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© 2020 American Association of Neuropathologists, Inc.Isoprenoids constitute the largest class of plant natural products and have diverse biological functions including in plant growth and development. In potato (Solanum tuberosum), the regulatory mechanism underlying the biosynthesis of isoprenoids through the mevalonate pathway is unclear. VY3135 We assessed the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) homologues in potato development and in the metabolic regulation of isoprenoid biosynthesis by generating transgenic lines with downregulated expression (RNAi-hmgr) or overexpression (OE) of one (StHMGR1 or StHMGR3) or two genes, HMGR and farnesyl diphosphate synthase (FPS; StHMGR1/StFPS1 or StHMGR3/StFPS1). Levels of sterols, steroidal glycoalkaloids (SGAs) and plastidial isoprenoids were elevated in the OE-HMGR1, OE-HMGR1/FPS1 and OE-HMGR3/FPS1 lines, and these plants exhibited early flowering, increased stem height, increased biomass and increased total tuber weight. However, OE-HMGR3 lines showed dwarfism and had the highest sterol amounts, but without an increase in SGA levels, supporting a rate-limiting role of HMGR3 in the accumulation of sterols. Potato RNAi-hmgr lines showed inhibited growth and reduced cytosolic isoprenoid levels. We also determined the relative importance of transcriptional control at regulatory points of isoprenoid precursor biosynthesis by assessing gene-to-metabolite correlations. These findings provide novel insights into specific end-products of the sterol pathway and could be important for crop yield and bioenergy crops. Published by Oxford University Press on behalf of the Society for Experimental Biology 2020.BACKGROUND Imagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although PDGF-AA overexpression may be an early event, critical details of the core biology of GBM are lacking. For example, existing PDGF-driven models replicate its microscopic appearance, but not its genomic architecture. Here we report a model that overcomes this barrier to authenticity. METHODS Using a method developed to establish neural stem cell cultures, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, one of the putative cells of origin of GBM. We micro-dissected SVZ tissue from p53-null and wild-type adult mice, cultured cells in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumorigenicity. RESULTS Counterintuitive to its canonical role as a growth factor, we observed abrupt and massive cell death in PDGF-AA wild-type cells did not survive, whereas a small fraction of null cells evaded apoptosis. Surviving null cells displayed attenuated proliferation accompanied by whole chromosome gains and losses. After approximately 100 days in PDGF-AA, cells suddenly proliferated rapidly, acquired growth factor independence, and became tumorigenic in immune-competent mice. Transformed cells had an oligodendrocyte precursor-like lineage marker profile, were resistant to PDGFR-α inhibition, and harbored highly abnormal karyotypes similar to human GBM. CONCLUSION This model associates genome instability in neural progenitor cells with chronic exposure to PDGF-AA, is the first to approximate the genomic landscape of human GBM, and the first in which the earliest phases of the disease can be studied directly. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.BACKGROUND Normal weight obesity (NWO), defined by a normal body mass index (BMI) but increased body fat percentage (BF%), is associated with an increased risk of cardiovascular disease and mortality. NWO is characterized by inflammation and muscle wasting in chronic kidney disease (CKD), but the underlying mechanisms remain largely unknown. Gut microbiota has been implicated in the regulation of host metabolism and may play important roles in the development of NWO in CKD. METHODS In this case-control study, we examined the gut microbial diversity and taxonomy in 96 hemodialysis patients with normal weight (BMI  35% for women; n = 32), and overweight/obesity (BMI ≥ 25 kg/m2; n = 32), matched for age, gender, and diabetes. BF% was measured using bioimpedance spectroscopy device. Gut microbiota was determined by 16S rRNA sequencing. RESULTS We found that α-diversity was significantly different among the 3 adiposity phenotypes, with NWO being the least diverse. α-diversity was positively correlated with BMI, subjective global assessment score, and physical activity, but negatively correlated with interleukin-6 and tumor necrosis factor-α. Patients with or without NWO were distinguished with respect to principal coordinate analysis of β-diversity. Notably, the relative abundance of butyrate-producing bacteria, such as Faecalibacterium prausnitzii and Coprococcus, was markedly reduced in patients with NWO. CONCLUSION Our findings support associations between gut dysbiosis and a proinflammatory and catabolic state in hemodialysis patients with NWO. © Endocrine Society 2020. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Public health preparedness for coronavirus disease 2019 (COVID-19) is challenging in the absence of setting-specific epidemiological data. Here we describe the epidemiology of seasonal coronaviruses (sCoVs) and other cocirculating viruses in the West of Scotland, UK. We analyzed routine diagnostic data for >70,000 episodes of respiratory illness tested molecularly for multiple respiratory viruses between 2005 and 2017. Statistical associations with patient age and sex differed between CoV-229E, CoV-OC43 and CoV-NL63. Furthermore, the timing and magnitude of sCoV outbreaks did not occur concurrently and coinfections were not reported. With respect to other cocirculating respiratory viruses, we found evidence of positive, rather than negative, interactions with sCoVs. These findings highlight the importance of considering cocirculating viruses in the differential diagnosis of COVID-19. Further work is needed to establish the occurrence/degree of cross-protective immunity conferred across sCoVs and with COVID-19, as well as the role of viral coinfection in COVID-19 disease severity. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.BACKGROUND AND AIMS The stomatal conductance (gs) of most plant species decreases in response to elevated atmospheric CO2 concentration. This response could have a significant impact on plant water use in a future climate. However, the regulation of the CO2-induced stomatal closure response is not fully understood. Moreover, the potential genetic links between short-term (within minutes-hours) and long-term (within weeks-months) responses of gs to increased atmospheric CO2 have not been explored. METHODS We used A. thaliana recombinant inbred lines originating from accessions Col-0 (strong CO2 response) and C24 (weak CO2 response) to study short-and long-term controls of gs. Quantitative trait locus (QTL) mapping was used to identify loci controlling short- and long-term gs responses to elevated CO2, as well as other stomata-related traits. KEY RESULTS Short- and long-term stomatal responses to elevated CO2 were significantly correlated. Both short- and long-term responses were associated with a major QTL at the end of chromosome 2. The location of this QTL was confirmed using near isogenic lines and it was fine mapped to a 410 kb region. The QTL did not correspond to any known gene involved in stomatal closure and had no effect on the responsiveness to ABA. Additionally, we identified numerous other loci associated with stomatal regulation. CONCLUSIONS We identified and confirmed the effect of a strong QTL corresponding to a yet unknown regulator of stomatal closure in response to elevated CO2 concentration. The correlation between short- and long-term stomatal CO2 responses and the genetic link between these traits highlight the importance of understanding guard cell CO2 signalling to predict and manipulate plant water use in a world with increasing atmospheric CO2 concentration. This study demonstrates the power of using natural variation to unravel the genetic regulation of complex traits. © The Author(s) 2020. Published by Oxford University Press on behalf of the Annals of Botany Company.Vasculogenic mimicry (VM), a newly defined pattern of tumor blood supply, has been identified in several malignant tumors, including hepatocellular carcinoma (HCC). Rho kinase (ROCK) plays an important role in various types of cancers. However, whether ROCK participates in transforming growth factor-β1 (TGF-β1)-induced VM formation is unclear. Here, we evaluated the role of ROCK in TGF-β1-induced VM formation in HCC. Our findings showed that the TGF-β1/ROCK signaling pathway is involved in VM formation by inducing the epithelial-mesenchymal transition. Furthermore, TGF-β1 and ROCK were found to play distinct roles in the cancer stem cell phenotype during VM formation. These results provide insights into potential antitumor therapies for inhibiting VM by targeting the TGF-β1/ROCK signaling pathway in HCC. © The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.To facilitate investigations of protein-protein interactions (PPIs), we developed a novel platform for quantitative mapping of protein binding specificity landscapes, which combines multi-target screening of a mutagenesis library into high- and low-affinity populations with sophisticated next-generation sequencing analysis. Importantly, this method generates accurate models to predict affinity and specificity values for any mutation within a protein complex, and requires only a small number of experimental binding affinity measurements using purified proteins for calibration. We demonstrated the utility of the approach by mapping quantitative landscapes for interactions between the N-terminal domain of the tissue inhibitor of metalloproteinase 2 (N-TIMP2) and three matrix metalloproteinases (MMPs) having homologous structures but different affinities (MMP-1, MMP-3 and MMP-14). The binding landscapes for N-TIMP2/MMP-1 and N-TIMP2/MMP-3 showed the PPIs to be almost fully optimized, with most single mutations giving a loss of affinity. In contrast, the non-optimized PPI for N‑TIMP2/MMP-14 was reflected in a wide range of binding affinities, where single mutations exhibited a far more attenuated effect on the PPI. Our new platform reliably and comprehensively identified not only hot- and cold-spot residues, but also specificity-switch mutations that shape target affinity and specificity. Thus, our approach provides a methodology giving an unprecedentedly rich quantitative analysis of the binding specificity landscape, which will broaden the understanding of the mechanisms and evolutionary origins of specific PPIs and facilitate the rational design of specific inhibitors for structurally similar target proteins. Copyright 2020 The Author(s).