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.

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

Dengue fever，caused by the dengue virus，is an acute viral infectious disease，which frequently outbreaks in tropical and subtropical regions worldwide，and has become a significant global health burden and threat. The development of dengue vaccines and antiviral drugs has made rapid and significant progress recently. The existing CYD-TDV vaccine is primarily suitable for individuals prior infection，while vaccines such as TAK-003 and Butantan-DV have demonstrated good safety and efficacy in uninfected individuals of different age groups；several other types of dengue vaccines have also entered clinical research stages. For antiviral drugs，an oral antiviral drug JNJ-1802 has shown significant antiviral activity against the dengue virus and good tolerability in clinical trials. It has now entered community field research to validate its effectiveness in real-world settings. Several other drugs are also under continuous development. This article reviews the research progress in the development of vaccines and antiviral drugs for dengue fever to provide reference for further study and clinical application.

Objective To investigate the clinical pathologic features of a distinct variant of focal cortical dysplasia (FCD) characterized by neuronal loss of layer four.Methods Between 2005 and 2017,approximately 3 000 surgeries were performed for the treatment of intractable epilepsy at Xuanwu Hospital,Capital Medical University and Yuquan Hospital,Tsinghua University.Retrospective analysis of clinic-pathological data of patients with epilepsy surgery was made and histological manifestations of neuronal loss of cortical layer four were included in this study.Results In this cohort,25 patients (22 males and three females) were identified with early onset pharmaco-resistant epilepsy and regionally circumscribed neuronal loss of cortical layer four in surgical specimens from the occipital lobe.Histologically,except for neuronal loss in cortical layer four in all cases,glial scar lesions were found in some patients.Thus the histology of those cases can be subdivided into two groups:group A (13 cases):neuronal loss of cortical layer four without glial scar lesions;and group B (12 cases):neuronal loss of cortical layer four with glial scar lesions.Due to the prominent horizontal disorganization of cortical layering and lack of any other microscopically visible principle lesion,group A should be classified hitherto as FCD International League Against Epilepsy (ILAE) type Ⅰ b,however,group B with scar lesions and cortical dysplasia around the main leision,should be classified as FCD ILAE type Ⅲd.This retrospective analysis of clinical histories revealed a perinatal distress in 20 patients (80％),suggesting an acquired pathomechanism.Magnetic resonance imaging revealed abnormal signals in the occipital lobe in all patients,and signal changes suggestive of encephalomalacia were found in 18 patients.Surgical treatment achieved favorable seizure control (Engel class Ⅰ and Ⅱ) in 18 patients (75％ among 24 available follow up).Comparion of the two groups with age at epilepsy onset (group A:5.00±2.76,group B:5.01±3.78),the proportion of perinatal distress (group A:11/13,group B:9/12) and the follow-up results (favorable seizure control of the two groups was 9/13,9/11 respectively) showed that there was no statistically significant difference between the two groups.Conculsion Neuronal loss of cortical layer four in the occipital lobe should be classified as a distinct variant of FCD ILAE type Ⅲd.

Objective To evaluate the applicability of the Chinese version of SF-36 ( v. 2 ) scale for evaluating the quality of life of hospitalized patients with chronic heart failure. Methods From September 2013 to December 2014, 159 patients with chronic heart failure(NYHA I-IV), who were older than 18 years, clear mind and well self-expressed, were selected as participants. Questionnaire surveys included general survey and SF-36(v. 2) scale. Internal consistency reliability, binary reliability and construct validity were all analyzed as indicators to evaluate SF-36 ( v. 2 ) scale. Results A total of 159 questionnaires were issued and 159 valid questionnaires were recovered. The eight dimensions of SF-36(v. 2) scale including physical function (PF), role-physical (RP), bodily pain (BP), general health (GH), social function (SF), vitality (VT), role-emotion(RE), and mental health (MH) score conversion were (41.57 ±24.86), (48.35 ±21.64), (69.18 ± 25. 68), (31. 28 ± 16. 01), (48. 90 ± 19. 53), (45. 05 ± 22. 76), (59. 43 ± 24. 31), (57. 55 ± 19. 03); the floor effects were 2. 5%, 4. 4%, 3. 1%, 4. 4%, 3. 1%, 6. 3%, 0. 6%, 1. 3%; the ceiling effects were 0. 0%, 3. 8%, 21. 4%, 0. 0%, 0. 0%, 1. 9%, 3. 1%, 0. 0%. The item-convergent validity all achieved the standard (r≥0. 4), and the total scaling success rate of item-convergent was 100. 00%; the dimensions′success rates of item-discriminant validity of RP, BP, RE and SF were all 100%, the rest of four dimensions were PF 95. 71%, GH 85. 71%, VT 89. 29%, MH 94. 29%, and the total success rate was 94. 69%. Internal consistency reliability ranged from 0. 738 to 0. 919; the binary reliability ranged from 0. 808 to 0. 963. Within factors analysis, two common factors were confirmed, separately representing physical health and mental health, altogether making contribution of 61. 66% cumulative variance. Conclusions As the revision of SF-36(v. 1), SF-36(v. 2) scale seemed more friendly in layout for questions and answers, the floor and ceiling effects significantly reduced. Additionally, it also shows good reliability and validity in the evaluation of quality of life of hospitalized patients with chronic heart failure, and the SF-36(v. 2) scale can be used to evaluate the quality of life ( QOL) of patients with chronic heart failure.

Objective To explore the clinical characteristics of mycoplasma pneumonia with pulmonary atelectasis and lavage interventional effect through fiberoptic bronchoscopy in children.Methods During Jun 2012 to Apr 2013,fifty-three children diagnosed of mycoplasma pneumonia with pulmonary atelectasis who received fiberoptic bronchoscopy were enrolled as the experimental group.Thirty-five children diagnosed of mycoplasma pneumonia without pulmonary atelectasis were chosen as control group.According to the lavage interventional time of fiberoptic bronchoscopy,we divided the patients in the experimental group into two groups,the early group and late group.Clinical data and laboratory finds were collected and analyzed.Results The duration of fever,hospital stay and C-reactive protein (CRP) of the experimental group were significantly higher than those of the control group (P ＜ 0.05).The location of pulmonary atelectasis in the experimental group were usually in the right middle lobe (18 cases,33.9％).Under fiberoptic bronchoscope,all patients had obviously bronchial mucosa congestive edema.Some of them had follicular hyperplasia (9 cases,17.0％),mucosal erosion (3 cases,5.7％),mucus plug formation (7 cases,13.2％) and poor ventilation of segmental bronchi (4 cases,7.5 ％).Neutrophils (43 cases,81.1％) increased and phagocytic cells (31 cases,58.5％) dereased obviously in bronchoalevolar lavage fluid.After treatment in the experimental group,52 children (98.1％) got complete recruitment of atelectasis.The average duration of fever and hospital stay of the early group were significantly shoter than those of late group (P ＜ 0.05).Conclusion Children diagnosed of mycoplasma pneumonia with pulmonary atelectasis had longer fever duration and higher CRP level.Bronchoscopic interventional therapy promoted the recovery of pulmonary atelectasis.Using bronchoscop early in shorten the duration of fever and hospitalization in children diagnosed of mycoplasm pneumonia with pulmonary atelectasis.

Vitamin is necessary and important for humans and an-imals to maintain normal physiological function, metabolism, and growth. The studies suggest that vitamin is one of the factors which play a role in the activity of enzymes, and it is coenzyme of many enzyme or an important component of coenzyme. The lack of vitamins causes a metabolic vitamin deficiency. Pharma-cogenomics research the relationship between human genetic vari-ation and drug reaction, using the information to solve the differ-ent reactions among the different individuals of the same drug. Vitamins, which constitute human tissues and maintain normal physiological functions, are also an important part for the phar-macogenomics study.

Objective To evaluate the clinic effect of dental operating microscope ( DOM) and ul-trasonic root canal technique in removing fractured root canal instruments .Methods Eight cases with frac-tured instruments located in different parts of root canals were treated with ultrasonic technique under DOM and the results were analyzed .The fractured instruments were divided into stainless steel file , Ni-Ti file and post according to material type .Results Twenty-seven fractured instruments were removed and the total success rate was71.1%.Among them, the success rate of stainless steel file was 71.4%,of Ni-Ti file was 37.5%and of post was 100%.No root canal perforation occurred .According to the place fractured instru-ments located , the success rate of stainless steel file located at upper 1/3 root canals was 100%,at middle 1/3 was 81.8%and at apex 1/3 was 33.3%;the success rate of Ni-Ti file located at middle 1/3 was 60%and at apex 1/3 was 0.In bent root canals , the success rate of stainless steel file located at bent part crown square was 86.7%and at bent part apex square was 20%;the success rate of Ni-Ti file located at bent part crown square was 60%and at bent part apex square was 0.Conclusion DOM combined with ultrasonic root canal technique in removing fractured instruments is effective , but the success rate is relatively low for Ni-Ti files and the cases fractured instruments located at root canal apex 1/3 or bent part apex square .

Objective To evaluate the effectiveness of transurethral holmium laser treatment for multiple complex bladder pathological changes.Methods Clinical data of 507 cases of transurethral holmium laser resection for multiple complex bladder pathological changes under endoscope from 2001 to 2005 were retrospectively reviewed.A total of 17 types of bladder pathological changes were encountered,and 2 or more types of pathological changes occurred simultaneously in 111 cases,including 36 cases of 3 types of coexisting changes.Results Primary operation was performed in 505 patients,and two-stage operation was performed in 2 patients.The operation time was 5~35 min(mean,20 min).No obturator nerve reflex and other complications were seen.The operation was accomplished in 3 patients with cardiac pacemaker and 3 patients with coronary stent.Follow-up examinations in all the cases for 12~24 months revealed no relapse.Conclusions Transurethral holmium laser resection for multiple complex bladder pathological changes is safe and reliable.During the procedure,the degree of resection depth in the bladder wall can be precisely controlled.It can be used as the first choice for minimally invasive treatment of multiple complex bladder pathological changes.

Objective:To observe clinical significance between changes of OPN,IL-18 levels and relation ship with hepatic function in patients with chronic hepatic disease infected by HBV.Methods:The levels of OPN,IL-18 in peripheral blood of 102 patients with chronic hepatitis B,34 patients with hepatitis B-related cirrhosis,95 HBV carriers and 20 healthy people as the control group were respectively detected with ELISA.Results:The levels of OPN and IL-18 in chronic hepatitis B and hepatitis B-related cirrhosis groups were significantly increased compared with that of health control group(P