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.

In compliance with the data requirements for monitoring medical service capacity and quality safety in the sec-ond part of the"Rules for the Implementation of Evaluation Standards for Tertiary General Hospitals in Hubei Province(2023 Edition)",this paper,in conjunction with the specific circumstances of a tertiary hospital,carried out a brief overview of the da-ta collection process and the challenges faced during the reevaluation of the tertiary hospital.By accurately addressing the prob-lems and challenges in medical services,this paper aimed to enhance medical quality management and advance the hospital's high-quality development.

Artemisia annua is the main natural source of artemisinin production. In A. annua, extended drought stress severely reduces its biomass and artemisinin production while short-term water-withholding or abscisic acid (ABA) treatment can increase artemisinin biosynthesis. ABA-responsive transcription factor AabZIP1 and JA signaling AaMYC2 have been shown in separate studies to promote artemisinin production by targeting several artemisinin biosynthesis genes. Here, we found AabZIP1 promote the expression of multiple artemisinin biosynthesis genes including AaDBR2 and AaALDH1, which AabZIP1 does not directly activate. Subsequently, it was found that AabZIP1 up-regulates AaMYC2 expression through direct binding to its promoter, and that AaMYC2 binds to the promoter of AaALDH1 to activate its transcription. In addition, AabZIP1 directly transactivates wax biosynthesis genes AaCER1 and AaCYP86A1. The biosynthesis of artemisinin and cuticular wax and the tolerance of drought stress were significantly increased by AabZIP1 overexpression, whereas they were significantly decreased in RNAi-AabZIP1 plants. Collectively, we have uncovered the AabZIP1-AaMYC2 transcriptional module as a point of cross-talk between ABA and JA signaling in artemisinin biosynthesis, which may have general implications. We have also identified AabZIP1 as a promising candidate gene for the development of A. annua plants with high artemisinin content and drought tolerance in metabolic engineering breeding.

The rapid changes in the research and development environment of new anti-tumor drugs in China have brought various challenges to drug innovation. How to explore the clinical advantages of new drugs in the early phase, and design scientific, reasonable and efficient pivotal clinical trials for drug registration accordingly, is one of the key challenges. This article takes innovative new drugs for hematological malignancies as an example, comprehensively elaborates the considerations on the timing for entering the pivotal clinical trial and the key elements of the trial design from the perspective of clinical reviewers.

Objective:To study effects of Orff rhythm-beat-tap training on positive emotions in elderly patients with mild dementia.Methods:Using the convenient sampling method, a total of 72 elderly patients with mild dementia who were treated in the Third People's Hospital of Huzhou from August 2018 to August 2019 were selected as the research objects and they were divided into two groups using the simple random sampling method. After the start of the study, 2 cases dropped out because of failure to persist in training, 1 case dropped out because of transfer during hospitalization and 1 case dropped out because of aggravation of the disease and changing drugs. A total of 68 cases were included in the study, including 33 cases in the intervention group and 35 cases in the control group. The control group received routine nursing, while the intervention group received 12-week Orff rhythm-beat-tap training on this basis. The scores of Positive and Negative Affect Schedule (PANAS) , Apathy Evaluation Scale (AES) and Dementia Mood Assessment Scale (DMAS) were evaluated before and after the intervention.Results:The score of positive emotion after intervention in the intervention group was (31.58±1.87) , higher than (26.66±2.93) in the control group, and the difference was statistically significant ( t=8.297, P<0.01) . After intervention, the score of negative emotion of the intervention group was (21.97±2.30) , the score of apathy was (44.88±5.22) , and the score of dementia mood was (23.18±4.33) , which were lower than (23.80±3.94) , (51.91±7.49) and (26.09±6.20) of the control group, and there were statistically significant differences in scores between the two groups ( t=-2.356, -4.514, -2.225; P<0.05) . Conclusions:Orff rhythm-beat-tap training is suitable for elderly patients with mild dementia, which can effectively enhance positive emotional experience of patients, improve apathy and optimize mood.

Objective:To observe the clinical effect of oxycodone hydrochloride sustained-release tablets in the treatment of pain in advanced malignant tumors.Methods:One hundred patients with advanced malignant tumor pain admitted to Hangzhou Cancer Hospital from June 2017 to August 2018 were selected.They were grouped according to the admission order.The observation group (50 cases) implemented oxycodone hydrochloride sustained-release tablets.The control group (50 cases) was treated with morphine sulfate sustained-release tablets.The onset time, analgesic effect, adverse reaction and KPS score were compared between the two groups.Results:The onset time [(0.79±0.22)h] of the observation group was significantly shorter than that of the control group [(2.56±1.02)h]( t=11.995, P<0.05). The total effective rate of analgesia in the observation group (98.00%) was higher than that in the control group(74.00%)( t=11.960, P<0.05). The incidence of adverse reactions in the observation group was 4.00%(2/50), which was lower than 30.00%(15/50) in the control group, (χ 2 =11.977, P<0.05). The KPS score after treatment in patients with advanced malignant tumor pain in the observation group[(79.45±1.23)points] was higher than that in the control group[(65.34±1.92)points] ( t=43.756, P<0.05). Conclusion:Oxycodone hydrochloride sustained-release tablets have significant effects in the treatment of advanced malignant tumor pain, and it is safe.

Brucella is an intracellular pathogen that invades a host and settles in its immune cells; however, the mechanism of its intracellular survival is unclear. Modification of small ubiquitin-related modifier (SUMO) occurs in many cellular activities. E2 conjugating enzyme 9 (Ubc9) is the only reported ubiquitin-conjugating enzyme that links the SUMO molecule with a target protein. Brucella's intracellular survival mechanism has not been studied with respect to SUMO-related proteins and Ubc9. Therefore, to investigate the relationship between Brucella melitensis 16M and SUMO, we constructed plasmids and cells lines suitable for overexpression and knockdown of SUMO1 and Ubc9 genes. Brucella 16M activated SUMO1/Ubc9 expression in a time-dependent manner, and Brucella 16M intracellular survival was inhibited by SUMO1/Ubc9 overexpression and promoted by SUMO1/Ubc9 depletion. In macrophages, Brucella 16M-dependent apoptosis and immune factors were induced by SUMO1/Ubc9 overexpression and restricted by SUMO1/Ubc9 depletion. We noted no effect on the expressions of SUMO1 and Ubc9 in B. melitensis 16M lipopolysaccharide-prestimulated mouse RAW264.7 macrophages. Additionally, intracellular survival of the 16M△VirB2 mutant was lower than that of Brucella 16M (p < 0.05). VirB2 can affect expression levels of Ubc9, thereby increasing intracellular survival of Brucella in macrophages at the late stage of infection. Collectively, our results demonstrate that B. melitensis 16M may use the VirB IV secretion system of Brucella to interact with SUMO-related proteins during infection of host cells, which interferes with SUMO function and promotes pathogen survival in host cells.
Animals ; Apoptosis ; Brucella melitensis ; Brucella ; Immunologic Factors ; Macrophages ; Mice ; Plasmids

Objective To investigate the application value of indomethacin in pancreatitis after endoscopic retrograde cholan-giopancreatography(ERCP)in the patients with choledocholithiasis.Methods Ninety elderly patients with choledocholithiasis were divided into the observation group and control group according to the random number table method,45 cases in each group.The two groups received the therapy of conventional ERCP scheme.The control group used diazepam,pethidine and anisodamine before op-eration.The observation group was preoperatively added with indomethacin on the basis of the control group.The therapeutic effects were analyzed and compared between the two groups.Results The number of intraoperative gastric peristalsis and operation time in the observation group were significantly lower than those in the control group(P<0.05).The level of serum amylase at postoperative 6,24 h in the observation group was significantly lower than that in the control group(P<0.05).The level of serum CRP and MMP-9 at postoperative 24 h in the observation group was significantly lower than that in the control group(P<0.05). The incidence rates of pancreatitis and hyperamylasemia in the observation group were significantly lower than those in the control group(P<0.05).Conclusion Indomethacin can effectively reduce the number of intraoperative gastric peristalsis,postoperative hy-peramylasemia and incidence rate of acute pancreatitis,reduces the level of serum inflammatory factors,and has fewer adverse reac-tions,which is worthy of application.

Objective To define the effect of hypothyroidism on oxidative stress,p38 and c-Jun N-terminal kinases (JNK) mRNA expression in testicular mitochondria of male rats,and to explore the mechanism of hypothyroidism on reproduction.Methods According to body weight (240-270 g),30 male Wistar rats were divided into control group (C group,1 ml/kg normal saline by intragastric administration),low-dose group (L group,0.1 mg/kg propylthiouracil 1 ml/kg by intragastric administration) and high-dose group (H group,10.0 mg/kg propylthiouracil 1 ml/kg by intragastric administration),10 rats in each group,body mass was weighed once every 3 days.After 60 days,all rats were killed.The levels of thyroid hormones [total triiodothyronine (TT3),total thyroxine (TT4),and thyroid stimulating hormone (TSH)] were measured by radioimmunoassay.The activities of superoxide dismutase (SOD) and catalase (CAT) in the testicular mitochondria were determined with spectrophotometric assay.The mRNA expression levels of p38 and JNK in testicular mitochondria were detected by real-time quantitative PCR.Results The weights of H group in 30 and 60 days [(265.73 ± 5.10),(253.72 ± 5.09) g] were significantly decreased in comparison with those of C group [(344.62 ± 4.69),(395.33 ± 8.36) g] and L group [(333.66 ± 3.53),(386.08 ± 7.70) g,P ＜0.05].While,testis organ coefficient of H group [(1.20 ± 0.05) g/100 g] were significantly increased compared with those of L group [(0.93 ± 0.03) g/100 g] and C group [(0.88 ± 0.03) g/100 g,P ＜ 0.05].The serum levels of TT3 [(0.39 ± 0.01) nmol/L] and TT4 [(15.47 ± 1.21) nmol/L] in H group were found to be significantly decreased compared with those of C group [(0.86 ± 0.07),(45.56 ± 1.52) nmol/L] and L group [(0.79 ± 0.06),(39.02 ± 1.33) nmol/L,P ＜ 0.05];whereas the level of TSH [(0.65 ± 0.09) mU/L)] was increased in comparison with those of the C group [(0.18 ± 0.06) mU/L] and L group [(0.27 ± 0.05) mU/L,P ＜ 0.05].In addition,the level of SOD in H group [(60.37 ± 3.14) U/mg prot] was decreased compared with that of C group [(75.18 ± 6.13) U/mg prot,P ＜ 0.05];the level of CAT in H group [(1.46 ± 0.25) U/mg prot] and L group [(1.67 ± 0.39) U/mg prot] decreased significantly compared with that of C group [(3.79 ± 0.44) U/mg prot,P ＜ 0.05].And compared with C (1.000 0 ± 0.000 0) and L (1.114 2 ± 0.124 1) groups,p38 mRNA expression in H group (1.387 4 ± 0.122 0) was significantly increased (P ＜ 0.05).However,there was no significant change in JNK mRNA expression between groups (F =0.95,P ＞ 0.05).Conclusion Hypothyroidism may induce oxidative stress of testicular mitochondria leading to the change of p38 cell signal path and then damage the reproductive system in male rats.

Objective To establish a modified dynamic 99Tcm-pertechnetate salivary gland scintigraphy(SGS) method,and to evaluate the value in the diagnosis of Sj(o)gren's syndrome(SS) by comparing SGS with labial gland biopsy (LGB).Methods A total of 204 patients (21 males,183 females,age range 20-85 years) with suspected SS who underwent the modified dynamic SGS and LGB were enrolled in this prospective study.Uptake ratio (UR) and excretion fraction (EF) of the left parotid gland (LPG),the right parotid gland (RPG),the left submandibular gland (LSG) and the right submandibular gland (RSG)were calculated.Two-sample t test was used for data analysis.The sensitivity,specificity,accuracy of the modified dynamic SGS and LGB were calculated,and x2 test was used for data analysis.Results SS was confirmed in 113 patients,including 79 patients with primary SS and 34 patients with secondary SS.SS was excluded in 88 patients.The UR and EF of the SS group (LPG:1.95±1.04 and (52.2±19.5)％,RPG:1.96±1.06 and (55.0±21.1)％,LSG:2.65±1.12 and (25.9±14.1)％,RSG:2.72±1.30 and (29.7± 14.7) ％) were significantly lower than those of the non-SS group (LPG:3.08± 1.10 and (65.9± 12.7) ％,RPG:3.26±1.16 and (66.4±12.6)％,LSG:3.71±1.31 and (43.2±12.3)％,RSG:3.74±1.39 and (46.6± 11.5) ％;t=4.40-9.00,all P＜0.05).The sensitivity,specificity,accuracy of the modified dynamic SGS were 99.1％ (112/113),72.7％ (64/88),87.6％ (176/201),respectively,while those of LGB were 83.2％ (94/113),96.6％ (85/88),89.1％ (179/201),respectively.The sensitivity and specificity of SGS method were significantly different from those of LGB (x2 =15.9,17.5,both P＜0.05).Conclusions The modified dynamic SGS can reduce the acquisition time and has a high sensitivity for SS.When combined with LGB,it will improve the diagnostic accuracy for SS.