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41.
Monte FL Kramer T Boländer A Plotkin B Eldar-Finkelman H Fuertes A Dominguez J Schmidt B 《Bioorganic & medicinal chemistry letters》2011,21(18):5610-5615
The glycogen synthase kinase 3 (GSK-3) is implicated in multiple cellular processes and has been linked to the pathogenesis of Alzheimer's disease (AD). In the course of our research topic we synthesized a library of potent GSK-3 inhibitors. We utilized the urea scaffold present in the potent and highly selective GSK-3 inhibitor AR-A014418 (AstraZeneca). This moiety suits both (a) a convergent approach utilizing readily accessible building blocks and (b) a divergent approach based on a microwave heating assisted Suzuki coupling. We established a chromatography-free purification method to generate products with sufficient purity for the biological assays. The structure-activity relationship of the library provided the rationale for the synthesis of the benzothiazolylurea 66 (IC(50)=140 nM) and the pyridylurea 62 (IC(50)=98 nM), which displayed two to threefold enhanced activity versus the reference compound 18 (AR-A014418: IC(50)=330 nM) in our assays. 相似文献
42.
Hagit Hochner Catherine Allard Einat Granot-Hershkovitz Jinbo Chen Colleen M. Sitlani Sandra Sazdovska Thomas Lumley Barbara McKnight Kenneth Rice Daniel A. Enquobahrie James B. Meigs Pui Kwok Marie-France Hivert Ingrid B. Borecki Felicia Gomez Ting Wang Cornelia van Duijn Najaf Amin Jerome I. Rotter John Stamatoyannopoulos Vardiella Meiner Orly Manor Josée Dupuis Yechiel Friedlander David S. Siscovick 《PLoS genetics》2015,11(10)
Loci identified in genome-wide association studies (GWAS) of cardio-metabolic traits account for a small proportion of the traits'' heritability. To date, most association studies have not considered parent-of-origin effects (POEs). Here we report investigation of POEs on adiposity and glycemic traits in young adults. The Jerusalem Perinatal Family Follow-Up Study (JPS), comprising 1250 young adults and their mothers was used for discovery. Focusing on 18 genes identified by previous GWAS as associated with cardio-metabolic traits, we used linear regression to examine the associations of maternally- and paternally-derived offspring minor alleles with body mass index (BMI), waist circumference (WC), fasting glucose and insulin. We replicated and meta-analyzed JPS findings in individuals of European ancestry aged ≤50 belonging to pedigrees from the Framingham Heart Study, Family Heart Study and Erasmus Rucphen Family study (total N≅4800). We considered p<2.7x10-4 statistically significant to account for multiple testing. We identified a common coding variant in the 4th exon of APOB (rs1367117) with a significant maternally-derived effect on BMI (β = 0.8; 95%CI:0.4,1.1; p = 3.1x10-5) and WC (β = 2.7; 95%CI:1.7,3.7; p = 2.1x10-7). The corresponding paternally-derived effects were non-significant (p>0.6). Suggestive maternally-derived associations of rs1367117 were observed with fasting glucose (β = 0.9; 95%CI:0.3,1.5; p = 4.0x10-3) and insulin (ln-transformed, β = 0.06; 95%CI:0.03,0.1; p = 7.4x10-4). Bioinformatic annotation for rs1367117 revealed a variety of regulatory functions in this region in liver and adipose tissues and a 50% methylation pattern in liver only, consistent with allelic-specific methylation, which may indicate tissue-specific POE. Our findings demonstrate a maternal-specific association between a common APOB variant and adiposity, an association that was not previously detected in GWAS. These results provide evidence for the role of regulatory mechanisms, POEs specifically, in adiposity. In addition this study highlights the benefit of utilizing family studies for deciphering the genetic architecture of complex traits. 相似文献
43.
Monitoring of tumor response to chemotherapy in vivo by a novel small-molecule detector of apoptosis 总被引:1,自引:0,他引:1
Hagit Grimberg Galit Levin Anat Shirvan Avi Cohen Merav Yogev-Falach Ayelet Reshef Ilan Ziv 《Apoptosis : an international journal on programmed cell death》2009,14(3):257-267
Utilization of molecular imaging of apoptosis for clinical monitoring of tumor response to anti-cancer treatments in vivo
is highly desirable. To address this need, we now present ML-9 (butyl-2-methyl-malonic acid; MW = 173), a rationally designed
small-molecule detector of apoptosis, based on a novel alkyl-malonate motif. In proof-of-concept studies, induction of apoptosis
in tumor cells by various triggers both in vitro and in vivo was associated with marked uptake of 3H-ML-9 administered in vivo, in correlation with the apoptotic hallmarks of DNA fragmentation, caspase-3 activation and membrane
phospholipid scrambling, and with correlative tumor regression. ML-9 uptake following chemotherapy was tumor-specific, with
rapid clearance of the tracer from the blood and other non-target organs. Excess of non-labeled “cold” compound competitively
blocked ML-9 tumor uptake, thus demonstrating the specificity of ML-9 binding. ML-9 may therefore serve as a platform for
a novel class of small-molecule imaging agents for apoptosis, useful for assessment of tumor responsiveness to treatment.
H. Grimberg, G. Levin and A. Shirvan contributed equally to this article. 相似文献
44.
Hagit Eldar-Finkelman Avital Licht-Murava Shmuel Pietrokovski Miriam Eisenstein 《Biochimica et Biophysica Acta - Proteins and Proteomics》2010,1804(3):598-603
Glycogen synthase kinase-3 (GSK-3) is a highly conserved protein serine/threonine kinase ubiquitously distributed in eukaryotes as a constitutively active enzyme. Abnormally high GSK-3 activity has been implicated in several pathological disorders, including diabetes and neuron degenerative and affective disorders. This led to the hypothesis that inhibition of GSK-3 may have therapeutic benefit. Most GSK-3 inhibitors developed so far compete with ATP and often show limited specificity. Our goal is to develop inhibitors that compete with GSK-3 substrates, as this type of inhibitor is more specific and may be useful for clinical applications. We have employed computational, biochemical, and molecular analyses to gain in-depth understanding of GSK-3's substrate recognition. Here we argue that GSK-3 is a promising drug discovery target and describe the strategy and practice for developing specific substrate-competitive inhibitors of GSK-3. 相似文献
45.
Monica Chagoyen Pedro Carmona-Saez Hagit Shatkay Jose M Carazo Alberto Pascual-Montano 《BMC bioinformatics》2006,7(1):41
Background
Experimental techniques such as DNA microarray, serial analysis of gene expression (SAGE) and mass spectrometry proteomics, among others, are generating large amounts of data related to genes and proteins at different levels. As in any other experimental approach, it is necessary to analyze these data in the context of previously known information about the biological entities under study. The literature is a particularly valuable source of information for experiment validation and interpretation. Therefore, the development of automated text mining tools to assist in such interpretation is one of the main challenges in current bioinformatics research. 相似文献46.
Combining multi-species genomic data for microRNA identification using a Naive Bayes classifier 总被引:7,自引:0,他引:7
Yousef M Nebozhyn M Shatkay H Kanterakis S Showe LC Showe MK 《Bioinformatics (Oxford, England)》2006,22(11):1325-1334
MOTIVATION: Most computational methodologies for microRNA gene prediction utilize techniques based on sequence conservation and/or structural similarity. In this study we describe a new technique, which is applicable across several species, for predicting miRNA genes. This technique is based on machine learning, using the Naive Bayes classifier. It automatically generates a model from the training data, which consists of sequence and structure information of known miRNAs from a variety of species. RESULTS: Our study shows that the application of machine learning techniques, along with the integration of data from multiple species is a useful and general approach for miRNA gene prediction. Based on our experiments, we believe that this new technique is applicable to an extensive range of eukaryotes' genomes. Specific structure and sequence features are first used to identify miRNAs followed by a comparative analysis to decrease the number of false positives (FPs). The resulting algorithm exhibits higher specificity and similar sensitivity compared to currently used algorithms that rely on conserved genomic regions to decrease the rate of FPs. 相似文献
47.
Isoprene emission from leaves is dynamically coupled to photosynthesis through the use of primary and recent photosynthate in the chloroplast. However, natural abundance carbon isotope composition (delta(13)C) measurements in myrtle (Myrtus communis), buckthorn (Rhamnus alaternus), and velvet bean (Mucuna pruriens) showed that only 72% to 91% of the variations in the delta(13)C values of fixed carbon were reflected in the delta(13)C values of concurrently emitted isoprene. The results indicated that 9% to 28% carbon was contributed from alternative, slow turnover, carbon source(s). This contribution increased when photosynthesis was inhibited by CO(2)-free air. The observed variations in the delta(13)C of isoprene under ambient and CO(2)-free air were consistent with contributions to isoprene synthesis in the chloroplast from pyruvate associated with cytosolic Glc metabolism. Irrespective of alternative carbon source(s), isoprene was depleted in (13)C relative to mean photosynthetically fixed carbon by 4 per thousand to 11 per thousand. Variable (13)C discrimination, its increase by partially inhibiting isoprene synthesis with fosmidomicin, and the associated accumulation of pyruvate suggested that the main isotopic discrimination step was the deoxyxylulose-5-phosphate synthase reaction. 相似文献
48.
The plant pathogenic fungus Colletotrichum gloeosporioides f. sp. aeschynomene utilizes external tryptophan to produce indole-3-acetic acid (IAA) through the intermediate indole-3-acetamide (IAM). We studied the effects of tryptophan, IAA, and IAM on IAA biosynthesis in fungal axenic cultures and on in planta IAA production by the fungus. IAA biosynthesis was strictly dependent on external tryptophan and was enhanced by tryptophan and IAM. The fungus produced IAM and IAA in planta during the biotrophic and necrotrophic phases of infection. The amounts of IAA produced per fungal biomass were highest during the biotrophic phase. IAA production by this plant pathogen might be important during early stages of plant colonization. 相似文献
49.
Cancer patients, treated by either chemo- or radiotherapy, frequently suffer from ovarian failure and infertility. One of the new emerging techniques to preserve reproductive potential of such patients is cryopreservation of ovarian fragments prior to treatment and their retransplantation after healing. A major obstacle in survival of the ovarian implants is vascular failure, which leads to tissue necrosis. In order to investigate the role of angiogenesis in implant preservation, we used a xenograft model in which rat ovaries were transplanted into immunodeficient mice. Graft reception and maintenance were monitored by magnetic resonance imaging (MRI) and histology. Two transplantation sites were explored, i.e., subcutaneous and intramuscular. Comparison between these two transplantation sites revealed the importance of vascular smooth muscle cells and pericytes in sustaining vascular and tissue integrity. Histological examination of the grafts, at different time points and sizes, revealed that loss of perivascular cells preceded damage to endothelial cells and was closely correlated with loss of follicular and oocyte integrity. Intramuscular implantation provided better maintenance of implant perivascular cells relative to subcutaneous implantation. Accordingly, follicular integrity was superior in the intramuscular implants and the number of damaged follicles was significantly lower compared with the subcutaneous transplantation site. These results suggest that improving ovarian implant maintenance should be directed toward preservation of perivascular support. 相似文献
50.
Rac2 regulation of phospholipase C-beta 2 activity and mode of membrane interactions in intact cells
Illenberger D Walliser C Strobel J Gutman O Niv H Gaidzik V Kloog Y Gierschik P Henis YI 《The Journal of biological chemistry》2003,278(10):8645-8652
Phospholipase C-beta (PLCbeta) isozymes play important roles in transmembrane signaling. Their activity is regulated by heterotrimeric G proteins. The PLCbeta(2) isozyme is unique in being stimulated also by Rho GTPases (Rac and Cdc42). However, the mechanism(s) of this stimulation are still unclear. Here, we employed fluorescence recovery after photobleaching to investigate the interaction of green fluorescent protein (GFP)-PLCbeta(2) with the plasma membrane. For either GFP-PLCbeta(2) or GFP-PLCbeta(2)Delta, a C-terminal deletion mutant lacking the region required for stimulation by Galpha(q), these interactions were characterized by a mixture of exchange with a cytoplasmic pool and lateral diffusion. Constitutively active Rac2(12V) stimulated the activity of both GFP-PLCbeta(2) and GFP-PLCbeta(2)Delta in live cells, and enhanced their membrane association as evidenced by the marked reduction in their fluorescence recovery rates. Both effects required the putative N-terminal pleckstrin homology (PH) domain of PLCbeta(2). Importantly, Rac2(12V) dramatically increased the contribution of exchange to the fluorescence recovery of GFP-PLCbeta(2), but had the opposite effect on GFP-PLCbeta(2)Delta, where lateral diffusion became dominant. Our results demonstrate for the first time the regulation of membrane association of a PLCbeta isozyme by a GTP-binding protein and assign a novel function to the PLCbeta(2) C-terminal region, regulating its exchange between membrane-bound and cytosolic states. 相似文献