as well as the upregulation of xCT and GPX4, especially in endothelial cells. We further investigated the effects of E2 on ferroptosis in endothelial cells induced by oxidized-low-density lipoprotein or ferroptosis inducer Erastin. It was found that E2 exhibited anti-ferroptosis effect through antioxidative functions, including improving mitochondrial dysfunction and upregulating GPX4 expression. Mechanistically, NRF2 inhibition attenuated the effect of E2 against ferroptosis as well as the upregulation of GPX4. Our findings revealed that endothelial cell ferroptosis played a pivotal role in postmenopausal atherosclerosis progression, and the NRF2/GPX4 pathway activation contributed to the protection of E2 against endothelial cell ferroptosis.

Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells.

BACKGROUND: Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. METHODS: The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE-/- mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE-/-RIPK3-/-). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. RESULTS: Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE-/- mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE-/- mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis. CONCLUSION: The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload.

TiB4 and SrB8 monolayers: high capacity and zero strain-like anode materials for Li/Na/K/Ca ion batteries.

Storage capacity, average open circuit voltage (OCV), diffusion barrier, lattice parameter changes, etc. are key indicators of whether a material would be suitable for use as a Li-ion or non-Li-ion battery (LIB or NLIB) anode. The rapid development of 2D materials over the past few decades has opened up new possibilities for these metrics. Using first-principles calculations, we prove that two 2D materials, TiB4 and SrB8, show excellent performance in terms of the above metrics when used as anodes for LIBs or NLIBs. As detailed, TiB4 has an Li\Na\K\Ca storage capacity of 588 mA h g-1, 588 mA h g-1, 588 mA h g-1, and 1176 mA h g-1, respectively, and SrB8 has an Li\Na\K\Ca storage capacity of 308 mA h g-1, 308 mA h g-1, 462 mA h g-1, and 616 mA h g-1, respectively, and they show good electrical conductivity whether existing Li, Na, K or Ca is adsorbed or not. The diffusion barriers on both surfaces are low, indicating good rate performance. The average OCV is also very low. In particular, the lattice parameters of the two materials change very little during the embedding of Li\Na\K\Ca. For Ti9B36 the corresponding values are about 0.37% (Li), 0.33% (Na), 0.64% (K) and 0.03% (Ca), and for Sr8B64 the corresponding values are about 0.70% (Li), 0.16% (Na), 0.13% (K) and 0.004% (Ca), which imply zero strain-like character and great cycling performance. All the above results show that TiB4 and SrB8 monolayers are very promising Li\Na\K\Ca ion battery anodes.

Co-exposure to fluoride and sulfur dioxide induces abnormal enamel mineralization in rats via the FGF9-mediated MAPK signaling pathway.

Fluoride (F) and sulfur dioxide (SO2) contamination is recognized as a public health concern worldwide. Our previous research has shown that Co-exposure to F and SO2 can cause abnormal enamel mineralization. Ameloblastin (AMBN) plays a crucial role in the process of enamel mineralization. However, the process by which simultaneous exposure to F and SO2 influences enamel formation by regulating AMBN expression still needs to be understood. This study aimed to establish in vivo and in vitro models of F-SO2 Co-exposure and investigate the relationship between AMBN and abnormal enamel mineralization. By overexpressing/knocking out the Fibroblast Growth Factor 9 (FGF9) gene, we investigated the impact of FGF9-mediated Mitogen-Activated Protein Kinase (MAPK) signaling on AMBN synthesis to elucidate the mechanism underlying the induction of abnormal enamel mineralization by F-SO2 Co-exposure in rats. The results showed that F-SO2 exposure damaged the structure of rat enamel and ameloblasts. When exposed to F or SO2, gradual increases in the protein expression of FGF9 and phosphorylated p38 mitogen-activated protein kinase (p-P38) were observed. Conversely, the protein levels of AMBN, phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated c-Jun N-terminal kinase (p-JNK) were decreased. AMBN expression was significantly correlated with FGF9, p-ERK, and p-JNK expression in ameloblasts. Interestingly, FGF9 overexpression reduced the levels of p-ERK and p-JNK, worsening the inhibitory effect of F-SO2 on AMBN. Conversely, FGF9 knockout increased the phosphorylation of ERK and JNK, partially reversing the F-SO2-induced downregulation of AMBN. Taken together, these findings strongly demonstrate that FGF9 plays a critical role in F-SO2-induced abnormal enamel mineralization by regulating AMBN synthesis through the JNK and ERK pathways.

VEGFC ameliorates salt-sensitive hypertension and hypertensive nephropathy by inhibiting NLRP3 inflammasome via activating VEGFR3-AMPK dependent autophagy pathway.

Salt-sensitivity hypertension (SSHTN) is an independent predictor for cardiovascular mortality. VEGFC has been reported to be a protective role in SSHTN and hypertensive kidney injury. However, the underlying mechanisms remain largely unclear. The current study aimed to explore the protective effects and mechanisms of VEGFC against SSHTN and hypertensive nephropathy. Here, we reported that VEGFC attenuated high blood pressure as well as protected against renal inflammation and fibrosis in SSHTN mice. Moreover, VEGFC suppressed the activation of renal NLRP3 inflammasome in SSHTN mice. In vitro, we found VEGFC inhibited NLRP3 inflammasome activation, meanwhile, upregulated autophagy in high-salt-induced macrophages, while these effects were reversed by an autophagy inhibitor 3MA. Furthermore, in vivo, 3MA pretreatment weakened the protective effects of VEGFC on SSHTN and hypertensive nephropathy. Mechanistically, VEGF receptor 3 (VEGFR3) kinase domain activated AMPK by promoting the phosphorylation at Thr183 via binding to AMPK, thus enhancing autophagy activity in the context of high-salt-induced macrophages. These findings indicated that VEGFC inhibited NLRP3 inflammasome activation by promoting VEGFR3-AMPK-dependent autophagy pathway in high-salt-induced macrophages, which provided a mechanistic basis for the therapeutic target in SSHTN and hypertensive kidney injury.

A case of neonatal tsutsugamushi disease diagnosed with the aid of rickettsial macrogenomic detection.

BACKGROUND: Tsutsugamushi, also known as bush typhus, is a naturally occurring disease caused by Orientia tsutsugamushi. We reported a case of vertical mother-to-newborn transmission of Orientia tsutsugamushi infection in a newborn from Yunnan (China). CASE PRESENTATION: Decreased fetal movements were observed at 39 weeks of gestation. After birth, the newborn (female) had recurrent fever, shortness of breath, and bruising around the mouth and extremities. At 5 h 58 min of age, the newborn was admitted for fever, shortness of breath and generalized rash. The liver was palpable 3 cm below the costal margin, and the limbs showed pitting edema. There was subcutaneous bleeding. Investigations suggested heavy infection, myocardial damage, decreased platelets. Treatment with cefotaxime and ampicillin failed. The mother was hospitalized at 29 weeks of gestation with a fever for 4 consecutive days, and an ulcerated crust was found in the popliteal fossa. Due to this pregnancy history, A diagnosis of Orientia tsutsugamushi infection was suspected in our index case and confirmed by macrogenomic testing and she was treated with vancomycin and meropenem, and later azithromycin for 1 week. The newborn was discharged in good general condition, gradually normalizing body temperature, and decreasing rash and jaundice. There were no abnormalities on subsequent blood macrogenomic tests for the baby. And one month later she showed good mental health, sleep, and food intake and no fever, rash, or jaundice. CONCLUSION: Determining the cause of symptoms is the key to treating diseases, especially the rare diseases that can be misdiagnosed. SUITABLE FOR PEOPLE WITH: Infectious Diseases; Neonatology; Obstetrics.

AlphaFold2 assists in providing novel mechanistic insights into the interactions among the LUBAC subunits.

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ligase complex in which the ubiquitin-like (UBL) domains of SHARPIN and HOIL-1L interact with HOIP to determine the structural stability of LUBAC. The interactions between subunits within LUBAC have been a topic of extensive research. However, the impact of the LTM motif on the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP remains unclear. Here, we discover that the absence of the LTM motif in the AlphaFold2-predicted LUBAC structure alters the HOIP-UBA structure. We employ GeoPPI to calculate the changes in binding free energy (ΔG) caused by single-point mutations between subunits, simulating their protein-protein interactions. The results reveal that the presence of the LTM motif decreases the interaction between the UBL domains of SHARPIN and HOIL-1L with HOIP, leading to a decrease in the structural stability of LUBAC. Furthermore, using the AlphaFold2-predicted results, we find that HOIP (629‒695) and HOIP-UBA bind to both sides of HOIL-1L-UBL, respectively. The experiments of Gromacs molecular dynamics simulations, SPR and ITC demonstrate that the elongated domain formed by HOIP (629‒695) and HOIP-UBA, hereafter referred to as the HOIP (466‒695) structure, interacts with HOIL-1L-UBL to form a structurally stable complex. These findings illustrate the collaborative interaction between HOIP-UBA and HOIP (629‒695) with HOIL-1L-UBL, which influences the structural stability of LUBAC.

Mining Real-World Big Data to Characterize Adverse Drug Reaction Quantitatively: Mixed Methods Study.

BACKGROUND: Adverse drug reactions (ADRs), which are the phenotypic manifestations of clinical drug toxicity in humans, are a major concern in precision clinical medicine. A comprehensive evaluation of ADRs is helpful for unbiased supervision of marketed drugs and for discovering new drugs with high success rates. OBJECTIVE: In current practice, drug safety evaluation is often oversimplified to the occurrence or nonoccurrence of ADRs. Given the limitations of current qualitative methods, there is an urgent need for a quantitative evaluation model to improve pharmacovigilance and the accurate assessment of drug safety. METHODS: In this study, we developed a mathematical model, namely the Adverse Drug Reaction Classification System (ADReCS) severity-grading model, for the quantitative characterization of ADR severity, a crucial feature for evaluating the impact of ADRs on human health. The model was constructed by mining millions of real-world historical adverse drug event reports. A new parameter called Severity_score was introduced to measure the severity of ADRs, and upper and lower score boundaries were determined for 5 severity grades. RESULTS: The ADReCS severity-grading model exhibited excellent consistency (99.22%) with the expert-grading system, the Common Terminology Criteria for Adverse Events. Hence, we graded the severity of 6277 standard ADRs for 129,407 drug-ADR pairs. Moreover, we calculated the occurrence rates of 6272 distinct ADRs for 127,763 drug-ADR pairs in large patient populations by mining real-world medication prescriptions. With the quantitative features, we demonstrated example applications in systematically elucidating ADR mechanisms and thereby discovered a list of drugs with improper dosages. CONCLUSIONS: In summary, this study represents the first comprehensive determination of both ADR severity grades and ADR frequencies. This endeavor establishes a strong foundation for future artificial intelligence applications in discovering new drugs with high efficacy and low toxicity. It also heralds a paradigm shift in clinical toxicity research, moving from qualitative description to quantitative evaluation.

Status quo and influencing factors of multiprofessional and multidisciplinary teamwork for early mobilization in mechanically ventilated patients in ICUs: A multi-centre survey study.

AIM: To understand the status quo of multiprofessional and multidisciplinary collaboration for early mobilization of mechanically ventilated patients in Chinese ICUs and identify any factors that may influence this practice. DESIGN: A multi-centre cross-sectional survey. METHODS: From October to November 2022, the convenience sampling method was used to select ICU multiprofessional and multidisciplinary early mobility members (including physicians, nurses and physiotherapists) from 27 tertiary general hospitals in 14 provinces, cities and autonomous regions of China. They were asked to complete an author-developed questionnaire on the status of collaboration and the Assessment of Inter-professional Team Collaboration Scale. A multiple linear regression model was used to analyse the factors associated with the level of collaboration. RESULTS: Physicians, nurses and physiotherapists mostly suffered from the lack of normative protocols, unclear division of responsibilities and unclear multiprofessional and multidisciplinary teams when using a collaborative approach to early activities. Multiple linear regression analysis showed that the number of ICU patients managed, the existence of norms and processes, the attitude of colleagues around them, the establishment of a team, communication methods and activity leaders were significant influences on the level of collaboration among members of the multiprofessional and multidisciplinary early activities. CONCLUSION: The collaboration of multiprofessional and multidisciplinary early activity members for mechanically ventilated patients in the ICU remains unclear, and the collaboration strategy needs to be constructed and improved, taking into account China's human resources and each region's economic development level. IMPACT: This study investigates the collaboration status of multiprofessional and multidisciplinary activity members from the perspective of teamwork, analyses the reasons affecting the level of collaboration and helps to develop better teamwork strategies to facilitate the implementation of early activities. PATIENT OR PUBLIC CONTRIBUTION: The participants in this study were multiprofessional and multidisciplinary medical staff who performed early activities for ICU patients.

Complement activation in wasp venom-induced acute kidney injury.

Previous studies have highlighted the significant role of complement activation in kidney injuries induced by rhabdomyolysis, intravascular hemolysis, sepsis, and ischemia-reperfusion. Nevertheless, the specific role and mechanism of complement activation in acute kidney injury (AKI) caused by wasp venom remain unclear. The aim of this study was to elucidate the specific complement pathway activated and investigate complement activation in AKI induced by wasp venom. In this study, a complement-depleted mouse model was used to investigate the role of complement in wasp venom-induced AKI. Mice were randomly categorized into control, cobra venom factor (CVF), AKI, and CVF + AKI groups. Compared to the AKI group, the CVF + AKI group showed improved pathological changes in kidneys and reduced blood urea nitrogen (BUN) levels. The expression levels of renal complement 3 (C3), complement 5 (C5), complement 1q (C1q), factor B (FB), mannose-binding lectin (MBL), and C5b-9 in AKI group were upregulated compared with the control group. Conversely, the renal tissue expression levels of C3, C5, C1q, FB, MBL, and C5b-9 were decreased in the CVF + AKI group compared to those in the AKI group. Complement activation occurs through all three pathways in AKI induced by wasp venom. Furthermore, complement depletion by CVF attenuates wasp venom-induced nephrotoxicity, suggesting that complement activation plays a primary role in the pathogenesis of wasp venom-induced AKI.

Cu(I)-Glutathione Assembly Supported on ZIF-8 as Robust and Efficient Catalyst for Mild CO2 Conversions.

The Cu-glutathione (GSH) redox system, essential in biology, is designed here as a supramacromolecular assembly in which the tetrahedral 18e Cu(I) center loses a thiol ligand upon adsorption onto ZIF-8, as shown by EXAFS and DFT calculation, to generate a very robust 16e planar trigonal single-atom Cu(I) catalyst. Synergy between Cu(I) and ZIF-8, revealed by catalytic experiments and DFT, affords CO2 conversion into high-value-added chemicals with a wide scope of substrates by reaction with terminal alkynes or propargyl amines in excellent yields under mild conditions and reuse at least 10 times without significant decrease in catalytic efficiency.

Cd Atom Goes into the Interior of Cluster Induced by Directional Consecutive Assembly of Tetrahedral Units on an Icosahedron Kernel.

"Core sliding" in metal nanoclusters drives the reconstruction of external structural units and provides an ideal platform for mapping their precise transformation mechanism and evolution pathway. However, observing the movement behavior of metal atoms in experiments is still challenging because of the uncertain stability of intermediates. In this work, a series of Au-Cd alloy nanoclusters with continuously assembled kernels (one icosahedral building block assembled with 0 to 3 tetrahedral units) were constructed. As the assembly continued, it eventually led to the Cd atom doping into the inner positions of the clusters. Importantly, the Cd doped into the interior of the cluster exhibits a different behavior than the surface or external Cd atoms (dispersion doping vs localized occupy), which provides experimental evidence of the sliding behavior in the nanocluster kernel. Furthermore, density functional theory (DFT) calculations reveal that this sliding behavior in the inner sites of nanoclusters is an energetically favorable process. In addition, these Au-Cd nanoclusters exhibit tunable optical properties with different assembly patterns in their kernels.

Homocysteine promotes atherosclerosis through macrophage pyroptosis via endoplasmic reticulum stress and calcium disorder.

BACKGROUND: Elevated plasma homocysteine levels, known as hyperhomocysteinemia, have been identified as an independent risk factor for atherosclerosis and related cardiovascular diseases. Macrophage pyroptosis-mediated inflammation is crucial in the development of atherosclerosis, but the underlying mechanisms remain unclear. METHODS: A hyperhomocysteinemia atherosclerotic model with ApoE-/- mice fed with a high-methionine diet was constructed to investigate the role of plasma homocysteine in atherosclerosis. THP-1-derived macrophages were used to investigate the mechanisms by which Hcy regulates pyroptosis. RESULTS: We found that hyperhomocysteinemia resulted in larger atherosclerotic plaques and more secretion of inflammatory cytokines, while these effects were attenuated in Caspase-1 knockdown mice. Likewise, in vitro experiments demonstrated that treatment of macrophages with homocysteine resulted in NLRP3 inflammasome activation and pyroptosis, as evidenced by cleavage of Caspase-1, production of downstream IL-1ß, elevation of lactate dehydrogenase activity, and extensive propidium iodide-positive staining of cells. These were all inhibited by Caspase-1 inhibitor. In addition, excessive generation of reactive oxygen species was associated with mitochondrial dysfunction, characterized by loss of mitochondrial membrane potential and ATP synthesis. Moreover, further experiments revealed that homocysteine induced endoplasmic reticulum stress, enhanced communication between the endoplasmic reticulum and mitochondria, and consequently contributed to calcium disorder. Furthermore, the endoplasmic reticulum stress inhibitor, 4PBA, the calcium chelator, BAPTA, and calcium channel inhibitor, 2-APB significantly improved macrophage pyroptosis. CONCLUSION: Homocysteine accelerates atherosclerosis progression by enhancing macrophages pyroptosis via promoting endoplasmic reticulum stress, endoplasmic reticulum-mitochondria coupling, and disturbing of calcium disorder.

Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive tumor with a dismal prognosis. Recent studies have demonstrated PTPN2 (protein tyrosine phosphatase nonreceptor type 2) as a potential target for cancer therapy. However, the functions of PTPN2 in PDAC progression remain poorly understood. In this study, we found PTPN2 expression was downregulated in PDAC tissues, and decreased PTPN2 expression was associated with unfavorable prognosis. Functional studies indicated that PTPN2 knockdown promoted the migration and invasion abilities of PDAC cells in vitro, and the liver metastasis in vivo through epithelial-mesenchymal transition process. Mechanistically, MMP-1 was identified as a downstream target of PTPN2 via RNA-seq data and was responsible for the enhanced metastasis of PDAC cells upon PTPN2 knockdown. Moreover, according to chromatin immunoprecipitation and electrophoretic mobility shift assay, PTPN2 depletion transcriptionally activated MMP-1 via regulating the interaction of p-STAT3 with its distal promoter. This study, for the first time, demonstrated that PTPN2 inhibited PDAC metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in PDAC progression.

Association between life's essential 8 and biological ageing among US adults.

BACKGROUND: Biological ageing is tightly linked to cardiovascular disease (CVD). We aimed to investigate the relationship between Life's Essential 8 (LE8), a currently updated measure of cardiovascular health (CVH), and biological ageing. METHODS: This cross-sectional study selected adults ≥ 20 years of age from the 2005-2010 National Health and Nutrition Examination Survey. LE8 scores (range 0-100) were obtained from measurements based on American Heart Association definitions, divided into health behavior and health factor scores. Biological ageing was assessed by different methods including phenotypic age, phenotypic age acceleration (PhenoAgeAccel), biological age and biological age acceleration (BioAgeAccel). Correlations were analyzed by weighted linear regression and restricted cubic spline models. RESULTS: Of the 11,729 participants included, the mean age was 47.41 ± 0.36 years and 5983 (51.01%) were female. The mean phenotypic and biological ages were 42.96 ± 0.41 and 46.75 ± 0.39 years, respectively, and the mean LE8 score was 67.71 ± 0.35. After adjusting for potential confounders, higher LE8 scores were associated with lower phenotypic age, biological age, PhenoAgeAccel, and BioAgeAccel, with nonlinear dose-response relationships. Negative associations were also found between health behavior and health factor scores and biological ageing, and were stronger for health factors. In health factor-specific analyses, the ß negativity was greater for blood glucose and blood pressure. The inverse correlations of LE8 scores with phenotypic age and biological age in the stratified analyses remained solid across strata. CONCLUSIONS: LE8 and its subscale scores were strongly negatively related to biological ageing. Encouraging optimal CVH levels may be advantageous in preventing and slowing down ageing.

Genetic evidence for the causal linkage between telomere length and aortic aneurysm risk: A Mendelian randomisation study.

BACKGROUND: Evidence of a clear causal relationship between telomere length and aortic aneurysms is limited by the potential for confounding or reverse causation effects. In this study, we used a Mendelian randomisation (MR) approach to investigate this putative causal association. METHODS: In total, 118 telomere length-associated single-nucleotide polymorphisms, identified in 472,174 individuals of European ancestry, were used as the instrumental variables. Summary statistics for genome-wide association studies of aortic aneurysms were obtained from the FinnGen consortium. For the primary MR analyses, the inverse-variance weighted random-effects method was used and was supplemented with multivariable MR, weighted median and MR-Egger approaches. The MR-Egger intercept test, Cochran's Q test and 'leave-one-out' sensitivity analysis were performed to evaluate the horizontal pleiotropy, heterogeneity and stability of the genetic variants. Forward and reverse MR analyses were performed. RESULTS: All forward univariable MR analyses showed that longer telomere lengths decreased aortic aneurysm risks (total aortic aneurysms: OR = 0.80, 95% CI 0.67-0.96, p = .015; thoracic aortic aneurysms: OR = 0.82, 95% CI 0.68-0.98, p = .026; abdominal aortic aneurysms: OR = 0.525, 95% CI 0.398-0.69, p < .001), whereas all reverse MR analyses suggested the absence of aortic aneurysm liability on telomere length. The sensitivity analysis results were robust, and no evidence of horizontal pleiotropy was observed. CONCLUSIONS: Our results support a possible causal association between telomere length and aortic aneurysms, providing new insights into the involvement of telomere biology in this condition and offering a potential avenue for targeted therapeutic interventions.

DFT Insights into the Variety in the Coordination Modes of the Equatorial Halides in [Au13 Ag12 (PR3 )10 X8 ]+ (X=Cl/Br) Clusters.

The bonding character within metal nanoclusters represents an intriguing topic, shedding light on the inherent driving force for the packing preference in nanomaterials. Herein, density functional theory (DFT) calculations were conducted to investigate the correlation of the series of isomeric [Au13 Ag12 (PR3 )10 X8 ]+ (X=Cl/Br) clusters, which are mainly differentiated by the coordination mode of the equatorial halides (µ2 -, µ3 - and µ4 -) in the rod-like, bi-icosahedral framework. The theoretical simulation corroborates the variety in the configuration of the Au13 Ag12 clusters and elucidates the fast isomerization kinetics among the different configurations. The easy tautomerization and the variety in chloride binding modes correspond to a fluxionality character of the equatorial halides and are verified by the potential energy curve analysis. The structural flexibility of the central Au3 Ag10 block is the main driving force, while the relatively stronger Ag-X bonding interaction (compared to that of Au-X), and a sufficient number of halides are also requisite for the associating Ag-X tautomerizations.