Spns1 is an iron transporter essential for megalin-dependent endocytosis.

Proximal tubule endocytosis is essential to produce protein free urine as well as to regulate system wide metabolic pathways, such as the activation of Vitamin D. We have determined that the proximal tubule expresses an endolysosomal membrane protein, protein spinster homolog1 (Spns1), which engenders a novel iron conductance that is indispensable during embryonic development. Conditional knockout of Spns1 with a novel Cre-LoxP construct specific to megalin-expressing cells led to the arrest of megalin receptor-mediated endocytosis as well as dextran pinocytosis in proximal tubules. The endocytic defect was accompanied by changes in megalin phosphorylation as well as enlargement of lysosomes confirming previous findings in Drosophila and Zebrafish. The endocytic defect was also accompanied by iron overload in proximal tubules. Remarkably, iron levels regulated the Spns1 phenotypes, because feeding an iron deficient diet or mating Spns1 knockout with divalent metal transporter1 (DMT1) knockout rescued the phenotypes. Conversely, iron loading wild type mice reproduced the endocytic defect, These data demonstrate a reversible, negative feedback for apical endocytosis, and raise the possibility that regulation of endocytosis, pinocytosis, megalin activation, and organellar size and function is nutrient-responsive.

Diverse Self-assembly Pathways in Nematic Compartment Network: Topological Percolation and Pathfinding.

The self-assembly of nematic molecules in microcompartments with unambiguously defined surface anchoring is well predictable and is likely to have a single stable topological structure. Here, in contrast, a confined nematic system comprising an array of microcompartments interconnected by channels is demonstrated, exhibiting diverse molecular assembly pathways leading to the formation of four types of topological structures and twelve different patterns randomly distributed. Intercompartment communication via channels plays a crucial role in the diversity of patterns and distributions. It determines the sizes and structures of domains separated by channel defects. The domain structure, which features a pathfinding algorithm and reverse tree structure, can be modelled by an isotropically directed bond percolation with additional restrictions. This system serves as a model for controlled randomness and restricted growth of networks, with potential applications in anticounterfeit protection as a physically unclonable function (PUF) with multiple-level communication protocols.

[Risk factors and prognosis of pediatric silent lupus nephritis with class â ¢ to â ¤]. / 儿童⠢~â ¤åž‹æ— ç—‡çŠ¶æ€§ç‹¼ç–®æ€§è‚¾ç‚Žçš„å±é™©å› ç´ åŠé¢„åŽåˆ†æž.

OBJECTIVES: To study the risk factors and prognostic characteristics of pediatric silent lupus nephritis (SLN) with class Ⅲ to V. METHODS: A retrospective study was conducted to collect clinical data from 30 children diagnosed with SLN at the Department of Pediatrics, Second Xiangya Hospital, Central South University, from May 2007 to April 2023. Based on renal pathological classification, the patients were divided into a class Ⅱ group (12 cases) and a class Ⅲ to Ⅴ group (18 cases). The risk factors for the occurrence of class Ⅲ to Ⅴ SLN were analyzed, and the prognostic characteristics were summarized. RESULTS: Among the 30 SLN patients, the median follow-up time was 61.50 months. There were no statistically significant differences in the proportions of patients who discontinued glucocorticoids or achieved low disease activity status, nor in the annual decline rate of estimated glomerular filtration rate (eGFR) between the class Ⅱ and class Ⅲ to V groups (P>0.05). However, three patients in the class Ⅱ group progressed to stage 1 chronic kidney disease (CKD), while eight patients in the class III to V group reached stage 1 CKD, and four patients reached stage 2 CKD. Among the 26 female SLN patients, serum complement C3 levels in the class III to V group were lower than those in the class Ⅱ group (P<0.05). Serum C3 levels in SLN patients, as well as in female SLN patients, were negatively correlated with the fluorescence intensity of IgA, IgG, and C3 immune complexes in the kidneys (P<0.05). Additionally, serum C3 levels in female SLN patients were negatively correlated with the renal pathological activity index (P<0.05). Binary logistic regression analysis indicated that being female and having low serum complement C3 levels were risk factors for the occurrence of class Ⅲ to V SLN in children (P<0.05). CONCLUSIONS: Class Ⅲ to V SLN is not uncommon among SLN children, and there remains a risk of long-term renal function progression. Being female and having low serum complement C3 levels are identified as risk factors for class Ⅲ to V SLN in children.

A Systematic Review of Online Medical Consultation Research.

Online medical consultation is a form of medical service that facilitates interactions between patients and doctors online, offering significant utility and value. This review aims to retrieve, screen, and analyze articles related to online medical consultations, formulating a theoretical framework and proposing future research directions. According to PRISMA guidelines, a systematic search was conducted in Web of Science, EBSCO, ScienceDirect, PubMed, and Scopus, retrieving a total of 4072 English records on 16 December 2023. After rigorous screening, 75 articles were included in this review. Among these, 8 articles focused on patients utilizing online medical consultation platforms, 5 on doctors participating in online medical platforms, 18 on patients' choice of doctors, 12 on doctors providing services, 7 on online reviews of patients, 14 on service quality for patients, 8 on rewards to doctors, and 11 on the spillover effect between online and offline services. These themes comprise the theoretical framework of the starting point, process, and outcomes of the online medical consultation system, providing a comprehensive understanding of the field and a foundation for future research.

[Clinical characteristics of children with anti-neutrophil cytoplasmic antibody-associated vasculitis]. / å„¿ç«¥æŠ—ä¸­æ€§ç²’ç»†èƒžèƒžè´¨æŠ—ä½“ç›¸å ³æ€§è¡€ç®¡ç‚Žä¸´åºŠç‰¹å¾åˆ†æž.

OBJECTIVES: To study the clinical characteristics of children with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A retrospective analysis was conducted on the clinical data of 25 children diagnosed with AAV at the Second Xiangya Hospital of Central South University from January 2010 to June 2022. RESULTS: Among the AAV children, there were 5 males and 20 females, with a median age of onset of 11.0 years. Involvement of the urinary system was seen in 18 cases (72%); respiratory system involvement in 10 cases (40%); skin involvement in 6 cases (24%); eye, ear, and nose involvement in 5 cases (20%); joint involvement in 4 cases (16%); digestive system involvement in 2 cases (8%). Eleven cases underwent kidney biopsy, with 5 cases (46%) showing focal type, 2 cases (18%) showing crescentic type, 2 cases (18%) showing mixed type, and 2 cases (18%) showing sclerotic type. Immune complex deposits were present in 5 cases (45%). Seven cases reached chronic kidney disease (CKD) stage V, with 2 cases resulting in death. Two cases underwent kidney transplantation. At the end of the follow-up period, 2 cases were at CKD stage II, and 1 case was at CKD stage III. Of the 16 cases of microscopic polyangiitis (MPA) group, 13 (81%) involved the urinary system. Of the 9 cases of granulomatosis with polyangiitis (GPA), 6 cases (66%) had sinusitis. Serum creatinine and uric acid levels were higher in the MPA group than in the GPA group (P<0.05), while red blood cell count and glomerular filtration rate were lower in the MPA group (P<0.05). CONCLUSIONS: AAV is more common in school-age female children, with MPA being the most common clinical subtype. The onset of AAV in children is mainly characterized by renal involvement, followed by respiratory system involvement. The renal pathology often presents as focal type with possible immune complex deposits. Children with MPA often have renal involvement, while those with GPA commonly have sinusitis. The prognosis of children with AAV is poor, often accompanied by renal insufficiency.

[Correlation of anti-C1q antibodies with active systemic lupus erythematosus and lupus nephritis in children]. / 抗C1qæŠ—ä½“ä¸Žå„¿ç«¥æ´»åŠ¨æ€§ç³»ç»Ÿæ€§çº¢æ–‘ç‹¼ç–®å’Œæ´»åŠ¨æ€§ç‹¼ç–®æ€§è‚¾ç‚Žçš„ç›¸å ³æ€§åˆ†æž.

OBJECTIVES: To study the correlation of anti-C1q antibodies with active systemic lupus erythematosus (SLE) and lupus nephritis (LN) in children, as well as their diagnostic value for active SLE and LN. METHODS: A retrospective selection of 90 hospitalized children with SLE at the Children's Medical Center of Second Xiangya Hospital, Central South University from January 2016 to March 2019 as the SLE group, all of whom were tested for anti-C1q antibodies. A control group was formed by collecting 70 hospitalized children with other autoimmune diseases (OAD) during the same period. The differences in anti-C1q antibody levels were compared between two groups.The correlation of anti-C1q antibodies with various indicators of SLE and LN was analyzed, and the diagnostic value of anti-C1q in SLE and LN was evaluated. RESULTS: The serum levels of anti-C1q antibodies in the SLE group were higher than those in the OAD group (P<0.05). The SLE disease activity index score was positively correlated with anti-C1q antibodies (rs=0.371, P<0.001) and positively correlated with anti-double-stranded DNA antibodies (rs=0.370, P<0.001). The sensitivity and specificity of anti-C1q antibodies for diagnosing active SLE were 89.90% and 53.90%, respectively, with an area under the curve of 0.720 (P<0.05) and a critical value of 5.45 U/mL. The sensitivity and specificity of anti-C1q antibody levels for diagnosing active LN were 58.50% and 85.00%, respectively, with an area under the curve of 0.675 (P<0.05) and a critical value of 22.05 U/mL. CONCLUSIONS: Anti-C1q antibodies can serve as non-invasive biomarkers for evaluating the activity of SLE or predicting the activity of LN in children.

An insertion in the promoter of a malate dehydrogenase gene regulates malic acid content in apple fruit.

Malic acid is an important flavor determinant in apple (Malus × domestica Borkh.) fruit. One known variation controlling malic acid is the A/G single nucleotide polymorphism in an aluminum-activated malate transporter gene (MdMa1). Nevertheless, there are still differences in malic acid content in apple varieties with the same Ma1 genotype (Ma1/Ma1 homozygous), such as 'Honeycrisp' (high malic acid content) and 'Qinguan' (low malic acid content), indicating that other loci may influence malic acid and fruit acidity. Here, the F1 (Filial 1) hybrid generation of 'Honeycrisp' × 'Qinguan' was used to analyze quantitative trait loci for malic acid content. A major locus (Ma7) was identified on chromosome 13. Within this locus, a malate dehydrogenase gene, MDH1 (MdMa7), was the best candidate for further study. Subcellular localization suggested that MdMa7 encodes a cytosolic protein. Overexpression and RNA interference of MdMa7 in apple fruit increased and decreased malic acid content, respectively. An insertion/deletion (indel) in the MdMa7 promoter was found to affect MdMa7 expression and malic acid content in both hybrids and other cultivated varieties. The insertion and deletion genotypes were designated as MA7 and ma7, respectively. The transcription factor MdbHLH74 was found to stimulate MdMa7 expression in the MA7 genotype but not in the ma7 genotype. Transient transformation of fruit showed that MdbHLH74 affected MdMa7 expression and malic acid content in 'Gala' (MA7/MA7) but not in 'Fuji' (ma7/ma7). Our results indicated that genetic variation in the MdMa7 (MDH1) promoter alters the binding ability of the transcription factor MdbHLH74, which alters MdMa7 (MDH1) transcription and the malic acid content in apple fruit, especially in Ma1/Ma1 homozygous accessions.

DNA methylation of IFI44L as a potential blood biomarker for childhood-onset systemic lupus erythematosus.

BACKGROUND: IFN-induced protein 44-like (IFI44L) promoter methylation has been demonstrated to serve as an effective blood diagnostic biomarker for adult-onset SLE. However, its utility as a diagnostic marker for childhood-onset SLE (cSLE) remains to be verified. METHODS: Initially, we conducted a differential analysis of gene methylation and mRNA expression patterns in cSLE whole blood samples obtained from the public GEO database to determine IFI44L gene expression and assess the methylation status at its CpG sites. Subsequently, we collected clinical whole blood samples from 49 cSLE patients and 12 healthy children, employing an HRM-qPCR-based IFI44L methylation detection technique to evaluate its diagnostic efficacy in pediatric clinical practice. RESULTS: A total of 26 hypomethylated, highly expressed genes in cSLE were identified by intersecting differentially expressed genes (DEGs) and differentially methylation genes (DMGs). GO enrichment analysis for these 26 genes indicated a robust association with type I IFN. Among the overlapping genes, IFI44L exhibited the most pronounced differential expression and methylation. In subsequent clinical validation experiments, IFI44L methylation was confirmed as an effective blood-based diagnostic biomarker for cSLE, achieving an AUC of 0.867, a sensitivity of 0.753, and a specificity of 1.000. CONCLUSIONS: IFI44L methylation is a promising blood biomarker for cSLE. IMPACT: IFI44L promoter methylation was reported to serve as a highly sensitive and specific diagnostic marker for adult-onset SLE. However, the diagnostic efficacy of IFI44L in childhood-onset SLE (cSLE) still remains to be confirmed. In this study, we utilized bioinformatics analysis and conducted clinical experiments to demonstrate that IFI44L methylation can also serve as a promising blood biomarker for cSLE. The findings of this study can facilitate the diagnosis of cSLE and broaden our understanding of its molecular mechanisms, with a particular focus on those related to type I interferons.

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss.

Sensorineural hearing loss (SNHL), a highly prevalent sensory impairment, results from a multifaceted interaction of genetic and environmental factors. As we continually gain insights into the molecular basis of auditory development and the growing compendium of deafness genes identified, research on gene therapy for SNHL has significantly deepened. Adeno-associated virus (AAV), considered a relatively secure vector for gene therapy in clinical trials, can deliver various transgenes based on gene therapy strategies such as gene replacement, gene silencing, gene editing, or gene addition to alleviate diverse types of SNHL. This review delved into the preclinical advances in AAV-based gene therapy for SNHL, spanning hereditary and acquired types. Particular focus is placed on the dual-AAV construction method and its application, the vector delivery route of mouse inner ear models (local, systemic, fetal, and cerebrospinal fluid administration), and the significant considerations in transforming from AAV-based animal model inner ear gene therapy to clinical implementation.