Benjamin W. Neuman, Alexandria Smart, Orian Gilmer, Redmond P. Smyth, Josef Vaas, Nicolai Böker, Dmitry V. Samborskiy, Ralf Bartenschlager, Stefan Seitz, Alexander E. Gorbalenya, Neva Caliskan, Chris Lauber
Positive-strand RNA viruses of the order Nidovirales have the largest known RNA genomes of vertebrate and invertebrate viruses with 36.7 and 41.1 kb, respectively. The acquisition of a proofreading exoribonuclease (ExoN) by an ancestral nidovirus enabled crossing of the 20 kb barrier. Other factors constraining genome size variations in nidoviruses remain poorly defined. We assemble 76 genome sequences of invertebrate nidoviruses from >500.000 published transcriptome experiments and triple the number of known nidoviruses with >36 kb genomes, including a 64 kb RNA genome. Many of the identified viral lineages acquired putative enzymatic and other protein domains linked to genome size, host phyla, or virus families. The inserted domains may regulate viral replication and virion formation, or modulate infection otherwise. We classify ExoN-encoding nidoviruses into seven groups and four subgroups, according to canonical and noncanonical modes of viral replicase expression by ribosomes and genomic organization (reModes). The most-represented group employing the canonical reMode comprises invertebrate and vertebrate nidoviruses, including coronaviruses. Six groups with noncanonical reModes include invertebrate nidoviruses with 31-to-64 kb genomes. Among them are viruses with segmented genomes and viruses utilizing dual ribosomal frameshifting that we validate experimentally. Moreover, largest polyprotein length and genome size in nidoviruses show reMode- and host phylum-dependent relationships. We hypothesize that the polyprotein length increase in nidoviruses may be limited by the host-inherent translation fidelity, ultimately setting a nidovirus genome size limit. Thus, expansion of ExoN-encoding RNA virus genomes, the vertebrate/invertebrate host division, the control of viral replicase expression, and translation fidelity are interconnected.
{"title":"Giant RNA genomes: Roles of host, translation elongation, genome architecture, and proteome in nidoviruses","authors":"Benjamin W. Neuman, Alexandria Smart, Orian Gilmer, Redmond P. Smyth, Josef Vaas, Nicolai Böker, Dmitry V. Samborskiy, Ralf Bartenschlager, Stefan Seitz, Alexander E. Gorbalenya, Neva Caliskan, Chris Lauber","doi":"10.1073/pnas.2413675122","DOIUrl":"https://doi.org/10.1073/pnas.2413675122","url":null,"abstract":"Positive-strand RNA viruses of the order <jats:italic>Nidovirales</jats:italic> have the largest known RNA genomes of vertebrate and invertebrate viruses with 36.7 and 41.1 kb, respectively. The acquisition of a proofreading exoribonuclease (ExoN) by an ancestral nidovirus enabled crossing of the 20 kb barrier. Other factors constraining genome size variations in nidoviruses remain poorly defined. We assemble 76 genome sequences of invertebrate nidoviruses from >500.000 published transcriptome experiments and triple the number of known nidoviruses with >36 kb genomes, including a 64 kb RNA genome. Many of the identified viral lineages acquired putative enzymatic and other protein domains linked to genome size, host phyla, or virus families. The inserted domains may regulate viral replication and virion formation, or modulate infection otherwise. We classify ExoN-encoding nidoviruses into seven groups and four subgroups, according to canonical and noncanonical modes of viral replicase expression by ribosomes and genomic organization (reModes). The most-represented group employing the canonical reMode comprises invertebrate and vertebrate nidoviruses, including coronaviruses. Six groups with noncanonical reModes include invertebrate nidoviruses with 31-to-64 kb genomes. Among them are viruses with segmented genomes and viruses utilizing dual ribosomal frameshifting that we validate experimentally. Moreover, largest polyprotein length and genome size in nidoviruses show reMode- and host phylum-dependent relationships. We hypothesize that the polyprotein length increase in nidoviruses may be limited by the host-inherent translation fidelity, ultimately setting a nidovirus genome size limit. Thus, expansion of ExoN-encoding RNA virus genomes, the vertebrate/invertebrate host division, the control of viral replicase expression, and translation fidelity are interconnected.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"29 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385163","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}
Jincheng Ma, Xiaodong Song, Hans-Peter Bunge, Andreas Fichtner, You Tian
The tectonic evolution of the Tibetan Plateau has been influenced by continental collision and postcollisional convergence of Indian and Eurasian plates, both of which have undoubtedly imposed their imprints on the lithosphere and upper-mantle structures beneath the collision zone. However, the mode by which the Indian Plate has subducted beneath Tibet, and its driving forces, have been highly uncertain. Here, we present seismic evidence from a full-waveform tomographic model that reveals flat subduction of the Indian Plate beneath nearly the entire plateau at ∼ 300 km depth, implying that the slab may have transitioned to positive/neutral buoyancy and is no longer capable of supporting steep-angle deep subduction. The horizontal distance over which the flat slab slides northward increases from west (where it collides with the Tarim lithospheric keel) to east (where it has resided approximately north of the Songpan-Ganzi Fold Belt beyond the Qiangtang Block). The Asian lithosphere is subducting beneath northeastern Tibet without colliding with the Indian slab. The low-velocity zone, with a thickness of 50 to 110 km, sandwiched between the Tibetan crust and Indian slab, is positively correlated with the high-elevation, low-relief topography of Tibet, suggesting partial melting of the uppermost mantle that has facilitated the growth and flatness of the plateau by adding buoyant material to its base. We propose that deep mantle convective currents, traced to the Réunion plume and imaged as large-scale low-velocity anomalies from the upper mantle under the Indian Plate downward toward the uppermost lower mantle under the Baikal-Mongolia Plateau, are the primary force driving the ongoing India–Asia postcollisional convergence.
{"title":"Wholesale flat subduction of the Indian slab and northward mantle convective flow: Plateau growth and driving force of the India–Asia collision","authors":"Jincheng Ma, Xiaodong Song, Hans-Peter Bunge, Andreas Fichtner, You Tian","doi":"10.1073/pnas.2411776122","DOIUrl":"https://doi.org/10.1073/pnas.2411776122","url":null,"abstract":"The tectonic evolution of the Tibetan Plateau has been influenced by continental collision and postcollisional convergence of Indian and Eurasian plates, both of which have undoubtedly imposed their imprints on the lithosphere and upper-mantle structures beneath the collision zone. However, the mode by which the Indian Plate has subducted beneath Tibet, and its driving forces, have been highly uncertain. Here, we present seismic evidence from a full-waveform tomographic model that reveals flat subduction of the Indian Plate beneath nearly the entire plateau at <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mo>∼</mml:mo> </mml:math> </jats:inline-formula> 300 km depth, implying that the slab may have transitioned to positive/neutral buoyancy and is no longer capable of supporting steep-angle deep subduction. The horizontal distance over which the flat slab slides northward increases from west (where it collides with the Tarim lithospheric keel) to east (where it has resided approximately north of the Songpan-Ganzi Fold Belt beyond the Qiangtang Block). The Asian lithosphere is subducting beneath northeastern Tibet without colliding with the Indian slab. The low-velocity zone, with a thickness of 50 to 110 km, sandwiched between the Tibetan crust and Indian slab, is positively correlated with the high-elevation, low-relief topography of Tibet, suggesting partial melting of the uppermost mantle that has facilitated the growth and flatness of the plateau by adding buoyant material to its base. We propose that deep mantle convective currents, traced to the Réunion plume and imaged as large-scale low-velocity anomalies from the upper mantle under the Indian Plate downward toward the uppermost lower mantle under the Baikal-Mongolia Plateau, are the primary force driving the ongoing India–Asia postcollisional convergence.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"12 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385187","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}
Breanna M. Schaeffer, Tadd T. Truscott, Andrew K. Dickerson
Samaras are known for their elegant and robust autorotation, a resilience that persists in the adverse conditions imposed by high-speed raindrops. Like flying insects, samaras descending from tall trees are likely to be struck by raindrops in an intense storm. In this study, we detail the collision dynamics for impact regions across the samara body and the drop-shedding mechanisms that samaras exhibit to return to autorotation. Impacts across the samara body can pitch the samara up to 60 degrees and, in some cases, induce spanwise roll. Raindrops may shatter or remain intact upon impact, pushing the undamaged samara downward before autorotation is recovered. Drops that strike near the wingtip elicit the greatest recovery distance, while impacts onto the nutlet mass are the least disruptive to the samara and most likely to cause the drop to induce fragmentation. Faster drops allow for quicker drop shedding and a subsequent rapid return to autorotation in less than 50 ms. Our results indicate that samaras are robust to raindrop impacts and consistently recover autorotation, resulting in a minor reduction in dispersal distance. To recover, the entire drop is shed from the spinning samara over a time closely tied to the shedding mode and ensuing drop rejection forces.
{"title":"Maple samaras recover autorotation following raindrop collisions","authors":"Breanna M. Schaeffer, Tadd T. Truscott, Andrew K. Dickerson","doi":"10.1073/pnas.2422641122","DOIUrl":"https://doi.org/10.1073/pnas.2422641122","url":null,"abstract":"Samaras are known for their elegant and robust autorotation, a resilience that persists in the adverse conditions imposed by high-speed raindrops. Like flying insects, samaras descending from tall trees are likely to be struck by raindrops in an intense storm. In this study, we detail the collision dynamics for impact regions across the samara body and the drop-shedding mechanisms that samaras exhibit to return to autorotation. Impacts across the samara body can pitch the samara up to 60 degrees and, in some cases, induce spanwise roll. Raindrops may shatter or remain intact upon impact, pushing the undamaged samara downward before autorotation is recovered. Drops that strike near the wingtip elicit the greatest recovery distance, while impacts onto the nutlet mass are the least disruptive to the samara and most likely to cause the drop to induce fragmentation. Faster drops allow for quicker drop shedding and a subsequent rapid return to autorotation in less than 50 ms. Our results indicate that samaras are robust to raindrop impacts and consistently recover autorotation, resulting in a minor reduction in dispersal distance. To recover, the entire drop is shed from the spinning samara over a time closely tied to the shedding mode and ensuing drop rejection forces.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"17 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385223","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}
Xin Yang, Ye Wang, Yi Qiao, Jingwen Lin, Jackie K. Y. Lau, Wing-Yu Fu, Amy K. Y. Fu, Nancy Y. Ip
Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cell-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which is associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.
包括促红细胞生成素肝细胞A4（EphA4）在内的细胞表面受体在调节海马突触丧失方面起着重要作用，而海马突触丧失是阿尔茨海默病（AD）记忆力衰退的主要驱动因素。然而，EphA4的细胞特异性作用和机制尚不清楚。在这里，我们发现 EphA4 在 AD 条件下的海马 CA1 星形胶质细胞中表达升高。特异性敲除星形胶质细胞 EphA4 能改善 AD 转基因小鼠模型中海马兴奋性突触的缺失。单核 RNA 测序分析表明，抑制 EphA4 能特异性减少具有丰富补体信号的反应性星形胶质细胞亚群，而补体信号与 AD 中星形胶质细胞消除突触有关。重要的是，在 AD 转基因小鼠模型中敲除星形胶质细胞 EphA4 会减少兴奋性突触和星形胶质细胞内兴奋性突触的补体标记。这些研究结果表明，EphA4在星形胶质细胞介导的消除AD兴奋性突触的过程中发挥了重要作用，并强调了星形胶质细胞在AD海马突触维持过程中的关键作用。
{"title":"Astrocytic EphA4 signaling is important for the elimination of excitatory synapses in Alzheimer’s disease","authors":"Xin Yang, Ye Wang, Yi Qiao, Jingwen Lin, Jackie K. Y. Lau, Wing-Yu Fu, Amy K. Y. Fu, Nancy Y. Ip","doi":"10.1073/pnas.2420324122","DOIUrl":"https://doi.org/10.1073/pnas.2420324122","url":null,"abstract":"Cell surface receptors, including erythropoietin-producing hepatocellular A4 (EphA4), are important in regulating hippocampal synapse loss, which is the key driver of memory decline in Alzheimer’s disease (AD). However, the cell-specific roles and mechanisms of EphA4 are unclear. Here, we show that EphA4 expression is elevated in hippocampal CA1 astrocytes in AD conditions. Specific knockout of astrocytic EphA4 ameliorates excitatory synapse loss in the hippocampus in AD transgenic mouse models. Single-nucleus RNA sequencing analysis revealed that EphA4 inhibition specifically decreases a reactive astrocyte subpopulation with enriched complement signaling, which is associated with synapse elimination by astrocytes in AD. Importantly, astrocytic EphA4 knockout in an AD transgenic mouse model decreases complement tagging on excitatory synapses and excitatory synapses within astrocytes. These findings suggest an important role of EphA4 in the astrocyte-mediated elimination of excitatory synapses in AD and highlight the crucial role of astrocytes in hippocampal synapse maintenance in AD.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"27 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385222","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}
Xing He, Mayanak K. Gupta, Douglas L. Abernathy, Garrett E. Granroth, Feng Ye, Barry L. Winn, Lynn Boatner, Olivier Delaire
Understanding the complex temporal and spatial correlations of ions in disordered perovskite oxides is critical to rationalize their functional properties. Here, we provide insights into the longstanding controversy regarding the off-centering of transition metal (TM) ions in the archetypal ferroelectric alloy KTa <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>1</mml:mn> <mml:mo>−</mml:mo> <mml:mi>x</mml:mi> </mml:mrow> </mml:msub> </mml:math> </jats:inline-formula> Nb <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mi>x</mml:mi> </mml:msub> </mml:math> </jats:inline-formula> O <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:msub> <mml:mrow/> <mml:mn>3</mml:mn> </mml:msub> </mml:math> </jats:inline-formula> (KTN). By mapping the full energy ( <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mi>E</mml:mi> </mml:math> </jats:inline-formula> ) and wavevector ( <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mi mathvariant="bold">Q</mml:mi> </mml:math> </jats:inline-formula> ) dependence of the dynamical structure factor <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mo stretchy="false">(</mml:mo> <mml:mi mathvariant="bold">Q</mml:mi> <mml:mo>,</mml:mo> <mml:mi>E</mml:mi> <mml:mo stretchy="false">)</mml:mo> </mml:mrow> </mml:math> </jats:inline-formula> using neutron scattering, and rationalizing our observations with atomistic simulations leveraging machine learning, we fully resolve the static <jats:italic>v</jats:italic> s dynamic nature of diffuse scattering sheets, as well as their composition ( <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mi>x</mml:mi> </mml:math> </jats:inline-formula> ) and temperature dependence. Our first-principles simulations, extended with machine-learning molecular dynamics, reproduce both inelastic neutron spectra and diffuse features, and establish how dynamically correlated TM off-centerings couple to phonons, unifying local and collective viewpoints. This study sheds light into an exemplary ferroelectric system and shows the importance of mapping the full <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" display="inline" overflow="scroll"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mo stretchy="false">(</mml:mo> <mml:mi mathvariant="bold">Q</mml:mi> <mml:mo>,</mml:mo> <mml:mi>E</mml:mi> <mml:mo stretchy="false">)</mml:mo> </mml:mrow> </mml:math> </jats:inline-formula> to reveal critical spatiotemporal correla
{"title":"Resolving the dynamic correlated disorder in KTa 1− x Nb x O 3","authors":"Xing He, Mayanak K. Gupta, Douglas L. Abernathy, Garrett E. Granroth, Feng Ye, Barry L. Winn, Lynn Boatner, Olivier Delaire","doi":"10.1073/pnas.2419159122","DOIUrl":"https://doi.org/10.1073/pnas.2419159122","url":null,"abstract":"Understanding the complex temporal and spatial correlations of ions in disordered perovskite oxides is critical to rationalize their functional properties. Here, we provide insights into the longstanding controversy regarding the off-centering of transition metal (TM) ions in the archetypal ferroelectric alloy KTa <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msub> <mml:mrow/> <mml:mrow> <mml:mn>1</mml:mn> <mml:mo>−</mml:mo> <mml:mi>x</mml:mi> </mml:mrow> </mml:msub> </mml:math> </jats:inline-formula> Nb <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msub> <mml:mrow/> <mml:mi>x</mml:mi> </mml:msub> </mml:math> </jats:inline-formula> O <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:msub> <mml:mrow/> <mml:mn>3</mml:mn> </mml:msub> </mml:math> </jats:inline-formula> (KTN). By mapping the full energy ( <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mi>E</mml:mi> </mml:math> </jats:inline-formula> ) and wavevector ( <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mi mathvariant=\"bold\">Q</mml:mi> </mml:math> </jats:inline-formula> ) dependence of the dynamical structure factor <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mo stretchy=\"false\">(</mml:mo> <mml:mi mathvariant=\"bold\">Q</mml:mi> <mml:mo>,</mml:mo> <mml:mi>E</mml:mi> <mml:mo stretchy=\"false\">)</mml:mo> </mml:mrow> </mml:math> </jats:inline-formula> using neutron scattering, and rationalizing our observations with atomistic simulations leveraging machine learning, we fully resolve the static <jats:italic>v</jats:italic> s dynamic nature of diffuse scattering sheets, as well as their composition ( <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mi>x</mml:mi> </mml:math> </jats:inline-formula> ) and temperature dependence. Our first-principles simulations, extended with machine-learning molecular dynamics, reproduce both inelastic neutron spectra and diffuse features, and establish how dynamically correlated TM off-centerings couple to phonons, unifying local and collective viewpoints. This study sheds light into an exemplary ferroelectric system and shows the importance of mapping the full <jats:inline-formula> <mml:math xmlns:mml=\"http://www.w3.org/1998/Math/MathML\" display=\"inline\" overflow=\"scroll\"> <mml:mrow> <mml:mi>S</mml:mi> <mml:mo stretchy=\"false\">(</mml:mo> <mml:mi mathvariant=\"bold\">Q</mml:mi> <mml:mo>,</mml:mo> <mml:mi>E</mml:mi> <mml:mo stretchy=\"false\">)</mml:mo> </mml:mrow> </mml:math> </jats:inline-formula> to reveal critical spatiotemporal correla","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"55 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385183","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}
Oara Neumann, Yilong Ju, Andres B. Sanchez-Alvarado, Guodong Zhou, Weiwu Jiang, Bhagavatula Moorthy, Melissa A. Suter, Ankit Patel, Peter Nordlander, Naomi J. Halas
The detection and identification of polycyclic aromatic hydrocarbons (PAHs) and their derivatives, polycyclic aromatic compounds (PACs), are essential for environmental and health monitoring, for assessing toxicological exposure and their associated health risks. PAHs/PACs are the most dangerous chemicals found in tobacco smoke, and cigarette use during pregnancy can convey these molecules to the developing fetus through the placenta. This exposure is associated with many negative health outcomes, from premature birth to sudden infant death syndrome and adverse neurodevelopmental disorders. This study demonstrates the use of surface-enhanced Raman and surface-enhanced infrared absorption spectroscopies for direct detection of PAHs/PACs in human placental tissue. We applied two spectroscopy-informed machine learning algorithms, Characteristic Peak Extraction (CaPE) and Characteristic Peak Similarity (CaPSim), to identify the specific PAHs and PACs present in the placenta of women who smoked tobacco cigarettes in pregnancy compared to spectra of the placenta from self-reported nonsmokers. CaPE and CaPSim analysis enabled a clear distinction between these two groups. Independent verification was accomplished by detecting PAH-DNA and PAC-DNA adducts in the smoking group by means of a 32 P-postlabeling assay. These findings highlight the effectiveness of combining surface-enhanced spectroscopies with informed ML analysis for the streamlined detection of hazardous environmental compounds in human tissues, suggesting broader applications in clinical diagnostics and public health surveillance.
{"title":"Machine learning–enhanced surface-enhanced spectroscopic detection of polycyclic aromatic hydrocarbons in the human placenta","authors":"Oara Neumann, Yilong Ju, Andres B. Sanchez-Alvarado, Guodong Zhou, Weiwu Jiang, Bhagavatula Moorthy, Melissa A. Suter, Ankit Patel, Peter Nordlander, Naomi J. Halas","doi":"10.1073/pnas.2422537122","DOIUrl":"https://doi.org/10.1073/pnas.2422537122","url":null,"abstract":"The detection and identification of polycyclic aromatic hydrocarbons (PAHs) and their derivatives, polycyclic aromatic compounds (PACs), are essential for environmental and health monitoring, for assessing toxicological exposure and their associated health risks. PAHs/PACs are the most dangerous chemicals found in tobacco smoke, and cigarette use during pregnancy can convey these molecules to the developing fetus through the placenta. This exposure is associated with many negative health outcomes, from premature birth to sudden infant death syndrome and adverse neurodevelopmental disorders. This study demonstrates the use of surface-enhanced Raman and surface-enhanced infrared absorption spectroscopies for direct detection of PAHs/PACs in human placental tissue. We applied two spectroscopy-informed machine learning algorithms, Characteristic Peak Extraction (CaPE) and Characteristic Peak Similarity (CaPSim), to identify the specific PAHs and PACs present in the placenta of women who smoked tobacco cigarettes in pregnancy compared to spectra of the placenta from self-reported nonsmokers. CaPE and CaPSim analysis enabled a clear distinction between these two groups. Independent verification was accomplished by detecting PAH-DNA and PAC-DNA adducts in the smoking group by means of a <jats:sup>32</jats:sup> P-postlabeling assay. These findings highlight the effectiveness of combining surface-enhanced spectroscopies with informed ML analysis for the streamlined detection of hazardous environmental compounds in human tissues, suggesting broader applications in clinical diagnostics and public health surveillance.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"13 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385186","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}
Kelsey M. Hallinen, Steven P. Bodine, Howard A. Stone, Tom W. Muir, Ned S. Wingreen, Zemer Gitai
Fluid flows are dominant features of many bacterial environments, and flow can often impact bacterial behaviors in unexpected ways. For example, the most common type of cardiovascular infection is heart valve colonization by gram-positive bacteria like Staphylococcus aureus and Enterococcus faecalis (endocarditis). This behavior is counterintuitive because heart valves experience high shear rates that would naively be expected to reduce colonization. To determine whether these bacteria preferentially colonize higher shear rate environments, we developed a microfluidic system to quantify the effect of flow conditions on the colonization of S. aureus and E. faecalis . We find that the preferential colonization in high flow of both species is not specific to heart valves and can be found in simple configurations lacking any host factors. This behavior enables bacteria that are outcompeted in low flow to dominate in high flow. Surprisingly, experimental and computational studies reveal that the two species achieve this behavior via distinct mechanisms. S. aureus grows in cell clusters and produces a dispersal signal whose transport is affected by shear rate. Meanwhile, E. faecalis grows in linear chains whose mechanical properties result in less dispersal in the presence of higher shear force. In addition to establishing two divergent mechanisms by which these bacteria each preferentially colonize high-flow environments, our findings highlight the importance of understanding bacterial behaviors at the level of collective interactions among cells. These results suggest that distinct multicellular nanocolony morphologies have previously unappreciated costs and benefits in different environments, like those introduced by fluid flow.
{"title":"Bacterial species with different nanocolony morphologies have distinct flow-dependent colonization behaviors","authors":"Kelsey M. Hallinen, Steven P. Bodine, Howard A. Stone, Tom W. Muir, Ned S. Wingreen, Zemer Gitai","doi":"10.1073/pnas.2419899122","DOIUrl":"https://doi.org/10.1073/pnas.2419899122","url":null,"abstract":"Fluid flows are dominant features of many bacterial environments, and flow can often impact bacterial behaviors in unexpected ways. For example, the most common type of cardiovascular infection is heart valve colonization by gram-positive bacteria like <jats:italic>Staphylococcus aureus</jats:italic> and <jats:italic>Enterococcus faecalis</jats:italic> (endocarditis). This behavior is counterintuitive because heart valves experience high shear rates that would naively be expected to reduce colonization. To determine whether these bacteria preferentially colonize higher shear rate environments, we developed a microfluidic system to quantify the effect of flow conditions on the colonization of <jats:italic>S. aureus</jats:italic> and <jats:italic>E. faecalis</jats:italic> . We find that the preferential colonization in high flow of both species is not specific to heart valves and can be found in simple configurations lacking any host factors. This behavior enables bacteria that are outcompeted in low flow to dominate in high flow. Surprisingly, experimental and computational studies reveal that the two species achieve this behavior via distinct mechanisms. <jats:italic>S. aureus</jats:italic> grows in cell clusters and produces a dispersal signal whose transport is affected by shear rate. Meanwhile, <jats:italic>E. faecalis</jats:italic> grows in linear chains whose mechanical properties result in less dispersal in the presence of higher shear force. In addition to establishing two divergent mechanisms by which these bacteria each preferentially colonize high-flow environments, our findings highlight the importance of understanding bacterial behaviors at the level of collective interactions among cells. These results suggest that distinct multicellular nanocolony morphologies have previously unappreciated costs and benefits in different environments, like those introduced by fluid flow.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"41 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385221","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}
Giorgio Gianini Morbioli, Keith R. Baillargeon, Monalisa N. Kalimashe, Vibha Kana, Hloniphile Zwane, Cheri van der Walt, Allison J. Tierney, Andrea C. Mora, Mark Goosen, Rivashni Jagaroo, Jessica C. Brooks, Ewaldé Cutler, Gillian Hunt, Michael R. Jordan, Alice Tang, Charles R. Mace
Quantifying viral load, a key indicator required to achieve control and elimination of the HIV epidemic, requires cell-free plasma or serum to ensure measurements are not biased by proviral DNA contained in infected CD4 T lymphocytes. Plasma separation cards (PSC) collect and preserve a dried specimen, which makes them practical solutions for decentralized sample collection and transport in limited-resource settings. However, physiological variations in hematocrit levels can introduce significant variability in the quality of plasma generated by commercial PSCs and can lead to inaccurate test results and clinical decisions. In addition to hematocrit-dependent sampling, the Roche PSC, a standard for dried plasma collection, is known to induce considerable hemolysis, which further impacts specimen quality, concordance with liquid plasma, and the overall benefit of microsampling. We address these gaps with a patterned dried plasma spot (pDPS) card, which generates plasma with improved hematocrit independence and minimal hemolysis. This study directly compares pDPS cards to the Roche PSC to measure HIV viral load. Analysis of viral load from 75 donors revealed strong agreement in sensitivity, specificity, overall accuracy, and viral load band placement between devices, with quantitative metrics suggesting improved performance for pDPS cards. In reflexive genotyping, remnant dried blood from pDPS cards exhibited greater success than Roche PSC in amplification and sequencing (71% vs. 62%) and detecting drug resistance mutations (63% vs. 42%). Based on this performance, pDPS cards can be versatile across multiple analytical platforms, integrate seamlessly into existing clinical laboratory workflows, and aid clinicians in making accurate treatment decisions.
病毒载量是控制和消除艾滋病疫情的一项关键指标，对其进行量化需要无细胞血浆或血清，以确保测量结果不会受到受感染的 CD4 T 淋巴细胞中所含的前病毒 DNA 的影响。血浆分离卡（PSC）可收集并保存干燥的样本，这使其成为在资源有限的环境中进行分散样本收集和运输的实用解决方案。然而，血细胞比容水平的生理变化会对商用血浆分离卡产生的血浆质量造成很大的影响，从而导致检测结果和临床决策的不准确。除了依赖血细胞比容采样外，众所周知，罗氏 PSC（干血浆采集的标准）会引起大量溶血，这进一步影响了标本质量、与液体血浆的一致性以及微采样的整体效益。我们采用图案化干血浆点（pDPS）卡弥补了这些不足，该卡生成的血浆具有更好的血细胞比容独立性，溶血现象极少。本研究将 pDPS 卡与罗氏 PSC 进行了直接比较，以测量 HIV 病毒载量。对 75 名捐献者的病毒载量进行分析后发现，两种设备在灵敏度、特异性、总体准确性和病毒载量带位置上都非常一致，定量指标表明 pDPS 卡的性能有所提高。在反射性基因分型中，pDPS 卡的残留干血在扩增和测序（71% 对 62%）以及检测耐药性突变（63% 对 42%）方面的成功率高于罗氏 PSC。基于这种性能，pDPS 卡可以在多个分析平台上通用，无缝集成到现有的临床实验室工作流程中，帮助临床医生做出准确的治疗决策。
{"title":"Clinical evaluation of patterned dried plasma spot cards to support quantification of HIV viral load and reflexive genotyping","authors":"Giorgio Gianini Morbioli, Keith R. Baillargeon, Monalisa N. Kalimashe, Vibha Kana, Hloniphile Zwane, Cheri van der Walt, Allison J. Tierney, Andrea C. Mora, Mark Goosen, Rivashni Jagaroo, Jessica C. Brooks, Ewaldé Cutler, Gillian Hunt, Michael R. Jordan, Alice Tang, Charles R. Mace","doi":"10.1073/pnas.2419160122","DOIUrl":"https://doi.org/10.1073/pnas.2419160122","url":null,"abstract":"Quantifying viral load, a key indicator required to achieve control and elimination of the HIV epidemic, requires cell-free plasma or serum to ensure measurements are not biased by proviral DNA contained in infected CD4 T lymphocytes. Plasma separation cards (PSC) collect and preserve a dried specimen, which makes them practical solutions for decentralized sample collection and transport in limited-resource settings. However, physiological variations in hematocrit levels can introduce significant variability in the quality of plasma generated by commercial PSCs and can lead to inaccurate test results and clinical decisions. In addition to hematocrit-dependent sampling, the Roche PSC, a standard for dried plasma collection, is known to induce considerable hemolysis, which further impacts specimen quality, concordance with liquid plasma, and the overall benefit of microsampling. We address these gaps with a patterned dried plasma spot (pDPS) card, which generates plasma with improved hematocrit independence and minimal hemolysis. This study directly compares pDPS cards to the Roche PSC to measure HIV viral load. Analysis of viral load from 75 donors revealed strong agreement in sensitivity, specificity, overall accuracy, and viral load band placement between devices, with quantitative metrics suggesting improved performance for pDPS cards. In reflexive genotyping, remnant dried blood from pDPS cards exhibited greater success than Roche PSC in amplification and sequencing (71% vs. 62%) and detecting drug resistance mutations (63% vs. 42%). Based on this performance, pDPS cards can be versatile across multiple analytical platforms, integrate seamlessly into existing clinical laboratory workflows, and aid clinicians in making accurate treatment decisions.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"48 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385178","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}
Yao Chen, Xin Wang, Vincent Colantonio, Zhuo Gao, Yangang Pei, Tara Fish, Jie Ye, Lance Courtney, Theodore W. Thannhauser, Zhibiao Ye, Yongsheng Liu, Zhangjun Fei, Mingchun Liu, James J. Giovannoni
Ripening is crucial for the development of fleshy fruits that release their seeds following consumption by frugivores and are important contributors to human health and nutritional security. Many genetic ripening regulators have been identified, especially in the model system tomato, yet more remain to be discovered and integrated into comprehensive regulatory models. Most tomato ripening genes have been studied in pericarp tissue, though recent evidence indicates that locule tissue is a site of early ripening-gene activities. Here, we identified and functionally characterized an Ethylene Response Factor (ERF) gene, SlERF.D6 , by investigating tomato transcriptome data throughout plant development, emphasizing genes elevated in the locule during fruit development and ripening. SlERF.D6 loss-of-function mutants resulting from CRISPR/Cas9 gene editing delayed ripening initiation and carotenoid accumulation in both pericarp and locule tissues. Transcriptome analysis of lines altered in SlERF.D6 expression revealed multiple classes of altered genes including ripening regulators, in addition to carotenoid, cell wall, and ethylene pathway genes, suggesting comprehensive ripening control. Distinct regulatory patterns in pericarp versus locule tissues were observed, indicating tissue-specific activity of this transcription factor (TF). Analysis of SlERF.D6 interaction with target promoters revealed an APETALA 2/ETHYLENE RESPONSE FACTOR (AP2/ERF) TF ( SlDEAR2 ) as a target of SlERF.D6. Furthermore, we show that a third TF gene, SlTCP12 , is a target of SlDEAR2, presenting a tricomponent module of ripening control residing in the larger SlERF.D6 regulatory network.
{"title":"Ethylene response factor SlERF.D6 promotes ripening in part through transcription factors SlDEAR2 and SlTCP12","authors":"Yao Chen, Xin Wang, Vincent Colantonio, Zhuo Gao, Yangang Pei, Tara Fish, Jie Ye, Lance Courtney, Theodore W. Thannhauser, Zhibiao Ye, Yongsheng Liu, Zhangjun Fei, Mingchun Liu, James J. Giovannoni","doi":"10.1073/pnas.2405894122","DOIUrl":"https://doi.org/10.1073/pnas.2405894122","url":null,"abstract":"Ripening is crucial for the development of fleshy fruits that release their seeds following consumption by frugivores and are important contributors to human health and nutritional security. Many genetic ripening regulators have been identified, especially in the model system tomato, yet more remain to be discovered and integrated into comprehensive regulatory models. Most tomato ripening genes have been studied in pericarp tissue, though recent evidence indicates that locule tissue is a site of early ripening-gene activities. Here, we identified and functionally characterized an Ethylene Response Factor (ERF) gene, <jats:italic>SlERF.D6</jats:italic> , by investigating tomato transcriptome data throughout plant development, emphasizing genes elevated in the locule during fruit development and ripening. <jats:italic>SlERF.D6</jats:italic> loss-of-function mutants resulting from CRISPR/Cas9 gene editing delayed ripening initiation and carotenoid accumulation in both pericarp and locule tissues. Transcriptome analysis of lines altered in <jats:italic>SlERF.D6</jats:italic> expression revealed multiple classes of altered genes including ripening regulators, in addition to carotenoid, cell wall, and ethylene pathway genes, suggesting comprehensive ripening control. Distinct regulatory patterns in pericarp versus locule tissues were observed, indicating tissue-specific activity of this transcription factor (TF). Analysis of SlERF.D6 interaction with target promoters revealed an APETALA 2/ETHYLENE RESPONSE FACTOR (AP2/ERF) TF ( <jats:italic>SlDEAR2</jats:italic> ) as a target of SlERF.D6. Furthermore, we show that a third TF gene, <jats:italic>SlTCP12</jats:italic> , is a target of SlDEAR2, presenting a tricomponent module of ripening control residing in the larger SlERF.D6 regulatory network.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"3 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385185","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}
According to classical Anfinsen’s dogma, a protein folds into a single unique conformation with minimal Gibbs energy under physiological conditions. However, certain proteins may fold into two or more conformations from single amino acid sequences. Here, we designed a protein that adopts interconvertible alternative functional conformations, termed “seesaw” protein (SSP). An SSP was engineered by fusing GFP lacking the C-terminal β-strand and dihydrofolate reductase (DHFR) lacking the N-terminal β-strand with an overlapping linker, which can be competitively incorporated into either the GFP or the DHFR moiety. In vivo and biochemical analyses, including atomic force microscopy (AFM) imaging, demonstrated that the SSP adopts two alternative conformations, which can be biased by point mutations and ligand binding. The drastic conformational change upon the ligand binding was directly visualized by high-speed AFM. Furthermore, the balance of the seesaw can be reversibly changed depending on buffer conditions. In summary, our design strategy for SSP provides a unique direction for creating artificial proteins with on–off behaviors.
{"title":"Seesaw protein: Design of a protein that adopts interconvertible alternative functional conformations and its dynamics","authors":"Toma Ikeda, Tatsuya Nojima, Souma Yamamoto, Ryusei Yamada, Tatsuya Niwa, Hiroki Konno, Hideki Taguchi","doi":"10.1073/pnas.2412117122","DOIUrl":"https://doi.org/10.1073/pnas.2412117122","url":null,"abstract":"According to classical Anfinsen’s dogma, a protein folds into a single unique conformation with minimal Gibbs energy under physiological conditions. However, certain proteins may fold into two or more conformations from single amino acid sequences. Here, we designed a protein that adopts interconvertible alternative functional conformations, termed “seesaw” protein (SSP). An SSP was engineered by fusing GFP lacking the C-terminal β-strand and dihydrofolate reductase (DHFR) lacking the N-terminal β-strand with an overlapping linker, which can be competitively incorporated into either the GFP or the DHFR moiety. In vivo and biochemical analyses, including atomic force microscopy (AFM) imaging, demonstrated that the SSP adopts two alternative conformations, which can be biased by point mutations and ligand binding. The drastic conformational change upon the ligand binding was directly visualized by high-speed AFM. Furthermore, the balance of the seesaw can be reversibly changed depending on buffer conditions. In summary, our design strategy for SSP provides a unique direction for creating artificial proteins with on–off behaviors.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"84 1","pages":""},"PeriodicalIF":11.1,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385184","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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