Evolutionary and functional analysis of metabotropic glutamate receptors in lampreys.

The metabotropic glutamate receptor (mGluR, GRM) family is involved in multiple signaling pathways and regulates neurotransmitter release. However, the evolutionary history, distribution, and function of the mGluRs family in lampreys have not been determined. Therefore, we identified the mGluRs gene family in the genome of Lethenteron reissneri, which has been conserved throughout vertebrate evolution. We confirmed that Lr-GRM3, Lr-GRM5, and Lr-GRM7 encode three types of mGluRs in lamprey. Additionally, we investigated the distribution of Lr-GRM3 within this species by qPCR and Western blotting. Furthermore, we conducted RNA sequencing to investigate the molecular function of Lr-GRM3 in lamprey. Our gene expression profile revealed that, similar to that in jawed vertebrates, Lr-GRM3 participates in multiple signal transduction pathways and influences synaptic excitability in lampreys. Moreover, it also affects intestinal motility and the inflammatory response in lampreys. This study not only enhances the understanding of mGluRs' gene evolution but also highlights the conservation of GRM3's role in signal transduction while expanding our knowledge of its functions specifically within lampreys. In summary, our experimental findings provide valuable insights for studying both the evolution and functionality of the mGluRs family.

Antiurolithiatic effect of triptonide in ethylene glycol-induced urolithiasis in rats.

Urolithiasis is one of the most prevalent benign urological disorders globally with a high incidence rate. Male Sprague-Dawley rats were chemically induced to have urolithiasis and treated with triptonide and the standard antiurolithic drug cystone. Kidney weight was measured to detect calculi formation, and urinary parameters such as pH, 24-h urine volume, and protein content were measured to analyze the urolithiasis induction in rats. The inorganic ions, organic solutes, antioxidant levels, and inflammatory cytokines were measured in the experimental rats. Triptonide treatment significantly modulated the urinary pH, decreased the protein concentration, and increased the urinary outflow in urolithiasis induced rats. It also significantly decreased the urinary excretion of calcium and phosphorous and increased the excretion of magnesium, potassium, sodium, creatinine, and uric acid. SOD, CAT, and GPx levels were increased in triptonide-treated rats, and it significantly reduced the MDA levels. Triptonide treatment also decreased the levels of inflammatory cytokines and prevented the renal tissue from inflammation. To conclude, our results prove that triptonide significantly prevents calculi formation and protects renal tissue from urolithiasis-induced damage in rats. Further studies may prove triptonide a potent alternative to currently available antiurolithic drugs.

Compressed sensing 3D T2WI radiomics model: improving diagnostic performance in muscle invasion of bladder cancer.

BACKGROUND: Preoperative discrimination between non-muscle-invasive bladder cancer (NMIBC) and the muscle invasive bladder cancer (MIBC) is a determinant of management. The purpose of this research is to employ radiomics to evaluate the diagnostic value in determining muscle invasiveness of compressed sensing (CS) accelerated 3D T2-weighted-SPACE sequence with high resolution and short acquisition time. METHODS: This prospective study involved 108 participants who underwent preoperative 3D-CS-T2-weighted-SPACE, 3D-T2-weighted-SPACE and T2-weighted sequences. The cohort was divided into training and validation cohorts in a 7:3 ratio. In the training cohort, a Rad-score was constructed based on radiomic features selected by intraclass correlation coefficients, pearson correlation coefficient and least absolute shrinkage and selection operator . Multivariate logistic regression was used to develop a nomogram combined radiomics and clinical indices. In the validation cohort, the performances of the models were evaluated by ROC, calibration, and decision curves. RESULTS: In the validation cohort, the area under ROC curve of 3D-CS-T2-weighted-SPACE, 3D-T2-weighted-SPACE and T2-weighted models were 0.87(95% confidence interval (CI):0.73-1.00), 0.79(95%CI:0.63-0.96) and 0.77(95%CI:0.60-0.93), respectively. The differences in signal-to-noise ratio and contrast-to-noise ratio between 3D-CS-T2-weighted-SPACE and 3D-T2-weighted-SPACE sequences were not statistically significant(p > 0.05). While the clinical model composed of three clinical indices was 0.74(95%CI:0.55-0.94) and the radiomics-clinical nomogram model was 0.88(95%CI:0.75-1.00). The calibration curves confirmed high goodness of fit, and the decision curve also showed that the radiomics model and combined nomogram model yielded higher net benefits than the clinical model. CONCLUSION: The radiomics model based on compressed sensing 3D T2WI sequence, which was acquired within a shorter acquisition time, showed superior diagnostic efficacy in muscle invasion of bladder cancer. Additionally, the nomogram model could enhance the diagnostic performance.

Iron Plaque: A Shield against Soil Contamination and Key to Sustainable Agriculture.

Soils play a dominant role in supporting the survival and growth of crops and they are also extremely important for human health and food safety. At present, the contamination of soil by heavy metals remains a globally concerning environmental issue that needs to be resolved. In the environment, iron plaque, naturally occurring on the root surface of wetland plants, is found to be equipped with an excellent ability at blocking the migration of heavy metals from soils to plants, which can be further developed as an environmentally friendly strategy for soil remediation to ensure food security. Because of its large surface-to-volume porous structure, iron plaque exhibits high binding affinity to heavy metals. Moreover, iron plaque can be seen as a reservoir to store nutrients to support the growth of plants. In this review, the formation process of iron plaque, the ecological role that iron plaque plays in the environment and the interaction between iron plaque, plants and microbes, are summarized.

Ultrathin cobalt-based nanosheets containing surface oxygen promoted near-complete nitrate removal.

Electrocatalytic nitrate removal offers a sustainable approach to alleviate nitrate pollution and to boost the anthropogenic nitrogen cycle, but it still suffers from limited removal efficiency at high rates, especially at low levels of nitrate. Herein, we report the near-complete removal of low-level nitrate (10-200 ppm) within 2 h using ultrathin cobalt-based nanosheets (CoNS) containing surface oxygen, which was fabricated from in-situ electrochemical reconstruction of conventional nanosheets. The average nitrate removal of 99.7 % with ammonia selectivity of 98.2 % in 9 cyclic runs ranked in the best of reported catalysts. Powered by a solar cell under the winter sun, the full-cell nitrate electrolysis system, equipped with ultrathin CoNS, achieved 100 % nitrogen gas selectivity and 99.6 % total nitrogen removal. The in-situ Fourier Transform Infrared included experiments and theoretical computations revealed that in-situ electrochemical reconstruction not only increased electrochemical active surface area but also constructed surface oxygen in active sites, leading to enhanced stabilization of nitrate adsorption in a symmetry breaking configuration and charge transfer, contributing to near-complete nitrate removal on ultrathin CoNS. This work provides a strategy to design ultrathin nanocatalysts for nitrate removal.

[Effect of Xuming Decoction in Records of Proved Prescriptions, Ancient a nd Modern on cerebral ischemic injury and angiogenesis in rat model of acute cerebral infarction].

This paper aims to explore the effect of Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern on cerebral ischemic injury and angiogenesis in the rat model of acute cerebral infarction. SD rats were randomized into 6 groups: sham group, model group, low-, medium-, and high-dose(5.13, 10.26, and 20.52 g·kg~(-1), respectively) Xuming Decoction groups, and butylphthalide(0.06 g·kg~(-1)) group. After the successful establishment of the rat model by middle cerebral artery occlusion(MCAO), rats in the sham and model groups were administrated with distilled water and those in other groups with corresponding drugs for 7 consecutive days. After the neurological function was scored, all the rats were sacrificed, and the brain tissue samples were collected. The degree of cerebral ischemic injury was assessed by the neurological deficit score and staining with 2,3,5-triphenyltetrazolium chloride. Hematoxylin-eosin staining was performed to observe the pathological changes in the brain. Transmission electron microscopy was employed to observe the ultrastructures of neurons and microvascular endothelial cells(ECs) on the ischemic side of the brain tissue. Immunofluorescence assay was employed to detect the expression of von Willebrand factor(vWF) and hematopoietic progenitor cell antigen CD34(CD34) in the ischemic brain tissue. Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of Runt-related transcription factor 1(RUNX1), vascular endothelial growth factor(VEGF), angiopoietin-1(Ang-1), angiopoietin-2(Ang-2), and VEGF receptor 2(VEGFR2) in the ischemic brain tissue. The results showed that compared with the sham group, the model group showed increased neurological deficit score and cerebral infarction area(P<0.01), pathological changes, and damaged ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Furthermore, the modeling up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.05 or P<0.01). Compared with the model group, high-dose Xuming Decoction and butylphthalide decreased the neurological deficit score and cerebral infarction area(P<0.01) and alleviated the pathological changes and damage of the ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Moreover, they up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01). The results suggest that Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern can promote the angiogenesis and collateral circulation establishment to alleviate neurological dysfunction of the ischemic brain tissue in MCAO rats by regulating the RUNX1/VEGF pathway.

Polyketides with α-glucosidase inhibitory and neuroprotective activities from Aspergillus versicolor associated with Pedicularis sylvatica.

Aspergillus versicolor, an endophytic fungus associated with the herbal medicine Pedicularis sylvatica, produced four new polyketides, aspeversins A-D (1-2 and 5-6) and four known compounds, O-methylaverufin (2), aversin (3), varilactone A (7) and spirosorbicillinol A (8). Their structures were elucidated by extensive spectroscopic data analysis, and their absolute configurations were determined by calculated electronic circular dichroism (ECD) and Mo2(AcO)4-induced CD data. Compound 5 was found to exhibit α-glucosidase inhibitory activity with an IC50 value of 25.57 µM. An enzyme kinetic study indicated that 5 was a typical uncompetitive inhibitor toward α-glucosidase, which was supported by a molecular docking study. Moreover, compounds 1-3 and 5 also improved the cell viability of PC12 cells on a 1-methyl-4-phenylpyridinium (MPP+)-induced Parkinson's disease model, indicating their neuroprotective potential as antiparkinsonian agents.

Foliar uptake screening: A promising strategy for identifying wheat varieties with low lead accumulation.

Lead (Pb) contamination in wheat grain is of great concern, especially in North China. Atmospheric deposition is a major contributor to Pb accumulation in wheat grain. Screening low Pb accumulating wheat varieties has been an effective method for addressing Pb contamination in wheat grain. However, identifying wheat varieties with low Pb accumulation based on foliar uptake of atmospheric Pb has been neglected. Therefore, two field trials with distinct atmospheric Pb deposition were conducted to screen for stable varieties with low Pb accumulation. It was verified that YB700 and CH58, which have high thousand-grain weights and stable low Pb accumulation in field 1 (0.19 and 0.13 mg kg-1) and field 2 (0.17 and 0.20 mg kg-1), respectively, were recommended for cultivation in atmospheric Pb contaminated farmlands in North China. Furthermore, indoor experiments were conducted to investigate Pb uptake by the roots and leaves of different wheat varieties. Our findings indicate that Pb accumulation in different wheat varieties is primarily influenced by foliar Pb uptake rather than root Pb uptake. Interestingly, there was a positive correlation (p < 0.05) between the Pb concentrations in leaves and the stomatal width and trichome length of the adaxial epidermal surface. Additionally, there is a positive correlation (p < 0.01) between the Pb concentration in the wheat grain and trichome length. In conclusion, the screening of wheat varieties with narrower stomatal widths or shorter trichomes based on foliar uptake pathways is an effective strategy for ensuring food safety in areas contaminated by atmospheric Pb.

Enhancing prognostic prediction of invasive candidiasis among cancer patients with a serum C5a-based scoring model.

PURPOSE: Invasive candidiasis poses a life-threatening risk, and early prognosis assessment is vital for timely interventions to reduce mortality. Serum C5a levels have recently been linked to prognosis, but confirmation in cancer patients is pending. METHODS: We detected the concentrations of serum C5a in hospitalized cancer patients with invasive candidiasis from 2020 to 2023, and retrospectively analyzed the clinical data. RESULTS: 372 cases were included in this study, with a 90-day mortality rate of 21.8%. Candida albicans (48.7%) remained the predominant pathogen, followed by Candida glabrata (25.5%), Candida tropicalis (12.4%), and Candida parapsilosis (8.3%). Gastrointestinal cancer was the most diagnosed pathology type (37.6%). Serum C5a demonstrated a noteworthy correlation with 90-day mortality, and employing a cutoff value of 36.7 ng/ml revealed significantly higher 90-day mortality in low-C5a patients (41.2%) compared to high-C5a patients (6.3%) (p < 0.001). We also identified no source control, no surgery, metastasis, or chronic renal failure independently correlated with the 90-day mortality. Based on this, a prognostic model combining C5a and clinical parameters was constructed, which performed better than models built solely on C5a or clinical parameters. Furthermore, we weighted scores to each parameter in the model and presented diagnostic sensitivity and specificity corresponding to different score points calculated by the model. CONCLUSION: We constructed a prognostic scoring model including serum C5a and clinical parameters, which would contribute to precise prognosis assessment and benefit the outcome among cancer patients.

Synthesis and Antifungal Activities of Novel Griseofulvin Derivatives as Potential Anti-Phytopathogenic Fungi Agents.

The extensive and repeated application of chemical fungicides results in the rapid development of fungicide resistance. Novel antifungal pesticides are urgently required. Natural products have been considered precious sources of pesticides. It is necessary to discover antifungal pesticides by using natural products. Herein, 42 various griseofulvin derivatives were synthesized. Their antifungal activities were evaluated in vitro. Most of them showed good antifungal activity, especially 3d exhibited a very broad antifungal spectrum and the most significant activities against 7 phytopathogenic fungi. In vivo activity results suggested that 3d protected apples and tomatoes from serious infection by phytopathogenic fungi. These proved that 3d had the potential to be a natural product-derived antiphytopathogenic fungi agent. Furthermore, docking analysis suggested that tubulin might be one of the action sites of 3d. It is reasonable to believe that griseofulvin derivatives are worth further development for the discovery of new pesticides.

Complete genome sequence of Pseudomonas aeruginosa L3, a bacterium with Mn(II) oxidative property isolated from heavy metal-contaminated soils.

Pseudomonas aeruginosa L3, isolated from heavy metal-contaminated soils, possesses the ability of Mn(II) oxidation. To further enhance the understanding of genes involved in Mn(II) oxidation, the complete genome of this strain was sequenced and annotated, which has a total size of 6.39 Mb with a G + C content of 66.39%.

Genome-wide analysis of in vivo-evolved Candida auris reveals multidrug-resistance mechanisms.

Candida auris, an emerging and multidrug-resistant fungal pathogen, has led to numerous outbreaks in China. While the resistance mechanisms against azole and amphotericin B have been studied, the development of drug resistance in this pathogen remains poorly understood, particularly in in vivo-generated drug-resistant strains. This study employed pathogen whole-genome sequencing to investigate the epidemiology and drug-resistance mutations of C. auris using 16 strains isolated from two patients. Identification was conducted through Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and antimicrobial susceptibilities were assessed using broth microdilution and Sensititre YeastOne YO10. Whole-genome sequencing revealed that all isolates belonged to the South Asian lineage, displaying genetic heterogeneity. Despite low genetic variability among patient isolates, notable mutations were identified, including Y132F in ERG11 and A585S in TAC1b, likely linked to increased fluconazole resistance. Strains from patient B also carried F214L in TAC1b, resulting in a consistent voriconazole minimum inhibitory concentration of 4 µg/mL across all isolates. Furthermore, a novel frameshift mutation in the SNG1 gene was observed in amphotericin B-resistant isolates compared to susceptible ones. Our findings suggest the potential transmission of C. auris and emphasize the need to explore variations related to antifungal resistance. This involves analyzing genomic mutations and karyotypes, especially in vivo, to compare sensitive and resistant strains. Further monitoring and validation efforts are crucial for a comprehensive understanding of the mechanisms of drug resistance in C. auris.

Regulation of VEGF gene expression by bisacridine derivative through promoter i-motif for cancer treatment.

BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed in most malignant tumors, which has important impact on tumor angiogenesis and development. Its gene promoter i-motif structure formed by C-rich sequence can regulate gene expression, which is a promising new target for anti-tumor therapy. METHODS: We screened various compounds and studied their effects on VEGF through extensive experiments, including SPR, MST, TO displacement, FRET, CD, ESI-MS, NMR, MTT, clone formation, qPCR, Western blot, dual-luciferase reporter assay, immunofluorescence, cell scrape, apoptosis, transwell assay, and animal model. RESULTS: After extensive screening, bisacridine derivative B09 was found to have selective binding and stabilization to VEGF promoter i-motif, which could down-regulate VEGF gene expression. B09 showed potent inhibition on MCF-7 and HGC-27 cell proliferation and metastasis. B09 significantly inhibited tumor growth in xenograft mice model with HGC-27 cells, showing decreased VEGF expression analyzed through immunohistochemistry. CONCLUSION: B09 could specifically regulate VEGF gene expression, possibly through interacting with promoter i-motif structure. As a lead compound, B09 could be further developed for innovative anti-cancer agent targeting VEGF.

The construction of a nomogram to predict the prognosis and recurrence risks of UPJO.

Objective: This study was conducted to explore the risk factors for the prognosis and recurrence of ureteropelvic junction obstruction (UPJO). Methods: The correlation of these variables with the prognosis and recurrence risks was analyzed by binary and multivariate logistic regression. Besides, a nomogram was constructed based on the multivariate logistic regression calculation. After the model was verified by the C-statistic, the ROC curve was plotted to evaluate the sensitivity of the model. Finally, the decision curve analysis (DCA) was conducted to estimate the clinical benefits and losses of intervention measures under a series of risk thresholds. Results: Preoperative automated peritoneal dialysis (APD), preoperative urinary tract infection (UTI), preoperative renal parenchymal thickness (RPT), Mayo adhesive probability (MAP) score, and surgeon proficiency were the high-risk factors for the prognosis and recurrence of UPJO. In addition, a nomogram was constructed based on the above 5 variables. The area under the curve (AUC) was 0.8831 after self cross-validation, which validated that the specificity of the model was favorable. Conclusion: The column chart constructed by five factors has good predictive ability for the prognosis and recurrence of UPJO, which may provide more reasonable guidance for the clinical diagnosis and treatment of this disease.

Identification and analysis of MSC-Exo-derived LncRNAs related to the regulation of EMT in hypospadias.

OBJECTIVE: This study aims to screen the differentially expressed long non-coding RNAs (DELncRNAs) related to the regulation of epithelial-mesenchymal transition (EMT) in hypospadias in mesenchymal stem cell-derived exosomes (MSC-Exons) and explore the potential mechanism of these lncRNAs for the EMT in hypospadias. METHODS: In this study, the microarray data related to MSC-Exos and hypospadias were downloaded from Gene Expression Omnibus (GEO). Besides, the lncRNAs highly expressed in MSC-Exos and the differentially expressed mRNAs and lncRNAs in children with hypospadias were screened, respectively. In addition, the lncRNAs enriched in MSC-Exos and differentially expressed lncRNAs in hypospadias were intersected to obtain the final DElncRNAs. Moreover, the co-expression interaction pairs of differentially expressed lncRNAs and mRNAs were analyzed to construct a Competing Endogenous RNA (ceRNA) network. Finally, the candidate lncRNAs in exosomes were subjected to in vitro cell function verification. RESULTS: In this study, a total of 4 lncRNAs were obtained from the microarray data analysis. Further, a ceRNA regulatory network of MSC-Exo-derived lncRNAs related to the regulation of EMT in hypospadias was constructed, including 4 lncRNAs, 2 mRNAs, and 6 miRNAs. The cell function verification results indicated that the exosomes secreted by MSCs may transport HLA complex group 18 (HCG18) into target cells, which promoted the proliferation, migration, and EMT of these cells. CONCLUSION: MSC-Exo-derived lncRNA HCG18 can enter target cells, and it may be involved in the regulation of EMT in hypospadias through the ceRNA network.

Intestinal flora: New perspective of type 2 diabetes.

Diabetes comprises a group of metabolic diseases characterized by hyperglycemia stemming from various factors. Current diabetes management primarily focuses on blood glucose control, yet it is inherently progressive, necessitating increased reliance on exogenous blood glucose control methods over time. Therefore, there is an urgent need to explore novel intervention strategies addressing both diabetes and its complications. The human intestinal microbiota, often referred to as the "second genome", exhibits significant diversity and plays a pivotal role in insulin resistance, glucose and lipid metabolism, and inflammatory response. Notably, Li and Guo have elucidated the involvement of intestinal flora in the pathogenesis of type 2 diabetes mellitus (T2DM) and proposed a novel therapeutic approach targeting intestinal microbes. This advancement enhances our comprehension of the multifaceted and multi-target regulation of T2DM by intestinal microflora, thereby offering fresh avenues for understanding its pathogenesis and clinical management. This letter briefly summarizes the role of intestinal flora in T2DM based on findings from animal experiments and clinical studies. Additionally, it discusses the potential clinical applications and challenges associated with targeting intestinal flora as therapeutic interventions.

Targeting estrogen mediated CYP4F2/CYP4F11-20-HETE metabolic disorder decelerates tumorigenesis in ER+ breast cancer.

Purpose: As the most common subset of breast cancer (BC), estrogen receptor positive (ER+) BC accounting for 80% of cases, has become a global public health concern. The female hormone estrogen (E2) unequivocally drives ER + breast malignancies. The reasons that estrogen affects BC development has long been considered, yet further study remains to be conducted of the molecular events in the E2-estrogen receptor α (ERα) signaling pathway in ER + BC progression, especially lipid metabolism, so providing more options for tailored and individualized therapy. Our aim is to find out new targets and clinical biomarkers for ER + breast cancer treatment from the perspective of lipid metabolism. Methods: Lipid metabolomics profiling was used to examine the membrane phospholipid stimulated by E2. Clinical BC samples were used to assess the association of CYP4F2, CYP4F11 expression with clinicopathological characteristics and patient outcomes. Some inhibitors of main enzymes in AA metabolism were used combined with E2 to assess roles of CYP4F2/CYP4F11 in the progression of ER + BC. CYP4F2, CYP4F11 overexpression and knockdown BC cell lines were employed to examine the effects of CYP4F2, CYP4F11 on cellular proliferation, apoptosis and tumor growth. Western blotting, qPCR, Immunohistochemical staining and flow cytometry were also conducted to determine the underlying mechanisms related to CYP4F2, CYP4F11 function. Results: The activation of the CYP450 signaling pathway in arachidonic acid metabolism contributed to ER + BC tumorigenesis. In ER + BC, CYP4F2 and CYP4F11 overexpression induced by E2 could promote cancer cell proliferation and resistance to apoptosis by producing the metabolite 20-HETE and activating the antiapoptotic protein Bcl-2. CYP4F2 and CYP4F11 elevation correlates with poorer overall survival and disease-free survival in ER + BC patients. Conclusion: CYP4F2, CYP4F11 and their metabolite 20-HETE could serve as effective prognostic markers and attractive therapeutic targets for novel anticancer drug development about ER + BC.

Spatial and emotional distances in parent-child relationships: Impacts on human capital development in rural Chinese boarding children.

BACKGROUND: The policy of merging remote rural elementary schools into centralized villages has led to the emergence of boarding schools as an essential means of providing compulsory education in rural areas of China. As boarding children reside in schools for extended periods, parents' influence on their human capital development is inevitably specificity. The development of rural boarding children is a serious social issue in China, and parent-child distance plays a crucial role in affecting the development of children's human capital. OBJECTIVE: While previous studies have focused on the relationship between parental absence and the development of human capital in rural boarding children, this study examines the effects of both spatial and emotional distance between parents and children on the human capital of rural boarding children. PARTICIPANTS AND SETTING: A stratified, multi-stage probabilities proportional to size (PPS) sampling method was used, and self-report questionnaires were completed by 2397 rural boarding children (54.2 % males; ages 12 to 18, M = 14.66, SD = 1.30). METHODS: Children's background, family, and school and teacher characteristics were used as control variables. An OLS regression model was used to assess the effects of parent-child spatial and emotional distance on the human capital of rural boarding children, and a CMP-OLS regression model was used to address endogeneity using parents' self-assessed family economic conditions as instrumental variables. RESULTS: Parent-child spatial distance had a significant positive effect (p < 0.05, p < 0.05), and emotional distance had a significant negative effect (p < 0.05, p < 0.01) on the cognitive and non-cognitive abilities development of rural boarding children. Living with grandparents heightened the negative effect on non-cognitive abilities development. CONCLUSIONS: The findings of this study strengthen the link between parent-child distance and rural boarding children and the moderating impact of living with grandparents on the effect of parent-child distance on rural boarding children's human capital providing new insights for promoting the development of rural boarding children. It also highlights the detrimental effects of emotional neglect on rural boarding children's development. This is important for realizing China's rural revitalization strategy and the healthy development of disadvantaged children in rural areas.

Hypoxia-activated selectivity-improved anti-PKM2 antibody combined with prodrug TH-302 for potentiated targeting therapy in hepatocellular carcinoma.

Background: Hypoxia induces hepatocellular carcinoma (HCC) malignancies; yet it also offers treatment opportunities, exemplified by developing hypoxia-activated prodrugs (HAPs). Although HAP TH-302 combined with therapeutic antibody (Ab) has synergistic effects, the clinical benefits are limited by the on-target off-tumor toxicity of Ab. Here, we sought to develop a hypoxia-activated anti-M2 splice isoform of pyruvate kinase (PKM2) Ab combined with TH-302 for potentiated targeting therapy. Methods: Codon-optimized and hypoxia-activation strategies were used to develop H103 Ab-azo-PEG5k (HAP103) Ab. Hypoxia-activated HAP103 Ab was characterized, and hypoxia-dependent antitumor and immune activities were evaluated. Selective imaging and targeting therapy with HAP103 Ab were assessed in HCC-xenografted mouse models. Targeting selectivity, systemic toxicity, and synergistic therapeutic efficacy of HAP103 Ab with TH-302 were evaluated. Results: Human full-length H103 Ab was produced in a large-scale bioreactor. Azobenzene (azo)-linked PEG5k conjugation endowed HAP103 Ab with hypoxia-activated targeting features. Conditional HAP103 Ab effectively inhibited HCC cell growth, enhanced apoptosis, and induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) functions. Analysis of HCC-xenografted mouse models showed that HAP103 Ab selectively targeted hypoxic HCC tissues and induced potent tumor-inhibitory activity either alone or in combination with TH-302. Besides the synergistic effects, HAP103 Ab had negligible side effects when compared to parent H103 Ab. Conclusion: The hypoxia-activated anti-PKM2 Ab safely confers a strong inhibitory effect on HCC with improved selectivity. This provides a promising strategy to overcome the on-target off-tumor toxicity of Ab therapeutics; and highlights an advanced approach to precisely kill HCC in combination with HAP TH-302.