Nanoporous amorphous carbon nanopillars with lightweight, ultrahigh strength, large fracture strain, and high damping capability.

Simultaneous achievement of lightweight, ultrahigh strength, large fracture strain, and high damping capability is challenging because some of these mechanical properties are mutually exclusive. Here, we utilize self-assembled polymeric carbon precursor materials in combination with scalable nano-imprinting lithography to produce nanoporous carbon nanopillars. Remarkably, nanoporosity induced via sacrificial template significantly reduces the mass density of amorphous carbon to 0.66 ~ 0.82 g cm-3 while the yield and fracture strengths of nanoporous carbon nanopillars are higher than those of most engineering materials with the similar mass density. Moreover, these nanopillars display both elastic and plastic behavior with large fracture strain. A reversible part of the sp2-to-sp3 transition produces large elastic strain and a high loss factor (up to 0.033) comparable to Ni-Ti shape memory alloys. The irreversible part of the sp2-to-sp3 transition enables plastic deformation, leading to a large fracture strain of up to 35%. These findings are substantiated using simulation studies. None of the existing structural materials exhibit a comparable combination of mass density, strength, deformability, and damping capability. Hence, the results of this study illustrate the potential of both dense and nanoporous amorphous carbon materials as superior structural nanomaterials.

Fetal weight growth trajectories and childhood development: A population-based cohort study.

This study aimed to investigate whether fetal growth trajectories (FGTs) could predict early childhood development, indicate intrauterine metabolic changes, and explore potential optimal and suboptimal FGTs. FGTs were developed by using an unsupervised machine-learning approach. Children's neurodevelopment, anthropometry, and respiratory outcomes in the first 6 years of life were assessed at different ages. In a subgroup of participants, we conducted a metabolomics analysis of cord blood to reveal the metabolic features of FGTs. We identified 6 FGTs: early decelerating, early decelerating with late catch-up growth, early accelerating, early accelerating with late medium growth, late decelerating, and late accelerating. The early accelerating with late medium growth pattern might be the optimal FGT due to its associations with better psychomotor development, mental development, intelligence quotient, and lung function and a lower risk of behaviour and respiratory problems. Compared with the optimal FGT, early decelerating and late decelerating FGTs were associated with poor neurodevelopment and lung function, while early accelerating FGT was associated with more severe autistic symptoms, poor lung function, and increased risks of overweight/obesity. Metabolic alterations were enriched in amino acid metabolism for early decelerating and late decelerating FGTs, whereas altered metabolites were enriched in lipid metabolism for early accelerating FGT. These findings suggest that FGTs are predictors of early life development and may indicate intrauterine adaptive metabolism. The discovery of optimal and suboptimal FGTs provides potential clues for the early identification and intervention of fetal origin dysplasia or disease, but further research on related mechanisms is still needed.

Risk factors and prediction model for osteonecrosis of the femoral head in female systemic lupus erythematosus.

Background: Osteonecrosis of the femoral head (ONFH) is a severe complication of systemic lupus erythematosus (SLE) and occurs more frequently in SLE patients than in other autoimmune diseases, which can influence patients' life quality. The objective of this research was to analyze risk factors for the occurrence of ONFH in female SLE patients, construct and validate a risk nomogram model. Methods: Clinical records of SLE patients who fulfilled the 1997 American College of Rheumatology SLE classification criteria were retrospectively analyzed. The Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis were used to summarize the independent risk factors of ONFH in female SLE patients, which were used to develop a nomogram. The predictive performance of the nomogram was assessed using the receiver characteristic (ROC) curve, calibration curves and decision curve analysis (DCA). Results: 793 female SLE patients were ultimately included in this study, of which 87 patients (10.9%) developed ONFH. Ten independent risk factors including disease duration, respiratory involvement, menstrual abnormalities, Sjögren's syndrome, osteoporosis, anti-RNP, mycophenolate mofetil, cyclophosphamide, biologics, and the largest daily glucocorticoid (GC) were identified to construct the nomogram. The area under the ROC curve of the nomogram model was 0.826 (95% CI: 0.780-0.872) and its calibration for forecasting the occurrence of ONFH was good (χ2 = 5.589, P = 0.693). DCA showed that the use of nomogram prediction model had certain application in clinical practice when the threshold was 0.05 to 0.95. In subgroup analysis, we found that the risk of ONFH was significantly increased in age at SLE onset of ≤ 50 years old, largest daily GC dose of ≥50 mg and the therapy of GC combined with immunosuppressant patients with menstrual abnormalities. Conclusion: Menstrual abnormalities were the first time reported for the risk factors of ONFH in female SLE patients, which remind that clinicians should pay more attention on female SLE patients with menstrual abnormalities and take early interventions to prevent or slow the progression of ONFH. Besides, the nomogram prediction model could provide an insightful and applicable tool for physicians to predict the risk of ONFH.

ER-associated degradation ligase HRD1 links ER stress to DNA damage repair by modulating the activity of DNA-PKcs.

Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) and DNA damage repair signaling pathways, with both pathways essential for carcinogenesis and drug resistance. How these signaling pathways coordinate with each other remains unexplored. We found that ER stress specifically induces the DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend DNA damage and impede cell death. Intriguingly, sustained ER stress rapidly decreased the activity of DNA-PKcs and DNA damage accumulated, facilitating a switch from adaptation to cell death. This DNA-PKcs inactivation was caused by increased KU70/KU80 protein degradation. Unexpectedly, the ERAD ligase HRD1 was found to efficiently destabilize the classic nuclear protein HDAC1 in the cytoplasm, by catalyzing HDAC1's polyubiquitination at lysine 74, at a late stage of ER stress. By abolishing HDAC1-mediated KU70/KU80 deacetylation, HRD1 transmits ER signals to the nucleus. The resulting enhanced KU70/KU80 acetylation provides binding sites for the nuclear E3 ligase TRIM25, resulting in the promotion of polyubiquitination and the degradation of KU70/KU80 proteins. Both in vitro and in vivo cancer models showed that genetic or pharmacological inhibition of HADC1 or DNA-PKcs sensitizes colon cancer cells to ER stress inducers, including the Food and Drug Administration-approved drug celecoxib. The antitumor effects of the combined approach were also observed in patient-derived xenograft models. These findings identify a mechanistic link between ER stress (ERAD) in the cytoplasm and DNA damage (NHEJ) pathways in the nucleus, indicating that combined anticancer strategies may be developed that induce severe ER stress while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.

Host genetics and gut microbiota synergistically regulate feed utilization in egg-type chickens.

BACKGROUND: Feed efficiency is a crucial economic trait in poultry industry. Both host genetics and gut microbiota influence feed efficiency. However, the associations between gut microbiota and host genetics, as well as their combined contributions to feed efficiency in laying hens during the late laying period, remain largely unclear. METHODS: In total, 686 laying hens were used for whole-genome resequencing and liver transcriptome sequencing. 16S rRNA gene sequencing was conducted on gut chyme (duodenum, jejunum, ileum, and cecum) and fecal samples from 705 individuals. Bioinformatic analysis was performed by integrating the genome, transcriptome, and microbiome to screen for key genetic variations, genes, and gut microbiota associated with feed efficiency. RESULTS: The heritability of feed conversion ratio (FCR) and residual feed intake (RFI) was determined to be 0.28 and 0.48, respectively. The ileal and fecal microbiota accounted for 15% and 10% of the FCR variance, while the jejunal, cecal, and fecal microbiota accounted for 20%, 11%, and 10% of the RFI variance. Through SMR analysis based on summary data from liver eQTL mapping and GWAS, we further identified four protein-coding genes, SUCLA2, TNFSF13B, SERTM1, and MARVELD3, that influence feed efficiency in laying hens. The SUCLA2 and TNFSF13B genes were significantly associated with SNP 1:25664581 and SNP rs312433097, respectively. SERTM1 showed significant associations with rs730958360 and 1:33542680 and is a potential causal gene associated with the abundance of Corynebacteriaceae in feces. MARVELD3 was significantly associated with the 1:135348198 and was significantly correlated with the abundance of Enterococcus in ileum. Specifically, a lower abundance of Enterococcus in ileum and a higher abundance of Corynebacteriaceae in feces were associated with better feed efficiency. CONCLUSIONS: This study confirms that both host genetics and gut microbiota can drive variations in feed efficiency. A small portion of the gut microbiota often interacts with host genes, collectively enhancing feed efficiency. Therefore, targeting both the gut microbiota and host genetic variation by supporting more efficient taxa and selective breeding could improve feed efficiency in laying hens during the late laying period.

Bone morphogenetic protein 4 inhibits corneal neovascularization by blocking NETs-induced disruption to corneal epithelial barrier.

Corneal neovascularization (CoNV) is the second leading cause of visual impairment worldwide, and current drugs have certain limitations. Inflammatory response is the core pathological process of CoNV. Neutrophil extracellular traps (NETs) are generated after neutrophil activation, which promotes neovascularization. Prior studies demonstrated that bone morphogenetic protein 4 (BMP4) could significantly reduce inflammation and CoNV formation, its exact molecular mechanism remains unclear. Therefore, we stimulated human peripheral blood neutrophils with phorbol myristate acetate (PMA) or deoxyribonuclease I (DNase I) to induce or inhibit NETs formation. By using corneal sutures and subconjunctival injections of NETs or DNase I, rat CoNV models were established. Compared with the suture group, NETs formation and inflammatory cell infiltration in the corneal stroma were significantly increased, corneal edema was aggravated, and the length, area and diameter of CoNV were significantly enhanced in the NETs group. Furthermore, by curetting the corneal epithelial apical junctional complexes (AJCs), a crucial component in preserving the function of the corneal epithelial barrier, we discovered that the damage of AJCs had a significant role in inducing CoNV formation. NETs could induce CoNV formation by injuring corneal epithelial AJCs. Finally, by comparing the aforementioned indicators after the intervention of BMP4, BMP4 inhibitor Noggin and NADPH oxidase (NOX) inhibitor, we finally demonstrated that BMP4 could inhibit NETs-induced inflammation and corneal epithelial AJC injury, repair corneal epithelial barrier function and eventually inhibit CoNV formation by blocking NOX-2-dependent NETs formation.

Molecular architecture of coronavirus double-membrane vesicle pore complex.

Coronaviruses remodel the intracellular host membranes during replication, forming double-membrane vesicles (DMVs) to accommodate viral RNA synthesis and modifications1,2. SARS-CoV-2 non-structural protein 3 (nsp3) and nsp4 are the minimal viral components required to induce DMV formation and to form a double-membrane-spanning pore, essential for the transport of newly synthesized viral RNAs3-5. The mechanism of DMV pore complex formation remains unknown. Here we describe the molecular architecture of the SARS-CoV-2 nsp3-nsp4 pore complex, as resolved by cryogenic electron tomography and subtomogram averaging in isolated DMVs. The structures uncover an unexpected stoichiometry and topology of the nsp3-nsp4 pore complex comprising 12 copies each of nsp3 and nsp4, organized in 4 concentric stacking hexamer rings, mimicking a miniature nuclear pore complex. The transmembrane domains are interdigitated to create a high local curvature at the double-membrane junction, coupling double-membrane reorganization with pore formation. The ectodomains form extensive contacts in a pseudo-12-fold symmetry, belting the pore complex from the intermembrane space. A central positively charged ring of arginine residues coordinates the putative RNA translocation, essential for virus replication. Our work establishes a framework for understanding DMV pore formation and RNA translocation, providing a structural basis for the development of new antiviral strategies to combat coronavirus infection.

Iron regulatory protein 1 is required for the propagation of inflammation in inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are complex disorders. Iron accumulates in the inflamed tissue of IBD patients, yet neither a mechanism for the accumulation nor its implication on the course of inflammation is known. We hypothesized that the inflammation modifies iron homeostasis, affects tissue iron distribution, and that this in turn perpetuates the inflammation. This study analyzed human biopsies, animal models, and cellular systems to decipher the role of iron homeostasis in IBD. We found inflammation-mediated modifications of iron distribution, and iron-decoupled activation of the iron regulatory protein (IRP) 1. To understand the role of IRP1 in the course of this inflammation-associated iron pattern, a novel cellular coculture model was established, which replicated the iron-pattern observed in vivo, and supported involvement of nitric oxide in the activation of IRP1 and the typical iron pattern in inflammation. Importantly, deletion of IRP1 from an IBD mouse model completely abolished both, the misdistribution of iron and intestinal inflammation. These findings suggest that IRP1 plays a central role in the coordination of the inflammatory response in the intestinal mucosa and that it is a viable candidate for therapeutic intervention in IBD.

Redistribution and fusion of protein-lipid assemblies within the egg yolk sphere under slight non-destructive deformation causing a change in thermal gel properties.

Egg yolk production processed after separating egg white is a common method to shorten cycle, but its taste quality will change even the vitelline membrane is intact. This might be related to the slight non-destructive deformation causing redistribution and fusion of protein-lipid assemblies within the egg yolk spheres. We investigated the mechanism of the change in thermal gel properties under slight deformation. The results of microscopic structural morphology revealed that the whole boiled egg yolk (WEY) underwent a transition in protein-lipid assembly morphology within yolk spheres, which changed from local aggregation to disordered fusion in shaken boiled egg yolks (SEYs). The spectroscopic and physicochemical properties analysis demonstrated that the redistribution of protein-lipid assemblies gave rise to marked changes in water migration, texture properties, molecular interactions, and oral sensation simulation of egg yolk thermal gels. This is benefit to guide the regulation of the taste quality egg yolk products in industry.

Determination of the Cryo-EM Structure of ATG9 from Arabidopsis thaliana.

Macroautophagy/autophagy is a highly conserved process for the degradation of cellular components and plays an essential role in cellular homeostasis maintenance. During autophagy, specialized double-membrane vesicles known as autophagosomes are formed and sequester cytoplasmic cargoes and deliver them to lysosomes or vacuoles for breakdown. Central to this process are autophagy-related (ATG) proteins, with the ATG9-the only integral membrane protein in this core machinery-playing a central role in mediating autophagosome formation. Recent years have witnessed the maturation of cryo-electron microscopy (cryo-EM) and single-particle analysis into powerful tools for high-resolution structural determination of protein complexes. These advancements have significantly deepened our understanding of the intricate molecular mechanisms underlying autophagosome biogenesis. In this study, we present a protocol detailing the acquisition of the three-dimensional structure of ATG9 from Arabidopsis thaliana. The structural resolution achieved 7.8 Å determined by single-particle cryo-electron microscopy (cryo-EM).

Enhanced fatty acid biosynthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in Helicobacter pylori.

The metabolic state of bacteria significantly contributes to their resistance to antibiotics; however, the specific metabolic mechanisms conferring antimicrobial resistance in Helicobacter pylori remain largely understudied. Employing transcriptomic and non-targeted metabolomics, we characterized the metabolic reprogramming of H. pylori when challenged with antibiotic agents. We observed a notable increase in both genetic and key proteomic components involved in fatty acid biosynthesis. Inhibition of this pathway significantly enhanced the antibiotic susceptibility of the sensitive and multidrug-resistant H. pylori strains while also disrupting their biofilm-forming capacities. Further analysis revealed that antibiotic treatment induced a stringent response, triggering the expression of the hp0560-hp0557 operon regulated by Sigma28 (σ28). This activation in turn stimulated the fatty acid biosynthetic pathway, thereby enhancing the antibiotic tolerance of H. pylori. Our findings reveal a novel adaptive strategy employed by H. pylori to withstand antibiotic stress.

Portable Photoacoustic Analytical System Combined with Wearable Hydrogel Patch for pH Monitoring in Chronic Wounds.

Timely diagnosis, monitoring, and management of chronic wounds play crucial roles in improving patients' quality of life, but clinical evaluation of chronic wounds is still ambiguous and relies heavily on the experience of clinician, resulting in increased social and financial burden and delay of optimal treatment. During the different stages of the healing process, specific and dynamic changes of pH values in the wound exudate can be used as biomarkers to reflect the wound status. Herein, a pH-responsive agent with well-behaved photoacoustic (PA) properties, nitrazine yellow (NY), was incorporated in poly(vinyl alcohol)/sucrose (PVA/Suc) hydrogel to construct a wearable pH-sensing patch (PVA/Suc/NY hydrogel) for monitoring of pH values during chronic wound healing. According to Rosencwaig-Gersho theory and the combination of 3D printing technology, the PA chamber volume and chopping frequency were systematically optimized to improve the sensitivity of the PA analytical system. The prepared PVA/Suc/NY hydrogel patch had excellent mechanical properties and flexibility and could maintain conformal contact with skin. Moreover, combined with the miniaturized PA analytical device, it had the potential to detect pH values (5.0-9.0) free from the color interference of blood and therapeutic drugs, which provides a valuable strategy for wound pH value monitoring by PA quantitation. This strategy of combining the wearable hydrogel patch with portable PA analysis offers broad new prospects for the treatment and management of chronic wounds due to its features of simple operation, time savings, and anti-interference.

High-Sensitivity Troponin T, NT-proBNP, and Cognitive Outcomes in SPRINT.

BACKGROUND: Hs-cTnT (cardiac troponin T measured with a highly sensitive assay) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) may identify adults with hypertension who derive greater cognitive benefits from lower systolic blood pressure targets. METHODS: In the SPRINT (Systolic Blood Pressure Intervention Trial) MIND study, participants were categorized as having both hs-cTnT and NT-proBNP in the lower 2 tertiles (n=4226), one in the highest tertile (n=2379), and both in the highest tertile (n=1506). We assessed the effect of intensive versus standard treatment on the composite of mild cognitive impairment (MCI) or probable dementia (PD) across biomarker categories. RESULTS: Over a median follow-up of 5.1 years, 830 of 8111 participants (10.2%) developed MCI or PD. Participants in the highest biomarker category were at higher risk of MCI or PD compared with those in the lowest category (hazard ratio, 1.34 [95% CI, 1.00-1.56]). The effect of intensive treatment on reducing the risk of MCI or PD was greater among participants in the lowest biomarker category (hazard ratio, 0.64 [95% CI, 0.50-0.81]) than those in the intermediate (hazard ratio, 1.01 [95% CI, 0.80-1.28]) or highest categories (hazard ratio, 0.90 [95% CI, 0.72-1.13]; Pinteraction=0.02). The 5-year absolute risk differences in MCI or PD with intensive treatment were -2.9% (-4.4%, -1.3%), -0.2% (-3.0%, 2.6%), and -1.9% (-6.2%, 2.4%) in the lowest, intermediate, and highest biomarker categories, respectively. CONCLUSIONS: In SPRINT, the relative effect of intensive systolic blood pressure lowering on preventing cognitive impairment appears to be stronger among participants with lower compared with higher cardiac biomarker levels, though the absolute risk reductions were similar.

The effects of creatine supplementation on cognitive function in adults: a systematic review and meta-analysis.

Background: This study aimed to evaluate the effects of creatine monohydrate supplementation on cognitive function in adults and explore its potential role in preventing and delaying cognitive impairment-related diseases. Methods: Following the PRISMA 2020 guidelines, a systematic review with meta-analysis was conducted. Randomized controlled trials (RCTs) published between 1993 and 2024 were retrieved from PubMed, Scopus, and Web of Science databases. The study protocol was registered with PROSPERO (registration number: CRD42024533557). The impact of creatine supplementation on overall cognitive function, memory, executive function, attention, and information processing speed was assessed using standardized mean differences (SMD) and Hedge's g with 95% confidence intervals (CI). Results: Sixteen RCTs involving 492 participants aged 20.8-76.4 years, including healthy individuals and patients with specific diseases, were selected. Creatine monohydrate was the form used in all included studies. Creatine supplementation showed significant positive effects on memory (SMD = 0.31, 95% CI: 0.18-0.44, Hedges's g = 0.3003, 95% CI: 0.1778-0.4228) and attention time (SMD = -0.31, 95% CI: -0.58 to -0.03, Hedges's g = -0.3004, 95% CI: -0.5719 to -0.0289), as well as significantly improving processing speed time (SMD = -0.51, 95% CI: -1.01 to -0.01, Hedges's g = -0.4916, 95% CI: -0.7852 to -0.1980). However, no significant improvements were found on overall cognitive function or executive function. Subgroup analyses revealed that creatine supplementation was more beneficial in individuals with diseases, those aged 18-60 years, and females. No significant differences were found between short- (<4 weeks) and long-term (≥4 weeks) interventions for improving cognitive function. Low-to-moderate risk of bias was found, and no significant publication bias was detected. The GRADE assessment indicates that the certainty of evidence for memory function is moderate, suggesting a reasonable level of confidence in the positive effects of creatine on memory. However, the evidence for processing speed, overall cognitive function, executive function, and attention is of low certainty, indicating that further research is needed to confirm these potential benefits. Conclusion: Current evidence suggests that creatine monohydrate supplementation may confer beneficial effects on cognitive function in adults, particularly in the domains of memory, attention time, and information processing speed. Larger robust clinical trials are warranted to further validate these findings. Furthermore, future research should investigate the influence of different populations and intervention durations on the effects of creatine monohydrate supplementation, as well as elucidate the precise mechanisms underlying its potential cognitive-enhancing properties.

Combined radiation and chemotherapy versus monotherapy for anaplastic thyroid cancer: A SEER retrospective analysis.

Background: The effect of combined radiation and chemotherapy (combination therapy) versus monotherapy on anaplastic thyroid carcinoma (ATC) has not yet been clear. Methods: We identified 516 ATC patients during 2010-2015 from the Surveillance, Epidemiology and End Results (SEER) database and evaluated their survival outcome using the Kaplan-Meier method, Cox regression analysis and propensity score matching (PSM) technique. Results: The median overall survival (OS) among the entire cohort was 3 months (95 % confidence interval [CI], 2.58-3.42 months), and the 6- and 12-month OS rates were 29 % (95 % CI, 25.01%-32.88 %) and 13 % (95 % CI, 10.60%-16.58 %), respectively. Multivariable analysis demonstrated that ATC patients not receiving radiotherapy or chemotherapy were unquestionably associated with worse OS (hazard ratio [HR] 3.000, 95 % CI, 2.390-3.764) and cancer-specific survival (CSS) (HR = 3.107, 95 % CI, 2.388-4.043), compared with those receiving combination therapy. However, combination therapy did not predict better prognosis compared with monotherapy (all P > 0.05). After PSM, the median OS and CSS were also not significantly improved in patients undergoing chemoradiotherapy versus chemotherapy alone (OS, P = 0.382; CSS, P = 0.420) or radiotherapy alone (OS, P = 0.065; CSS, P = 0.251). Conclusion: Combination therapy, compared to monotherapy, does not have the expected improvement in survival beyond the benefits achievable with each single-modality treatment, necessitating further prospective research to tailor its treatment management.

Metabolism score and machine learning models for the prediction of esophageal squamous cell carcinoma progression.

The incomplete prediction of prognosis in esophageal squamous cell carcinoma (ESCC) patients is attributed to various therapeutic interventions and complex prognostic factors. Consequently, there is a pressing demand for enhanced predictive biomarkers that can facilitate clinical management and treatment decisions. This study recruited 491 ESCC patients who underwent surgical treatment at Huashan Hospital, Fudan University. We incorporated 14 blood metabolic indicators and identified independent prognostic indicators for overall survival through univariate and multivariate analyses. Subsequently, a metabolism score formula was established based on the biochemical markers. We constructed a nomogram and machine learning models utilizing the metabolism score and clinically significant prognostic features, followed by an evaluation of their predictive accuracy and performance. We identified alkaline phosphatase, free fatty acids, homocysteine, lactate dehydrogenase, and triglycerides as independent prognostic indicators for ESCC. Subsequently, based on these five indicators, we established a metabolism score that serves as an independent prognostic factor in ESCC patients. By utilizing this metabolism score in conjunction with clinical features, a nomogram can precisely predict the prognosis of ESCC patients, achieving an area under the curve (AUC) of 0.89. The random forest (RF) model showed superior predictive ability (AUC = 0.90, accuracy = 86%, Matthews correlation coefficient = 0.55). Finally, we used an RF model with optimal performance to establish an online predictive tool. The metabolism score developed in this study serves as an independent prognostic indicator for ESCC patients.

Visualizing cancer resistance via nano-quenching and recovery detector of CD44.

Drug resistance to chemotherapy in cancers remains significant clinical challenges. CD44 modulates cellular adhesion, migration and growth, which plays a pivotal role in driving cancer resistance and even recurrence. Despite ongoing efforts, accurate, safe, and real-time dynamic monitoring techniques for CD44 expression remain inadequate in guiding the management of drug-resistant cancer treatment. In this study, we developed a nano-quenching and recovery detector of CD44 (Cy3-AptCD44@BPNSs) for visualizing cancer drug resistance. The fluorescence recovery of the detector is directly related to the CD44 expression level on cancer cells, which can be used to indicate the degree of drug resistance. It's confirmed that downregulating CD44 expression on cancer cells results in a corresponding decrease in the fluorescence intensity of the detector, which enables precise and dynamic monitoring of CD44. In addition, the Cy3-AptCD44@BPNSs also exhibited specificity in detecting CD44. This visualizing strategy may open up a wide range of possibilities for rapid recognition to cancer drug resistance, which is more efficient and flexible.

Iron regulatory protein 2 contributes to antimicrobial immunity by preserving lysosomal function in macrophages.

Colorectal cancer and Crohn's disease patients develop pyogenic liver abscesses due to failures of immune cells to fight off bacterial infections. Here, we show that mice lacking iron regulatory protein 2 (Irp2), globally (Irp2-/-) or myeloid cell lineage (Lysozyme 2 promoter-driven, LysM)-specifically (Irp2ΔLysM), are highly susceptible to liver abscesses when the intestinal tissue was injured with dextran sodium sulfate treatment. Further studies demonstrated that Irp2 is required for lysosomal acidification and biogenesis, both of which are crucial for bacterial clearance. In Irp2-deficient liver tissue or macrophages, the nuclear location of transcription factor EB (Tfeb) was remarkably reduced, leading to the downregulation of Tfeb target genes that encode critical components for lysosomal biogenesis. Tfeb mislocalization was reversed by hypoxia-inducible factor 2 inhibitor PT2385 and, independently, through inhibition of lactic acid production. These experimental findings were confirmed clinically in patients with Crohn's disease and through bioinformatic searches in databases from Crohn's disease or ulcerative colitis biopsies showing loss of IRP2 and transcription factor EB (TFEB)-dependent lysosomal gene expression. Overall, our study highlights a mechanism whereby Irp2 supports nuclear translocation of Tfeb and lysosomal function, preserving macrophage antimicrobial activity and protecting the liver against invading bacteria during intestinal inflammation.

How culture affects the way in which psychopathologies manifest in behavior: The case of Confucianism in China.

BACKGROUND: Internalizing disorders in children and adolescents are about as frequent as externalizing disorders in the US, but three times more prevalent than externalizing disorders in China. AIMS: To examine why and how mental predispositions and stress lead to psychopathology in general and manifest as internalizing or externalizing problems in particular, and which role intercultural differences may play in understanding this. METHOD: A review of the literature. RESULTS/CONCLUSIONS: The interplay of personal freedom and societal duties in an individual's development crucially influences whether psychopathologies appear as externalizing or internalizing issues. Eastern and especially Chinese cultures have long favored societal obligations over individual autonomy, guided by Confucian principles, promoting internalization over externalization. Understanding culture's role in behavior can improve mental healthcare by fostering tailored, culturally informed interventions for children and adolescents.

Manganese-enriched prussian blue nanohybrids with smaller electrode potential and lower charge transfer resistance to enhance combination therapy.

Prussian blue (PB) is authenticated in clinical treatment, while it generally exhibits unfavorable chemodynamic therapy (CDT) performance. Herein, we developed manganese-doped prussian blue (PBM) nanoparticles to significantly enhance both CDT and photothermal therapy (PTT) effect. The lower redox potential of Mn3+/2+ (0.088 V) in PBM against that of Fe2+/3+ (0.192 V) in PB leads to favorable electron transfer of PBM with respect to PB. Besides, PBM has a lower charge-transfer resistance (Rct) of 2.98 Ω than 4.83 Ω of PB. Once PBM entering the tumor microenvironment (TME), Mn3+ may be readily reduced by glutathione (GSH) and therein to enhance intracellular oxidative stress. Meanwhile, the superoxide dismutase (SOD)-like activity of PBM facilitates the conversion of endogenous superoxide (O2•-) into H2O2. Mn2+ subsequently catalyzes H2O2 to generate toxic hydroxyl radicals (•OH). Notably, the PBM plus laser irradiation can effectively trigger a robust immunogenic cell death (ICD) due to the combination therapy of CDT and PTT. Additionally, the mice treated by PBM followed by laser irradiation efficiently avoided splenomegaly and lung metastasis, along with significant up-regulation of the Stimulator of Interferon Genes (STING) expression. Overall, PBM significantly inhibits tumor growth and metastasis, making it a promising multifunctional nanoplatform for cancer treatment.