Rewiring T-cell responses to soluble factors with chimeric antigen receptors

January 29th, 2018 by ZeNan L Chang

Rewiring T-cell responses to soluble factors with chimeric antigen receptors

Rewiring T-cell responses to soluble factors with chimeric antigen receptors, Published online: 29 January 2018; doi:10.1038/nchembio.2565

Chimeric antigen receptor (CAR)-expressing T cells were engineered to recognize soluble protein ligands that, by inducing CAR dimerization, mechanically couple ligand binding and receptor signaling to produce immune effector molecules.
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Lytic xylan oxidases from wood-decay fungi unlock biomass degradation

January 29th, 2018 by Marie Couturier

Lytic xylan oxidases from wood-decay fungi unlock biomass degradation

Lytic xylan oxidases from wood-decay fungi unlock biomass degradation, Published online: 29 January 2018; doi:10.1038/nchembio.2558

A new type of fungal lytic polysaccharide monooxygenase (LPMO) catalyzes the oxidative degradation of xylan components of cellulosic biomass and offers potential in wood biorefining.
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Genetically Encoded Circuit for Remote Regulation of Cell Migration by Magnetic Fields

January 26th, 2018 by Abdullah A. Mosabbir and Kevin Truong

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.7b00415

Stringency of Synthetic Promoter Sequences in Clostridium Revealed and Circumvented by Tuning Promoter Library Mutation Rates

January 26th, 2018 by Paweł M. Mordaka and John T. Heap

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.7b00398
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Leptin enhances hypothalamic LDHA-dependent glucose sensing to lower glucose production in high-fat fed rats. [Metabolism]

January 26th, 2018 by Mona A. Abraham, Mozhgan Rasti, Paige V. Bauer, Tony K.T. Lam

The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo. In both rodents and humans, glucose sensing is lost in diabetes and obesity but the site(s) of impairment remain elusive. We here first report that short-term high-fat feeding dirsupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral-LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high-fat fed rats. In summary, our findings illustrate that leptin enhances LDH-A-dependent glucose sesning in the hypothalamus to lower glucose production in high-fat fed rodents in vivo.

The cytochrome P450 24A1 interaction with adrenodoxin relies on multiple recognition sites that vary among species [Molecular Biophysics]

January 25th, 2018 by D. Fernando Estrada

Mitochondrial cytochromes P450 (P450s) are responsible for important metabolic reactions, including steps involved in steroid and vitamin D metabolism. The mitochondrial P450 24A1 (CYP24A1) is responsible for deactivation of the bioactive form of vitamin D, 1,25(OH)2D3. Its function relies on formation of a P450–redox partner complex with the ferredoxin and electron donor adrenodoxin (Adx). However, very little is known about how the Adx–CYP24A1 complex forms. In this study, we report the results of solution NMR in which we monitor isotopically labeled full-length Adx as it binds CYP24A1 in complex with the P450 inhibitor clotrimazole. The NMR titration data suggested a mode for P450–Adx interactions in which formation of the complex relies on contributions from multiple recognition sites on the Adx core domain, some of which have not previously been reported. To evaluate differences among CYP24A1­–Adx complexes from different mammalian species and displaying distinct regioselectivity for 1,25(OH)2D3, all bound spectra were acquired in parallel for human (carbon-23 and -24 hydroxylase), rat (carbon-24 hydroxylase), and opossum (carbon-23 hydroxylase) CYP24A1 isoforms. Binding data from a series of single and double charge–neutralizing substitutions of Adx confirmed that species-specific CYP24A1 isoforms differ in binding to Adx, providing evidence that variations in redox partner interactions correlate with P450 regioselectivity. In summary, these findings reveal that CYP24A1-Adx interactions rely on several recognition sites and that variations in CYP24A1 isoforms modulate formation of the complex, thus providing insight into the variable and complex nature of mitochondrial P450-Adx interactions.

Transcriptional and post-transcriptional regulation of autophagy in the yeast Saccharomyces cerevisiae [Cell Biology]

January 25th, 2018 by Elizabeth Delorme-Axford, Daniel J. Klionsky

Autophagy is a highly conserved catabolic pathway that is vital for development, cell survival and the degradation of dysfunctional organelles and toxic aggregates. Dysregulation of autophagy is associated with cancer, neurodegeneration and lysosomal storage diseases. Accordingly, autophagy is precisely regulated at multiple levels (transcriptional, post-transcriptional, epigenetic, translational and post-translational) to prevent aberrant activity. Various model organisms exist to study autophagy but the baker's yeast Saccharomyces cerevisiae continues to be very advantageous for genetic and biochemical analysis of non-selective and selective autophagy. In this review, we focus on the cellular mechanisms that regulate autophagy transcriptionally and post-transcriptionally in S. cerevisiae.

A Molecular Perspective of Mammalian Autophagosome Biogenesis [Membrane Biology]

January 25th, 2018 by Thomas J. Mercer, Andrea Gubas, Sharon A. Tooze

Autophagy is a highly conserved process, essential for the maintenance of cellular homeostasis. Autophagy occurs at a basal level in all cells, but can be upregulated during stress, starvation, or infection. Misregulation of autophagy has been linked to various disorders, including cancer, neurodegeneration and immune diseases. Here, we discuss the essential proteins acting in the formation of an autophagosome, with a focus on the ULK and VPS34 kinase complexes, PI3P effector proteins and the transmembrane autophagy-related protein ATG9. The function and regulation of these and other autophagy-related proteins, acting during formation will be addressed, in particular, during amino acid starvation.

Analyzing and Tuning Ribozyme Activity by Deep Sequencing To Modulate Gene Expression Level in Mammalian Cells

January 24th, 2018 by Shungo Kobori and Yohei Yokobayashi

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ACS Synthetic Biology
DOI: 10.1021/acssynbio.7b00367
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A whole-animal platform to advance a clinical kinase inhibitor into new disease space

January 22nd, 2018 by Masahiro Sonoshita

A whole-animal platform to advance a clinical kinase inhibitor into new disease space

A whole-animal platform to advance a clinical kinase inhibitor into new disease space, Published online: 22 January 2018; doi:10.1038/nchembio.2556

Combining Drosophila genetics with chemistry and computation led to the development of novel kinase inhibitors based on the RAF-targeting drug sorafenib that reveal the RET oncogene as an enhancer of drug action and improve the therapeutic window in medullary thyroid carcinoma models.
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