Effective dosage and mode of exercise for enhancing cognitive function in Alzheimer's disease and dementia: a systematic review and Bayesian Model-Based Network Meta-analysis of RCTs.

OBJECTIVE: Research the dose-response relationship between overall and certain types of exercise and cognitive function in older adults with Alzheimer's disease and dementia. DESIGN: Systemic and Bayesian Model-Based Network Meta-Analysis. METHODS: In our study, we analyzed data from randomized controlled trials investigating the effects of different exercises on cognitive outcomes in older adults with AD. We searched the Web of Science, PubMed, Cochrane Central Register of Controlled Trials, and Embase up to November 2023. Using the Cochrane Risk of Bias tool (Rob2) for quality assessment and R software with the MBNMA package for data analysis, we determined standard mean differences (SMDs) and 95% confidence intervals (95%CrI) to evaluate exercise's impact on cognitive function in AD. RESULTS: Twenty-seven studies with 2,242 AD patients revealed a nonlinear relationship between exercise and cognitive improvement in AD patients. We observed significant cognitive enhancements at an effective exercise dose of up to 1000 METs-min/week (SMDs: 0.535, SD: 0.269, 95% CrI: 0.023 to 1.092). The optimal dose was found to be 650 METs-min/week (SMDs: 0.691, SD: 0.169, 95% CrI: 0.373 to 1.039), with AE (Aerobic exercise) being particularly effective. For AE, the optimal cognitive enhancement dose was determined to be 660 METs-min/week (SMDs: 0.909, SD: 0.219, 95% CrI: 0.495 to 1.362). CONCLUSION: Nonlinear dose-response relationship between exercise and cognitive improvement in Alzheimer's disease, with the optimal AE dose identified at 660 METs-min/week for enhancing cognitive function in AD.

Comparative analysis of two-hour creatinine clearance and the C-G formula for renal function assessment in critically ill patients.

Objective and rationale: To investigate if the 2-h creatinine clearance (Ccr2) provides a more precise and timely assessment of renal function in critically ill patients compared to the Cockcroft-Gault formula (CrC-G). Materials and methods: This cohort study incorporated 74 patients who were hospitalized for more than 48 h in the Intensive Care Unit over 6 months. A 24-h urine collection protocol was observed, and concurrently, 316 2-h urine specimens were obtained. Then calculated and analyzed the correlation and consistency between Ccr2, CrC-G, and 24-h creatinine clearance (Ccr24) values. The rates of change in Ccr2(ΔCcr2) and CrC-G(ΔCrC-G) were compared over two consecutive samples. Results: The R-values of Ccr2 and Ccr24 in the early, middle and late 24 h were 0.640, 0.886 and 0.854 (P < 0.001), with biases of -2.1, 1.7, and 6.3 ml/min/1.73 m2, respectively. Meanwhile, the R-values for CrC-G and Ccr24 at these time points were 0.618, 0.822, and 0.828(P < 0.001), with biases of -14.0, -5.2, and -1.8 ml/min/1.73 m2, respectively. For patients with Ccr24≥60 ml/min/1.73 m2, the R-value of Ccr2 and Ccr24 during the middle 2 h was 0.852(P < 0.001), while the R-values for CrC-G and Ccr24 were 0.763(P < 0.001), with biases of -2.3 ml/min/1.73 m2 and -14.2 ml/min/1.73 m2 respectively. For the group with Ccr24 ≥ 120 ml/min/1.73 m2 (n = 72), both Ccr2 and Ccr24 displayed a statistically significant elevation compared to CrC-G (P < 0.001), yet no significant difference was observed between Ccr2 and Ccr24 (P = 0.289). Out of 50 patients, 46(92 %) experienced a ΔCcr2≥20 % at least once, compared to 20(40 %) with a ΔCrC-G≥20 %(P < 0.001). 25(50 %) with a ΔCcr2≥50 %, compared to 3(6 %) with a ΔCrC-G≥50 %(P < 0.001). Conclusion: Ccr2 demonstrates a more accurate and more timely indicator of renal function in critically ill patients than CrC-G.

Tunneling Proton Grotthuss Transfer Channels by Hydrophilic-Zincophobic Heterointerface Shielding for High-Performance Zn-MnO2 Batteries.

Hollandite-type manganese dioxide (α-MnO2) is recognized as a promising cathode material upon high-performance aqueous zinc-ion batteries (ZIBs) owing to the high theoretical capacities, high working potentials, unique Zn2+/H+ co-insertion chemistry, and environmental friendliness. However, its practical applications limited by Zn2+ accommodation, where the strong coulombic interaction and sluggish kinetics cause significant lattice deformation, fast capacity degradation, insufficient rate capability, and undesired interface degradation. It remains challenging to accurately modulate H+ intercalation while suppressing Zn2+ insertion for better lattice stability and electrochemical kinetics. Herein, proton Grotthuss transfer channels are first tunneled by shielding MnO2 with hydrophilic-zincophobic heterointerface, fulfilling the H+-dominating diffusion with the state-of-the-art ZIBs performance. Local atomic structure and theoretical simulation confirm that surface-engineered α-MnO2 affords to the synergy of Mn electron t2g-eg activation, oxygen vacancy enrichment, selective H+ Grotthuss transfer, and accelerated desolvation kinetics. Consequently, fortified α-MnO2 achieves prominent low current density cycle stability (≈100% capacity retention at 1 C after 400 cycles), remarkable long-lifespan cycling performance (98% capacity retention at 20 C after 12 000 cycles), and ultrafast rate performance (up to 30 C). The study exemplifies a new approach of heterointerface engineering for regulation of H+-dominating Grotthuss transfer and lattice stabilization in α-MnO2 toward reliable ZIBs.

Synthesis of Azo-Substituted Bicyclo[1.1.1]pentanes (BCPs) via Base-Promoted Halogen Atom Transfer.

Because of the three-dimensional bioisosteric feature, bicyclo[1.1.1]pentylamines (BCPAs) are valuable scaffolds in synthetic chemistry and medicinal chemistry. Here, we report a Halogen Atom Transfer (XAT) mediated radical C-N coupling between C3-iodo-BCPs and diazonium salts in the presence of base. Similarly, a multicomponent reaction (MCR) enables the simultaneous construction of the C-C bond and C-N bond simultaneously. Versatile roles of diazonium salts were also explored.

Causative role of a novel intronic indel variant in FBN1 and maternal germinal mosaicism in Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is an autosomal dominant connective tissue disease with wide clinical heterogeneity, and mainly caused by pathogenic variants in fibrillin-1 (FBN1). METHODS: A Chinese 4-generation MFS pedigree with 16 family members was recruited and exome sequencing (ES) was performed in the proband. Transcript analysis (patient RNA and minigene assays) and in silico structural analysis were used to determine the pathogenicity of the variant. In addition, germline mosaicism in family member (Ι:1) was assessed using quantitative fluorescent polymerase chain reaction (QF-PCR) and short tandem repeat PCR (STR) analyses. RESULTS: Two cis-compound benign intronic variants of FBN1 (c.3464-4 A > G and c.3464-5G > A) were identified in the proband by ES. As a compound variant, c.3464-5_3464-4delGAinsAG was found to be pathogenic and co-segregated with MFS. RNA studies indicated that aberrant transcripts were found only in patients and mutant-type clones. The variant c.3464-5_3464-4delGAinsAG caused erroneous integration of a 3 bp sequence into intron 28 and resulted in the insertion of one amino acid in the protein sequence (p.Ile1154_Asp1155insAla). Structural analyses suggested that p.Ile1154_Asp1155insAla affected the protein's secondary structure by interfering with one disulfide bond between Cys1140 and Cys1153 and causing the extension of an anti-parallel ß sheet in the calcium-binding epidermal growth factor-like (cbEGF)13 domain. In addition, the asymptomatic family member Ι:1 was deduced to be a gonadal mosaic as assessed by inconsistent results of sequencing and STR analysis. CONCLUSIONS: To our knowledge, FBN1 c.3464-5_3464-4delGAinsAG is the first identified pathogenic intronic indel variant affecting non-canonical splice sites in this gene. Our study reinforces the importance of assessing the pathogenic role of intronic variants at the mRNA level, with structural analysis, and the occurrence of mosaicism.

Understanding the multi-functionality and tissue-specificity of decellularized dental pulp matrix hydrogels for endodontic regeneration.

Dental pulp is the only soft tissue in the tooth which plays a crucial role in maintaining intrinsic multi-functional behaviors of the dentin-pulp complex. Nevertheless, the restoration of fully functional pulps after pulpitis or pulp necrosis, termed endodontic regeneration, remained a major challenge for decades. Therefore, a bioactive and in-situ injectable biomaterial is highly desired for tissue-engineered pulp regeneration. Herein, a decellularized matrix hydrogel derived from porcine dental pulps (pDDPM-G) was prepared and characterized through systematic comparison against the porcine decellularized nerve matrix hydrogel (pDNM-G). The pDDPM-G not only exhibited superior capabilities in facilitating multi-directional differentiation of dental pulp stem cells (DPSCs) during 3D culture, but also promoted regeneration of pulp-like tissues after DPSCs encapsulation and transplantation. Further comparative proteomic and transcriptome analyses revealed the differential compositions and potential mechanisms that endow the pDDPM-G with highly tissue-specific properties. Finally, it was realized that the abundant tenascin C (TNC) in pDDPM served as key factor responsible for the activation of Notch signaling cascades and promoted DPSCs odontoblastic differentiation. Overall, it is believed that pDDPM-G is a sort of multi-functional and tissue-specific hydrogel-based material that holds great promise in endodontic regeneration and clinical translation. STATEMENT OF SIGNIFICANCE: Functional hydrogel-based biomaterials are highly desirable for endodontic regeneration treatments. Decellularized extracellular matrix (dECM) preserves most extracellular matrix components of its native tissue, exhibiting unique advantages in promoting tissue regeneration and functional restoration. In this study, we prepared a porcine dental pulp-derived dECM hydrogel (pDDPM-G), which exhibited superior performance in promoting odontogenesis, angiogenesis, and neurogenesis of the regenerating pulp-like tissue, further showed its tissue-specificity compared to the peripheral nerve-derived dECM hydrogel. In-depth proteomic and transcriptomic analyses revealed that the activation of tenascin C-Notch axis played an important role in facilitating odontogenic regeneration. This biomaterial-based study validated the great potential of the dental pulp-specific pDDPM-G for clinical applications, and provides a springboard for research strategies in ECM-related regenerative medicine.

Protective Interphases of Advanced Znic Anodes: Structure, Mechanisms, Fabrication Strategies and Characterization Techniques.

Aqueous zinc ion batteries (AZIBs) with metallic Zn anode have the potential for large-scale energy storage application due to their cost-effectiveness, safety, environmental-friendliness, and ease of preparation. However, the concerns regarding dendrite growth and side reactions on Zn anode surface hamper AZIB's commercialization. This review aims to give a comprehensive evaluation of the protective interphase construction and provide guildance to further improve the electrochemical performance of AZIBs. The failure behaviors of Zn metal anode including dendrite growth, corrosion, and hydrogen evolution are analyzed. Then, the applications and mechanisms of the constructed interphases are introduced, classified by the material species. The fabrication methods of the artificial interfaces are summarized and evaluated, including the in-situ strategy and ex-situ strategy. Finally, the characterization means of the interphases are discussed to give a full view for the study of Zn anode protection. Based on the analysis of this review, a stable and high-performance Zn anode could be designed by carefully choosing applied material, corresponding protective mechanism, and appropriate construction technique. Additionally, this review for Zn anode modification and construction techniques for anode protection in AZIBs may be helpful in other aqueous metal batteries with similar problems.

Coastal ecological security assessment in Laizhou Bay, China: from the perspective of demographic-social-economic-natural complex ecosystem.

Assessment of ecological security is essential for understanding the status of bay ecosystem and developing appropriate management strategy. Based on the driving force-pressure-state-impact-response (DPSIR) model, the demographic, economic, social, and ecological data of Laizhou Bay and its three neighboring counties were selected for the period from 2015 to 2021. An ecological security evaluation index system of Laizhou Bay containing 26 indicators was established, and the weights of each indicator were determined by the methods of AHP and EWM, and a comprehensive evaluation of the ecological security of Laizhou Bay was carried out by ESI. Correlations between indicators were analyzed by the Spearman's rank coefficient of correlation. The results showed that there were significant correlations between marine conditions and indicators such as population size in the surrounding area, mariculture area, industrial and domestic wastewater discharge, and treatment rate. Overall, from 2015 to 2021, the ecological security of Laizhou Bay showed a favorable trend, from a relatively unsafe level to a generally safe level, and then to a relatively safe level. Through the comprehensive evaluation of the ecological security of Laizhou Bay, we can recognize the utilization of marine resources and ecological carrying capacity, guide the rational development and utilization of marine resources, and promote the sustainable development of the marine economy.

Cardioprotective effects of curcumin against Diabetic Cardiomyopathies: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: As a common complication of diabetes, diabetic cardiomyopathy (DCM) often leads to further damage to the heart muscle. Curcumin has been proven to have a variety of cardioprotective effects, however, the protective effect against DCM has not been systematically reviewed. PURPOSE: In this study, we aimed to analyze the preclinical (animal model) evidence of curcumin's therapeutic effects in DCM. METHODS: Eight databases and two registry systems were searched from the time of library construction to 1 November 2023. We performed rigorous data extraction and quality assessment. The included studies' methodological quality was appraised using the SYRCLE RoB tool, statistical analyses were carried out using RevMan 5.4 software, and Funnel plots and Egger's test were performed using Stata 17.0 software to assess publication bias. RESULTS: This study included 32 trials with a total of 681 animals. Meta-analysis showed that curcumin significantly improved cardiac function indices (LVEF, LVFS, and LVSd) (p < 0.01), decreased markers of myocardial injury, HW/BW ratio, and randomized blood glucose compared to the control group, in addition to showing beneficial effects on mechanistic indices of myocardial oxidation, inflammation, apoptosis, and autophagy (p < 0.05). CONCLUSIONS: Curcumin may exert cardioprotective effects in DCM through its antioxidant, anti-inflammatory, autophagy-enhancing, and anti-apoptotic effects. Its protective effect is proportional to the dose, and the efficacy may be further increased at a concentration of more than 200 mg/kg, and further validation is needed.

Sustained delivery of NT-3 and curcumin augments microenvironment modulation effects of decellularized spinal cord matrix hydrogel for spinal cord injury repair.

Decellularized extracellular matrix hydrogel, especially that derived from spinal cord (DSCM hydrogel), has been actively considered as a functional biomaterial for remodeling the extracellular matrix of the native tissue, due to its unique characteristics in constructing pro-regenerative microenvironment for neural stem cells (NSCs). Furthermore, DSCM hydrogel can provide multiple binding domains to growth factors and drugs. Therefore, both exogenous neurotrophic factors and anti-inflammatory drugs are highly desired to be incorporated into DSCM hydrogel, which may synergistically modulate the complex microenvironment at the lesion site after spinal cord injury (SCI). Herein, neurotrophin-3 (NT-3) and curcumin (Cur) were integrated into DSCM hydrogel for SCI therapy. Due to different affinities to the DSCM hydrogel, NT-3 underwent a controlled release manner, while curcumin released explosively within the first 24 h, followed by rather sustained but slower release. The integration of both NT-3 and curcumin significantly enhanced NSCs proliferation and their neuronal differentiation. Meanwhile, the release of curcumin promoted macrophages polarization into anti-inflammatory subtypes, which further facilitated NSCs differentiation into neurons. The in situ injected DSCM + NT3 + Cur hydrogel exerted superior capability in alleviating the inflammatory responses in rat contused spinal cord. Compared to DSCM hydrogel alone, DSCM + NT3 + Cur hydrogel more significantly promoted the recruitment of NSCs and their neuronal differentiation at the lesion site. These outcomes favored functional recovery, as evidenced by the improved hind limb movement. Overall, the bioactive DSCM hydrogel can serve as a multifunctional carrier for cooperatively release of growth factors and drugs, which significantly benefits microenvironment regulation and nerve regeneration after SCI.

Siloxane-containing phosphine (oxide) ligands for enhanced catalytic activity of cobalt complexes for hydrosilylation reactions.

A series of siloxane-containing phosphine (oxide) ligands have been designed and synthesized. These phosphine (oxide) ligands contain silicon atoms, which can impart better solubility in the relevant media, thereby improving certain catalytic performances. The hydrosilylation of olefins catalyzed by these metal phosphine (oxide) complexes has been conducted under mild reaction conditions.

Engagement of N6-methyladenisine methylation of Gng4 mRNA in astrocyte dysfunction regulated by CircHECW2.

The N6-methyladenosine (m6A) modification is the most prevalent modification of eukaryotic mRNAs and plays a crucial role in various physiological processes by regulating the stability or function of target mRNAs. Accumulating evidence has suggested that m6A methylation may be involved in the pathological process of major depressive disorder (MDD), a common neuropsychiatric disorder with an unclear aetiology. Here, we found that the levels of the circular RNA HECW2 (circHECW2) were significantly increased in the plasma of both MDD patients and the chronic unpredictable stress (CUS) mouse model. Notably, the downregulation of circHECW2 attenuated astrocyte dysfunction and depression-like behaviors induced by CUS. Furthermore, we demonstrated that the downregulation of circHECW2 increased the expression of the methylase WTAP, leading to an increase in Gng4 expression via m6A modifications. Our findings provide functional insight into the correlation between circHECW2 and m6A methylation, suggesting that circHECW2 may represent a potential target for MDD treatment.

CDC45 promotes the stemness and metastasis in lung adenocarcinoma by affecting the cell cycle.

OBJECTIVE: This study aimed to assess the functions of cell division cycle protein 45 (CDC45) in Non-small cell lung cancer (NSCLC) cancer and its effects on stemness and metastasis. METHODS: Firstly, differentially expressed genes related to lung cancer metastasis and stemness were screened by differential analysis and lasso regression. Then, in vitro, experiments such as colony formation assay, scratch assay, and transwell assay were conducted to evaluate the impact of CDC45 knockdown on the proliferation and migration abilities of lung cancer cells. Western blotting was used to measure the expression levels of related proteins and investigate the regulation of CDC45 on the cell cycle. Finally, in vivo model with subcutaneous injection of lung cancer cells was performed to verify the effect of CDC45 on tumor growth. RESULTS: This study identified CDC45 as a key gene potentially influencing tumor stemness and lymph node metastasis. Knockdown of CDC45 not only suppressed the proliferation and migration abilities of lung cancer cells but also caused cell cycle arrest at the G2/M phase. Further analysis revealed a negative correlation between CDC45 and cell cycle-related proteins, stemness-related markers, and tumor mutations. Mouse experiments confirmed that CDC45 knockdown inhibited tumor growth. CONCLUSION: As a novel regulator of stemness, CDC45 plays a role in regulating lung cancer cell proliferation, migration, and cell cycle. Therefore, CDC45 may serve as a potential target for lung cancer treatment and provide a reference for further mechanistic research and therapeutic development.

Challenges and Breakthroughs in Enhancing Temperature Tolerance of Sodium-Ion Batteries.

Lithium-based batteries (LBBs) have been highly researched and recognized as a mature electrochemical energy storage (EES) system in recent years. However, their stability and effectiveness are primarily confined to room temperature conditions. At temperatures significantly below 0 °C or above 60 °C, LBBs experience substantial performance degradation. Under such challenging extreme contexts, sodium-ion batteries (SIBs) emerge as a promising complementary technology, distinguished by their fast dynamics at low-temperature regions and superior safety under elevated temperatures. Notably, developing SIBs suitable for wide-temperature usage still presents significant challenges, particularly for specific applications such as electric vehicles, renewable energy storage, and deep-space/polar explorations, which requires a thorough understanding of how SIBs perform under different temperature conditions. By reviewing the development of wide-temperature SIBs, the influence of temperature on the parameters related to battery performance, such as reaction constant, charge transfer resistance, etc., is systematically and comprehensively analyzed. The review emphasizes challenges encountered by SIBs in both low and high temperatures while exploring recent advancements in SIB materials, specifically focusing on strategies to enhance battery performance across diverse temperature ranges. Overall, insights gained from these studies will drive the development of SIBs that can handle the challenges posed by diverse and harsh climates.

S100P facilitates LUAD progression via PKA/c-Jun-mediated tumor-associated macrophage recruitment and polarization.

S100P, a member of the S100 calcium-binding protein family, is closely associated with abnormal proliferation, invasion, and metastasis of various cancers. However, its role in the lung adenocarcinoma (LUAD) tumor microenvironment (TME) remains unclear. In this study, we observed specific expression of S100P on tumor cells in LUAD patients through tissue immunofluorescence analysis. Furthermore, this expression was strongly correlated with the recruitment and polarization of tumor-associated macrophages (TAMs). Bioinformatics analysis revealed that high S100P expression is associated with poorer overall survival in LUAD patients. Subsequently, a subcutaneous mouse model demonstrated that S100P promotes recruitment and polarization of TAMs towards the M2 type. Finally, in vitro studies on LUAD cells revealed that S100P enhances the secretion of chemokines and polarizing factors by activating the PKA/c-Jun pathway, which is implicated in TAM recruitment and polarization towards the M2 phenotype. Moreover, inhibition of c-Jun expression impedes the ability of TAMs to infiltrate and polarize towards the M2 phenotype. In conclusion, our study demonstrates that S100P facilitates LUAD cells growth by recruiting M2 TAMs through PKA/c-Jun signaling, resulting in the production of various cytokines. Considering these findings, S100P holds promise as an important diagnostic marker and potential therapeutic target for LUAD.

Ultra-High Temperature Operated Ni-Rich Cathode Stabilized by Thermal Barrier for High-Energy Lithium-Ion Batteries.

The pursuit of high energy density batteries has expedited the fast development of Ni-rich cathodes. However, the chemo-mechanical degradation induced by local thermal accumulation and anisotropic lattice strain is posing great obstacles for its wide applications. Herein, a highly-antioxidative BaZrO3 thermal barrier engineered LiNi0.8 Co0.1 Mn0.1 O2 cathode through an in situ construction strategy is first reported to circumvent the above issues. It is found that the Zr ions are incorporated to Ni-rich material lattice and influence on the topotactic lithiation as well as enhance the oxygen electronegativity through the rigid Zr─O bonds, which effectively alleviates the lattice strain propagation and decreases the excessive oxidization of lattice oxygen for charge compensation. More importantly, the BaZrO3 thermal barrier with an ultra-low thermal conductivity validly impedes the fast heat exchange between electrode and electrolyte to mitigate the severe surface side reactions. This helps an ultra-high mass loading Li-ion pouch cell deliver a specific energy density of 690 Wh kg-1 at active material level and an excellent capacity retention of 92.5% after 1400 cycles under 1 C at 25 °C. Tested at a high temperature of 55 °C, the pouch type full-cell also exhibits 88.7% in capacity retention after 1200 cycles.

Development of High-Performance Iron-Based Phosphate Cathodes toward Practical Na-Ion Batteries.

Iron-based phosphate cathode of Na4Fe3(PO4)2(P2O7) has been regarded as a low-cost and structurally stable cathode material for Na-ion batteries (NIBs). However, their practical application is greatly hindered by the insufficient electrochemical performance and limited energy density. Here, we report a new iron-based phosphate cathode of Na4.5Fe3.5(PO4)2.5(P2O7) with the intergrown heterostructure of the maricite-type NaFePO4 and orthorhombic Na4Fe3(PO4)2(P2O7) phases at a mole ratio of 0.5:1. Benefited from the increased composition ratio and the spontaneous activation of the maricite-type NaFePO4 phase, the as-prepared Na4.5Fe3.5(PO4)2.5(P2O7) composites deliver a reversible capacity over 130 mA h g-1 and energy density close to 400 W h kg-1, which is far beyond that of the single-phase Na4Fe3(PO4)2(P2O7) cathode (∼120 mA h g-1 and ∼350 W h kg-1). Moreover, the kg-level products from the scale-up synthesis demonstrate a stable cycling performance over 2000 times at 3 C in pouch cells. We believe that our findings could show the way forward the practical application of the iron-based phosphate cathodes for NIBs.

AQP4-DARPin1: A Chimeric Antigen Based on Scaffold Protein DARPin for Efficient Detection of AQP4-IgG in NMOSD.

AQP4-IgG is an autoantibody associated with neuromyelitis optica spectroscopic disorder (NMOSD), a central nervous system inflammatory disease that requires early diagnosis and treatment. We designed two fusion proteins, AQP4-DARPin1 and AQP4-DARPin2, comprising the complete antigenic epitopes of aquaporin-4 (AQP4) and the constant region of the scaffold protein DARPin. These fusion proteins were expressed and purified from Escherichia coli and coated on microplates to develop an efficient method for detecting AQP4-IgG. Molecular dynamics simulation revealed that the fusion of AQP4 extracellular epitopes with DARPin did not alter the main structure of DARPin. The purified AQP4-DARPins bound recombinant antibody rAb-53 (AQP4-IgG) with affinities of 135 and 285 nM, respectively. Enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation demonstrated that AQP4-DARPin1 specifically recognized AQP4-IgG in the NMOSD patient serum. AQP4-DARPin1 as a coated antigen showed higher ELISA signal and end point dilution ratio than full-length AQP4. Our AQP4-DARPin1-coated AQP4-IgG ELISA had 100% specificity and 90% sensitivity. These results indicate that AQP4-DARPin1, compared to existing detection strategies that use full-length or extracellular loop peptides of AQP4, provides a new and more effective approach to the ELISA detection of NMOSD.

GPX8+ cancer-associated fibroblast, as a cancer-promoting factor in lung adenocarcinoma, is related to the immunosuppressive microenvironment.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment of lung adenocarcinoma (LUAD) and are often associated with poorer clinical outcomes. This study aimed to screen for CAF-specific genes that could serve as promising therapeutic targets for LUAD. METHODS: We established a single-cell transcriptional profile of LUAD, focusing on genetic changes in fibroblasts. Next, we identified key genes associated with fibroblasts through weighted gene co-expression network analysis (WGCNA) and univariate Cox analysis. Then, we evaluated the relationship between glutathione peroxidase 8 (GPX8) and clinical features in multiple independent LUAD cohorts. Furthermore, we analyzed immune infiltration to shed light on the relationship between GPX8 immune microenvironment remodeling. For clinical treatment, we used the tumor immune dysfunction and exclusion (TIDE) algorithm to assess the immunotherapy prediction efficiency of GPX8. After that, we screened potential therapeutic drugs for LUAD by the connectivity map (cMAP). Finally, we conducted a cell trajectory analysis of GPX8+ CAFs to show their unique function. RESULTS: Fibroblasts were found to be enriched in tumor tissues. Then we identified GPX8 as a key gene associated with CAFs through comprehensive bioinformatics analysis. Further analysis across multiple LUAD cohorts demonstrated the relationship between GPX8 and poor prognosis. Additionally, we found that GPX8 played a role in inducing the formation of an immunosuppressive microenvironment. The TIDE method indicated that patients with low GPX8 expression were more likely to be responsive to immunotherapy. Using the cMAP, we identified beta-CCP as a potential drug-related to GPX8. Finally, cell trajectory analysis provided insights into the dynamic process of GPX8+ CAFs formation. CONCLUSIONS: This study elucidates the association between GPX8+ CAFs and poor prognosis, as well as the induction of immunosuppressive formation in LUAD. These findings suggest that targeting GPX8+ CAFs could potentially serve as a therapeutic strategy for the treatment of LUAD.