Tau conformation, distribution and PET imaging correlations in progressive supranuclear palsy.
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Progressive supranuclear palsy (PSP) is a primary tauopathy characterized by aggregation of pathological tau. Recent advances in cryo-electron microscopy have enabled the classification of tauopathies at near-atomic resolution, revealing disease-specific tau filament conformations. These microstructural differences may influence the intracellular localization, intercellular propagation, and spatial distribution of tau pathology, as well as the microscopic binding profiles and macroscopic imaging signatures of tau positron emission tomography (PET) tracers. This review focuses on PSP by delineating its specific tau architecture and cellular and spatial distributions and how they differ in comparison with other major tauopathies and by critically discussing the clinical utility and limitations of tau PET. Through this integrative perspective, we aim to bridge neuropathological insights with in vivo PET findings. Engineered immunoglobulin M (IgM) antibodies typically exhibit superior neutralization potency and avidity compared to their parental IgG counterparts, primarily due to multivalent binding to repeated epitopes on a targeting antigen. In this study, we characterize the neutralization breadth and mechanism of action of IgM-14, a previously reported intranasally deliverable antibody targeting SARS-CoV-2. IgM-14 demonstrates remarkably potent antiviral activity against all pre-Omicron variants but significantly reduced efficacy against Omicron BA.1, and complete loss of activity against the later subvariant JN.1. Resistance selection identified two key mutations in the receptor-binding domain (RBD), G476D and F486P, which disrupt IgM-14 binding and confer strong resistance. Cryo-electron microscopy analysis uncovered two distinct Fab-RBD interfaces: a primary interface overlapping the angiotensin-converting enzyme 2 (ACE2)-binding region, and a unique secondary interface formed only when the RBD adopts the ACE2-inaccessible "down" conformation, involving a neighboring spike protomer. Site-directed mutagenesis and structural modeling revealed a critical role of this secondary site in IgM-14-mediated neutralization. Unlike IgG-14, structural modeling suggested that IgM-14 can simultaneously engage both interfaces in diverse modes, indicating a noncanonical avidity mechanism. Collectively, these findings highlight the structural and functional uniqueness of IgM-14 and offer valuable insights into the rational design of next-generation spike-targeted antibody therapeutics with enhanced breadth and potency. Retrograde transport is central to endomembrane homeostasis, yet the identity and origin of plant retrograde carriers remain unresolved. Prevailing models propose that plant vacuolar sorting receptors (VSRs) recycle either from multivesicular bodies (MVBs) to the trans-Golgi network (TGN) or from the TGN to the Golgi apparatus and/or endoplasmic reticulum (ER). However, the ultrastructural features of plant retrograde transport carriers remain largely unresolved. Here, we show that plant retrograde transport is likely mediated by a previously unrecognized class of MVB-derived spherical vesicles. Using correlative light and electron microscopy and three-dimensional electron tomography, we identify a distinct population of ~30-50 nm spherical vesicles adjacent to MVBs, including nascent vesicles budding from the MVB limiting membrane in Arabidopsis root cells. Immunogold labeling shows that these vesicles are enriched in retromer components and VSRs, suggesting that they possibly function as retrograde transport carriers. To investigate their biogenesis, we perform cryo-electron microscopy and liposome tubulation assays, showing that Arabidopsis SNX1 generates shorter membrane tubules than its mammalian counterpart, consistent with reduced membrane affinity linked to differences in the amphipathic helix. Notably, the SNX1-SNX2 heterodimer produces heterogeneous structures, including spherical vesicles, recapitulating in vivo observations. Lastly, knockdown of SNX1 or SNX2 results in vacuolar mislocalization and increased degradation of GFP-VSR2, and defects in SNX1 and VPS29 inhibit formation of spherical vesicles adjacent to MVBs, resulting in embryonic lethality before the globular stage. Together, these findings establish MVB-derived spherical vesicles as plant retrograde carriers and reveal a distinct SNX-mediated mechanism underlying their formation. To study the effect of embryo cryopreservation duration on pregnancy and neonatal outcomes in women transferred with high-quality blastocyst during frozen embryo transfer (FET) cycles. Multicenter Retrospective cohort study. Three tertiary-care academic medical centers. This retrospective study included a total of 24,101 women who underwent single high-quality blastocyst transfer during their first FET cycles at three tertiary academic medical centers between January 2016 and June 2023. Women were categorized into two groups according to the duration of embryo cryopreservation: the short Cryo group consisted of 23,933 women with a storage time of 0-5 years, while the long Cryo group included 168 women with a storage time > 5 years. Women in the long Cryo group were matched to those in the short Cryo group using propensity score matching with a 1:4 ratio. The pregnancy outcomes and the neonatal outcomes. After adjusting for potential confounding factors, no significant differences were observed between the two groups in pregnancy outcomes, including biochemical pregnancy (adjust odds ratio [aOR] 1.04, 95% confidence interval [CI], 0.70-1.56; P = 0.831), clinical pregnancy (aOR 1.10, 95% CI, 0.75-1.60; P = 0.638), ectopic pregnancy (aOR 2.15, 95% CI, 0.37-12.56; P = 0.394), miscarriage (aOR 0.95, 95% CI, 0.54-1.69; P = 0.871), and live birth (aOR 1.09, 95% CI, 0.76-1.55; P = 0.646). In addition, no significant differences were observed in neonatal outcomes, including very preterm birth, preterm birth, very low birth weight, low birth weight, high birth weight, birth weight, and gestational age. Our analysis found no evidence of significant associations between prolonged cryopreservation of high-quality blastocysts and adverse pregnancy or neonatal outcomes. Cfr methylates C 8 of adenosine 2503 (A2503) in 23 S ribosomal RNA (rRNA) and will also methylate C 2 of A2503 after methylating C 8 . C 8 methylation confers resistance to more than five classes of clinically used antibiotics, highlighting it as a worrisome mechanism of antibiotic resistance. Here, we report the structure of Cfr, determined by cryogenic electron microscopy (Cryo-EM). Despite its small size (∼36 kDa), we exploit a transient protein-RNA crosslink that forms during catalysis, which requires Cys105 to resolve. Using a Cfr Cys105Ala variant and an 87-nucleotide strand of rRNA, we isolate the crosslinked species and determine its structure to 3.0 Å resolution. Notably, the 87-mer rRNA adopts an L-shaped conformation characteristic of tRNAs, rather than the conformation it assumes in the ribosome. Cryo-EM structure of Cfr, a radical S-adenosylmethionine methylase that confers antibiotic resistance. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in metabolism, cell motility, development, and immune responses. Its dysregulation is linked to various diseases, including cancer, in which it can enhance tumor progression and suppress immune responses. High-resolution cryo-electron microscopy (cryo-EM) structures of the human cytosolic AHR complex have recently been solved and have provided insights into its agonist-binding mechanisms. However, our understanding of AHR antagonist binding remains limited. Our computational study, using the structure of the indirubin-bound human cytosolic AHR complex together with state-of-the-art docking algorithms and molecular dynamics simulations, suggests that AHR antagonists may bind either to the ligand-binding pocket or to alternative, as yet