Gene Expression Analyses Support Fallopian Tube Epithelium as the Cell of Origin of Epithelial Ovarian Cancer

Folate receptor alpha (FOLR1/FRA) is reported to be overexpressed in epithelial ovarian cancers (EOC), especially the serous histotype. Further, while dysregulation of the folate-dependent 1-carbon cycle has been implicated in tumorogenesis, little is known relative to the potential mechanism of action of FOLR1 expression in these processes. We therefore investigated the expression of FOLR1, other folate receptors, and genes within the 1-carbon cycle in samples of EOC, normal ovary and fallopian tube on a custom TaqMan Low Density Array. Also included on this array were known markers of EOC such as MSLN, MUC16 and HE4. While few differences were observed in the expression profiles of genes in the 1-carbon cycle, genes previously considered to be overexpressed in EOC (e.g., FOLR1, MSLN, MUC16 and HE4) showed significantly increased expression when comparing EOC to normal ovary. However, when the comparator was changed to normal fallopian tube, these differences were abolished, supporting the hypothesis that EOC derives from fallopian fimbriae and, further, that markers previously considered to be upregulated or overexpressed in EOC are most likely not of ovarian origin, but fallopian in derivation. Our findings therefore support the hypothesis that the cell of origin of EOC is tubal epithelium.     

The Effect of Different Intensities of Treadmill Exercise on Cognitive Function Deficit Following a Severe Controlled Cortical Impact in Rats

Exercise has been proposed for the treatment of traumatic brain injury (TBI). However, the proper intensity of exercise in the early phase following a severe TBI is largely unknown. To compare two different treadmill exercise intensities on the cognitive function following a severe TBI in its early phase, rats experienced a controlled cortical impact (CCI) and were forced to treadmill exercise for 14 days. The results revealed that the rats in the low intensity exercise group had a shorter latency to locate a platform and a significantly better improvement in spatial memory in the Morris water maze (MWM) compared to the control group (p < 0.05). The high intensity exercise group showed a longer latency and a mild improvement in spatial memory compared to the control group rats in the MWM; however, this difference was not statistically significant (p > 0.05). The brain-derived neurotrophic factor (BDNF) and p-CREB protein levels in the contralateral hippocampus were increased significantly in the low intensity exercise group. Our results suggest that 2 weeks of low intensity of treadmill exercise is beneficial for improving cognitive function and increasing hippocampal BDNF expression after a severe TBI in its early phase.     

Clinical Utility of a Unique Genome-Wide DNA Methylation Signature for KMT2A-Related Syndrome

Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.     

N4-Allyldeoxycytidine: A New DNA Tag with Chemical Sequencing Power for Pinpointing Labelling Sites,Mapping Epigenetic Markers,and In Situ Imaging

DNA tagging with base analogues has found numerous applications. To precisely record the DNA labelling information, it would be highly beneficial to develop chemical sequencing tags that can be encoded into DNA as regular bases and decoded as mutant bases following a mild, efficient and bioorthogonal chemical treatment. Here we reported such a DNA tag, N⁴-allyldeoxycytidine (a⁴dC), for labeling and identifying DNA by in vitro assays. The iodination of a⁴dC led to fast and complete formation of 3 , N⁴-cyclized deoxycytidine, which induced base misincorporation during DNA replication and thus could be located at single base resolution. We explored the applications of a⁴dC in pinpointing DNA labelling sites at single base resolution, mapping epigenetic marker N⁴-methyldeoxycytidine, and imaging nucleic acids in situ. In addition, mammalian cellular DNA could be metabolically labelled with a⁴dC. Our study sheds light on the design of next generation DNA tags with chemical sequencing power.     

1-甲基-2，4，5-三硝基咪唑合成工艺优化

以咪唑为原料,通过两步硝化制得1,4-二硝基咪唑,然后在氯苯中热重排得2,4-二硝基咪唑,将2,4-二硝基咪唑进-步硝化并制得2,4,5-三硝基咪唑的钾盐,最后将钾盐甲基化,得到1-甲基-2,4,5-三硝基咪唑（MTNI）,收率23％。采用红外光谱、元素分析、核磁共振的方法对其结构进行表征。用DSC进行了热分解研究。优化了2,4-二硝基咪唑的合成工艺：反应温度为123±2℃,反应时间为6h,n（1,4-二硝基咪唑）：n（氯苯）=1：9。改进了前两步硝化条件和2,4,5-三硝基咪唑钾盐的合成工艺。     

Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase 1

A series of DNA methyltransferase 1 (DNMT1) inhibitors were modeled by docking and molecular dynamics studies to rationalize their activity. Our findings will be valuable in guiding research efforts toward the rational design and virtual screening of novel DNMT inhibitors.

     

海藻酸-羧甲基葡甘聚糖共混膜的结构与性能研究

对魔芋葡甘聚糖进行羧甲基化改性,制得醚化度为0.54的羧甲基葡甘聚糖。再利用溶液共混法制备海藻酸钠-羧甲基葡甘聚糖共混膜,通过红外光谱、X-射线衍射、原子吸收光谱和扫描电镜对共混膜的结构进行了表征;并测定了不同配比共混膜的拉伸强度、断裂伸长率,吸水率和水蒸汽透过率,同时考察了NaCl浓度对共混膜吸水率的影响。结果表明:共混膜中海藻酸和羧甲基葡甘聚糖间具有较强的相互作用,良好的相容性。共混膜具有良好的力学性能,在生物材料领域有潜在利用价值。