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Eight patients had received anti-VEGF therapy 1.75 ± 1.06 times. Follow-up OCTA images demonstrated smaller and fewer hot spot lesions with lesser blood flow signal. CONCLUSIONS OCTA is a noninvasive, fast imaging modality for detecting microvascular changes, and it provides more detail of the RAP lesion and related vessels than ICGA or FA. OCTA would be a valuable tool for follow-up observation. The OCTA patterns of RAP may be helpful in understanding its pathology. [Ophthalmic Surg Lasers Imaging Retina. buy ON123300 2020;51136-144.]. Copyright 2020, SLACK Incorporated.Of all the oral sensations that are experienced, "metallic" is one that is rarely reported in healthy participants. So why, then, do chemotherapy patients so frequently report that "metallic" sensations overpower and interfere with their enjoyment of food and drink? This side-effect of chemotherapy-often referred to (e.g., by patients) as "metal mouth"-can adversely affect their appetite, resulting in weight loss, which potentially endangers (or at the very least slows) their recovery. The etiology of "metal mouth" is poorly understood, and current management strategies are largely unevidenced. As a result, patients continue to suffer as a result of this poorly understood phenomenon. Here, we provide our perspective on the issue, outlining the evidence for a range of possible etiologies, and highlighting key research questions. We explore the evidence for "metallic" as a putative taste, and whether "metal mouth" might therefore be a form of phantageusia, perhaps similar to already-described "release-of-inhibition" phenomena. We comment on the possibility that "metal mouth" may simply be a direct effect of chemotherapy drugs. We present the novel theory that "metal mouth" may be linked to chemotherapy-induced sensitization of TRPV1. Finally, we discuss the evidence for retronasal olfaction of lipid oxidation products in the etiology of "metal mouth." This article seeks principally to guide much-needed future research which will hopefully one day provide a basis for the development of novel supportive therapies for future generations of patients undergoing chemotherapy. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail [email protected] synaptonemal complex (SC) is an ordered but highly dynamic structure assembled between homologous chromosomes to control interhomologous crossover formation, ensuring accurate meiotic chromosome segregation. However, the mechanisms regulating SC assembly and dynamics remain unclear. Here, we identified two new SC components, SYP-5 and SYP-6, in Caenorhabditis elegans that have distinct expression patterns and form distinct SC assembly units with other SYPs through stable interactions. SYP-5 and SYP-6 exhibit diverse in vivo SC regulatory functions and distinct phase separation properties in cells. Charge-interacting elements (CIEs) are enriched in SC intrinsically disordered regions (IDRs), and IDR deletion or CIE removal confirmed a requirement for these elements in SC regulation. Our data support the theory that multivalent weak interactions between the SC units drive SC formation and that CIEs confer multivalency to the assembly units. © 2020 Zhang et al.The synaptonemal complex (SC) is a tripartite protein scaffold that forms between homologous chromosomes during meiosis. Although the SC is essential for stable homologue pairing and crossover recombination in diverse eukaryotes, it is unknown how individual components assemble into the highly conserved SC structure. Here we report the biochemical identification of two new SC components, SYP-5 and SYP-6, in Caenorhabditis elegans. SYP-5 and SYP-6 are paralogous to each other and play redundant roles in synapsis, providing an explanation for why these genes have evaded previous genetic screens. Superresolution microscopy reveals that they localize between the chromosome axes and span the width of the SC in a head-to-head manner, similar to the orientation of other known transverse filament proteins. Using genetic redundancy and structure-function analyses to truncate C-terminal tails of SYP-5/6, we provide evidence supporting the role of SC in both limiting and promoting crossover formation. © 2020 Hurlock et al.Peroxisomes play a central role in human health and have biochemical properties that promote their use in many biotechnology settings. With a primary role in lipid metabolism, peroxisomes share a niche with lipid droplets within the endomembrane-secretory system. Notably, factors in the ER required for the biogenesis of peroxisomes also impact the formation of lipid droplets. The dynamic interface between peroxisomes and lipid droplets, and also between these organelles and the ER and mitochondria, controls their metabolic flux and their dynamics. Here, we review our understanding of peroxisome biogenesis to propose and reframe models for understanding how peroxisomes are formed in cells. To more fully understand the roles of peroxisomes and to take advantage of their many properties that may prove useful in novel therapeutics or biotechnology applications, we recast mechanisms controlling peroxisome biogenesis in a framework that integrates inference from these models with experimental data. © 2020 Mast et al.It is unclear how phosphatidylinositol (PI), the precursor of polyphosphoinositides, is distributed within cell membranes. Pemberton et al. (2020. J. Cell. Biol.https//doi.org/10.1083/jcb.201906130) and Zewe et al. (2020. J. Cell. Biol.https//doi.org/10.1083/jcb.201906127) describe new approaches to map the subcellular PI abundance and clarify how polyphosphoinositide metabolism relates to PI distribution. © 2020 Drin.The mechanisms of quality control for extracellular proteins are still poorly understood. In this issue, Itakura et al. (2020. J. Cell. Biol.https//doi.org/10.1083/jcb.201911126) show that upon binding to misfolded proteins, the extracellular chaperone clusterin is internalized via the heparan sulfate receptor to undergo lysosomal degradation. © 2020 Sánchez-Martín and Komatsu.NUP188 encodes a scaffold component of the nuclear pore complex (NPC) and has been implicated as a congenital heart disease gene through an ill-defined function at centrioles. Here, we explore the mechanisms that physically and functionally segregate Nup188 between the pericentriolar material (PCM) and NPCs. Pulse-chase fluorescent labeling indicates that Nup188 populates centrosomes with newly synthesized protein that does not exchange with NPCs even after mitotic NPC breakdown. In addition, the steady-state levels of Nup188 are controlled by the sensitivity of the PCM pool, but not the NPC pool, to proteasomal degradation. Proximity-labeling and super-resolution microscopy show that Nup188 is vicinal to the inner core of the interphase centrosome. Consistent with this, we demonstrate direct binding between Nup188 and Cep152. We further show that Nup188 functions in centriole duplication at or upstream of Sas6 loading. Together, our data establish Nup188 as a component of PCM needed to duplicate the centriole with implications for congenital heart disease mechanisms. © 2020 Vishnoi et al.Phosphatidylinositol (PI) is an essential structural component of eukaryotic membranes that also serves as the common precursor for polyphosphoinositide (PPIn) lipids. Despite the recognized importance of PPIn species for signal transduction and membrane homeostasis, there is still a limited understanding of the relationship between PI availability and the turnover of subcellular PPIn pools. To address these shortcomings, we established a molecular toolbox for investigations of PI distribution within intact cells by exploiting the properties of a bacterial enzyme, PI-specific PLC (PI-PLC). Using these tools, we find a minor presence of PI in membranes of the ER, as well as a general enrichment within the cytosolic leaflets of the Golgi complex, peroxisomes, and outer mitochondrial membrane, but only detect very low steady-state levels of PI within the plasma membrane (PM) and endosomes. Kinetic studies also demonstrate the requirement for sustained PI supply from the ER for the maintenance of monophosphorylated PPIn species within the PM, Golgi complex, and endosomal compartments. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these lipids' role in health and disease. PPIn are derived from the major structural lipid, phosphatidylinositol (PI). However, although the distribution of most PPIn has been characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, we used several orthogonal approaches to map the subcellular distribution of PI, including localizing exogenous fluorescent PI, as well as detecting lipid conversion products of endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. We report that PI is broadly distributed throughout intracellular membrane compartments. However, there is a surprising lack of PI in the plasma membrane compared with the PPIn. These experiments implicate regulation of PI supply to the plasma membrane, as opposed to regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM. © 2020 Zewe et al.The accumulation of aberrant proteins leads to various neurodegenerative disorders. Mammalian cells contain several intracellular protein degradation systems, including autophagy and proteasomal systems, that selectively remove aberrant intracellular proteins. Although mammals contain not only intracellular but also extracellular proteins, the mechanism underlying the quality control of aberrant extracellular proteins is poorly understood. Here, using a novel quantitative fluorescence assay and genome-wide CRISPR screening, we identified the receptor-mediated degradation pathway by which misfolded extracellular proteins are selectively captured by the extracellular chaperone Clusterin and undergo endocytosis via the cell surface heparan sulfate (HS) receptor. Biochemical analyses revealed that positively charged residues on Clusterin electrostatically interact with negatively charged HS. Furthermore, the Clusterin-HS pathway facilitates the degradation of amyloid β peptide and diverse leaked cytosolic proteins in extracellular space. Our results identify a novel protein quality control system for preserving extracellular proteostasis and highlight its role in preventing diseases associated with aberrant extracellular proteins. © 2020 Itakura et al.Distal appendages (DAs) of the mother centriole are essential for the initial steps of ciliogenesis in G1/G0 phase of the cell cycle. DAs are released from centrosomes in mitosis by an undefined mechanism. Here, we show that specific DAs lose their centrosomal localization at the G2/M transition in a manner that relies upon Nek2 kinase activity to ensure low DA levels at mitotic centrosomes. Overexpression of active Nek2A, but not kinase-dead Nek2A, prematurely displaced DAs from the interphase centrosomes of immortalized retina pigment epithelial (RPE1) cells. This dramatic impact was also observed in mammary epithelial cells with constitutively high levels of Nek2. Conversely, Nek2 knockout led to incomplete dissociation of DAs and cilia in mitosis. As a consequence, we observed the presence of a cilia remnant that promoted the asymmetric inheritance of ciliary signaling components and supported cilium reassembly after cell division. Together, our data establish Nek2 as an important kinase that regulates DAs before mitosis.