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<jats:title>Abstract</jats:title><jats:p>Eukaryotes have evolved towards one of two extremes along a spectrum of strategies for remodelling the nuclear envelope during cell division: disassembling the nuclear envelope in an open mitosis or constructing an intranuclear spindle in a closed mitosis<jats:sup>1,2</jats:sup>. Both classes of mitotic remodelling involve key differences in the core division machinery but the evolutionary reasons for adopting a specific mechanism are unclear. Here we use an integrated comparative genomics and ultrastructural imaging approach to investigate mitotic strategies in Ichthyosporea, close relatives of animals and fungi. We show that species in this clade have diverged towards either a fungal-like closed mitosis or an animal-like open mitosis, probably to support distinct multinucleated or uninucleated states. Our results indicate that multinucleated life cycles favour the evolution of closed mitosis.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells<jats:sup>1</jats:sup>. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies<jats:sup>2</jats:sup>. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs<jats:sup>2–5</jats:sup>. Here we demonstrate that an antibody–drug conjugate (ADC) targeting the pan-haematopoietic marker CD45 enables the antigen-specific depletion of the entire haematopoietic system, including HSCs. Pairing this ADC with the transplantation of human HSCs engineered to be shielded from the CD45-targeting ADC enables the selective eradication of leukaemic cells with preserved haematopoiesis. The combination of CD45-targeting ADCs and engineered HSCs creates an almost universal strategy to replace a diseased haematopoietic system, irrespective of disease aetiology or originating cell type. We propose that this approach could have broad implications beyond haematological malignancies.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Metal–organic frameworks (MOFs) are useful synthetic materials that are built by the programmed assembly of metal nodes and organic linkers<jats:sup>1</jats:sup>. The success of MOFs results from the isoreticular principle<jats:sup>2</jats:sup>, which allows families of structurally analogous frameworks to be built in a predictable way. This relies on directional coordinate covalent bonding to define the framework geometry. However, isoreticular strategies do not translate to other common crystalline solids, such as organic salts<jats:sup>3–5</jats:sup>, in which the intermolecular ionic bonding is less directional. Here we show that chemical knowledge can be combined with computational crystal-structure prediction<jats:sup>6</jats:sup> (CSP) to design porous organic ammonium halide salts that contain no metals. The nodes in these salt frameworks are tightly packed ionic clusters that direct the materials to crystallize in specific ways, as demonstrated by the presence of well-defined spikes of low-energy, low-density isoreticular structures on the predicted lattice energy landscapes<jats:sup>7,8</jats:sup>. These energy landscapes allow us to select combinations of cations and anions that will form thermodynamically stable, porous salt frameworks with channel sizes, functionalities and geometries that can be predicted a priori. Some of these porous salts adsorb molecular guests such as iodine in quantities that exceed those of most MOFs, and this could be useful for applications such as radio-iodine capture<jats:sup>9–12</jats:sup>. More generally, the synthesis of these salts is scalable, involving simple acid–base neutralization, and the strategy makes it possible to create a family of non-metal organic frameworks that combine high ionic charge density with permanent porosity.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Kainate receptors, a subclass of ionotropic glutamate receptors, are tetrameric ligand-gated ion channels that mediate excitatory neurotransmission<jats:sup>1–4</jats:sup>. Kainate receptors modulate neuronal circuits and synaptic plasticity during the development and function of the central nervous system and are implicated in various neurological and psychiatric diseases, including epilepsy, depression, schizophrenia, anxiety and autism<jats:sup>5–11</jats:sup>. Although structures of kainate receptor domains and subunit assemblies are available<jats:sup>12–18</jats:sup>, the mechanism of kainate receptor gating remains poorly understood. Here we present cryo-electron microscopy structures of the kainate receptor GluK2 in the presence of the agonist glutamate and the positive allosteric modulators lectin concanavalin A and BPAM344. Concanavalin A and BPAM344 inhibit kainate receptor desensitization and prolong activation by acting as a spacer between the amino-terminal and ligand-binding domains and a stabilizer of the ligand-binding domain dimer interface, respectively. Channel opening involves the kinking of all four pore-forming M3 helices. Our structures reveal the molecular basis of kainate receptor gating, which could guide the development of drugs for treatment of neurological disorders.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Human feline leukaemia virus subgroup C receptor-related proteins 1 and 2 (FLVCR1 and FLVCR2) are members of the major facilitator superfamily<jats:sup>1</jats:sup>. Their dysfunction is linked to several clinical disorders, including PCARP, HSAN and Fowler syndrome<jats:sup>2–7</jats:sup>. Earlier studies concluded that FLVCR1 may function as a haem exporter<jats:sup>8–12</jats:sup>, whereas FLVCR2 was suggested to act as a haem importer<jats:sup>13</jats:sup>, yet conclusive biochemical and detailed molecular evidence remained elusive for the function of both transporters<jats:sup>14–16</jats:sup>. Here, we show that FLVCR1 and FLVCR2 facilitate the transport of choline and ethanolamine across the plasma membrane, using a concentration-driven substrate translocation process. Through structural and computational analyses, we have identified distinct conformational states of FLVCRs and unravelled the coordination chemistry underlying their substrate interactions. Fully conserved tryptophan and tyrosine residues form the binding pocket of both transporters and confer selectivity for choline and ethanolamine through cation–π interactions. Our findings clarify the mechanisms of choline and ethanolamine transport by FLVCR1 and FLVCR2, enhance our comprehension of disease-associated mutations that interfere with these vital processes and shed light on the conformational dynamics of these major facilitator superfamily proteins during the transport cycle.</jats:p>