Peelekirkpatrick8226

© 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. Vismodegib Stem Cells inhibitor 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).BACKGROUND HIV infection leads to blood-brain barrier (BBB) dysfunction that does not resolve despite viral suppression on antiretroviral therapy and is associated with adverse clinical outcomes. In preclinical models, cannabis restores BBB integrity. METHODS We studied people with HIV (PWH) and HIV- individuals who had used cannabis recently. We assessed two biomarkers of BBB permeability the cerebrospinal fluid [CSF]-to-serum albumin ratio [CSAR], and CSF levels of soluble urokinase plasminogen activator receptor [suPAR], a receptor for uPA, a matrix-degrading proteolytic enzyme that disrupts the BBB. A composite index of the BBB markers was created using principal components analysis. Neural injury was assessed using neurofilament light (NFL) in CSF by immunoassay. RESULTS Participants were 45 PWH and 30 HIV- individuals of similar age and ethnicity. Among PWH, higher CSF suPAR levels correlated with higher CSAR values (r=0.47; p less then 0.001). PWH had higher (more abnormal) BBB index values than HIV- individuals (mean +/- SD 0.361 +/-1.20 versus -0.501 +/- 1.11; p=0.0214). HIV serostatus interacted with cannabis use frequency such that more frequent use of cannabis was associated with lower BBB index values in PWH but not in HIV-. Worse BBB Index values was associated with higher NFL in CSF (r=0.380, p=0.0169). CONCLUSIONS Cannabis may have a beneficial impact on HIV-associated BBB injury. Since BBB disruption may permit increased entry of toxins such as microbial antigens and inflammatory mediators, with consequent CNS injury, these results support a potential therapeutic role of cannabis among PWH and may have important treatment implications for ART effectiveness and toxicity. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.