mTOR inhibition in COVID‐19: A commentary and review of efficacy in RNA viruses

In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We discuss the current literature on mTOR in SARS-CoV-2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019

Necdin Protects Embryonic Motoneurons from Programmed Cell Death

NECDIN belongs to the type II Melanoma Associated Antigen Gene Expression gene family and is located in the Prader-Willi Syndrome (PWS) critical region. Necdin-deficient mice develop symptoms of PWS, including a sensory and motor deficit. However, the mechanisms underlying the motor deficit remain elusive. Here, we show that the genetic ablation of Necdin, whose expression is restricted to post-mitotic neurons in the spinal cord during development, leads to a loss of 31% of specified motoneurons. The increased neuronal loss occurs during the period of naturally-occurring cell death and is not confined to specific pools of motoneurons. To better understand the role of Necdin during the period of programmed cell death of motoneurons we used embryonic spinal cord explants and primary motoneuron cultures from Necdin-deficient mice. Interestingly, while Necdin-deficient motoneurons present the same survival response to neurotrophic factors, we demonstrate that deletion of Necdin leads to an increased susceptibility of motoneurons to neurotrophic factor deprivation. We show that by neutralizing TNFα this increased susceptibility of Necdin-deficient motoneurons to trophic factor deprivation can be reduced to the normal level. We propose that Necdin is implicated through the TNF-receptor 1 pathway in the developmental death of motoneurons

Transcriptomic analysis of a marine bacterial community enriched with dimethylsulfoniopropionate

11 páginas, 4 figuras.Dimethylsulfoniopropionate (DMSP) is an important source of reduced sulfur and carbon for marine microbial communities, as well as the precursor of the climate-active gas dimethylsulfide (DMS). In this study, we used metatranscriptomic sequencing to analyze gene expression profiles of a bacterial assemblage from surface waters at the Bermuda Atlantic Time-series Study (BATS) station with and without a short-term enrichment of DMSP (25 nm for 30 min). An average of 303 143 reads were obtained per treatment using 454 pyrosequencing technology, of which 51% were potential protein-encoding sequences. Transcripts from Gammaproteobacteria and Bacteroidetes increased in relative abundance on DMSP addition, yet there was little change in the contribution of two bacterioplankton groups whose cultured members harbor known DMSP degradation genes, Roseobacter and SAR11. The DMSP addition led to an enrichment of transcripts supporting heterotrophic activity, and a depletion of those encoding light-related energy generation. Genes for the degradation of C3 compounds were significantly overrepresented after DMSP addition, likely reflecting the metabolism of the C3 component of DMSP. Mapping these transcripts to known biochemical pathways indicated that both acetyl-CoA and succinyl-CoA may be common entry points of this moiety into the tricarboxylic acid cycle. In a short time frame (30 min) in the extremely oligotrophic Sargasso Sea, different gene expression patterns suggest the use of DMSP by a diversity of marine bacterioplankton as both carbon and sulfur sources.This study was funded by a Marie Curie Fellowship (to MVC), the Gordon and Betty Moore Foundation, and the National Science Foundation (OCE0724017 to MAM and OCE0425166 to J Dacey and D Toole)Peer reviewe

Abstract A18: Targeting the MNK kinases for the treatment of NF1-mutant cancers

Abstract NF1 mutant cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While MEK inhibitors promote regression of NF1-deficient premalignant lesions, they are ineffective in advanced cancers. Our lab and others have shown that the addition of a PI3K/AKT/mTORC1 inhibitor can co-operate with MEK inhibition to elicit tumor regression in pre-clinical Ras-driven tumor models; however, one concern is that these combinations might not be tolerated in the clinic due to toxicity. Therefore our goal has been to identify more refined, cancer-specific signaling nodes within these pathways. Here we find that eIF4E, a key downstream effector of mTORC1, is constitutively phosphorylated by the MAP kinase-interacting kinases (MNK1 and 2) in NF1 mutant malignant peripheral nerve sheath tumors (MPNSTs). Moreover, we find that combined genetic or chemical suppression of MNK kinases can cooperate with MEK inhibition to reduce cell viability to a similar extent as broad mTOR inhibition. Surprisingly, we find that the MNK kinases are important, previously unrecognized direct targets of the receptor tyrosine kinase inhibitor cabozantinib. Furthermore, we find that cabozantinib but not a more selective MET inhibitor kills NF1-deficient tumor cells when combined with MEK inhibition, and does so in part via eIF4E phosphorylation inhibition. Finally, we show that combining cabozantinib and MEK inhibitors triggers dramatic tumor regression in an aggressive genetically engineered mouse model of MPNSTs. Together, these results identify MNK/eIF4E as a targetable signaling axis when combined with MEK inhibition in these Ras-driven tumors and highlight the utility of both drug repurposing and developing more specific MNK inhibitors for these and other malignancies. Citation Format: Rebecca Lock, Rachel Ingraham, Ophélia Maertens, Bruce Konicek, Sau-chi Yan, Jeremy Graff, Karen Cichowski. Targeting the MNK kinases for the treatment of NF1-mutant cancers. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A18.</jats:p

Opposing effects of acute and repeated nicotine exposure on boldness in zebrafish

AbstractNicotine is an addictive compound that activates neuronal nicotinic acetylcholine receptors (nAChRs) and causes behavioural effects that vary with dose, schedule of administration, and animal model. In zebrafish (Danio rerio), acute doses of nicotine have been consistently found to have anxiolytic properties, whereas, chronic exposure elicits anxiogenic effects. To date, however, studies on repeated nicotine administration and the effects of nicotine withdrawal have not been well explored using this model. In this study, we administered nicotine with three different dosing regimens: 1. Single exposures of a “high” dose (25, 50, 100, or 400 mg/L) for 3 minutes. 2. Single exposures to a “low” dose (2.5, 5, or 20 mg/L) for one hour. 3. Repeated one-hour exposure to a “low” dose (2.5, 5, or 20 mg/L) for 21 days. The novel object approach test was used to examine boldness based on the tendency of the fish to explore a novel object. Acutely, nicotine significantly increased the time spent approaching the object with both three-minute and onehour durations of exposure, indicating increased boldness. Conversely, after repeated nicotine exposure for 21 days, fish spent less time approaching the object suggesting a decrease in boldness. Distance moved was unaffected one hour after repeated nicotine exposure, yet decreased after a two-day withdrawal period. Our work suggests that nicotine can have opposing effects on boldness that vary based on dosage and schedule of exposure.</jats:p

Supplementary Table 1 from Defining Key Signaling Nodes and Therapeutic Biomarkers in <i>NF1</i>-Mutant Cancers

PDF file - 75KB, Reported in vitro isoform specificities of PI3K inhibitors. The IC50 (nM) reported in the literature for each PI3K inhibitor against Class IA catalytic isoforms in in vitro binding assays is shown. The source for each data set is listed. A66-(S) is termed a p110alphaspecific inhibitor, AZD-6482 is classified as a p110beta-specific inhibitor, and CAL-101 shows selectivity for p110delta. GDC-0941 does not show significant isoform selectivity.</p

Supplementary Figure 1 from Defining Key Signaling Nodes and Therapeutic Biomarkers in <i>NF1</i>-Mutant Cancers

PDF file - 47KB, Supplementary Figure 1 shows that AKT inhibition does not slow proliferation in a human MPNST cell line.</p

Supplementary Figure Legends from Defining Key Signaling Nodes and Therapeutic Biomarkers in <i>NF1</i>-Mutant Cancers

PDF file - 58KB</p