Proceedings of the National Academy of Sciences最新文献

{"title":"Paradoxical stabilization of relative position in moving frames","authors":"Mert Özkan, S. Anstis, B. M. ’t Hart, M. Wexler, P. Cavanagh","doi":"10.1101/2021.01.23.427924","DOIUrl":"https://doi.org/10.1101/2021.01.23.427924","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81652900","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}

{"title":"Herbert Tabor, 1918–2020: Polyamines, NIH, and the JBC","authors":"R. Wickner","doi":"10.1073/pnas.2023986118","DOIUrl":"https://doi.org/10.1073/pnas.2023986118","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86916503","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}

{"title":"Single-neuron firing cascades underlie global spontaneous brain events","authors":"Xiao Liu, D. Leopold, Yifan Yang","doi":"10.1101/2021.01.22.427798","DOIUrl":"https://doi.org/10.1101/2021.01.22.427798","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78751655","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}

{"title":"Structural insights into a dimeric Psb27-photosystem II complex from a cyanobacterium Thermosynechococcus vulcanus","authors":"Guoqiang Huang, Yanan Xiao, X. Pi, Liang Zhao, Qingjun Zhu, Wenda Wang, T. Kuang, G. Han, S. Sui, Jian-Ren Shen","doi":"10.2210/pdb7czl/pdb","DOIUrl":"https://doi.org/10.2210/pdb7czl/pdb","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82396094","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}

{"title":"Mechanosensitive remodeling of the bacterial flagellar motor is independent of direction of rotation","authors":"N. Wadhwa, Y. Tu, H. Berg","doi":"10.1101/2021.01.19.427295","DOIUrl":"https://doi.org/10.1101/2021.01.19.427295","url":null,"abstract":"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).","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"55 4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88471759","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}

{"title":"Impact of an alpha helix and a cysteine–cysteine disulfide bond on the resistance of bacterial adhesion pili to stress","authors":"Joseph L. Baker, Tobias Dahlberg, E. Bullitt, Magnus Andersson","doi":"10.1101/2021.01.18.427124","DOIUrl":"https://doi.org/10.1101/2021.01.18.427124","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82262104","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}

{"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}

{"title":"The cost of correcting for error during sensorimotor adaptation","authors":"Ehsan Sedaghat-Nejad, R. Shadmehr","doi":"10.1101/2021.01.13.426535","DOIUrl":"https://doi.org/10.1101/2021.01.13.426535","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84061557","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}

{"title":"Algorithmic monoculture and social welfare","authors":"J. Kleinberg, Manish Raghavan","doi":"10.1145/3603195.3603202","DOIUrl":"https://doi.org/10.1145/3603195.3603202","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82038025","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}

{"title":"Identification of fluoxetine as a direct NLRP3 inhibitor to treat atrophic macular degeneration","authors":"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","doi":"10.1101/2021.01.11.425135","DOIUrl":"https://doi.org/10.1101/2021.01.11.425135","url":null,"abstract":"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.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84904492","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}