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      The Multifaceted Biology of PCSK9

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          Abstract

          This article reviews the discovery of PCSK9, its structure–function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating low-density lipoprotein (LDL)-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain, its binding to the secreted cytosolic cyclase associated protein 1, and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the antitumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors that reduces by 50% to 60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 monoclonal antibody or small interfering RNA could be added to current immunotherapies in cancer/metastasis.

          Graphical Abstract

          Graphical Abstract

          By modulating the trafficking of key secretory proteins, PCSK9 is implicated in the regulation of major diseases. Secreted PCSK9 shortens the half-life of cell surface receptors, such as LDLR and MHC-I, by escorting them into the lysosomal pathway. The functional consequences of PCSK9 activity in different diseases is indicated.

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          The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).

          Definitions of sepsis and septic shock were last revised in 2001. Considerable advances have since been made into the pathobiology (changes in organ function, morphology, cell biology, biochemistry, immunology, and circulation), management, and epidemiology of sepsis, suggesting the need for reexamination.
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            A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity.

            Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide bacteria and archaea with adaptive immunity against viruses and plasmids by using CRISPR RNAs (crRNAs) to guide the silencing of invading nucleic acids. We show here that in a subset of these systems, the mature crRNA that is base-paired to trans-activating crRNA (tracrRNA) forms a two-RNA structure that directs the CRISPR-associated protein Cas9 to introduce double-stranded (ds) breaks in target DNA. At sites complementary to the crRNA-guide sequence, the Cas9 HNH nuclease domain cleaves the complementary strand, whereas the Cas9 RuvC-like domain cleaves the noncomplementary strand. The dual-tracrRNA:crRNA, when engineered as a single RNA chimera, also directs sequence-specific Cas9 dsDNA cleavage. Our study reveals a family of endonucleases that use dual-RNAs for site-specific DNA cleavage and highlights the potential to exploit the system for RNA-programmable genome editing.
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              2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk

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                Author and article information

                Contributors
                Journal
                Endocr Rev
                Endocr Rev
                edrv
                Endocrine Reviews
                Oxford University Press (US )
                0163-769X
                1945-7189
                June 2022
                09 October 2021
                09 October 2021
                : 43
                : 3
                : 558-582
                Affiliations
                Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) , Montreal, QC, Canada
                Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal) , Montreal, QC, Canada
                Author notes
                Correspondence: Nabil G. Seidah, Laboratory of Biochemical Neuroendocrinology, Montreal Clinical Research Institute (IRCM, affiliated to the University of Montreal), 110 Pine Ave West, Montreal, QC, H2W 1R7, Canada. Email: seidahn@ 123456ircm.qc.ca .
                Author information
                https://orcid.org/0000-0001-6503-9342
                https://orcid.org/0000-0002-8007-5277
                Article
                bnab035
                10.1210/endrev/bnab035
                9113161
                35552680
                1fededfa-b0fc-4299-8678-b5527360996a
                © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 02 July 2021
                : 04 October 2021
                : 02 November 2021
                Page count
                Pages: 25
                Funding
                Funded by: Canadian Institutes of Health Research, DOI 10.13039/501100000024;
                Award ID: 148363
                Categories
                Review
                AcademicSubjects/MED00250

                β-cells,cancer/metastases,hypercholesterolemia,major histocompatibility complex i,sepsis

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