来自用户 盼盼 的文献。
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1.
盼盼
(2024-08-31 22:13):
#paper doi: 10.1038/s41586-024-07185-7. APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia 美国斯坦福大学医学院的Tony 团队在Nature上发表题目为APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia的文章,通过对AD患者死后脑组织的核RNA测序,发现一种表达由脂滴相关酶ACSL1的小胶质细胞状态,其中ACSL1阳性的小胶质细胞在APOE4/4基因型AD患者中最为丰富。在iMG中证实纤维状淀粉样蛋白-β(fAβ)可以以APOE依赖的方式诱导ACSL1表达和脂滴积累,并且含有脂滴积累的小胶质细胞的培养基可以APOE依赖的方式介导Tau磷酸化和神经毒性。这歌研究提示我们小胶质细胞代谢状态的改变,可能是神经退行性疾病进展因素,这为AD的治疗提供了新策略。
Abstract:
Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid …
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Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.
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2.
盼盼
(2024-07-26 17:56):
#paper DOI: 10.1093/procel/pwae037 ,本研究报告了一项自体造血干细胞基因治疗(HSCGT)已发病的青少年型异染性脑白质营养不良(MLD)患者将近10年的安全性和有效性随访研究。该团队于2013年开创了亚洲首个造血干细胞基因疗法应用于有症状的青少年型MLD患者,随后进行了一项长期的多中心、开放临床试验,通过分析治疗后短期和长期随访期间发生的不良事件以评估该疗法的长期安全性,通过ARSA活性检测、MRI评分及神经功能评分等评估结果展示HSCGT 是安全的,使晚发型青年mld患者临床获益。
Abstract:
Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for …
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Metachromatic leukodystrophy (MLD) is an inherited disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). Lentivirus-modified autologous hematopoietic stem cell gene therapy (HSCGT) has recently been approved for clinical use in pre- and early-symptomatic children with MLD to increase ARSA activity. Unfortunately, this advanced therapy is not available for most patients with MLD who have progressed to more advanced symptomatic stages at diagnosis. Patients with late-onset juvenile MLD typically present with a slower neurological progression of symptoms and represent a significant burden to the economy and healthcare system, whereas those with early-onset infantile MLD die within a few years of symptom onset. We conducted a pilot study to determine the safety and benefit of HSCGT in patients with post-symptomatic juvenile MLD and report preliminary results. The safety profile of HSCGT was favorable in this long-term follow-up over nine years. The most common adverse events (AEs) within two months of HSCGT were related to busulfan conditioning, and all AEs resolved. No HSCGT-related AEs and no evidence of distorted hematopoietic differentiation during long-term follow-up for up to 9.6 years. Importantly, to date, patients have maintained remarkably improved ARSA activity with a stable disease state, including increased Functional Independence Measure (FIM) score and decreased magnetic resonance imaging (MRI) lesion score. This long-term follow-up pilot study suggests that HSCGT is safe and provides clinical benefit to patients with post-symptomatic juvenile MLD.
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3.
盼盼
(2024-04-30 22:50):
#paper doi:https://doi.org/10.1038/s41587-021-00830-w Robust decomposition of cell type mixtures in spatial transcriptomics
空间转录组学技术的局限在于,每个spot的测序数值可能来自于不同细胞的贡献,这样不利于细胞特异性和空间表达模式特异性的挖掘。本篇文章的作者开发了一个稳定性比较高的软件:RCTD,它利用从单细胞数据中细胞特异性谱图的表达水平,预测每个spot中细胞类型,并计算出每种细胞的权重。RCTD计算了小鼠Slide-seq跟visium数据集中准确的再现了已知的细胞类型和亚型细胞定位模式。不过这个方法结果的可靠程度依赖于注释好的单细胞数据集的质量,因此选择质量好的单细胞数据集,或者细胞注释准确度高的与空间数据匹配好的单细胞数据集是非常重要的。选择RCTD对空间数据spot的细胞类型的空间成分,揭示生物组织中细胞组织的新原理。
Abstract:
A limitation of spatial transcriptomics technologies is that individual measurements may contain contributions from multiple cells, hindering the discovery of cell-type-specific spatial patterns of localization and expression. Here, we develop …
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A limitation of spatial transcriptomics technologies is that individual measurements may contain contributions from multiple cells, hindering the discovery of cell-type-specific spatial patterns of localization and expression. Here, we develop robust cell type decomposition (RCTD), a computational method that leverages cell type profiles learned from single-cell RNA-seq to decompose cell type mixtures while correcting for differences across sequencing technologies. We demonstrate the ability of RCTD to detect mixtures and identify cell types on simulated datasets. Furthermore, RCTD accurately reproduces known cell type and subtype localization patterns in Slide-seq and Visium datasets of the mouse brain. Finally, we show how RCTD's recovery of cell type localization enables the discovery of genes within a cell type whose expression depends on spatial environment. Spatial mapping of cell types with RCTD enables the spatial components of cellular identity to be defined, uncovering new principles of cellular organization in biological tissue. RCTD is publicly available as an open-source R package at https://github.com/dmcable/RCTD .
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4.
盼盼
(2024-03-31 20:55):
https://linkinghub.elsevier.com/retrieve/pii/S0092867421005018本文应用成熟小鼠的脑组织借助merish技术对55张小鼠的冠状脑组切片测序空间转录组,同时测序对应样本的单细胞(质控后4 000 000个)。依据不同切面不同脑区的时空组表达特征的不同,每张切片都分成不同的功能分区,而大脑总的大分区11个region,时空组都可以很好地再现不同脑区的结构和空间特征。作者还应用RCTD的方法联合时空和单细胞数据,预测不同脑区的细胞类型,整个大脑组织的脑细胞分为34个亚群,其中90%的亚群种类都是神经元细胞,其中每个区的兴奋性神经元数量都是高于抑制性神经元。不同脑区神经元除了表达神经元细胞共有marker以外,还表达具有空间特异性的神经元marker,且不同脑区的神经元细胞种类差异非常大,以中脑和后脑的神经元细胞种类最为丰富。该文献展示了成年小鼠脑细胞的分子和空间特征图谱,为后来的小鼠大脑组织研究提供了数据支持。
Abstract:
The isocortex and hippocampal formation (HPF) in the mammalian brain play critical roles in perception, cognition, emotion, and learning. We profiled ∼1.3 million cells covering the entire adult mouse isocortex …
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The isocortex and hippocampal formation (HPF) in the mammalian brain play critical roles in perception, cognition, emotion, and learning. We profiled ∼1.3 million cells covering the entire adult mouse isocortex and HPF and derived a transcriptomic cell-type taxonomy revealing a comprehensive repertoire of glutamatergic and GABAergic neuron types. Contrary to the traditional view of HPF as having a simpler cellular organization, we discover a complete set of glutamatergic types in HPF homologous to all major subclasses found in the six-layered isocortex, suggesting that HPF and the isocortex share a common circuit organization. We also identify large-scale continuous and graded variations of cell types along isocortical depth, across the isocortical sheet, and in multiple dimensions in hippocampus and subiculum. Overall, our study establishes a molecular architecture of the mammalian isocortex and hippocampal formation and begins to shed light on its underlying relationship with the development, evolution, connectivity, and function of these two brain structures.
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5.
盼盼
(2024-02-27 16:38):
DOI: 10.1038/s41586-018-0453-z
目前我们已经发现数千种长链非编码RNA(lncRNA),但是明确功能的只有十几种。德克萨斯西南医学研究中心Mendell教授发现lncRNA-NORAD可以在维持基因组稳定性上非常重要。此外,还报道了PUMILIO是NORAD唯一相互作用的RNA结合蛋白,但是相关的作用机制我们并不清楚。最近 哈弗-麻省理工学院lander教授提出了NORAD和RNA结合蛋白PUMILIO的相互作用,对NORAD功能发挥具有重要作用。NORAD和PUMILIO结合后,NORAD调节PUMILIO组装拓补异构酶复合物的能力,该复合物在维持基因组稳定性具有重要作用。实验证明细胞在PUMILIO敲除后的表型,与PUMILIO敲除表型密切相关,都表现为染色质分离增加,复制叉速度降低和细胞周期改变。在PUMILIO正常表达的细胞,补充NORAD,可以补救NORAD缺失引起的基因组不稳定,但是在NORAD的作用位点缺失以后,挽救效果就很差。这说明NORAD是通过特定位点与PUMILIO相互作用,促进拓补异构酶复合物组装并参与维持基因组稳定性。但是对于NORAD与PUMILIO的相互作用如何促进拓补异构酶复合物组装的,lander教授提出了多个可能的机制,这些机制还有待进一步实验验证。
Abstract:
The human genome contains thousands of long non-coding RNAs, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen. A specific long non-coding RNA-non-coding RNA …
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The human genome contains thousands of long non-coding RNAs, but specific biological functions and biochemical mechanisms have been discovered for only about a dozen. A specific long non-coding RNA-non-coding RNA activated by DNA damage (NORAD)-has recently been shown to be required for maintaining genomic stability, but its molecular mechanism is unknown. Here we combine RNA antisense purification and quantitative mass spectrometry to identify proteins that directly interact with NORAD in living cells. We show that NORAD interacts with proteins involved in DNA replication and repair in steady-state cells and localizes to the nucleus upon stimulation with replication stress or DNA damage. In particular, NORAD interacts with RBMX, a component of the DNA-damage response, and contains the strongest RBMX-binding site in the transcriptome. We demonstrate that NORAD controls the ability of RBMX to assemble a ribonucleoprotein complex-which we term NORAD-activated ribonucleoprotein complex 1 (NARC1)-that contains the known suppressors of genomic instability topoisomerase I (TOP1), ALYREF and the PRPF19-CDC5L complex. Cells depleted for NORAD or RBMX display an increased frequency of chromosome segregation defects, reduced replication-fork velocity and altered cell-cycle progression-which represent phenotypes that are mechanistically linked to TOP1 and PRPF19-CDC5L function. Expression of NORAD in trans can rescue defects caused by NORAD depletion, but rescue is significantly impaired when the RBMX-binding site in NORAD is deleted. Our results demonstrate that the interaction between NORAD and RBMX is important for NORAD function, and that NORAD is required for the assembly of the previously unknown topoisomerase complex NARC1, which contributes to maintaining genomic stability. In addition, we uncover a previously unknown function for long non-coding RNAs in modulating the ability of an RNA-binding protein to assemble a higher-order ribonucleoprotein complex.
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6.
盼盼
(2024-01-31 18:29):
https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.29430本文应用浙江大学第二附属医院神经内科随访的亨廷顿病人信息,构建模型,经过分析发现患者血液中神经丝轻蛋白(Neurofilament light protein)可以预测Huntington's disease亨廷顿病人的发病年龄。这个蛋白主要跟发病年龄,发病前脑白质病变程度有关,但是跟发病之后的严重程度没有统计学关联。亨廷顿基因的串联重复序列数目越多,发病年龄也越早,而发病前重复序列数目多的患者,其NFL水平也比较高。总之,NFL可以作为预测亨廷顿病发病年龄的生物学marker,是本文解决的一个重要临床问题。
IF:7.400Q1
Movement disorders : official journal of the Movement Disorder Society,
2023-07.
DOI: 10.1002/mds.29430
PMID: 37148558
Abstract:
BACKGROUND: Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with …
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BACKGROUND: Neurofilament light protein (NfL) has been proven to be a sensitive biomarker for Huntington's disease (HD). However, these studies did not include HD patients at advanced stages or with larger CAG repeats (>50), leading to a knowledge gap of the characteristics of NfL.METHODS: Serum NfL (sNfL) levels were quantified using an ultrasensitive immunoassay. Participants were assessed by clinical scales and 7.0 T magnetic resonance imaging. Longitudinal samples and clinical data were obtained.RESULTS: Baseline samples were available from 110 controls, 90 premanifest HD (pre-HD) and 137 HD individuals. We found levels of sNfL significantly increased in HD compared to pre-HD and controls (both P < 0.0001). The increase rates of sNfL were differed by CAG repeat lengths. However, there was no difference in sNfL levels in manifest HD from early to late stages. In addition, sNfL levels were associated with cognitive measures in pre-HD and manifest HD group, respectively. The increased levels of sNfL were also closely related to microstructural changes in white matter. In the longitudinal analysis, baseline sNfL did not correlate with subsequent clinical function decline. Random forest analysis revealed that sNfL had good power for predicting disease onset.CONCLUSIONS: Although sNfL levels are independent of disease stages in manifest HD, it is still an optimal indicator for predicting disease onset and has potential use as a surrogate biomarker of treatment effect in clinical trials. © 2023 International Parkinson and Movement Disorder Society.
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