Prognostic value of serum immunoglobulin M levels in patients with acute coronary syndrome.

BACKGROUND AND AIMS: The immuno-inflammatory response is a crucial early step in the development of acute coronary syndrome (ACS). In this study, we investigated whether immunoglobulin M (IgM) in the body's initial immune response can predict the prognosis of patients with ACS. METHODS: This prospective cohort study enrolled 1556 ACS patients at Beijing Hospital between March 2017 and October 2020. All patients underwent coronary angiography (CAG). The serum IgM concentration and biochemical indicators were evaluated prior to CAG. The primary endpoint was the composite endpoint of major adverse cardiovascular and cerebrovascular events (MACCEs). Multivariate Cox proportional hazards models was used to explore the association between IgM levels and the endpoint. RESULTS: The average serum IgM levels of the population was 61.3 (42.6-88.4) mg/dL. During the median follow-up period of 55 months, 150 MACCEs occurred. Kaplan-Meier analysis showed that low serum IgM levels were associated with occurrence of MACCEs (log-rank p = 0.009). Univariate Cox proportional hazards models showed that low serum IgM (≤78.05 mg/dL) was associated with MACCEs (hazard ratio (HR) 1.648, 95 % confidence interval (CI): 1.129-2.406, p = 0.010). In patients with IgM ≤78.05 mg/dL, the HR for partially adjusted MACCEs events was 1.576 (95 % CI: 1.075-2.310) and 1.930 (95 % CI: 1.080-3.449) after adjusting for multiple covariates. The subgroup analysis showed that for patients in ≤24 BMI, never smoking and non-dyslipidemia subgroup, the lower serum IgM levels was significantly associated with the risk of MACCEs (pinteraction < 0.001, pinteraction = 0.037, pinteraction = 0.024, respectively). CONCLUSIONS: Low serum IgM levels was independently associated with MACCEs in ACS patients, especially for patients without obesity, smoking and dyslipidemia.

Transforming Cell-Drug Interaction through Granular Hydrogel-Mediated Delivery of Polyplex Nanoparticles for Enhanced Safety and Extended Efficacy in Gene Therapy.

The utilization of hydrogels for DNA/cationic polymer polyplex nanoparticle (polyplex) delivery has significantly advanced gene therapy in tissue regeneration and cancer treatment. However, persistent challenges related to the efficacy and safety of encapsulated polyplexes, stemming from issues such as aggregation, degradation, or difficulties in controlled release during or postintegration with hydrogel scaffolds, necessitate further exploration. Here, we introduce an injectable gene therapy gel achieved by incorporating concentrated polyplexes onto densely packed hydrogel microparticles (HMPs). Polyplexes, when uniformly adhered to the gene therapy gel through reversible electrostatic interactions, can detach from the HMP surface in a controlled manner, contrasting with free polyplexes, and thereby reducing dose-dependent toxicity during transfection. Additionally, the integration of RGD cell adhesion peptides enhances the scaffolding characteristics of the gel, facilitating cell adhesion, migration, and further minimizing toxicity during gene drug administration. Notably, despite the overall transfection efficiency showing average performance, utilizing confocal microscopy to meticulously observe and analyze the cellular states infiltrating into various depths of the gene therapy gel resulted in the groundbreaking discovery of significantly enhanced local transfection efficiency, with primary cell transfection approaching 80%. This phenomenon could be potentially attributed to the granular hydrogel-mediated delivery of polyplex nanoparticles, which revolutionizes the spatial and temporal distribution and thus the "encounter" mode between polyplexes and cells. Moreover, the gene therapy gel's intrinsic injectability and self-healing properties offer ease of administration, making it a highly promising candidate as a novel gene transfection gel dressing with significant potential across various fields, including regenerative medicine and innovative living materials.

Markov State Models Reveal How Folding Kinetics Influence Absorption Spectra of Foldamers.

Self-assembly of platinum(II) complex foldamers is an essential approach to fabricate advanced luminescent materials. However, a comprehensive understanding of folding kinetics and their absorption spectra remains elusive. By constructing Markov state models (MSMs) from large-scale molecular dynamics simulations, we reveal that two largely similar dinuclear alknylplatinum(II) terpyridine foldamers, Pt-PEG and Pt-PE with slightly different bridges, exhibit distinctive folding kinetics. Particularly, Pt-PEG bears bridge-dominant, plane-dominant, and cooperative pathways, while Pt-PE only prefers the plane-dominant pathway. Such preference originates from their difference in intrabridge electrostatic interactions, leading to contrastive distributions of metastable states. We also found that the bridge-dominant pathway for Pt-PEG becomes more favorable when lowering the temperature. Interestingly, based on the comprehensive conformation ensembles from our MSMs, we reveal the conformation-dependent absorption spectra of Pt-PEG and Pt-PE. Our theoretical spectra not only align with experimental results but also reveal the contributions of diverse conformations to the overall absorption bands explicitly, facilitating the rational design of stimuli-responsive smart luminescent molecules.

Electro-Chemo-Mechanically Stable and Sodiophilic Interface for Na Metal Anode in Liquid-based and Solid-State Batteries.

Na metal batteries (NMBs) are attracting increasing attention because of their high energy density. However, the widespread application of NMBs is hindered by the growth of Na dendrites and interface instability. The design of artificial solid electrolyte interphase (SEI) with tuned chemical/electrochemical/mechanical properties is the key to achieving high-performance NMBs. This work develops a metal-doped nanoscale polymeric film with tunable composition, sodiophilic sites and improved stiffness. The incorporation of metal crosslinkers in the polymer chains results in exceptional electrochemical stability for Na metal anodes, leading to a significantly prolonged lifespan even at high current densities, which is at the top of the reported literature. The mechanical properties measurements and electro-chemo-mechanical phase-field model are performed to interpret the impact of the ionic transportation capability (decoupled mechanical) and mechanic property in the metal-doped polymer interface. In addition, this approach provides a promising strategy for the rational design of electrode interfaces, providing enhanced mechanical stability and improved sodiophilicity, which can open up opportunities for the fabrication of next-generation energy storage.

Effect of family intervention on relapse rate of Chinese patients with alcohol-dependent.

Objective: This study explored the impact of a family intervention on the relapse rate of Chinese patients with alcohol dependence. Methods: A total of 151 male patients with alcohol dependence who were discharged from the Substance Dependence Department of the Wenzhou Seventh People's Hospital from January to December 2020 were selected. They were divided into the control (n = 73) and experimental (n = 78) groups. Patients in both groups received routine alcohol cessation treatment. Moreover, patients in the experimental group were followed up by a professional psychiatrist to carry out individual family intervention. The Family Function Rating Scale (FAD), a Self-made general information questionnaire, and the Chinese version of the Family Intimacy and Adaptability Scale (FACESI-CV) were performed. Re-drinking rate and readmission rate were assessed. Results: Family intervention could reduce relapse rate (31, 39.74%) and rehospitalization (27, 34.62%) compared with the control group. After family training, FAD factor scores were improved in the experiment group in comparison with the control group. Family training improved communication (18.2 ± 3.7), role (20.8 ± 2.5), emotional response (10.8 ± 1.8), emotional involvement (13.7 ± 1.2), behavioral control (19.8 ± 1.2), and overall functionality (23.5 ± 2.1) in the experiment group in comparison with the control group. After family training, intimacy (70.5 ± 8.7) and adaptability (64.1 ± 6.9) in the experiment group was higher than in the control group. After family intervention, Michigan Alcohol Dependence Scale (MAST) (9.21 ± 0.68) and Short-Form 36 (SF-36) (80.32 ± 4.47) in the experiment group were higher than the control group. Conclusion: Family intervention for families of patients with alcohol dependence can improve their family function, increase their family intimacy and adaptability, and reduce the rate of relapse.

Identifying determinants of spatial agglomeration of healthcare resources by using spatial econometric methods: a longitudinal study in China.

Background: Healthcare resources are necessary for individuals to maintain their health. The Chinese government has implemented policies to optimize the allocation of healthcare resources and achieve the goal of equality in healthcare for the Chinese people since the implementation of the new medical reform in 2009. Given that no study has investigated regional differences from the perspective of healthcare resource agglomeration, this study aimed to investigate China's healthcare agglomeration from 2009 to 2017 in China and identify its determinants to provide theoretical evidence for the government to develop and implement scientific and rational healthcare policies. Methods: The study was conducted using 2009-2017 data to analyze health-resource agglomeration on institutions, beds, and workforce in China. An agglomeration index was applied to evaluate the degree of regional differences in healthcare resource allocation, and spatial econometric models were constructed to identify determinants of the spatial agglomeration of healthcare resources. Results: From 2009 to 2017, all the agglomeration indexes of healthcare exhibited a downward trend except for the number of institutions in China. Population density (PD), government health expenditures (GHE), urban resident's disposable income (URDI), geographical location (GL), and urbanization level (UL) all had positive significant effects on the agglomeration of beds, whereas both per capita health expenditures (PCHE), number of college students (NCS), and maternal mortality rate (MMR) had significant negative effects on the agglomeration of institutions, beds, and the workforce. In addition, population density (PD) and per capita gross domestic product (PCGDP) in one province had negative spatial spillover effects on the agglomeration of beds and the workforce in neighboring provinces. However, MMR had a positive spatial spillover effect on the agglomeration of beds and the workforce in those regions. Conclusion: The agglomeration of healthcare resources was observed to remain at an ideal level in China from 2009 to 2017. According to the significant determinants, some corresponding targeted measures for the Chinese government and other developing countries should be fully developed to balance regional disparities in the agglomeration of healthcare resources across administrative regions.

Photothermal modulation of gingival fibroblasts via polydopamine-coated zirconia: A novel approach for promoting peri-implant soft tissue integration.

Achieving robust soft tissue integration around dental implants is crucial for long-term clinical success, as it forms a protective biological seal against bacterial invasion. However, the soft tissue attachment to implants is relatively deficient compared to natural teeth, particularly in the connective tissue region lacking sufficient gingival fibroblasts and collagen fiber alignment. This study proposed an innovative strategy to enhance peri­implant soft tissue integration by modulating gingival fibroblast behavior via photothermal conversion. Zirconia surfaces were coated with polydopamine (PDA), a melanin-like polymer exhibiting near-infrared (NIR) absorption for photothermal conversion. Under NIR irradiation, the PDA coating enabled mild hyperthermia (42-43 °C) on the zirconia surface. Remarkably, this mild photothermal stimulation significantly promoted human gingival fibroblast proliferation, adhesion, and collagen production compared to unmodified zirconia in vitro. By utilizing the photothermal properties of PDA coatings to modulate cellular behaviors beneficial for connective tissue formation, this approach provides a promising avenue to achieve improved soft tissue integration and long-term stability of dental implants. The findings highlight the innovative potential of combining biomaterial surface engineering with photothermal therapy for applications in implant dentistry.

Liensinine sensitizes colorectal cancer cells to oxaliplatin by targeting HIF-1α to inhibit autophagy.

BACKGROUND: Oxaliplatin is the most common chemotherapeutic agent for patients with colorectal cancer. However, its anti-cancer efficacy is restricted by drug resistance occurring through several mechanisms, including autophagy. Liensinine exerts a considerable anti-tumor effect and can regulate autophagy. Inhibition of autophagy is a strategy to reverse resistance to oxaliplatin. The aim of this study was to check if liensinine can enhance the therapeutic efficacy of oxaliplatin in colorectal cancer and if so, elucidate its mechanism. METHODS: Two colorectal cancer cell lines, HCT116 and LoVo, and one normal intestinal epithelial cell, NCM-460 were used for in vitro experiments. Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays were used to evaluate the cytotoxicity of liensinine and oxaliplatin. Network pharmacology analysis and Human XL Oncology Array were used to screen targets of liensinine. Transfections and autophagy regulators were used to confirm these targets. The relationship between the target and clinical effect of oxaliplatin was analyzed. Patient-derived xenograft (PDX) models were used to validate the effects of liensinine and oxaliplatin. RESULTS: CCK-8 and colony formation assays both showed that the combination treatment of liensinine and oxaliplatin exerted synergistic effects. Results of the network pharmacology analysis and Human XL Oncology Array suggested that liensinine can inhibit autophagy by targeting HIF-1α/eNOS. HIF-1α was identified as the key factor modulated by liensinine in autophagy and induces resistance to oxaliplatin. HIF-1α levels in tumor cells and prognosis for FOLFOX were negatively correlated in clinical data. The results from three PDX models with different HIF-1α levels showed their association with intrinsic and acquired resistance to oxaliplatin in these models, which could be reversed by liensinine. CONCLUSIONS: Research on the relationship between HIF-1α levels and the clinical effect of oxaliplatin is lacking, and whether liensinine regulates HIF-1α is unknown. Our findings suggest that liensinine overcomes the resistance of colorectal cancer cells to oxaliplatin by suppressing HIF-1α levels to inhibit autophagy. Our findings can contribute to improving prognosis following colorectal cancer therapy.

Universal, minute-scale synthesis of transition metal compound nanocatalysts via graphene-microwave system for enhancing sulfur kinetics in lithium-sulfur batteries.

The application of Li-S batteries on large scale is held back by the sluggish sulfur kinetics and low synthesis efficiency of sulfur host. In addition, the preparation of catalysts that promote polysulfide redox kinetics is complex and time-consuming, reducing the cost of raw materials in Li-S. Here, a universal synthetic strategy for rapid fabrication of sulfur cathode and metal compounds nanocatalysts is reported based on microwave heating of graphene. Heat-sensitive materials can achieve rapid heating due to graphene reaching 500 ℃ within 4 s via microwave irradiation. The MoP-MoS2/rGO catalyst demonstrated in this work was synthesized within 60 s. When used for catalysts for Li-S batteries whose graphene/sulfur cathodes were also synthesized by microwave heating, enhanced catalytic effect for sulfur redox reaction was verified via experimental and DFT theoretical results. Benefiting from fast redox reaction (MoP), smooth Li+ diffusion pathways (MoS2), and large conductive network (rGO), the assembled Li-S battery with MoP-MoS2/rGO-Add@CS displays a remarkable initial specific capacity, stable lithium anode and good cycle stability (in pouch cells) using this two-pronged strategy. The work provides a practical strategy for advanced Li-S batteries toward a wide range of applications.

Association of non-insulin-based insulin resistance indices with disease severity and adverse outcome in idiopathic pulmonary arterial hypertension: a multi-center cohort study.

BACKGROUND: Insulin resistance (IR) plays an important role in the pathophysiology of cardiovascular disease. Recent studies have shown that diabetes mellitus and impaired lipid metabolism are associated with the severity and prognosis of idiopathic pulmonary arterial hypertension (IPAH). However, the relationship between IR and pulmonary hypertension is poorly understood. This study explored the association between four IR indices and IPAH using data from a multicenter cohort. METHODS: A total of 602 consecutive participants with IPAH were included in this study between January 2015 and December 2022. The metabolic score for IR (METS-IR), triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, triglyceride and glucose (TyG) index, and triglyceride-glucose-body mass index (TyG-BMI) were used to quantify IR levels in patients with IPAH. The correlation between non-insulin-based IR indices and long-term adverse outcomes was determined using multivariate Cox regression models and restricted cubic splines. RESULTS: During a mean of 3.6 years' follow-up, 214 participants experienced all-cause death or worsening condition. Compared with in low to intermediate-low risk patients, the TG/HDL-C ratio (2.9 ± 1.7 vs. 3.3 ± 2.1, P = 0.003) and METS-IR (34.5 ± 6.7 vs. 36.4 ± 7.5, P < 0.001) were significantly increased in high to intermediate-high risk patients. IR indices correlated with well-validated variables that reflected the severity of IPAH, such as the cardiac index and stroke volume index. Multivariate Cox regression analyses indicated that the TyG-BMI index (hazard ratio [HR] 1.179, 95% confidence interval [CI] 1.020, 1.363 per 1.0-standard deviation [SD] increment, P = 0.026) and METS-IR (HR 1.169, 95% CI 1.016, 1.345 per 1.0-SD increment, P = 0.030) independently predicted adverse outcomes. Addition of the TG/HDL-C ratio and METS-IR significantly improved the reclassification and discrimination ability beyond the European Society of Cardiology (ESC) risk score. CONCLUSIONS: IR is associated with the severity and long-term prognosis of IPAH. TyG-BMI and METS-IR can independently predict clinical worsening events, while METS-IR also provide incremental predictive performance beyond the ESC risk stratification.

Tensor Network Message Passing.

When studying interacting systems, computing their statistical properties is a fundamental problem in various fields such as physics, applied mathematics, and machine learning. However, this task can be quite challenging due to the exponential growth of the state space as the system size increases. Many standard methods have significant weaknesses. For instance, message-passing algorithms can be inaccurate and even fail to converge due to short loops, while tensor network methods can have exponential computational complexity in large graphs due to long loops. In this Letter, we propose a new method called "tensor network message passing." This approach allows us to compute local observables like marginal probabilities and correlations by combining the strengths of tensor networks in contracting small subgraphs with many short loops and the strengths of message-passing methods in globally sparse graphs, thus addressing the crucial weaknesses of both approaches. Our algorithm is exact for systems that are globally treelike and locally dense-connected when the dense local graphs have a limited tree width. We have conducted numerical experiments on synthetic and real-world graphs to compute magnetizations of Ising models and spin glasses, and have demonstrated the superiority of our approach over standard belief propagation and the recently proposed loopy message-passing algorithm. In addition, we discuss the potential applications of our method in inference problems in networks, combinatorial optimization problems, and decoding problems in quantum error correction.

Interannual precipitation variability dominates the growth of alpine grassland above-ground biomass at high elevations on the Tibetan Plateau.

The impact of global climate change on mountainous regions with significant elevational gaps is complex and often unpredictable. In particular, alpine grassland ecosystems, are experiencing changes in their spatial patterns along elevational gradients, which increases their vulnerability to degradation. Therefore, a more detailed understanding of spatiotemporal changes in alpine grassland productivity along elevational gradients and an elevation-dependent characterization of the effects of climatic variables on grassland productivity dynamics are essential. Thus, we conducted a study in the Tibetan Plateau, where we collected 2251 above-ground biomass (AGB) observations collected from 1986 to 2020. Mean annual temperature (TMP), annual precipitation (PRE), interannual precipitation variability (CVP), and snowmelt (SNMM) were chosen as influential variables. Using the Random Forest algorithm, we generated an AGB raster dataset covering the period 1989-2020 based on earth observation data at 30 m resolution to examine the dynamics of alpine grasslands and their response to climate change with respect to elevation. The results showed that the AGB of alpine grassland on the Tibetan Plateau was 49.17 g/m2. We observed an increasing trend in grassland AGB at high elevations, with a growth rate of about 0.28 g/m2 per year within the interval of 3100-4800 m. However, above the elevation of approximately 4400-4600 m, we observed a decoupling trend between grassland AGB and TMP. Moreover, at most elevations, the proportion of maximum partial correlation coefficients for CVP, PRE, and SNMM surpassed that of TMP. We found the dominant role of precipitation variability on grassland AGB dynamics, with 22.80 % and 18.86 % for CVP+ and CVP-, respectively. The proportion of CVP+ did not vary much at different elevations, whereas the proportion of CVP- increased with elevation, varying between 12.85 and 30.25 %. In the future, precipitation on the Tibetan plateau is expected to increase, potentially reversing its original positive impact.

Declined terrestrial ecosystem resilience.

Terrestrial ecosystem resilience is crucial for maintaining the structural and functional stability of ecosystems following disturbances. However, changes in resilience over the past few decades and the risk of future resilience loss under ongoing climate change are unclear. Here, we identified resilience trends using two remotely sensed vegetation indices, analyzed the relative importance of potential driving factors to resilience changes, and finally assessed the risk of future resilience loss based on the output data of eight models from CMIP6. The results revealed that more than 60% of the ecosystems experienced a conversion from an increased trend to a declined trend in resilience. Attribution analysis showed that the most important driving factors of declined resilience varied regionally. The declined trends in resilience were associated with increased precipitation variability in the tropics, decreased vegetation cover in arid region, increased temperature variability in temperate regions, and increased average temperature in cold regions. CMIP6 reveals that terrestrial ecosystems under SPP585 are expected to experience more intense declines in resilience than those under SSP126 and SSP245, particularly in cold regions. These results highlight the risk of continued degradation of ecosystem resilience in the future and the urgency of climate mitigation actions.

Hierarchical Porous Fibers for Intrinsically Thermally Insulated and Self-Sensing Integrated Smart Textile.

Here, stretchable hierarchical porous polyurethane fibers were designed, fabricated, and employed as a three-dimensional hierarchical interconnected framework for conductive networks interwoven with silver nanoparticles and carbon nanotubes. The fiber possessed favorable thermal insulation, strain sensing, and electric heating properties. The core-shell layered porous structure of fiber made the fiber have high heat insulation performance (the difference value of temperature |ΔT| = 3.54, 8.9, and 12.7 °C at heating stage temperatures of 35, 50, and 65 °C) and ultrahigh elongation at break (813%). Importantly, after conductive filler decoration, the fiber could exhibit real-time strain-sensing capacities with a high gauge factor. In addition, the fibers could be heated at low voltage, like an electrical heater. The development of flexible, stretchable, and multifunctional porous fibers had great potential applications in intelligent wearable devices for integrated thermal management, strain sensing, and intrinsic self-warming capability.

Tumor biomarkers in evaluating the severity and prognosis of idiopathic pulmonary arterial hypertension: A comprehensive analysis.

Inflammation contributes to development of idiopathic pulmonary arterial hypertension (IPAH), and tumor biomarkers can reflect inflammatory and immune status. We aimed to determine the value of tumor biomarkers in IPAH comprehensively. We enrolled 315 patients with IPAH retrospectively. Tumor biomarkers were correlated with established indicators of pulmonary hypertension severity. Multivariable Cox regression found that AFP (hazard ratio [HR]: 1.587, 95% confidence interval [CI]: 1.014-2.482, p = 0.043) and CA125 (HR: 2.018, 95% CI: 1.163-3.504, p = 0.013) could independently predict prognosis of IPAH. The changes of AFP over time were associated with prognosis of patients, each 1 ng/mL increase in AFP was associated with 5.4% increased risk of clinical worsening (HR: 1.054, 95% CI: 1.001-1.110, p = 0.046), enabling detection of disease progression. Moreover, beyond well-validated PH biomarkers, CA125 was still of prognostic value in the low-risk patients (HR: 1.014, 95% CI: 1.004-1.024, p = 0.004), allowing for more accurate risk stratification and prediction of disease outcomes. AFP and CA125 can serve for prognosis prediction, risk stratification, and dynamic monitor in patients with IPAH.

Design and synthesis of pyrene-based probes and their fluorescent detection of Sb(III).

A series of pyrene-based fluorescent (FL) probes for Sb(III) were designed and synthesized. All of them exhibited luminescence by pyrene excimers in the mixture of DMSO and water and showed enhanced emission with the addition of Sb(III). By comparing their FL response to Sb(III), the effects of intramolecular hydrogen bond, inductive effect, and steric effect were investigated. Meanwhile, the FL enhancement factor of the best performing probe reached 10.28 and the detection limit was calculated to be 0.0535 mg/L, indicating that it might be used as a potential candidate for the treatment of Sb(III) in printing and dyeing wastewater.

Competitive mechanism of salt-tolerance/degradation-performance of organic pollutant in bacteria: Na+/H+ antiporters contribute to salt-stress resistance but impact phenol degradation.

Phenolic-laden wastewater is typically characterized by its high toxicity and high salinity, imposing serious limits on the application of bioremediation. Although a few halotolerant microorganisms have been reported to degrade phenol, their removal efficiency on high concentrations of phenol remains unsatisfactory. What's more, the deep interaction molecular mechanism of salt-tolerance/phenol-degradation performance has not been clearly revealed. Here, a halotolerant strain Aeribacillus pallidus W-12 employed a meta-pathway to efficiently degrade high concentration of phenol even under high salinity conditions. Investigation of salt-tolerance strategy indicated that four Na+/H+ antiporters, which are widely distributed in bacteria, synergistically endowed the strain with excellent salt adaptability. All these antiporters differentially but positively responded to salinity changes and induction of phenol, forming a synergistic transport effect on salt ions and phenol. In-depth analysis revealed a competitive relationship between salt tolerance and degradation performance, which significantly impaired the degradation efficiency at relatively high salinity. The efficient degradation performance of W-12 under different phenol concentrations and salinity conditions indicated its bioremediation potential for multiple types of phenolic wastewater. Collectively, the competitive mechanism of salt tolerance and degradation performance enlightens a new strategy of introducing or re-constructing Na+/H+ antiporters to further improve bioremediation efficiency of hypersaline organic wastewater.

Constructing a Hydrophilic Microsensor for High-Antifouling Neurotransmitter Dopamine Sensing.

Real-time sensing of dopamine is essential for understanding its physiological function and clarifying the pathophysiological mechanism of diseases caused by impaired dopamine systems. However, severe fouling from nonspecific protein adsorption, for a long time, limited conventional neural recording electrodes concerning recording stability. This study reported a high-antifouling nanocrystalline boron-doped diamond microsensor grown on a carbon fiber substrate. The antifouling properties of this diamond sensor were strongly related to the grain size (i.e., nanocrystalline and microcrystalline) and surface terminations (i.e., oxygen and hydrogen terminals). Experimental observations and molecular dynamics calculations demonstrated that the oxygen-terminated nanocrystalline boron-doped diamond microsensor exhibited enhanced antifouling characteristics against protein adsorption, which was attributed to the formation of a strong hydration layer as a physical and energetic barrier that prevents protein adsorption on the surface. This finally allowed for in vivo monitoring of dopamine in rat brains upon potassium chloride stimulation, thus presenting a potential solution for the design of next-generation antifouling neural recording sensors. Experimental observations and molecular dynamics calculations demonstrated that the oxygen-terminated nanocrystalline boron-doped diamond (O-NCBDD) microsensor exhibited ultrahydrophilic properties with a contact angle of 4.9°, which was prone to forming a strong hydration layer as a physical and energetic barrier to withstand the adsorption of proteins. The proposed O-NCBDD microsensor exhibited a high detection sensitivity of 5.14 µA µM-1 cm-2 and a low detection limit of 25.7 nM. This finally allowed for in vivo monitoring of dopamine with an average concentration of 1.3 µM in rat brains upon 2 µL of potassium chloride stimulation, thus presenting a potential solution for the design of next-generation antifouling neural recording sensors.

Physiological and transcriptomic analysis revealed the alleviating effect of 1,25(OH)2D3 on environmental iron overloading induced ferroptosis in zebrafish.

Iron overload in the aquatic environment can cause damage in fish bodies. Vitamin D3 (VD3) has been proven to have antioxidant and regulatory effects on iron transport. The current research investigated the effects of environmental iron overload on larval zebrafish and explored the effects of 1,25(OH)2D3 on ferroptosis in zebrafish larvae and zebrafish liver cells (ZFL) caused by iron overload in the environment and its possible regulatory mechanisms. The results showed that 1,25(OH)2D3 alleviated liver damage in zebrafish larvae and mitochondrial damage in ZFL after excessive ammonium ferric citrate (FAC) treatment, and improved the survival rate of ZFL. 1,25(OH)2D3 cleared and inhibited excessive FAC induced abnormal accumulation of ROS, lipid ROS, MDA, and Fe2+ in zebrafish larvae and ZFL, as well as enhanced the activity of antioxidant enzyme GPx4. Transcriptomic analysis showed that 1,25(OH)2D3 can regulate ferroptosis in ZFL by regulating signaling pathways related to oxidative stress, iron homeostasis, mitochondrial function, and ERS, mainly including ferroptosis, neoptosis, p53 signaling pathway, apoptosis, FoxO signaling pathway. Validation of transcriptome data showed that 1,25(OH)2D3 inhibits ferroptosis in zebrafish larvae and ZFL caused by excessive FAC via promoting the expression of slc40a1 and hmox1a genes and increasing SLC40A1 protein levels. In summary, 1,25(OH)2D3 can resist ferroptosis in zebrafish caused by iron overload in the environment mainly via regulating antioxidant capacity and iron ion transport.

Andrographolide sensitizes KRAS-mutant colorectal cancer cells to cetuximab by inhibiting the EGFR/AKT and PDGFRß/AKT signaling pathways.

BACKGROUND: Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism. PURPOSE: This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT. METHODS: The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRß were used to evaluate the role of andrographolide on PDGFRß. The western blotting was used to investigate Wnt/ß-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo. RESULTS: Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRß and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/ß-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo. CONCLUSIONS: Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRß /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.