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Weill-Marchesani syndrome (WMS) is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, glaucoma and occasionally heart defects. Given these complex clinical manifestations and genetic heterogeneity, WMS patients presented misdiagnosed as high myopia or angle closure glaucoma. Here, we report ADAMTS17 mutations, a member of the extracellular matrix protease family, from a Chinese family. Patients have features that fall within the WMS spectrum. The exome (protein-coding regions of the genome) makes up ~1 % of the genome, it contains about 85% of known disease-related variants. Whole exome sequencing (WES) has been performed to identify the disease-associated genes, including one patient, his healthy sister, and his asymptomatic wife. Genome-wide homozygosity map was used to identify the disease caused locus. SNVs and INDELs were further predicted with MutationTaster, LRT, SIFT and SiPhy and compared to dbSNP150 and 1000 Genomes project. Filtered mutation was confirmed with Sanger sequencing in whole family members. The Genome-wide homozygosity map based on WES identified a total of 20 locus which were possible pathogenic. Further, a novel nonsense mutation c.1051A >T result in p.(lys351Ter) in ADAMTS17 had been identified in a candidate loci. The Sanger sequencing data has verified two consanguineous WMS patients in the family pedigree and revealed autosomal recessive (AR) inheritance pattern. The nonsense mutation in ADAMTS17 was analyzed in silico to explore its effects on protein function. We predicted the mutation produced non-function protein sequence. A novel nonsense mutation c.1051 A > T in ADAMTS17 had been identified caused autosomal recessive WMS in the Chinese family.

Malaria remains one of the most significant public health challenges globally, particularly in tropical and subtropical regions. Throughout evolutionary history, malaria-induced natural selection has profoundly influenced human genetic evolution, leading to the emergence of numerous genetic variations that confer resistance to the disease. These adaptations highlight the complicated interplay between pathogens and human genetics. This review focuses on key genetic variations associated with malaria resistance, including hemoglobinopathies (such as sickle cell trait and thalassemia), glucose-6-phosphate dehydrogenase deficiency, blood group polymorphisms and genetic variants related to inflammation and immune regulation. The prevalence of these genetic adaptations varies widely across different geographic regions, reflecting the historical burden of malaria in those areas. Despite significant advancements in genetic research, the precise mechanisms by which these mutations confer protection against malaria remain incompletely understood. Furthermore, the interactions between these genetic factors and environmental influences add to another layer of complexity. A comprehensive understanding of these genetic variations and their functional implications is crucial for advancing malaria epidemiology, improving diagnostic tools, and developing targeted prevention and control strategies, ultimately contributing to global efforts to eradicate malaria.

Background Renal fibrosis is characterized by the formation of scar tissue in the kidney parenchyma. Obesity, with its rising global incidence, has become a significant cause of renal fibrosis. This study investigates the effect of Scutellarin (SCU) on obesity-induced renal fibrosis. Methods Rats were fed a high-fat and high-sugar diet (HFSD) for 40 weeks. SCU was administered orally at doses of 25, 50, and 100 mg/kg/day during the last 8 weeks. Metabolic function was assessed by measuring serum triglycerides (TG), total cholesterol (TC), and glucose levels. Renal function was evaluated by analyzing serum uric acid (UA), creatinine (CRE), and blood urea nitrogen (BUN). RNA-seq was used to evaluate transcriptome changes in the kidney. Histopathological changes were examined using HE and Masson staining. Protein expressions and localization of FOS, JUN, FN, and TGF-β1 were analyzed by western blot, immunohistochemistry, and immunofluorescence. Results HFSD-fed rats exhibited significant increases in body weight, serum TG, TC, and glucose levels, alongside elevated UA, CRE, and BUN levels, indicating metabolic and renal dysfunction. SCU treatment significantly improved these metabolic and renal parameters across all doses. Biochemical analyses and RNA-seq results confirmed the absence of dose-dependency in the effects of SCU. Histopathological analysis showed a reduction in glomerular hypertrophy and collagen deposition in the SCU-treated groups. RNA-seq data indicated a downregulation of Activator Protein 1 (AP-1), composed of FOS and JUN, at the transcriptional level. Western blot analysis confirmed that SCU treatment reduced both the expression and phosphorylation levels of FOS and JUN. Additionally, SCU downregulated the expression of fibrosis-related proteins TGF-β1 and FN, contributing to a reduction in renal fibrosis. Conclusion SCU alleviates obesity-induced renal fibrosis through the downregulation of AP-1 activity and the expression level of fibrosis-related proteins TGF-β1 and FN.

Epidemiological studies provide compelling evidence that glucose-6-phosphate dehydrogenase (G6PD) deficiency individuals are relatively protected against Plasmodium parasite infection. However, the animal model studies on this subject are lacking. Plus, the underlying mechanism in vivo is poorly known. In this study, we used a G6pd-deficient mice infected with the rodent parasite Plasmodium berghei ( P.berghei ) to set up a malaria model in mice. We analyzed the pathological progression of experimental cerebral malaria (ECM) and acute liver injury in mice with different G6pd activity infected with P.berghei . We performed dual RNA-seq for host-parasite transcriptomics and validated the changes of proinflammatory response in the murine model. G6pd-deficient mice exhibited a survival advantage, less severe ECM and mild liver injury compared to the wild type mice. Analysis based on dual RNA-seq suggests that G6pd-deficient mice are protected from ECM and acute liver injury were related to proinflammatory responses. Th1 differentiation and dendritic cell maturation in the liver and spleen were inhibited in G6pd-deficient mice. The levels of proinflammatory cytokines were reduced, chemokines and vascular adhesion molecules in the brain were significantly down-regulated, these led to decreased cerebral microvascular obstruction in G6pd-deficient mice. We generated the result that G6pd-deficiency mediated protection against ECM and acute liver injury were driven by the regulatory proinflammatory responses. Furthermore, bioinformatics analyses showed that P.berghei might occur ribosome loss in G6pd-deficient mice. Our findings provide a novel perspective of the underlying mechanism of G6PD deficiency mediated protection against malaria in vivo .

Presenile cataract is a relatively rare type of cataract, but its genetic mechanisms are currently not well understood. The precise identification of these causative genes is crucial for effective genetic counseling for patients and their families. The aim of our study was to identify the causative gene associated with presenile cataract in a Chinese family. In February 2020, a four-generation pedigree of presenile cataract patients was recruited at the 2nd Affiliated Hospital of Kunming Medical University. One patient and her healthy husband from the family underwent whole exome sequencing. The variant was validated through sanger sequencing, and co-segregation analysis was conducted in all family members to assess its pathogenicity. Molecular dynamics simulation (MDS) was used to analyze the conformation of both the wild type and pathogenic mutant loci p.Y153H of CRYBA2. We identified presenile cataract in the pedigree, which follows an autosomal-dominant pattern of inheritance. The family includes five clinically affected patients who all developed presenile cataract between the ages from 24 to 30. We confirmed the pathogenicity of a heterozygous missense variant (NM_057093:c.457T >C) in CRYBA2 within this family. The affected amino acid demonstrates high conservation across species. Subsequent sanger sequencing confirmed co-segregation of the disease in all family members. MDS analysis revealed that the p.Y153H mutant disrupted hydrogen bond formation between Y153 and R193 within the two β-strands of the fourth Greek key domain, leading to destabilization of the βA2-crystallin. In conclusion, a novel causative mutation (NM_057093:c.457T>C) in CRYBA2 might contribute to autosomal dominant presenile cataract.

Abiotic stress reduces plant yield and quality. WRKY transcription factors play key roles in abiotic stress responses in plants, but the molecular mechanisms by which WRKY transcription factors mediate responses to drought and osmotic stresses in apple (Malus × domestica Borkh.) remain unclear. Here, we functionally characterized the apple Group III WRKY gene MdWRKY115. qRT-PCR analysis showed that MdWRKY115 expression was up-regulated by drought and osmotic stresses. GUS activity analysis revealed that the promoter activity of MdWRKY115 was enhanced under osmotic stress. Subcellular localization and transactivation assays indicated that MdWRKY115 was localized to the nucleus and had a transcriptional activity domain at the N-terminal region. Transgenic analysis revealed that the overexpression of MdWRKY115 in Arabidopsis plants and in apple callus markedly enhanced their tolerance to drought and osmotic stresses. DNA affinity purification sequencing showed that MdWRKY115 binds to the promoter of the stress-related gene MdRD22. This binding was further verified by an electrophoretic mobility shift assay. Collectively, these findings suggest that MdWRKY115 is an important regulator of osmotic and drought stress tolerance in apple.

Summary Glomerella leaf spot (GLS), caused by the fungus Colletotrichum fructicola, is considered one of the most destructive diseases affecting apples. The VQ‐WRKY complex plays a crucial role in the response of plants to biotic stresses. However, our understanding of the defensive role of the VQ‐WRKY complex on woody plants, particularly apples, under biotic stress, remains limited. In this study, we elucidated the molecular mechanisms underlying the defensive role of the apple MdVQ37‐MdWRKY100 module in response to GLS infection. The overexpression of MdWRKY100 enhanced resistance to C. fructicola, whereas MdWRKY100 RNA interference in apple plants reduced resistance to C. fructicola by affecting salicylic acid (SA) content and the expression level of the CC‐NBS‐LRR resistance gene MdRPM1. DAP‐seq, Y1H, EMSA, and RT‐qPCR assays indicated that MdWRKY100 inhibited the expression of MdWRKY17, a positive regulatory factor gene of SA degradation, upregulated the expression of MdPAL1, a key enzyme gene of SA biosynthesis, and promoted MdRPM1 expression by directly binding to their promotors. Transient overexpression and silencing experiments showed that MdPAL1 and MdRPM1 positively regulated GLS resistance in apples. Furthermore, the overexpression of MdVQ37 increased the susceptibility to C. fructicola by reducing the SA content and expression level of MdRPM1. Additionally, MdVQ37 interacted with MdWRKY100, which repressed the transcriptional activity of MdWRKY100. In summary, these results revealed the molecular mechanism through which the apple MdVQ37‐MdWRKY100 module responds to GLS infection by regulating SA content and MdRPM1 expression, providing novel insights into the involvement of the VQ‐WRKY complex in plant pathogen defence responses.

Multi-slice magnetic resonance images of the fetal brain are usually contaminated by severe and arbitrary fetal and maternal motion. Hence, stable and robust motion correction is necessary to reconstruct high-resolution 3D fetal brain volume for clinical diagnosis and quantitative analysis. However, the conventional registration-based correction has a limited capture range and is insufficient for detecting relatively large motions. Here, we present a novel Affinity Fusion-based Framework for Iteratively Random Motion (AFFIRM) correction of the multi-slice fetal brain MRI. It learns the sequential motion from multiple stacks of slices and integrates the features between 2D slices and reconstructed 3D volume using affinity fusion, which resembles the iterations between slice-to-volume registration and volumetric reconstruction in the regular pipeline. The method accurately estimates the motion regardless of brain orientations and outperforms other state-of-the-art learning-based methods on the simulated motion-corrupted data, with a 48.4% reduction of mean absolute error for rotation and 61.3% for displacement. We then incorporated AFFIRM into the multi-resolution slice-to-volume registration and tested it on the real-world fetal MRI scans at different gestation stages. The results indicated that adding AFFIRM to the conventional pipeline improved the success rate of fetal brain super-resolution reconstruction from 77.2% to 91.9%.

Purpose: Slice-to-volume registration and super-resolution reconstruction (SVR-SRR) is commonly used to generate 3D volumes of the fetal brain from 2D stacks of slices acquired in multiple orientations. A critical initial step in this pipeline is to select one stack with the minimum motion as a reference for registration. An accurate and unbiased motion assessment (MA) is thus crucial for successful selection. Methods: We presented a MA method that determines the minimum motion stack based on 3D low-rank approximation using CANDECOMP/PARAFAC (CP) decomposition. Compared to the current 2D singular value decomposition (SVD) based method that requires flattening stacks into matrices to obtain ranks, in which the spatial information is lost, the CP-based method can factorize 3D stack into low-rank and sparse components in a computationally efficient manner. The difference between the original stack and its low-rank approximation was proposed as the motion indicator. Results: Compared to SVD-based methods, our proposed CP-based MA demonstrated higher sensitivity in detecting small motion with a lower baseline bias. Experiments on randomly simulated motion illustrated that the proposed CP method achieved a higher success rate of 95.45% in identifying the minimum motion stack, compared to SVD-based method with a success rate of 58.18%. We further demonstrated that combining CP-based MA with existing SRR-SVR pipeline significantly improved 3D volume reconstruction. Conclusion: The proposed CP-based MA method showed superior performance compared to SVD-based methods with higher sensitivity to motion, success rate, and lower baseline bias, and can be used as a prior step to improve fetal brain reconstruction.