Nature - Publication

4 Publications found
Noonindoles G–L: Indole Diterpene Glycosides from the Australian Marine-Derived Fungus Aspergillus noonimiae CMB-M0339
Noonindoles G–L: Indole Diterpene Glycosides from the Australian Marine-Derived Fungus Aspergillus noonimiae CMB-M0339

Authors: Sarani Kankanamge , Zeinab G. Khalil , Thulasi Sritharan , Robert J. Capon

In Other, Nature

By NCBI Pubmed

Fungal indole diterpenes (IDTs) occupy a valuable region of bioactive natural product chemical space, displaying potent and selective inhibition of therapeutically important ion channels and with potential application in the treatment of glaucoma, cancer, and neurodegenerative diseases, as well as insecticides and antivirals. We have employed an integrated workflow of analytical scale chemical profiling using GNPS (Global Natural Products Social molecular networking) and cultivation profiling (also known as “MATRIX” miniaturized microbioreactor) to detect, prioritize, optimize the production, isolate, characterize, and identify a new series of indole diterpenes, noonindoles G–L (7–12), from an Australian marine-derived fungus, Aspergillus noonimiae CMB-M0339. The first reported examples of IDT glycosides, the molecular structures for 7–12, were assigned on the basis of detailed spectroscopic analysis and biosynthetic considerations.

Functional T cells are capable of supernumerary cell division and longevity
Functional T cells are capable of supernumerary cell division and longevity

Authors: Andrew G. Soerens , Marco Künzli , Clare F. Quarnstrom , Milcah C. Scott , Lee Swanson , JJ. Locquiao , Hazem E. Ghoneim , Dietmar Zehn , Benjamin Youngblood , Vaiva Vezys , David Masopust

In Life Sciences, Nature

By NCBI Pubmed

Differentiated somatic mammalian cells putatively exhibit species-specific division limits that impede cancer but may constrain lifespans1,2,3. To provide immunity, transiently stimulated CD8+ T cells undergo unusually rapid bursts of numerous cell divisions, and then form quiescent long-lived memory cells that remain poised to reproliferate following subsequent immunological challenges. Here we addressed whether T cells are intrinsically constrained by chronological or cell-division limits. We activated mouse T cells in vivo using acute heterologous prime–boost–boost vaccinations4, transferred expanded cells to new mice, and then repeated this process iteratively. Over 10 years (greatly exceeding the mouse lifespan)5 and 51 successive immunizations, T cells remained competent to respond to vaccination. Cells required sufficient rest between stimulation events. Despite demonstrating the potential to expand the starting population at least 1040-fold, cells did not show loss of proliferation control and results were not due to contamination with young cells. Persistent stimulation by chronic infections or cancer can cause T cell proliferative senescence, functional exhaustion and death6. We found that although iterative acute stimulations also induced sustained expression and epigenetic remodelling of common exhaustion markers (including PD1, which is also known as PDCD1, and TOX) in the cells, they could still proliferate, execute antimicrobial functions and form quiescent memory cells. These observations provide a model to better understand memory cell differentiation, exhaustion, cancer and ageing, and show that functionally competent T cells can retain the potential for extraordinary population expansion and longevity well beyond their organismal lifespan.

Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia
Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia

Authors: Yingyue Zhou , Mari Tada , Zhangying Cai , Prabhakar S. Andhey , Amanda Swain , Kelly R. Miller , Susan Gilfillan , Maxim N. Artyomov , Masaki Takao , Akiyoshi Kakita , Marco Colonna

In Life Sciences, Nature

By NCBI Pubmed

The TREM2–DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer’s disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu–Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.