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 investigate the clinical efficacy of Qi Shi Shen Shu Capsule combined with dapagliflozin in treating type 2 diabetic nephropathy.Methods 120 patients with type 2 diabetic nephropathy(qi-yin liangxu syndrome)admitted to the endocrinology department in the inpatient and outpatient depart-ments of endocrinology from May 2022 to December 2023 were randomly divided into control and observation groups(60 cases each).The control group received dapagliflozin plus placebo capsules,while the observation group received dapagliflozin plus Qi Shi Shen Shu Capsule for 6 months.The therapeutic effects were observed between the two groups.Parameters including serum creatinine(Scr),urinary albumin-to-creatinine ratio(uACR),24-hour urinary protein quantification(24hUP),glycated hemoglobin(HbA1c),and tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),and high sensitivity-C reactive protein(hs-CRP)were measured be-fore and after treatment.Results The total effective rate was higher(P＜0.05)in the observation group(93.33％)than in the control group(78.33％).After treatment,both groups showed decreased levels of uACR,Scr,24hUP,HbA1c,TNF-α,IL-6,and hs-CRP compared with baseline,with lower levels in the obser-vation group(P＜0.05).Conclusion Qi Shi Shen Shu Capsule combined with dapagliflozin can effectively re-duce uACR,Scr levels and serum inflammatory cytokines levels in patients with type 2 diabetic nephropathy.

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*

Objective:To analyse the pathogenicity of a family with Fabry disease and to characterise its clinical phenotype and genetic variants.Methods:A proband with Fabry disease admitted to Beijing Anzhen Hospital, Capital Medical University in December 2021 was enrolled. Clinical data, including medical history, biochemical parameters, echocardiography, and electrocardiogram, were collected from the proband and family members. The proband and his daughter underwent α-galactosidase A (α-Gal A) enzyme activity assay and Sanger sequencing of the GLA gene. Candidate variants were analyzed and classified according to the American College of Medical Genetics and Genomics guidelines.Results:The male proband (69 years old) presented with chronic renal insufficiency, electrocardiogram findings of ST-T changes, bundle branch block, and left ventricular high voltage, and echocardiographic evidence of left ventricular hypertrophy. His α-Gal A activity was markedly reduced, and genetic testing identified a hemizygous GLA c.511G>C (p.Gly171Arg) variant on the X chromosome. The proband′s asymptomatic daughter also exhibited significantly decreased α-Gal A activity and carried the heterozygous GLA c.511G>C (p.Gly171Arg) variant. Based on the American College of Medical Genetics and Genomics guidelines, this variant was classified as “likely pathogenic” and considered the underlying cause of Fabry disease in this family.Conclusion:The proband manifested chronic renal insufficiency and cardiac hypertrophy, with the GLA c.511G>C (p.Gly171Arg) variant identified as the likely-pathogenic cause of Fabry disease in this family.

This study constructed a porcine reproductive and respiratory syndrome virus(PRRSV)NADC30-like strain GP3 recombinant adenovirus vector vaccine through in vitro homologous re-combination to explore its immunological efficacy evaluation at the mouse level.Using type 5 ade-novirus as a vector,a recombinant adenovirus expressing PRRSV GP3 protein was prepared and i-dentified in vitro by fluorescence observation,PCR,and Western blot analysis.Immunize mice with recombinant adenovirus and detect humoral and cellular immune responses induced by recombi-nant adenovirus using indirect ELISA and ELISpot methods.The recombinant adenovirus rAdGP3 was identified by enzyme digestion,PCR,fluorescence and Western blot,indicating that the recom-binant adenovirus rAdGP3 was successfully constructed and packaged.After immunizing mice,spe-cific antibodies and neutralizing antibodies were produced,indicating that the recombinant adenovi-rus could elicit strong humoral immunity.ELISpot and lymphocyte proliferation assays showed that the recombinant adenovirus vaccine could stimulate the secretion of IFN-γ-specific T lymphocytes and induce the proliferation of lymphocytes,indicating that the recombinant adenovi-rus could enhance the level of cellular immune response.In this study,rAdGP3 recombinant adeno-virus was successfully constructed and had good immunogenicity at the mouse level,which provid-ed a reference for the development of novel PRRSV vaccines.

This study constructed a porcine reproductive and respiratory syndrome virus(PRRSV)NADC30-like strain GP3 recombinant adenovirus vector vaccine through in vitro homologous re-combination to explore its immunological efficacy evaluation at the mouse level.Using type 5 ade-novirus as a vector,a recombinant adenovirus expressing PRRSV GP3 protein was prepared and i-dentified in vitro by fluorescence observation,PCR,and Western blot analysis.Immunize mice with recombinant adenovirus and detect humoral and cellular immune responses induced by recombi-nant adenovirus using indirect ELISA and ELISpot methods.The recombinant adenovirus rAdGP3 was identified by enzyme digestion,PCR,fluorescence and Western blot,indicating that the recom-binant adenovirus rAdGP3 was successfully constructed and packaged.After immunizing mice,spe-cific antibodies and neutralizing antibodies were produced,indicating that the recombinant adenovi-rus could elicit strong humoral immunity.ELISpot and lymphocyte proliferation assays showed that the recombinant adenovirus vaccine could stimulate the secretion of IFN-γ-specific T lymphocytes and induce the proliferation of lymphocytes,indicating that the recombinant adenovi-rus could enhance the level of cellular immune response.In this study,rAdGP3 recombinant adeno-virus was successfully constructed and had good immunogenicity at the mouse level,which provid-ed a reference for the development of novel PRRSV vaccines.

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 analyse the pathogenicity of a family with Fabry disease and to characterise its clinical phenotype and genetic variants.Methods:A proband with Fabry disease admitted to Beijing Anzhen Hospital, Capital Medical University in December 2021 was enrolled. Clinical data, including medical history, biochemical parameters, echocardiography, and electrocardiogram, were collected from the proband and family members. The proband and his daughter underwent α-galactosidase A (α-Gal A) enzyme activity assay and Sanger sequencing of the GLA gene. Candidate variants were analyzed and classified according to the American College of Medical Genetics and Genomics guidelines.Results:The male proband (69 years old) presented with chronic renal insufficiency, electrocardiogram findings of ST-T changes, bundle branch block, and left ventricular high voltage, and echocardiographic evidence of left ventricular hypertrophy. His α-Gal A activity was markedly reduced, and genetic testing identified a hemizygous GLA c.511G>C (p.Gly171Arg) variant on the X chromosome. The proband′s asymptomatic daughter also exhibited significantly decreased α-Gal A activity and carried the heterozygous GLA c.511G>C (p.Gly171Arg) variant. Based on the American College of Medical Genetics and Genomics guidelines, this variant was classified as “likely pathogenic” and considered the underlying cause of Fabry disease in this family.Conclusion:The proband manifested chronic renal insufficiency and cardiac hypertrophy, with the GLA c.511G>C (p.Gly171Arg) variant identified as the likely-pathogenic cause of Fabry disease in this family.

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.