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cell O-1663 Id1 expression is proliferation, CBD than more inhibiting active at invasion and



  • cell O-1663 Id1 expression is proliferation, CBD than more inhibiting active at invasion and
  • US9254272B2 - Resorcinol derivatives - Google Patents
  • Cannabinoids, Education
  • Table S1 CBD inhibits Id1 expression in lung metastatic foci. .. O is more active than CBD at inhibiting cell proliferation, invasion and Id1 expression. CBD was able to inhibit Id-1 expression at the mRNA and protein USA) through the National Institute of Drug Abuse, and O was obtained from Organix, Inc. . cancer metastasis that CBD was more potent than THC at inhibiting . CBD inhibits cell proliferation and invasion of 4T1 cells (mammary. A61K31/00 Medicinal preparations containing organic active ingredients 3A- C provides data indicating that CBD inhibits the expression of Id-1 gene at .. O- CBD analog is more potent than CBD at inhibiting cancer cell growth and The percentage relative proliferation/viability and invasion were calculated as.

    cell O-1663 Id1 expression is proliferation, CBD than more inhibiting active at invasion and

    While CBD has been shown to inhibit breast cancer metastasis in vivo , a detailed pharmacological analysis to determine potency and efficacy has not been performed. Utilizing the 4T1 i. The potency of CBD at targeting metastasis in the i. CBD was also effective at reducing metastatic progression in an orthotopic model utilizing 4T1 cells Supporting Information Fig. S2A—C even when the drug was administered three times a week as opposed to daily, but the cannabinoid did not inhibit primary tumour growth.

    In both the i. Since orthotopic models suffer from significant variability and CBD did not inhibit primary tumour growth, we continued our investigations into the anti-metastatic activity of CBD using the i.

    In the culture, the ability of CBD to inhibit breast cancer aggressiveness is the direct result of down-regulation of Id1 expression McAllister et al. To determine whether the anti-metastatic activity of CBD was directly related to the down-regulation of Id1 in vivo , we first determined whether CBD down-regulated Id1 gene expression in the tumour tissue.

    We have previously shown that CBD does not inhibit Id1 expression and invasion in these cells in the culture McAllister et al. Inhibition of Id1 expression in vivo is necessary for the anti-metastatic activity of CBD.

    A Immunohistochemical detection of Id1 and Ki67 was performed in lung tissues of vehicle left and CBD right treated 4T1-derived tumours. Nuclei are visible in blue haematoxylin staining. B The intensity of Id1 expression is shown. C The percentage of Ki67 positive cells per lung metastatic foci was evaluated. Two days after the injection, the tumour bearing mice were injected i. We found that CBD dose-dependently reduced the growth of established lung metastatic foci, reduced the formation of new metastatic foci and increased survival Figure 2B—D.

    Based upon these findings, we expected that synthesis of more active analogues based upon CBD would result in the development of a compound that could produce more robust inhibition of advanced stages of metastasis. CBD reduces the formation of metastatic foci and increases survival in advanced stages of metastatic progression. A The pictures are representative of tumour formation observed at days 5, 7 and 9.

    B Seven days after the injection of tumour cells, mice were injected i. Our past studies McAllister et al. S4A and B suggested the unique activity inhibition of Id1 gene expression of CBD was related to the opened pyran ring, the possession of an extended alkyl side chain and was not due to interactions with the abnormal CBD receptor. While selective activation of CB 2 receptors leads to anti-tumour activity Blazquez et al. We reasoned however that a CB 2 selective cannabinoid agonist, having limited activity at CB 1 receptors psychoactivity , could be developed to target Id1, resulting in a single compound that could efficiently target multiple pathways associated with cannabinoid activity leading to enhanced anti-tumour activity.

    Experiments were carried out as previously described McAllister et al. Data represent the mean with corresponding confidence limits for three to six independent determinations. O was previously synthesized in a series of bicyclic resorcinol derivatives that resembled CBD Supporting Information Fig. S4A Wiley et al. It has been previously shown to have lower affinity for CB 1 receptors compared with THC and produces little activity in the tetrad assay measure of psychoactivity in vivo Wiley et al.

    In all studies, the drugs were co-administered. The antago nist alone had no significant effects on cell viability Supporting Information Fig. The ability of the cells to migrate and invade in modified Boyden chambers was then determined. Id2 expression was also determined in 4T1 cells treated with vehicle control , 1. While no reversal of CBD activity was observed using the CB 2 receptor antagonist SR, it was able to partially reverse the inhibitory effects of O Id2 is a marker of good prognosis in breast cancer patients and is specifically up-regulated following inhibition of Id1 expression Itahana et al.

    S5C is a primary mechanism that leads to the inhibition of Id1 expression, cell growth, invasion and survival across multiple cancers Ligresti et al. D A representative example of the Western blot analysis for LC3 is shown. E The number of cells positive for annexin staining after 2 days treatment with 1. A primary mechanism for the anti-tumour activity of the mixed CB 1 and CB 2 receptor agonist THC and CB 2 selective agonists is the up-regulation of the autophagy pathway Velasco et al.

    We found that O was 2. Moreover, no overt toxicity was noted with O in the mouse models of metastasis as assessed by weight, appearance and general activity data not shown. O is more potent than CBD at inhibiting breast cancer metastasis. One day after the injection, the tumour-bearing mice were i. In agreement with our findings in the culture, the anti-metastatic activity of CBD was not affected by co-administration with SR SR2 , whereas the anti-metastatic activity of O was partially reversed by the antagonist.

    Seven days after i. O produces a significant inhibition of advanced stage breast metastasis. A, B One week after the injection of 4T1 cells, the tumour-bearing mice were injected i.

    Indicates where one animal responding well to treatment with O based on BLI was removed in order to stain and visualize lung metastatic foci. We next utilized MDA-MBluc-D3H2LN cells in order to determine whether O would produce robust anti-metastatic activity against a human breast cancer cell line in advanced stages of disease progression. This variant is significantly more aggressive than the parental line with a rapid disease progression with a time course more closely resembling the 4T1 model.

    Additionally, the expression of luciferase allowed us to assess the activity of the drug treatments longitudinally in real time using BLI and to demonstrate that metastases were present in the lung when the treatment was initiated. This cell line was therefore significantly less sensitive to the effects of CBD but not O While regression did occur beyond the initial size of the tumour in some mice, the tumour did adapt over time and began to progress again.

    One mouse, where the tumour was regressing in the lung, was removed from the study to confirm the imaging results by visualizing the lung using an India ink stain and a dissecting microscope Supporting Information Fig.

    We therefore initiated treatment with CBD 2 days after mice were i. While CBD inhibited disease progression in a subset of the mice, overall survival was not significantly improved Supporting Information Fig. CBD has been reported to have a wide variety of therapeutic indications and has been shown to be non-toxic, safe and well-tolerated in clinical trials Zuardi, One of the most exciting recent areas of study for the therapeutic application of CBD resides in its ability to decrease cancer cell invasion and metastasis Ligresti et al.

    In this investigation, we determined that CBD was effective at inhibiting metastatic progression, leading to prolonged survival in multiple preclinical models of breast cancer. Id1 has been shown to play a key role in mediating breast cancer tumourigenicity and metastasis to the lung Fong et al. We previously reported that CBD could down-regulate Id1 gene expression in breast cancer cell lines in culture McAllister et al.

    Here, we demonstrated that treatment with CBD can also lead to the inhibition of Id1 gene expression and tumour cell proliferation in lung metastatic foci in a mouse model of breast cancer. In addition, ectopic expression of Id1 in breast cancer cells reversed the anti-metastatic activity of CBD.

    Overall, these data suggest that the anti-metastatic activity of CBD is directly related to the down-regulation of Id1 gene expression; Id1 therefore represents a potential biomarker for predicting whether CBD will be effective at inhibiting tumour progression.

    Additional mechanisms in vivo that have been implicated in the anti-metastatic activities of CBD include the up-regulation of intercellular adhesion molecule-1 and tissue inhibitor of matrix metalloproteinases-1 in lung cancer Ramer et al. In contrast to the moderate doses of CBD needed to inhibit metastatic progression, higher doses of CBD have been required to inhibit tumour growth after s.

    In our previous work, daily administration of CBD only produced a minor delay in primary tumour growth in a model where 4T1 cells where s. In the present manuscript, we observed no inhibition of primary tumour growth in the orthotopic model where the cells where injected into the MFP and when the mice were treated three times a week with CBD.

    Taken together, the ability of CBD to inhibit primary tumour growth at the doses evaluated in our current investigation is limited. The differences in the potency of CBD for targeting processes involved in cancer cell growth and survival versus invasion and metastasis may explain why the cannabinoid is less efficient at inhibiting primary tumour growth. We noted that, in both the orthotopic and the i. This led us to hypothesize that CBD could be effective at inhibiting the growth of secondary tumours even after their initial establishment in the lung.

    While CBD was effective at inhibiting metastatic progression even in more advanced stages of the disease, it was not efficacious enough to produce substantial increases in survival at this stage. We therefore underwent a screening strategy of cannabinoid analogues focused on inhibition of Id1, cell proliferation and invasion. We therefore further envisioned a cannabinoid analogue that could target Id1 and activate cannabinoid receptors.

    This effect can be reproduced using CB 2 selective agonists, which is an advantage since activation of CB 1 receptors leads to psychotropic effects Salazar et al. We hypothesized that targeting of Id1 expression and cannabinoids receptors with a single compound would result in an even more robust inhibition of advanced stages of metastasis. Screening a library of resorcinol derivatives, we discovered a cannabinoid analogue O that could activate CB 2 receptors and was more potent at inducing the formation of ROS and inhibiting Id1 expression in comparison to CBD.

    This activity was not related to the activation of CB 1 , CB 2 or vanilloid receptor 1 similar to the results reported previously in human breast cancer cells Ligresti et al. Taken together, these studies suggest the existence of a unique intracellular interaction site for CBD that regulates calcium homeostasis, leading to generation of ROS. This activity may be one of the initial events leading to the downstream anti-tumour activity of CBD. In addition to inhibiting Id1 expression, the resorcinol derivate O was also found to be an efficacious CB 2 selective agonist.

    The ability of O to inhibit breast cancer aggressiveness in the culture and in vivo was partially reversed by a CB 2 receptor antagonist. CBD did not efficiently activate autophagy and did not induce apoptosis in cell culture at concentrations that produce ROS and target Id1 gene expression. A recent study showed CBD increased autophagy-mediated cell death in breast cancer cells in the culture Shrivastava et al.

    However, the concentration of CBD used in the culture to produce this effect was significantly higher approximately three times than that needed to target Id1 gene expression in our investigations. CBD was also shown to be ineffective at inducing autophagy in vivo when targeting glioblastoma Torres et al. O was significantly more potent and efficacious than CBD in multiple preclinical models of breast cancer.

    O also produced a significant increase in survival in advanced stages of mouse and human breast cancer metastasis, and in certain instances, O produced regression of established metastatic foci. We propose that this is the result of efficiently targeting cannabinoid anti-tumour pathways that have been associated with the activity of both CBD and THC.

    In agreement with this hypothesis, the combined administration of CBD and THC produced a similar magnitude of anti-metastatic activity when compared with O alone. O, however, is significantly less potent than THC at targeting CB 1 receptors and demonstrated limited activity in in vivo assays that predict the potential psychotropic activity of cannabinoids Wiley et al.

    In addition to the direct anti-tumour activity of cannabinoids, the targeting of Id1 expression and autophagy has been shown to result in the enhanced the activity of first-line agents Hu et al. Similar to what was accomplished in this investigation using the Id1 gene as a target for CBD, if primary mechanisms for the beneficial effect of CBD in non-cancer-related diseases could be identified, then there is the potential to develop more potent analogues that retain the activity of THC and CBD.

    Overall, this study suggests that the use of cannabinoid compounds may represent a potential approach for the treatment of patients with metastatic breast cancer and provides a framework for the synthesis of additional novel cannabinoid analogues based on our lead compound. All authors have made substantial contributions to the conception and design of the study, or acquisition of data, or analysis and interpretation of data, or drafting of the manuscript.

    Figure S1 CBD produces a dose-dependent reduction of metastatic spread to the lung and increases survival. A One day after the injection, the tumour-bearing mice were injected i. National Center for Biotechnology Information , U. Journal List Br J Pharmacol v. Published online Sep 5. Mukkanti Amere 2 Organix, Inc. Ramesh Gujjar 2 Organix, Inc. Anu Mahadevan 2 Organix, Inc. Author information Article notes Copyright and License information Disclaimer.

    This article has been cited by other articles in PMC. Key Results CBD reduced breast cancer metastasis in advanced stages of the disease as the direct result of down-regulating the transcriptional regulator Id1. Conclusions and Implications O prolonged survival in advanced stages of breast cancer metastasis. Open in a separate window. Methods Cell culture and drugs All cell lines were cultured as we previously described McAllister et al.

    Mouse models of breast cancer For the in vivo studies, 6—8 week old female mice were used. Western blotting Western blotting was performed as previously described McAllister et al. Id proteins are helix-loop-helix transcription factors that regulate the proliferation and differentiation of cells from multiple tissues, including adipocytes. We screened mouse tissues for the expression of Id 1 and found that Id 1 protein is highly expressed in brown adipose tissue BAT and white adipose tissue WAT , suggesting a role for Id 1 in adipogenesis and cell metabolism.

    Serum levels of triglycerides Id 1 deficiency protected mice against age- and high-fat-diet-induced adiposity, insulin resistance, and hepatosteatosis. Our findings suggest that Id 1 plays a critical role in the regulation of energy homeostasis and could be a potential target in the treatment of insulin resistance and fatty liver disease.

    It has been shown that the up-regulation of ID 1 is correlated with poor prognosis and the resistance to chemotherapy of human cancers. However, the underlying molecular mechanism remains elusive. Here, we determined for the first time that up-regulating ID 1 upon etoposide activation was mediated through AP-1 binding sites within the ID 1 promoter and confirmed that ID 1 enhanced cell resistance to DNA damage-induced apoptosis in esophageal squamous cell carcinoma cells.

    More importantly, simultaneous high expression of ID 1 and c-Jun or c-Fos was correlated with poor survival in cancer patients. ID 1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Then, they may become addicted to the circuits.

    Id - 1 inhibitor of differentiation or DNA binding-1 has been positively associated with cell proliferation, cell cycle progression, and invasiveness during tumorigenesis. Midkine-A functions upstream of Id 2 a to regulate cell cycle kinetics in the developing vertebrate retina. Background Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish.

    Results The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth.

    Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id 2 a. Gene expression analysis shows Mdka regulates id 2 a expression, and co-injection of Mdka morpholinos and id 2 a mRNA rescues the Mdka loss-of-function phenotype. Conclusions These data show that in zebrafish, Mdka resides in a shared Id 2 a pathway to regulate cell cycle kinetics in retinal progenitors.

    This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins. Midkine is a small heparin binding growth factor expressed in numerous tissues during development. In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche.

    The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. These data show that in zebrafish, Mdka resides in a shared Id 2 a pathway to regulate cell cycle kinetics in retinal progenitors. However, it is not known if AMPK regulates other potency factors or regulates them before the blastocyst stage.

    The caudal-related homeodomain protein Cdx 2 is a regulatory gene for determining TSC, the earliest placental lineage in the preimplantation mouse embryo, but is expressed in the oocyte and in early cleavage stage embryos before TSC arise.

    We assayed the expression of putative potency-maintaining phosphorylated Cdx2 ser60 in the oocyte, two-cell stage embryo, blastocyst, and in TSC. We studied the loss of Cdx2 phospho ser60 expression induced by hyperosmolar stress and its underlying mechanisms. Hyperosmolar stress caused rapid loss of nuclear Cdx2 phospho ser60 and Id 2 in the two-cell stage embryo by 0. In the two-cell stage embryo and TSC hyperosmolar, stress caused AMPK-mediated loss of Cdx2 phospho ser60 as detected by immunofluorescence and immunoblot.

    Since AMPK mediates potency loss in embryos and stem cells it will be important to measure, test mechanisms for, and manage the AMPK function to optimize the stem cell and embryo quality in vitro and in vivo.

    The epithelial-mesenchymal transition EMT is a fundamental process that underlies development and cancer. These findings establish a novel function for Id 2 in regulating Snai1 that has significant implications for the regulation of epithelial gene expression.

    The transcription factor ID 2 is an important repressor of neural differentiation strongly implicated in nervous system cancers. Notably, the two miRNAs show an inverse correlation with ID 2 during neuroblastoma cell differentiation induced by retinoic acid. Overexpression of miR-9 and miR in neuroblastoma cells reduces proliferation and promotes differentiation, as it was shown to occur upon ID 2 inhibition.

    Conversely, an ID 2 mutant that cannot be targeted by either miRNA prevents retinoic acid-induced differentiation more efficient than wild-type ID 2.

    These findings reveal a new regulatory module involving two microRNAs upregulated during neural differentiation that directly target expression of the key differentiation inhibitor ID 2 , suggesting that its alteration may be involved in neural cancer development.

    A new module in neural differentiation control: Here we show that two miRNAs upregulated on differentiation of neuroblastoma cells--miR-9 and miRrestrain ID 2 expression by directly targeting the coding sequence and 3' untranslated region of the ID 2 encoding messenger RNA, respectively. Abstract Inhibitor of DNA binding Id 2 is a member of the helix-loop-helix HLH transcription factor family whose members play important roles in cell differentiation and proliferation.

    Id 2 has been linked to the development of cardiovascular diseases since thiazolidinediones, Disruption of alpha beta but not of gamma delta T cell development by overexpression of the helix-loop-helix protein Id 3 in committed T cell progenitors.

    Furthermore, Id 3 impedes expression of recombination activating genes and downregulates pre-Talpha mRNA. These observations suggest possible mechanisms by which Id 3 overexpression can differentially affect development of pre-T cells into TCRalpha beta and gamma delta cells.

    These cells had properties of both natural killer NK and pre-T cells. Inhibitor of differentiation or DNA binding Id - 1 is a helix-loop-helix protein that is over-expressed in many types of cancer including esophageal cancer. We found elevated expression of phosphorylated forms of Akt, glycogen synthase kinase 3beta and inhibitor of kappa B, as well as increased nuclear translocation of NFkappaB subunit p65 and NFkappaB DNA-binding activity, in esophageal cancer cells with stable ectopic Id - 1 expression.

    Treatment with tumor necrosis factor-alpha TNF-alpha elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFkappaB in the Id - 1 -over-expressing cells, compared with the vector control.

    Inactivation of Id - 1 may provide us with a novel strategy to improve the treatment and survival of patients with esophageal cancer. The enhancement of re-endothelialisation is a critical therapeutic option for repairing injured blood vessels.

    Endothelial progenitor cells EPCs are the major source of cells that participate in endothelium repair and contribute to re-endothelialisation by reducing neointima formation after vascular injury. Spleen-derived EPCs were cultured as previously described. Id 1 was presented at low levels in EPCs, and was rapidly up-regulated by stimulation with vascular endothelial growth factor. Id 2 leaves the chromatin of the E2F4—pcontrolled c-myc promoter during hepatocyte priming for liver regeneration.

    The Id inhibitor of DNA binding or inhibitor of differentiation helix—loop—helix proteins are involved in the regulation of cell growth, differentiation and cancer. The fact that the molecular mechanisms of liver regeneration are not completely understood prompted us to study the fate of Id 2 in proliferating liver.

    Id 2 increases in liver regeneration after partial hepatectomy, following the early induction of its gene. Co-immunoprecipitation shows that Id 2 forms a complex with E2F4, p and mSin3A in quiescent liver and all these components are present at the c-myc promoter as shown using ChIP chromatin immunoprecipitation. Moreover, as the G0—G1 transition progresses, Id 2 and HDAC again bind the c-myc promoter concomitantly with the repression of this gene.

    The time course of c-myc binding to the Id 2 promoter, as determined by ChIP assays is compatible with a role of the oncoprotein as a transcriptional inducer of Id 2 in liver regeneration.

    Immunohistochemical analysis shows that Id 2 also increases in proliferating hepatocytes after bile duct ligation. In this case, the pattern of Id 2 presence in the c-myc promoter parallels that found in regenerating liver.

    Our results may suggest a control role for Id 2 in hepatocyte priming, through a p dissociation-independent regulation of c-myc. High fat diet rescues disturbances to metabolic homeostasis and survival in the Id 2 null mouse in a sex-specific manner. Our previous studies have demonstrated that Id 2 null mice have altered expression of circadian genes involved in lipid metabolism, altered circadian feeding behavior, and sex-specific enhancement of insulin sensitivity and elevated glucose uptake in skeletal muscle and brown adipose tissue.

    In summary, these data provides valuable insights into the impact of Id 2 deficiency on metabolic homeostasis of mice in a sex-specific manner. The inhibitor of differentiation-1 Id 1 enables lung cancer liver colonization through activation of an EMT program in tumor cells and establishment of the pre-metastatic niche.

    Id 1 promotes carcinogenesis and metastasis, and predicts prognosis of non-small cell lung cancer NSCLC -adenocarcionoma patients. We hypothesized that Id 1 may play a critical role in lung cancer colonization of the liver by affecting both tumor cells and the microenvironment.

    Histologically, the presence of Id 1 in tumor cells of liver metastasis was responsible for liver colonization. Therefore, Id 1 enables both LLC and the host microenvironment for an effective liver colonization, and may represent a novel therapeutic target to avoid NSCLC liver metastasis. Genetic modification of human B-cell development: B-cell development is inhibited by the dominant negative helix loop helix factor Id 3. Transgenic and gene targeted mice have contributed greatly to our understanding of the mechanisms underlying B-cell development.

    We describe here a model system that allows us to apply molecular genetic techniques to the analysis of human B-cell development. We constructed a retroviral vector with a multiple cloning site connected to a gene encoding green fluorescent protein by an internal ribosomal entry site.

    We ligated the gene encoding the dominant negative helix loop helix HLH factor Id 3 that inhibits many enhancing basic HLH transcription factors into this vector. In addition, we cultured the transduced cells in a reaggregate culture system with an SV-transformed human fibroblast cell line SV It was observed that overexpression of Id 3 inhibited development of B cells in both culture systems. B-cell development was arrested at a stage before expression of the IL-7Ralpha.

    These findings confirm the essential role of bHLH factors in B-cell development and demonstrate the feasibility of retrovirus-mediated gene transfer as a tool to genetically modify human B-cell development.

    It is the current leading candidate for a vaccine to prevent PM. Based on detailed analysis of polymorphisms in the sequence of its ligand-binding N-terminal region, currently the main focus for vaccine development, we assessed var2csa from parasite isolates infecting pregnant women. The results reveal for the first time the presence of a major dimorphic region in the functionally critical N-terminal ID 1 domain. Parasite isolates expressing VAR2CSA with particular motifs present within this domain are associated with gravidity- and parasite density-related effects.

    These observations are of particular interest in guiding efforts with respect to optimization of the VAR2CSA-based vaccines currently under development. Angiogenesis plays an essential role in tumor development.

    Blocking angiogenesis in tumor has become a promising tactic in limiting cancer progression. Here, an arabinogalactan polysaccharide, RN1 was isolated from flowers of Panax notoginseng. Its structure was determined to possess a backbone of 1,6-linked Galp branched at C3 by side 1,3-linked Galp, with branches attached at position O-3 of it. The branches mainly contained 1,5-linked, 1,3,5-linked, terminal Arabinose and terminal Galactose.

    RN1 could inhibit microvessel formation in the BxPC-3 pancreatic cancer cell xenograft tumor in nude mice. The antiangiogenesis assay showed that RN1 could reduce the migratory activity of endothelial cells and their ability of tube formation on matrigel, but no effect on endothelial cells growth. All those data indicated the RN1 had an antiangiogenic effect via BMP2 signaling and could be a potential novel inhibitor of angiogenesis. Hypoxia, a feature common to most solid tumors, is known to regulate many aspects of tumorigenesis.

    Recently, it was suggested that hypoxia increased the size of the cancer stem-cell CSC subpopulations and promoted the acquisition of a CSC-like phenotype. However, candidate hypoxia-regulated mediators specifically relevant to the stemness-related functions of colorectal CSCs have not been examined in detail. In the present study, we showed that hypoxia specifically promoted the self-renewal potential of CSCs.

    These affect HOXA over-expression and treatment resistance. A comparable epigenetic phenotype was identified among adult AML patients needing novel intervention. It plays an important role in regulating the progression of breast cancer. Cell proliferation and differentiation are interdependent processes. Here, we have asked to what extent the two processes of neural progenitor cell amplification and differentiation are functionally separated.

    As a model we used the Tis21 knockout mouse, whose dentate gyrus neurons, as demonstrated by us and others, have an intrinsic defect of terminal differentiation. We first tested the effect of two proliferative as well as differentiative neurogenic stimuli, one pharmacological fluoxetine , the other cognitive the Morris water maze MWM training.

    Both effectively enhanced the number of new dentate gyrus neurons produced, and fluoxetine also reduced the S-phase length of Tis21 knockout dentate gyrus progenitor cells and increased the rate of differentiation of control cells, but neither factor enhanced the defective rate of differentiation. In contrast, the defect of terminal differentiation was fully rescued by in vivo infection of proliferating dentate gyrus progenitor cells with retroviruses either silencing Id 3 , an inhibitor of neural differentiation, or expressing NeuroD2, a proneural gene expressed in terminally differentiated dentate gyrus neurons.

    This is the first demonstration that NeuroD2 or the silencing of Id 3 can activate the differentiation of dentate gyrus neurons, complementing a defect of differentiation. The inhibitor of DNA binding and cell differentiation 2 Id 2 is a helix-loop-helix HLH protein that acts as negative dominant regulator of basic-HLH transcription factors during development and in cancer. The structural properties of Id 2 have been investigated so far by using synthetic or recombinant fragments reproducing single domains N-terminus, HLH, C-terminus: In this work, the intact protein was expressed in E.

    Moreover, it existed in a self-assembled state, in which the N-terminus remained highly flexible, while the HLH domain and, surprisingly, part of the C-terminus, which corresponds to the nuclear export signal NES , both were involved in slowly tumbling, rigid structures. The protein oligomers also formed twisted fibrils that were several micrometers long and up to 80 nm thick. These results show that self-assembly decreases the backbone flexibility of those two protein regions HLH and NES that are important for interaction with basic-HLH transcription factors or for nucleocytoplasmic shuttling.

    Tob subfamily proteins have similar anti-proliferative effects on cell cycle progression in cultured tumor cells. New metrics for evaluating channel networks extracted in grid digital elevation models. Channel networks are critical components of drainage basins and delta regions. Despite the important role played by these systems in hydrology and geomorphology, there are at present no well-defined methods to evaluate numerically how two complex channel networks are geometrically far apart.

    The present study introduces new metrics for evaluating numerically channel networks extracted in grid digital elevation models with respect to a reference channel network see the figure below. Streams of the evaluated network EN are delineated as in the Horton ordering system and examined through a priority climbing algorithm based on the triple index ID 1 , ID 2 , ID 3 , where ID 1 is a stream identifier that increases as the elevation of lower end of the stream increases, ID 2 indicates the ID 1 of the draining stream, and ID 3 is the ID 1 of the corresponding stream in the reference network RN.

    Streams of the EN are processed in the order of increasing ID 1 plots a-l in the figure below. The mean stream planar distance MSPD and the mean stream elevation drop MSED are computed as the mean distance and drop, respectively, between corresponding streams. The MSPD is shown to be useful for evaluating slope direction methods and thresholds for channel initiation, whereas the MSED is shown to indicate the ability of grid coarsening strategies to retain the profiles of observed channels.

    The developed metrics fill a gap in the existing literature by allowing hydrologists and geomorphologists to compare descriptions of a fixed physical system obtained by using different terrain analysis methods, or different physical systems.

    In this paper we study about classification algorithms for farm DSS. By applying classification algorithms i. The graphical results obtained from tool are compared to suggest best technique to develop farm Decision Support System. This analysis would help to researchers to design effective and fast DSS for farmer to take decision for enhancing their yield.

    Building of fuzzy decision trees using ID 3 algorithm. Decision trees are widely used in the field of machine learning and artificial intelligence. Such popularity is due to the fact that with the help of decision trees graphic models, text rules can be built and they are easily understood by the final user.

    Because of the inaccuracy of observations, uncertainties, the data, collected in the environment, often take an unclear form. Therefore, fuzzy decision trees becoming popular in the field of machine learning. This article presents a method that includes the features of the two above-mentioned approaches: The approach uses such advantages as high comprehensibility of decision trees and the ability to cope with inaccurate and uncertain information in fuzzy representation.

    The received learning method is suitable for classifying problems with both numerical and symbolic features. In the article, solution illustrations and numerical results are given. Bone morphogenic protein 4 induces inhibitor of DNA binding proteins ID 1 , ID 3 , which suppress transcription factor activities to regulate gene expression.

    Intracellular ID 1 and ID 3 protein localization was studied by immunocytochemistry. Basal expression of ID 1 -3 was detected in primary human TM cells.

    Novel family of terpene synthases evolved from trans-isoprenyl diphosphate synthases in a flea beetle. Sesquiterpenes play important roles in insect communication, for example as pheromones. However, no sesquiterpene synthases, the enzymes involved in construction of the basic carbon skeleton, have been identified in insects to date.

    We investigated the biosynthesis of the sesquiterpene 6R,7S -himachala-9,diene in the crucifer flea beetle Phyllotreta striolata, a compound previously identified as a male-produced aggregation pheromone in several Phyllotreta species. A 6R,7S -himachala-9,diene—producing sesquiterpene synthase activity was detected in crude beetle protein extracts, but only when Z,E -farnesyl diphosphate [ Z,E -FPP] was offered as a substrate.

    No sequences resembling sesquiterpene synthases from plants, fungi, or bacteria were found in the P. Using Cell- ID 1. This unit describes a method for quantifying various cellular features e. It includes procedures for tracking cells over time. One purposefully defocused transmission image sometimes referred to as bright-field or BF is acquired to segment the image and locate each cell.

    Fluorescent images one for each of the color channels to be analyzed are then acquired by conventional wide-field epifluorescence or confocal microscopy. This method uses the image processing capabilities of Cell-ID Gordon et al. Both Cell-ID and the analysis package are open-source. The Fanconi anemia ID 2 complex: Fanconi anemia FA is a rare recessive genetic disease characterized by congenital abnormalities, bone marrow failure and heightened cancer susceptibility in early adulthood.

    FA is caused by biallelic germ-line mutation of any one of 16 genes. Dueling saxes at the crossroads. Cancer stem cell-related gene expression as a potential biomarker of response for first-in-class imipridone ONC in solid tumors.

    Cancer stem cells CSCs correlate with recurrence, metastasis and poor survival in clinical studies. In this study, we demonstrate that the anti-CSC effects of ONC involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC downregulates stem cell pathways such as Wnt signaling and modulates genes ID 1 , ID 2 , ID 3 and ALDH7A1 known to regulate self-renewal in colorectal, prostate cancer and glioblastoma.

    Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC treatment. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC response in ongoing clinical studies.

    Black-Right-Pointing-Pointer Induction of Id 3 expression is critical determinant in Wnt3a-induced cell proliferation and differentiation. Canonical Wnt signaling plays important roles in regulating cell proliferation and differentiation. In this study, we report that inhibitor of differentiation Id 3 is a Wnt-inducible gene in mouse C2C12 myoblasts.

    Bone morphogenetic protein BMP also potently induced Id 3 expression. Functional studies showed that Id 3 depletion in C2C12 cells impaired Wnt3a-induced cell proliferation and alkaline phosphatase activity, an early marker of osteoblast cells. Id 3 depletion elevated myogenin induction during myogenic differentiation and partially impaired Wnt3a suppressed myogenin expression in C2C12 cells. Mistletoe effects on Scots pine decline following drought events: Forest decline has been attributed to the interaction of several stressors including biotic factors such as mistletoes and climate-induced drought stress.

    However, few data exist on how mistletoes are spatially arranged within trees and how this spatial pattern is related to changes in radial growth, responses to drought stress and carbon use. We used dendrochronology to quantify how mistletoe Viscum album L. Basal area increment BAI trends and comparisons between trees of three different infestation degrees without mistletoe, ID 1 ; moderately infested trees, ID 2 ; and severely infested trees, ID 3 were performed using linear mixed-effects models.

    To identify the main climatic drivers of tree growth tree-ring widths were converted into indexed chronologies and related to climate data using correlation functions. We performed spatial analyses of the 3D distribution of mistletoe individuals and their ages within the crowns of three severely infested pines to describe their patterns.

    Lastly, we quantified carbohydrate and nitrogen concentrations in needles and sapwood of branches from severely infested trees and from trees without mistletoe.

    Mistletoe individuals formed strongly clustered groups of similar age within tree crowns and their age increased towards the crown apex. We found that BAI of severely infested trees and moderately or non-infested trees diverged since and such divergence was magnified by drought. Infested trees had lower concentrations of soluble sugars in their needles than non-infested ones.

    We conclude that mistletoe infestation causes growth decline and increases the sensitivity of trees to drought. Solution structure and function of the "tandem inactivation domain" of the neuronal A-type potassium channel Kv1. Different from all other Kvalpha subunits, Kv1.

    Here we report the solution structure and function of this "tandem inactivation domain" using NMR spectroscopy and patch clamp recordings. Inactivation domain 1 ID 1 , residues consists of a flexible N terminus anchored at a 5-turn helix, whereas ID 2 residues is a 2.

    Functional analysis suggests that only ID 1 may work as a pore-occluding ball domain, whereas ID 2 most likely acts as a "docking domain" that attaches ID 1 to the cytoplasmic face of the channel. Deletion of ID 2 slows inactivation considerably and largely impairs cumulative inactivation. Identification of putative estrogen receptor-mediated endocrine disrupting chemicals using QSAR- and structure-based virtual screening approaches.

    Identification of endocrine disrupting chemicals is one of the important goals of environmental chemical hazard screening. We report on the development of validated in silico predictors of chemicals likely to cause estrogen receptor ER -mediated endocrine disruption to facilitate their prioritization for future screening. We found that all four ER conformations discriminated their corresponding ligands from presumed non-binders. Finally, both QSAR models and ER structures were employed in parallel to virtually screen several large libraries of environmental chemicals to derive a ligand- and structure-based prioritized list of putative estrogenic compounds to be used for in vitro and in vivo experimental validation.

    Consumer Approach to Textiles and Clothing. This competency-based preservice home economics teacher education module on consumer approach to textiles and clothing is the first in a set of four modules on consumer education related to textiles and clothing. This set is part of a larger series of sixty-seven modules on the Management Approach to Teaching Consumer and Homemaking Education….

    The 19 mm date recorders: Confusion over the use of non-video 19 mm data recorders is becoming more pronounced in the world of high performance computing. The following issues are addressed: Also, an attempt is made to clear up any misconceptions there might be about 19 mm tape recorders. The equivalent model for the active inductor with parasitic components is also shown in Fig. The values of the equivalent model are The 19 mm data recorders similarities and differences.

    Confusion over the use of non-video 19 mm data recorders is becoming more pronounced as we enter the world of high performance computing. This paper addresses the following: DD-2 and 19 mm instrumentation recorders have missions for which each is well designed.

    While the differences may appear subtle, understanding the difference between the two is the key to picking the right recorder for a particular application. Volume 38, Issue 1, January-February However, their community specificity has hindered comprehensive screening of genetic diversity. The following community compositions were observed: At the genus taxonomic level, no overlaps among these clone libraries were observed, except for ID 2 and ID 3.

    The CO2-assimilating prokaryotes mainly consist of Proteobacteria. Considering the high sequence specificities of these marker genes, we propose that the joint use of multiple primers may be utilized in unveiling the diversity of CO2-assimilating organisms.

    In addition, designing novel RuBisCO gene primers that generate longer amplicons and have broader phylogenetic coverage may be necessary in the future. Irrigation dose and plant density affect the volatile composition and sensory quality of dill Anethum graveolens L. The highest plant yield was obtained with intermediate conditions of both irrigation dose ID0 and plant density PD0.

    The highest irrigation dose ID 2 produced the highest concentrations of most of the main compounds: A similar pattern was found for the highest plant density PD2: The use of descriptive sensory analysis helped in reaching a final decision, and the dill plants with the highest sensory quality were those of the ID 2 and PD0 treatments.

    The final recommendation is to use the irrigation dose ID 2 and the plant density PD2 if the objective is to produce dill samples with the highest aromatic and sensory quality; however, if the only objective is to produce high amounts of dill, the best options are ID0 and PD0. Vitrinite reflectance and Raman spectra of carbonaceous material as indicators of frictional heating on faults: Constraints from friction experiments. Vitrinite reflectance Ro and Raman spectra of carbonaceous material RSCM are both widely used as indicators of the maximum attained temperatures in sedimentary and metamorphic rocks.

    However, the potential of these methods to estimate temperature increases associated with fault slip has not been closely studied. To examine this issue, friction experiments were conducted on a mixture of powdered clay-rich fault material and carbonaceous material CM at slip rates of 0.

    However, the conventionally used Ro and RSCM geothermometers are inadequate for the estimation of peak temperature during seismic fault slip. The reaction kinetics incorporating the effects of rapid heating at high slip rates and studies of the original microtexture and composition of CM are required to establish a reliable thermometer for frictional heating on faults. Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis.

    Murase, Ryuichi; Christian, Rigel T. Invasion and metastasis of aggressive breast cancer cells are the final and fatal steps during cancer progression. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Therefore, effective, targeted, and non-toxic therapies are urgently required.

    Id - 1 , an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers.

    We previously reported that cannabidiol CBD , a cannabinoid with a low toxicity pro-file, down-regulated Id - 1 gene expression in aggressive human breast cancer cells in culture. Using cell proliferation and invasion assays, cell flow cytometry to examine cell cycle and the formation of reactive oxygen species, and Western analysis, we determined pathways leading to the down-regulation of Id - 1 expression by CBD and consequently to the inhibition of the proliferative and invasive phenotype of human breast cancer cells.

    Then, using the mouse 4T1 mammary tumor cell line and the ranksum test, two different syngeneic models of tumor metastasis to the lungs were chosen to determine whether treatment with CBD would reduce metastasis in vivo.

    We show that CBD inhibits human breast cancer cell proliferation and invasion through differential modulation of the extracellular signal-regulated kinase ERK and reactive oxygen species ROS pathways, and that both pathways lead to down-regulation of Id - 1 expression. Moreover, we demonstrate that CBD up-regulates the pro-differentiation factor, Id - 2.

    Using immune competent mice, we then show that treatment with CBD significantly reduces primary tumor mass as well as the size and number of lung metastatic foci in two models of metastasis. Our data demonstrate the efficacy of CBD in pre-clinical models of breast cancer.

    The results have the potential to lead to the development of novel non-toxic compounds for the treatment of breast cancer metastasis. First detection of pike fry-like rhabdovirus in barbel and spring viraemia of carp virus in sturgeon and pike in aquaculture in the Czech Republic.

    Rapid antigen detection enzyme-linked immunosorbent assay ELISA testing of cell cultures with organ homogenate from fish, collected from farms with a predominance of common carp or in natural aquaculture in the Czech Republic between and , identified piscine vesiculovirus in 27 of samples.

    Using reverse transcription semi-nested PCR, targeting a nucleotide region of the glycoprotein G gene, piscine vesiculovirus was confirmed in 23 of the 27 organ samples diagnosed by ELISA as infected. PCR products were amplified and sequenced from 18 isolates from common carp Cyprinus carpio family Cyprinidae , 2 isolates from northern pike Esox lucius family Esocidae , and 1 isolate each from Siberian sturgeon Acipenser baerii family Acipenseridae , common barbel Barbus barbus family Cyprinidae , and koi carp Cyprinus carpio koi family Cyprinidae.

    The sequences based on nucleotides clustered into 2 genogroups. The 22 isolates could be further subdivided into 2 groups: It was specifically found in all sequences of Id 1 isolates when testing SVCV originating from different countries.

    The remaining isolate from barbel, was classified in the pike fry-like rhabdovirus Genogroup IV. This is the first confirmation of natural SVCV infection in sturgeon and pike, and pike fry-like rhabdovirus infection in barbel. In the case of the pike fry-like rhabdovirus, this is also its first identification in the Czech Republic. We observed three massive subhalos in the Coma cluster with Suzaku.

    The gas mass to weak-lensing mass ratio is also about 0. The temperature of the excess is about 0. We also studied the effect of the Kelvin—Helmholtz instability to strip the gas. Although we found X-ray clumps associated with the weak-lensing subhalos, their X-ray luminosities are much lower than the total ICM luminosity in the cluster outskirts.

    The processing by the analysis centers used the latest GRACE-derived gravity models, forward modelling of atmospheric gravity, updates to the radiation pressure modelling to improve the DORIS geocenter solutions, denser parameterization of empirically determined drag coefficients to improve station and EOP solutions, especially near the solar maximum in , updated troposphere mapping functions, and an ITRFderived station set for orbit determination, DPOD Between the development of the initial solution IDS - 1 , and the final solution, IDS - 3 , the ACs improved their analysis strategies and submitted updated solutions to eliminate troposphere-derived biases in the solution scale, to reduce drag-related degradations in station positioning, and to refine the estimation strategy to improve the combination geocenter solution.

    An analysis of the frequency content of the individual AC geocenter and scale solutions was used as the basis to define the. Anti-diarrheal constituents of Alpinia oxyphylla.

    Isolation, screening and in vivo assays have been used for evaluating anti-diarrhea bioactive of Alpinia oxyphylla. Chemical analysis results displayed that Nootkatone, Tectochrysin and yakuchinone A may be bioactive ingredients for curing diarrhea. Bioinformatic computational method as molecular docking has been complementary to experimentally work to explore the potential mechanism.

    Tectochrysin indicated minimum energy score and the highest number of interactions with active site residues. These results suggested that A. Published by Elsevier B. Memory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity.

    Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator s underpinning this process remains unknown.

    Ezh2 activates Id 3 while silencing Id 2 , Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors.

    Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies. Although potent androgen receptor pathway inhibitors ARPI improve overall survival of metastatic prostate cancer patients, treatment-induced neuroendocrine prostate cancer t-NEPC as a consequence of the selection pressures of ARPI is becoming a more common clinical issue.

    Rather than inducing neuroendocrine trans-differentiation of cells in prostate adenocarcinoma, MEAF upregulation stimulates cell proliferation, anchorage-independent cell growth, invasion and xenograft tumor growth.

    These findings suggest that the MEAF variant does not induce neuroendocrine differentiation of prostate cancer cells, but rather facilitates t-NEPC progression by increasing the proliferation rate of cells that have acquired neuroendocrine phenotypes. Selenoproteins and maternal nutrition.

    Selenium Se is an essential trace element of fundamental importance to health due to its antioxidant, anti-inflammatory and chemopreventive properties attributed to its presence within at least 25 selenoproteins Sel. In this review, we describe some of the recent progress in our understanding of the mechanisms of Sel synthesis.

    The impact of maternal Se intake on offspring is also discussed. The key regulatory point of Sel synthesis is Se itself, which acts predominantly at post-transcriptional levels, although recent findings indicate transcriptional and redox regulation. Maternal nutrition affects the performance and health of the progeny.

    Both maternal and offspring Se supplementations are essential for the antioxidant protection of the offspring. Prenatal Se supplementation provides an effective antioxidant system that is already in place at the time of birth while, postnatal Se supplementation becomes the main determinant of progeny Se status after the first few days of progeny life. Characterization of the pigment fraction in sweet bell peppers Capsicum annuum L.

    Offline multidimensional supercritical fluid chromatography combined with reversed-phase liquid chromatography was employed for the carotenoid and chlorophyll characterization in different sweet bell peppers Capsicum annuum L. This approach allowed the determination of different compounds belonging to chlorophylls, free xanthophylls, free carotenes, xanthophyll monoesters, and xanthophyll diesters, and proved to be a significant improvement in the pigments determination compared to the conventional one-dimensional liquid chromatography approach so far applied to the carotenoid analysis in the studied species.

    Moreover, the present study also aimed to investigate and to compare the carotenoid stability and composition in overripe yellow and red bell peppers collected directly from the plant, thus also evaluating whether biochemical changes are linked to carotenoid degradation in the nonclimacteric investigated fruits, for the first time.

    Identification of apoptosis-related PLZF target genes. In this paper, we investigate proliferation, survival, and gene expression regulation in stable clones from the human haematopoietic K, DG75, and Jurkat cell lines with inducible expression of PLZF.

    Analysis of each branch current of serial solar cells by using an equivalent circuit model. In this paper, based on the equivalent single diode circuit model of the solar cell, an equivalent circuit diagram for two serial solar cells is drawn. Its equations of current and voltage are derived from Kirchhoff's current and voltage law.

    Then, by regarding photo-generated current, shunt resistance, serial resistance of the first solar cell, and resistance load as the variables. The properties of shunt currents Ish1 and Ish2 , diode currents ID 1 and ID 2 , and load current IL for the whole two serial solar cells are numerically analyzed in these four cases for the first time, and the corresponding physical explanations are made.

    We find that these parameters have different influences on the internal currents of solar cells. Our results will provide a reference for developing higher efficiency solar cell module and contribute to the better understanding of the reason of efficiency loss of solar cell module. Doritchamou, Justin; Arango, Eliana M. In pregnancy, parity-dependent immunity is observed in response to placental infection with Plasmodium falciparum.

    Antibodies recognize the surface antigen, VAR2CSA, expressed on infected red blood cells and inhibit cytoadherence to the placental tissue. In most settings of malaria endemicity, antibodies against VAR2CSA are predominantly observed in multigravid women and infrequently in men, children, and nulligravid women. Surprisingly, these antibodies were observed only in pregnant women, men, and children exposed either to P.

    Moreover, the anti-VAR2CSA antibodies are of high avidity and efficiently inhibit adherence of infected red blood cells to chondroitin sulfate A in vitro, suggesting that they are specific and functional. These unexpected results suggest that there may be genotypic or phenotypic differences in the parasites of this region or in the host response to either P.

    These findings may hold significant clinical relevance to the pathophysiology and outcome of malaria infections in this region. Residual dipolar couplings RDCs acquired by nuclear magnetic resonance NMR spectroscopy are an indispensable source of information in investigation of molecular structures and dynamics. Here, we present a comprehensive strategy for structure calculation and reconstruction of discrete-state dynamics from RDC data that is based on the singular value decomposition SVD method of order tensor estimation.

    In addition to structure determination, we provide a mechanism of producing an ensemble of conformations for the dynamical regions of a protein from RDC data. The docking procedure allowed us to study the similarities and differences in the recognition binding site s for tested ligands. The residues identified by us during docking procedure Ser, Ser, Asp, Lys, Asn, Tyr, Asp were experimentally indicated in functional and biophysical studies as being very important for the agonist-receptor interactions.

    Moreover, the additional space, an extension of the orthosteric pocket, was identified and described. Our research offers new insights into the ligand stereoselective interaction with one of the most important GPCR member.

    This study may also facilitate the design of improved selective medications, which can be used to treat, prevent and control heart failure symptoms. Segregation of striated and smooth muscle lineages by a Notch-dependent regulatory network.

    Background Lineage segregation from multipotent epithelia is a central theme in development and in adult stem cell plasticity. Previously, we demonstrated that striated and smooth muscle cells share a common progenitor within their epithelium of origin, the lateral domain of the somite-derived dermomyotome.

    However, what controls the segregation of these muscle subtypes remains unknown. We use this in vivo bifurcation of fates as an experimental model to uncover the underlying mechanisms of lineage diversification from bipotent progenitors. Results Using the strength of spatio-temporally controlled gene missexpression in avian embryos, we report that Notch harbors distinct pro-smooth muscle activities depending on the duration of the signal; short periods prevent striated muscle development and extended periods, through Snail1, promote cell emigration from the dermomyotome towards a smooth muscle fate.

    Furthermore, we define a Muscle Regulatory Network, consisting of Id 2 , Id 3 , FoxC2 and Snail1, which acts in concert to promote smooth muscle by antagonizing the pro-myogenic activities of Myf5 and Pax7, which induce striated muscle fate. In turn, components of the network strengthen Notch signaling, while Pax7 silences this signaling. These feedbacks augment the robustness and flexibility of the network regulating muscle subtype segregation.

    Conclusions Our results demarcate the details of the Muscle Regulatory Network, underlying the segregation of muscle sublineages from the lateral dermomyotome, and exhibit how factors within the network promote the smooth muscle at the expense of the striated muscle fate. This network acts as an exemplar demonstrating how lineage segregation occurs within epithelial primordia by integrating inputs from competing factors.

    Z-scores were calculated by using assay-specific age-specific normative range values. All treatment decisions were based upon results obtained by the IM assay. In contrast, in acromegaly, mean IGF-1 Z-scores did not differ significantly between both assays.

    Our study suggests that replacement of the IM assay by the ID assay may have far-reaching consequences for the clinical diagnosis and treatment of GHD. Chief Psychologist, GovSource, Inc. Understanding the dynamics of muscle transcriptome during development and between breeds differing in muscle growth is necessary to uncover the complex mechanism underlying muscle development. The data demonstrated that myogenesis was almost completed before 77 dpc, but the muscle phenotypes were still changed from 77 dpc to 28 dpn.

    Comparative analysis of the two breeds suggested that myogenesis started earlier but progressed more slowly in LT than in LR, the stages ranging from 49 dpc to 77 dpc are critical for formation of different muscle phenotypes. We also identified several genes which might contribute to intramuscular adipose differentiation.

    Overall, this study contributes to elucidating the mechanism underlying muscle development, which could provide valuable information for pig meat quality improvement. The raw data have been submitted to Gene Expression. Comparative analyses by sequencing of transcriptomes during skeletal muscle development between pig breeds differing in muscle growth rate and fatness.

    A National Cross-sectional Study. We conducted 25 interviews and disseminated a Web-based survey to graduating IM residents in the United States utilizing a 2-stage sampling strategy.

    Participants were categorized into 3 groups based on interest in ID: We conducted all analysis using poststratification adjustment weights with survey data analysis procedures. Category 2 chose salary as the most dissuading factor and the most likely intervention to increase ID interest. In this nationally representative sample of graduating IM residents, most develop an interest in their ultimate career before residency. Factors influencing this decision reside in both medical school and residency, which is consistent with career decision-making constructs.

    By identifying career determining factors and understanding how they fit into medical training frameworks, we can develop targeted initiatives to reinvigorate interest in ID. For permissions, e-mail journals. Comparison of functional assays used in the clinical development of a placental malaria vaccine.

    Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. The purpose of this study was to evaluate the robustness and comparability of binding inhibition assays used in the clinical development of placental malaria vaccines.

    The ability of sera from animals immunised with different VAR2CSA constructs to inhibit IE binding to CSA was investigated in three in vitro assays using well plates, petri dishes, capillary flow and an ex vivo placental perfusion assay.

    The inter-assay variation was not uniform between assays and ranged from above ten-fold in the flow assay to two-fold in the perfusion assay. The intra-assay variation was highest in the petri dish assay. A positive correlation between IE binding avidity and the level of binding after antibody inhibition in the petri dish assay indicate that high avidity IE binding is more difficult to inhibit.

    The highest binding inhibition sensitivity was found in the well and petri dish assays compared to the flow and perfusion assays where binding inhibition required higher antibody titers. The inhibitory capacity of antibodies is not easily translated between assays and the high sensitivity of the well and petri dish assays stresses the need for comparing serial dilutions of serum.

    Furthermore, IE binding avidity must be in the same range when comparing data from different days. There was an overall concordance in the capacity of antibody-mediated inhibition, when comparing the in vitro assays with the perfusion assay, which more closely represents in vivo conditions. Importantly the ID 1 - ID 2 a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue.

    Statistical analyses were performed using SPSS version Allele and genotypic frequency was calculated by direct gene counting method. Comparison of the different genotypes was done by using Chi square test.

    Iron deficiency, anemia, and mortality in renal transplant recipients. Anemia is associated with poor outcome, but the role of ID is unknown. Therefore, we aimed to investigate the association of ID, irrespective of anemia, with all-cause mortality in RTR.

    Cox regression analyses were used to investigate prospective associations. During follow-up for 3. In univariable analysis, anemia [HR, 1. In multivariable analysis, the association of anemia with mortality became weaker after adjustment for ID [ 1. The association of IDA with mortality attenuated after adjustment for potential confounders.

    In contrast, the association of ID with mortality remained independent of potential confounders, including anemia [1. In conclusion, ID is highly prevalent among RTR and is associated with an increased risk of mortality, independent of anemia.

    As ID is a modifiable factor, correction of ID could be a target to improve survival. Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. Reprograming of metabolism is one of the central hallmarks of cancer.

    US9254272B2 - Resorcinol derivatives - Google Patents

    5A-C demonstrates that CBD decreases Id-1 expression and Ki staining .. more potent than CBD at inhibiting cancer cell growth and invasion, and Id-1 (B ) MDA-MB cells were treated with CBD or O CBD Supplementary active compounds can also be incorporated into the compositions. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to the active components of marijuana and their derivatives, inhibit cell cycle . We show that CBD inhibits human breast cancer cell proliferation and invasion . Conclusions and implications: O prolonged survival in advanced. is given in repeated doses to increase cell proliferation and induce subsequent BRAIN CANCER. It is estimated that more than 23, individuals will be newly .. O , , 10 mg/kg. CBD; mg/kg. O (i.p.). Decreased tumor .. that CBD inhibited Id-1 expression which occurred coincident.

    Cannabinoids, Education



    5A-C demonstrates that CBD decreases Id-1 expression and Ki staining .. more potent than CBD at inhibiting cancer cell growth and invasion, and Id-1 (B ) MDA-MB cells were treated with CBD or O CBD Supplementary active compounds can also be incorporated into the compositions.


    The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to the active components of marijuana and their derivatives, inhibit cell cycle . We show that CBD inhibits human breast cancer cell proliferation and invasion . Conclusions and implications: O prolonged survival in advanced.

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