ObjectiveThe malaria parasites remodel the host erythrocyte structure by exporting parasite proteins that interact with the membrane skeleton proteins of red blood cells (RBCs), facilitating their intracellular survival and pathogenicity. Skeleton-binding protein 1 (SBP1) is a conserved exported protein across Plasmodium species. In Plasmodium falciparum, SBP1 has been reported to interact with erythrocyte membrane skeleton proteins 4.1R and spectrin, while its contribution to erythrocyte remodeling and parasite virulence in Plasmodium berghei (Pb) remains unclear. This study aims to determine whether PbSBP1 associates with the host cytoskeletal protein 4.1R and to investigate its role in the remodeling of host RBCs and the pathogenicity of Plasmodium berghei. MethodsIn Plasmodium berghei, the relationship between PbSBP1 and the erythrocyte cytoskeletal protein 4.1R was examined using co-immunoprecipitation. A Pbsbp1 gene knockout mutant of Plasmodium berghei (Pbsbp1∆) was generated based on the principle of double crossover homologous recombination. The deformability of erythrocytes infected with Pbsbp1∆ parasites was assessed using microfluidic methods. Microchannels with an array of cylindrical pillars were used to detect modifications in infected RBC deformability. The infected RBCs were squashed between the rows and recovered between the columns and the transit velocity (μm/s) of infected RBCs travelling through the microchannel was recorded. The component of the erythrocyte membrane skeleton junctional complex, tropomodulin (TMOD), was fluorescently labeled, and the cytoskeletal network of infected erythrocytes was imaged using super-resolution stochastic optical reconstruction microscopy (STORM) to analyze ultrastructural changes in the cytoskeleton of wild-type (WT) and Pbsbp1∆-infected erythrocytes. Actin-based junctional complexes were displayed as individual clusters by the labeled TMOD in the STORM images, and the cluster densities and distances between adjacent clusters of infected RBCs were calculated. Additionally, rodent malaria models (BALB/c mice) and experimental cerebral malaria models (C57BL/6 mice) were employed to monitor the growth of Pbsbp1∆ and WT parasites during the intraerythrocytic stage and their capacity to induce cerebral malaria in mice. ResultsPbSBP1 may participate in the remodeling of infected erythrocytes through direct or indirect interaction with the erythrocyte cytoskeletal protein 4.1R. Microfluidic assays revealed that the deformability of erythrocytes infected with Pbsbp1∆ parasites was significantly enhanced compared to those infected with WT parasites. STORM imaging further demonstrated that the ultrastructure of the erythrocyte cytoskeleton in Pbsbp1∆-infected cells was altered relative to that in WT-infected erythrocytes. The distances between nearest neighbors of clusters had a tendency to increase while the cluster densities were decreased in Pbsbp1∆-infected RBCs compared to WT-infected RBCs. Subsequent phenotypic analysis indicated that the growth rate of Pbsbp1∆ parasites during the intraerythrocytic stage was significantly slower than that of WT parasites, and their ability to induce cerebral malaria in mice was also attenuated. These findings suggest that PbSBP1 is involved in the remodeling of the erythrocyte membrane skeleton, likely through its direct or indirect interaction with protein 4.1R, thereby regulating the deformability of infected erythrocytes and influencing the pathogenicity of the blood-stage parasites. ConclusionThis study establishes a role for PbSBP1 in host erythrocyte remodeling and parasite virulence, providing new research strategies for the prevention and treatment of malaria.

BACKGROUND:At present,osteoarthritis has become a major disease affecting the quality of life of the elderly,and the therapeutic effect is poor,often focusing on preventing the disease process,and the pathogenesis of osteoarthritis is still not fully understood.Bioinformatics analysis was carried out to explore the main pathogenesis of osteoarthritis and related mechanisms of gene coding regulation. OBJECTIVE:To screen core differential genes with a major role in osteoarthritis by gene expression profiling. METHODS:Datasets were downloaded from the Gene Expression Omnibus(GEO):GSE114007,GSE117999,and GSE129147.Differential genes in the GSE114007 and GSE117999 data collections were screened using R software,performing differential genes to weighted gene co-expression network analysis.The module genes most relevant to osteoarthritis were selected to perform protein interaction analysis.Candidate core genes were selected using the cytocape software.The candidate core genes were subsequently subjected to least absolute shrinkage and selection operator regression and COX analysis to identify the core genes with a key role in osteoarthritis.The accuracy of the core genes was validated using an external dataset,GSE129147. RESULTS AND CONCLUSION:(1)A total of 477 differential genes were identified,265 differential genes associated with osteoarthritis were obtained by weighted gene co-expression network analysis,and 8 candidate core genes were identified.The least absolute shrinkage and selection operator regression analysis finally yielded a differential gene ASPM with core value that was externally validated.(2)It is concluded that abnormal gene ASPM expression screened by bioinformatics plays a key central role in osteoarthritis.

Sensorineural hearing loss is one of the most common sensory disorders. In recent years, auditory neuropathy spectrum disorders caused by mutations in the OTOF gene have garnered significant attention worldwide, marking it as the first deafness gene with breakthroughs in gene therapy. Most patients with OTOF gene mutations present with stable, congenital, or prelingual onset of hearing loss, which can range from severe to profound and even complete hearing loss. However, a minority of patients may exhibit mild to moderate progressive hearing loss or temperature-sensitive hearing loss. This review further explores the genotype-phenotype relationship of the OTOF gene based on reported cases in China and abroad. Additionally, we analyze the characteristics of the natural history of OTOF gene mutations within the Chinese population. This study aims to provide a reference for the clinical diagnosis, evaluation, and treatment of hearing loss associated with OTOF gene mutations.
Humans ; Mutation ; Phenotype ; Genotype ; Hearing Loss, Sensorineural/genetics* ; Membrane Proteins/genetics*

Objective:The clinical significance of aural fullness in patients with vestibular migraine（VM） remains unclear, and it is yet to be determined whether VM with aural fullness represents a distinct subtype of VM; this study aimed to compare differences in demographic characteristics, clinical manifestations, audiological findings, and vestibular function tests between VM patients with and without aural fullness, and explore whether the former is a subtype of VM and whether it requires differentiated treatment. Methods:A total of 174 VM patients were enrolled, including 75 with aural fullness（aural fullness group） and 99 without aural fullness（non-aural fullness group）; demographic data, vertigo characteristics, medical history, family history, pure-tone audiometry, and vestibular function tests were thoroughly recorded, and independent samples t-test and chi-square test were used for inter-group comparisons. Results:①Regarding demographic characteristics, the age of the aural fullness group was significantly lower than that of the non-aural fullness group[（44.08±13.97） years vs. （49.45±16.05） years, P=0.020）, while the two groups showed consistent gender distribution（more females than males） with no statistically significant difference. ②For aural fullness characteristics, unilateral aural fullness accounted for 65.0% in the aural fullness group, significantly higher than bilateral aural fullness（35.0%, P<0.001）. ③In terms of vertigo characteristics, there were no statistically significant inter-group differences in the nature of attacks（rotational vertigo: 36.0% vs. 41.4%, P=0.463; dizziness: 21.3% vs. 11.1%, P=0.064; rotational vertigo or dizziness: 29.3% vs. 25.3%, P=0.548; dizziness with unsteady gait: 9.3% vs. 11.1%, Fisher P=0.806; visual oscillation with unsteady gait: 4.0% vs. 11.1%, Fisher P=0.086）, duration（several hours: 34.7% vs. 33.3%, P=0.841; several minutes: 22.7% vs. 21.2%, P=0.808; several seconds: 5.3% vs. 8.1%, Fisher P=0.557; several days: 9.3% vs. 9.1%, Fisher P=1.000; multiple combined patterns: 17.3% vs. 15.2%, P=0.686）, or incidence of nausea and vomiting（84.0% vs. 72.7%, P=0.071, no statistical significance）. ④No statistically significant inter-group differences were found in medical history and family history, including motion sickness history（8.0% vs. 4.0%, Fisher P=0.337）, headache history（22.7% vs. 34.3%, P=0.084）, and family history of dizziness（12.0% vs. 14.1%, P=0.666）. ⑤For audiological characteristics, 21.3%（16/75） of patients in the aural fullness group had low-frequency hearing loss, significantly higher than 5.1% in the non-aural fullness group（χ²=10.66, P=0.001）; among patients with unilateral aural fullness, 28.6%（14/49） had ipsilateral low-frequency hearing loss, significantly higher than 7.7%（2/26） of those with bilateral aural fullness（χ²=4.41, P=0.036）; however, there was no statistically significant difference in the rate of bilateral high-frequency hearing loss between the two groups（54.7%[41/75]vs. 50.5%[50/99], χ²=0.30, P=0.586）. ⑥In vestibular function tests, no statistically significant inter-group differences were observed in smooth pursuit type Ⅲ/Ⅳ（12.5% vs. 13.1%, P=0.913）, caloric test with CP>25%（31.2% vs. 37.4%, P=0.411）, abnormal video head impulse test（vHIT） rate（30.8% vs. 32.6%, P=0.865）, or abnormal vestibular evoked myogenic potential（VEMP） rate（53.8% vs. 38.9%, Fisher P=0.484）. Conclusion:VM patients with aural fullness have an earlier age of onset, with nearly 1/4 accompanied by low-frequency hearing loss; VM patients with and without aural fullness are highly consistent in gender distribution, nature/duration of vertigo, vestibular function impairment, and presence of bilateral high-frequency hearing loss, suggesting that the core clinical phenotypes of the two groups are consistent, while the former has an earlier age of onset and a higher proportion of unilateral hearing loss, which may be related to the pathological mechanism of VM and inner ear microcirculation disorders.
Humans ; Female ; Male ; Middle Aged ; Adult ; Migraine Disorders/classification* ; Young Adult ; Vertigo ; Age of Onset ; Aged ; Hearing Loss

Objective To investigatethe relationship between gastroesophageal reflux disease (GERD) symptoms and clinicopathological characteristics, p53 expression, and survival of Chinese patients with esophageal adenocarcinoma. Methods A total of 3882 patients with esophageal adenocarcinoma, 970 matched patients with esophageal squamous cell carcinoma, and 970 matched patients with gastric cardia adenocarcinoma were included to compare the incidence of GERD symptoms. Patients with esophageal adenocarcinoma were divided into two groups according to the presence and absence of GERD symptoms. The differences in clinicopathological characteristics and p53 expression between the two groups were compared by chi-square test, and the differences in survival between the two groups were compared by landmark analysis. Results The incidence of GERD symptoms increased successively in esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastric cardia adenocarcinoma. In patients with esophageal adenocarcinoma, the proportions of male, less than 65 years old, lower thoracic tumors, tumors without squamous cell carcinoma, poorly differentiation, early tumors (stage 0-I), and p53-positive tumors in the group with GERD symptoms were higher than those in the group without GERD symptoms; moreover, the long-term survival (≥15 years) was better. Conclusion GERD symptom is an important clinical sign of esophageal adenocarcinoma. It is closely related to specific clinicopathological characteristics, p53 overexpression, and good long-term prognosis.

AIM: To investigate the correlation of serum interleukin-35(IL-35), immunoglobulin 4/immunoglobulin(IgG4/IgG), thyroid stimulating immunoglobulin(TSI)levels with the activity and severity of thyroid associated ophthalmopathy(TAO).METHODS:Prospective study. A total of 148 TAO patients admitted to our hospital from January 2023 to July 2024 were selected as the observation group. They were assigned into an active group(75 cases)and an inactive group(73 cases)based on their activity level, and were assigned into a severe group(95 cases)and a mild group(53 cases)based on the severity of their condition; another 148 healthy patients who underwent physical examinations were regarded as the control group. The levels of IL-35, IgG4/IgG, and TSI in serum were compared between the two groups. The correlation between serum IL-35, IgG4/IgG, and TSI levels and TAO activity and severity of illness were analyzed. A multivariate Logistic regression was performed to analyze the influencing factors of TAO patients developing severe symptoms. ROC curve was applied to analyze the diagnostic value of serum IL-35, IgG4/IgG, and TSI levels for the development of severe TAO in patients.RESULTS: Compared with the control group, the serum IL-35 level in the observation group was significantly lower, while IgG4/IgG and TSI levels were significantly higher(all P<0.01). Compared with non-active TAO patients, active TAO patients had significantly lower serum IL-35 level and significantly higher IgG4/IgG and TSI levels(all P<0.01). Compared with the mild TAO patients, severe TAO patients had significantly lower serum IL-35 level and significantly higher disease duration, IgG4/IgG, and TSI levels(all P<0.01). The serum IL-35 level was negatively correlated with TAO activity and disease severity(r=-0.529, -0.554, both P<0.01), while serum IgG4/IgG level was positively correlated with TAO activity and disease severity(r=0.625, 0.663, both P<0.01). Serum TSI levels were positively correlated with TAO activity and disease severity(r=0.594, 0.607, both P<0.01). Multivariate Logistic regression analysis showed that serum IL-35, IgG4/IgG, and TSI levels were all factors influencing the progression of TAO patients to severe disease(all P<0.01). The areas under the curve(AUC)for diagnosing the progression of TAO patients to severe disease using serum IL-35, IgG4/IgG, and TSI levels were 0.868, 0.859, and 0.830, respectively. The combined AUC for the three markers was 0.955, significantly higher than that of each individual marker(Zthree factors combination-IL-35=2.893, Zthree factors combination-IL-35=3.510, Zthree factors combination-IL-35=4.157, P=0.004, <0.01, <0.01).CONCLUSION: Serum IL-35 level is significantly downregulated in TAO patients, while IgG4/IgG and TSI levels are significantly upregulated. The levels of IL-35, IgG4/IgG, and TSI are correlated with the activity and severity of TAO, and their combination has high diagnostic value for TAO developing into severe.

Objective: To investigate the correlation among α2, 6-sialyltransferase (ST6Gal-Ⅰ), CD36 desialylation, and caveolin-1 (Cav-1) in phorbol ester (PMA)-induced MEG-01 cell model, as well as their potential mechanism in immune thrombocytopenia (ITP). Methods: MEG-01 cells were treated with 10 ng/mL PMA for 48 hours (control group: 0.1% DMSO). Flow cytometry was used to detect cell surface markers: desialylation (CD41 RCA ) and α2, 6-sialylation (CD41 SNA ). Western blot was performed to analyze the protein expressions of ST6Gal-Ⅰ, CD36, and Cav-1. Results: Flow cytometry analysis revealed that, compared with the control group (set as 100%), the proportion of CD41 RCA positive cells in the MEG-01 cells after PMA intervention significantly increased to (127.79±2.01)%, while the proportion of CD41 SNA positive cells significantly decreased to (78.09±1.76)% (both P<0.05). Western blot analysis results showed that, compared with the control group, PMA intervention significantly downregulated the expression of ST6Gal-Ⅰ protein (0.602±0.023 vs 0.768±0.068) and Cav-1 protein (1.012±0.028 vs 1.253±0.068) (both P<0.05), while significantly upregulating the expression of CD36 protein (0.936±0.033 vs 0.694±0.070, P<0.05). Conclusion: PMA can significantly inhibit the expression of ST6Gal-Ⅰ, accompanied by increased desialylation (β-galactose exposure), elevated CD36, and downregulated Cav-1. These changes suggest that the increased exposure of CD36 antigen and the disorder of membrane microenvironment may be involved in the pathological process of ITP, providing a new direction for mechanism research.

19 cinnamamide/ester-triazole compounds were designed, synthesized and evaluated for their anti-Alzheimer's disease (AD) activity. Among them, compound 4f displayed excellent anti-β-amyloid protein (Aβ)-mediated cytotoxicity (EC₅₀ = 2.03 ± 2.45 μmol·L^-1) in APPswe cells and acetylcholinesterase inhibiton (IC₅₀ = 4.88 ± 4.70 μmol·L^-1). Further study indicated that, at dosages of (1, 5 and 25 mg·kg^-1), compound 4f was effective in improving spatial learning and memory deficits in Aβ_1-42-impaired mice, which was achieved by promoting the nonamyloidogenic signaling and inhibiting the amyloidogenic pathway, along with the suppression of Aβ-induced Tau phosphorylation. All animal experiments in this study were approved by the Experimental Animal Care and Use Committee of the Institute of Medicinal Biotechnology (IMB-20220908D701). In conclusion, compound 4f holds promise as a lead candidate for AD treatment, and the present study lays the foundation for its subsequent development.