bluuebunny/crossref_metadata_2025 huggingface dataset:
Case report: Prenatal diagnosis of Kagami–Ogata syndrome in a Chinese family
Authors: Hu Junjie , Zhang Ying , Yang Yanmei , Wang Liya , Sun Yixi , Dong Minyue
Published: August 2022

The aim of this work was to explore the genetic cause of the proband (Ⅲ2) presenting with polyhydramnios and gastroschisis. Copy number variation sequencing (CNV-seq), methylation-specific multiplex PCR (MS-PCR), and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used to characterize the genetic etiology. CNV-seq revealed a deletion of 732.26 kb at 14q32.2q32.31 in the proband (Ⅲ2) and its mother (Ⅱ2). MS-PCR showed the maternal allele was missing in the proband, while paternal allele was missing in its mother. MS-MLPA showed deletion of the DLK1, MEG3, MIR380, and RTL1 genes of both the proband and its mother. MEG3 imprinting gene methylation increased in the proband, while decreased in its mother. It was indicated that a maternally transmitted deletion was responsible for Kagami–Ogata syndrome in the proband (Ⅲ2), and the de novo paternal deletion resulted in Temple syndrome in the mother (Ⅱ2). Prenatal diagnosis was provided at 17+3 weeks of pregnancy on the mother’s fourth pregnancy (Ⅲ4). Fortunately, the karyotype and single-nucleotide polymorphism array (SNP array) results were normal. The current investigation provided the detection methods for imprinted gene diseases, expanded the phenotype spectrum of the disease, and obtained the insight into the diagnosis, prenatal diagnosis, and genetic counseling of the disease.
Prediction of metal ion ligand binding residues by adding disorder value and propensity factors based on deep learning algorithm
Authors: Hao Sixi , Hu Xiuzhen , Feng Zhenxing , Sun Kai , You Xiaoxiao , Wang Ziyang , Yang Caiyun
Published: August 2022

Proteins need to interact with different ligands to perform their functions. Among the ligands, the metal ion is a major ligand. At present, the prediction of protein metal ion ligand binding residues is a challenge. In this study, we selected Zn2+, Cu2+, Fe2+, Fe3+, Co2+, Mn2+, Ca2+ and Mg2+ metal ion ligands from the BioLip database as the research objects. Based on the amino acids, the physicochemical properties and predicted structural information, we introduced the disorder value as the feature parameter. In addition, based on the component information, position weight matrix and information entropy, we introduced the propensity factor as prediction parameters. Then, we used the deep neural network algorithm for the prediction. Furtherly, we made an optimization for the hyper-parameters of the deep learning algorithm and obtained improved results than the previous IonSeq method.
ROCK inhibition with Y-27632 reduces joint inflammation and damage in serum-induced arthritis model and decreases in vitro osteoclastogenesis in patients with early arthritis
Authors: Rodríguez-Trillo Angela , Pena Carmen , García Samuel , Pérez-Pampín Eva , Rodríguez-López Marina , Mera-Varela Antonio , González Antonio , Conde Carmen
Published: August 2022

Rheumatoid arthritis (RA) is a common chronic inflammatory disease affecting primarily peripheral joints, which is only partially controlled with current treatments. RA leads to pain, disability, deformities, and life expectancy shortening. Its pathogenesis is complex involving multiple cell types and signaling pathways that we incompletely understand. One of the pathways we have elucidated starts with WNT5A signaling and contributes to the aggressive phenotype of the RA synoviocytes through RYK-RhoA/ROCK signaling. Now, we have explored the contribution of ROCK to arthritisin vivo, using the K/BxN serum-transfer arthritis model; and to osteoclastogenesis, using the arthritis model and cells from patients with inflammatory arthritis. The mice and cells were treated with the ROCK inhibitor Y-27632 that caused a significant improvement of arthritis and reduction of osteoclastogenesis. The improvement in mouse arthritis was observed in the clinical evaluation and, histologically, in synovial inflammation, cartilage damage, bone erosion, and the abundance of multinucleated TRAP+ cells. Expression of inflammatory mediators in the arthritic joints, as assessed by real-time PCR, was also significantly reduced. The effect on bone was confirmed within vitroassays using bone marrow precursors of arthritic mice and peripheral blood monocytes of patients with inflammatory arthritis. These assays showed dramatically reduced osteoclastogenesis and bone resorption. Overall, our findings suggest that ROCK inhibition could be part of a therapeutic strategy for RA by its dual action on inflammation and bone erosion.
Integrated analysis to reveal potential therapeutic targets and prognostic biomarkers of skin cutaneous melanoma
Authors: Zhou Xuezhi , Rong Rong , Xiong Siqi , Song Weitao , Ji Dan , Xia Xiaobo
Published: August 2022

Skin cutaneous melanoma (SKCM) is a malignant tumor with high mortality rate in human, and its occurrence and development are jointly regulated by genes and the environment. However, the specific pathogenesis of SKCM is not completely understood. In recent years, an increasing number of studies have reported the important role of competing endogenous RNA (ceRNA) regulatory networks in various tumors; however, the complexity and specific biological effects of the ceRNA regulatory network of SKCM remain unclear. In the present study, we obtained a ceRNA regulatory network of long non-coding RNAs, microRNAs, and mRNAs related to the phosphatase and tensin homolog (PTEN) in SKCM and identified the potential diagnostic and prognostic markers related to SKCM. We extracted the above three types of RNA involved in SKCM from The Cancer Genome Atlas database. Through bioinformatics analysis, the OIP5-AS1-hsa-miR-186-5p/hsa-miR-616-3p/hsa-miR-135a-5p/hsa-miR-23b-3p/hsa-miR-374b-5p-PTPRC/IL7R/CD69 and MALAT1-hsa-miR-135a-5p/hsa-miR-23b-3p/hsa-miR-374b-5p-IL7R/CD69 ceRNA networks were found to be related to the prognosis of SKCM. Finally, we determined the OIP5-AS1-PTPRC/IL7R/CD69 and MALAT1-IL7R/CD69 axes in ceRNA as a clinical prognostic model using correlation and Cox regression analyses. Additionally, we explored the possible role of these two axes in affecting gene expression and immune microenvironment changes and the occurrence and development of SKCM through methylation and immune infiltration analyses. In summary, the ceRNA-based OIP5-AS1-PTPRC/IL7R/CD69 and MALAT1-IL7R/CD69 axes may be a novel and important approach for the diagnosis and prognosis of SKCM.
Reconstitution of the immune system and clinical correlates after stem cell transplantation for systemic sclerosis
Authors: Kawashima-Vasconcelos Marianna Y. , Santana-Gonçalves Maynara , Zanin-Silva Djúlio C. , Malmegrim Kelen C. R. , Oliveira Maria Carolina
Published: August 2022

Systemic sclerosis (SSc) is a chronic autoimmune disease that includes fibrosis, diffuse vasculopathy, inflammation, and autoimmunity. Autologous hematopoietic stem cell transplantation (auto-HSCT) is considered for patients with severe and progressive SSc. In recent decades, knowledge about patient management and clinical outcomes after auto-HSCT has significantly improved. Mechanistic studies have contributed to increasing the comprehension of how profound and long-lasting are the modifications to the immune system induced by transplantation. This review revisits the immune monitoring studies after auto-HSCT for SSc patients and how they relate to clinical outcomes. This understanding is essential to further improve clinical applications of auto-HSCT and enhance patient outcomes.
Shear Characteristics of Gravel Soil With Different Fillers
Authors: Zhang Huahua , Luo Yi , Yuan Siyu , Zhou Yuru , Zhou Qiong , Zeng Fanrong , Feng Wei
Published: August 2022

In recent years, China has established many large water conservancy projects in the western mountainous areas. However, dam foundation excavation produces a huge amount of waste rock mixture. A soil-rock mixture with unique structural characteristics can easily cause geological disasters, such as collapse, landslide, and debris flow following an earthquake, rainfall, and engineering disturbance. Therefore, research on the strength and shear characteristics of the soil-rock mixture is beneficial to avoiding soil-rock mixture disasters. In this study, the soil-rock mixture in the slag dump site of Jinping Hydropower station is taken as the research object. The influence of different fillers on the gravel soil shear characteristics is investigated through a large-scale triaxial test of coarse-grained soil. The slope stability of the slag dump site is analyzed using Midas GTS. Then, the most unfavorable sliding surface of the slag dump site is discovered and the slope stability coefficient under the most unfavorable conditions is calculated. The results lay a scientific foundation for the design and construction of a slag dump slope.
Cross-sectional and longitudinal associations of serum Cysteine-rich 61 with severity and prognosis among community-acquired pneumonia patients in China
Authors: Yao Meng-Xing , Cheng Jia-Yi , Liu Ying , Sun Jing , Hua Dong-Xu , He Qi-Yuan , Liu Hong-Yan , Fu Lin , Zhao Hui
Published: August 2022

Background

Cysteine-rich 61 (CYR61) is implicated in many pulmonary diseases. However, the relationship between CYR61 and community-acquired pneumonia (CAP) patients was unknown. This research aimed to estimate the correlations of serum CYR61 with severity and prognosis in CAP patients through a prospective cohort study.

Methods

All 541 CAP patients were enrolled in this study. Fasting venous blood was collected. Clinical characteristics and demographic information were obtained. CYR61 and inflammatory cytokines were detected in serum using ELISA.

Results

Serum CYR61 was gradually increased in parallel with severity scores in CAP patients. Correlative analysis indicated that serum CYR61 was strongly associated with many clinical parameters in CAP patients. Moreover, mixed logistic and linear regression models found that there were positive correlations between serum CYR61 and CAP severity scores after adjusted for age, BMI, and respiratory rate. Stratified analyses suggested that age affected the associations between serum CYR61 and severity scores. On admission, higher serum CYR61 levels elevated the risks of mechanical ventilation, vasoactive agent, ICU admission, death, and longer hospital stays during hospitalization. Moreover, serum CYR61 in combination with severity scores upregulated the predictive capacities for severity and death than single serum CYR61 or severity scores in CAP patients.

Conclusion

There are significantly positive dose-response associations of serum CYR61 on admission with the severity and adverse prognostic outcomes, demonstrating that CYR61 is involved in the pathophysiology of CAP. Serum CYR61 may be used as a potential biomarker for the diagnosis and prognosis in CAP patients.
Molecular identification of T-box transcription factor 6 and prognostic assessment in patients with congenital scoliosis: A single-center study
Authors: Zhang Wenyan , Yao Ziming , Guo Ruolan , Li Haichong , Zhao Shuang , Li Wei , Zhang Xuejun , Hao Chanjuan
Published: August 2022

Background

Congenital scoliosis (CS) is characterized by vertebral malformations. The precise etiology of CS is not fully defined. A compound inheritance of TBX6 was identified in 10% of patients with CS in Han Chinese and formed a distinguishable subtype named TBX6-associated congenital scoliosis (TACS).

Methods

To investigate the variants and risk haplotype of TBX6, we recruited 121 patients with CS at Beijing Children’s Hospital. We collected the clinical characteristics and surgical treatment options and followed their postoperative prognoses.

Results

Eight patients (6.6%) were molecularly diagnosed with TACS and carried the previously defined pathogenic TBX6 compound heterozygous variants. All the eight patients with TACS had the typical TACS clinical feature of hemivertebrae in the lower part of the spine. These patients received posterior hemivertebra resection combined with segmental fusion. Follow-ups revealed satisfactory correction without postoperative complications.

Conclusion

We observed a 6.6% prevalence of TACS in our CS cohort. Follow-ups further highlighted that surgical treatment of hemivertebra resection combined with segmental fusion performed well with prognosis for patients with TACS. This could provide valuable information for CS individuals with compound heterozygosity in TBX6.
Cloning of a novel tetrahydrofolate-dependent dicamba demethylase gene from dicamba-degrading consortium and characterization of the gene product
Authors: Li Na , Chen Le , Chen E. , Yuan Cansheng , Zhang Hao , He Jian
Published: August 2022

Dicamba, an important hormone-type systemic herbicide, is widely used to control more than 200 kinds of broadleaf weeds in agriculture. Due to its broad-spectrum, high efficiency and effectively killing glyphosate-resistant weeds, dicamba is considered as an excellent target herbicide for the engineering of herbicide-resistant crops. In this study, an efficient dicamba-degrading microbial consortium was enriched from soil collected from the outfall of a pesticide factory. The enriched consortium could almost completely degrade 500 mg/L of dicamba within 12 h of incubation. A novel tetrahydrofolate (THF)-dependent dicamba demethylase gene, named dmt06, was cloned from the total DNA of the enriched consortium. Dmt06 shared the highest identity (72.3%) with dicamba demethylase Dmt50 from Rhizorhabdus dicambivorans Ndbn-20. Dmt06 was expressed in Escherichia coli BL21 and purified to homogeneity using Co2+-charged nitrilotriacetic acid affinity chromatography. The purified Dmt06 catalyzed the transfer of methyl from dicamba to THF, generating the herbicidally inactive metabolite 3,6-dichlorosalicylate (3,6-DCSA) and 5-methyl-THF. The optimum pH and temperature for Dmt06 were detected to be 7.4 and 35°C, respectively. Under the optimal condition, the specific activity of Dmt06 reached 165 nmol/min/mg toward dicamba, which was much higher than that of Dmt and Dmt50. In conclusion, this study cloned a novel gene, dmt06, encoding an efficient THF-dependent dicamba demethylase, which was a good candidate for dicamba-resistant transgenic engineering.
Development of Nanomaterials to Target Articular Cartilage for Osteoarthritis Therapy
Authors: Rao Chenyu , Shi Sirong
Published: August 2022

Osteoarthritis (OA) is an obstinate, degradative, and complicated disease that has drawn much attention worldwide. Characterized by its stubborn symptoms and various sequela, OA causes much financial burden on both patients and the health system. What’s more, conventional systematic therapy is not effective enough and causes multiple side effects. There’s much evidence that nanoparticles have unique properties such as high penetration, biostability, and large specific surface area. Thus, it is urgent to exploit novel medications for OA. Nanomaterials have been sufficiently studied, exploiting diverse nano-drug delivery systems (DDSs) and targeted nano therapeutical molecules. The nanomaterials are primarily intra-articular injected under the advantages of high topical concentration and low dosage. After administration, the DDS and targeted nano therapeutical molecules can specifically react with the components, including cartilage and synovium of a joint in OA, furthermore attenuate the chondrocyte apoptosis, matrix degradation, and macrophage recruitment. Thus, arthritis would be alleviated. The DDSs could load with conventional anti-inflammatory drugs, antibodies, RNA, and so on, targeting chondrocytes, synovium, or extracellular matrix (ECM) and releasing the molecules sequentially. The targeted nano therapeutical molecules could directly get to the targeted tissue, alleviating the inflammation and promoting tissue healing. This review will comprehensively collect and evaluate the targeted nanomaterials to articular cartilage in OA.
Discriminating different materials by means of vibrations
Authors: Lisini Baldi Tommaso , Marullo Sara , D’Aurizio Nicole , Prattichizzo Domenico
Published: August 2022

Material characterization and discrimination is of interest for multiple applications, ranging from mechanical engineering to medical and industrial sectors. Despite the need for automated systems, the majority of the existing approaches necessitate expensive and bulky hardware that cannot be used outside ad-hoc laboratories. In this work, we propose a novel technique for discriminating between different materials and detecting intra-material variations using active stimulation through vibration and machine learning techniques. A voice-coil actuator and a tri-axial accelerometer are used for generating and sampling mechanical vibration propagated through the materials. Results of the present analysis confirm the effectiveness of the proposed approach. Processing a mechanical vibration signal that propagates through a material by means of a neural network is a viable means for material classification. This holds not only for distinguishing materials having gross differences, but also for detecting whether a material underwent some slight changes in its structure. In addition, mechanical vibrations at 500 Hz demonstrated an ability to provide a compact and meaningful representation of the data, sufficient to categorize 8 different materials, and to distinguish reference materials from other defective materials, with an average accuracy greater than 90%.
The role of neutrophils in the dysfunction of central nervous system barriers
Authors: Santos-Lima Bruno , Pietronigro Enrica Caterina , Terrabuio Eleonora , Zenaro Elena , Constantin Gabriela
Published: August 2022

Leukocyte migration into the central nervous system (CNS) represents a central process in the development of neurological diseases with a detrimental inflammatory component. Infiltrating neutrophils have been detected inside the brain of patients with several neuroinflammatory disorders, including stroke, multiple sclerosis and Alzheimer’s disease. During inflammatory responses, these highly reactive innate immune cells can rapidly extravasate and release a plethora of pro-inflammatory and cytotoxic factors, potentially inducing significant collateral tissue damage. Indeed, several studies have shown that neutrophils promote blood-brain barrier damage and increased vascular permeability during neuroinflammatory diseases. Recent studies have shown that neutrophils migrate into the meninges and choroid plexus, suggesting these cells can also damage the blood-cerebrospinal fluid barrier (BCSFB). In this review, we discuss the emerging role of neutrophils in the dysfunction of brain barriers across different neuroinflammatory conditions and describe the molecular basis and cellular interplays involved in neutrophil-mediated injury of the CNS borders.
Novel insight into m6A regulator-mediated methylation modification patterns and immune characteristics in intracranial aneurysm
Authors: Li Shifu , Zhang Qian , Weng Ling , Han Ying , Li Jian
Published: August 2022

Background

Growing evidence demonstrated that m6A modification in cardiovascular diseases. However, how it is involved in the intracranial aneurysm (IA) is still unclear. This study aimed to identify the role of m6A modification in IA.

Methods

Three datasets downloaded from the Gene Expression Omnibus (GEO) database were used, including GSE122897, GSE15629, and GSE3679. The landscapes of 24 m6A regulators were depicted using the STRING database, Pearson’s correlation analysis, and Wilcoxon test. The targets of differentially expressed m6A (DEm6A) were predicted in the m6A2Target database and the modification m6A sites of hub targets were identified in SRAMP online tool. A diagnostic model based on DEm6A was constructed and verified in training and test databases. A consensus clustering algorithm was performed to classify IA patients into distinct m6A-related clusters. Functional analyses including gene ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set variation analysis, and gene set enrichment analysis analyses were conducted to elucidate the underlying mechanisms. ssGSEA algorithm was performed to uncover the immune characteristics. A PCA method was adopted to quantify the m6A score.

Results

Nine DEm6A (IGF2BP1, IGF2BP3, YTHDF2, ZNF217, RBM15, YTHDF3, YTHDC1, FTO, and LRPPRC) significantly differed between IA and controls. Biological annotations showed that immune-related pathways (such as complement activation, inflammatory response, and interleukin signaling) and apoptosis were more enriched in IAs than in controls. Immune analyses indicate that the abundance of immune cells, immune responses, and HLA gene expression were elevated in IA samples than in controls. PCA results showed that IA has a lower m6A score than controls. An immune/apoptosis-related network modified by DEm6A was constructed. The m6A sites of six hub targets (CDK1, ASPM, AURKB, BUB1B, MKI67, and TPX2) were predicted with very high confidence. A diagnostic model with four genes (LRPPRC, YTHDF3, IGF2BP1, and ZNF217) was constructed and verified. Two m6A modification subtypes were identified with unsupervised cluster analysis. Immune infiltration analysis revealed that cluster 1 had higher immune activation than cluster 2. Further study showed that cluster 1 had a larger proportion of ruptured IAs.

Conclusion

The m6A modification may shape the IAs microenvironment and participates in the formation and rupture of IAs by regulating immune infiltration.
Cytoarchitecture, intersubject variability, and 3D mapping of four new areas of the human anterior prefrontal cortex
Authors: Bruno Ariane , Bludau Sebastian , Mohlberg Hartmut , Amunts Katrin
Published: August 2022

The dorsolateral prefrontal cortex (DLPFC) plays a key role in cognitive control and executive functions, including working memory, attention, value encoding, decision making, monitoring, and controlling behavioral strategies. However, the relationships between this variety of functions and the underlying cortical areas, which specifically contribute to these functions, are not yet well-understood. Existing microstructural maps differ in the number, localization, and extent of areas of the DLPFC. Moreover, there is a considerable intersubject variability both in the sulcal pattern and in the microstructure of this region, which impedes comparison with functional neuroimaging studies. The aim of this study was to provide microstructural, cytoarchitectonic maps of the human anterior DLPFC in 3D space. Therefore, we analyzed 10 human post-mortem brains and mapped their borders using a well-established approach based on statistical image analysis. Four new areas (i.e., SFS1, SFS2, MFG1, and MFG2) were identified in serial, cell-body stained brain sections that occupy the anterior superior frontal sulcus and middle frontal gyrus, i.e., a region corresponding to parts of Brodmann areas 9 and 46. Differences between areas in cytoarchitecture were captured using gray level index profiles, reflecting changes in the volume fraction of cell bodies from the surface of the brain to the cortex-white matter border. A hierarchical cluster analysis of these profiles indicated that areas of the anterior DLPFC displayed higher cytoarchitectonic similarity between each other than to areas of the neighboring frontal pole (areas Fp1 and Fp2), Broca's region (areas 44 and 45) of the ventral prefrontal cortex, and posterior DLPFC areas (8d1, 8d2, 8v1, and 8v2). Area-specific, cytoarchitectonic differences were found between the brains of males and females. The individual areas were 3D-reconstructed, and probability maps were created in the MNI Colin27 and ICBM152casym reference spaces to take the variability of areas in stereotaxic space into account. The new maps contribute to Julich-Brain and are publicly available as a resource for studying neuroimaging data, helping to clarify the functional and organizational principles of the human prefrontal cortex.
Guilt is effectively induced by a written auto-biographical essay but not reduced by experimental pain
Authors: Schär Selina , Vehlen Antonia , Ebneter Julia , Schicktanz Nathalie , de Quervain Dominique J. F. , Wittmann Lutz , Götzmann Lutz , grosse Holtforth Martin , Protic Sonja , Wettstein Alexander , Egloff Niklaus , Streitberger Konrad , Schwegler Kyrill I. M.
Published: August 2022

Introduction

The aim of the present study was (1) to validate the method of guilt-induction by means of a written auto-biographical essay and (2) to test whether experimental pain is apt to alleviate the mental burden of guilt, a concept receiving support from both empirical research and clinical observation.

Methods

Three independent groups of healthy male participants were recruited. Group allocation was not randomized but within group pain/sham administration was counterbalanced over the two test-days. Groups were tested in the following consecutive order: Group A: guilt induction, heat-pain/sham, N = 59; Group B: guilt induction, cold-pressure-pain/sham,N= 43; Group C: emotionally neutral induction, heat-pain/sham,N= 39. Guilt was induced on both test-days in group A and B before pain/sham administration. Visual analog scale (VAS) guilt ratings immediately after pain/sham stimulation served as the primary outcome. In a control group C the identical heat-pain experiment was performed like in group A but a neutral emotional state was induced.

Results

A consistently strong overall effect of guilt-induction (heat-pain:p< 0.001,effect size r= 0.71; CPT-painp< 0.001,r= 0.67) was found when compared to the control-condition (p= 0.25,r= 0.08). As expected, heat- and cold-pressure-stimuli were highly painful in all groups (p< 0.0001,r= 0.89). However, previous research supporting the hypothesis that pain is apt to reduce guilt was not replicated.

Conclusion

Although guilt-induction was highly effective on both test-days no impact of pain on behavioral guilt-ratings in healthy individuals could be identified. Guilt induction per se did not depend on the order of testing. The result questions previous experimental work on the impact of pain on moral emotions.
Expanding the clinicopathological-genetic spectrum of glycogen storage disease type IXd by a Chinese neuromuscular center
Authors: Huang Kun , Duan Hui-Qian , Li Qiu-Xiang , Luo Yue-Bei , Bi Fang-Fang , Yang Huan
Published: August 2022

Background

Glycogen storage disease (GSDs) is characterized by abnormally inherited glycogen metabolism. GSD IXd, which is caused by mutations in the PHKA1 gene, is an X-linked rare disease with mild myopathic symptoms. To date, only 13 patients with GSD IXd have been reported. In this study, we aimed to expand the clinicopathological-genetic spectrum of GSD IXd at a neuromuscular center in China.

Methods

Data on patients diagnosed with GSD IXd at our neuromuscular center were collected retrospectively. Clinical features, electrophysiology, muscle pathology, and genetic information were analyzed.

Results

Between 2015 and 2021, three patients were diagnosed with GSD IXd based on clinical manifestations, pathological findings, and genetic testing. One patient presented with mitochondrial myopathy. All patients exhibited muscle weakness and elevated levels of creatine kinase. Electromyography-detected myopathic changes were found in two patients, whereas one patient refused to undergo this examination. Pathological examinations in all patients revealed subsarcolemmal accumulation of glycogen under PAS staining. All patients had mutations in the PHKA1 gene and the patient with mitochondrial myopathy also had a mutation in the MT-TL1 gene.

Conclusion

Our study expands the clinicogenotype and phenotype of GSD IXd in a Chinese population. Our study also expands the known mutation spectrum for GSD IXd, contributing to a better characterization and understanding of this ultrarare neuromuscular disorder.
A radiomics nomogram for invasiveness prediction in lung adenocarcinoma manifesting as part-solid nodules with solid components smaller than 6 mm
Authors: Zhang Teng , Zhang Chengxiu , Zhong Yan , Sun Yingli , Wang Haijie , Li Hai , Yang Guang , Zhu Quan , Yuan Mei
Published: August 2022

Objective

To investigate whether radiomics can help radiologists and thoracic surgeons accurately predict invasive adenocarcinoma (IAC) manifesting as part-solid nodules (PSNs) with solid components <6 mm and provide a basis for rational clinical decision-making.

Materials and Methods

In total, 1,210 patients (mean age ± standard deviation: 54.28 ± 11.38 years, 374 men and 836 women) from our hospital and another hospital with 1,248 PSNs pathologically diagnosed with adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), or IAC were enrolled in this study. Among them, 1,050 cases from our hospital were randomly divided into a derivation set (n = 735) and an internal validation set (n = 315), 198 cases from another hospital were used for external validation. Each labeled nodule was segmented, and 105 radiomics features were extracted. Least absolute shrinkage and selection operator (LASSO) was used to calculate Rad-score and build the radiomics model. Multivariable logistic regression was conducted to identify the clinicoradiological predictors and establish the clinical-radiographic model. The combined model and predictive nomogram were developed based on identified clinicoradiological independent predictors and Rad-score using multivariable logistic regression analysis. The predictive performances of the three models were compared via receiver operating characteristic (ROC) curve analysis. Decision curve analysis (DCA) was performed on both the internal and external validation sets to evaluate the clinical utility of the nomogram.

Results

The radiomics model showed superior predictive performance than the clinical-radiographic model in both internal and external validation sets (Az values, 0.884 vs. 0.810, p = 0.001; 0.924 vs. 0.855, p < 0.001, respectively). The combined model showed comparable predictive performance to the radiomics model (Az values, 0.887 vs. 0.884, p = 0.398; 0.917 vs. 0.924, p = 0.271, respectively). The clinical application value of the nomogram developed based on the Rad-score, maximum diameter, and lesion shape was confirmed, and DCA demonstrated that application of the Rad-score would be beneficial for radiologists predicting invasive lesions.

Conclusions

Radiomics has the potential as an independent diagnostic tool to predict the invasiveness of PSNs with solid components <6 mm.
Comprehensive analysis of ferroptosis-related gene signatures as a potential therapeutic target for acute myeloid leukemia: A bioinformatics analysis and experimental verification
Authors: Zheng Zhiyuan , Hong Xiaoying , Huang Xiaoxue , Jiang Xiandong , Jiang He , Huang Yingying , Wu Wei , Xue Yan , Lin Donghong
Published: August 2022

Background

Ferroptosis plays an important role in the development of acute myeloid leukemia (AML); however, the exact role of ferroptosis-related genes in the prognosis of AML patients is unclear.

Methods

RNA sequencing data and the clinicopathological characteristics of AML patients were obtained from The Cancer Genome Atlas database, and ferroptosis-related genes were obtained from the FerrDb database. Cox regression analysis and least absolute shrinkage and selection operator analysis were performed to identify ferroptosis-related gene signatures. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and single-sample gene set enrichment analysis (ssGSEA) were performed to explore the biological functions of the ferroptosis-related genes. Finally, ferroptosis of AML cells was induced by erastin and sulfasalazine to detect the changes in the expression of relevant prognostic genes and explore the underlying mechanisms using quantitative real-time polymerase chain reaction (qRT-PCR).

Results

Seven ferroptosis-related gene signatures (SOCS1, ACSF2, MYB, EIF2AK4, AIFM2, SLC7A11, and GPX4) were identified in the training group. Kaplan-Meier and Cox regression analyses confirmed that risk score was an independent prognostic predictor of AML in the training and validation groups (P<0.05). Further, functional enrichment analysis revealed that seven ferroptosis-related genes were associated with many immune-related biological processes. Most importantly, erastin and sulfasalazine can induce the ferroptosis of AML cells. Overall, SLC7A11 and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and potential regulatory pathway in erastin- and sulfasalazine-induced ferroptosis of AML cells.

Conclusions

A novel signature involving seven ferroptosis-related genes that could accurately predict AML prognosis was identified. Further, the Food and Drug Administration-approved drug, sulfasalazine, was demonstrated for the first time to induce the ferroptosis of AML cells. SLC7A11 and the SLC7A11/xCT-GSH-GPX4 pathway may be the respective key gene and underlying mechanism in this process, ultimately providing new insights into the strategies for the development of new AML therapies.
Crocin-I Protects Against High-Fat Diet-Induced Obesity via Modulation of Gut Microbiota and Intestinal Inflammation in Mice
Authors: Xie Xiaoxian , Zhang Mengya , Sun Lei , Wang Ting , Zhu Zhengyan , Shu Ruonan , Wu Fengchun , Li Zezhi
Published: August 2022

Crocin-I can regulate physiological changes in the human body by altering inflammation and microbial composition. Gut microbiota are also involved in modulating the pathophysiology of obesity. However, crocin-I’s effect on obesity and the mechanism underlying its effects on gut microbiota and inflammation remain poorly understood. Here, high-fat diet (HFD) -induced obese mice were administrated crocin-I (20 mg/kg/day) for 10 weeks using an oral gavage (HFD-C20 group). HFD-C20, HFD, and Normal chow (NC) groups were compared. The fat content, colon tissue inflammatory cytokine levels, gut microbiota, and short-chain fatty acids (SCFAs) levels were measured. We show that crocin-I reduced body weight and liver weight and improved glucose resistance in HFD-induced mice, and reduced the lipid accumulation in the liver. Strikingly, crocin-I alleviated intestinal microbial disorders and decreased the F/B ratio and the abundance of Proteobacteria in HFD-induced obese mice. Crocin-I also rescued the decrease in the levels of SCFAs and repaired altered intestinal barrier functioning and intestinal inflammation in HFD-induced obese mice. These findings indicate that crocin-I may inhibit obesity by modulating the composition of gut microbiota and intestinal inflammation.
Posaconazole inhibits the stemness of cancer stem-like cells by inducing autophagy and suppressing the Wnt/β-catenin/survivin signaling pathway in glioblastoma
Authors: Wang Hua , Tan Yinfeng , Jia Hao , Liu Danqi , Liu Rangru
Published: August 2022

Posaconazole (POS) has been reported to present potential antitumor activity for glioblastoma (GBM). However, its molecular mechanisms remain unclear. In this study, we found that POS has potent cytotoxicity and inhibits cell viability and proliferation in GBM. In addition, we adopted a sphere formation assay to detect the self-renewal capacity, performed western blotting to measure cancer stem-like cells (CSCs) marker proteins (CD133, SOX2, Nanog and Oct4) and applied flow cytometry to monitor the subpopulation of CD144+/CD33+ cells, and the results all demonstrated that POS can remarkably weaken CSCs stemness. Furthermore, western blotting, immunoflurescence, transmission electron microscopy and acridine orange staining were performed to detect autophagy-related proteins (LC3, SQSTM1, Beclin 1 and Atg5), count the numbers of endogenous LC3 puncta, visually observe the ultrastructural morphology of autophagosomes and judge the formation of acidic vesicular organelles, respectively, and the results validated that POS promotes autophagy induction. Importantly, the suppressive effect of POS on CSCs stemness was partially relieved when autophagy was blocked by the autophagy inhibitor chloroquine (CQ) or Atg5 shRNA. Bioinformatic techniques, including weighted gene coexpression network analysis (WGCNA), gene set difference analysis (GSVA) and KEGG pathway analysis, combined with experimental validations showed that survivin, which is implicated in both autophagy and the stem cell index, is one of the target proteins of POS and that POS weakens CSCs stemness via suppressing the Wnt/β-catenin signaling pathway in GBM. Besides, POS-induced autophagy and the Wnt/β-catenin signaling pathway are negative regulators for each other. Finally, the antitumor activity of POS was confirmed in GBM xenograft models in vivo. Consistent with the in vitro conclusions, POS upregulated the expression of LC3 and decreased the expression of CD133, survivin and β-catenin, as shown by the immunohistochemistry analysis. In summary, this work provides an experimental foundation for exploiting POS as a CSCs-targeting antitumor drug for GBM treatment.
Chaperone activity of niflumic acid on ClC-1 chloride channel mutants causing myotonia congenita
Authors: Altamura Concetta , Conte Elena , Campanale Carmen , Laghetti Paola , Saltarella Ilaria , Camerino Giulia Maria , Imbrici Paola , Desaphy Jean-François
Published: August 2022

Myotonia congenita (MC) is an inherited rare disease characterized by impaired muscle relaxation after contraction, resulting in muscle stiffness. It is caused by loss-of-function mutations in the skeletal muscle chloride channel ClC-1, important for the stabilization of resting membrane potential and for the repolarization phase of action potentials. Thanks to in vitro functional studies, the molecular mechanisms by which ClC-1 mutations alter chloride ion influx into the cell have been in part clarified, classifying them in “gating-defective” or “expression-defective” mutations. To date, the treatment of MC is only palliative because no direct ClC-1 activator is available. An ideal drug should be one which is able to correct biophysical defects of ClC-1 in the case of gating-defective mutations or a drug capable to recover ClC-1 protein expression on the plasma membrane for trafficking-defective ones. In this study, we tested the ability of niflumic acid (NFA), a commercial nonsteroidal anti-inflammatory drug, to act as a pharmacological chaperone on trafficking-defective MC mutants (A531V, V947E). Wild-type (WT) or MC mutant ClC-1 channels were expressed in HEK293 cells and whole-cell chloride currents were recorded with the patch-clamp technique before and after NFA incubation. Membrane biotinylation assays and western blot were performed to support electrophysiological results. A531V and V947E mutations caused a decrease in chloride current density due to a reduction of ClC-1 total protein level and channel expression on the plasma membrane. The treatment of A531V and V947E-transfected cells with 50 µM NFA restored chloride currents, reaching levels similar to those of WT. Furthermore, no significant difference was observed in voltage dependence, suggesting that NFA increased protein membrane expression without altering the function of ClC-1. Indeed, biochemical experiments confirmed that V947E total protein expression and its plasma membrane distribution were recovered after NFA incubation, reaching protein levels similar to WT. Thus, the use of NFA as a pharmacological chaperone in trafficking defective ClC-1 channel mutations could represent a good strategy in the treatment of MC. Because of the favorable safety profile of this drug, our study may easily open the way for confirmatory human pilot studies aimed at verifying the antimyotonic activity of NFA in selected patients carrying specific ClC-1 channel mutations.
Histological, physiological, and transcriptomic responses of hepatopancreas to air exposure in asian freshwater clam Corbicula fluminea
Authors: Zhang Ting , Xu Dongpu , Lv Guohua , Wang Anqi , Wen Haibo
Published: August 2022

Corbicula fluminea (C. fluminea) is an important freshwater economy shellfish in China, but it often suffers from air exposure during transportation. In this study, we investigated the histological, physiological (mainly including respiratory metabolism, antioxidant capacity, and immune function), and transcriptomic responses of hepatopancreas in C. fluminea to different times of air exposure. At histological level, air exposure caused vacuolation of digestive cells (24–96 h) and enlargement of digestive tubule lumen (6–96 h) in hepatopancreas. At physiological level, the activities of enzymes related to glycolysis (hexokinase and pyruvate kinase) and anaerobic respiration (lactate dehydrogenase) were increased first (6–24 h) of air exposure, then came back to normal level or even decreased. The activity of aerobic respiration-related enzyme (succinic dehydrogenase) began to reduce from 24 h of air exposure. The activities of antioxidant enzymes (superoxide dismutase and catalase) were enhanced during 6–48 h of air exposure and then returned to control level or even inhibited. The content of malondialdehyde (MDA) increased from 96 h of air exposure. The activities of immune-related enzymes (acid phosphatase and alkaline phosphatase) increased during 6–48 h, then returned to normal or began to decline. At transcriptome level, 44 differentially expressed genes (DEGs) in the hepatopancreas were identified after 96-h air exposure. Among these DEGs, 8 were associated with glycolysis, TCA cycle, immune, and antioxidant, and were downregulated after 96-h air exposure. Taken together, these findings illuminated the response of C. fluminea to air exposure at histological, physiological, and transcriptomic levels, which will be beneficial to the aquaculture and transportation of C. fluminea.
Plant Growth-Promoting Rhizobacteria Eliminate the Effect of Drought Stress in Plants: A Review
Authors: Ahmad Hafiz Muhammad , Fiaz Sajid , Hafeez Sumaira , Zahra Sadaf , Shah Adnan Noor , Gul Bushra , Aziz Omar , Mahmood-Ur-Rahman  , Fakhar Ali , Rafique Mazhar , Chen Yinglong , Yang Seung Hwan , Wang Xiukang
Published: August 2022

Plants evolve diverse mechanisms to eliminate the drastic effect of biotic and abiotic stresses. Drought is the most hazardous abiotic stress causing huge losses to crop yield worldwide. Osmotic stress decreases relative water and chlorophyll content and increases the accumulation of osmolytes, epicuticular wax content, antioxidant enzymatic activities, reactive oxygen species, secondary metabolites, membrane lipid peroxidation, and abscisic acid. Plant growth-promoting rhizobacteria (PGPR) eliminate the effect of drought stress by altering root morphology, regulating the stress-responsive genes, producing phytohormones, osmolytes, siderophores, volatile organic compounds, and exopolysaccharides, and improving the 1-aminocyclopropane-1-carboxylate deaminase activities. The use of PGPR is an alternative approach to traditional breeding and biotechnology for enhancing crop productivity. Hence, that can promote drought tolerance in important agricultural crops and could be used to minimize crop losses under limited water conditions. This review deals with recent progress on the use of PGPR to eliminate the harmful effects of drought stress in traditional agriculture crops.
Physiological and transcriptional responses to heat stress and functional analyses of PsHSPs in tree peony (Paeonia suffruticosa)
Authors: Ma Jin , Wang Jie , Wang Qun , Shang Linxue , Zhao Yu , Zhang Guozhe , Ma Qingqing , Hong Sidan , Gu Cuihua
Published: August 2022

Tree peony (Paeonia suffruticosa) is a traditional Chinese flower that is not resistant to high temperatures, and the frequent sunburn during summer limits its normal growth. The lack of understanding of the molecular mechanisms in tree peony has greatly restricted the improvement of novel heat-tolerant varieties. Therefore, we treated tree peony cultivar “Yuhong” (P. suffruticosa “Yuhong”) at normal (25°C) and high temperatures (40°C) and sequenced the transcriptomes, to investigate the molecular responsive mechanisms to heat stress. By comparing the transcriptomes, a total of 7,673 differentially expressed genes (DEGs) were detected comprising 4,220 upregulated and 3,453 downregulated genes. Functional annotation showed that the DEGs were mainly related to the metabolic process, cells and binding, carbon metabolism, and endoplasmic reticulum protein processing. qRT-PCR revealed that three sHSP genes (PsHSP17.8, PsHSP21, and PsHSP27.4) were upregulated in the response of tree peony to heat stress. Tissue quantification of the transgenic lines (Arabidopsis thaliana) showed that all three genes were most highly expressed in the leaves. The survival rates of transgenic lines (PsHSP17.8, PsHSP21, and PsHSP27.4) restored to normal growth after high-temperature treatment were 43, 36, and 31%, respectively. In addition, the activity of superoxide dismutase, accumulation of free proline, and chlorophyll level was higher than those of the wild-type lines, while the malondialdehyde content and conductivity were lower, and the membrane lipid peroxidation reaction of the wild-type plant was more intense. Our research found several processes and pathways related to heat resistance in tree peony including metabolic process, single-organism process, phenylpropane biosynthesis pathway, and endoplasmic reticulum protein synthesis pathway. PsHSP17.8, PsHSP21, and PsHSP27.4 improved heat tolerance by increasing SOD activity and proline content. These findings can provide genetic resources for understanding the heat-resistance response of tree peony and benefit future germplasm innovation.
Fertility analysis of intraspecific hybrids in Vitis vinifera and screening of superior hybrid combinations
Authors: Wang Zhi-Lei , Yao Fei , Hui Miao , Wu Dong , Wang Ying , Han Xing , Cao Xiao , Li Yi-Han , Li Hua , Wang Hua
Published: August 2022

The correlations were explored between fertility indicators of intraspecific V. vinifera hybrids and different cultivars were subjected to selfing or used in reciprocal crosses by testing them as female parents or male parents. Two cold-resistant and four high-quality cultivars were selected, and the offspring of fourteen crosses and six self-combinations were evaluated. The pollen viability of the six cultivars was determined by TTC staining. Compatibility and the rates of fruit-setting, seediness, germination, emergence, and seedling were measured as parameters that can affect fertility of both hybridization and self-crossing processes. Using principal component analysis, the six fertility indexes were transformed into comprehensive principal components, and the weights of the indexes were determined. Combined with the membership function method, the fertility index was comprehensively evaluated for different crosses to screen for hybrid combinations with higher fertility. The results showed a high positive correlation between the pollen viability of the cultivar subjected to selfing and the fruit-setting rate, seediness rate, and hybrid compatibility index of the cultivar used as the male parent for crossing. Additionally, there was a one-to-one positive correlation between the fruit-setting rate, germination rate, emergence rate, and seedling rate of the selfed cultivar and the fruit-setting rate, germination rate, and seedling rate of the cultivar used as the female parent for crossing. There was some variation in the comprehensive fertility index values for the parents and combinations in different years. The comprehensive fertility index was always the highest for Ecolly as the male parent. The composite fertility index values were relatively high when Dunkelfelder, Cabernet Sauvignon, or Marselan were used as the female parent. The combinations of C1 (Cabernet Sauvignon × Ecolly), C3 (Marselan × Ecolly) and C6 (Dunkelfelder × Ecolly) exhibited relatively high comprehensive fertility indices, and pedigree clustering shows that these three combinations cluster into one class of highly fertile hybrid combinations. This study provides the basis for effective intraspecific hybrid breeding of grape (V. vinifera).