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Paradoxical stabilization of relative position in moving frames 运动框架中相对位置的矛盾稳定
Pub Date : 2021-01-25 DOI: 10.1101/2021.01.23.427924
Mert Özkan, S. Anstis, B. M. ’t Hart, M. Wexler, P. Cavanagh
Significance Every eye movement drags the visual scene over our retinas and yet nothing appears to move. We now report a small-scale version of this visual stability with a square frame moving on a monitor in a well-lit room. Probes flashed before and after the frame’s motion are also stabilized in the frame’s coordinates—as if the frame were stationary—shifting perceived locations by up to half the screen’s width from their physical locations. Paradoxically, with these small frames, this ∼100% stabilization occurs despite visible frame motion. Unlike motion-induced position shifts, frame-induced shifts are independent of speed and depend instead on the distance the frame travels. This powerful discounting of motion may reveal a critical component of visual stability. To capture where things are and what they are doing, the visual system may extract the position and motion of each object relative to its surrounding frame of reference [K. Duncker, Routledge and Kegan Paul, London 161–172 (1929) and G. Johansson, Acta Psychol (Amst.) 7, 25–79 (1950)]. Here we report a particularly powerful example where a paradoxical stabilization is produced by a moving frame. We first take a frame that moves left and right and we flash its right edge before, and its left edge after, the frame’s motion. For all frame displacements tested, the two edges are perceived as stabilized, with the left edge on the left and right edge on the right, separated by the frame’s width as if the frame were not moving. This stabilization is paradoxical because the motion of the frame itself remains visible, albeit much reduced. A second experiment demonstrated that unlike other motion-induced position shifts (e.g., flash lag, flash grab, flash drag, or Fröhlich), the illusory shift here is independent of speed and is set instead by the distance of the frame’s travel. In this experiment, two probes are flashed inside the frame at the same physical location before and after the frame moves. Despite being physically superimposed, the probes are perceived widely separated, again as if they were seen in the frame’s coordinates and the frame were stationary. This paradoxical stabilization suggests a link to visual stability across eye movements where the displacement of the entire visual scene may act as a frame to stabilize the perception of relative locations.
每一次眼球运动都会把视觉场景拖过视网膜,但似乎没有任何东西在移动。我们现在报告了这种视觉稳定性的一个小规模版本,在一个光线充足的房间里,一个方形框架在监视器上移动。在帧运动前后闪烁的探针也在帧的坐标中稳定下来——就好像帧是静止的——将感知到的位置从它们的物理位置移动到屏幕宽度的一半。矛盾的是,对于这些小帧,尽管可见的帧运动,这种~ 100%的稳定仍然发生。与运动引起的位置移位不同,帧引起的移位与速度无关,而是取决于帧移动的距离。这种对运动的强烈忽视可能揭示了视觉稳定性的一个关键组成部分。为了捕捉物体的位置和它们正在做什么,视觉系统可以提取每个物体相对于周围参照系的位置和运动[K]。Duncker, Routledge和Kegan Paul, London 161-172(1929)和G. Johansson, Acta Psychol (Amst.) 7,25 - 79(1950)]。这里我们报告一个特别有力的例子,其中一个悖论稳定是由一个运动的框架产生的。我们首先选取一个左右移动的帧,在帧运动之前和之后分别闪现它的右边缘和左边缘。对于所有测试的帧位移,两个边缘被认为是稳定的,左边边缘在左边,右边边缘在右边,被帧的宽度分开,就好像帧没有移动一样。这种稳定是矛盾的,因为框架本身的运动仍然可见,尽管大大减少。第二个实验表明,与其他运动引起的位置移动(例如,闪光延迟,闪光抓取,闪光拖动或Fröhlich)不同,这里的错觉移动与速度无关,而是由帧移动的距离设置的。在本实验中,在帧移动前后,在帧内相同的物理位置闪烁两个探头。尽管在物理上是重叠的,但这些探针被认为是分开的,就好像它们在框架的坐标中被看到,而框架是静止的。这种矛盾的稳定性表明,通过眼球运动,整个视觉场景的位移可以作为一个框架来稳定相对位置的感知,这与视觉稳定性有关。
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引用次数: 6
Herbert Tabor, 1918–2020: Polyamines, NIH, and the JBC Herbert Tabor, 1918-2020:多胺,NIH和JBC
Pub Date : 2021-01-25 DOI: 10.1073/pnas.2023986118
R. Wickner
On August 20, 2020, at the age of 101, Herbert Tabor died peacefully at his home on the National Institutes of Health campus in Bethesda, Maryland. Herb was best known for his elucidation of the biochemical pathways for polyamines, including characterization of the biosynthetic enzymes, their genes and regulation, and the functions of the polyamines, chiefly using Escherichia coli and Saccharomyces cerevisiae. He was Editor-in-Chief of The Journal of Biological Chemistry (JBC) for nearly 40 years, overseeing its dramatic expansion and modernization, leading conversion from the traditional means of distribution of scientific information to the present web-based system. Herbert Tabor was born November 28, 1918, in New York City, and was graduated from Townsend Harris High School in 1933 at the age of 14. At Harvard College he entered the Biochemical Sciences program headed by John Edsall. Graduating in 1937, Herb attended Harvard Medical School, where his work with A. Baird Hastings on the ionization constant of MgHPO4 was the subject of his first paper, fittingly in the JBC (1). As an intern at Yale-New Haven Hospital in 1942, Herb gave a patient with streptococcal septicemia an injection of penicillin, the first dose in the first major clinical trial of the drug in the United States (it worked!). Unbeknownst to Herb at the time (until 25 years later), that dose was prepared at Merck by Gilbert Ashwell, later to be a distinguished colleague and close friend of Herb at the NIH. In January 1943, Herb joined the US Public Health Service and was assigned as the Medical Officer to the Coast Guard cutter USCGC Duane, escorting convoys between the United States and Britain. The events challenged his limited surgical training [recounted in the article, “It all started on a streetcar in Boston” (2)], but he managed without untoward sequellae.
2020年8月20日,101岁的赫伯特·塔博尔在马里兰州贝塞斯达国立卫生研究院校园的家中平静地去世。赫伯以阐明多胺的生化途径而闻名,包括生物合成酶的特征、它们的基因和调控,以及多胺的功能,主要是利用大肠杆菌和酿酒酵母。他担任《生物化学杂志》(The Journal of Biological Chemistry, JBC)总编辑近40年,主持了该杂志的急剧扩张和现代化,领导了从传统的科学信息分发方式向现代基于网络的系统的转变。赫伯特·塔博尔1918年11月28日出生在纽约市,1933年14岁时从汤森哈里斯高中毕业。在哈佛大学,他进入了由约翰·埃德萨尔领导的生化科学专业。1937年毕业后,赫伯进入哈佛医学院学习,在那里,他与a . Baird Hastings关于MgHPO4电离常数的研究成为他第一篇论文的主题,正好发表在JBC(1)。1942年,作为耶鲁-纽黑文医院的实习生,赫伯给一位链球菌败血症患者注射了青霉素,这是该药物在美国第一次重大临床试验中的第一剂(它起作用了!)。赫伯当时(直到25年后)都不知道,这一剂量是由吉尔伯特·阿什韦尔(Gilbert Ashwell)在默克公司准备的,他后来成为赫伯在NIH的杰出同事和密友。1943年1月,赫伯加入了美国公共卫生服务,并被分配为海岸警卫队快艇USCGC Duane的医务官,护送美国和英国之间的车队。这些事件挑战了他有限的外科训练[在文章中叙述,“一切都始于波士顿的有轨电车”[2]],但他成功了,没有留下任何不幸的后遗症。
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引用次数: 2
Single-neuron firing cascades underlie global spontaneous brain events 单个神经元的放电级联是全球自发大脑活动的基础
Pub Date : 2021-01-24 DOI: 10.1101/2021.01.22.427798
Xiao Liu, D. Leopold, Yifan Yang
Significance The resting brain consumes enormous energy and shows highly organized spontaneous activity as often measured by functional MRI (fMRI). Using large-scale recordings from thousands of neurons, we showed a highly structured brain activity that involves the majority (∼70%) of surveyed neurons from various brain regions. It takes the form of sequential activations between two distinct neuronal ensembles and relates to low-frequency (∼0.1 Hz) modulations of arousal and hippocampal ripple activity. The finding provides a cellular-level understanding of the resting-state global brain activity often observed with fMRI and further suggests that this global activity may represent an “offline” process that links cholinergic function, memory consolidation, and perivascular clearance of brain waste. The resting brain consumes enormous energy and shows highly organized spontaneous activity. To investigate how this activity is manifest among single neurons, we analyzed spiking discharges of ∼10,000 isolated cells recorded from multiple cortical and subcortical regions of the mouse brain during immobile rest. We found that firing of a significant proportion (∼70%) of neurons conformed to a ubiquitous, temporally sequenced cascade of spiking that was synchronized with global events and elapsed over timescales of 5 to 10 s. Across the brain, two intermixed populations of neurons supported orthogonal cascades. The relative phases of these cascades determined, at each moment, the response magnitude evoked by an external visual stimulus. Furthermore, the spiking of individual neurons embedded in these cascades was time locked to physiological indicators of arousal, including local field potential power, pupil diameter, and hippocampal ripples. These findings demonstrate that the large-scale coordination of low-frequency spontaneous activity, which is commonly observed in brain imaging and linked to arousal, sensory processing, and memory, is underpinned by sequential, large-scale temporal cascades of neuronal spiking across the brain.
功能磁共振成像(fMRI)经常测量静止的大脑消耗巨大的能量并表现出高度有组织的自发活动。使用来自数千个神经元的大规模记录,我们显示了一个高度结构化的大脑活动,涉及来自不同大脑区域的大多数(~ 70%)被调查的神经元。它在两个不同的神经元群之间采取顺序激活的形式,与低频(~ 0.1 Hz)唤醒和海马纹波活动的调节有关。这一发现为fMRI观察到的静息状态大脑整体活动提供了细胞水平的理解,并进一步表明,这种整体活动可能代表了一个“离线”过程,该过程将胆碱能功能、记忆巩固和脑废物的血管周围清除联系起来。休息时的大脑消耗大量能量,表现出高度组织化的自发活动。为了研究这种活动如何在单个神经元中表现出来,我们分析了在静止休息期间从小鼠大脑的多个皮层和皮层下区域记录的约10,000个分离细胞的峰值放电。我们发现,相当大比例(约70%)的神经元的放电符合一个普遍存在的、有时间序列的级联峰,该级联峰与全球事件同步,并在5到10秒的时间尺度上流逝。在整个大脑中,两个混杂的神经元群支持正交级联。这些级联的相对阶段决定了,在每个时刻,由外部视觉刺激引起的反应强度。此外,嵌入这些级联中的单个神经元的尖峰与觉醒的生理指标(包括局部场电位、瞳孔直径和海马体波纹)是时间锁定的。这些发现表明,低频自发活动的大规模协调,通常在脑成像中观察到,与觉醒、感觉处理和记忆有关,是由大脑中连续的、大规模的神经元峰级联支撑的。
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引用次数: 15
Structural insights into a dimeric Psb27-photosystem II complex from a cyanobacterium Thermosynechococcus vulcanus 蓝藻热共生球菌二聚体psb27 -光系统II复合体的结构分析
Pub Date : 2021-01-20 DOI: 10.2210/pdb7czl/pdb
Guoqiang Huang, Yanan Xiao, X. Pi, Liang Zhao, Qingjun Zhu, Wenda Wang, T. Kuang, G. Han, S. Sui, Jian-Ren Shen
Significance Photosystem II (PSII) is a light-driven water:plastoquinone oxidoreductase in oxygenic photosynthetic organisms. Several inactive PSII intermediates are involved in the biogenesis of the multisubunit PSII complexes as well as in their repair after unavoidable oxidative damage targeted to PSII under light. Psb27 is one of the assembly factors associated with inactive PSII intermediate and plays important roles in the biogenesis/repair of PSII. Here, we report the structure of a dimeric Psb27-PSII from a thermophilic cyanobacterium Thermosynechococcus vulcanus by cryo-electron microscopy. Our results reveal the location and binding properties of Psb27 in the intermediate PSII and show the structural differences between the intermediate and native PSII. These results provide important clues for the roles of Psb27 in the biogenesis/repair of PSII. Photosystem II (PSII) is a multisubunit pigment-protein complex and catalyzes light-driven water oxidation, leading to the conversion of light energy into chemical energy and the release of molecular oxygen. Psb27 is a small thylakoid lumen-localized protein known to serve as an assembly factor for the biogenesis and repair of the PSII complex. The exact location and binding fashion of Psb27 in the intermediate PSII remain elusive. Here, we report the structure of a dimeric Psb27-PSII complex purified from a psbV deletion mutant (ΔPsbV) of the cyanobacterium Thermosynechococcus vulcanus, solved by cryo-electron microscopy. Our structure showed that Psb27 is associated with CP43 at the luminal side, with specific interactions formed between Helix 2 and Helix 3 of Psb27 and a loop region between Helix 3 and Helix 4 of CP43 (loop C) as well as the large, lumen-exposed and hydrophilic E-loop of CP43. The binding of Psb27 imposes some conflicts with the N-terminal region of PsbO and also induces some conformational changes in CP43, CP47, and D2. This makes PsbO unable to bind in the Psb27-PSII. Conformational changes also occurred in D1, PsbE, PsbF, and PsbZ; this, together with the conformational changes occurred in CP43, CP47, and D2, may prevent the binding of PsbU and induce dissociation of PsbJ. This structural information provides important insights into the regulation mechanism of Psb27 in the biogenesis and repair of PSII.
光系统II (Photosystem II, PSII)是含氧光合生物中一种光驱动的水质体醌氧化还原酶。几种无活性的PSII中间体参与了多亚基PSII复合物的生物发生,以及在光照下PSII不可避免的氧化损伤后的修复。Psb27是与PSII无活性中间体相关的组装因子之一,在PSII的生物发生/修复中起重要作用。在这里,我们报告了一个二聚体Psb27-PSII的结构,从嗜热的蓝藻热共生球菌vulcanus。我们的研究结果揭示了Psb27在中间PSII中的位置和结合特性,并显示了中间PSII和天然PSII之间的结构差异。这些结果为Psb27在PSII生物发生/修复中的作用提供了重要线索。光系统II (Photosystem II, PSII)是一种多亚基色素蛋白复合物,催化光驱动水氧化,将光能转化为化学能并释放分子氧。Psb27是一种小的类囊体腔定位蛋白,已知作为PSII复合体的生物发生和修复的组装因子。Psb27在中间PSII中的确切位置和结合方式尚不清楚。在这里,我们报道了从蓝细菌热共生球菌的psbV缺失突变体(ΔPsbV)中纯化的二聚体Psb27-PSII复合物的结构,并通过低温电子显微镜进行了解析。我们的结构表明Psb27在管腔侧与CP43结合,Psb27的螺旋2和螺旋3、CP43的螺旋3和螺旋4之间形成了特定的相互作用(环C),以及CP43的大的、管腔暴露的亲水性e环。Psb27的结合会与PsbO的n端产生一定的冲突,并引起CP43、CP47和D2的构象变化。这使得PsbO无法在Psb27-PSII中结合。D1、PsbE、PsbF和PsbZ的构象也发生了变化;这与CP43、CP47和D2发生的构象变化可能会阻止PsbU的结合并诱导PsbJ的解离。这一结构信息为了解Psb27在PSII生物发生和修复中的调控机制提供了重要的见解。
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引用次数: 34
Mechanosensitive remodeling of the bacterial flagellar motor is independent of direction of rotation 细菌鞭毛马达的机械敏感性重塑与旋转方向无关
Pub Date : 2021-01-19 DOI: 10.1101/2021.01.19.427295
N. Wadhwa, Y. Tu, H. Berg
Significance Macromolecular machines carry out most of the biological functions in living organisms. Despite their significance, we do not yet understand the rules that govern the self-assembly of large multiprotein complexes. The bacterial flagellar motor tunes the assembly of its torque-generating stator complex with changes in external load. Here, we report that clockwise and counterclockwise rotating motors have identical remodeling responses to changes in the external load, suggesting a purely mechanical mechanism for this regulation. Autonomous control of self-assembly may be a general strategy for tuning the functional output of protein complexes. The flagellar motor is a prime example of a macromolecular machine in which the functional regulation of assembly can be rigorously studied. Motility is important for the survival and dispersal of many bacteria, and it often plays a role during infections. Regulation of bacterial motility by chemical stimuli is well studied, but recent work has added a new dimension to the problem of motility control. The bidirectional flagellar motor of the bacterium Escherichia coli recruits or releases torque-generating units (stator units) in response to changes in load. Here, we show that this mechanosensitive remodeling of the flagellar motor is independent of direction of rotation. Remodeling rate constants in clockwise rotating motors and in counterclockwise rotating motors, measured previously, fall on the same curve if plotted against torque. Increased torque decreases the off rate of stator units from the motor, thereby increasing the number of active stator units at steady state. A simple mathematical model based on observed dynamics provides quantitative insight into the underlying molecular interactions. The torque-dependent remodeling mechanism represents a robust strategy to quickly regulate output (torque) in response to changes in demand (load).
意义大分子机器在生物体中执行大部分生物功能。尽管它们意义重大,但我们还不了解控制大型多蛋白复合物自组装的规则。细菌鞭毛马达根据外部负载的变化调整其产生扭矩的定子复合体的组装。在这里,我们报道顺时针和逆时针旋转的电机对外部负载的变化有相同的重塑响应,表明这种调节的纯机械机制。自我组装的自主控制可能是调节蛋白质复合物功能输出的一般策略。鞭毛马达是大分子机器的一个主要例子,其中组装的功能调节可以被严格地研究。运动性对许多细菌的生存和传播很重要,并且在感染过程中经常起作用。化学刺激对细菌运动的调节已经得到了很好的研究,但最近的工作为运动控制问题增加了一个新的维度。大肠杆菌的双向鞭毛马达根据负载的变化招募或释放扭矩产生单元(定子单元)。在这里,我们发现鞭毛马达的机械敏感性重塑与旋转方向无关。先前测量的顺时针旋转电机和逆时针旋转电机的重塑速率常数,如果与转矩绘制,则落在同一曲线上。增加的转矩降低了电机定子单元的断开率,从而增加了稳定状态下活跃定子单元的数量。基于观察到的动力学的简单数学模型提供了对潜在分子相互作用的定量洞察。扭矩依赖的重塑机制代表了一种强大的策略,可以根据需求(负载)的变化快速调节输出(扭矩)。
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引用次数: 21
Impact of an alpha helix and a cysteine–cysteine disulfide bond on the resistance of bacterial adhesion pili to stress α螺旋和半胱氨酸-半胱氨酸二硫键对细菌粘附菌毛抗逆性的影响
Pub Date : 2021-01-19 DOI: 10.1101/2021.01.18.427124
Joseph L. Baker, Tobias Dahlberg, E. Bullitt, Magnus Andersson
Significance Adhesion pili are often essential virulence factors for attachment of pathogenic bacteria in specific environmental niches. We provide mechanistic details of structural differences impacting the biophysical properties of pili found on bacteria in the urinary and intestinal tracts. First, we see that P pili from urinary tract bacteria withstand higher forces than CFA/I pili expressed on enterotoxigenic bacteria, due to a disulfide bond that limits subunit unraveling. Second, the greater elasticity of P pili is due to an α-helical motif that can unfold, absorbing force that could otherwise lead to bacteria detachment. Our work provides insight into the central role of pilus structural and biophysical properties for the sustained bacterial adherence necessary to initiate disease. Escherichia coli express adhesion pili that mediate attachment to host cell surfaces and are exposed to body fluids in the urinary and gastrointestinal tracts. Pilin subunits are organized into helical polymers, with a tip adhesin for specific host binding. Pili can elastically unwind when exposed to fluid flow forces, reducing the adhesin load, thereby facilitating sustained attachment. Here we investigate biophysical and structural differences of pili commonly expressed on bacteria that inhabit the urinary and intestinal tracts. Optical tweezers measurements reveal that class 1a pili of uropathogenic E. coli (UPEC), as well as class 1b of enterotoxigenic E. coli (ETEC), undergo an additional conformational change beyond pilus unwinding, providing significantly more elasticity to their structure than ETEC class 5 pili. Examining structural and steered molecular dynamics simulation data, we find that this difference in class 1 pili subunit behavior originates from an α-helical motif that can unfold when exposed to force. A disulfide bond cross-linking β-strands in class 1 pili stabilizes subunits, allowing them to tolerate higher forces than class 5 pili that lack this covalent bond. We suggest that these extra contributions to pilus resiliency are relevant for the UPEC niche, since resident bacteria are exposed to stronger, more transient drag forces compared to those experienced by ETEC bacteria in the mucosa of the intestinal tract. Interestingly, class 1b ETEC pili include the same structural features seen in UPEC pili, while requiring lower unwinding forces that are more similar to those of class 5 ETEC pili.
黏附菌毛是病原菌在特定环境中附着的重要毒力因子。我们提供的机制细节结构差异影响毛的生物物理性质发现细菌在泌尿和肠道。首先,我们发现来自尿路细菌的P菌毛比产肠毒素细菌表达的CFA/I菌毛承受更高的力,这是由于二硫键限制了亚基的展开。其次,毛菌具有更大的弹性是由于α-螺旋基序可以展开,吸收可能导致细菌脱离的力。我们的工作提供了对菌毛结构和生物物理特性的核心作用的深入了解,这些特性对于启动疾病所需的持续细菌粘附是必要的。大肠杆菌表达黏附毛,介导附着于宿主细胞表面,并暴露于尿道和胃肠道的体液中。Pilin亚基被组织成螺旋状聚合物,顶端有一个粘附素用于特定的宿主结合。当暴露于流体流动力时,毛毛可以弹性舒展,减少粘附素负荷,从而促进持续附着。在这里,我们研究了毛的生物物理和结构上的差异,毛通常表达在细菌栖息在泌尿道和肠道。光学镊子测量显示,尿路致病性大肠杆菌(UPEC)的1a类菌毛,以及产肠毒素大肠杆菌(ETEC)的1b类菌毛,除了菌毛展开外,还经历了额外的构象变化,比ETEC 5类菌毛的结构提供了更大的弹性。通过分析结构和定向分子动力学模拟数据,我们发现1类菌毛亚基行为的差异源于α-螺旋基序,该基序在外力作用下可以展开。1类菌毛中的二硫键交联β-链稳定了亚基,使它们比缺乏共价键的5类菌毛承受更高的力。我们认为,这些对菌毛弹性的额外贡献与UPEC生态位有关,因为与肠道粘膜中的ETEC细菌相比,常驻细菌暴露于更强、更短暂的阻力。有趣的是,1b类ETEC菌毛包括与UPEC菌毛相同的结构特征,同时需要更低的解绕力,与5类ETEC菌毛更相似。
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引用次数: 5
Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci 克莱恩-莱文综合征与出生困难和TRANK1基因位点的遗传变异有关
Pub Date : 2021-01-16 DOI: 10.1101/2021.01.08.20249006
A. Ambati, Ryan P Hillary, S. Leu-Semenescu, H. Ollila, Ling Lin, E. During, N. Farber, Thomas J. Rico, J. Faraco, E. Leary, A. Goldstein-Piekarski, Yu-Shu Huang, Fang Han, Y. Sivan, M. Lecendreux, P. Dodet, M. Honda, N. Gadoth, S. Nevšímalová, F. Pizza, T. Kanbayashi, R. Peraita-Adrados, G. Leschziner, R. Hasan, F. Canellas, K. Kume, M. Daniilidou, P. Bourgin, David Rye, J. Vicario, B. Hogl, S. Hong, G. Plazzi, G. Mayer, A. Landtblom, Y. Dauvilliers, I. Arnulf, E. Mignot
Significance Genetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment is suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulates newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impacts birth and KLS. Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.
TRANK1基因及其邻近基因的遗传标记与双相情感障碍和精神分裂症的相关性较弱(风险增加10%)。我们发现相同的多态性与Kleine-Levin综合征相关(风险增加50%),这是一种罕见的睡眠障碍,以反复发作的严重嗜睡和认知异常为特征。对锂治疗的反应提示KLS和双相情感障碍之间的病理生理重叠。该研究还表明,当患者难产时,TRANK1基因区域的变异可能易导致KLS,这表明TRANK1基因区域调节新生儿对脑损伤的反应,对成年后的精神和神经健康产生影响。另一种可能是多态性影响出生和KLS。Kleine-Levin综合征(KLS)是一种罕见的疾病,以严重的发作性嗜睡为特征,伴有认知障碍,并伴有冷漠或去抑制。病理生理学尚不清楚,尽管影像学研究表明在发作期间下丘脑/丘脑区域的活动减少。家族性发病率增加,风险与难产报告有关。我们对14年来收集的673例KLS病例进行了全球病例对照全基因组关联研究,并对15341名对照个体进行了种族匹配。我们发现,在TRANK1基因位点的3 '区存在强的全基因组显著关联(rs71947865,比值比[OR] = 1.48, P = 8.6 × 10−9),之前与双相情感障碍和精神分裂症相关。引人注目的是,携带rs71947865变异的KLS病例中难产的报告显著增加。由于围产期结果在过去40年中显著改善,我们进一步按出生年份对样本进行分层,发现近期病例的rs71947865相关性显著降低。rs71947865与KLS的关联在171例KLS患者的整个随访样本中没有重复,但在59例报告出生困难的KLS患者的子集随访样本中,rs71947865与KLS显著相关(OR = 1.54, P = 0.01)。多基因风险评分解释的KLS遗传倾向性增加(拟R2 = 0.15;P < 2.0 × 10−22 (P = 0.5阈值)。遗传关联通路分析发现,KLS病例中昼夜节律调节通路基因富集。我们的研究结果表明KLS、昼夜节律调节和双相情感障碍之间存在联系,并表明TRANK1多态性与报道的出生困难可能易患KLS。
{"title":"Kleine-Levin syndrome is associated with birth difficulties and genetic variants in the TRANK1 gene loci","authors":"A. Ambati, Ryan P Hillary, S. Leu-Semenescu, H. Ollila, Ling Lin, E. During, N. Farber, Thomas J. Rico, J. Faraco, E. Leary, A. Goldstein-Piekarski, Yu-Shu Huang, Fang Han, Y. Sivan, M. Lecendreux, P. Dodet, M. Honda, N. Gadoth, S. Nevšímalová, F. Pizza, T. Kanbayashi, R. Peraita-Adrados, G. Leschziner, R. Hasan, F. Canellas, K. Kume, M. Daniilidou, P. Bourgin, David Rye, J. Vicario, B. Hogl, S. Hong, G. Plazzi, G. Mayer, A. Landtblom, Y. Dauvilliers, I. Arnulf, E. Mignot","doi":"10.1101/2021.01.08.20249006","DOIUrl":"https://doi.org/10.1101/2021.01.08.20249006","url":null,"abstract":"Significance Genetic markers in TRANK1 gene and its vicinity have been weakly associated with bipolar disorder and schizophrenia (10% increased risk). We found that the same polymorphisms are associated with Kleine-Levin syndrome (50% increased risk), a rare sleep disorder characterized by recurrent episodes of severe hypersomnia and cognitive abnormalities. Response to lithium treatment is suggestive of a pathophysiological overlap between KLS and bipolar disorder. The study also shows that variants in the TRANK1 gene region may predispose to KLS when patients have had a difficult birth, suggesting that TRANK1 gene region modulates newborns’ response to brain injury, with consequences for mental and neurological health in adulthood. Another possibility may be that the polymorphism impacts birth and KLS. Kleine-Levin syndrome (KLS) is a rare disorder characterized by severe episodic hypersomnia, with cognitive impairment accompanied by apathy or disinhibition. Pathophysiology is unknown, although imaging studies indicate decreased activity in hypothalamic/thalamic areas during episodes. Familial occurrence is increased, and risk is associated with reports of a difficult birth. We conducted a worldwide case−control genome-wide association study in 673 KLS cases collected over 14 y, and ethnically matched 15,341 control individuals. We found a strong genome-wide significant association (rs71947865, Odds Ratio [OR] = 1.48, P = 8.6 × 10−9) within the 3′region of TRANK1 gene locus, previously associated with bipolar disorder and schizophrenia. Strikingly, KLS cases with rs71947865 variant had significantly increased reports of a difficult birth. As perinatal outcomes have dramatically improved over the last 40 y, we further stratified our sample by birth years and found that recent cases had a significantly reduced rs71947865 association. While the rs71947865 association did not replicate in the entire follow-up sample of 171 KLS cases, rs71947865 was significantly associated with KLS in the subset follow-up sample of 59 KLS cases who reported birth difficulties (OR = 1.54, P = 0.01). Genetic liability of KLS as explained by polygenic risk scores was increased (pseudo R2 = 0.15; P < 2.0 × 10−22 at P = 0.5 threshold) in the follow-up sample. Pathway analysis of genetic associations identified enrichment of circadian regulation pathway genes in KLS cases. Our results suggest links between KLS, circadian regulation, and bipolar disorder, and indicate that the TRANK1 polymorphisms in conjunction with reported birth difficulties may predispose to KLS.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80786877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 24
The cost of correcting for error during sensorimotor adaptation 在感觉运动适应过程中纠正错误的代价
Pub Date : 2021-01-15 DOI: 10.1101/2021.01.13.426535
Ehsan Sedaghat-Nejad, R. Shadmehr
Significance Improving the process of learning from error can play a critical role in applied settings such as rehabilitation. Previous work has generally focused on reward as a variable that may modulate learning. However, in response to an erroneous movement, the nervous system often engages a reflex that corrects for that error, thus expending time and energy. Here, we modulated this cost of error and found that increasing the cost increased how much the brain learned from error. Thus, the landscape of the loss associated with the act of correcting for error regulates the rates of sensorimotor learning. Learning from error is often a slow process. In machine learning, the learning rate depends on a loss function that specifies a cost for error. Here, we hypothesized that during motor learning, error carries an implicit cost for the brain because the act of correcting for error consumes time and energy. Thus, if this implicit cost could be increased, it may robustly alter how the brain learns from error. To vary the implicit cost of error, we designed a task that combined saccade adaptation with motion discrimination: movement errors resulted in corrective saccades, but those corrections took time away from acquiring information in the discrimination task. We then modulated error cost using coherence of the discrimination task and found that when error cost was large, pupil diameter increased and the brain learned more from error. However, when error cost was small, the pupil constricted and the brain learned less from the same error. Thus, during sensorimotor adaptation, the act of correcting for error carries an implicit cost for the brain. Modulating this cost affects how much the brain learns from error.
意义改进从错误中学习的过程可以在康复等应用环境中发挥关键作用。以前的研究通常把奖励作为调节学习的一个变量。然而,对于一个错误的动作,神经系统通常会进行反射来纠正这个错误,从而花费时间和精力。在这里,我们调整了错误的成本,发现成本的增加增加了大脑从错误中学到的东西。因此,与纠正错误行为相关的损失的情况调节了感觉运动学习的速率。从错误中学习往往是一个缓慢的过程。在机器学习中,学习率取决于指定错误代价的损失函数。在这里,我们假设在运动学习过程中,错误会给大脑带来隐性成本,因为纠正错误的行为会消耗时间和精力。因此,如果这种隐性成本可以增加,它可能会有力地改变大脑从错误中学习的方式。为了改变隐式错误代价,我们设计了一个结合扫视适应和运动识别的任务:运动错误导致纠正性扫视,但这些纠正占用了辨别任务中获取信息的时间。然后,我们利用识别任务的一致性调节错误代价,发现当错误代价较大时,瞳孔直径增大,大脑从错误中学到的东西更多。然而,当错误代价较小时,瞳孔收缩,大脑从同样的错误中学到的东西也较少。因此,在感觉运动适应过程中,纠正错误的行为给大脑带来了隐性成本。调节这种成本会影响大脑从错误中学习的程度。
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引用次数: 6
Algorithmic monoculture and social welfare 算法单一文化和社会福利
Pub Date : 2021-01-14 DOI: 10.1145/3603195.3603202
J. Kleinberg, Manish Raghavan
Significance Algorithmic monoculture is a growing concern in the use of algorithms for high-stakes screening decisions in areas such as employment and lending. If many firms use the same algorithm, even if it is more accurate than the alternatives, the resulting “monoculture” may be susceptible to correlated failures, much as a monocultural system is in biological settings. To investigate this concern, we develop a model of selection under monoculture. We find that even without any assumption of shocks or correlated failures—i.e., under “normal operations”—the quality of decisions may decrease when multiple firms use the same algorithm. Thus, the introduction of a more accurate algorithm may decrease social welfare—a kind of “Braess’ paradox” for algorithmic decision-making. As algorithms are increasingly applied to screen applicants for high-stakes decisions in employment, lending, and other domains, concerns have been raised about the effects of algorithmic monoculture, in which many decision-makers all rely on the same algorithm. This concern invokes analogies to agriculture, where a monocultural system runs the risk of severe harm from unexpected shocks. Here, we show that the dangers of algorithmic monoculture run much deeper, in that monocultural convergence on a single algorithm by a group of decision-making agents, even when the algorithm is more accurate for any one agent in isolation, can reduce the overall quality of the decisions being made by the full collection of agents. Unexpected shocks are therefore not needed to expose the risks of monoculture; it can hurt accuracy even under “normal” operations and even for algorithms that are more accurate when used by only a single decision-maker. Our results rely on minimal assumptions and involve the development of a probabilistic framework for analyzing systems that use multiple noisy estimates of a set of alternatives.
在就业和贷款等领域使用算法进行高风险筛选决策时,算法单一文化日益受到关注。如果许多公司使用相同的算法,即使它比替代算法更准确,由此产生的“单一文化”可能容易受到相关失败的影响,就像单一文化系统在生物环境中一样。为了研究这个问题,我们开发了一个单一栽培下的选择模型。我们发现,即使没有任何冲击或相关失效的假设——即。在“正常操作”下,当多个公司使用相同的算法时,决策的质量可能会下降。因此,引入更精确的算法可能会减少社会福利——这是算法决策的一种“布雷斯悖论”。随着算法越来越多地应用于筛选就业、贷款和其他领域高风险决策的申请人,人们开始担心算法单一文化的影响,因为许多决策者都依赖于相同的算法。这种担忧与农业有相似之处,在农业中,单一栽培系统面临着因意外冲击而遭受严重损害的风险。在这里,我们展示了算法单一文化的危险要深得多,因为一组决策代理在单一算法上的单一文化收敛,即使算法对任何一个单独的代理都更准确,也会降低代理的整体决策质量。因此,暴露单一文化的风险并不需要意外的冲击;即使在“正常”操作下,甚至对于仅由单个决策者使用时更准确的算法,它也会损害准确性。我们的结果依赖于最小的假设,并涉及一个概率框架的发展,用于分析使用一组备选方案的多个噪声估计的系统。
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引用次数: 31
Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration 氟西汀作为直接NLRP3抑制剂治疗萎缩性黄斑变性的鉴定
Pub Date : 2021-01-12 DOI: 10.1101/2021.01.11.425135
Meenakshi Ambati, Ivana Apicella, Shao-bin Wang, S. Narendran, Hannah Leung, Felipe Pereira, Yosuke Nagasaka, Peirong Huang, Akhil Varshney, Kirstie L. Baker, Kenneth M. Marion, Mehrdad Shadmehr, Cliff I. Stains, B. Werner, S. Sadda, E. Taylor, S. Sutton, J. Magagnoli, Bradley D. Gelfand
Significance Dry age-related macular degeneration (AMD) affects the vision of millions of people worldwide. There is currently no Food and Drug Administration–approved treatment for dry AMD. The inflammasome components NLRP3 and ASC have been implicated in the pathogenesis of dry AMD. We report that fluoxetine, which is approved for the treatment of clinical depression, directly binds the NLRP3 protein and prevents NLRP3-ASC inflammasome assembly and activation. Fluoxetine prevents the degeneration of retinal pigmented epithelium cells in an animal model of dry AMD. We also present evidence from a big data analysis of health insurance databases that fluoxetine use is associated with reduced risk of developing dry AMD. These studies identify a potential repurposing candidate for a prevalent cause of blindness. The atrophic form of age-related macular degeneration (dry AMD) affects nearly 200 million people worldwide. There is no Food and Drug Administration (FDA)-approved therapy for this disease, which is the leading cause of irreversible blindness among people over 50 y of age. Vision loss in dry AMD results from degeneration of the retinal pigmented epithelium (RPE). RPE cell death is driven in part by accumulation of Alu RNAs, which are noncoding transcripts of a human retrotransposon. Alu RNA induces RPE degeneration by activating the NLRP3-ASC inflammasome. We report that fluoxetine, an FDA-approved drug for treating clinical depression, binds NLRP3 in silico, in vitro, and in vivo and inhibits activation of the NLRP3-ASC inflammasome and inflammatory cytokine release in RPE cells and macrophages, two critical cell types in dry AMD. We also demonstrate that fluoxetine, unlike several other antidepressant drugs, reduces Alu RNA–induced RPE degeneration in mice. Finally, by analyzing two health insurance databases comprising more than 100 million Americans, we report a reduced hazard of developing dry AMD among patients with depression who were treated with fluoxetine. Collectively, these studies identify fluoxetine as a potential drug-repurposing candidate for dry AMD.
干性老年性黄斑变性(AMD)影响着全世界数百万人的视力。目前还没有食品和药物管理局批准的治疗干性黄斑变性的方法。炎性体成分NLRP3和ASC与干性AMD的发病机制有关。我们报道被批准用于治疗临床抑郁症的氟西汀直接结合NLRP3蛋白,阻止NLRP3- asc炎症小体的组装和激活。氟西汀可防止干性AMD动物模型中视网膜色素上皮细胞的变性。我们还提供了来自健康保险数据库的大数据分析的证据,表明氟西汀的使用与干性AMD的风险降低有关。这些研究为一种普遍的致盲原因确定了一种潜在的重新利用的候选物。萎缩性老年性黄斑变性(干性AMD)影响全球近2亿人。目前还没有美国食品和药物管理局(FDA)批准的治疗这种疾病的方法,这种疾病是50岁以上人群中导致不可逆失明的主要原因。干性AMD的视力丧失是由视网膜色素上皮(RPE)变性引起的。RPE细胞死亡部分是由Alu rna的积累驱动的,Alu rna是人类反转录转座子的非编码转录本。Alu RNA通过激活NLRP3-ASC炎性体诱导RPE变性。我们报道,氟西汀是一种fda批准的治疗临床抑郁症的药物,在硅、体外和体内结合NLRP3,抑制干性AMD的两种关键细胞类型RPE细胞和巨噬细胞中NLRP3- asc炎性体的激活和炎症细胞因子的释放。我们还证明氟西汀与其他几种抗抑郁药物不同,可以减少小鼠Alu rna诱导的RPE变性。最后,通过分析包含超过1亿美国人的两个健康保险数据库,我们报告了氟西汀治疗的抑郁症患者患干性黄斑变性的风险降低。总的来说,这些研究确定氟西汀是干性AMD的潜在药物再利用候选药物。
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引用次数: 32
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Proceedings of the National Academy of Sciences
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