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Haplotype-aware inference of human chromosome abnormalities 人类染色体异常的单倍型感知推断
Pub Date : 2021-05-20 DOI: 10.1101/2021.05.18.444721
Daniel Ariad, Stephanie M. Yan, A. Victor, F. Barnes, C. Zouves, M. Viotti, R. McCoy
Significance Whole-chromosome gains and losses (aneuploidies) are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8,154 in vitro fertilization (IVF) embryos. We reclassified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were previously hidden. Our method complements standard protocols for preimplantation genetic testing, while offering insight into the biology of early development. Extra or missing chromosomes—a phenomenon termed aneuploidy—frequently arise during human meiosis and embryonic mitosis and are the leading cause of pregnancy loss, including in the context of in vitro fertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing for aneuploidy (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy, may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05 × and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.
整个染色体的获得和丢失(非整倍体)是人类妊娠失败和先天性疾病的主要原因。最近的研究表明,除了有害的减数分裂非整倍体外,有丝分裂非整倍体(导致镶嵌胚胎含有不同数量染色体的细胞)也可能在着床前胚胎中常见,但可能与健康出生相容。在这里,我们开发并测试了一种方法来区分这些形式的非整倍体使用基因检测数据从8154体外受精(IVF)胚胎。我们根据减数分裂和有丝分裂错误的特征重新分类胚胎,同时也揭示了以前隐藏的致命形式的染色体异常。我们的方法补充了胚胎植入前基因检测的标准方案,同时提供了对早期发育生物学的深入了解。染色体额外或缺失——一种被称为非整倍体的现象——经常出现在人类减数分裂和胚胎有丝分裂期间,是导致妊娠流产的主要原因,包括在体外受精(IVF)的情况下。虽然减数分裂非整倍体影响所有细胞并且是有害的,但有丝分裂错误产生镶嵌现象,这可能与健康的活产相兼容。大规模的异常,如三倍体和单倍体也会导致不良的妊娠结果,但仍然隐藏在基于标准测序的非整倍体植入前基因检测方法(PGT-A)中。因此,能够可靠地区分减数分裂和有丝分裂非整倍体,以及全基因组倍体的异常,可能对提高IVF结果有价值。在这里,我们描述了一种基于低覆盖率全基因组测序数据分析的统计方法来区分这些形式的非整倍体,这是该领域的当前标准。我们的方法通过利用在种群参考面板中测量的等位基因频率和连锁不平衡(LD)来克服数据的稀疏性。该方法被我们称为LD-informed PGT-A (LD-PGTA),其准确度低至0.05 ×,在更高的覆盖率下,还可以根据跨越着丝粒的特征区分减数分裂I和减数分裂II错误。LD-PGTA为人类染色体异常的起源提供了基本的见解,也是一种实用的工具,有可能改善试管婴儿期间的基因检测。
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引用次数: 9
Large-scale genomic study reveals robust activation of the immune system following advanced Inner Engineering meditation retreat 大规模的基因组研究揭示了免疫系统在高级内在工程冥想撤退后的强大激活
Pub Date : 2021-05-18 DOI: 10.1101/2021.05.18.444668
Vijayendran Chandran, Mei-Ling Bermúdez, Mert Koka, Brindha Chandran, Dhanashri Pawale, Ramana V Vishnubhotla, Suresh Alankar, R. Maturi, B. Subramaniam, S. Sadhasivam
Significance Several studies on the impact of yoga and meditation on mental and physical health have demonstrated beneficial effects. However, the potential molecular mechanisms and critical genes involved in this beneficial outcome have yet to be comprehensively elucidated. This study identified and characterized the transcriptional program associated with advanced meditation practice, and we bioinformatically integrated various networks to identify meditation-specific core network. This core network links several immune signaling pathways, and we showed that this core transcriptional profile is dysfunctional in multiple sclerosis and severe COVID-19 infection. Very importantly, we demonstrated that the meditative practice enhanced immune function without activating inflammatory signals. Together, these results make meditation an effective behavioral intervention for treating various conditions associated with a weakened immune system. The positive impact of meditation on human well-being is well documented, yet its molecular mechanisms are incompletely understood. We applied a comprehensive systems biology approach starting with whole-blood gene expression profiling combined with multilevel bioinformatic analyses to characterize the coexpression, transcriptional, and protein–protein interaction networks to identify a meditation-specific core network after an advanced 8-d Inner Engineering retreat program. We found the response to oxidative stress, detoxification, and cell cycle regulation pathways were down-regulated after meditation. Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon signaling, were up-regulated, with no significant expression changes in the inflammatory genes. This robust meditation-specific immune response network is significantly dysregulated in multiple sclerosis and severe COVID-19 patients. The work provides a foundation for understanding the effect of meditation and suggests that meditation as a behavioral intervention can voluntarily and nonpharmacologically improve the immune response for treating various conditions associated with excessive or persistent inflammation with a dampened immune system profile.
几项关于瑜伽和冥想对身心健康影响的研究已经证明了有益的效果。然而,潜在的分子机制和参与这一有益结果的关键基因尚未得到全面阐明。本研究确定并表征了与高级冥想练习相关的转录程序,并通过生物信息学整合各种网络来确定冥想特异性核心网络。这个核心网络连接了几个免疫信号通路,我们发现这个核心转录谱在多发性硬化症和严重的COVID-19感染中功能失调。非常重要的是,我们证明了冥想练习在不激活炎症信号的情况下增强了免疫功能。总之,这些结果使冥想成为一种有效的行为干预,可以治疗与免疫系统减弱相关的各种疾病。冥想对人类福祉的积极影响是有据可查的,但其分子机制尚不完全清楚。我们应用了全面的系统生物学方法,从全血基因表达谱开始,结合多层次生物信息学分析,表征共表达、转录和蛋白质-蛋白质相互作用网络,以确定在高级8-d内部工程静修计划后冥想特异性核心网络。我们发现冥想后对氧化应激、解毒和细胞周期调节途径的反应下调。引人注目的是,220个与免疫反应直接相关的基因,包括68个与干扰素信号相关的基因,表达上调,而炎症基因的表达无显著变化。这种强大的冥想特异性免疫反应网络在多发性硬化症和严重的COVID-19患者中显着失调。这项工作为理解冥想的作用提供了基础,并表明冥想作为一种行为干预可以自愿和非药物地改善免疫反应,以治疗与过度或持续炎症相关的各种疾病,并抑制免疫系统。
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引用次数: 22
Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells 白细胞介素-6介导tsc2缺陷细胞PSAT1表达和丝氨酸代谢
Pub Date : 2021-05-17 DOI: 10.1101/2021.05.17.444471
Ji Wang, H. Filippakis, Thomas R. Hougard, H. Du, Chenyang Ye, Heng-Jia Liu, Long Zhang, Khadijah Hindi, Shefali Bagwe, Julie Nijmeh, J. Asara, W. Shi, S. El-Chemaly, E. Henske, H. Lam
Significance The tumor suppressor syndrome tuberous sclerosis complex (TSC) affects 1:10,000 live births. We discovered that the inflammatory cytokine Interleukin-6 (IL-6) promotes the proliferation and migration of TSC2-deficient cells in part through the regulation of PSAT1 and de novo serine biosynthesis. Importantly, IL-6 neutralizing antibody treatments reduced renal cyst and cystadenoma formation in Tsc2+/− mice. This study highlights a therapeutically targetable vulnerability of TSC, which may have broad clinical application to mTORC1-activated tumors. Tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM) are caused by aberrant mechanistic Target of Rapamycin Complex 1 (mTORC1) activation due to loss of either TSC1 or TSC2. Cytokine profiling of TSC2-deficient LAM patient–derived cells revealed striking up-regulation of Interleukin-6 (IL-6). LAM patient plasma contained increased circulating IL-6 compared with healthy controls, and TSC2-deficient cells showed up-regulation of IL-6 transcription and secretion compared to wild-type cells. IL-6 blockade repressed the proliferation and migration of TSC2-deficient cells and reduced oxygen consumption and extracellular acidification. U-13C glucose tracing revealed that IL-6 knockout reduced 3-phosphoserine and serine production in TSC2-deficient cells, implicating IL-6 in de novo serine metabolism. IL-6 knockout reduced expression of phosphoserine aminotransferase 1 (PSAT1), an essential enzyme in serine biosynthesis. Importantly, recombinant IL-6 treatment rescued PSAT1 expression in the TSC2-deficient, IL-6 knockout clones selectively and had no effect on wild-type cells. Treatment with anti–IL-6 (αIL-6) antibody similarly reduced cell proliferation and migration and reduced renal tumors in Tsc2+/− mice while reducing PSAT1 expression. These data reveal a mechanism through which IL-6 regulates serine biosynthesis, with potential relevance to the therapy of tumors with mTORC1 hyperactivity.
肿瘤抑制综合征结节性硬化症(TSC)患病率为1:10 000。我们发现炎症细胞因子白介素-6 (IL-6)促进tsc2缺陷细胞的增殖和迁移,部分通过调节PSAT1和新生丝氨酸生物合成。重要的是,IL-6中和抗体治疗减少了Tsc2+/−小鼠肾囊肿和囊腺瘤的形成。这项研究强调了TSC的治疗可靶向性,这可能在mtorc1激活的肿瘤中具有广泛的临床应用。结节性硬化症(TSC)和淋巴管平滑肌瘤病(LAM)是由于TSC1或TSC2缺失导致雷帕霉素复合体1 (mTORC1)异常激活的机制引起的。tsc2缺陷LAM患者来源细胞的细胞因子谱显示白细胞介素-6 (IL-6)显著上调。与健康对照相比,LAM患者血浆中循环IL-6含量增加,tsc2缺陷细胞与野生型细胞相比,IL-6转录和分泌上调。IL-6阻断抑制tsc2缺陷细胞的增殖和迁移,减少氧消耗和细胞外酸化。U-13C葡萄糖示踪显示,IL-6敲除减少了tsc2缺陷细胞中3-磷酸丝氨酸和丝氨酸的产生,暗示IL-6参与了从头丝氨酸代谢。IL-6敲除降低了丝氨酸生物合成中必需酶磷酸丝氨酸转氨酶1 (PSAT1)的表达。重要的是,重组IL-6处理选择性地恢复了tsc2缺陷、IL-6敲除克隆中PSAT1的表达,而对野生型细胞没有影响。抗il -6 (αIL-6)抗体同样可以减少Tsc2+/−小鼠的细胞增殖和迁移,减少肾肿瘤,同时降低PSAT1的表达。这些数据揭示了IL-6调节丝氨酸生物合成的机制,与mTORC1高活性肿瘤的治疗有潜在的相关性。
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引用次数: 11
Functional alterations in cortical processing of speech in glioma-infiltrated cortex 胶质瘤浸润的皮质语言加工功能的改变
Pub Date : 2021-05-17 DOI: 10.1101/2021.05.14.444263
A. Aabedi, Benjamin Lipkin, J. Kaur, Sofia Kakaizada, Sheantel J. Reihl, Jacob S. Young, Anthony T. Lee, S. Krishna, E. Chang, D. Brang, Shawn L. Hervey Jumper
Significance As gliomas proliferate, they infiltrate healthy brain tissue. Often, patients with such tumors in the language areas of the brain develop aphasia. Understanding how gliomas interact with normal neural circuits is critical for developing neuroprostheses that restore speech. Recent evidence demonstrates that glioma cells interact synaptically with neurons and thus can modulate neural circuits. However, it is unclear the extent to which glioma-infiltrated cortex participates in cognitive processing. Using electrocorticography to record both glioma-infiltrated and normal-appearing cortex during speech, we found that glioma-infiltrated cortex is capable of coordinated neural responses but has reduced capacity for information encoding. Instead, glioma-infiltrated cortex recruits a broader network of cortical regions during speech, which may represent a compensatory mechanism with implications for future neuroprostheses. Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma–neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.
随着胶质瘤的增殖,它们浸润到健康的脑组织中。通常,患有这种肿瘤的大脑语言区患者会患上失语症。了解胶质瘤如何与正常神经回路相互作用,对于开发恢复语言的神经假体至关重要。最近的证据表明,胶质瘤细胞与神经元突触相互作用,从而可以调节神经回路。然而,神经胶质瘤浸润的皮层参与认知加工的程度尚不清楚。利用脑皮质电图记录神经胶质瘤浸润和正常表现的大脑皮层,我们发现神经胶质瘤浸润的大脑皮层具有协调神经反应的能力,但信息编码能力下降。相反,神经胶质瘤浸润的皮层在说话时招募了更广泛的皮层区域网络,这可能代表了一种代偿机制,对未来的神经假体有影响。恶性胶质瘤生物学的最新进展表明,胶质瘤细胞通过旁分泌信号传导和电化学突触与神经元相互作用。因此,胶质瘤-神经元的相互作用调节了局部神经元回路的兴奋性,目前尚不清楚胶质瘤浸润的皮层在多大程度上可以有意义地参与神经计算。例如,胶质瘤可能导致局部活动紊乱,从而阻碍神经振荡的短暂同步。另外,神经胶质瘤浸润的皮层可能保留了与正常皮层类似的同步活动能力,但表现出其他改变的时空活动模式,从而对认知处理产生影响。在这里,我们使用硬脑膜下皮质电图对说话时表现正常和胶质瘤浸润的皮层进行取样。我们发现,神经胶质瘤浸润的皮层在任务执行过程中以类似于正常皮层的方式参与同步活动,但招募了一个弥漫性的空间网络。在时间尺度上,我们发现来自胶质瘤浸润皮层的信号熵降低,这可能会影响其在细微任务(如单音节词和多音节词的产生)中编码信息的能力。此外,我们还表明,区分单音节和多音节单词的时间解码策略对于来自正常皮层的信号是可行的,而对于来自胶质瘤浸润的皮层的信号则不可行。这些发现为我们理解慢性疾病状态下的认知加工提供了信息,并对恶性神经胶质瘤患者的神经调节和修复具有指导意义。
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引用次数: 20
A fluorescence-based genetic screen reveals diverse mechanisms silencing small RNA signaling in E. coli 基于荧光的遗传筛选揭示了大肠杆菌中沉默小RNA信号的多种机制
Pub Date : 2021-05-12 DOI: 10.1101/2021.05.11.443692
Jiandong Chen, Leann To, Francois de Mets, Xing Luo, N. Majdalani, Chin-Hsien Tai, S. Gottesman
Significance The ability to promptly switch genes on and off allows bacteria to adapt rapidly to changing environments for better survival. Many small regulatory RNAs (sRNAs), including RyhB, a sRNA made in response to iron starvation, are important switches in bacteria. We discovered factors that can keep the sRNA switch off by using a facile genetic screen platform. These factors include an RNA sponge and an adaptor protein for a ribonuclease, providing distinct perspectives on controlling sRNA signaling in bacteria. As key players of gene regulation in many bacteria, small regulatory RNAs (sRNAs) associated with the RNA chaperone Hfq shape numerous phenotypic traits, including metabolism, stress response and adaptation, as well as virulence. sRNAs can alter target messenger RNA (mRNA) translation and stability via base pairing. sRNA synthesis is generally under tight transcriptional regulation, but other levels of regulation of sRNA signaling are less well understood. Here we used a fluorescence-based functional screen to identify regulators that can quench sRNA signaling of the iron-responsive sRNA RyhB in Escherichia coli. The identified regulators fell into two classes, general regulators (affecting signaling by many sRNAs) and RyhB-specific regulators; we focused on the specific ones here. General regulators include three Hfq-interacting sRNAs, CyaR, ChiX, and McaS, previously found to act through Hfq competition, RNase T, a 3′ to 5′ exonuclease not previously implicated in sRNA degradation, and YhbS, a putative GCN5-related N-acetyltransferase (GNAT). Two specific regulators were identified. AspX, a 3′end-derived small RNA, specifically represses RyhB signaling via an RNA sponging mechanism. YicC, a previously uncharacterized but widely conserved protein, triggers rapid RyhB degradation via collaboration with the exoribonuclease PNPase. These findings greatly expand our knowledge of regulation of bacterial sRNA signaling and suggest complex regulatory networks for controlling iron homeostasis in bacteria. The fluorescence-based genetic screen system described here is a powerful tool expected to accelerate the discovery of novel regulators of sRNA signaling in many bacteria.
细菌具有迅速开启和关闭基因的能力,能够迅速适应不断变化的环境,从而更好地生存。许多小调控rna (sRNAs),包括RyhB,一种响应铁饥饿的sRNA,是细菌中的重要开关。我们通过使用简单的遗传筛选平台发现了可以保持sRNA关闭的因素。这些因子包括RNA海绵和核糖核酸酶的衔接蛋白,为控制细菌中的sRNA信号提供了不同的视角。作为许多细菌基因调控的关键角色,与RNA伴侣Hfq相关的小调控RNA (sRNAs)塑造了许多表型性状,包括代谢、应激反应和适应以及毒力。sRNAs可以通过碱基配对改变靶信使RNA (mRNA)的翻译和稳定性。sRNA合成通常受到严格的转录调控,但sRNA信号传导的其他水平调控尚不清楚。在这里,我们使用基于荧光的功能筛选来鉴定可以抑制大肠杆菌中铁反应性sRNA RyhB的sRNA信号传导的调节因子。确定的调节因子分为两类,一般调节因子(影响许多srna的信号传导)和ryhb特异性调节因子;我们在这里关注的是特定的。一般的调节因子包括三个Hfq相互作用的sRNAs, CyaR, ChiX和McaS,以前发现它们通过Hfq竞争起作用,RNase T,一种以前未涉及sRNA降解的3 '至5 '外切酶,以及YhbS,一种假定的gcn5相关的n -乙酰转移酶(GNAT)。确定了两个特定的监管机构。AspX是一种3 '端衍生的小RNA,通过RNA海绵机制特异性抑制RyhB信号。YicC是一种以前未被鉴定但广泛保守的蛋白,通过与外核糖核酸酶PNPase协同作用触发RyhB的快速降解。这些发现极大地扩展了我们对细菌sRNA信号调控的认识,并提示了控制细菌铁稳态的复杂调控网络。本文描述的基于荧光的遗传筛选系统是一种强大的工具,有望加速发现许多细菌中sRNA信号传导的新调节因子。
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引用次数: 14
Chirality-matched catalyst-controlled macrocyclization reactions 手性匹配催化剂控制的大环化反应
Pub Date : 2021-05-10 DOI: 10.26434/CHEMRXIV.14556006.V1
Jaeyeon Hwang, B. Mercado, Scott J. Miller
Significance Chiral catalysts are generally used to control stereochemistry in organic reactions. Generally, they control enantioselectivity or diastereoselectivity. In recent years, applications have expanded to include control over site selectivity in reactions involving complex molecules. Even more rarely, they can control chemoselectivity along with stereochemistry. We report herein that a carefully chosen chiral catalyst can also be decisive for efficient macrocyclization reactions in cases where simple achiral catalysts or stereochemically mismatched catalysts fail. Notably, in these reactions, a chiral catalyst proves essential for control of a reaction in which no new static (i.e., not “dynamic”) stereogenic elements are introduced. While fundamentally intriguing, these observations could also influence strategies for efficient synthesis of macrocyclic compounds in a variety of settings. Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not “dynamic”) stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.
在有机反应中,手性催化剂通常用于控制立体化学反应。通常,它们控制对映选择性或非对映选择性。近年来,应用范围已扩大到包括控制涉及复杂分子的反应的位点选择性。更罕见的是,它们可以控制化学选择性和立体化学。我们在此报告,在简单的非手性催化剂或立体不匹配催化剂失效的情况下,精心选择的手性催化剂也可以对有效的大环化反应起决定性作用。值得注意的是,在这些反应中,手性催化剂对于控制没有引入新的静态(即非“动态”)立体元素的反应是必不可少的。虽然从根本上讲很有趣,但这些观察结果也可能影响在各种情况下有效合成大环化合物的策略。大环,正式定义为含有12个或更多原子的环的化合物,由于其在物理,药理学和环境科学中的重要应用而继续引起人们的极大兴趣。在大环化合物的合成中,促进分子内而非分子间的合环反应往往是一个关键的挑战。此外,具有立体元素的大环的合成带来了额外的挑战,而获得这种大环是非常有趣的。在此,我们报道了肽基催化剂在促进高效大环化反应方面的显著作用。我们表明,催化剂的手性对于促进有利的、匹配的过渡态关系是必不可少的,这种过渡态关系有利于底物与预先存在的立体元素的大环化;奇怪的是,即使没有产生新的静态(即不是“动态”)立体元素,催化剂的手性对于成功的反应也是必不可少的。涉及催化剂的非手性变体或催化剂的对映体形式的对照实验在头对头比较中未能提供大量的大环。这种现象的普遍性,在这里用一些底物来证明,刺激类似于酶催化剂产生自然发生的大环,可能是通过相关的,催化剂定义的外周相互作用与它们的无环底物。
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引用次数: 3
A theory of direction selectivity for macaque primary visual cortex 猕猴初级视觉皮层的方向选择理论
Pub Date : 2021-05-03 DOI: 10.1101/2021.05.02.442297
Logan Chariker, R. Shapley, M. Hawken, L. Young
Significance Motion perception is important for primates, and direction selectivity (DS), the ability to perceive the direction a target is moving, is an essential part of motion perception. Yet no satisfactory mechanistic explanation has been proposed for the origin of DS in the primate visual cortex up until now. In this paper, we hypothesize that DS is initiated in feed-forward LGN input as a result of the dynamic differences between the ON and OFF pathways. The mechanisms we propose are biology based, and our theory explains experimental data for all spatial and temporal frequencies in visual stimuli. Exploiting temporal biases in parallel pathways is relevant beyond visual neuroscience; similar ideas likely apply to other types of neural signal processing. This paper offers a theory for the origin of direction selectivity (DS) in the macaque primary visual cortex, V1. DS is essential for the perception of motion and control of pursuit eye movements. In the macaque visual pathway, neurons with DS first appear in V1, in the Simple cell population of the Magnocellular input layer 4Cα. The lateral geniculate nucleus (LGN) cells that project to these cortical neurons, however, are not direction selective. We hypothesize that DS is initiated in feed-forward LGN input, in the summed responses of LGN cells afferent to a cortical cell, and it is achieved through the interplay of 1) different visual response dynamics of ON and OFF LGN cells and 2) the wiring of ON and OFF LGN neurons to cortex. We identify specific temporal differences in the ON/OFF pathways that, together with item 2, produce distinct response time courses in separated subregions; analysis and simulations confirm the efficacy of the mechanisms proposed. To constrain the theory, we present data on Simple cells in layer 4Cα in response to drifting gratings. About half of the cells were found to have high DS, and the DS was broadband in spatial and temporal frequency (SF and TF). The proposed theory includes a complete analysis of how stimulus features such as SF and TF interact with ON/OFF dynamics and LGN-to-cortex wiring to determine the preferred direction and magnitude of DS.
运动感知对灵长类动物非常重要,而方向选择(direction selectivity, DS),即感知目标运动方向的能力,是运动感知的重要组成部分。然而,对于退行性椎体滑移在灵长类视觉皮层的起源,至今还没有令人满意的机制解释。在本文中,我们假设由于ON和OFF通路之间的动态差异,DS是在前馈LGN输入中启动的。我们提出的机制是基于生物学的,我们的理论解释了视觉刺激中所有空间和时间频率的实验数据。利用平行通路中的时间偏差不仅仅是视觉神经科学;类似的想法可能适用于其他类型的神经信号处理。本文为猕猴初级视觉皮层(V1)中方向选择性(DS)的起源提供了一种理论。DS对运动的感知和眼球运动的控制至关重要。在猕猴视觉通路中,具有DS的神经元首先出现在大细胞输入层4Cα的V1简单细胞群中。然而,投射到这些皮质神经元的外侧膝状核(LGN)细胞没有方向选择性。我们假设,退行性视觉是在LGN前馈输入、LGN细胞传入皮质细胞的总反应中启动的,它是通过1)ON和OFF LGN细胞不同的视觉反应动力学和2)ON和OFF LGN神经元连接到皮质的相互作用实现的。我们确定了开/关通路的具体时间差异,与项目2一起,在分离的次区域产生不同的响应时间过程;分析和仿真验证了所提机制的有效性。为了约束这一理论,我们给出了4Cα层中响应漂移光栅的简单细胞的数据。大约一半的细胞具有高DS,且DS在时空频率(SF和TF)上具有宽频。所提出的理论包括对SF和TF等刺激特征如何与开/关动力学和lgn -皮质连接相互作用的完整分析,以确定DS的首选方向和大小。
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引用次数: 6
Thermal niches of planktonic foraminifera are static throughout glacial–interglacial climate change 浮游有孔虫的热生态位在整个冰期-间冰期气候变化过程中是静态的
Pub Date : 2021-04-26 DOI: 10.1130/abs/2020am-357068
Gwen S. Antell, Isabel S. Fenton, P. Valdes, E. Saupe
Significance We examined the degree to which temperature tolerances changed on 8,000-y timescales across 700,000 y of glacial–interglacial climate change. We coupled a new fossil occurrence database of planktonic foraminifera, an abundant type of zooplankton, with Atmosphere–Ocean Global Circulation Model reconstructions of past climates. Our suite of analyses demonstrated that foraminiferal species have not shifted their temperature tolerances in response to glacial cycles; species occupied the same temperature conditions regardless of the magnitude of global temperature change. The limited tendency of planktonic foraminifera to change their tolerances suggests that ongoing global change could hasten local or global extinctions of plankton and other widely dispersing marine species. Abiotic niche lability reduces extinction risk by allowing species to adapt to changing environmental conditions in situ. In contrast, species with static niches must keep pace with the velocity of climate change as they track suitable habitat. The rate and frequency of niche lability have been studied on human timescales (months to decades) and geological timescales (millions of years), but lability on intermediate timescales (millennia) remains largely uninvestigated. Here, we quantified abiotic niche lability at 8-ka resolution across the last 700 ka of glacial–interglacial climate fluctuations, using the exceptionally well-known fossil record of planktonic foraminifera coupled with Atmosphere–Ocean Global Climate Model reconstructions of paleoclimate. We tracked foraminiferal niches through time along the univariate axis of mean annual temperature, measured both at the sea surface and at species’ depth habitats. Species’ temperature preferences were uncoupled from the global temperature regime, undermining a hypothesis of local adaptation to changing environmental conditions. Furthermore, intraspecific niches were equally similar through time, regardless of climate change magnitude on short timescales (8 ka) and across contrasts of glacial and interglacial extremes. Evolutionary trait models fitted to time series of occupied temperature values supported widespread niche stasis above randomly wandering or directional change. Ecotype explained little variation in species-level differences in niche lability after accounting for evolutionary relatedness. Together, these results suggest that warming and ocean acidification over the next hundreds to thousands of years could redistribute and reduce populations of foraminifera and other calcifying plankton, which are primary components of marine food webs and biogeochemical cycles.
我们研究了在70万y的冰期-间冰期气候变化的8000 y时间尺度上的温度容忍度变化程度。我们将浮游有孔虫(一种丰富的浮游动物)的新的化石发生数据库与过去气候的大气-海洋全球环流模式重建相结合。我们的一系列分析表明,有孔虫物种的温度耐受性并没有随着冰川循环而改变;无论全球温度变化的大小,物种都占据相同的温度条件。浮游有孔虫改变其耐受性的有限趋势表明,正在进行的全球变化可能加速浮游生物和其他广泛分散的海洋物种的局部或全球灭绝。非生物生态位的稳定性使物种能够适应不断变化的环境条件,从而减少灭绝的风险。相比之下,具有静态生态位的物种在寻找合适的栖息地时必须跟上气候变化的速度。生态位不稳定性的速率和频率已经在人类时间尺度(数月至数十年)和地质时间尺度(数百万年)上进行了研究,但在中间时间尺度(数千年)上的不稳定性仍未得到研究。本文利用众所周知的浮游有孔虫化石记录,结合古气候的大气-海洋全球气候模式重建,以8ka分辨率量化了过去700 ka冰期-间冰期气候波动期间的非生物生态位稳定性。我们沿着年平均温度的单变量轴跟踪有孔虫生态位,测量了海洋表面和物种的深度栖息地。物种的温度偏好与全球温度机制不耦合,破坏了局部适应不断变化的环境条件的假设。此外,无论在短时间尺度(8 ka)上的气候变化幅度如何,以及在冰期和间冰期极端时期的对比,种内生态位在时间上都同样相似。适应时间序列的进化特征模型支持广泛的生态位停滞,而不是随机漫游或定向变化。在考虑了进化亲缘关系后,生态型解释了物种水平上生态位稳定性差异的微小变化。总之,这些结果表明,在接下来的几百到几千年里,变暖和海洋酸化可能会重新分配和减少有孔虫和其他钙化浮游生物的数量,这些浮游生物是海洋食物网和生物地球化学循环的主要组成部分。
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引用次数: 14
Developmental HCN channelopathy results in decreased neural progenitor proliferation and microcephaly in mice 发育性HCN通道病变导致小鼠神经祖细胞增殖和小头畸形减少
Pub Date : 2021-04-24 DOI: 10.1101/2021.04.24.441237
Anna Katharina Schlusche, S. Vay, N. Kleinenkuhnen, S. Sandke, R. Campos-Martin, Marta Florio, W. Huttner, A. Tresch, J. Roeper, M. A. Rueger, I. Jakovcevski, M. Stockebrand, D. Isbrandt
Significance Impaired cell cycle regulation of neural stem and progenitor cells can affect cortical development and cause microcephaly. During cell cycle progression, the cellular membrane potential changes through ion channel activity and tends to be more depolarized in proliferating cells. Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels, which mediate a depolarizing current in neurons and cardiac cells, are linked to neurodevelopmental diseases and also contribute to the control of cell cycle progression and proliferation of neuronal precursor cells. In this study, HCN channel deficiency during embryonic brain development resulted in marked microcephaly of mice with impaired HCN channel function in dorsal forebrain progenitors. The findings suggest that HCN channel subunits are part of a general mechanism influencing cortical development in mammals. The development of the cerebral cortex relies on the controlled division of neural stem and progenitor cells. The requirement for precise spatiotemporal control of proliferation and cell fate places a high demand on the cell division machinery, and defective cell division can cause microcephaly and other brain malformations. Cell-extrinsic and -intrinsic factors govern the capacity of cortical progenitors to produce large numbers of neurons and glia within a short developmental time window. In particular, ion channels shape the intrinsic biophysical properties of precursor cells and neurons and control their membrane potential throughout the cell cycle. We found that hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits are expressed in mouse, rat, and human neural progenitors. Loss of HCN channel function in rat neural stem cells impaired their proliferation by affecting the cell-cycle progression, causing G1 accumulation and dysregulation of genes associated with human microcephaly. Transgene-mediated, dominant-negative loss of HCN channel function in the embryonic mouse telencephalon resulted in pronounced microcephaly. Together, our findings suggest a role for HCN channel subunits as a part of a general mechanism influencing cortical development in mammals.
神经干细胞和祖细胞的细胞周期调节受损可影响皮质发育,导致小头畸形。在细胞周期进程中,细胞膜电位通过离子通道活性变化,在增殖细胞中倾向于更多地去极化。超极化激活的环核苷酸门控阳离子(HCN)通道介导神经元和心脏细胞的去极化电流,与神经发育疾病有关,也有助于控制细胞周期进程和神经元前体细胞的增殖。在本研究中,胚胎脑发育过程中HCN通道缺乏导致背前脑祖细胞HCN通道功能受损的小鼠出现明显的小头畸形。研究结果表明,HCN通道亚基是影响哺乳动物皮质发育的一般机制的一部分。大脑皮层的发育依赖于神经干细胞和祖细胞的受控分裂。对细胞增殖和细胞命运的精确时空控制对细胞分裂机制提出了很高的要求,细胞分裂缺陷可导致小头畸形和其他脑畸形。细胞外源性和内源性因素控制皮层祖细胞在短发育时间内产生大量神经元和胶质细胞的能力。特别是,离子通道塑造了前体细胞和神经元的内在生物物理特性,并在整个细胞周期中控制它们的膜电位。我们发现超极化激活的环核苷酸门控阳离子(HCN)通道亚基在小鼠、大鼠和人类神经祖细胞中表达。大鼠神经干细胞中HCN通道功能的缺失通过影响细胞周期进程,导致G1积累和人类小头畸形相关基因的失调,从而损害其增殖。转基因介导的胚胎小鼠端脑HCN通道功能的显性阴性丧失导致明显的小头畸形。总之,我们的研究结果表明HCN通道亚基作为影响哺乳动物皮质发育的一般机制的一部分。
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引用次数: 5
Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1 缺乏小胶质细胞适配蛋白Iba1的小鼠突触连通性和脑功能的改变
Pub Date : 2021-04-23 DOI: 10.1101/2021.04.23.441023
Pablo J. Lituma, E. Woo, B. O’Hara, P. Castillo, N. Sibinga, Sayan Nandi
Significance Abnormal microglia–neuron interaction is increasingly implicated in neurodevelopmental and neuropsychiatric conditions, such as autism spectrum disorders and schizophrenia, as well as in neurodegenerative disorders, such as Alzheimer’s disease. This study demonstrates that the deletion of the microglia-specific protein Iba1, which has long been utilized as a selective microglial marker but whose role has remained unidentified, results in microglial structural and functional impairments that significantly impact synaptic development and behavior. These findings not only highlight the importance of microglia in brain function but may also suggest that modifying the microglial function could provide a therapeutic strategy for the treatment of neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Growing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation as well as synaptic transmission and plasticity. Iba1 (ionized Ca+2-binding adapter protein 1), encoded by the Allograft inflammatory factor 1 (Aif1) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global, Iba1-deficient (Aif1−/−) mice to characterize microglial activity, synaptic function, and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1−/− microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1−/− brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1−/− mice displayed deficits in the excitatory synapse number and synaptic drive assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1−/− mice. During early postnatal development, when synapse formation is a predominant event in the hippocampus, the excitatory synapse number was still reduced in Aif1−/− mice. Together, these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in adulthood and correlated with significant behavioral changes in adult Aif1−/− mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuroglia developmental processes that may deeply influence behavior.
异常的小胶质细胞-神经元相互作用越来越多地涉及神经发育和神经精神疾病,如自闭症谱系障碍和精神分裂症,以及神经退行性疾病,如阿尔茨海默病。这项研究表明,小胶质细胞特异性蛋白Iba1的缺失导致小胶质细胞结构和功能损伤,显著影响突触发育和行为。Iba1长期以来一直被用作选择性小胶质细胞标志物,但其作用尚未确定。这些发现不仅强调了小胶质细胞在脑功能中的重要性,而且可能表明,改变小胶质细胞的功能可以为神经发育、神经精神和神经退行性疾病的治疗提供一种治疗策略。越来越多的证据表明,小胶质细胞通过调节突触的修剪和形成以及突触的传递和可塑性来影响脑功能。Iba1(离子化Ca+2结合适配蛋白1)是小胶质细胞中的一种肌动蛋白相互作用蛋白,由同种异体炎症因子1 (Aif1)基因编码。尽管Iba1一直被用作小胶质细胞的细胞标记物,但其功能作用尚不清楚。在这里,我们使用全局iba1缺陷(Aif1−/−)小鼠来表征小胶质细胞活性、突触功能和行为。幼年小鼠急性海马切片和固定组织的小胶质细胞成像显示,Aif1−/−小胶质细胞分别表现出atp诱导的运动性和分支性的减少。生化分析进一步表明,Aif1−/−脑组织表现出与突触修剪相关的小胶质富集蛋白的表达改变。与这些变化一致,幼年Aif1−/−小鼠在急性海马切片中表现出兴奋性突触数量和突触驱动的缺陷,通过神经元标记和全细胞膜片钳记录来评估。出乎意料的是,小胶质突触吞噬能力在幼年Aif1−/−小鼠中减弱。在出生后发育早期,当突触形成是海马的主要事件时,Aif1−/−小鼠的兴奋性突触数量仍然减少。总之,这些发现支持了Iba1在幼年小鼠兴奋性突触生长中的整体作用。最后,出生后突触缺陷在成年期持续存在,并与成年Aif1 - / -小鼠的显著行为变化相关,表现出物体识别、记忆和社会互动方面的障碍。这些结果表明,Iba1对潜在的神经胶质发育过程的小胶质活性起着关键作用,而这些过程可能会深刻影响行为。
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引用次数: 28
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Proceedings of the National Academy of Sciences
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