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The high heterogeneity of receptor expression and varied chemotherapeutic sensitivity seriously compromise the therapeutic outcome of triple‐negative breast cancer (TNBC)‐targeting nanodrugs. In this work, a TNBC‐targeting nanodrug (designated as CPU) equipped with self‐promoted targeting property through chemotherapeutic upregulation of CD47 is constructed, enabling synergistic chemo/photodynamic therapy. Specifically, the hydrophobic docetaxel (DOC), which can upregulate the expression of CD47 in TNBC cells, is loaded in the nanomicelles (designated as P‐Pep) assembled from a protoporphyrin IX (PPIX)‐labeled amphiphilic chimeric peptide of Fmoc‐K(PPIX)‐AWSATWSNYWRH, obtaining the ca. 196 nm CPU. Aided by the enhanced permeability and retention effect and guidance of CD47‐binding peptide sequence, CPU is verified to prefer to accumulate in CD47 overexpressed TNBC cells, which can recruit more CPU by upregulating CD47 expression post‐treatment of DOC. Both in vitro and in vivo results demonstrate the superior tumor targeting ability, which can extensively amplify chemotherapeutic and photodynamic therapeutic effects while evading obvious adverse effects. The self‐promoted targeting strategy will inspire the design of nanodrugs for the personalized therapy of tumors with high heterogeneity and resistance. [ABSTRACT FROM AUTHOR]

This paper investigates how human capital agglomeration interplays with institutional factors to affect migration destination choice in China. Over the last decades, China has experienced massive internal migration, substantial human capital investment, and the relaxation of its hukou system, thus providing us with a valuable opportunity to examine the role of human capital externality in migration choice. Based on rich data on province‐to‐province migration flows for different education and hukou groups, we find that migrants in China, especially highly educated and urban‐to‐urban migrants, have a strong preference to move to provinces with a high agglomeration of human capital. Further examination reveals that low‐skilled migrants in China are less likely to benefit from human capital agglomeration because of their lower ability to overcome hukou restrictions. Our findings raise the concern that labor migration under the skill‐biased hukou system would enlarge China's regional disparities in human capital and economic development. [ABSTRACT FROM AUTHOR]

Introduction: The pathophysiology of diabetic nephropathy (DN) is fundamentally dependent on glomerular endothelial cells (GECs), which are a crucial portion of the glomerular filtration barrier. This study aimed to identify biomarker candidates associated with GECs dysfunction in DN by combining microarray and single-cell sequencing dataset analysis., Methods: Microarray dataset GSE30528 was downloaded from the Gene expression omnibus (GEO) database. Key gene sets for diabetic kidney disease (DKD) were selected by using weighted gene co-expression network analysis (WGCNA). Biomarker candidates were then identified using least absolute shrinkage and selection operator (LASSO) logistic regression. The single-cell sequencing data (GSE131882) was used to explore the biological functional differences in glomerular endothelium between the control and DKD groups. The diagnostic efficiency of the selected biomarker was tested in the Receiver operating characteristic (ROC) curve. Moreover, we used the single-sample gene set enrichment analysis (ssGSEA) to compare immune cell infiltration between DKD and control groups. RT-PCR was used to validate the selected gene expression in cultured glomerular endothelial cells under high glucose stimulation., Results: Phosphatase and actin regulator 4 (PHACTR4) was ultimately selected as the key GEC-related biomarker in DKD. Significantly downregulated PHACTR4 mRNA expression was further validated in human glomerular endothelial cells (HGECs) under high glucose stimulation by using RT-PCR. The decreased PHACTR4 was found to be associated with abnormal endothelial proliferation and neo-angiogenesis. Additionally, immune infiltration analysis revealed that PHACTR4 was negatively associated with inflammatory infiltration, especially pro-inflammatory cells including activated CD4 and CD8 T cells, B cells, and Mast cells, indicating PHACTR4 downregulation may exacerbate inflammatory reaction., Conclusion: PHACTR4 is a potential diagnostic marker for DKD and plays an essential role in aberrant glomerular endothelial proliferation and inflammation in DKD.  DOI: 10.52547/ijkd.7858.

Glomerular angiogenesis is a characteristic feature of diabetic nephropathy (DN). Enhanced glycolysis plays a crucial role in angiogenesis. The present study was designed to investigate the role of glycolysis in glomerular endothelial cells (GECs) in a mouse model of DN. Mouse renal cortex and isolated glomerular cells were collected for single-cell and RNA sequencing. Cultured GECs were exposed to high glucose in the presence (proangiogenic) and absence of a vascular sprouting regimen. MicroRNA-590-3p was delivered by lipofectamine in vivo and in vitro. In the present study, a subgroup of GECs with proangiogenic features was identified in diabetic kidneys by using sequencing analyses. In cultured proangiogenic GECs, high glucose increased glycolysis and phosphofructokinase/fructose bisphosphatase 3 (PFKFB3) protein expression, which were inhibited by overexpressing miRNA-590-3p. Mimics of miRNA-590-3p also increased receptor for sphingosine 1-phosphate (S1pR1) expression, an angiogenesis regulator, in proangiogenic GECs challenged with high glucose. Inhibition of PFKFB3 by pharmacological and genetic approaches upregulated S1pR1 protein in vitro. Mimics of miRNA-590-3p significantly reduced migration and angiogenic potential in proangiogenic GECs challenged with high glucose. Ten-week-old type 2 diabetic mice had elevated urinary albumin levels, reduced renal cortex miRNA-590-3p expression, and disarrangement of glomerular endothelial cell fenestration. Overexpressing miRNA-590-3p via perirenal adipose tissue injection restored endothelial cell fenestration and reduced urinary albumin levels in diabetic mice. Therefore, the present study identifies a subgroup of GECs with proangiogenic features in mice with DN. Local administration of miRNA-590-3p mimics reduces glycolytic rate and upregulates S1pR1 protein expression in proangiogenic GECs. The protective effects of miRNA-590-3p provide therapeutic potential in DN treatment. NEW & NOTEWORTHY Proangiogenetic glomerular endothelial cells (GECs) are activated in diabetic nephropathy. High glucose upregulates glycolytic enzyme phosphofructokinase/fructose bisphosphatase 3 (PFKFB3) in proangiogenetic cells. PFKFB3 protects the glomerular filtration barrier by targeting endothelial S1pR1. MiRNA-590-3p restores endothelial cell function and mitigates diabetic nephropathy.