IDA

神经氨酸酶缺乏症
  • 文章类型: Journal Article
    吡丙醚(PPF)荧光探针的开发是至关重要的,因为它对人类健康的潜在威胁。然而,PPF的化学惰性和低溶解度对使用荧光探针检测水溶液中的PPF提出了重大挑战。在这里,我们最初提出了一种基于2-(4-(二甲基氨基)苯基)-3-羟基-6,7-二甲氧基-4H-色烯-4-酮(HOF)和血清白蛋白(SA)的配合物作为双模荧光探针,HOF@SA。该探针利用指示剂置换测定(IDA)在低PPF浓度(<10µM)下从探针中释放染料HOF,并将游离染料HOF嵌入高浓度(>10µM)的PPF胶束中。这导致PPF的双模式荧光响应特性:低浓度下的关闭响应和高浓度下的比率响应。对用于PPF检测的HOF@SA的感测行为的调查显示出快速响应(<60s),高灵敏度(LOD〜4.7ppb),高选择性,和优良的视觉检测能力(从青色到黄色)。此外,借助便携式设备,该方法能够分析环境和食品样品中的PPF。这些结果促进了用于环境和食品中PPF分析的荧光探针方法的发展。
    The development of a fluorescent probe for pyriproxyfen (PPF) is crucial due to its potential threat to human health. However, the chemical inertness and low solubility of PPF present significant challenges for the detection of PPF in aqueous solutions using fluorescent probes. Herein, we have originally proposed a complex based on 2-(4-(dimethylamino)phenyl)-3-hydroxy-6,7-dimethoxy-4 H-chromen-4-one (HOF) and serum albumin (SA) as a dual-mode fluorescent probe, HOF@SA. This probe utilizes an indicator displacement assay (IDA) to release the dye HOF from the probe at low PPF concentrations (< 10 µM) and embeds the free dye HOF into the micelle of PPF at high concentrations (> 10 µM). This results in dual-mode fluorescent response characteristics for PPF: a turn-off response at low concentrations and a ratiometric response at high concentrations. An investigation of sensing behavior of HOF@SA for PPF detection exhibits rapid response (< 60 s), high sensitivity (LOD ∼4.7 ppb), high selectivity, and excellent visual detection capability (from cyan to yellow). Moreover, with the aid of a portable device, this method enables to analyze PPF in environmental and food samples. These results promote the advancement of a fluorescent probe approach for PPF analysis in environment and food.
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  • 文章类型: Journal Article
    内动力蛋白臂(IDAs)由蛋白质复合物形成,该复合物对于适当的鞭毛弯曲和跳动至关重要。以前,IDA缺陷与弱精子症(AZS)和男性不育的发生率有关。富含睾丸的ZMYND12蛋白与衣藻中鉴定的IDA成分同源。ZMYND12缺乏症以前与男性不育有关,然而,潜在的机制仍然不确定。这里,采用CRISPR/Cas9方法来产生Zmynd12敲除(Zmynd12-/-)小鼠。这些Zmynd12-/-小鼠表现出显著的雄性不育症,精子运动速度降低,和能力受损。通过免疫共沉淀和质谱联用,发现ZMYND12与TTC29和PRKACA相互作用。这些Zmynd12-/-小鼠的精子中PRKACA水平明显下降,表明这种变化可能是男性生育能力下降的原因。此外,在一组AZS患者中,确定了一名携带ZMYND12变体的患者,扩展已知的AZS相关变体谱。一起,这些发现表明ZMYND12对于鞭毛跳动至关重要,获能,男性生育能力。
    Inner dynein arms (IDAs) are formed from a protein complex that is essential for appropriate flagellar bending and beating. IDA defects have previously been linked to the incidence of asthenozoospermia (AZS) and male infertility. The testes-enriched ZMYND12 protein is homologous with an IDA component identified in Chlamydomonas. ZMYND12 deficiency has previously been tied to infertility in males, yet the underlying mechanism remains uncertain. Here, a CRISPR/Cas9 approach was employed to generate Zmynd12 knockout (Zmynd12-/-) mice. These Zmynd12-/- mice exhibited significant male subfertility, reduced sperm motile velocity, and impaired capacitation. Through a combination of co-immunoprecipitation and mass spectrometry, ZMYND12 was found to interact with TTC29 and PRKACA. Decreases in the levels of PRKACA were evident in the sperm of these Zmynd12-/- mice, suggesting that this change may account for the observed drop in male fertility. Moreover, in a cohort of patients with AZS, one patient carrying a ZMYND12 variant was identified, expanding the known AZS-related variant spectrum. Together, these findings demonstrate that ZMYND12 is essential for flagellar beating, capacitation, and male fertility.
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  • 文章类型: Journal Article
    CCDC39和CCDC40中的致病双等位基因DNA变体是原发性纤毛运动障碍(PCD)遗传性疾病的常见原因。编码的蛋白质形成分子标尺复合物,对于沿睫状轴突保持96nm重复单元至关重要。这些蛋白质的缺陷会导致僵硬,快速,闪烁的纤毛跳动模式,反复呼吸道感染,轴突紊乱,GAS8、CCDC39和DNALI1的异常组装。我们对由于CCDC39和CCDC40中的致病变异导致的96nm轴突标尺中的缺陷进行了分子表征,并分析了对其他轴突成分的影响。我们通过下一代测序技术确定了51名CCDC39和CCDC40中具有致病变异的个体,并通过免疫荧光分析证明IDA重链DNAH1,DNAH6和DNAH7在呼吸道睫状轴突中明显缺失。因此,我们首次显示包含IDA的centrin2(CETN2)也受到影响。这些发现强调了CCDC39和CCDC40在人呼吸道纤毛中IDAs的组装和功能中的关键作用。因此,我们的数据通过进一步表征相关的分子IDA缺陷,改善了轴突尺缺陷的诊断。
    Disease-causing bi-allelic DNA variants in CCDC39 and CCDC40 are frequent causes of the hereditary disorder of primary ciliary dyskinesia (PCD). The encoded proteins form a molecular ruler complex, crucial for maintaining the 96 nm repeat units along the ciliary axonemes. Defects of those proteins cause a stiff, rapid, and flickery ciliary beating pattern, recurrent respiratory infections, axonemal disorganization, and abnormal assembly of GAS8, CCDC39, and DNALI1. We performed molecular characterization of the defects in the 96 nm axonemal ruler due to disease-causing variants in CCDC39 and CCDC40 and analyzed the effect on additional axonemal components. We identified a cohort of 51 individuals with disease-causing variants in CCDC39 and CCDC40 via next-generation sequencing techniques and demonstrated that the IDA heavy chains DNAH1, DNAH6, and DNAH7 are conspicuously absent within the respiratory ciliary axonemes by immunofluorescence analyses. Hence, we show for the first time that the centrin2 (CETN2) containing IDAs are also affected. These findings underscore the crucial role of CCDC39 and CCDC40 in the assembly and function of IDAs in human respiratory cilia. Thus, our data improve the diagnostics of axonemal ruler defects by further characterizing the associated molecular IDA defects.
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  • 文章类型: Journal Article
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  • 文章类型: Journal Article
    植物在发育过程中或暴露于不利条件时已经进化出器官脱落的机制。1不受控制的花瓣脱落,水果,或叶子会损害农业生产力。2,3,4,5尽管它对脱落进程很重要,我们对IDA信号通路及其调控的理解仍然不完整。IDA分泌到质外体,其中它被受体HAESA(HAE)和HAESA-LIKE2(HSL2)和体细胞胚胎发生受体激酶(SERK)共同受体感知。6,7,8,9这些质膜受体通过未知的机制激活丝裂原活化蛋白激酶(MAPK)的细胞内级联10,11,12此处,我们将油菜素类固醇信号激酶(BSKs)描述为拟南芥花器官脱落的调节因子。BSK1定位于脱落区细胞的质膜,它与HAESA受体相互作用以调节脱落。此外,我们证明YODA(YDA)在其他MAPKKs中在控制HAESA/BSK复合物下游的脱落中起着主导作用。这个激酶轴,包含富含亮氨酸的重复受体激酶,一个BSK,还有一个图形,已知调节气孔模式,早期胚胎发育,和免疫。10,13,14,15,16尽管通过共同效应子进行信号传导,但如何获得特定的细胞应答尚不清楚。我们表明,已鉴定的BSK1的脱落促进等位基因也增强了其他BSK介导的途径中的受体信号传导,建议信号机制的保守性。此外,我们提供了遗传证据支持BSK1功能与其激酶活性在几个发育过程中的独立性。一起,我们的研究结果表明,BSK1通过植物发育多个方面的保守机制促进质膜受体激酶和MAPKKs之间的信号传导。
    Plants have evolved mechanisms to abscise organs as they develop or when exposed to unfavorable conditions.1 Uncontrolled abscission of petals, fruits, or leaves can impair agricultural productivity.2,3,4,5 Despite its importance for abscission progression, our understanding of the IDA signaling pathway and its regulation remains incomplete. IDA is secreted to the apoplast, where it is perceived by the receptors HAESA (HAE) and HAESA-LIKE2 (HSL2) and somatic embryogenesis receptor kinase (SERK) co-receptors.6,7,8,9 These plasma membrane receptors activate an intracellular cascade of mitogen-activated protein kinases (MAPKs) by an unknown mechanism.10,11,12 Here, we characterize brassinosteroid signaling kinases (BSKs) as regulators of floral organ abscission in Arabidopsis. BSK1 localizes to the plasma membrane of abscission zone cells, where it interacts with HAESA receptors to regulate abscission. Furthermore, we demonstrate that YODA (YDA) has a leading role among other MAPKKKs in controlling abscission downstream of the HAESA/BSK complex. This kinase axis, comprising a leucine-rich repeat receptor kinase, a BSK, and an MAPKKK, is known to regulate stomatal patterning, early embryo development, and immunity.10,13,14,15,16 How specific cellular responses are obtained despite signaling through common effectors is not well understood. We show that the identified abscission-promoting allele of BSK1 also enhances receptor signaling in other BSK-mediated pathways, suggesting conservation of signaling mechanisms. Furthermore, we provide genetic evidence supporting independence of BSK1 function from its kinase activity in several developmental processes. Together, our findings suggest that BSK1 facilitates signaling between plasma membrane receptor kinases and MAPKKKs via conserved mechanisms across multiple facets of plant development.
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  • 文章类型: Journal Article
    ADHD是一种普遍存在的神经发育障碍,其特征是注意力不集中和过度活动冲动。执行功能受损(EF)是多动症模型的核心,而α波段频谱功率事件相关降低(ERD)已成为ADHD中EF的推定脑电图(EEG)生物标志物。人们对EF和αERD的作用以及它们与ADHD症状的相互作用知之甚少。
    我们估计了ADHD症状的网络模型,并将alphaERD测量值整合到症状网络中。
    EF是连接alphaERD和多动/冲动和注意力不集中症状的桥梁网络节点。我们发现EF与一部分症状密切相关,即运动症状,\"seat\"(难以坐),和“奔跑”(过度奔跑或攀爬)。
    EF充当连接alphaERD和ADHD症状网络的桥节点。运动型症状和EF缺陷可能构成行为/症状之间相互作用的重要节点,认知,多动症的神经生理标志物。
    UNASSIGNED: ADHD is a prevalent neurodevelopmental disorder characterized by symptoms of inattention and hyperactivity-impulsivity. Impairments in executive functioning (EF) are central to models of ADHD, while alpha-band spectral power event-related decreases (ERD) have emerged as a putative electroencephalography (EEG) biomarker of EF in ADHD. Little is known about the roles of EF and alpha ERD and their interactions with symptoms of ADHD.
    UNASSIGNED: We estimated network models of ADHD symptoms and integrated alpha ERD measures into the symptom network.
    UNASSIGNED: EF emerges as a bridge network node connecting alpha ERD and the hyperactivity/impulsivity and inattention symptoms. We found that EF most closely relates to a subset of symptoms, namely the motoric symptoms, \"seat\" (difficulty staying seated), and \"runs\" (running or climbing excessively).
    UNASSIGNED: EF functions as a bridge node connecting alpha ERD and the ADHD symptom network. Motoric-type symptoms and EF deficits may constitute important nodes in the interplay between behavior/symptoms, cognition, and neurophysiological markers of ADHD.
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  • 文章类型: Journal Article
    在严重的急性营养不良中,微量营养素缺乏以及蛋白质能量营养不良是生长发育的主要障碍。缺铁是营养性贫血的主要原因。知情同意后,211名具有正常营养状况的SAM儿童和211名年龄和性别匹配的健康儿童被纳入研究。MUAC用于诊断SAM。5部分自动血细胞分析仪用于测量全血细胞计数和红细胞指数,和外周涂片法测定红细胞形态。我们测量了血清铁蛋白,使用ELISA方法的维生素B12和叶酸。与对照组相比,患有SAM的儿童红细胞指数明显降低,血小板计数,和白细胞计数。在SAM儿童中最常见的临床症状是腹泻,肺炎,急性胃肠炎,和急性呼吸道感染。患有SAM的儿童更有可能患有铁缺乏和B12缺乏。严重的维生素B12缺乏更常与严重的贫血相关。SAM儿童的严重贫血不断改变身体的防御机制,影响造血.在这项研究中,建议使用血液学指标来预测贫血的严重程度,描述了造血的变化,为了改善SAM儿童的预期护理和预后。
    In severe acute malnutrition, micronutrient deficiency as well as protein energy malnutrition is a major obstacle to growth & development. Iron deficiency dominates the spectrum of nutritional anemia. After taking informed consent, 211 SAM children and 211 age-and sex-matched healthy children with normal nutritional status were enrolled for the study. MUAC was used to diagnose SAM. A 5-part automated hematoanalyzer was used to measure the complete blood count and red cell indices, and the peripheral smear method to determine the red cell morphology. We measured serum ferritin, Vitamin B12, and folic acid using the ELISA method. Compared to controls, children with SAM had significantly lower red cell indices, platelet counts, and white cell counts. The most common clinical symptoms seen in SAM children were diarrhea, pneumonia, acute gastroenteritis, and acute respiratory infection. Children with SAM are more likely to suffer from iron deficiency and B12 deficiency. Severe vitamin B12 deficiency was more frequently associated with severe anemia. The severe anemia in SAM children constantly changes the body\'s defense mechanism, affecting the haematopoiesis. In this study, haematological indices are recommended for predicting severity of anemia, and hematopoietic changes are described, in order to improve anticipatory care and outcome in children with SAM.
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  • 文章类型: Journal Article
    植物像叶子一样脱落器官,花瓣或果实通过脱落的过程。监控像年龄这样的线索,资源可用性,生物和非生物胁迫允许植物及时摘除器官。这些信号如何整合到驱动脱落的分子途径中在很大程度上是未知的。缺失缺失(IDA)基因是拟南芥花器官脱落的主要驱动因素之一,已知对大多数脱落调节线索有转录反应。通过计算机模拟和体外研究IDA启动子,我们鉴定了可以潜在地调节IDA表达的转录因子。我们探讨了花器官脱落过程中ERF和WRKY结合位点对IDA表达的重要性,WRKYs与介导IDA上调特别相关,以响应注定要分离的组织中的生物应激。我们进一步将WRKY57定性为脱落区IDA和IDA样基因表达的正调节因子。我们的发现强调了启动子元件靶向方法的前景,以调节IDA信号通路的响应性,以利用受控的脱落时间来提高作物生产力。
    Plants shed organs such as leaves, petals, or fruits through the process of abscission. Monitoring cues such as age, resource availability, and biotic and abiotic stresses allow plants to abscise organs in a timely manner. How these signals are integrated into the molecular pathways that drive abscission is largely unknown. The INFLORESCENCE DEFICIENT IN ABSCISSION (IDA) gene is one of the main drivers of floral organ abscission in Arabidopsis and is known to transcriptionally respond to most abscission-regulating cues. By interrogating the IDA promoter in silico and in vitro, we identified transcription factors that could potentially modulate IDA expression. We probed the importance of ERF- and WRKY-binding sites for IDA expression during floral organ abscission, with WRKYs being of special relevance to mediate IDA up-regulation in response to biotic stress in tissues destined for separation. We further characterized WRKY57 as a positive regulator of IDA and IDA-like gene expression in abscission zones. Our findings highlight the promise of promoter element-targeted approaches to modulate the responsiveness of the IDA signaling pathway to harness controlled abscission timing for improved crop productivity.
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  • 文章类型: Journal Article
    缺铁性贫血(IDA)是世界上最常见的营养相关健康问题。多糖铁复合物(PIC)等常用铁补充剂的功效尚缺乏综合比较研究,用于IDA的蛋白质琥珀酸铁(IPS)和琥珀酸亚铁(FS)。在这项研究中,我们比较了PIC,通过胃内给药对IDA大鼠的IPS和FS功效。结果表明,三种铁补充剂具有相似的功效。PIC/IPS/FS以15mgFe/kg/d的剂量持续10d使血液学和血清生化参数增加到2.15/2.12/2.18(Hb),1.71/1.67/1.69(RBC),2.10/2.11/2.12(HCT),1.26/1.22/1.22(MCV),所有1.34(MCH),1.15/1.15/1.14(MCHC),1.94/1.82/1.91(SF),9.75/9.67/9.53(SI),23.30/22.68/21.64(TS)次,并将TIBC降低至0.42/0.43/0.44倍,与未经治疗的IDA大鼠相比。PIC在恢复MCV水平方面略优于IPS和FS。同时,心脏,脾脏和肾脏系数降低到67%/74%/65%(心脏),所有59%(脾脏)和87%/88%/88%(肾脏),肝脏系数增加到116%/115%/116%,与未经治疗的IDA大鼠相比。发现肝脏铁含量比脾脏铁含量受IDA影响更大。与未治疗的IDA大鼠相比,PIC/IPS/FS在15mgFe/kg/d时在10d内将器官铁含量增加至4.20/3.97/4.03倍(肝脏)和1.36/1.24/1.41倍(脾脏),PIC-H和FS在恢复脾脏铁含量方面略优于IPS。这项研究的结果可以为三种铁补充剂的比较提供有用的数据信息,PIC,IPS和FS。
    Iron deficiency anemia (IDA) is the most common nutrient-related health problem in the world. There is still a lack of comprehensive comparative study on the efficacies of commonly used iron supplements such as polysaccharide iron complex (PIC), iron protein succinylate (IPS) and ferrous succinate (FS) for IDA. In this study, we compared the PIC, IPS and FS efficacies in IDA rats via intragastric administration. The results showed that the three iron supplements had similar efficacies. PIC/IPS/FS at a dose of 15 mg Fe/kg/d for 10 d increased the hematological and serum biochemical parameters to 2.15/2.12/2.18 (Hb), 1.71/1.67/1.69 (RBC), 2.10/2.11/2.12 (HCT), 1.26/1.22/1.22 (MCV), all 1.34 (MCH), 1.15/1.15/1.14 (MCHC), 1.94/1.82/1.91 (SF), 9.75/9.67/9.53 (SI), and 23.30/22.68/21.64 (TS) times, and reduced TIBC to 0.42/0.43/0.44 times, compared to untreated IDA rats. PIC performed slightly better than IPS and FS in restoring MCV level. Meanwhile, the heart, spleen and kidney coefficients reduced to 67%/74%/65% (heart), all 59% (spleen) and 87%/88%/88% (kidney), and the liver coefficient increased to 116%/115%/116%, compared to untreated IDA rats. The liver iron content was found to be more affected by IDA than the spleen iron content. PIC/IPS/FS at 15 mg Fe/kg/d increased organ iron contents to 4.20/3.97/4.03 times (liver) and 1.36/1.24/1.41 times (spleen) within 10 d compared to untreated IDA rats, and PIC-H and FS were slightly better than IPS in restoring spleen iron content. The results of this study can provide useful data information for the comparison of three iron supplements, PIC, IPS and FS.
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  • 文章类型: Journal Article
    背景:铁缺乏(ID)的检测仍然具有挑战性。我们旨在评估网织红细胞血红蛋白当量(Ret-He)作为评估大型儿科队列中ID和缺铁性贫血(IDA)的潜在诊断标记物的性能。
    方法:对3158例患者(年龄15天至19岁,中位年龄8.5岁;60.2%为女性)进行了回顾性研究。进行了统计分析(a)评估Ret-He与其他相关全血细胞计数和铁面板参数的关系;(b)比较ID和IDA组中的Ret-He水平与对照组;(c)评估ID中Ret-He的敏感性和特异性。IDA,和无ID组的贫血。
    结果:Ret-He值与铁蛋白和转铁蛋白饱和度(TSAT)呈显著正相关。ID的Ret-He中位数明显较低。≤30.0pg的Ret-He临界值将ID病例与对照组区分开来,灵敏度为90.2%,特异性为59.5%,曲线下面积(AUC)为0.88。Ret-He在IDA组中显示出更好的诊断性能,而在没有贫血的情况下,ID表现可接受。敏感性,特异性,AUC为90.1%,80.9%,在≤27.4pg的截止值时,IDA为0.93,80.8%,51.1%,在≤30.8pg的截止值下,无贫血的ID为0.70,分别。
    结论:我们的大型儿科三级护理医院研究表明,Ret-He是帮助确认儿科人群中IDA的可靠标志物。然而,需要进一步研究以捕获ID的早期阶段。
    BACKGROUND: Detection of iron deficiency (ID) remains challenging. We aimed to evaluate the performance of reticulocyte hemoglobin equivalent (Ret-He) as a potential diagnostic marker to assess ID and iron deficiency anemia (IDA) in a large pediatric cohort.
    METHODS: A total of 3158 patients (aged 15 days to 19 years with a median age of 8.5 years; 60.2% female) were retrospectively studied. Statistical analysis was performed (a) to evaluate relationship of Ret-He with other relevant complete blood count and iron panel parameters; (b) to compare the levels of Ret-He in ID and IDA groups to a control group; and (c) to assess sensitivity and specificity of Ret-He in ID, IDA, and anemia without ID groups.
    RESULTS: Ret-He values were significantly positively correlated to ferritin and transferrin saturation (TSAT). The median Ret-He was significantly lower in ID. A Ret-He cutoff of ≤30.0 pg distinguished cases of ID from the control group with a sensitivity of 90.2%, specificity of 59.5%, and area under curve (AUC) of 0.88. Ret-He showed better diagnostic performance in the IDA group and acceptable performance for ID without anemia. The sensitivity, specificity, and AUC were 90.1%, 80.9%, and 0.93 for IDA at cutoff value of ≤27.4 pg, and 80.8%, 51.1%, and 0.70 for ID without anemia at cutoff value of ≤30.8 pg, respectively.
    CONCLUSIONS: Our large pediatric tertiary care hospital study demonstrates that Ret-He is a reliable marker to help confirm IDA in pediatric population. However, further studies are needed for its use to capture the early stages of ID.
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