Hudson Institute of Medical Research is an independent, not-for-profit medical research institute, based in the Melbourne suburb of Clayton in Victoria.The institute hosts approximately 450 researchers, postgraduate students and support staff. Research at Hudson Institute works to understand, prevent and treat women's and baby health, cancer, innate immunity and infectious diseases, and reproductive health.The current director and CEO is distinguished researcher and international authority on microbiology and immunology, Professor Elizabeth Hartland.The institute is partnered with Monash University and Monash Health, and is co-located with both organisations at the Monash Health Translation Precinct in Clayton.
Abstract STING is an important component in the host innate immune system where its activation by cyclic dinucleotides culminates in the production of interferons and pro-inflammatory cytokines that mediate host defence against infection. While the mechanisms that govern STING-induced interferon production have been comprehensively characterised, how pro-inflammatory cytokines are produced downstream of STING remains less understood. Here we discover that IRF3 is critical for effective STING-mediated inflammatory cytokine production from macrophages as those lacking IRF3 display significant defects. Interestingly, the loss of IRF3 does not impact the activation of the prominent pro-inflammatory transcription factor, NF-κB, but rather affects the AP-1 transcriptional complex. We further discover the role of IRF3 in STING inflammatory responses is independent of its phosphorylation and distinct from its role as a transcription factor for induction of type I interferons. This additional activity of IRF3 is dependent on its recruitment to the previously defined IRF3 binding motif within the C-terminal tail of STING. Hence, our findings reveal an unexpected noncanonical function of IRF3 that is critical for mediating STING-induced pro-inflammatory cytokines from macrophages.
We identified Phyllochlorin sodium as a novel chlorin-derived photosensitising agent, formed via the decarboxylation of Chlorin e4 in solution. Purified Phyllochlorin sodium had similar spectral properties to other chlorin-based photosensitising agents Chlorin e4 disodium (Ce4) and Talaporfin sodium (Talaporfin) and with Soret band at 406 nm and a single fluorescence emission peak at 668 nm. In vitro Phyllochlorin sodium exhibited almost exclusively singlet oxygen production when activated, with superior rate and yield of reactive oxygen species (ROS) generation compared to Talaporfin and Ce4. Against a broad array of cancer cells Phyllochlorin sodium had phototoxic IC90 in the low nM range, and was well tolerated by cells (up to µM concentrations) in the absence of light-induced activation. Illumination at 660 nm induced rapid cell death in a dose-dependent manner, with caspase-3/7 activation preceding phosphatidylserine externalisation at higher doses suggesting the involvement of multiple cell death processes, including apoptotic and non-apoptotic mechanisms under intense oxidative stress. Intracellular localisation was observed primarily to the ER indicating this as the primary site of oxidative stress induced following ROS production. Our data suggest Phyllochlorin sodium as a promising candidate for next-generation PDT.
Testicular germ cell tumors (TGCT) are the leading malignancy in adolescent and young adult males, yet the immunological and cellular mechanisms governing their tumor microenvironment (TME) remain poorly understood. Here, we present a comprehensive review of TGCT pathobiology with a focus on the immune landscape, particularly the role of tumor-infiltrating T lymphocytes. The mammalian testis represents an immune-privileged organ maintained by the coordinated actions of somatic cells (Sertoli and Leydig cells) and resident immune populations that collectively foster immune tolerance and suppress deleterious inflammatory responses. Immune privilege is disrupted in TGCT, resulting in significant alterations in the composition and function of immune cell subsets such as macrophages, mast cells, dendritic cells, and especially T cells. The phenotypic diversity and functional adaptability of CD4+ T cell subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) along with CD8+ T cell subsets (Tc1, Tc2, Tc9, Tc17, and Tc22) are critically evaluated in terms of their roles in anti-tumor immune responses, modulating immune regulation, and enabling tumor immune evasion within the TME of TGCT. Despite the success of immunotherapies such as immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA4, and emerging CAR-T cell strategies in other malignancies, their efficacy in TGCT is limited due to the unique testicular immune milieu and limited understanding of T cell dynamics in TME. Recent advances in single-cell transcriptomics and clinical studies highlight the necessity for high-resolution characterization of T cell subpopulations and their intercellular interactions within the TGCT TME. Elucidating these mechanisms is critical for the rational development of novel immunotherapeutic strategies aimed at overcoming resistance, minimizing long-term treatment-related sequelae, and enhancing clinical outcomes for TGCT patients.
STUDY OBJECTIVES:Fetal sleep is a vital yet underexplored aspect of prenatal neurodevelopment. Its cyclic organization reflects the maturation of central neural circuits, and disturbances in these patterns may offer some of the earliest detectable signs of neurological compromise. This is the first review to integrate more than seven decades of research into a unified, cross-species synthesis of fetal sleep. We examine: (1) Physiology and Ontogeny-comparing human fetuses with animal models; and (2) Methodological Evolution-transitioning from invasive neurophysiology to non-invasive monitoring and deep learning frameworks. METHODS:A structured narrative synthesis was guided by a systematic literature search across four databases (PubMed, Scopus, IEEE Xplore, and Google Scholar). From 2925 identified records, 169 studies involving fetal sleep-related physiology, sleep-state classification, or signal-based monitoring were included in this review. RESULTS:Across the 169 studies, fetal sleep states become clearly observable as the brain matures. In fetal sheep and baboons, organized cycling between active and quiet sleep emerges at approximately 80%-90% gestation. In humans, this differentiation occurs later, around 95% gestation, with full maturation reached near term. Despite extensive animal research, no unified, clinically validated framework exists for defining fetal sleep states, limiting translation into routine obstetric practice. CONCLUSIONS:By integrating evidence across species, methodologies, and clinical contexts, this review provides the scientific foundation for developing objective, multimodal, and non-invasive fetal sleep monitoring technologies-tools that may ultimately support earlier detection of neurological compromise and guide timely prenatal intervention.
Protein ubiquitination is a key post-translational modification that governs protein stability and cellular homeostasis. KLHDC3 is a substrate recognition receptor in the recently identified C-terminal degron-mediated DesCEND ubiquitination pathway. It selectively binds proteins with C-terminal RxxxG motifs, targeting them for degradation. While N-terminal degron pathways are well-characterized, the physiological roles of C-terminal degrons remain poorly understood. To explore KLHDC3’s function in a physiological context, we generated mice deficient in the Klhdc3 gene. Klhdc3-deficient mice exhibited sub-Mendelian birth rates and progressive postnatal lethality, with a median survival of 136 days and a maximum lifespan of approximately one year. Surviving mice showed early growth retardation followed by normalization of body mass, and later developed pronounced obesity, with some individuals reaching fat mass levels exceeding 50
