Identifying depression's genetic role as a precursor to sepsis and increased mortality risk: Comprehensive insights from mendelian randomization analysis.

BACKGROUND: Previous retrospective studies have shown a correlation between depression and increased risk of infections, including a moderate rise in sepsis likelihood associated with severe depression and anxiety. To investigate the potential causal links between depression, sepsis, and mortality risks, while considering confounding factors, we employed a Mendelian randomization (MR) approach. METHODS: In this two-sample Mendelian randomization study, we analyzed data from a large-scale genome-wide association study on depression, involving 807,553 European individuals (246,363 cases, 561,190 controls). We extracted SNP associations with sepsis and 28-day mortality from UK Biobank GWAS outcomes. The correlation analysis primarily employed the inverse-variance weighted method, supplemented by sensitivity analyses for heterogeneity and pleiotropy assessment. RESULTS: Our analysis revealed a potential causal link between depression and an increased risk of sepsis (OR = 1.246, 95% CI: 1.076-1.442, P = 0.003), but no causal association was found with sepsis-induced mortality risk (OR = 1.274, 95% CI: 0.891-1.823, P = 0.184). Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: We identified a potential causal association between depression and heightened sepsis risk, while no link was found with sepsis-induced mortality. These findings suggest that effective management of depression could be important in preventing sepsis.

Renoprotective effect of rosmarinic acid by inhibition of indoxyl sulfate-induced renal interstitial fibrosis via the NLRP3 inflammasome signaling.

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1ß/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1ß showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1ß/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1ß, collagen I, fibronectin and α-SMA, and TGF- ß 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.

A Vision/Inertial Navigation/Global Navigation Satellite Integrated System for Relative and Absolute Localization in Land Vehicles.

This paper presents an enhanced ground vehicle localization method designed to address the challenges associated with state estimation for autonomous vehicles operating in diverse environments. The focus is specifically on the precise localization of position and orientation in both local and global coordinate systems. The proposed approach integrates local estimates generated by existing visual-inertial odometry (VIO) methods into global position information obtained from the Global Navigation Satellite System (GNSS). This integration is achieved through optimizing fusion in a pose graph, ensuring precise local estimation and drift-free global position estimation. Considering the inherent complexities in autonomous driving scenarios, such as the potential failures of a visual-inertial navigation system (VINS) and restrictions on GNSS signals in urban canyons, leading to disruptions in localization outcomes, we introduce an adaptive fusion mechanism. This mechanism allows seamless switching between three modes: utilizing only VINS, using only GNSS, and normal fusion. The effectiveness of the proposed algorithm is demonstrated through rigorous testing in the Carla simulation environment and challenging UrbanNav scenarios. The evaluation includes both qualitative and quantitative analyses, revealing that the method exhibits robustness and accuracy.

RBS and ABS Coordinated Control Strategy Based on Explicit Model Predictive Control.

During the braking process of electric vehicles, both the regenerative braking system (RBS) and anti-lock braking system (ABS) modulate the hydraulic braking force, leading to control conflict that impacts the effectiveness and real-time capability of coordinated control. Aiming to enhance the coordinated control effectiveness of RBS and ABS within the electro-hydraulic composite braking system, this paper proposes a coordinated control strategy based on explicit model predictive control (eMPC-CCS). Initially, a comprehensive braking control framework is established, combining offline adaptive control law generation, online optimized control law application, and state compensation to effectively coordinate braking force through the electro-hydraulic system. During offline processing, eMPC generates a real-time-oriented state feedback control law based on real-world micro trip segments, improving the adaptiveness of the braking strategy across different driving conditions. In the online implementation, the developed three-dimensional eMPC control laws, corresponding to current driving conditions, are invoked, thereby enhancing the potential for real-time braking strategy implementation. Moreover, the state error compensator is integrated into eMPC-CCS, yielding a state gain matrix that optimizes the vehicle braking status and ensures robustness across diverse braking conditions. Lastly, simulation evaluation and hardware-in-the-loop (HIL) testing manifest that the proposed eMPC-CCS effectively coordinates the regenerative and hydraulic braking systems, outperforming other CCSs in terms of braking energy recovery and real-time capability.

Intelligent Vehicle Path Planning Based on Optimized A* Algorithm.

With the rapid development of the intelligent driving technology, achieving accurate path planning for unmanned vehicles has become increasingly crucial. However, path planning algorithms face challenges when dealing with complex and ever-changing road conditions. In this paper, aiming at improving the accuracy and robustness of the generated path, a global programming algorithm based on optimization is proposed, while maintaining the efficiency of the traditional A* algorithm. Firstly, turning penalty function and obstacle raster coefficient are integrated into the search cost function to increase the adaptability and directionality of the search path to the map. Secondly, an efficient search strategy is proposed to solve the problem that trajectories will pass through sparse obstacles while reducing spatial complexity. Thirdly, a redundant node elimination strategy based on discrete smoothing optimization effectively reduces the total length of control points and paths, and greatly reduces the difficulty of subsequent trajectory optimization. Finally, the simulation results, based on real map rasterization, highlight the advanced performance of the path planning and the comparison among the baselines and the proposed strategy showcases that the optimized A* algorithm significantly enhances the security and rationality of the planned path. Notably, it reduces the number of traversed nodes by 84%, the total turning angle by 39%, and shortens the overall path length to a certain extent.

Asiatic acid inhibits osteosarcoma cell migration and invasion via the AKT/Sp1/MMP1 axis.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti-tumor, anti-inflammatory, and anti-oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non-toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down-regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA-induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti-invasive effect of AA on osteosarcoma cells via the p-AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma.

Modulator-assisted solvent-free synthesis of amorphous zirconium terephthalate catalyst for efficient oxidative desulfurization.

Oxidative desulfurization (ODS) emerges as a critical player in enhancing efficient fuel desulfurization and promoting sustainable clean energy. Metal-organic frameworks (MOFs) show great potential as ODS catalysts because of their exceptional porosity and versatility. This study explores the use of amorphous metal-organic frameworks (aMOFs), which combine MOFs' structural advantages with unique properties of amorphous materials, to enhance catalytic efficiency in ODS. Traditional methods for synthesizing MOFs rely on solvent-thermal or solvent-free methods, each with limitations in environmental impact or scalability. To address this, we introduce a novel strategy utilizing a small quantity of benzoic acid (BA) modifier to facilitate the solvent-free, one-pot, mechanical synthesis of amorphous zirconium terephthalate (GU-2BA-3h). The resulting GU-2BA-3h demonstrates exceptional ODS performance, efficiently removing 1000 ppm of dibenzothiophene (DBT) in just 6 min at 60 °C. Amorphous GU-2BA-3h features an expanded external surface area, increased acidic sites, and exceptional stability, resulting in a high turnover frequency (19.6 h-1) and outstanding catalytic activity (53.2 mmol g-1 h-1), establishing it as a highly efficient ODS catalyst. This remarkable performance arises from the formation of dangling carboxyl groups and active metal sites due to the competitive coordination of benzoic acid with the linker. Experimental evidence confirms that these carboxyl groups and exposed Zr-OH sites interact with oxidants, generating hydroxyl radicals that effectively eliminate sulfur-containing compounds. Furthermore, the methodology exhibits universality in constructing amorphous Zr-based MOFs, and provides an eco-friendly, cost-effective route for efficient ODS catalyst production.

Pharmacokinetics, safety, and efficacy of 20% subcutaneous immunoglobulin (Ig20Gly) administered weekly or every 2 weeks in Japanese patients with primary immunodeficiency diseases: a phase 3, open-label study.

This phase 3, open-label, multidose study (NCT04346108) evaluated the pharmacokinetics, safety, tolerability, and efficacy of immunoglobulin subcutaneous (human) 20% solution (Ig20Gly) administered weekly and every 2 weeks in Japanese patients with primary immunodeficiency diseases (PIDs). The study was conducted at eight study sites in Japan and enrolled patients aged ≥2 years with PIDs treated using a stable intravenous immunoglobulin dose for ≥3 months prior to the study. Patients received intravenous immunoglobulin every 3 or 4 weeks at pre-study dose (200-600 mg/kg) for 13 weeks (Epoch 1), subcutaneous Ig20Gly (50-200 mg/kg) once weekly for 24 weeks (Epoch 2), and Ig20Gly (100-400 mg/kg) every 2 weeks for 12 weeks (Epoch 3). The primary endpoint was serum total immunoglobulin G (IgG) trough levels during Epochs 2 and 3. Overall, 17 patients were enrolled (median [range] age: 24 [5-69] years; 59% male) and participated in Epochs 1 and 2; seven patients entered Epoch 3. Serum total IgG trough levels were maintained at >8 g/l: geometric means (95% confidence intervals) at the end of Epochs 2 and 3 were 8.56 (8.03-9.12) g/l and 8.39 (7.89-8.91) g/l, respectively. Related treatment-emergent adverse events were all mild in severity; the most common treatment-emergent adverse events (excluding infections) in Epochs 2 and 3 were injection site swelling (24%) and injection site erythema (18%). This is the first trial to demonstrate the efficacy and favourable safety profile of 20% subcutaneous immunoglobulin administered every 2 weeks in adult and paediatric Japanese patients with PIDs.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

Near-UV Extinction of Submicron Thickness Ice Films in the 290-350 nm Range at 258 K.

Ice clouds affect the energy balance of the atmosphere through absorption, reflection, and scattering of solar radiation. We have developed a new experimental technique to simultaneously measure thin ice film extinction and its thickness (about 0.06-0.21 µm) by combining Brewster angle cavity ring-down spectroscopy and quartz crystal microbalance. The ice film serves as a proxy for ice clouds. Thin ice films were formed by water vapor deposition on a silica surface at 258 K. The average extinction cross sections of ice films were determined to be about 6.6 × 10-23, 8.1 × 10-23, 5.3 × 10-23, 5.6 × 10-23, 5.2 × 10-23, 5.1 × 10-23, and 3.9 × 10-23 cm2/molecule at wavelengths of 290, 300, 310, 320, 330, 340, and 350 nm at 258 K, respectively. Atmospheric implications of the results are discussed.

YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD-L1/VEGFA Axis.

N6-methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5'-untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand-1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA-containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.

Liquid-liquid phase separation in Alzheimer's disease.

The pathological aggregation and misfolding of tau and amyloid-ß play a key role in Alzheimer's disease (AD). However, the underlying pathological mechanisms remain unclear. Emerging evidences indicate that liquid-liquid phase separation (LLPS) has great impacts on regulating human health and diseases, especially neurodegenerative diseases. A series of studies have revealed the significance of LLPS in AD. In this review, we summarize the latest progress of LLPS in AD, focusing on the impact of metal ions, small-molecule inhibitors, and proteinaceous partners on tau LLPS and aggregation, as well as toxic oligomerization, the role of LLPS on amyloid-ß (Aß) aggregation, and the cross-interactions between amyloidogenic proteins in AD. Eventually, the fundamental methods and techniques used in LLPS study are introduced. We expect to present readers a deeper understanding of the relationship between LLPS and AD.

Defining Bacterial RNA-RNA Interactomes Using CLASH.

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterial pathogen accounting for high mortality rates among infected patients. Transcriptomic regulation by small RNAs (sRNAs) has been shown to regulate networks promoting antibiotic resistance and virulence in S. aureus. Yet, the biological role of most sRNAs during MRSA host infection remains unknown. To fill this gap, in collaboration with the lab of Jai Tree, we performed comprehensive RNA-RNA interactome analyses in MRSA using CLASH under conditions that mimic the host environment. Here we present a detailed version of this optimized CLASH (cross-linking, ligation, and sequencing of hybrids) protocol we recently developed, which has been tailored to explore the RNA interactome in S. aureus as well as other Gram-positive bacteria. Alongside, we introduce a compilation of helpful Python functions for analyzing folding energies of putative RNA-RNA interactions and streamlining sRNA and mRNA seed discovery in CLASH data. In the accompanying computational demonstration, we aim to establish a standardized strategy to evaluate the likelihood that observed chimeras arise from true RNA-RNA interactions.

Preparation of nitrogen-doped activated carbon used for catalytic oxidation removal of H2S.

In this study, nitrogen-doped modified activated carbons were synthesized for H2S removal from Zhuxi activated carbon and 4,4'-bipyridine as raw material and nitrogen source, respectively. The synthesis strategy was hydrothermal treatment and subsequent NH3 annealing, and the formation and conversion patterns of the different N configurations were investigated. When the annealing temperatures were 500 °C and 600 °C, N-5 account for the majority. As the annealing temperature increased, the proportion of N-6 gradually increased. After the temperature increased to 1000 °C, N-5 and N-6 were converted to N-Q to a certain degree, while the amount of nitrogen doping decreased significantly. The sample H160-0.2-800 exhibited excellent H2S removal with a high sulfur capacity of up to 206.89 mg/g, significantly higher than that of the original activated carbon ZX1200 (67.56 mg/g). The reason for this is that the micropores (Vmic = 0.5155 cm3/g) and specific surface area (SBET = 1369.5 m2/g) of the modified activated carbon are more developed than those of the original activated carbon. A high nitrogen content (3.14 wt%) and N-6 configuration proportion (73.56 %) are significant reasons for the excellent adsorption properties. The mechanism of the catalytic oxidation was investigated. The introduction of surface nitrogen-containing functional groups alkalizes the activated carbon surface, enhancing the adsorption and dissociation of H2S and O2 and facilitating the formation of sulfur radicals and elemental sulfur.

Progress and summary of reinforcement learning on energy management of MPS-EV.

The escalating environmental concerns and energy crisis caused by internal combustion engines (ICE) have become unacceptable under environmental regulations and the energy crisis. As a promising alternative solution, multi-power source electric vehicles (MPS-EVs) integrate various clean energy systems to enhance the powertrain efficiency. The energy management strategy (EMS) is plays a pivotal role for MPS-EVs to maximize efficiency, fuel economy, and range. Reinforcement Learning (RL) has emerged as an effective methodology for EMS development, attracting continuous attention and research. However, a systematic analysis of the design elements of RL-based EMS is currently lacking. This paper addresses this gap by presenting a comprehensive analysis of current research on RL-based EMS (RL-EMS) and summarizing its design elements. This paper first summarizes the previous applications of RL in EMS from five aspects: algorithm, perception scheme, decision scheme, reward function, and innovative training method. It highlights the contributions of advanced algorithms to training effectiveness, provides a detailed analysis of perception and control schemes, classifies different reward function settings, and elucidates the roles of innovative training methods. Finally, by comparing the development routes of RL and RL-EMS, this paper identifies the gap between advanced RL solutions and existing RL-EMS. Potential development directions are suggested for implementing advanced artificial intelligence (AI) solutions in EMS.

Dissolving microneedle system containing Ag nanoparticle-decorated silk fibroin microspheres and antibiotics for synergistic therapy of bacterial biofilm infection.

Most cases of delayed wound healing are associated with bacterial biofilm infections due to high antibiotic resistance. To improve patient compliance and recovery rates, it is critical to develop minimally invasive and efficient methods to eliminate bacterial biofilms as an alternative to clinical debridement techniques. Herein, we develop a dissolving microneedle system containing Ag nanoparticles (AgNPs)-decorated silk fibroin microspheres (SFM-AgNPs) and antibiotics for synergistic treatment of bacterial biofilm infection. Silk fibroin microspheres (SFM) are controllably prepared in an incompatible system formed by a mixture of protein and carbohydrate solutions by using a mild all-aqueous phase method and serve as biological templates for the synthesis of AgNPs. The SFM-AgNPs exert dose- and time-dependent broad-spectrum antibacterial effects by inducing bacterial adhesion. The combination of SFM-AgNPs with antibiotics breaks the limitation of the antibacterial spectrum and achieves better efficacy with reduced antibiotic dosage. Using hyaluronic acid (HA) as the soluble matrix, the microneedle system containing SFM-AgNPs and anti-Gram-positive coccus drug (Mupirocin) inserts into the bacterial biofilms with sufficient strength, thereby effectively delivering the antibacterial agents and realizing good antibiofilm effect on Staphylococcus aureus-infected wounds. This work demonstrates the great potential for the development of novel therapeutic systems for eradicating bacterial biofilm infections.

Modulation of Buried Interface by 1-(3-aminopropyl)-Imidazole for Efficient Inverted Formamidinium-Cesium Perovskite Solar Cells.

Considering the direct influence of substrate surface nature on perovskite (PVK) film growth, buried interfacial engineering is crucial to obtain ideal perovskite solar cells (PSCs). Herein, 1-(3-aminopropyl)-imidazole (API) is introduced at polytriarylamine (PTAA)/PVK interface to modulate the bottom property of PVK. First, the introduction of API improves the growth of PVK grains and reduces the Pb2+ defects and residual PbI2 present at the bottom of the film, contributing to the acquisition of high-quality PVK film. Besides, the presence of API can optimize the energy structure between PVK and PTAA, which facilitates the interfacial charge transfer. Density functional theory (DFT) reveals that the electron donor unit (R-C ═ N) of the API prefers to bind with Pb2+ traps at the PVK interface, while the formation of hydrogen bonds between the R-NH2 of API and I- strengthens the above binding ability. Consequently, the optimum API-treated inverted formamidinium-cesium (FA/Cs) PSCs yields a champion power conversion efficiency (PCE) of 22.02% and exhibited favorable stability.

Nb2AlC MAX Nanosheets Supported Ru Nanocrystals as Efficient Catalysts for Boosting pH-Universal Hydrogen Production.

MAX phase combines both ceramic and metallic properties, which exhibits widespread application prospects. 2D MAX nanosheets have more abundant surface-active sites, being anticipated to improve the performance of surface-related applications. Herein, for the first time, 2D Nb2AlC nanosheets (NSs) as novel supports anchored with Ru catalysts for overall water splitting are developed. The optimized catalyst of Ru@Nb2AlC NSs exhibit Pt-comparable kinetics and superior catalytic activity toward hydrogen evolution reaction (HER) (low overpotentials of 61 and 169 mV at 10 and 100 mA cm-2, respectively) with excellent durability (5000 cycles or 80 h) in alkaline media. In particular, Ru@Nb2AlC NSs achieve a mass activity of ≈4.8 times larger than the commercial Pt/C (20 wt.%) catalyst. The post-oxidation resultant catalyst of RuO2@Nb2AlC NSs also exhibit boosting HER and oxygen evolution reaction activities and ≈100% Faraday efficiency for overall water splitting with a cell voltage of 1.61 V to achieve 10 mA cm-2. Therefore, the novel category of 2D MAX supports anchored with Ru nanocrystals offers a novel strategy for designing a wide range of MAX-supported metal catalysts for the renewable energy field.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation.

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.