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<jats:p> Carbonaceous meteorites are thought to be fragments of C-type (carbonaceous) asteroids. Samples of the C-type asteroid (162173) Ryugu were retrieved by the Hayabusa2 spacecraft. We measure the mineralogy, bulk chemical and isotopic compositions of Ryugu samples. They are mainly composed of materials similar to carbonaceous chondrite meteorites, particularly the CI (Ivuna-type) group. The samples consist predominantly of minerals formed in aqueous fluid on a parent planetesimal. The primary minerals were altered by fluids at a temperature of 37 ± 10°C, <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mrow> <mml:msubsup> <mml:mrow> <mml:mn>5.2</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>0.8</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>0.7</mml:mn> </mml:mrow> </mml:msubsup> </mml:mrow> </mml:math> </jats:inline-formula> (Stat.) <jats:inline-formula> <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mrow> <mml:msubsup> <mml:mrow /> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>2.1</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>+</mml:mo> <mml:mn>1.6</mml:mn> </mml:mrow> </mml:msubsup> </mml:mrow> </mml:math> </jats:inline-formula> (Syst.) million years after formation of the first solids in the Solar System. After aqueous alteration, the Ryugu samples were likely never heated above ~100°C. The samples have a chemical composition that more closely resembles the Sun’s photosphere than other natural samples do. </jats:p>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>The nuclear pore complex (NPC) is the molecular conduit in the nuclear membrane of eukaryotic cells that regulates import and export of biomolecules between the nucleus and the cytosol, with vertebrate NPCs ~110 to 125 MDa in molecular mass and ~120 nm in diameter. NPCs are organized into four main rings: the cytoplasmic ring (CR) at the cytosolic side, the inner ring and the luminal ring on the plane of the nuclear membrane, and the nuclear ring facing the nucleus. Each ring possesses an approximate eightfold symmetry and is composed of multiple copies of different nucleoporins. NPCs have been implicated in numerous biological processes, and their dysfunctions are associated with a growing number of serious human diseases. However, despite pioneering studies from many groups over the past two decades, we still lack a full understanding of NPCs’ organization, dynamics, and complexity.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p> We used the <jats:italic>Xenopus laevis</jats:italic> oocyte as a model system for the structural characterization because each oocyte possesses a large number of NPC particles that can be visualized on native nuclear membranes without the aid of detergent extraction. We used single-particle cryo–electron microscopy (cryo-EM) analysis on data collected at different stage tilt angles for three-dimensional reconstruction and structure prediction with AlphaFold for model building. </jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> We reconstructed the CR map of <jats:italic>X. laevis</jats:italic> NPC at 6.9 and 6.7 Å resolutions for the full CR protomer and a core region, respectively, and predicted the structures of the individual nucleoporins using AlphaFold because no high-resolution models of <jats:italic>X. laevis</jats:italic> Nups were available. For any ambiguous subunit interactions, we also predicted complex structures, which further guided model fitting of the CR protomer. We placed the nucleoporin or complex structures into the CR density to obtain an almost full CR atomic model, composed of the inner and outer Y-complexes, two copies of Nup205, two copies of the Nup214-Nup88-Nup62 complex, one Nup155, and five copies of Nup358. In particular, we predicted the largest protein in the NPC, Nup358, as having an S-shaped globular domain, a coiled-coil domain, and a largely disordered C-terminal region containing phenylalanine-glycine (FG) repeats previously shown to form a gel-like condensate phase for selective cargo passage. Four of the Nup358 copies clamp around the inner and outer Y-complexes to stabilize the CR, and the fifth Nup358 situates in the center of the cluster of clamps. AlphaFold also predicted a homo-oligomeric, likely specifically pentameric, coiled-coil structure of Nup358 that may provide the avidity for Nup358 recruitment to the NPC and for lowering the threshold for Nup358 condensation in NPC biogenesis. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>Our studies offer an example of integrative cryo-EM and structure prediction as a general approach for attaining more precise models of megadalton protein complexes from medium-resolution density maps. The more accurate and almost complete model of the CR presented here expands our understanding of the molecular interactions in the NPC and represents a substantial step forward toward the molecular architecture of a full NPC, with implications for NPC function, biogenesis, and regulation.</jats:p> <jats:fig fig-type="image" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title> Cryo-EM structure of the cytoplasmatic ring of the nuclear pore complex from <jats:italic>X. leavis</jats:italic> . </jats:title> <jats:p>The 6.9 Å map was generated with single-particle cryo-EM, and the model was built with AlphaFold structure prediction. The secondary structural elements guided EM map fitting, resulting in an almost complete model of the complex. The approach allowed the identification of five copies of Nup358 and a second copy of the trimeric Nup214-Nup88-Nup62 complex.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.abm9326-fa.tif" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>The subcellular compartmentalization of eukaryotic cells requires selective transport of folded proteins and protein–nucleic acid complexes. Embedded in nuclear envelope pores, which are generated by the circumscribed fusion of the inner and outer nuclear membranes, nuclear pore complexes (NPCs) are the sole bidirectional gateways for nucleocytoplasmic transport. The ~110-MDa human NPC is an ~1000-protein assembly that comprises multiple copies of ~34 different proteins, collectively termed nucleoporins. The symmetric core of the NPC is composed of an inner ring encircling the central transport channel and outer rings formed by Y‑shaped coat nucleoporin complexes (CNCs) anchored atop both sides of the nuclear envelope. The outer rings are decorated with compartment‑specific asymmetric nuclear basket and cytoplasmic filament nucleoporins, which establish transport directionality and provide docking sites for transport factors and the small guanosine triphosphatase Ran. The cytoplasmic filament nucleoporins also play an essential role in the irreversible remodeling of messenger ribonucleoprotein particles (mRNPs) as they exit the central transport channel. Unsurprisingly, the NPC’s cytoplasmic face represents a hotspot for disease‑associated mutations and is commonly targeted by viral virulence factors.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>Previous studies established a near-atomic composite structure of the human NPC’s symmetric core by combining (i) biochemical reconstitution to elucidate the interaction network between symmetric nucleoporins, (ii) crystal and single-particle cryo–electron microscopy structure determination of nucleoporins and nucleoporin complexes to reveal their three-dimensional shape and the molecular details of their interactions, (iii) quantitative docking in cryo–electron tomography (cryo-ET) maps of the intact human NPC to uncover nucleoporin stoichiometry and positioning, and (iv) cell‑based assays to validate the physiological relevance of the biochemical and structural findings. In this work, we extended our approach to the cytoplasmic filament nucleoporins to reveal the near-atomic architecture of the cytoplasmic face of the human NPC.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> Using biochemical reconstitution, we elucidated the protein-protein and protein-RNA interaction networks of the human and <jats:italic>Chaetomium thermophilum</jats:italic> cytoplasmic filament nucleoporins, establishing an evolutionarily conserved heterohexameric cytoplasmic filament nucleoporin complex (CFNC) held together by a central heterotrimeric coiled‑coil hub that tethers two separate mRNP‑remodeling complexes. Further biochemical analysis and determination of a series of crystal structures revealed that the metazoan‑specific cytoplasmic filament nucleoporin NUP358 is composed of 16 distinct domains, including an N‑terminal S‑shaped α‑helical solenoid followed by a coiled‑coil oligomerization element, numerous Ran‑interacting domains, an E3 ligase domain, and a C‑terminal prolyl‑isomerase domain. Physiologically validated quantitative docking into cryo-ET maps of the intact human NPC revealed that pentameric NUP358 bundles, conjoined by the oligomerization element, are anchored through their N‑terminal domains to the central stalk regions of the CNC, projecting flexibly attached domains as far as ~600 Å into the cytoplasm. Using cell‑based assays, we demonstrated that NUP358 is dispensable for the architectural integrity of the assembled interphase NPC and RNA export but is required for efficient translation. After NUP358 assignment, the remaining 4-shaped cryo‑ET density matched the dimensions of the CFNC coiled‑coil hub, in close proximity to an outer-ring NUP93. Whereas the N-terminal NUP93 assembly sensor motif anchors the properly assembled related coiled‑coil channel nucleoporin heterotrimer to the inner ring, biochemical reconstitution confirmed that the NUP93 assembly sensor is reused in anchoring the CFNC to the cytoplasmic face of the human NPC. By contrast, two <jats:italic>C. thermophilum</jats:italic> CFNCs are anchored by a divergent mechanism that involves assembly sensors located in unstructured portions of two CNC nucleoporins. Whereas unassigned cryo‑ET density occupies the NUP358 and CFNC binding sites on the nuclear face, docking of the nuclear basket component ELYS established that the equivalent position on the cytoplasmic face is unoccupied, suggesting that mechanisms other than steric competition promote asymmetric distribution of nucleoporins. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>We have substantially advanced the biochemical and structural characterization of the asymmetric nucleoporins’ architecture and attachment at the cytoplasmic and nuclear faces of the NPC. Our near‑atomic composite structure of the human NPC’s cytoplasmic face provides a biochemical and structural framework for elucidating the molecular basis of mRNP remodeling, viral virulence factor interference with NPC function, and the underlying mechanisms of nucleoporin diseases at the cytoplasmic face of the NPC.</jats:p> <jats:fig fig-type="image-half-right" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title>Cytoplasmic face of the human NPC.</jats:title> <jats:p>Near-atomic composite structure of the NPC generated by docking high-resolution crystal structures into a cryo‑ET reconstruction of an intact human NPC. The symmetric core, embedded in the nuclear envelope, is decorated with NUP358 (red) domains bound to Ran (gray), flexibly projected into the cytoplasm, and CFNCs (pink) overlooking the central transport channel.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.abm9129-fa.tif" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>The nuclear pore complex (NPC) resides on the nuclear envelope (NE) and mediates nucleocytoplasmic cargo transport. As one of the largest cellular machineries, a vertebrate NPC consists of cytoplasmic filaments, a cytoplasmic ring (CR), an inner ring, a nuclear ring, a nuclear basket, and a luminal ring. Each NPC has eight repeating subunits. Structure determination of NPC is a prerequisite for understanding its functional mechanism. In the past two decades, integrative modeling, which combines x-ray structures of individual nucleoporins and subcomplexes with cryo–electron tomography reconstructions, has played a crucial role in advancing our knowledge about the NPC.</jats:p> <jats:p> The CR has been a major focus of structural investigation. The CR subunit of human NPC was reconstructed by cryo–electron tomography through subtomogram averaging to an overall resolution of ~20 Å, with local resolution up to ~15 Å. Each CR subunit comprises two Y-shaped multicomponent complexes known as the inner and outer Y complexes. Eight inner and eight outer Y complexes assemble in a head-to-tail fashion to form the proximal and distal rings, respectively, constituting the CR scaffold. To achieve higher resolution of the CR, we used single-particle cryo–electron microscopy (cryo-EM) to image the intact NPC from the NE of <jats:italic>Xenopus laevis</jats:italic> oocytes. Reconstructions of the core region and the Nup358 region of the <jats:italic>X. laevis</jats:italic> CR subunit had been achieved at average resolutions of 5 to 8 Å, allowing identification of secondary structural elements. </jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>Packing interactions among the components of the CR subunit were poorly defined by all previous EM maps. Additional components of the CR subunit are strongly suggested by the EM maps of 5- to 8-Å resolution but remain to be identified. Addressing these issues requires improved resolution of the cryo-EM reconstruction. Therefore, we may need to enhance sample preparation, optimize image acquisition, and develop an effective data-processing strategy.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> To reduce conformational heterogeneity of the sample, we spread the opened NE onto the grids with minimal force and used the chemical cross-linker glutaraldehyde to stabilize the NPC. To alleviate orientation bias of the NPC, we tilted sample grids and imaged the sample with higher electron dose at higher angles. We improved the image-processing protocol. With these efforts, the average resolutions for the core and the Nup358 regions have been improved to 3.7 and 4.7 Å, respectively. The highest local resolution of the core region reaches 3.3 Å. In addition, a cryo-EM structure of the N-terminal α-helical domain of Nup358 has been resolved at 3.0-Å resolution. These EM maps allow the identification of five copies of Nup358, two copies of Nup93, two copies of Nup205, and two copies of Y complexes in each CR subunit. Relying on the EM maps and facilitated by AlphaFold prediction, we have generated a final model for the CR of the <jats:italic>X. laevis</jats:italic> NPC. Our model of the CR subunit includes 19,037 amino acids in 30 nucleoporins. </jats:p> <jats:p>A previously unknown C-terminal fragment of Nup160 was found to constitute a key part of the vertex, in which the short arm, long arm, and stem of the Y complex meet. The Nup160 C-terminal fragment directly binds the β-propeller proteins Seh1 and Sec13. Two Nup205 molecules, which do not contact each other, bind the inner and outer Y complexes through distinct interfaces. Conformational elasticity of the two Nup205 molecules may underlie their versatility in binding to different nucleoporins in the proximal and distal CR rings. Two Nup93 molecules, each comprising an N-terminal extended helix and an ACE1 domain, bridge the Y complexes and Nup205. Nup93 and Nup205 together play a critical role in mediating the contacts between neighboring CR subunits. Five Nup358 molecules, each in the shape of a shrimp tail and named “the clamp,” hold the stems of both Y complexes. The innate conformational elasticity allows each Nup358 clamp to adapt to a distinct local environment for optimal interactions with neighboring nucleoporins. In each CR subunit, the α-helical nucleoporins appear to provide the conformational elasticity; the 12 β-propellers may strengthen the scaffold.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p> Our EM map–based model of the <jats:italic>X. laevis</jats:italic> CR subunit substantially expands the molecular mass over the reported composite models of vertebrate CR subunit. In addition to the Y complexes, five Nup358, two Nup205, and two Nup93 molecules constitute the key components of the CR. The improved EM maps reveal insights into the interfaces among the nucleoporins of the CR. </jats:p> <jats:fig fig-type="image" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title> Cryo-EM structure of the double-layered CR of the <jats:italic>X. laevis</jats:italic> NPC. </jats:title> <jats:p> The <jats:italic>X. laevis</jats:italic> CR, containing eight repeating subunits, is modeled on the basis of cryo-EM reconstructions (top left panel). One CR subunit is shown in two different views to highlight nucleoporins of key interest (bottom left and right panels). The inner and outer Y complexes are colored dark and light gray, respectively. Two Nup205, two Nup93, and five Nup358 molecules are colored blue, red, and purple, respectively. </jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.abl8280-fa.tif" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>In eukaryotic cells, the selective bidirectional transport of macromolecules between the nucleus and cytoplasm occurs through the nuclear pore complex (NPC). Embedded in nuclear envelope pores, the ~110-MDa human NPC is an ~1200-Å-wide and ~750-Å-tall assembly of ~1000 proteins, collectively termed nucleoporins. Because of the NPC’s eightfold rotational symmetry along the nucleocytoplasmic axis, each of the ~34 different nucleoporins occurs in multiples of eight. Architecturally, the NPC’s symmetric core is composed of an inner ring encircling the central transport channel and two outer rings anchored on both sides of the nuclear envelope. Because of its central role in the flow of genetic information from DNA to RNA to protein, the NPC is commonly targeted in viral infections and its nucleoporin constituents are associated with a plethora of diseases.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>Although the arrangement of most scaffold nucleoporins in the NPC’s symmetric core was determined by quantitative docking of crystal structures into cryo–electron tomographic (cryo-ET) maps of intact NPCs, the topology and molecular details of their cohesion by multivalent linker nucleoporins have remained elusive. Recently, in situ cryo-ET reconstructions of NPCs from various species have indicated that the NPC’s inner ring is capable of reversible constriction and dilation in response to variations in nuclear envelope membrane tension, thereby modulating the diameter of the central transport channel by ~200 Å. We combined biochemical reconstitution, high-resolution crystal and single-particle cryo–electron microscopy (cryo-EM) structure determination, docking into cryo-ET maps, and physiological validation to elucidate the molecular architecture of the linker-scaffold interaction network that not only is essential for the NPC’s integrity but also confers the plasticity and robustness necessary to allow and withstand such large-scale conformational changes.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> By biochemically mapping scaffold-binding regions of all fungal and human linker nucleoporins and determining crystal and single-particle cryo-EM structures of linker-scaffold complexes, we completed the characterization of the biochemically tractable linker-scaffold network and established its evolutionary conservation, despite considerable sequence divergence. We determined a series of crystal and single-particle cryo-EM structures of the intact Nup188 and Nup192 scaffold hubs bound to their Nic96, Nup145N, and Nup53 linker nucleoporin binding regions, revealing that both proteins form distinct question mark–shaped keystones of two evolutionarily conserved hetero‑octameric inner ring complexes. Linkers bind to scaffold surface pockets through short defined motifs, with flanking regions commonly forming additional disperse interactions that reinforce the binding. Using a structure‑guided functional analysis in <jats:italic>Saccharomyces cerevisiae</jats:italic> , we confirmed the robustness of linker‑scaffold interactions and established the physiological relevance of our biochemical and structural findings. The near-atomic composite structures resulting from quantitative docking of experimental structures into human and <jats:italic>S. cerevisiae</jats:italic> cryo-ET maps of constricted and dilated NPCs structurally disambiguated the positioning of the Nup188 and Nup192 hubs in the intact fungal and human NPC and revealed the topology of the linker-scaffold network. The linker-scaffold gives rise to eight relatively rigid inner ring spokes that are flexibly interconnected to allow for the formation of lateral channels. Unexpectedly, we uncovered that linker‑scaffold interactions play an opposing role in the outer rings by forming tight cross-link staples between the eight nuclear and cytoplasmic outer ring spokes, thereby limiting the dilatory movements to the inner ring. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p> We have substantially advanced the structural and biochemical characterization of the symmetric core of the <jats:italic>S. cerevisiae</jats:italic> and human NPCs and determined near-atomic composite structures. The composite structures uncover the molecular mechanism by which the evolutionarily conserved linker‑scaffold establishes the NPC’s integrity while simultaneously allowing for the observed plasticity of the central transport channel. The composite structures are roadmaps for the mechanistic dissection of NPC assembly and disassembly, the etiology of NPC‑associated diseases, the role of NPC dilation in nucleocytoplasmic transport of soluble and integral membrane protein cargos, and the anchoring of asymmetric nucleoporins. </jats:p> <jats:fig fig-type="image" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title>Linker-scaffold architecture in the human NPC’s symmetric core.</jats:title> <jats:p>Near‑atomic composite structure of the NPC’s symmetric core obtained by quantitative docking of high-resolution crystal and single-particle cryo-EM structures into a cryo-ET reconstruction of the intact human NPC. Schematic representations of the intricate linker-scaffold topology of the cytoplasmic outer ring, inner ring, and nuclear outer ring (clockwise from top) are depicted for the boxed regions. C, C terminus; N, N terminus.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.abm9798-fa.tif" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>The eukaryotic nucleus pro­tects the genome and is enclosed by the two membranes of the nuclear envelope. Nuclear pore complexes (NPCs) perforate the nuclear envelope to facilitate nucleocytoplasmic transport. With a molecular weight of ∼120 MDa, the human NPC is one of the larg­est protein complexes. Its ~1000 proteins are taken in multiple copies from a set of about 30 distinct nucleoporins (NUPs). They can be roughly categorized into two classes. Scaf­fold NUPs contain folded domains and form a cylindrical scaffold architecture around a central channel. Intrinsically disordered NUPs line the scaffold and extend into the central channel, where they interact with cargo complexes. The NPC architecture is highly dynamic. It responds to changes in nuclear envelope tension with conforma­tional breathing that manifests in dilation and constriction movements. Elucidating the scaffold architecture, ultimately at atomic resolution, will be important for gaining a more precise understanding of NPC function and dynamics but imposes a substantial chal­lenge for structural biologists.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>Considerable progress has been made toward this goal by a joint effort in the field. A synergistic combination of complementary approaches has turned out to be critical. In situ structural biology techniques were used to reveal the overall layout of the NPC scaffold that defines the spatial reference for molecular modeling. High-resolution structures of many NUPs were determined in vitro. Proteomic analysis and extensive biochemical work unraveled the interaction network of NUPs. Integra­tive modeling has been used to combine the different types of data, resulting in a rough outline of the NPC scaffold. Previous struc­tural models of the human NPC, however, were patchy and limited in accuracy owing to several challenges: (i) Many of the high-resolution structures of individual NUPs have been solved from distantly related species and, consequently, do not comprehensively cover their human counterparts. (ii) The scaf­fold is interconnected by a set of intrinsically disordered linker NUPs that are not straight­forwardly accessible to common structural biology techniques. (iii) The NPC scaffold intimately embraces the fused inner and outer nuclear membranes in a distinctive topol­ogy and cannot be studied in isolation. (iv) The conformational dynamics of scaffold NUPs limits the resolution achievable in structure determination.</jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>In this study, we used artificial intelligence (AI)–based prediction to generate an exten­sive repertoire of structural models of human NUPs and their subcomplexes. The resulting models cover various domains and interfaces that so far remained structurally uncharac­terized. Benchmarking against previous and unpublished x-ray and cryo–electron micros­copy structures revealed unprecedented accu­racy. We obtained well-resolved cryo–electron tomographic maps of both the constricted and dilated conformational states of the hu­man NPC. Using integrative modeling, we fit­ted the structural models of individual NUPs into the cryo–electron microscopy maps. We explicitly included several linker NUPs and traced their trajectory through the NPC scaf­fold. We elucidated in great detail how mem­brane-associated and transmembrane NUPs are distributed across the fusion topology of both nuclear membranes. The resulting architectural model increases the structural coverage of the human NPC scaffold by about twofold. We extensively validated our model against both earlier and new experimental data. The completeness of our model has enabled microsecond-long coarse-grained molecular dynamics simulations of the NPC scaffold within an explicit membrane en­vironment and solvent. These simulations reveal that the NPC scaffold prevents the constriction of the otherwise stable double-membrane fusion pore to small diameters in the absence of membrane tension.</jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>Our 70-MDa atomically re­solved model covers &gt;90% of the human NPC scaffold. It captures conforma­tional changes that occur during dilation and constriction. It also reveals the precise anchoring sites for intrinsically disordered NUPs, the identification of which is a prerequisite for a complete and dy­namic model of the NPC. Our study exempli­fies how AI-based structure prediction may accelerate the elucidation of subcellular ar­chitecture at atomic resolution.</jats:p> <jats:fig fig-type="image" orientation="portrait" position="float" specific-use="distribute"> <jats:caption> <jats:title>A 70-MDa model of the human nuclear pore complex scaffold architecture.</jats:title> <jats:p>The structural model of the human NPC scaffold is shown for the constricted state as a cut-away view. High-resolution models are color coded according to nucleoporin subcomplex membership. The nuclear envelope is shown as a gray surface.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="science.abm9506-fa.tif" /> </jats:fig> </jats:sec>

<jats:p> Should businesses worry about climate risk because doing so is good for their bottom line, or because their responsibilities ought to go beyond mere financial returns to shareholders? What if expanding one’s lens to include environmental, social, and corporate governance turns out to be good for business? What if not? These fundamental questions lie at the core of numerous ambitious efforts to align tools and resources of finance with global action to address climate change. And they have been raised again with alarm in recent weeks after the head of responsible investment for HSBC Asset Management, appearing at a <jats:italic>Financial Times</jats:italic> “Moral Money” event, gave a talk that was neither responsible nor moral. </jats:p>

<jats:p>Favored shot is a seemingly safer smallpox vaccine, but researchers debate how best to use it</jats:p>

<jats:p>New constitution may help reset relationship between scientists and communities</jats:p>