A novel inhibitor rescues cerebellar defects in a zebrafish model of Down syndrome–associated kinase Dyrk1A overexpression

The highly conserved dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1A) plays crucial roles during central nervous system development and homeostasis. Furthermore, its hyperactivity is considered responsible for some neurological defects in individuals with Down syndrome. We set out to establish a zebrafish model expressing human Dyrk1A that could be further used to characterize the interaction between Dyrk1A and neurological phenotypes. First, we revealed the prominent expression of dyrk1a homologs in cerebellar neurons in the zebrafish larval and adult brains. Overexpression of human dyrk1a in postmitotic cerebellar Purkinje neurons resulted in a structural misorganization of the Purkinje cells in cerebellar hemispheres and a compaction of this cell population. This impaired Purkinje cell organization was progressive, leading to an age-dependent dispersal of Purkinje neurons throughout the cerebellar molecular layer with larval swim deficits resulting in miscoordination of swimming and reduced exploratory behavior in aged adults. We also found that the structural misorganization of the larval Purkinje cell layer could be rescued by pharmacological treatment with Dyrk1A inhibitors. We further reveal the in vivo efficiency of a novel selective Dyrk1A inhibitor, KuFal194. These findings demonstrate that the zebrafish is a well-suited vertebrate organism to genetically model severe neurological diseases with single cell type specificity. Such models can be used to relate molecular malfunction to cellular deficits, impaired tissue formation, and organismal behavior and can also be used for pharmacological compound testing and validation.     

六味地黄丸联合小剂量雌孕激素替代疗法对围绝经期综合征患者性激素、骨密度和血脂的影响

摘要 目的：探讨六味地黄丸联合小剂量雌孕激素替代疗法对围绝经期综合征（PMS）患者性激素、骨密度和血脂的影响。方法：研究对象选取2018年12月~2020年5月期间我院接收的PMS患者93例,根据乱数表法将患者随机分为对照组（n=46）和研究组（n=47）,对照组给予小剂量雌孕激素替代疗法,研究组给予六味地黄丸联合小剂量雌孕激素替代疗法,28d为一个治疗周期,对比两组患者治疗3个周期后的疗效、性激素、腰椎L2～L4骨密度、血脂、子宫内膜厚度及不良反应。结果：治疗3个周期后,研究组的总有效率为91.49%（43/47）,高于对照组的76.09%（35/46）（P<0.05）。治疗3个周期后,研究组改良Kupperman评分表（KMI）、总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、促卵泡刺激素(FSH)、促黄体生成素(LH)低于对照组,高密度脂蛋白胆固醇（HDL-C）、子宫内膜厚度、腰椎L2～L4骨密度、雌二醇（E2）高于对照组（P<0.05）。两组不良反应总发生率对比差异无统计学意义（P>0.05）。结论：六味地黄丸联合小剂量雌孕激素替代疗法治疗PMS患者,可有效缓解临床症状,提高骨密度,改善PMS患者的性激素及血脂水平,疗效确切。     

HFOV联合PS对治疗新生儿ALI/ARDS的疗效及对肺动态顺应性的影响

摘要 目的：探讨高频振荡通气（HFOV）联合肺表面活性物质（PS）对治疗新生儿急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）的疗效及对肺动态顺应性的影响。方法：选择2018年1月至2020年12月我院新生儿科收治的160例ALI/ARDS患儿进行研究,按照随机数表法分为观察组和对照组,每组80例。对照组患儿给予常频通气（CMV）模式联合PS治疗,观察组患儿给予HFOV模式联合PS治疗。比较两组患儿一般治疗情况、治疗前后肺动态顺应性、动脉血氧分压（PaO₂）、动脉二氧化氮分压（PaCO₂）、氧合指数（OI）、血清肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-6、IL-10的变化,以及治疗期间并发症发生情况。结果：观察组胸片恢复正常时间、机械通气时间、氧暴露时间、ICU停留时间、住院时间结果均明显短于对照组（P＜0.05）,两组患儿病死率相比较,无统计学意义（P＞0.05）;治疗后12 h、24 h、48 h时,观察组肺动态顺应性及PaO₂、OI结果明显高于对照组,PaCO₂明显比对照组低,差异有统计学意义（P＜0.05）;治疗后48 h时,观察组血清TNF-α、IL-6水平均明显低于对照组,IL-10明显比对照组高,差异有统计学意义（P＜0.05）;两组治疗期间,呼吸机相关性肺损伤、颅内出血、气漏、呼吸道感染的总发生率比较,无统计学意义（P＞0.05）。结论：HFOV联合PS治疗新生儿ALI/ARDS疗效明显,可有效改善患儿肺动态顺应性,促进血气分析指标恢复,且可降低炎症因子的表达,值得推广应用。     

Structure and Function of N-Terminal Zinc Finger Domain of SARS-CoV-2 NSP2

Virologica Sinica - SARS-CoV-2 has become a global pandemic threatening human health and safety. It is urgent to find effective therapeutic agents and targets with the continuous emergence of novel...     

Generation and Characterization of a Nanobody Against SARS-CoV

Virologica Sinica - The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) has caused global panic in 2003, and the risk of SARS-CoV outbreak still exists. However, no...     

The protective effect of sulforaphane against oxidative stress in granulosa cells of patients with polycystic ovary syndrome (PCOS) through activation of AMPK/AKT/NRF2 signaling pathway

Increased production of reactive oxygen species (ROS) in granulosa cells (GCs) causes oxidative stress (OS) and plays a role in pathogenesis of polycystic ovary syndrome (PCOS). Sulforaphane (SFN) has received a great deal of attention as potent antioxidant because of its ability to induce expression of antioxidant enzymes through nuclear factor (erythroid-derived 2)-like 2 (NRF2) signaling pathway. Therefore, the present study was done to investigate the protective effect of SFN against OS in granulosa-lutein cells (GLCs) of patients with PCOS through activation of AMP-activated protein kinase (AMPK)/AKT/NRF2 signaling pathway. GLCs were isolated from patients with PCOS and healthy fertile women, as control group, during egg retrieval procedure. Level of intracellular ROS and apoptosis was determined in the isolated cells. For investigating the protective effect of SFN against ROS production and apoptosis in GLCs, the cells were cultured for 24 h in the presence or absence of SFN. Finally, expression of AMPK, AKT, and NRF2 proteins and genes was evaluated by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. The results indicated the increased ROS and apoptosis levels in GLCs isolated from patients with PCOS compared to the control group. Addition of SFN to culture medium of GLCs of patients with PCOS reduced intracellular ROS and apoptosis levels, and increased expression of AMPK, AKT, and NRF2 proteins and genes. Our findings demonstrated the protective effect of SFN against OS by lowering level of ROS and apoptosis possibly through activation of AMPK, AKT, and NRF2 proteins and genes expression.     

彩色多普勒超声对盆腔瘀血综合征的诊断价值及与临床因素的相关性研究

目的:探讨盆腔瘀血综合征患者彩色多普勒超声的影像学特征及与临床因素的相关性。方法:对112例盆腔瘀血综合征患者行彩色多普勒超声检查,按超声诊断分级Ⅰ级、Ⅱ级、Ⅲ级分为62例、27例、23例,观察彩色多普勒超声的影像学特征,分析静脉内径与病程的相关性,并分析超声诊断分级与临床症状积分、体质量指数(BMI)、妊娠次数、既往工作站立时间的相关性。结果:不同超声诊断分级患者的静脉内径、静脉丛范围和静脉流速差异具有统计学意义(P<0.05)。静脉内径与病程呈正相关(P<0.05),超声诊断分级与临床症状积分、妊娠次数、既往工作站立时间呈显著正相关(P<0.05),与BMI呈负相关(P<0.05)。结论:彩色多普勒超声对盆腔瘀血综合征具有特异性的诊断价值,超声诊断分级、静脉内径与临床因素存在一定的的关联性。     

Population-based carrier screening and prenatal diagnosis of fragile X syndrome in East Asian populations

Identification of carriers of fragile X syndrome (FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers. The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization; the integral risks of full mutation expansion were approximately 6.0%, 43.8%, and 100% for premutation alleles with 55–74, 75–89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG (adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75–89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXS-associated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.