X-linked lymphoproliferative syndrome (XLP) is a rare X-linked recessive inborn errors of immunity. The pathogenesis of XLP might be related to phophatidylinositol-3-kinase (PI3K)-associated pathways but insight details remain unclear. This study was to study an infant XLP-1 case caused by a mutation in SH2D1A gene, investigate the structural and functional alteration of mutant SAP protein, and explore the potential role of PI3K-associated pathways in the progression of XLP-1.The proband's condition was monitored by laboratory and imagological examinations. Whole exome sequencing and Sanger sequencing were performed to detect the genetic disorder. Bioinformatics tools including PolyPhen-2, SWISS-MODEL and SWISS-PDB Viewer were used to predict the pathogenicity and estimate structural change of mutant protein. Flow cytometry was used to investigate expression of SAP and PI3K-associated proteins.The proband was diagnosed with XLP-1 caused by a hemizygous mutation c.96G > T in SH2D1A gene resulting in a missense substitution of Arginine to Serine at the site of amino acid 32 (p.R32S). The mutant protein contained a hydrogen bond turnover at the site of mutation and was predicted to be highly pathogenic. Expression of SH2D1A encoded protein SAP was downregulated in proband. The PI3K-AKT-mTOR signaling pathway was fully activated in XLP-1 patients, but it was inactive or only partially activated in healthy people or HLH patients.The mutation c.96G > T in SH2D1A gene caused structural and functional changes in the SAP protein, resulting in XLP-1. The PI3K-AKT-mTOR signaling pathway may play a role in XLP-1 pathogenesis.
Scutellariae Radix(SR), derived from the dried root of Scutellaria baicalensis in the family Lamiaceae, commonly serves as Chinese medicinal material. Affected by producing areas, growing years, and harvesting periods, the quality of SR fluctuates in the market. However, baicalin≥9% in SR required in the Chinese Pharmacopoeia(2020 edition) can only determine the qualified SR but cannot identify high-quality SR. To improve the quality control methods of SR, the present study analyzed the accumulation of metabolites in SR of different growth years by plant metabolomics, and identified 28 metabolites increasing with growth years(1-3 years). Subsequently, 14 main metabolites were quantitatively analyzed by ultra-high performance liquid chromatography-tandem triple quadrupole mass spectrometry(UPLC-QQQ-MS). Among them, baicalin, wogonoside, baicalein, and wogonin with high content and good activity were selected as the index components of SR for quality evaluation. A high-performance liquid chromatography(HPLC) method was established to determine the content of four index components in 32 batches of SR from different producing areas, harvesting perio-ds, and growth years. The results showed that the growth years could greatly affect the content of index components. The total content of four index components in 2-year SR was the highest, followed by the 3-/4-year SR and 1-year SR. Based on HPLC data and verification results by enterprises, baicalin ≥12.0%, wogonoside ≥2.3%, baicalein ≥0.1%, and wogonin ≥0.03% were proposed as the evaluation criteria for the high-quality SR. The findings of this study are expected to provide a basis for improving the quality of SR.
Enhancing the willingness to pay (WTP) for earthquake insurance for rural houses (EIRH) and transferring earthquake risk is extremely important for rural economic growth, especially in the Xinjiang Uygur Autonomous Region (Xinjiang), where earthquake disasters frequently occur. However, there is a gap between the WTP found in EIRH research and the actual demand present in this field. In this paper, we collect 400 questionnaires from among farmers in Xinjiang and conducted one-on-one empirical interviews with four government managers. Via descriptive statistics, the control variable method, and binary regression analysis, we examine the effects of farmers' basic information, risk perception, and risk transfer on WTP. The results reveal that (1) the WTP of farmers is positively correlated with their education level, and the WTP of farmers with poor disaster resistance (aged 40-49 or incomes below 30,000 RMB) is higher. (2) Among earthquake risk perceptions, awareness is correlated positively with WTP, worry and experience are negatively correlated with WTP, and likelihood and controllability are irrelevant with regard to WTP. (3) Farmers recognize EIRH as a risk transfer mechanism, but they are more dependent on government assistance. (4) The increase in WTP is more obvious when the proportion of government subsidies is in the range of either 30-50% or 70-90%. Thus, we suggest that Xinjiang promotes EIRH by adjusting the proportion of subsidies and strengthening the popularization of disaster risk knowledge, which is of great practical significance to promoting the stable development of the rural economy in Xinjiang.
Kawasaki disease (KD) is a systemic vasculitis that is caused by immunological dysregulation in children exposed to pathogens like Epstein-Barr virus (EBV). Myocardial ischemia or infarction due to coronary artery lesions (CALs) might be lethal. However, it is unclear how pathogens, immunomodulation, and CALs interact, particularly in KD patients co-infected with the most widespread virus, EBV.We investigated pathogen carriage and fundamental clinical data in 281 KD patients. Immunological differences between CALs and non-CALs in KD patients under different conditions were analyzed. Then, the effect of infection by different pathogens on the immune response was excluded, and most EBV co-infected KD patients were included to assess the incidence of CALs, the level of immune modulation, and regulatory mechanisms in different EBV infection states.Our results showed multiple pathogenic infections occur in KD patients, with EBV being the most prevalent. The incidence of CALs in the EBV-DNA (+) acute infection group, EBV-DNA (-) acute infection group, and EBV latent infection group was 0 (0/6), 27.27% (3/11) and 41.67% (10/24), respectively. The two groups were younger and had increased IL-6 levels and B cells, decreasing CD8+ T cells than the EBV-DNA (+) acute infection group. Interestingly, the increased B cells were not associated with immunoglobulin release. Additionally, these patients down-regulated α7 nicotinic acetylcholine receptor (α7nAChR) and downstream molecule PI3K/AKT/mTOR while activating the NF-κB.Patients with different EBV infection statuses exhibit different incidences of CALs. In acute EBV-DNA (-) infected and latent EBV-infected patients, the number of CD8+ T cells decreased and downregulated CD8+ T cells' α7nAChR and PI3K/AKT/mTOR, which may associate with CALs, while the expression of NF-κB and the pro-inflammatory factor IL-6 was upregulated by inhibiting the anti-inflammatory molecule α7nAChR.
Abstract Rationale: Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by thrombocytopenia, small platelets, eczema, immunodeficiency, and an increased risk of autoimmunity and malignancies. X-linked thrombocytopenia (XLT), the milder phenotype of WAS, is always limited to thrombocytopenia with absent or slight infections and eczema. Here, we illustrated the clinical and molecular characteristics of 2 unrelated patients with WAS from Chinese minorities. Patient concerns: Patient 1, a 13-day-old male newborn of the Chinese Lahu minority, showed a classic WAS phenotype, including thrombocytopenia, small platelets, buttock eczema, and recurrent infections. Patient 2, an 8-year-and 8-month-old boy of the Chinese Zhuang minority, presented an XLT phenotype without eczema and repeated infections. Diagnosis: Next-generation sequencing was performed to investigate the genetic variations. Flow cytometry was used to quantify the expression of WAS protein and analyze the lymphocyte subsets. A novel frameshift WAS mutation (c.927delC, p.Q310Rfs∗135) and a known nonsense WAS mutation (c.1090C>T, p.R364X) were identified in Patient 1 and Patient 2, respectively. Both patients were confirmed to have WAS protein deficiency, which was more severe in Patient 1. Meanwhile, the analysis of lymphocyte subsets revealed an abnormality in Patient 1, but not in Patient 2. Combined with the above clinical data and genetic characteristics, Patient 1 and Patient 2 were diagnosed as classic WAS and XLT, respectively. In addition, many miliary nodules were accidentally found in abdominal cavity of Patient 2 during appendectomy. Subsequently, Patient 2 was confirmed with pulmonary and abdominal tuberculosis through further laboratory and imaging examinations. To our knowledge, there have been only a few reports about WAS/XLT with tuberculosis. Interventions: Both patients received anti-infection therapy, platelet transfusions, and intravenous immunoglobulins. Moreover, Patient 2 also received antituberculosis treatment with ethambutol and amoxicillin-clavulanate. Outcomes: The clinical symptoms and hematological parameters of these 2 patients were significantly improved. Regrettably, both patients discontinued the treatment for financial reasons. Lessons: Our report expands the pathogenic mutation spectrum of WAS gene and emphasizes the importance of molecular genetic testing in diagnosing WAS. Furthermore, researching and reporting rare cases of WAS from different populations will facilitate diagnosis and treatment of this disease.
The eco-hydrological process related to vegetation on the Qinghai–Tibet Plateau is special, and the impact of snow cover on the growth of vegetation is unique and important. In this study, we analyzed the multi-year variations in the normalized difference vegetation index (NDVI) and snow cover on the Qinghai–Tibet Plateau from spatial and temporal perspectives and determined the relationship between the changes in the NDVI and snow cover. Results showed that in the last 40 years, the rate of change in the snow depth on the plateau was −0.016 mm/a, and the NDVI changed by 0.0005/a. The correlations (|R| values) between the different factors and the NDVI followed the order of precipitation (0.77) > snow depth (0.76) > temperature (0.67) > solar radiation (0.21). The responses of the NDVI to changes in meteorological elements were synchronous, whereas the opposite was found for the snow cover. The snow cover had more significant impacts on vegetation at higher elevations. The NDVI had a lag of about 2 months from the onset of the snow cover, and heavy snow events had negative impacts on the NDVI for more than 3 years. Our findings will facilitate studies of ecological vulnerability and the predictions of changes in vegetation on the plateau.
Abstract Background Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare autosomal recessive disorder characterized by severe pre‐ and postnatal growth restrictions, microcephaly, skeletal dysplasia, severe teeth deformities, and typical facial features. Previous studies have shown that MOPD II is associated with mutations in the pericentrin ( PCNT ) gene. Methods We evaluated the clinical features of a 10‐year and 7‐month‐old Chinese girl with MOPD II. Subsequently, next‐generation sequencing and flow cytometry were performed to investigate genetic characteristics and the expression of PCNT protein respectively. Results The patient presented with short stature, microcephaly, typical craniofacial features, teeth deformity, thrombocytosis, and a delayed bone age (approximately 7 years). No abnormality in growth hormone or insulin‐like growth factor 1 was detected. Notably, the patient was found to carry a novel homozygous PCNT mutation (c.6157G>T, p.Glu2053Ter), which was inherited from her healthy heterozygous parents. Meanwhile, significant deficiency of PCNT expression was identified in the patient. Conclusion Our study identified a novel PCNT mutation associated with MOPD II, expanded the mutation spectrum of the PCNT gene and improved our understanding of the molecular basis of MOPD II.
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