MCT1-mediated endothelial cell lactate shuttle as a target for promoting axon regeneration after spinal cord injury.

Rationale: Spinal cord injury (SCI)-induced vascular damage causes ischemia and hypoxia at the injury site, which, in turn, leads to profound metabolic disruptions. The effects of these metabolic alterations on neural tissue remodeling and functional recovery have yet to be elucidated. The current study aimed to investigate the consequences of the SCI-induced hypoxic environment at the epicenter of the injury. Methods: This study employed metabolomics to assess changes in energy metabolism after SCI. The use of a lactate sensor identified lactate shuttle between endothelial cells (ECs) and neurons. Reanalysis of single-cell RNA sequencing data demonstrated reduced MCT1 expression in ECs after SCI. Additionally, an adeno-associated virus (AAV) overexpressing MCT1 was utilized to elucidate its role in endothelial-neuronal interactions, tissue repair, and functional recovery. Results: The findings revealed markedly decreased monocarboxylate transporter 1 (MCT1) expression that facilitates lactate delivery to neurons to support their energy metabolism in ECs post-SCI. This decreased expression of MCT1 disrupts lactate transport to neurons, resulting in a metabolic imbalance that impedes axonal regeneration. Strikingly, our results suggested that administering adeno-associated virus specifically to ECs to restore MCT1 expression enhances axonal regeneration and improves functional recovery in SCI mice. These findings indicate a novel link between lactate shuttling from endothelial cells to neurons following SCI and subsequent neural functional recovery. Conclusion: In summary, the current study highlights a novel metabolic pathway for therapeutic interventions in the treatment of SCI. Additionally, our findings indicate the potential benefits of targeting lactate transport mechanisms in recovery from SCI.

Metamodel for Groundwater Leaching Assessment in Europe.

Under Regulation (EC) 1107/2009, FOCUS leaching models forecast the concentration of plant protection product (PPP) active substances in groundwater, known as the predicted environmental concentration (PECGW), based on parameters like DT50, KOC, and application rate. This study used simulated PECGW from PEARL and PELMO for training with over 870 combinations of KOC and DT50 across 174 different crop-location-software scenarios. Generalized additive models (GAMs) were trained on these simulations, achieving 96-99% accuracy for in-sample and out-of-sample validation, comparing the predicted environmental concentration in GAM (PECGAM) with the simulated PECGW relative to the 0.1 µg/L regulatory limit. Our GAM approach offers rapid PEC calculations for numerous substances across 174 scenarios, significantly accelerating early-stage molecule development analogue selection.

Highly Active Photoreduction of Atmospheric-Concentration CO2 into CH3COOH over Palladium Particles on Nb2O5 Nanosheets.

The endeavor to drive CO2 photoreduction towards the synthesis of C2 products is largely thwarted by the colossal energy hurdle inherent in C-C coupling. Herein, we load active metal particles on metal oxide nanosheets to build the dual metal pair sites for steering C-C coupling to form C2 products. Taking Pd particles anchored on the Nb2O5 nanosheets as an example, the high-angle annular dark-field image and X-ray photoelectron spectroscopy demonstrate the presence of Pd-Nb metal pair sites on the Pd-Nb2O5 nanosheets. Density functional theory calculations reveal these sites exhibit a low reaction energy barrier of only 1.02 eV for C-C coupling, implying that the introduction of Pd particles effectively tailors the reaction step to form C2 products. Therefore, the Pd-Nb2O5 nanosheets achieve a CH3COOH evolution rate of 13.5 µmol g-1 h-1 in photoreduction of atmospheric-concentration CO2, outshining all other single photocatalysts reported to date under analogous conditions.

Enteric-coated cerium dioxide nanoparticles for effective inflammatory bowel disease treatment by regulating the redox balance and gut microbiome.

Reactive oxygen species (ROS) play crucial roles in the pathogenesis of inflammatory bowel disease (IBD) by disrupting the mucosal barrier and subsequently leading to the dysregulation of the gut microbiome. Therefore, ROS scavengers present a promising and comprehensive strategy for the effective IBD treatment. In the current work, we explored the therapeutic potential of cerium dioxide (CeO2) nano-enzyme, which is well-known for their potent antioxidant properties and capability to mimic natural antioxidant enzymes in the regulation of oxidative stress. We developed a novel enteric-coated nanomedicine (CeO2@S100) aiming at improving the oral delivery efficacy of CeO2 in the complex gastrointestinal environment. CeO2@S100 is composed of a CeO2 nanoparticle core and a protective polyacrylic acid resin shell (Eudragit S100), ensuring targeted delivery of the core specifically at inflamed intestinal sites due to the negative surface charge. In vivo experiments revealed CeO2@S100 significantly alleviates the IBD by balancing oxidative stress and regulating gut microbiota in a dextran sulfate sodium-induced mouse colitis model. The uncomplicated synthesis of CeO2@S100 highlights its promise for clinical use, presenting an effective and safe approach to managing IBD.

Engineering vascularised organoid-on-a-chip: strategies, advances and future perspectives.

In recent years, advances in microfabrication technology and tissue engineering have propelled the development of a novel drug screening and disease modelling platform known as organoid-on-a-chip. This platform integrates organoids and organ-on-a-chip technologies, emerging as a promising approach for in vitro modelling of human organ physiology. Organoid-on-a-chip devices leverage microfluidic systems to simulate the physiological microenvironment of specific organs, offering a more dynamic and flexible setting that can mimic a more comprehensive human biological context. However, the lack of functional vasculature has remained a significant challenge in this technology. Vascularisation is crucial for the long-term culture and in vitro modelling of organoids, holding important implications for drug development and personalised medical approaches. This review provides an overview of research progress in developing vascularised organoid-on-a-chip models, addressing methods for in vitro vascularisation and advancements in vascularised organoids. The aim is to serve as a reference for future endeavors in constructing fully functional vascularised organoid-on-a-chip platforms.

The MRE11-RAD50-NBS1 complex both starts and extends DNA end resection in mouse meiosis.

Nucleolytic resection of DNA ends is critical for homologous recombination, but its mechanism is not fully understood, particularly in mammalian meiosis. Here we examine roles of the conserved MRN complex (MRE11, RAD50, and NBS1) through genome-wide analysis of meiotic resection in mice with various MRN mutations, including several that cause chromosomal instability in humans. Meiotic DSBs form at elevated levels but remain unresected if Mre11 is conditionally deleted, thus MRN is required for both resection initiation and regulation of DSB numbers. Resection lengths are reduced to varying degrees in MRN hypomorphs or if MRE11 nuclease activity is attenuated in a conditional nuclease-dead Mre11 model. These findings unexpectedly establish that MRN is needed for longer-range extension of resection, not just resection initiation. Finally, resection defects are additively worsened by combining MRN and Exo1 mutations, and mice that are unable to initiate resection or have greatly curtailed resection lengths experience catastrophic spermatogenic failure. Our results elucidate multiple functions of MRN in meiotic recombination, uncover unanticipated relationships between short- and long-range resection, and establish the importance of resection for mammalian meiosis.

C3 Selective chalcogenation and fluorination of pyridine using classic Zincke imine intermediates.

Regioselective C-H functionalization of pyridines remains a persistent challenge due to their inherent electronically deficient properties. In this report, we present a strategy for the selective pyridine C3-H thiolation, selenylation, and fluorination under mild conditions via classic N-2,4-dinitrophenyl Zincke imine intermediates. Radical inhibition and trapping experiments, as well as DFT theoretical calculations, indicated that the thiolation and selenylation proceeds through a radical addition-elimination pathway, whereas fluorination via a two-electron electrophilic substitution pathway. The pre-installed electron-deficient activating N-DNP group plays a crucial and positive role, with the additional benefit of recyclability. The practicability of this protocol was demonstrated in the gram-scale synthesis and the late-stage modification of pharmaceutically relevant pyridines.

Blocking Metallothionein-2 Expression by Copper-Doped Carbon Dots Induces Cellular Antioxidant System Collapse for Antitumor Therapy.

The insufficient antioxidant reserves in tumor cells play a critical role in reactive oxygen species (ROS)-mediated therapeutics. Metallothionein-2 (MT-2), an intracellular cysteine-rich protein renowned for its potent antioxidant properties, is intricately involved in tumor development and correlates with a poor prognosis. Consequently, MT-2 emerges as a promising target for tumor therapy. Herein, we present the development of copper-doped carbon dots (Cu-CDs) to target MT-2 to compromise the delicate antioxidant reserves in tumor cells. These Cu-CDs with high tumor accumulation and prolonged body retention can effectively suppress tumor growth by inducing oxidative stress. Transcriptome sequencing unveils a significant decrease in MT-2 expression within the in vivo tumor samples. Further mechanical investigations demonstrate that the antitumor effect of Cu-CDs is intricately linked to apolipoprotein E (ApoE)-mediated downregulation of MT-2 expression and the collapse of the antioxidant system. The robust antitumor efficacy of Cu-CDs provides invaluable insights into developing MT-2-targeted nanomedicine for cancer therapies.

Nurses' burnout and patient safety culture: The moderating effect of structural empowerment.

AIMS: To identify correlations among job burnout, structural empowerment, and patient safety culture (PSC), and to explore the potential moderating effect of structural empowerment on the associations between burnout and PSC. DESIGN: The study used a cross-sectional survey design. METHODS: Convenient sampling was employed. We conducted an anonymous online survey in January 2024 among nurses employed at hospitals in three regions of China. Job burnout, structural empowerment, and perceptions of PSC were assessed. A total of 1026 useable surveys were included in the analyses. Descriptive statistics were performed using SPSS software. A latent structural equation modeling approach using Mplus software was used to analyze the moderating effect. RESULTS: The proposed hypothetical model was supported. Job burnout had a strong direct negative effect on structural empowerment and PSC. Structural empowerment had a significant moderating effect on the relationship between job burnout and PSC. CONCLUSION: The empirically validated moderation model and study results suggest that managers of healthcare organisations can improve patient safety and care quality by fostering empowerment and providing sufficient support to clinical nurses. IMPLICATION: The findings of this study suggest that providing more support, resources, and information is likely to be effective in weakening the detrimental impact of job burnout on PSC. This study provides insights into the possible approaches that may improve patient safety. To control the impact of nurses' burnout on care quality, nurse managers should increase empowerment as well as staff nurse engagement. REPORTING METHOD: We have adhered to relevant EQUATOR guidelines and conducted an observational study, following the STROBE checklist. PUBLIC CONTRIBUTION: During the data collection phase of this study, clinical caregivers participated in completing the online survey.

Synergistic increase in coproporphyrin III biosynthesis by mitochondrial compartmentalization in engineered Saccharomyces cerevisiae.

Coproporphyrin III (CP III), a natural porphyrin derivative, has extensive applications in the biomedical and material industries. S. cerevisiae has previously been engineered to highly accumulate the CP III precursor 5-aminolevulinic acid (ALA) through the C4 pathway. In this study, a combination of cytoplasmic metabolic engineering and mitochondrial compartmentalization was used to enhance CP III production in S. cerevisiae. By integrating pathway genes into the chromosome, the CP III titer gradually increased to 32.5 ± 0.5 mg/L in shake flask cultivation. Nevertheless, increasing the copy number of pathway genes did not consistently enhance CP III synthesis. Hence, the partial synthesis pathway was compartmentalized in mitochondria to evaluate its effectiveness in increasing CP III production. Subsequently, by superimposing the mitochondrial compartmentalization strategy on cytoplasmic metabolic engineered strains, the CP III titer was increased to 64.3 ± 1.9 mg/L. Furthermore, augmenting antioxidant pathway genes to reduce reactive oxygen species (ROS) levels effectively improved the growth of engineered strains, resulting in a further increase in the CP III titer to 82.9 ± 1.4 mg/L. Fed-batch fermentations in a 5 L bioreactor achieved a titer of 402.8 ± 9.3 mg/L for CP III. This study provides a new perspective on engineered yeast for the microbial production of porphyrins.

The Application Potential of the Regulation of Tregs Function by Irisin in the Prevention and Treatment of Immune-Related Diseases.

Irisin is a muscle factor induced by exercise, generated through the proteolytic cleavage of the membrane protein fibronectin type III domain-containing protein 5 (FNDC-5). Numerous studies have shown that irisin plays a significant role in regulating glucose and lipid metabolism, inhibiting oxidative stress, reducing systemic inflammatory responses, and providing neuroprotection. Additionally, irisin can exert immunomodulatory functions by regulating regulatory T cells (Tregs). Tregs are a highly differentiated subset of mature T cells that play a key role in maintaining self-immune homeostasis and are closely related to infections, inflammation, immune-related diseases, and tumors. Irisin exerts persistent positive effects on Treg cell functions through various mechanisms, including regulating Treg cell differentiation and proliferation, improving their function, modulating the balance of immune cells, increasing the production of anti-inflammatory cytokines, and enhancing metabolic functions, thereby helping to maintain immune homeostasis and prevent immune-related diseases. As an important myokine, irisin interacts with receptors on the cell membrane, activating multiple intracellular signaling pathways to regulate cell metabolism, proliferation, and function. Although the specific receptor for irisin has not been fully identified, integrins are considered potential receptors. Irisin activates various signaling pathways, including AMPK, MAPK, and PI3K/Akt, through integrin receptors, thereby exerting multiple biological effects. These research findings provide important clues for understanding the mechanisms of irisin's action and theoretical basis for its potential applications in metabolic diseases and immunomodulation. This article reviews the relationship between irisin and Tregs, as well as the research progress of irisin in immune-related diseases such as multiple sclerosis, myasthenia gravis, acquired immune deficiency syndrome, type 1 diabetes, sepsis, and rheumatoid arthritis. Studies have revealed that irisin plays an important role in immune regulation by improving the function of Tregs, suggesting its potential application value in the treatment of immune-related diseases.

Three-dimensional finite element analysis of the biomechanical behaviour of different dental implants under immediate loading during three masticatory cycles.

The study aimed to evaluate the impact of varying modulus of elasticity (MOE) values of dental implants on the deformation and von Mises stress distribution in implant systems and peri-implant bone tissues under dynamic cyclic loading. The implant-bone interface was characterised as frictional contact, and the initial stress was induced using the interference fit method to effectively develop a finite element model for an immediately loaded implant-supported denture. Using the Ansys Workbench 2021 R2 software, an analysis was conducted to examine the deformation and von Mises stress experienced by the implant-supported dentures, peri-implant bone tissue, and implants under dynamic loading across three simulated masticatory cycles. These findings were subsequently evaluated through a comparative analysis. The suprastructures showed varying degrees of maximum deformation across zirconia (Zr), titanium (Ti), low-MOE-Ti, and polyetheretherketone (PEEK) implant systems, registering values of 103.1 µm, 125.68 µm, 169.52 µm, and 844.06 µm, respectively. The Zr implant system demonstrated the lowest values for both maximum deformation and von Mises stress (14.96 µm, 86.71 MPa) in cortical bone. As the MOE increased, the maximum deformation in cancellous bone decreased. The PEEK implant system exhibited the highest maximum von Mises stress (59.12 MPa), whereas the Ti implant system exhibited the lowest stress (22.48 MPa). Elevating the MOE resulted in reductions in both maximum deformation and maximum von Mises stress experienced by the implant. Based on this research, adjusting the MOE of the implant emerged as a viable approach to effectively modify the biomechanical characteristics of the implant system. The Zr implant system demonstrated the least maximum von Mises stress and deformation, presenting a more favourable quality for preserving the stability of the implant-bone interface under immediate loading.

Radical meta-C-H Halogenation of Azines via N-Benzyl Activation Strategy.

Regioselective halogenation of six-membered N-heteroarenes is crucial for precise functional derivatization. We present a meta-selective halogenation method for pyridines, quinolines, and isoquinolines via electrophilic halogen radical addition utilizing an N-benzyl activation strategy. This method achieves C3- and C5-dihalogenation in pyridines, C3- and C6-dihalogenation in quinolines, and C3-monohalogenation in isoquinolines. The feasibility and potential applications of this method were validated through scale-up reactions and the bromination of quinoline derivatives with biomolecular fragments.

Different depths of food restriction and high-fat diet refeeding in mice impact host obesity and metabolic phenotypes with correlative changes in the gut microbiota.

Overweight and obesity affect almost 2 billion adults worldwide, and food restriction (FR) is commonly used to reduce body fat. Whether refeeding (Re) after FR at different ages and to different degrees leads to overweight and its possible mechanisms are uncertain. In this study, adult and young mice were both restricted to 15% and 40% of their casual food intake, and then were fed 60% high-fat chow (FR15%-Re, FR40%-Re), whereas the control groups(CON) consumed high-fat or normal food throughout, respectively. The results of the study suggest that mild FR-heavy feeding may lead to more significant abnormal fat accumulation, liver damage, and increased recruitment of intestinal inflammatory factors and immune cells in mice of different ages and involves multiple types of alterations in the gut microbiota. Further fecal transplantation experiments as well as serum and liver enzyme-linked immunosorbent assay experiments preliminarily suggest that the link between lipid metabolism and inflammatory responses and the gut microbiota may be related to the regulation of the gut and live by Lipopolysaccharides(LPS) and Peroxisome Proliferator-Activated Receptor-Alpha(PPAR-α). In addition, our study may also serve as a reference for studying obesity prevention and treatment programs at different ages.

N-Vacancy Enriched Porous BN Fibers for Enhanced Polysulfides Adsorption and Conversion in High-Performance Lithium-Sulfur Batteries.

Severe shuttle effect of soluble polysulfides and sluggish redox kinetics have been thought of as the critical issues hindering the extensive applications of lithium-sulfur batteries (LSBs). Herein, one-dimensional boron nitride (1D BN) fibers with abundant pores and sufficient N-vacancy defects were synthesized using a thermal crystallization following a pre-condensation step. The 1D structure of BN facilitates unblocked ions diffusion pathways during charge/discharge cycles. The embedded pores within the polar BN strengthen the immobilization of polysulfides via both physical confinement and chemical interaction. Moreover, the highly exposed active surface area and intentionally created N-vacancy sites substantially promote reaction kinetics by lowering the energy barriers of the rate-limiting steps. After incorporating with conductive carbon networks and elemental S, the as-prepared S/Nv-BN@CBC cathode of LSBs deliver an initial discharge capacity of up to 1347 mAh g-1 at 200 mA g-1, while maintaining a low decay rate of 0.03% per cycle over 1000 cycles at 1600 mA g-1. This work offers an effective strategy to mitigate the shuttle effect and highlights the significant potential of defect-engineered BN in accelerating the reaction kinetics of LSBs.

The role of neutrophil extracellular traps in ß-methylamino L-alanine-induced liver injury in mice.

The non-protein amino acid ß-N-methylamino-L-alanine (BMAA), produced by cyanobacteria, has been recognized as a neurotoxin. L-serine as an antagonist of BMAA can effectively alleviate BMAA-induced neurotoxicity. Although BMAA has long been emphasized as a neurotoxin, with the emergence of BMAA detected in a variety of algae in freshwater around the world and its clear biological enrichment effect, it is particularly important to study the non-neurotoxic adverse effects of BMAA. However, there is only limited evidence to support the ability of BMAA to cause oxidative damage in the liver. The exact molecular mechanism of BMAA-induced liver injury is still unclear. The formation of neutrophil extracellular traps (NETs) is a 'double-edged sword' for the organism, excessive formation of NETs is associated with inflammatory diseases of the liver. Our results innovatively confirmed that BMAA was able to cause the formation of NETs in the liver during the liver injury. The possible mechanism may associated with the regulation of ERK/p38 and cGAS/STING signaling pathways. The massive formation of NETs was able to exacerbate the BMAA-induced oxidative stress and release of inflammatory factors in the mice liver. And the removal of NETs could alleviate this injury. This article will bring a new laboratory evidence for BMAA-induced non-neurotoxicity and immunotoxicity.

Suppression of GATA3 promotes epithelial-mesenchymal transition and simultaneous cellular senescence in human extravillous trophoblasts.

The regulatory mechanism of the transcription factor GATA3 in the differentiation and maturation process of extravillous trophoblasts (EVT) in early pregnancy placenta, as well as its relevance to the occurrence of pregnancy disorders, remains poorly understood. This study leveraged single-cell RNA sequencing data from placental organoid models and placental tissue to explore the dynamic changes in GATA3 expression during EVT maturation. The expression pattern exhibited an initial upregulation followed by subsequent downregulation, with aberrant GATA3 localization observed in cases of recurrent miscarriage (RM). By identifying global targets regulated by GATA3 in primary placental EVT cells, JEG3, and HTR8/SVneo cell lines, this study offered insights into its regulatory mechanisms across different EVT cell models. Shared regulatory targets among these cell types and activation of trophoblast cell marker genes emphasized the importance of GATA3 in EVT differentiation and maturation. Knockdown of GATA3 in JEG3 cells led to repression of GATA3-induced epithelial-mesenchymal transition (EMT), as evidenced by changes in marker gene expression levels and enhanced migration ability. Additionally, interference with GATA3 accelerated cellular senescence, as indicated by reduced proliferation rates and increased activity levels for senescence-associated ß-galactosidase enzyme, along with elevated expression levels for senescence-associated genes. This study provides comprehensive insights into the dual role of GATA3 in regulating EMT and cellular senescence during EVT differentiation, shedding light on the dynamic changes in GATA3 expression in normal and pathological placental conditions.

Exercise therapy in postoperative patients with temporomandibular joint internal derangement: A systematic review.

OBJECTIVE: Postoperative patients with temporomandibular joint internal derangement (ID) often have problems such as limited mouth opening and pain. Exercise therapy can be advantageous for improving the recovery of patients following surgery. However, there is continuing discussion on the precise aspects of the exercise program, including the optimal timing, length, intensity, and use of assistive equipment. Hence, this study aimed to incorporate pre-existing exercise treatment regimens and investigate their impact. METHODS: Publications that detailed the clinical treatment of patients with temporomandibular joint ID who received postoperative exercise therapy interventions were included. Nine databases were searched until October 1st, 2023. The JBI critical appraisal tools were used to assess the methodological quality of the included studies. RESULTS: Five studies were finally included for subsequent analysis; two were randomised controlled studies, and three were quasi-experimental. Exercises suitable for such patients encompass vertical, transverse, and horizontal stretching, among which vertical stretch can be divided into active and passive movements. The start time ranged from the first to the fifth week after surgery, with a duration of 1-6 months. Although the data in the studies could not be integrated and further analysed, preliminary results showed that maximum mouth opening and pain in patients improved significantly. The therapeutic effect of combining three exercise methods was best and was related to patient compliance. CONCLUSION: Exercise therapy positively affects postoperative rehabilitation in patients with temporomandibular joint ID. It is proposed that targeted, comprehensive studies be conducted to provide a basis for designing more sophisticated exercise therapy regimens and further confirm its curative effect.

Enhancing the Thermostability and Catalytic Activity of the Lipase from Rhizopus oryzae via Introducing N-Glycosylation.

Lipase from Rhizopus oryzae (ROL) exhibits remarkable sn-1,3 stereoselectivity and catalytic activity, but its poor thermostability limits its applications in the production of 1,3-dioleoyl-2-palmitoyl glycerol (OPO, a high-quality substitute for human milk fat). In this work, a semirational method was proposed to engineer the thermostability and catalytic activity of 4M (ROL mutant in our previous study). First, a computer-aided design is performed using 4M as a template, and N-glycosylation mutants are then recombinantly expressed and screened in Pichia pastoris, the optimal mutant N227 exhibited a half-life of 298.8 h at 45 °C, which is 7.23-folds longer than that of 4M. Its catalytic activity also reached 1043.80 ± 61.98 U/mg, representing a 29.2% increase compared to 4M (808.02 ± 47.02 U/mg). Molecular dynamics simulations of N227 suggested that the introduction of glycan enhanced the protein rigidity, while the strong hydrogen bonds formed between the glycan and the protein stabilized the lipase structure, thereby improving its thermostability. The acidolysis reaction between oleic acid (OA) and glycerol tripalmitate (PPP) was successfully carried out using immobilized N227, achieving a molar conversion rate of 90.2% for PPP. This engineering strategy guides the modification of lipases, while the glycomutants obtained in this study have potential applications in the biosynthesis of OPO.