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Science (New York, N.Y.) Nov 2020New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Leveraging the...
New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant Leveraging the microbiomes of marine animals and cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as
Topics: Animals; Antifungal Agents; Benzopyrans; Candida; Candidiasis, Invasive; Disease Models, Animal; Drug Resistance, Multiple, Fungal; Fungal Proteins; Isoquinolines; Mice; Microbiota; Micromonospora; Phospholipid Transfer Proteins; Urochordata
PubMed: 33214279
DOI: 10.1126/science.abd6919 -
Nature Sep 2020The mitochondrial electron transport chain (ETC) is necessary for tumour growth and its inhibition has demonstrated anti-tumour efficacy in combination with targeted...
The mitochondrial electron transport chain (ETC) is necessary for tumour growth and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to the generation of ATP-that is, oxidative phosphorylation and the production of metabolites by the tricarboxylic acid (TCA) cycle. Mitochondrial complexes I and II donate electrons to ubiquinone, resulting in the generation of ubiquinol and the regeneration of the NAD+ and FAD cofactors, and complex III oxidizes ubiquinol back to ubiquinone, which also serves as an electron acceptor for dihydroorotate dehydrogenase (DHODH)-an enzyme necessary for de novo pyrimidine synthesis. Here we show impaired tumour growth in cancer cells that lack mitochondrial complex III. This phenotype was rescued by ectopic expression of Ciona intestinalis alternative oxidase (AOX), which also oxidizes ubiquinol to ubiquinone. Loss of mitochondrial complex I, II or DHODH diminished the tumour growth of AOX-expressing cancer cells deficient in mitochondrial complex III, which highlights the necessity of ubiquinone as an electron acceptor for tumour growth. Cancer cells that lack mitochondrial complex III but can regenerate NAD+ by expression of the NADH oxidase from Lactobacillus brevis (LbNOX) targeted to the mitochondria or cytosol were still unable to grow tumours. This suggests that regeneration of NAD+ is not sufficient to drive tumour growth in vivo. Collectively, our findings indicate that tumour growth requires the ETC to oxidize ubiquinol, which is essential to drive the oxidative TCA cycle and DHODH activity.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Ciona intestinalis; Citric Acid Cycle; Cytosol; Dihydroorotate Dehydrogenase; Electron Transport; Electron Transport Complex I; Electron Transport Complex II; Electron Transport Complex III; Humans; Levilactobacillus brevis; Male; Mice; Mitochondria; Mitochondrial Proteins; Multienzyme Complexes; NAD; NADH, NADPH Oxidoreductases; Neoplasms; Oxidative Phosphorylation; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Plant Proteins; Ubiquinone
PubMed: 32641834
DOI: 10.1038/s41586-020-2475-6 -
Current Topics in Developmental Biology 2020Tunicates are a diverse group of invertebrate marine chordates that includes the larvaceans, thaliaceans, and ascidians. Because of their unique evolutionary position as... (Review)
Review
Tunicates are a diverse group of invertebrate marine chordates that includes the larvaceans, thaliaceans, and ascidians. Because of their unique evolutionary position as the sister group of the vertebrates, tunicates are invaluable as a comparative model and hold the promise of revealing both conserved and derived features of chordate gastrulation. Descriptive studies in a broad range of tunicates have revealed several important unifying traits that make them unique among the chordates, including invariant cell lineages through gastrula stages and an overall morphological simplicity. Gastrulation has only been studied in detail in ascidians such as Ciona and Phallusia, where it involves a simple cup-shaped gastrula driven primarily by endoderm invagination. This appears to differ significantly from vertebrate models, such as Xenopus, in which mesoderm convergent extension and epidermal epiboly are major contributors to involution. These differences may reflect the cellular simplicity of the ascidian embryo.
Topics: Animals; Body Patterning; Cell Lineage; Embryo, Nonmammalian; Endoderm; Evolution, Molecular; Gastrula; Gastrulation; Gene Expression Regulation, Developmental; Morphogenesis; Urochordata
PubMed: 31959289
DOI: 10.1016/bs.ctdb.2019.09.001 -
Current Biology : CB Oct 2020The appendicularian tunicate Oikopleura epitomizes the degree to which evolution can constrain both genome and cellular composition, while at the same time unleashing...
The appendicularian tunicate Oikopleura epitomizes the degree to which evolution can constrain both genome and cellular composition, while at the same time unleashing fantastic specializations.
Topics: Animals; Brain; Genome; Movement; Polysaccharides; Urochordata
PubMed: 33080189
DOI: 10.1016/j.cub.2020.07.075 -
Molecules (Basel, Switzerland) Dec 2022Meridianins are a family of indole alkaloids derived from Antarctic tunicates with extensive pharmacological activities. A series of meridianin derivatives had been... (Review)
Review
Meridianins are a family of indole alkaloids derived from Antarctic tunicates with extensive pharmacological activities. A series of meridianin derivatives had been synthesized by drug researchers. This article reviews the extraction and purification methods, biological activities and pharmacological applications, pharmacokinetic characters and chemical synthesis of meridianins and their derivatives. And prospects on discovering new bioactivities of meridianins and optimizing their structure for the improvement of the ADMET properties are provided.
Topics: Animals; Indole Alkaloids; Urochordata; Antarctic Regions
PubMed: 36557848
DOI: 10.3390/molecules27248714 -
Marine Drugs Sep 2019The occurrence of sulfated steroids and phenolics in marine organisms is quite widespread, being typically reported from Echinoderms. In contrast, alkane and alkene... (Review)
Review
The occurrence of sulfated steroids and phenolics in marine organisms is quite widespread, being typically reported from Echinoderms. In contrast, alkane and alkene aliphatic sulfates are considerably rarer with examples being reported from a diverse array of organisms including echinoderms, sponges and ascidians. While no ecological roles for these metabolites have been proposed, they do exhibit a diverse array of biological activities including thrombin inhibition; the ability to induce metamorphosis in larvae; antiproliferative, antibacterial and antifungal properties; and metalloproteinase inhibition. Of particular interest and an avenue for future development is the finding of antifouling properties with low or nontoxic effects to the environment. This review focuses on alkyl sulfates and related sulfamates, their structures and biological activities. Spectroscopic and spectrometric techniques that can be used to recognize the presence of sulfate groups are also discussed, data for which will enhance the ability of researchers to recognize this class of chemically- and biologically-interesting marine natural products.
Topics: Animals; Antifungal Agents; Aquatic Organisms; Biological Products; Echinodermata; Humans; Invertebrates; Larva; Sulfates; Urochordata
PubMed: 31505775
DOI: 10.3390/md17090527 -
Integrative and Comparative Biology Sep 2021Ascidians are invertebrate chordates, with swimming chordate tadpole larvae that have distinct heads and tails. The head contains the small brain, sensory organs,... (Review)
Review
Ascidians are invertebrate chordates, with swimming chordate tadpole larvae that have distinct heads and tails. The head contains the small brain, sensory organs, including the ocellus (light) and otolith (gravity) and the presumptive endoderm, while the tail has a notochord surrounded by muscle cells and a dorsal nerve cord. One of the chordate features is a post-anal tail. Ascidian tadpoles are nonfeeding, and their tails are critical for larval locomotion. After hatching the larvae swim up toward light and are carried by the tide and ocean currents. When competent to settle, ascidian tadpole larvae swim down, away from light, to settle and metamorphose into a sessile adult. Tunicates are classified as chordates because of their chordate tadpole larvae; in contrast, the sessile adult has a U-shaped gut and very derived body plan, looking nothing like a chordate. There is one group of ascidians, the Molgulidae, where many species are known to have tailless larvae. The Swalla Lab has been studying the evolution of tailless ascidian larvae in this clade for over 30 years and has shown that tailless larvae have evolved independently several times in this clade. Comparison of the genomes of two closely related species, the tailed Molgula oculata and tailless Molgula occulta reveals much synteny, but there have been multiple insertions and deletions that have disrupted larval genes in the tailless species. Genomics and transcriptomics have previously shown that there are pseudogenes expressed in the tailless embryos, suggesting that the partial rescue of tailed features in their hybrid larvae is due to the expression of intact genes from the tailed parent. Yet surprisingly, we find that the notochord gene regulatory network is mostly intact in the tailless M. occulta, although the notochord does not converge and extend and remains as an aggregate of cells we call the "notoball." We expect that eventually many of the larval gene networks will become evolutionarily lost in tailless ascidians and the larval body plan abandoned, with eggs developing directly into an adult. Here we review the current evolutionary and developmental evidence on how the molgulids lost their tails.
Topics: Animals; Biological Evolution; Larva; Notochord; Tail; Urochordata
PubMed: 33881514
DOI: 10.1093/icb/icab022 -
Nucleic Acids Research Jul 2023The interferon inducible protein 16 (IFI16) is a prominent sensor of nuclear pathogenic DNA, initiating innate immune signaling and suppressing viral transcription....
The interferon inducible protein 16 (IFI16) is a prominent sensor of nuclear pathogenic DNA, initiating innate immune signaling and suppressing viral transcription. However, little is known about mechanisms that initiate IFI16 antiviral functions or its regulation within the host DNA-filled nucleus. Here, we provide in vitro and in vivo evidence to establish that IFI16 undergoes liquid-liquid phase separation (LLPS) nucleated by DNA. IFI16 binding to viral DNA initiates LLPS and induction of cytokines during herpes simplex virus type 1 (HSV-1) infection. Multiple phosphorylation sites within an intrinsically disordered region (IDR) function combinatorially to activate IFI16 LLPS, facilitating filamentation. Regulated by CDK2 and GSK3β, IDR phosphorylation provides a toggle between active and inactive IFI16 and the decoupling of IFI16-mediated cytokine expression from repression of viral transcription. These findings show how IFI16 switch-like phase transitions are achieved with temporal resolution for immune signaling and, more broadly, the multi-layered regulation of nuclear DNA sensors.
Topics: Cytokines; Herpesvirus 1, Human; Immunity, Innate; Interferons; Phosphorylation; Herpes Simplex; Embryo, Mammalian; Urochordata; Gene Expression Regulation, Viral; Cyclin-Dependent Kinase 2; Glycogen Synthase Kinase 3 beta; Humans; Animals
PubMed: 37283074
DOI: 10.1093/nar/gkad449 -
Neuron Feb 2020The connectomes of organisms of the same species show remarkable architectural and often local wiring similarity, raising the question: where and how is neuronal...
The connectomes of organisms of the same species show remarkable architectural and often local wiring similarity, raising the question: where and how is neuronal connectivity encoded? Here, we start from the hypothesis that the genetic identity of neurons guides synapse and gap-junction formation and show that such genetically driven wiring predicts the existence of specific biclique motifs in the connectome. We identify a family of large, statistically significant biclique subgraphs in the connectomes of three species and show that within many of the observed bicliques the neurons share statistically significant expression patterns and morphological characteristics, supporting our expectation of common genetic factors that drive the synapse formation within these subgraphs. The proposed connectome model offers a self-consistent framework to link the genetics of an organism to the reproducible architecture of its connectome, offering experimentally falsifiable predictions on the genetic factors that drive the formation of individual neuronal circuits.
Topics: Animals; Brain; Caenorhabditis elegans; Ciona intestinalis; Connectome; Drosophila; Models, Genetic; Nerve Net
PubMed: 31806491
DOI: 10.1016/j.neuron.2019.10.031 -
Marine Drugs Feb 2022Patellamides are highly bioactive compounds found along with other cyanobactins in the symbiosis between didemnid ascidians and the enigmatic cyanobacterium . The... (Review)
Review
Patellamides are highly bioactive compounds found along with other cyanobactins in the symbiosis between didemnid ascidians and the enigmatic cyanobacterium . The biosynthetic pathway of patellamide synthesis is well understood, the relevant operons have been identified in the genome and genes involved in patellamide synthesis are among the most highly transcribed cyanobacterial genes in hospite. However, a more detailed study of the in vivo dynamics of patellamides and their function in the ascidian- symbiosis is complicated by the fact that remains uncultivated despite numerous attempts since its discovery in 1975. A major challenge is to account for the highly dynamic microenvironmental conditions experienced by in hospite, where light-dark cycles drive rapid shifts between hyperoxia and anoxia as well as pH variations from pH ~6 to ~10. Recently, work on patellamide analogues has pointed out a range of different catalytic functions of patellamide that could prove essential for the ascidian- symbiosis and could be modulated by the strong microenvironmental dynamics. Here, we review fundamental properties of patellamides and their occurrence and dynamics in vitro and in vivo. We discuss possible functions of patellamides in the ascidian- symbiosis and identify important knowledge gaps and needs for further experimental studies.
Topics: Animals; Humans; Hydrogen-Ion Concentration; Peptides, Cyclic; Prochloron; Symbiosis; Urochordata
PubMed: 35200648
DOI: 10.3390/md20020119