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Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.

Abstract: The electronic, structural, and optical properties of 2 red phosphors, Rb2HfF6:Mn4+ and Cs2HfF6:Mn4+, are evaluated using the first‐principles and crystal field theory methods. The calculated trigonal splitting of the Mn4+ orbital triplets perfectly matches the experimental excitation spectra. The structural and electronic properties of the mixed compound RbCsHfF6 are also studied theoretically. In the mixed compound, the inversion center symmetry around the Hf site is removed. This symmetry lowering may result in an increase in the Mn4+2E→4A2 zero phonon line (ZPL) intensity, which is very weak in the 2 end members. This finding may be of interest for increasing the phosphor luminosity. It is believed that such a mechanism of local site symmetry lowering by preparing solid solutions may be used for other systems as well, to gain ZPL intensity and perhaps to minimize thermal losses, eventually leading to improved phosphor materials. [ABSTRACT FROM AUTHOR]

Cessation of highly active antiretroviral therapy (HAART) in HIV-infected individual leads to a rebound of viral replication due to reactivation of a viral reservoir composed largely of latently infected memory CD4+ T cells. Efforts to deplete this reservoir have focused on reactivation of transcriptionally silent latent proviruses. HIV provirus transcription depends critically on the positive transcription elongation factor b (P-TEFb), whose core components are cyclin-dependent kinase 9 (CDK9) and cyclin T1. In resting CD4+ cells, the functional levels of P-TEFb are extremely low. Cellular activation upregulates cyclin T1 protein levels and CDK9 T-loop (T186) phosphorylation. The broad-spectrum histone deacetylase inhibitors (HDACis) vorinostat and panobinostat have been shown to reactivate latent virus in vivo in HAART-treated individuals. In this study, we have found that vorinostat and panobinostat activate P-TEFb in resting primary CD4+ T cells through induction of CDK9 T-loop phosphorylation. In contrast, tacedinaline and romidepsin, HDAC 1 and 2 inhibitors, were unable to activate CDK9 T-loop phosphorylation. We used a CCL19 primary CD4+ T-cell model HIV latency to assess the correlation between induction of CDK9 T-loop phosphorylation and reactivation of latent HIV virus by HDACis. Vorinostat and panobinostat treatment of cells harboring latent HIV increased CDK9 T-loop phosphorylation and reactivation of latent virus, whereas tacedinaline and romidepsin failed to induce T-loop phosphorylation or reactivate latent virus. We conclude that the ability of vorinostat and panobinostat to induce latent HIV is, in part, likely due to the ability of the broad-spectrum HDACis to upregulate P-TEFb through increased CDK9 T-loop phosphorylation. [ABSTRACT FROM AUTHOR]

Abstract: The electronic, structural, and optical properties of 2 red phosphors, Rb2HfF6:Mn4+ and Cs2HfF6:Mn4+, are evaluated using the first‐principles and crystal field theory methods. The calculated trigonal splitting of the Mn4+ orbital triplets perfectly matches the experimental excitation spectra. The structural and electronic properties of the mixed compound RbCsHfF6 are also studied theoretically. In the mixed compound, the inversion center symmetry around the Hf site is removed. This symmetry lowering may result in an increase in the Mn4+2E→4A2 zero phonon line (ZPL) intensity, which is very weak in the 2 end members. This finding may be of interest for increasing the phosphor luminosity. It is believed that such a mechanism of local site symmetry lowering by preparing solid solutions may be used for other systems as well, to gain ZPL intensity and perhaps to minimize thermal losses, eventually leading to improved phosphor materials. [ABSTRACT FROM AUTHOR]

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMP-activated protein kinase and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin-positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk, and organism longevity., Competing Interests: YY, SG, YG, PH, QZ, JL, BJ, QZ, DS, MA, SJ, MW No competing interests declared, (© 2024, Yu, Gao, Guan et al.)

The related NEAT1_1 and NEAT1_2 long noncoding RNAs (lnc RNAs) have been recently implicated in innate immunity against viral infection. We used CRISPR-Cas9 to generate Jurkat CD4 + T cell lines with a knockout (KO) of the NEAT1 gene. Viabilities of NEAT1 KO Jurkat lines were indistinguishable from parental Jurkat cells, as was the induction of CD69 after T cell activation. The KO lines were however more sensitive to the induction of apoptosis than parental Jurkat cells. HIV-1 replication was higher in the KO lines than parental Jurkat cells, demonstrating an anti-HIV function of NEAT1 lncRNAs. We observed a strong down-regulation of NEAT1 lncRNAs following activation of resting peripheral blood mononuclear cells and purified CD4 + T cells. These findings indicate that HIV-1 infection exploits the normal down-regulation of anti-viral NEAT1 lncRNAs in activated CD4 + T cells to enhance viral replication., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The latent HIV-1 reservoir of memory CD4 + T cells that persists during combination antiviral therapy prevents a cure of infection. Insight into mechanisms of latency and viral reactivation are essential for the rational design of strategies to reduce the latent reservoir. In this study, we quantified the levels of >2,600 proteins in the CCL19 primary CD4 + T cell model of HIV-1 latency. We profiled proteins under conditions that promote latent infection and after cells were treated with phorbol 12-myristate 13-acetate (PMA) + ionomycin, which is known to efficiently induce reactivation of latent HIV-1. In an analysis of cells from two healthy blood donors, we identified 61 proteins that were upregulated ≥2-fold, and 36 proteins that were downregulated ≥2-fold under conditions in which latent viruses were reactivated. These differentially expressed proteins are, therefore, candidates for cellular factors that regulate latency or viral reactivation. Two unexpected findings were obtained from the proteomic data: (1) the interactions among the majority of upregulated proteins are largely undetermined in published protein-protein interaction networks and (2) downregulated proteins are strongly associated with Gene Ontology terms related to mitochondrial protein synthesis. This proteomic data set provides a useful resource for future mechanistic studies of HIV-1 latency.