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    Caspase-2 does not play a critical role in cell death induction and bacterial clearance during Salmonella infection
    Engel, S ; Doerflinger, M ; Lee, AR ; Strasser, A ; Herold, MJ ; Bedoui, S ; Bachem, A (Springer Nature, 2021-12)
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    Emerging connectivity of programmed cell death pathways and its physiological implications
    Bedoui, S ; Herold, MJ ; Strasser, A (Nature Research, 2020-11)
    The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.
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    Plasmodium GPI-anchored micronemal antigen is essential for parasite transmission through the mosquito host
    Jennison, C ; Armstrong, JM ; Dankwa, DA ; Hertoghs, N ; Kumar, S ; Abatiyow, BA ; Naung, M ; Minkah, NK ; Swearingen, KE ; Moritz, R ; Barry, AE ; Kappe, SHI ; Vaughan, AM (Wiley, 2023-06-14)
    Plasmodium parasites, the eukaryotic pathogens that cause malaria, feature three distinct invasive forms tailored to the host environment they must navigate and invade for life cycle progression. One conserved feature of these invasive forms is the micronemes, apically oriented secretory organelles involved in egress, motility, adhesion, and invasion. Here we investigate the role of GPI-anchored micronemal antigen (GAMA), which shows a micronemal localization in all zoite forms of the rodent-infecting species Plasmodium berghei. ∆GAMA parasites are severely defective for invasion of the mosquito midgut. Once formed, oocysts develop normally, however, sporozoites are unable to egress and exhibit defective motility. Epitope-tagging of GAMA revealed tight temporal expression late during sporogony and showed that GAMA is shed during sporozoite gliding motility in a similar manner to circumsporozoite protein. Complementation of P. berghei knockout parasites with full-length P. falciparum GAMA partially restored infectivity to mosquitoes, indicating conservation of function across Plasmodium species. A suite of parasites with GAMA expressed under the promoters of CTRP, CAP380, and TRAP, further confirmed the involvement of GAMA in midgut infection, motility, and vertebrate infection. These data show GAMA's involvement in sporozoite motility, egress, and invasion, implicating GAMA as a regulator of microneme function.
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    Artificial intelligence takes center stage: exploring the capabilities and implications of ChatGPT and other AI-assisted technologies in scientific research and education
    Borger, JG ; Ng, AP ; Anderton, H ; Ashdown, GW ; Auld, M ; Blewitt, ME ; Brown, D ; Call, MJ ; Collins, P ; Freytag, S ; Harrison, LC ; Hesping, E ; Hoysted, J ; Johnston, A ; Mcinneny, A ; Tang, P ; Whitehead, L ; Jex, A ; Naik, SH (WILEY, 2023-11)
    The emergence of large language models (LLMs) and assisted artificial intelligence (AI) technologies have revolutionized the way in which we interact with technology. A recent symposium at the Walter and Eliza Hall Institute explored the current practical applications of LLMs in medical research and canvassed the emerging ethical, legal and social implications for the use of AI-assisted technologies in the sciences. This paper provides an overview of the symposium's key themes and discussions delivered by diverse speakers, including early career researchers, group leaders, educators and policy-makers highlighting the opportunities and challenges that lie ahead for scientific researchers and educators as we continue to explore the potential of this cutting-edge and emerging technology.
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    Display of Native Antigen on cDC1 That Have Spatial Access to Both T and B Cells Underlies Efficient Humoral Vaccination.
    Kato, Y ; Steiner, TM ; Park, H-Y ; Hitchcock, RO ; Zaid, A ; Hor, JL ; Devi, S ; Davey, GM ; Vremec, D ; Tullett, KM ; Tan, PS ; Ahmet, F ; Mueller, SN ; Alonso, S ; Tarlinton, DM ; Ploegh, HL ; Kaisho, T ; Beattie, L ; Manton, JH ; Fernandez-Ruiz, D ; Shortman, K ; Lahoud, MH ; Heath, WR ; Caminschi, I (American Association of Immunologists, 2020-10-01)
    Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.
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    Platelet intrinsic apoptosis
    Josefsson, EC (PERGAMON-ELSEVIER SCIENCE LTD, 2023-11)
    In a healthy individual, the lifespan of most platelets is tightly regulated by intrinsic, or mitochondrial, apoptosis. This is a special form of programmed cell death governed by the BCL-2 family of proteins, where the prosurvival protein BCL-XL maintains platelet viability by restraining the prodeath proteins BAK and BAX. Restriction of platelet lifespan by activation of BAK and BAX mediated intrinsic apoptosis is essential to maintain a functional, haemostatically reactive platelet population. This review focuses on the molecular regulation of intrinsic apoptosis in platelets, reviews conditions linked to enhanced platelet death, discusses ex vivo storage of platelets and describes caveats associated with the assessment of platelet apoptosis.
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    A placental model of SARS-CoV-2 infection reveals ACE2-dependent susceptibility and differentiation impairment in syncytiotrophoblasts (vol 25, pg 1223, 2023)
    Chen, J ; Neil, JA ; Tan, JP ; Rudraraju, R ; Mohenska, M ; Sun, YBY ; Walters, E ; Bediaga, NG ; Sun, G ; Zhou, Y ; Li, Y ; Drew, D ; Pymm, P ; Tham, WH ; Wang, Y ; Rossello, FJ ; Nie, G ; Liu, X ; Subbarao, K ; Polo, JM (NATURE PORTFOLIO, 2024-02)
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    HBO1 (KAT7) Does Not Have an Essential Role in Cell Proliferation, DNA Replication, or Histone 4 Acetylation in Human Cells
    Kueh, AJ ; Eccles, S ; Tang, L ; Garnham, AL ; May, RE ; Herold, MJ ; Smyth, GK ; Voss, AK ; Thomas, T (American Society for Microbiology, 2020-02-01)
    HBO1 (MYST2/KAT7) is essential for histone 3 lysine 14 acetylation (H3K14ac) but is dispensable for H4 acetylation and DNA replication in mouse tissues. In contrast, previous studies using small interfering RNA (siRNA) knockdown in human cell lines have suggested that HBO1 is essential for DNA replication. To determine if HBO1 has distinctly different roles in immortalized human cell lines and normal mouse cells, we performed siRNA knockdown of HBO1. In addition, we used CRISPR/Cas9 to generate 293T, MCF7, and HeLa cell lines lacking HBO1. Using both techniques, we show that HBO1 is essential for all H3K14ac in human cells and is unlikely to have a direct effect on H4 acetylation and only has minor effects on cell proliferation. Surprisingly, the loss of HBO1 and H3K14ac in HeLa cells led to the secondary loss of almost all H4 acetylation after 4 weeks. Thus, HBO1 is dispensable for DNA replication and cell proliferation in immortalized human cells. However, while cell proliferation proceeded without HBO1 and H3K14ac, HBO1 gene deletion led to profound changes in cell adhesion, particularly in 293T cells. Consistent with this phenotype, the loss of HBO1 in both 293T and HeLa principally affected genes mediating cell adhesion, with comparatively minor effects on other cellular processes.
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    Agm1/Pgm-3-mediated sugar nucleotide synthesis is essential for hematopoiesis and development
    Greig, KT ; Antonchuk, J ; Metcalf, D ; Morgan, PO ; Krebs, DL ; Zhang, J-G ; Hacking, DF ; Bode, L ; Robb, L ; Kranz, C ; de Graaf, C ; Bahlo, M ; Nicola, NA ; Nutt, SL ; Freeze, HH ; Alexander, WS ; Hilton, DJ ; Kile, BT (AMER SOC MICROBIOLOGY, 2007-08)
    Carbohydrate modification of proteins includes N-linked and O-linked glycosylation, proteoglycan formation, glycosylphosphatidylinositol anchor synthesis, and O-GlcNAc modification. Each of these modifications requires the sugar nucleotide UDP-GlcNAc, which is produced via the hexosamine biosynthesis pathway. A key step in this pathway is the interconversion of GlcNAc-6-phosphate (GlcNAc-6-P) and GlcNAc-1-P, catalyzed by phosphoglucomutase 3 (Pgm3). In this paper, we describe two hypomorphic alleles of mouse Pgm3 and show there are specific physiological consequences of a graded reduction in Pgm3 activity and global UDP-GlcNAc levels. Whereas mice lacking Pgm3 die prior to implantation, animals with less severe reductions in enzyme activity are sterile, exhibit changes in pancreatic architecture, and are anemic, leukopenic, and thrombocytopenic. These phenotypes are accompanied by specific rather than wholesale changes in protein glycosylation, suggesting that while universally required, the functions of certain proteins and, as a consequence, certain cell types are especially sensitive to reductions in Pgm3 activity.
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    Mof (MYST1 or KAT8) is essential for progression of embryonic development past the blastocyst stage and required for normal chromatin architecture
    Thomas, T ; Dixon, MP ; Kueh, AJ ; Voss, AK (AMER SOC MICROBIOLOGY, 2008-08)
    Acetylation of histone tails is a hallmark of transcriptionally active chromatin. Mof (males absent on the first; also called MYST1 or KAT8) is a member of the MYST family of histone acetyltransferases and was originally discovered as an essential component of the X chromosome dosage compensation system in Drosophila. In order to examine the role of Mof in mammals in vivo, we generated mice carrying a null mutation of the Mof gene. All Mof-deficient embryos fail to develop beyond the expanded blastocyst stage and die at implantation in vivo. Mof-deficient cell lines cannot be derived from Mof(-/-) embryos in vitro. Mof(-/-) embryos fail to acetylate histone 4 lysine 16 (H4K16) but have normal acetylation of other N-terminal histone lysine residues. Mof(-/-) cell nuclei exhibit abnormal chromatin aggregation preceding activation of caspase 3 and DNA fragmentation. We conclude that Mof is functionally nonredundant with the closely related MYST histone acetyltransferase Tip60. Our results show that Mof performs a different role in mammals from that in flies at the organism level, although the molecular function is conserved. We demonstrate that Mof is required specifically for the maintenance of H4K16 acetylation and normal chromatin architecture of all cells of early male and female embryos.