Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO ^+/- ) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1^mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.

[摘 要] 目的：探讨内吞作用相关基因FCHO2在各亚型乳腺癌中的表达及其与乳腺癌患者的预后和免疫细胞浸润的相关性。方法：应用免疫组化法和bc-GenExMiner v5.0数据库数据分析FCHO2在各亚型乳腺癌组织中的表达，通过GEO和TIMER数据库数据分析FCHO2与各亚型乳腺癌患者预后和免疫细胞浸润的关系，利用STRING和GEPIA数据库数据分析与FCHO2的互作蛋白网络和其与互作蛋白的相关性，通过UALCAN和DAVID数据库数据对乳腺癌组织中FCHO2表达相关基因进行KEGG和GO分析。结果：免疫组化法结果显示，FCHO2在管腔型和HER2+乳腺癌组织中均呈高表达（均P<0.05），且与HER2和Ki67表达有关联（P=0.03和P=0.007）。FCHO2高表达的管腔型乳腺癌患者总生存期（OS）和无复发生存期（RFS）均明显缩短（均P<0.05）。FCHO2蛋白与EPS15等多种蛋白表达相关且构成蛋白-蛋白互作网络。KEGG和GO分析显示，乳腺癌组织中FCHO2相关表达基因主要与昼夜节律、自噬等生物学过程有关，涉及叉头框蛋白O（FoxO）和TGF-β等信号通路。FCHO2表达与各亚型乳腺癌组织中的免疫细胞浸润相关（均P<0.05）。结论：FCHO2在管腔型、HER2+乳腺癌组织中呈高表达，且与管腔型乳腺癌患者预后及免疫细胞浸润相关，其可能成为乳腺癌治疗的潜在靶点。

[摘 要] 目的：探讨内吞作用相关基因FCHO2在各亚型乳腺癌中的表达及其与乳腺癌患者的预后和免疫细胞浸润的相关性。方法：应用免疫组化法和bc-GenExMiner v5.0数据库数据分析FCHO2在各亚型乳腺癌组织中的表达，通过GEO和TIMER数据库数据分析FCHO2与各亚型乳腺癌患者预后和免疫细胞浸润的关系，利用STRING和GEPIA数据库数据分析与FCHO2的互作蛋白网络和其与互作蛋白的相关性，通过UALCAN和DAVID数据库数据对乳腺癌组织中FCHO2表达相关基因进行KEGG和GO分析。结果：免疫组化法结果显示，FCHO2在管腔型和HER2+乳腺癌组织中均呈高表达（均P<0.05），且与HER2和Ki67表达有关联（P=0.03和P=0.007）。FCHO2高表达的管腔型乳腺癌患者总生存期（OS）和无复发生存期（RFS）均明显缩短（均P<0.05）。FCHO2蛋白与EPS15等多种蛋白表达相关且构成蛋白-蛋白互作网络。KEGG和GO分析显示，乳腺癌组织中FCHO2相关表达基因主要与昼夜节律、自噬等生物学过程有关，涉及叉头框蛋白O（FoxO）和TGF-β等信号通路。FCHO2表达与各亚型乳腺癌组织中的免疫细胞浸润相关（均P<0.05）。结论：FCHO2在管腔型、HER2+乳腺癌组织中呈高表达，且与管腔型乳腺癌患者预后及免疫细胞浸润相关，其可能成为乳腺癌治疗的潜在靶点。

Objective:To investigate the incidence rate and gene variation of methylmalonic academia (MMA) in Ji′nan city by analyzing biochemical and genetic screening results, and to explore the carrier frequency of MMA-related pathogenic genes in the population in Ji′nan.Methods:The children diagnosed with MMA by tandem mass spectrometry screening in Ji′nan Neonatal Disease Screening Centre from May 2011 to May 2022 were enrolled in this study.Their genetic test results were retrospectively analyzed and summarized.The dried heel blood tablets collected from 6 800 newborns were tested for neonatal gene screening. MMAA, MMAB, MMACHC and MMUT genes in 4 800 cases were detected by high-throughput sequencing+ target area capture technology.Ultra-multiplex polymerase chain reaction+ target gene locus capture technology was used to detect 174 target loci of 8 genes related to MMA in 2 000 cases.The hotspot mutation and related gene carrier rate of MMA were analyzed. Results:A total of 367 452 newborns were screened by tandem mass spectrometry, and 103 cases (56 males and 47 females) were diagnosed with MMA by screening.The estimated incidence of MMA was 1∶3 567.Among the 103 MMA cases, 76 were genetically diagnosed, and 4 gene variants of MMA ( MMAHC, MMUT, MMAA, MMADHC) were identified.A total of 6 800 neonates underwent neonatal genetic screening.Three of them were diagnosed with MMA.About 318 infants carried pathogenic variants of MMA, with a total carrier rate of 4.68%.Specifically, the carrier rates of MMACHC and MMUT gene variants were 3.09%(210/6 800) and 1.43% (97/6 800), respectively. Conclusions:MMA is the most common organic acid metabolism disorder in our country.The incidence and carrier rate of this disease are high in Jinan city.Neonatal genetic screening is an important supplement to neonatal biochemical screening.Carrier screening for MMA-related pathogenic genes is recommended for couples of childbearing age in Jinan.

Objective:To investigate more safe, effective and standard perioperative managements of infant patients with Kasabach-Merritt phenomenon (KMP).Methods:We made a retrospective analysis on the clinical data of KMP infant patients, who received surgical intervention in our department between January 2017 and September 2019. Inclusion criteria : (1) diagnosed as KMP that characterized by a large hemangioma (located in trunk or limb), profound thrombocytopenia and consumptive coagulopathy; (2) received surgical treatment in our center during January 2017 and September 2019; (3) age ≤1 year. Before surgical treatment, all the patients were given glucocorticoid and continued to the operation day in the sensitive group. The insensitive group received single large dose of platelet (PLT) transfusion 1 day before surgery, for the purpose of correcting thrombocytopenia and coagulopathy. Endotracheal intubation and intravenous anesthesia, combined with deep vein catheterization, arterial puncture catheterization and continuous invasive blood pressure monitoring were used to maintain hemodynamic stability. Radical resection of the tumor, combined with flap plasty or in situ skin grafting was carried out when necessary; after the operation, the endotracheal tube was routinely taken to ICU, and the endotracheal tube was removed as appropriate after the recovery of respiratory and circulation. The patient was kept overnight in ICU, and patient was transferred out after evaluation of stability. The dynamic changes of platelet were monitored and nutritional support was strengthened. Patients with lesions in limbs (except those with in situ skin grafting) were given passive rehabilitation training on the third day after surgery. The patients were followed up for 6-36 months. Routine blood examination, coagulation function, color Doppler ultrasonography and MRI were performed when necessary. The range of motion and muscle strength of adjacent joints were examined during the follow-up visit. Results:A total of 55 infant patients with KMP were included in this study. Peripheral blood test at 1 h before surgery showed platelets > 100×10 9/L in 54 cases and > 80×10 9/L in 1 case, and hemoglobin was corrected to more than 10 g/L. The operation time was 48-135 min, with an average of 87 min. There was no intraoperative or postoperative death. It took 4 to 36 hours for platelet to return to normal level, with an average of 8.4 hours. All surgical specimens were found to be KMP. The hospital stay was 9-30 d, with an average period of 16.7 d. Delayed incision healing in 3 cases, scar contracture in 1 case, scar hyperplasia in 3 cases. There was no death during the follow-up period, and the platelet was stable in the normal range. Conclusions:Surgical treatment of vascular tumors complicated with KMP has definite curative effect, rapid effect, short course of treatment and low cost. A series of perioperative treatments, including active preoperative preparation, effective coagulation function correction measures, perfect anesthesia and monitoring methods, stable hemodynamic support, fine surgical operation and early postoperative rehabilitation exercise are the necessary guarantee for the success of surgical treatment.

Objective:To investigate more safe, effective and standard perioperative managements of infant patients with Kasabach-Merritt phenomenon (KMP).Methods:We made a retrospective analysis on the clinical data of KMP infant patients, who received surgical intervention in our department between January 2017 and September 2019. Inclusion criteria : (1) diagnosed as KMP that characterized by a large hemangioma (located in trunk or limb), profound thrombocytopenia and consumptive coagulopathy; (2) received surgical treatment in our center during January 2017 and September 2019; (3) age ≤1 year. Before surgical treatment, all the patients were given glucocorticoid and continued to the operation day in the sensitive group. The insensitive group received single large dose of platelet (PLT) transfusion 1 day before surgery, for the purpose of correcting thrombocytopenia and coagulopathy. Endotracheal intubation and intravenous anesthesia, combined with deep vein catheterization, arterial puncture catheterization and continuous invasive blood pressure monitoring were used to maintain hemodynamic stability. Radical resection of the tumor, combined with flap plasty or in situ skin grafting was carried out when necessary; after the operation, the endotracheal tube was routinely taken to ICU, and the endotracheal tube was removed as appropriate after the recovery of respiratory and circulation. The patient was kept overnight in ICU, and patient was transferred out after evaluation of stability. The dynamic changes of platelet were monitored and nutritional support was strengthened. Patients with lesions in limbs (except those with in situ skin grafting) were given passive rehabilitation training on the third day after surgery. The patients were followed up for 6-36 months. Routine blood examination, coagulation function, color Doppler ultrasonography and MRI were performed when necessary. The range of motion and muscle strength of adjacent joints were examined during the follow-up visit. Results:A total of 55 infant patients with KMP were included in this study. Peripheral blood test at 1 h before surgery showed platelets > 100×10 9/L in 54 cases and > 80×10 9/L in 1 case, and hemoglobin was corrected to more than 10 g/L. The operation time was 48-135 min, with an average of 87 min. There was no intraoperative or postoperative death. It took 4 to 36 hours for platelet to return to normal level, with an average of 8.4 hours. All surgical specimens were found to be KMP. The hospital stay was 9-30 d, with an average period of 16.7 d. Delayed incision healing in 3 cases, scar contracture in 1 case, scar hyperplasia in 3 cases. There was no death during the follow-up period, and the platelet was stable in the normal range. Conclusions:Surgical treatment of vascular tumors complicated with KMP has definite curative effect, rapid effect, short course of treatment and low cost. A series of perioperative treatments, including active preoperative preparation, effective coagulation function correction measures, perfect anesthesia and monitoring methods, stable hemodynamic support, fine surgical operation and early postoperative rehabilitation exercise are the necessary guarantee for the success of surgical treatment.

Objective:To analyze the characteristics of malaria epidemic situation before and after malaria elimination in Qiandongnan Prefecture, and to provide the basis for establishment of effective strategies and measures to consolidate the achievements of malaria prevention and control.Methods:The data of malaria cases in 16 counties (cities) of Qiandongnan Prefecture from 2005 to 2018 were collected, and descriptive epidemiological method was used to analyze the infection rate of Plasmodium among local residents and floating population before (2005-2011) and after (2012-2018) elimination of malaria, and the characteristics of population distribution, seasonal distribution, species of Plasmodium and types of malaria vectors were analyzed. Results:Before elimination of malaria, total of 1 412 cases of malaria were reported, among those cases, 1 361 cases were local cases, accounting for 96.39% of the total cases. After elimination of malaria, total of 17 cases were reported, all of them were imported cases. After comparison of malaria cases before and after the elimination, the proportion of people aged from 18 to 60 was 70.54% (996/1 412) before the elimination, all 17 imported cases were 18-60 years old after the elimination, and the proportion of children/students decreased from 24.65% (348/1 412) before the elimination to 0 after the elimination. The peak incidence of malaria cases before the elimination was from June to October, and cases occurred every month. After the elimination, the imported cases were sporadic. Plasmodium vivax was the main species of Plasmodium before the elimination (98.58%, 1 392/1 412), and Plasmodium falciparum was mainly imported after the elimination (70.59%, 12/17). Before and after the elimination, Anopheles sinensis, the malaria vector, was the dominant population, but no distribution of Anopheles minimus and Anopheles anthropophagus was found after 2015. Conclusions:After the elimination of malaria in Qiandongnan Prefecture, there is a risk of local malaria cases caused by imported cases. It is suggested that local authorities should focus on the treatment of suspected malaria cases and vector surveillance of overseas returnees in the future.

The aim of this study was to screen the active regions and transcription factor binding sites in the promoter of the CBD103 gene related to Arctic fox coat color, and to provide a basis for revealing the molecular genetic mechanism of CBD103 gene regulating the coat color formation. The 5'-flanking region fragment 2 123 bp of Arctic fox CBD103 gene was cloned, and 4 truncated promoter reporter vectors of different lengths were constructed. The promoter activity was detected by the dual-luciferase reporter assay system. Point mutations were performed on the 3 predicted specificity protein 1 (Sp1) transcription factor binding sites in the highest promoter active region, and 3 mutant vectors were constructed. The activity was then detected by the dual-luciferase reporter assay system. The results showed that the region 1 656 (-1 604/+51) had the highest activity in the 4 truncated promoters of different lengths, and the promoter activity of the three mutant vectors constructed in this region were significantly lower than that of the wild type (fragment 1 656). The region of -1 604 /+51 was the core promoter region of CBD103 gene in Arctic fox and -1 552/-1 564, -1 439/-1 454 and -329/-339 regions were positive regulatory regions. This study successfully obtained the core promoter region and positive regulation regions of the Arctic fox CBD103 gene, which laid a foundation for further study on the molecular genetic mechanism of this gene regulating Arctic fox coat color.
Animals ; Binding Sites ; Foxes ; Luciferases ; Promoter Regions, Genetic ; Sp1 Transcription Factor ; beta-Defensins

Intraocular pressure detection has a great significance for understanding the status of eye health, prevention and treatment of diseases such as glaucoma. Traditional intraocular pressure detection needs to be held in the hospital. It is not only time-consuming to doctors and patients, but also difficult to achieve 24 hour-continuous detection. Microminiaturization of the intraocular pressure sensor and wearing it as a contact lens, which is convenient, comfortable and noninvasive, can solve this problem because the soft contact lens with an embedded micro fabricated strain gauge allows the measurement of changes in corneal curvature to correlate to variations of intraocular pressure. We fabricated a strain gauge using micro-electron mechanical systems, and integrated with the contact lens made of polydimethylsiloxane (PDMS) using injection molding. The experimental results showed that the sensitivity was 100. 7 µV/µm. When attached to the corneal surface, the average sensitivity of sensor response of intraocular pressure can be 125.8 µV/mm Hg under the ideal condition.
Contact Lenses, Hydrophilic ; Dimethylpolysiloxanes ; Glaucoma ; Humans ; Intraocular Pressure ; Tonometry, Ocular ; instrumentation