The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes much milder changes in far fewer genes. The abnormal gene expression is cardiomyocyte-autonomous and can be rescued by an enzyme-dead HDAC3 mutant but not by an HDAC3 mutant (Δ33-70) that lacks interaction with the nuclear-envelope protein lamina-associated polypeptide 2β (LAP2β). Tethering LAP2β to the HDAC3 Δ33-70 mutant restored its ability to rescue gene expression. Finally, HDAC3 depletion, not loss of HDAC3 enzymatic activity, exacerbates cardiac contractile functions upon aortic constriction. These results suggest that the cardiac function of HDAC3 in adults is not attributable to its enzyme activity, which has implications for understanding the cardioprotective effects of HDIs.

Objective:To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS).Methods:An adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was enrolled as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X).Results:Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c. 206+ 2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the patients mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+ PM2_Supporting). Conclusion:The heterozygous splice site variant c. 206+ 2T>G of the SMAD3 gene probably underlay the disease of this patient. The discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.

OBJECTIVE: To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS). METHODS: A adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was selected as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X). RESULTS: Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c.206+2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the proband's mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION The heterozygous splice site variant c.206+2T>G of the SMAD3 gene probably underlay the disease in this patient. Above discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.
Adult ; Humans ; Male ; Exome Sequencing ; Loeys-Dietz Syndrome/genetics* ; Mutation ; Pedigree ; Smad3 Protein/genetics*

Dysregulated RNA splicing is a well-recognized characteristic of colorectal cancer (CRC); however, its intricacies remain obscure, partly due to challenges in profiling full-length transcript variants at the single-cell level. Here, we employ high-depth long-read scRNA-seq to define the full-length transcriptome of colorectal epithelial cells in 12 CRC patients, revealing extensive isoform diversities and splicing alterations. Cancer cells exhibited increased transcript complexity, with widespread 3'-UTR shortening and reduced intron retention. Distinct splicing regulation patterns were observed between intrinsic-consensus molecular subtypes (iCMS), with iCMS3 displaying even higher splicing factor activities and more pronounced 3'-UTR shortening. Furthermore, we revealed substantial shifts in isoform usage that result in alterations of protein sequences from the same gene with distinct carcinogenic effects during tumorigenesis of CRC. Allele-specific expression analysis revealed dominant mutant allele expression in key oncogenes and tumor suppressors. Moreover, mutated PPIG was linked to widespread splicing dysregulation, and functional validation experiments confirmed its critical role in modulating RNA splicing and tumor-associated processes. Our findings highlight the transcriptomic plasticity in CRC and suggest novel candidate targets for splicing-based therapeutic strategies.
Humans ; Colorectal Neoplasms/metabolism* ; RNA Isoforms/metabolism* ; Single-Cell Analysis ; RNA Splicing ; Gene Expression Regulation, Neoplastic ; RNA, Neoplasm/metabolism* ; Transcriptome

Objective:To explore the genetic basis of a patient suspected for Loeys-Dietz syndrome (LDS).Methods:An adult male patient with aneurysmal dilation of the aortic root identified during the treatment for chronic myeloid leukemia at Anzhen Hospital of Capital Medical University in 2021 was enrolled as the study subject. Clinical data of the patient were retrospectively collected. Peripheral blood samples were collected from the patient and his family members and subjected to whole-exome sequencing (WES). Candidate variant was verified by bioinformatic analysis, with a focus on the genes associated with hereditary aortic aneurysms. Candidate variant was validated by Sanger sequencing. The online SpliceAI software was used for the prediction of protein function. The results, combined with information from public databases, were used to classify the pathogenicity of the candidate variant according to the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Ethics Committee of Beijing Anzhen Hospital (Ethics No. 2023163X).Results:Imaging analysis revealed that the patient had aneurysmal dilation of the aortic root. Based on his clinical features and past history, a provisional diagnosis of LDS was established. WES revealed that the patient had harbored a heterozygous splice site variant c. 206+ 2T>G in the SMAD3 gene (NM_005902). The variant was not reported in public databases and was predicted to be pathogenic by SpliceAI. Sanger sequencing showed that the variant was also present in the patients mother, sister, nephew, and daughter, but not in his father. Based on the guidelines from the ACMG, the variant was classified as likely pathogenic (PVS1+ PM2_Supporting). Conclusion:The heterozygous splice site variant c. 206+ 2T>G of the SMAD3 gene probably underlay the disease of this patient. The discovery has enriched the mutational spectrum of LDS, which may facilitate delineation of the genotype-phenotype correlation and provide a basis for further risk stratification and personalized treatment of LDS.

Discrimination against patients with mental disorders and the resulting stigma will not only affect patients’ medical treatment, but also bring about community isolation and lack of resources. Mental health problems have become a major public health problem and a prominent social problem. From the perspective of bioethics, the existence of public mental disorders stigma violates the principles of justice and respect. This paper quantitatively described the status quo of public mental disorders stigma in China, and explored its influencing factors through factor analysis and binary logistic regression analysis. The public stigma of mental disorders score was (54.64±11.048). Factor analysis extracted 4 common factors, namely isolation, pain, contact, and empathy, with a cumulative explained variance of 68.948%. The results showed that age and contact history were the main factors affecting the public stigma of mental disorders. It is recommended to reduce discrimination by enhancing understanding and improving empathy. Specifically, it is to implement the personal liability for discrimination through ethical regulation and legal construction, and strengthen the concept of a community of shared future for mankind by creating a tolerant social atmosphere, so as to achieve an appropriate balance between public safety and individual rights and interests.

This paper reports the inpatient care and nine-year follow-up management experience of a patient with Type 3 Long QT Syndrome.During hospitalization,efforts were focused on accurate symptom identification and emergency intervention.Key points in post-discharge follow-up care include medication education to prevent the use of drugs that prolong the QT interval on ECG,the application of anticipatory care to enhance the patient's self-management skills,and the joint development of a family emergency plan by relatives and healthcare providers.Additionally,the comprehensive family genetic health management was implemented.Through systematic screening,disease education,and continuous follow-up,the patient was maintained on long-term oral metoprolol post-discharge,with no further cardiac adverse events.The cardiac function of the patient improved,and during follow-up,the patient exhibited good recovery,being able to perform self-monitoring as required,and retumed to normal life.

This paper reports the inpatient care and nine-year follow-up management experience of a patient with Type 3 Long QT Syndrome.During hospitalization,efforts were focused on accurate symptom identification and emergency intervention.Key points in post-discharge follow-up care include medication education to prevent the use of drugs that prolong the QT interval on ECG,the application of anticipatory care to enhance the patient's self-management skills,and the joint development of a family emergency plan by relatives and healthcare providers.Additionally,the comprehensive family genetic health management was implemented.Through systematic screening,disease education,and continuous follow-up,the patient was maintained on long-term oral metoprolol post-discharge,with no further cardiac adverse events.The cardiac function of the patient improved,and during follow-up,the patient exhibited good recovery,being able to perform self-monitoring as required,and retumed to normal life.

Objective:To conduct clinical and genetic analysis in two cases of cholestatic liver disease to determine the specific etiology of cholestasis.Methods:Clinical data and the medical histories in family members of two cases were collected. The gene variation was detected by whole-exome sequencing technology. Sanger sequencing validation and bioinformatics analysis were performed on patients and their parents with suspected pathogenic mutations.Results:Whole-exome sequencing showed that the ABCB4 gene of case 1 (a male, 16 years old) had compound heterozygous mutations of c.646C > T from the father and c.927T > A from the mother, while the ABCB4 gene of case 2 (a female, 17 years old) had a compound heterozygous mutation of c.2784-1G > A from the father and c.646C > T from the mother. New mutation sites that had not been previously reported were c.646C > T, c.927T > A, and c.2784-1G > A.Conclusion:In this study, both cases had progressive familial intrahepatic cholestasis type 3 (PFIC-3) caused by ABCB4 gene mutations, and it also enriched the ABCB4 pathogenic variant spectrum. Whole-exome sequencing technology provides a reliable diagnostic tool for etiological analysis.

Objective　To study the efficacy and safety of hard channel puncture drainage in the treatment of multiple septated chronic subdural hematoma (CSDH) in the elderly by comparison with drilling drainage. Methods Twenty-one over-80-year-old patients with unilateral multiple septated CSDH were treated with drilling drainage in 9 cases (drilling group) and hard channel puncture drainage in 12 cases (hard channel group). The operation time, hematoma clearance rate in 1 week after operation, postoperative complications and hematoma recurrence in 3 months after operation were compared between the two groups. Results　The two groups of patients successfully completed the operation. The operation time ranged from 50 to 95 min with a mean of (78±14) min in the drilling group and 22 to 40 min with a mean of (29±5) min in the hard channel group. The difference was significant (P<0.05); One week after operation, the hematoma clearance rate ranged from 92% to100% with a mean of 96%±3% in the drilling group and 90% to 100% with a mean of 94%±3% in the hard channel group. The difference was not significant (P>0.05). Postoperative complications: there was no epilepsy in the drilling group, and 1 epilepsy in the hard channel group (8.3%). The difference was not significant (P>0.05). There were no other complications such as intracranial space occupying gas, brain parenchyma injury, intracranial infection in both groups. Hematoma recurrence 3 months after operation: there was no recurrence in the drilling group and 3 cases (25%) in the hard channel group. The difference was not significant (P>0.05). Conclusions　Hard channel puncture drainage is safe and effective in the treatment of elderly multiple septated CSDH. Compared with drilling drainage, it has shorter operation time, less trauma and is more suitable for patients with important organ diseases.