ZCCHC8 p.P410A disrupts nucleocytoplasmic localization, promoting idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. METHODS: Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. RESULTS: Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. CONCLUSIONS: We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.

A compound heterozygous mutation of ERCC8 is responsible for a family with Cockayne syndrome.

BACKGROUND: Cockayne syndrome is an inherited heterogeneous defect in transcription-coupled DNA repair (TCR) cause severe clinical syndromes, which may affect the nervous system development of infants and even lead to premature death in some cases. ERCC8 diverse critical roles in the nucleotide excision repair (NER) complex, which is one of the disease-causing genes of Cockayne syndrome. METHODS AND RESULTS: The mutation of ERCC8 in the patient was identified and validated using WES and Sanger sequencing. Specifically, a compound heterozygous mutation (c.454_460dupGTCTCCA p. T154Sfs*13 and c.755_759delGTTTT p.C252Yfs*3) of ERCC8 (CSA) was found, which could potentially be the genetic cause of Cockayne syndrome in the proband. CONCLUSION: In this study, we identified a novel heterozygous mutation of ERCC8 in a Chinese family with Cockayne syndrome, which enlarging the genetic spectrum of the disease.

Analysis of Antioxidant Compounds in Vitex negundo Leaves Using Offline 2D-LC-ECD and LC-MS/MS.

Vitex negundo has strong antioxidant activity, but its primary antioxidant components are not clear. In this study, the antioxidant components were screened by offline two-dimensional liquid chromatography coupled with electrochemical detection (2D-LC-ECD) and subsequently assessed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) identification, radical scavenging capacity, and molecular docking. Various fractions were isolated from Vitex negundo leaves, and 39 antioxidant components were screened and identified. All of the fractions containing the antioxidant components exhibited certain antioxidant activity. Correlation analysis revealed a strong correlation between the response of LC-ECD and the in vitro antioxidant activity of the fractions. Molecular docking demonstrated that components with high response to LC-ECD exhibited robust interaction with antioxidant-related target proteins. The main antioxidant components of Vitex negundo leaves were isoorientin, chlorogenic acid, agnuside, cynaroside, and scutellarin. The 2D-LC-ECD combined with LC-MS/MS was rapid and effective in screening the antioxidant components in Vitex negundo leaves and could also provide technical support for the discovery of antioxidant components with different polarities and contents in other medicinal and edible plants.

Characterizing the remobilization flux of cadmium from pre-anthesis vegetative pools in rice during grain filling using an improved stable isotope labeling method.

A clear understanding of the allocation of Cd to grains is essential to manage the level of Cd in cereal diets effectively. Yet, debate remains over whether and how the pre-anthesis pools contribute to grain Cd accumulation, resulting in uncertainty regarding the need to control plant Cd uptake during vegetative growth. To this end, rice seedlings were exposed to 111Cd labeled solution until tillering, transplanted to unlabeled soils, and grown under open-air conditions. The remobilization of Cd derived from pre-anthesis vegetative pools was studied through the fluxes of 111Cd-enriched label among organs during grain filling. The 111Cd label was continuously allocated to the grain after anthesis. The lower leaves remobilized the Cd label during the earlier stage of grain development, which was allocated almost equally to the grains and husks + rachis. During the final stage, the Cd label was strongly remobilized from the roots and, less importantly, the internodes, which was strongly allocated to the nodes and, to a less extent, the grains. The results show that the pre-anthesis vegetative pools are an important source of Cd in rice grains. The lower leaves, internodes, and roots are the source organs, whereas the husks + rachis and nodes are the sinks competing with the grain for the remobilized Cd. This study provides insight into understanding the ecophysiological mechanism of Cd remobilization and setting agronomic measures for lowering grain Cd levels.

Differential Effects of Senescence on the Phloem Exports of Cadmium and Zinc from Leaves to Grains in Rice during Grain Filling.

In rice, non-essential toxic cadmium (Cd) and the essential nutrient zinc (Zn) share similar transport pathways, which makes it challenging to differentially regulate the allocation of these elements to the grain. The phloem is the main pathway for the loading of these elements into rice grains. It has long been accepted that tissue senescence makes the nutrients (e.g., Zn) stored in leaves available for further phloem export toward the grain. Whether senescence could drive the phloem export of Cd remains unclear. To this end, the stable isotopes 111Cd and 67Zn were used to trace the phloem export and the subsequent allocation of Cd and Zn from the flag leaves, where senescence was accelerated by spraying abscisic acid. Furthermore, changes upon senescence in the distribution of these elements among the leaf subcellular fractions and in the expression of key transporter genes were investigated. Abscisic acid-induced senescence enhanced the phloem export of Zn but had no impact on that of Cd, which was explained by the significant release of Zn from the chloroplast and cytosol fractions (concentrations decreased by ~50%) but a strong allocation of Cd to the cell wall fraction (concentration increased by ~90%) during senescence. Nevertheless, neither Zn nor Cd concentrations in the grain were affected, since senescence strengthened the sequestration of phloem-exported Zn in the uppermost node, but did not impact that of phloem-exported Cd. This study suggests that the agronomic strategies affecting tissue senescence could be utilized to differentially regulate Cd and Zn allocation in rice during grain filling.

Prognostic factors for squamous cervical carcinoma identified by competing-risks analysis: A study based on the SEER database.

Cervical cancer has a high incidence of malignant tumors and a high mortality rate, with squamous cervical carcinoma (SCC) accounting for 80% of cases. A competing-risks model is recommended as being more feasible for evaluating the prognosis and guiding clinical practice in the future compared to Cox regression. Data originating from the Surveillance, epidemiology, and end results (SEER) database during 2004 to 2013 were analyzed. Univariate analysis with the cumulative incidence function was performed to assess the potential risk of each covariate. Significant covariates (P < .05) were extracted for inclusion in a Cox regression analysis and a competing-risks model that included a cause-specific (CS) hazard function model and a sub-distribution (SD) hazard function model. A total of 5591 SCC patients met the inclusion criteria. The three methods (Cox regression analysis, CS analysis, and SD analysis) showed that age, metastasis, American Joint Committee on Cancer stage, surgery, chemotherapy, radiation sequence with surgery, lymph node dissection, tumor size, and tumor grade were prognostic factors affecting survival in patients with SCC. In contrast, race and radiation status were prognostic factors affecting survival in the Cox regression and CS analysis, but the results were different in the SD analysis. Being separated, divorced, or widowed was an independent prognostic factor in the Cox regression analysis, but the results were different in the CS and SD analyses. A competing-risks model was used as a new statistical method to more accurately identify prognostic factors than conventional Cox regression analysis leading to bias in the results. This study found that the SD model may be better suited to estimate the clinical prognosis of a patient, and that the results of an SD model analysis were close to those of a CS analysis.