A computational framework to explore large-scale biosynthetic diversity

November 25th, 2019 by Jorge C. Navarro-Muñoz

Nature Chemical Biology, Published online: 25 November 2019; doi:10.1038/s41589-019-0400-9

Two bioinformatic tools, BiG-SCAPE and CORASON, enable sequence similarity network and phylogenetic analysis of gene clusters and their families across hundreds of strains and in large datasets, leading to the discovery of new natural products.
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[ASAP] Unravelling the Biosynthetic Flexibility of UK-2A Enables Enzymatic Synthesis of Its Structural Variants

November 25th, 2019 by

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.9b00387
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[ASAP] Enhanced Population Control in a Synthetic Bacterial Consortium by Interconnected Carbon Cross-Feeding

November 25th, 2019 by Pauli S. Losoi*, Ville P. Santala, and Suvi M. Santala

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.9b00316
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Influenza A virus-induced host caspase and viral PA-X antagonise the antiviral host factor, histone deacetylase 4 [Microbiology]

November 22nd, 2019 by Henry D Galvin, Matloob Husain

Influenza A virus (IAV) effectively manipulates host machinery to replicate. There is a growing evidence that an optimal acetylation environment in the host cell is favourable to IAV proliferation and vice versa. The histone deacetylases (HDACs) – a family of 18 host enzymes classified into four classes, are central to negatively regulating the acetylation level, hence the HDACs would not be favourable to IAV. Indeed, by using the RNA interference and overexpression strategies, we found that human HDAC4 – a class II member, possesses anti-IAV properties and is a component of host innate antiviral response. We discovered that IAV multiplication was augmented in HDAC4-depleted cells and abated in HDAC4-supplemented cells. Likewise, the expression of IFITM3, ISG15, and viperin – some of the critical markers of host anti-IAV response was abated in HDAC4-depleted cells and augmented in HDAC4-supplemented cells. In turn, IAV strongly antagonises the HDAC4, by downregulating its expression both at mRNA level via viral RNA endonuclease PA-X and at polypeptide level by inducing its cleavage via host caspase 3 in infected cells. Such HDAC4 polypeptide cleavage resulted in a ~30 kDa fragment which is also observed in some heterologous systems and may have a significant role in IAV replication.

[ASAP] Measurement of Net Rate Constants from Enzyme Progress Curves without Curve Fitting

November 22nd, 2019 by Mark W. Ruszczycky*† and Hung-wen Liu†‡

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Biochemistry
DOI: 10.1021/acs.biochem.9b00762

[ASAP] Discovery of Influenza Polymerase PA–PB1 Interaction Inhibitors Using an <italic toggle=”yes”>In Vitro</italic> Split-Luciferase Complementation-Based Assay

November 21st, 2019 by Jiantao Zhang, Yanmei Hu, Nan Wu, and Jun Wang*

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ACS Chemical Biology
DOI: 10.1021/acschembio.9b00552
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A proteolytic C-terminal fragment of Nogo-A (reticulon-4A) is released in exosomes and potently inhibits axon regeneration [Cell Biology]

November 20th, 2019 by Yuichi Sekine, Jane A. Lindborg, Stephen M. Strittmatter

Glial signals are known to inhibit axonal regeneration and functional recovery after mammalian central nervous system (CNS) trauma, including spinal cord injury. Such signals include membrane-associated proteins of the oligodendrocyte plasma membrane and astrocyte-derived matrix-associated proteins. Here, using cell lines and primary cortical neuron cultures, recombinant protein expression, immunoprecipitation and immunoblotting assays, transmission EM of exosomes, and axon-regeneration assays, we explored the secretion and activity of the myelin-associated, neurite outgrowth inhibitor Nogo-A and observed exosomal release of a 24-kDa, C-terminal Nogo-A fragment from cultured cells. We found that the cleavage site in this 1192-amino-acid-long fragment is located between amino acids 961–971. We also detected a Nogo-66 receptor (NgR1)-interacting Nogo-66 domain on the exosome surface. Enzyme inhibitor treatment and siRNA knockdown revealed that β-secretase 1 (BACE1) is the protease responsible for the Nogo-A cleavage. Functionally, exosomes with the Nogo-66 domain on their surface potently inhibited axonal regeneration of mechanically injured cerebral cortex neurons from mice. The production of this fragment was observed in the exosomal fraction from neuronal tissue lysates after spinal cord crush injury of mice. We also noted that relative to the exosomal marker Alix, a Nogo-immunoreactive 24-kDa protein is enriched in exosomes two-fold after injury. We conclude that membrane-associated Nogo-A produced in oligodendrocytes is processed proteolytically by BACE1, is released via exosomes, and represents a potent diffusible inhibitor of regenerative growth in NgR1-expressing axons.

Axonal dispatch of iron in neuronal signaling

November 18th, 2019 by Peng Lei

Nature Chemical Biology, Published online: 18 November 2019; doi:10.1038/s41589-019-0394-3

The regulation of brain iron homeostasis, previously thought to be cell autonomous and modulated by local factors in the interstitial fluid, is reported by Wang et al. to be strongly influenced by axonal transport of iron in an activity-dependent and unidirectional manner between functionally associated regions. The supply of iron from the ventral hippocampus to the middle prefrontal cortex subserved an anxiolytic phenotype and mediated the neuropharmacological actions of diazepam and lithium chloride in rodent models.

Choosing a mating site

November 18th, 2019 by Mirella Bucci

Nature Chemical Biology, Published online: 18 November 2019; doi:10.1038/s41589-019-0418-z

Choosing a mating site

Iodine goes viral

November 18th, 2019 by Caitlin Deane

Nature Chemical Biology, Published online: 18 November 2019; doi:10.1038/s41589-019-0416-1

Iodine goes viral