Pub Date : 2024-09-17Epub Date: 2024-09-05DOI: 10.1073/pnas.2404035121
Katrin Auspurg, Josef Brüderl
We discuss a relatively new meta-scientific research design: many-analyst studies that attempt to assess the replicability and credibility of research based on large-scale observational data. In these studies, a large number of analysts try to answer the same research question using the same data. The key idea is the greater the variation in results, the greater the uncertainty in answering the research question and, accordingly, the lower the credibility of any individual research finding. Compared to individual replications, the large crowd of analysts allows for a more systematic investigation of uncertainty and its sources. However, many-analyst studies are also resource-intensive, and there are some doubts about their potential to provide credible assessments. We identify three issues that any many-analyst study must address: 1) identifying the source of variation in the results; 2) providing an incentive structure similar to that of standard research; and 3) conducting a proper meta-analysis of the results. We argue that some recent many-analyst studies have failed to address these issues satisfactorily and have therefore provided an overly pessimistic assessment of the credibility of science. We also provide some concrete guidance on how future many-analyst studies could provide a more constructive assessment.
{"title":"Toward a more credible assessment of the credibility of science by many-analyst studies.","authors":"Katrin Auspurg, Josef Brüderl","doi":"10.1073/pnas.2404035121","DOIUrl":"https://doi.org/10.1073/pnas.2404035121","url":null,"abstract":"<p><p>We discuss a relatively new meta-scientific research design: many-analyst studies that attempt to assess the replicability and credibility of research based on large-scale observational data. In these studies, a large number of analysts try to answer the same research question using the same data. The key idea is the greater the variation in results, the greater the uncertainty in answering the research question and, accordingly, the lower the credibility of any individual research finding. Compared to individual replications, the large crowd of analysts allows for a more systematic investigation of uncertainty and its sources. However, many-analyst studies are also resource-intensive, and there are some doubts about their potential to provide credible assessments. We identify three issues that any many-analyst study must address: 1) identifying the source of variation in the results; 2) providing an incentive structure similar to that of standard research; and 3) conducting a proper meta-analysis of the results. We argue that some recent many-analyst studies have failed to address these issues satisfactorily and have therefore provided an overly pessimistic assessment of the credibility of science. We also provide some concrete guidance on how future many-analyst studies could provide a more constructive assessment.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":9.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ryan L. Woltz, Yang Zheng, Woori Choi, Khoa Ngo, Pauline Trinh, Lu Ren, Phung N. Thai, Brandon J. Harris, Yanxiao Han, Kyle C. Rouen, Diego Lopez Mateos, Zhong Jian, Ye Chen-Izu, Eamonn J. Dickson, Ebenezer N. Yamoah, Vladimir Yarov-Yarovoy, Igor Vorobyov, Xiao-Dong Zhang, Nipavan Chiamvimonvat
Small-conductance Ca 2+ -activated K + channels (SK, K Ca 2) are gated solely by intracellular microdomain Ca 2+ . The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca 2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca 2+ -CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.
小传导 Ca 2+ 激活 K + 通道（SK，K Ca 2）仅由细胞内微域 Ca 2+ 触发。该通道已成为心律失常的治疗靶点。钙调蛋白（Calmodulin，CaM）与 SK 通道的 CaM 结合域（CaMBD）相互作用，充当门控通道的强制性 Ca 2+ 传感器。在异源表达系统中，磷脂酰肌醇 4,5-二磷酸（PIP2）与 CaM 相互协调，共同调节 SK 通道。然而，PIP2 在调节心肌细胞 SK 通道中的作用和机制仍然未知。在这里，光遗传学、磁性纳米粒子、Rosetta结构建模和分子动力学（MD）模拟相结合，揭示了PIP2如何与Ca 2+ -CaM协同激活SK通道的原子机制。我们的计算研究证明了 S6 跨膜片段中氨基酸残基 R395 的关键作用，该残基与细胞内疏水门相邻。该残基与邻近亚基的 S6 跨膜段中的残基 E398 形成盐桥。R395 和 E398 在 SK 通道的所有已知同工型中都是保守的。我们的研究结果表明，PIP2 与 R395 残基的结合会破坏 R395:E398 盐桥，增加跨膜段 S6 的灵活性并激活通道。重要的是，我们的发现为测试基于结构的药物设计提供了一个平台，可用于治疗 SK 通道家族的抑制剂和激活剂。这项研究非常及时，因为 SK 通道抑制剂目前正处于治疗房性心律失常的临床试验阶段。
{"title":"Atomistic mechanisms of the regulation of small-conductance Ca 2+ -activated K + channel (SK2) by PIP2","authors":"Ryan L. Woltz, Yang Zheng, Woori Choi, Khoa Ngo, Pauline Trinh, Lu Ren, Phung N. Thai, Brandon J. Harris, Yanxiao Han, Kyle C. Rouen, Diego Lopez Mateos, Zhong Jian, Ye Chen-Izu, Eamonn J. Dickson, Ebenezer N. Yamoah, Vladimir Yarov-Yarovoy, Igor Vorobyov, Xiao-Dong Zhang, Nipavan Chiamvimonvat","doi":"10.1073/pnas.2318900121","DOIUrl":"https://doi.org/10.1073/pnas.2318900121","url":null,"abstract":"Small-conductance Ca <jats:sup>2+</jats:sup> -activated K <jats:sup>+</jats:sup> channels (SK, K <jats:sub>Ca</jats:sub> 2) are gated solely by intracellular microdomain Ca <jats:sup>2+</jats:sup> . The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca <jats:sup>2+</jats:sup> sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with <jats:italic>Rosetta</jats:italic> structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca <jats:sup>2+</jats:sup> -CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas F. Epper, Ernst Fehr, Claus Thustrup Kreiner, Søren Leth-Petersen, Isabel Skak Olufsen, Peer Ebbesen Skov
Rising inequality has brought redistribution back on the political agenda. In theory, inequality aversion drives people’s support for redistribution. People can dislike both advantageous inequality (comparison relative to those worse off) and disadvantageous inequality (comparison relative to those better off). Existing experimental evidence reveals substantial variation across people in these preferences. However, evidence is scarce on the broader role of these two distinct forms of inequality aversion for redistribution in society. We provide evidence by exploiting a unique combination of data. We use an incentivized experiment to measure inequality aversion in a large population sample (≈9,000 among 20- to 64-y-old Danes). We link the elicited inequality aversion to survey information on individuals’ support for public redistribution (policies that reduce income differences) and administrative records revealing their private redistribution (real-life donations to charity). In addition, the link to administrative data enables us to include a large battery of controls in the empirical analysis. Theory predicts that support for public redistribution increases with both types of inequality aversion, while private redistribution should increase with advantageous inequality aversion, but decrease with disadvantageous inequality aversion. A strong dislike for disadvantageous inequality makes people willing to sacrifice own income to reduce the income of people who are better off, thereby reducing the distance to people with more income than themselves. Public redistribution schemes achieve this but private donations to charity do not. Our empirical results provide strong support for these predictions and with quantitatively large effects compared to other predictors.
{"title":"Inequality aversion predicts support for public and private redistribution","authors":"Thomas F. Epper, Ernst Fehr, Claus Thustrup Kreiner, Søren Leth-Petersen, Isabel Skak Olufsen, Peer Ebbesen Skov","doi":"10.1073/pnas.2401445121","DOIUrl":"https://doi.org/10.1073/pnas.2401445121","url":null,"abstract":"Rising inequality has brought redistribution back on the political agenda. In theory, inequality aversion drives people’s support for redistribution. People can dislike both advantageous inequality (comparison relative to those worse off) and disadvantageous inequality (comparison relative to those better off). Existing experimental evidence reveals substantial variation across people in these preferences. However, evidence is scarce on the broader role of these two distinct forms of inequality aversion for redistribution in society. We provide evidence by exploiting a unique combination of data. We use an incentivized experiment to measure inequality aversion in a large population sample (≈9,000 among 20- to 64-y-old Danes). We link the elicited inequality aversion to survey information on individuals’ support for public redistribution (policies that reduce income differences) and administrative records revealing their private redistribution (real-life donations to charity). In addition, the link to administrative data enables us to include a large battery of controls in the empirical analysis. Theory predicts that support for public redistribution increases with both types of inequality aversion, while private redistribution should increase with advantageous inequality aversion, but decrease with disadvantageous inequality aversion. A strong dislike for disadvantageous inequality makes people willing to sacrifice own income to reduce the income of people who are better off, thereby reducing the distance to people with more income than themselves. Public redistribution schemes achieve this but private donations to charity do not. Our empirical results provide strong support for these predictions and with quantitatively large effects compared to other predictors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Connectomics research is making rapid advances, although models revealing general principles of connectional architecture are far from complete. Our analysis of 10 6 published connection reports indicates that the adult rat brain interregional connectome has about 76,940 of a possible 623,310 axonal connections between its 790 gray matter regions mapped in a reference atlas, equating to a network density of 12.3%. We examined the sexually dimorphic network using multiresolution consensus clustering that generated a nested hierarchy of interconnected modules/subsystems with three first-order modules and 157 terminal modules in females. Top–down hierarchy analysis suggests a mirror-image primary module pair in the central nervous system’s rostral sector (forebrain–midbrain) associated with behavior control, and a single primary module in the intermediate sector (rhombicbrain) associated with behavior execution; the implications of these results are considered in relation to brain development and evolution. Bottom–up hierarchy analysis reveals known and unfamiliar modules suggesting strong experimentally testable hypotheses. Global network analyses indicate that all hubs are in the rostral module pair, a rich club extends through all three primary modules, and the network exhibits small-world attributes. Simulated lesions of all regions individually enabled ranking their impact on global network organization, and the visual path from the retina was used as a specific example, including the effects of cyclic connection weight changes from the endogenous circadian rhythm generator, suprachiasmatic nucleus. This study elucidates principles of interregional neuronal network architecture for a mammalian brain and suggests a strategy for modeling dynamic structural connectivity.
{"title":"Neural network architecture of a mammalian brain","authors":"Larry W. Swanson, Joel D. Hahn, Olaf Sporns","doi":"10.1073/pnas.2413422121","DOIUrl":"https://doi.org/10.1073/pnas.2413422121","url":null,"abstract":"Connectomics research is making rapid advances, although models revealing general principles of connectional architecture are far from complete. Our analysis of 10 <jats:sup>6</jats:sup> published connection reports indicates that the adult rat brain interregional connectome has about 76,940 of a possible 623,310 axonal connections between its 790 gray matter regions mapped in a reference atlas, equating to a network density of 12.3%. We examined the sexually dimorphic network using multiresolution consensus clustering that generated a nested hierarchy of interconnected modules/subsystems with three first-order modules and 157 terminal modules in females. Top–down hierarchy analysis suggests a mirror-image primary module pair in the central nervous system’s rostral sector (forebrain–midbrain) associated with behavior control, and a single primary module in the intermediate sector (rhombicbrain) associated with behavior execution; the implications of these results are considered in relation to brain development and evolution. Bottom–up hierarchy analysis reveals known and unfamiliar modules suggesting strong experimentally testable hypotheses. Global network analyses indicate that all hubs are in the rostral module pair, a rich club extends through all three primary modules, and the network exhibits small-world attributes. Simulated lesions of all regions individually enabled ranking their impact on global network organization, and the visual path from the retina was used as a specific example, including the effects of cyclic connection weight changes from the endogenous circadian rhythm generator, suprachiasmatic nucleus. This study elucidates principles of interregional neuronal network architecture for a mammalian brain and suggests a strategy for modeling dynamic structural connectivity.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We consider the refractive lensing effects of ionized cool ( T∼104K ) gas cloudlets in the circumgalactic medium (CGM) of galaxies. In particular, we discuss the combined effects of lensing from these cloudlets and scintillation from plasma screens in the Milky Way interstellar medium (ISM). We show that, if the CGM comprises a mist of subparsec cloudlets with column densities of order 1017cm−2 (as predicted by [M. McCourt, S. P. Oh, R. O’Leary, A. M. Madigan, MNRAS 473 , 5407–5431 (2018)]), then fast radio bursts (FRBs) whose sightlines pass within a virial radius of a CGM halo will may be lensed into tens of refractive images with a ∼10 ms scattering timescale. When these images are formed, they will be resolved by scintillating screens in the Milky Way ISM and will suppress the observed scintillation. We illustrate this effect in refractive lensing and argue that positive detections of FRB scintillation may constrain the properties of these cool-gas cloudlets, with current scintillation observation weakly disfavoring the cloudlet model. We propose that sheet-like geometries for the cool gas in the CGM can reconcile quasar absorption measurements (from which we infer the presence of the cool gas with structure on subparsec scales) and the unexpected lack of lensing signals from this gas thus far observed.
我们考虑了星系环银河介质（CGM）中电离冷（T ∼ 10 4 K）气体云团的折射透镜效应。我们特别讨论了这些小云团的透镜效应和银河系星际介质（ISM）中等离子屏幕的闪烁效应的综合效应。我们的研究表明，如果 CGM 由柱密度约为 10 17 cm - 2 的亚秒级小云雾组成（如 [M. McCourt, S. P. Oho] 所预测的那样），那么银河系星际介质（ISM）中的等离子体屏幕就会产生闪烁。McCourt, S. P. Oh, R. O'Leary, A. M. Madigan, MNRAS 473 , 5407-5431 (2018)]预测的那样），那么视线在 CGM 光环的病毒半径内通过的快速射电暴（FRBs）将可能被透镜化为数十个折射图像，散射时间尺度为 10 毫秒。当这些图像形成时，它们将被银河 ISM 中的闪烁屏分辨出来，并抑制观测到的闪烁。我们在折射透镜中说明了这一效应，并认为FRB闪烁的正向探测可能会制约这些冷气体小云的性质，而目前的闪烁观测结果并不支持小云模型。我们提出，CGM 中冷气体的片状几何结构可以调和类星体吸收测量结果（我们从测量结果中推断出冷气体在亚秒级尺度上具有结构）和迄今为止观测到的冷气体意外缺乏透镜信号的情况。
{"title":"Refractive lensing of scintillating FRBs by subparsec cloudlets in the multiphase CGM","authors":"Dylan L. Jow, Xiaohan Wu, Ue-Li Pen","doi":"10.1073/pnas.2406783121","DOIUrl":"https://doi.org/10.1073/pnas.2406783121","url":null,"abstract":"We consider the refractive lensing effects of ionized cool ( <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi>T</mml:mi> <mml:mo>∼</mml:mo> <mml:msup> <mml:mn>10</mml:mn> <mml:mn>4</mml:mn> </mml:msup> <mml:mi mathvariant=\"normal\">K</mml:mi> </mml:mrow> </mml:math> </jats:inline-formula> ) gas cloudlets in the circumgalactic medium (CGM) of galaxies. In particular, we discuss the combined effects of lensing from these cloudlets and scintillation from plasma screens in the Milky Way interstellar medium (ISM). We show that, if the CGM comprises a mist of subparsec cloudlets with column densities of order <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:msup> <mml:mn>10</mml:mn> <mml:mn>17</mml:mn> </mml:msup> <mml:msup> <mml:mrow> <mml:mi mathvariant=\"normal\">cm</mml:mi> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>2</mml:mn> </mml:mrow> </mml:msup> </mml:mrow> </mml:math> </jats:inline-formula> (as predicted by [M. McCourt, S. P. Oh, R. O’Leary, A. M. Madigan, <jats:italic>MNRAS</jats:italic> 473 , 5407–5431 (2018)]), then fast radio bursts (FRBs) whose sightlines pass within a virial radius of a CGM halo will may be lensed into tens of refractive images with a ∼10 ms scattering timescale. When these images are formed, they will be resolved by scintillating screens in the Milky Way ISM and will suppress the observed scintillation. We illustrate this effect in refractive lensing and argue that positive detections of FRB scintillation may constrain the properties of these cool-gas cloudlets, with current scintillation observation weakly disfavoring the cloudlet model. We propose that sheet-like geometries for the cool gas in the CGM can reconcile quasar absorption measurements (from which we infer the presence of the cool gas with structure on subparsec scales) and the unexpected lack of lensing signals from this gas thus far observed.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mammalian Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and Drosophila Yorkie (Yki) are transcription cofactors of the highly conserved Hippo signaling pathway. It has been long assumed that the YAP/TAZ/Yki signaling drives cell proliferation during organ growth. However, its instructive role in regulating developmentally programmed organ growth, if any, remains elusive. Out-of-context gain of YAP/TAZ/Yki signaling often turns oncogenic. Paradoxically, mechanically strained, and differentiated squamous epithelia display developmentally programmed constitutive nuclear YAP/TAZ/Yki signaling. The unknown, therefore, is how a growth-promoting YAP/TAZ/Yki signaling restricts proliferation in differentiated squamous epithelia. Here, we show that reminiscent of a tumor suppressor, Yki negatively regulates the cell growth–promoting PI3K/Akt/TOR signaling in the squamous epithelia of Drosophila tubular organs. Thus, downregulation of Yki signaling in the squamous epithelium of the adult male accessory gland (MAG) up-regulates PI3K/Akt/TOR signaling, inducing cell hypertrophy, exit from their cell cycle arrest, and, finally, culminating in squamous cell carcinoma (SCC). Thus, blocking PI3K/Akt/TOR signaling arrests Yki loss-induced MAG-SCC. Further, MAG-SCCs, like other lethal carcinomas, secrete a cachectin, Impl2—the Drosophila homolog of mammalian IGFBP7—inducing cachexia and shortening the lifespan of adult males. Moreover, in the squamous epithelium of other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, downregulation of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy. Our results reveal that Yki signaling plays an instructive, antiproliferative role in the squamous epithelia of tubular organs.
{"title":"Hippo effector, Yorkie, is a tumor suppressor in select Drosophila squamous epithelia","authors":"Rachita Bhattacharya, Jaya Kumari, Shweta Banerjee, Jyoti Tripathi, Saurabh Singh Parihar, Nitin Mohan, Pradip Sinha","doi":"10.1073/pnas.2319666121","DOIUrl":"https://doi.org/10.1073/pnas.2319666121","url":null,"abstract":"Mammalian Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) and <jats:italic>Drosophila</jats:italic> Yorkie (Yki) are transcription cofactors of the highly conserved Hippo signaling pathway. It has been long assumed that the YAP/TAZ/Yki signaling drives cell proliferation during organ growth. However, its instructive role in regulating developmentally programmed organ growth, if any, remains elusive. Out-of-context gain of YAP/TAZ/Yki signaling often turns oncogenic. Paradoxically, mechanically strained, and differentiated squamous epithelia display developmentally programmed constitutive nuclear YAP/TAZ/Yki signaling. The unknown, therefore, is how a growth-promoting YAP/TAZ/Yki signaling restricts proliferation in differentiated squamous epithelia. Here, we show that reminiscent of a tumor suppressor, Yki negatively regulates the cell growth–promoting PI3K/Akt/TOR signaling in the squamous epithelia of <jats:italic>Drosophila</jats:italic> tubular organs. Thus, downregulation of Yki signaling in the squamous epithelium of the adult male accessory gland (MAG) up-regulates PI3K/Akt/TOR signaling, inducing cell hypertrophy, exit from their cell cycle arrest, and, finally, culminating in squamous cell carcinoma (SCC). Thus, blocking PI3K/Akt/TOR signaling arrests Yki loss-induced MAG-SCC. Further, MAG-SCCs, like other lethal carcinomas, secrete a cachectin, Impl2—the <jats:italic>Drosophila</jats:italic> homolog of mammalian IGFBP7—inducing cachexia and shortening the lifespan of adult males. Moreover, in the squamous epithelium of other tubular organs, like the dorsal trunk of larval tracheal airways or adult Malpighian tubules, downregulation of Yki signaling triggers PI3K/Akt/TOR-induced cell hypertrophy. Our results reveal that Yki signaling plays an instructive, antiproliferative role in the squamous epithelia of tubular organs.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
One of the longstanding aims of network neuroscience is to link a connectome’s topological properties—i.e., features defined from connectivity alone–with an organism’s neurobiology. One approach for doing so is to compare connectome properties with annotational maps. This type of analysis is popular at the meso-/macroscale, but is less common at the nano-scale, owing to a paucity of neuron-level connectome data. However, recent methodological advances have made possible the reconstruction of whole-brain connectomes at single-neuron resolution for a select set of organisms. These include the fruit fly, Drosophila melanogaster , and its developing larvae. In addition to fine-scale descriptions of connectivity, these datasets are accompanied by rich annotations. Here, we use a variant of the stochastic blockmodel to detect multilevel communities in the larval Drosophila connectome. We find that communities partition neurons based on function and cell type and that most interact assortatively, reflecting the principle of functional segregation. However, a small number of communities interact nonassortatively, forming form a “rich-club” of interneurons that receive sensory/ascending inputs and deliver outputs along descending pathways. Next, we investigate the role of community structure in shaping communication patterns. We find that polysynaptic signaling follows specific trajectories across modular hierarchies, with interneurons playing a key role in mediating communication routes between modules and hierarchical scales. Our work suggests a relationship between system-level architecture and the biological function and classification of individual neurons. We envision our study as an important step toward bridging the gap between complex systems and neurobiological lines of investigation in brain sciences.
{"title":"Hierarchical communities in the larval Drosophila connectome: Links to cellular annotations and network topology","authors":"Richard Betzel, Maria Grazia Puxeddu, Caio Seguin","doi":"10.1073/pnas.2320177121","DOIUrl":"https://doi.org/10.1073/pnas.2320177121","url":null,"abstract":"One of the longstanding aims of network neuroscience is to link a connectome’s topological properties—i.e., features defined from connectivity alone–with an organism’s neurobiology. One approach for doing so is to compare connectome properties with annotational maps. This type of analysis is popular at the meso-/macroscale, but is less common at the nano-scale, owing to a paucity of neuron-level connectome data. However, recent methodological advances have made possible the reconstruction of whole-brain connectomes at single-neuron resolution for a select set of organisms. These include the fruit fly, <jats:italic>Drosophila melanogaster</jats:italic> , and its developing larvae. In addition to fine-scale descriptions of connectivity, these datasets are accompanied by rich annotations. Here, we use a variant of the stochastic blockmodel to detect multilevel communities in the larval <jats:italic>Drosophila</jats:italic> connectome. We find that communities partition neurons based on function and cell type and that most interact assortatively, reflecting the principle of functional segregation. However, a small number of communities interact nonassortatively, forming form a “rich-club” of interneurons that receive sensory/ascending inputs and deliver outputs along descending pathways. Next, we investigate the role of community structure in shaping communication patterns. We find that polysynaptic signaling follows specific trajectories across modular hierarchies, with interneurons playing a key role in mediating communication routes between modules and hierarchical scales. Our work suggests a relationship between system-level architecture and the biological function and classification of individual neurons. We envision our study as an important step toward bridging the gap between complex systems and neurobiological lines of investigation in brain sciences.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Saurja DasGupta, Zoe Weiss, Collin Nisler, Jack W. Szostak
The acquisition of new RNA functions through evolutionary processes was essential for the diversification of RNA-based primordial biology and its subsequent transition to modern biology. However, the mechanisms by which RNAs access new functions remain unclear. Do RNA enzymes need completely new folds to support new but related functions, or is reoptimization of the active site sufficient? What are the roles of neutral and adaptive mutations in evolutionary innovation? Here, we address these questions experimentally by focusing on the evolution of substrate specificity in RNA-catalyzed RNA assembly. We use directed in vitro evolution to show that a ligase ribozyme that uses prebiotically relevant 5′-phosphorimidazole-activated substrates can be evolved to catalyze ligation with substrates that are 5′-activated with the biologically relevant triphosphate group. Interestingly, despite catalyzing a related reaction, the new ribozyme folds into a completely new structure and exhibits promiscuity by catalyzing RNA ligation with both triphosphate and phosphorimidazole-activated substrates. Although distinct in sequence and structure, the parent phosphorimidazolide ligase and the evolved triphosphate ligase ribozymes can be connected by a series of point mutations where the intermediate sequences retain at least some ligase activity. The existence of a quasi-neutral pathway between these distinct ligase ribozymes suggests that neutral drift is sufficient to enable the acquisition of new substrate specificity, thereby providing opportunities for subsequent adaptive optimization. The transition from RNA-catalyzed RNA assembly using phosphorimidazole-activated substrates to triphosphate-activated substrates may have foreshadowed the later evolution of the protein enzymes that use monomeric triphosphates (nucleoside triphosphates, NTPs) for RNA synthesis.
{"title":"Evolution of the substrate specificity of an RNA ligase ribozyme from phosphorimidazole to triphosphate activation","authors":"Saurja DasGupta, Zoe Weiss, Collin Nisler, Jack W. Szostak","doi":"10.1073/pnas.2407325121","DOIUrl":"https://doi.org/10.1073/pnas.2407325121","url":null,"abstract":"The acquisition of new RNA functions through evolutionary processes was essential for the diversification of RNA-based primordial biology and its subsequent transition to modern biology. However, the mechanisms by which RNAs access new functions remain unclear. Do RNA enzymes need completely new folds to support new but related functions, or is reoptimization of the active site sufficient? What are the roles of neutral and adaptive mutations in evolutionary innovation? Here, we address these questions experimentally by focusing on the evolution of substrate specificity in RNA-catalyzed RNA assembly. We use directed in vitro evolution to show that a ligase ribozyme that uses prebiotically relevant 5′-phosphorimidazole-activated substrates can be evolved to catalyze ligation with substrates that are 5′-activated with the biologically relevant triphosphate group. Interestingly, despite catalyzing a related reaction, the new ribozyme folds into a completely new structure and exhibits promiscuity by catalyzing RNA ligation with both triphosphate and phosphorimidazole-activated substrates. Although distinct in sequence and structure, the parent phosphorimidazolide ligase and the evolved triphosphate ligase ribozymes can be connected by a series of point mutations where the intermediate sequences retain at least some ligase activity. The existence of a quasi-neutral pathway between these distinct ligase ribozymes suggests that neutral drift is sufficient to enable the acquisition of new substrate specificity, thereby providing opportunities for subsequent adaptive optimization. The transition from RNA-catalyzed RNA assembly using phosphorimidazole-activated substrates to triphosphate-activated substrates may have foreshadowed the later evolution of the protein enzymes that use monomeric triphosphates (nucleoside triphosphates, NTPs) for RNA synthesis.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated.
{"title":"Causal interpretations of family GWAS in the presence of heterogeneous effects","authors":"Carl Veller, Molly Przeworski, Graham Coop","doi":"10.1073/pnas.2401379121","DOIUrl":"https://doi.org/10.1073/pnas.2401379121","url":null,"abstract":"Family-based genome-wide association studies (GWASs) are often claimed to provide an unbiased estimate of the average causal effects (or average treatment effects; ATEs) of alleles, on the basis of an analogy between the random transmission of alleles from parents to children and a randomized controlled trial. We show that this claim does not hold in general. Because Mendelian segregation only randomizes alleles among children of heterozygotes, the effects of alleles in the children of homozygotes are not observable. This feature will matter if an allele has different average effects in the children of homozygotes and heterozygotes, as can arise in the presence of gene-by-environment interactions, gene-by-gene interactions, or differences in linkage disequilibrium patterns. At a single locus, family-based GWAS can be thought of as providing an unbiased estimate of the average effect in the children of heterozygotes (i.e., a local average treatment effect; LATE). This interpretation does not extend to polygenic scores (PGSs), however, because different sets of SNPs are heterozygous in each family. Therefore, other than under specific conditions, the within-family regression slope of a PGS cannot be assumed to provide an unbiased estimate of the LATE for any subset or weighted average of families. In practice, the potential biases of a family-based GWAS are likely smaller than those that can arise from confounding in a standard, population-based GWAS, and so family studies remain important for the dissection of genetic contributions to phenotypic variation. Nonetheless, their causal interpretation is less straightforward than has been widely appreciated.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuan Yuan, Tahani Al Bulushi, Anand V. Sastry, Cigdem Sancar, Richard Szubin, Susan S. Golden, Bernhard O. Palsson
Synechococcus elongatus is an important cyanobacterium that serves as a versatile and robust model for studying circadian biology and photosynthetic metabolism. Its transcriptional regulatory network (TRN) is of fundamental interest, as it orchestrates the cell’s adaptation to the environment, including its response to sunlight. Despite the previous characterization of constituent parts of the S. elongatus TRN, a comprehensive layout of its topology remains to be established. Here, we decomposed a compendium of 300 high-quality RNA sequencing datasets of the model strain PCC 7942 using independent component analysis. We obtained 57 independently modulated gene sets, or iModulons, that explain 67% of the variance in the transcriptional response and 1) accurately reflect the activity of known transcriptional regulations, 2) capture functional components of photosynthesis, 3) provide hypotheses for regulon structures and functional annotations of poorly characterized genes, and 4) describe the transcriptional shifts under dynamic light conditions. This transcriptome-wide analysis of S. elongatus provides a quantitative reconstruction of the TRN and presents a knowledge base that can guide future investigations. Our systems-level analysis also provides a global TRN structure for S. elongatus PCC 7942.
{"title":"Machine learning reveals the transcriptional regulatory network and circadian dynamics of Synechococcus elongatus PCC 7942","authors":"Yuan Yuan, Tahani Al Bulushi, Anand V. Sastry, Cigdem Sancar, Richard Szubin, Susan S. Golden, Bernhard O. Palsson","doi":"10.1073/pnas.2410492121","DOIUrl":"https://doi.org/10.1073/pnas.2410492121","url":null,"abstract":"<jats:italic>Synechococcus elongatus</jats:italic> is an important cyanobacterium that serves as a versatile and robust model for studying circadian biology and photosynthetic metabolism. Its transcriptional regulatory network (TRN) is of fundamental interest, as it orchestrates the cell’s adaptation to the environment, including its response to sunlight. Despite the previous characterization of constituent parts of the <jats:italic>S. elongatus</jats:italic> TRN, a comprehensive layout of its topology remains to be established. Here, we decomposed a compendium of 300 high-quality RNA sequencing datasets of the model strain PCC 7942 using independent component analysis. We obtained 57 independently modulated gene sets, or iModulons, that explain 67% of the variance in the transcriptional response and 1) accurately reflect the activity of known transcriptional regulations, 2) capture functional components of photosynthesis, 3) provide hypotheses for regulon structures and functional annotations of poorly characterized genes, and 4) describe the transcriptional shifts under dynamic light conditions. This transcriptome-wide analysis of <jats:italic>S. elongatus</jats:italic> provides a quantitative reconstruction of the TRN and presents a knowledge base that can guide future investigations. Our systems-level analysis also provides a global TRN structure for <jats:italic>S. elongatus</jats:italic> PCC 7942.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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