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71.
The central role of protein kinase C (PK-C) in cellular signal transduction has established it as an important therapeutic target for cancer and other diseases. We have developed a series of 4,4-disubstituted-gamma-butyrolactones, which contain a constrained glycerol backbone (DAG-lactones) and behave as potent and selective activating ligands of PK-C with affinities that approach those of the structurally complex natural product agonists, such as the phorbol esters. This Account traces the design and construction of these molecules. Initially, we examined the consequences of reducing the entropic penalty associated with the transformation of a DAG into a DAG-lactone. Then, using molecular modeling to extend insights arising from the newly solved crystal structure of a C1 domain complexed with phorbol ester, we incorporated amino acid-specific branched hydrophobic chains to provide a new generation of DAG-lactones that have the capacity to bind to PK-C with low nanomolar affinity. Depending on the specific pattern of hydrophobic substitution, some DAG-lactones are able to induce selective translocation of individual PK-C isozymes to different cellular compartments, and since the specific nature of these hydrophobic interactions influences biological outcome, some of these compounds exhibit cell-specific antitumor activity. The ability to direct specific PK-C isozyme translocation with sets of structurally simple, yet highly potent molecules provides a powerful tool for engineering a plethora of molecules with novel biological functions. 相似文献
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Iryna Danilina Alan R. Gillespie Lee Balick Amit Mushkin Matthew Smith Dan Blumberg 《International journal of remote sensing》2013,34(9-10):3425-3436
Emissivity spectra recovered from spectral radiance images may have lowered spectral contrast due to irradiance from nearby surface elements (‘cavity effect’). For analysis based only on photointerpretation or Reststrahlen band identification, it is not always necessary to account for cavity effects, but for full spectral analysis it may be desirable. We present an approach to compensate thermal infrared (TIR) images for cavity radiation. This approach is based on optical estimates of subpixel surface roughness and estimation of cavity contribution for different natural surfaces using a TIR radiosity model. It was tested using tripod-mounted Hyper-Cam (Telops, Inc., Quebec City, Canada) hyperspectral TIR images of natural targets from the Mojave Desert, California, USA, along with centimetre-scale digital elevation models of similar targets measured by ground lidar. For remote subpixel roughness estimation, Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) nadir- and aft-looking (27.6°) near-infrared (NIR) brightness ratios, as well as synthetic aperture radar (SAR) images calibrated to roughness root mean square (RMS), were used. The TIR compensation approach is adaptable for different spectral resolutions, including hyperspectral. 相似文献
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N. Goldshleger E. Ben-Dor Y. Benyamini D. Blumberg M. Agassi 《International journal of remote sensing》2013,34(19):3909-3920
In this study, a controlled spectral investigation of the properties of structural crust, using infiltration rate as an indicator, was carried out, on a grumusol (typic chromoxerets) soil. The scope of this paper is to investigate the spectral relationship between structural crust and the infiltration rate and some related properties of a grumusol soil. Structural crust is a thin compact layer generated on the soil's surface after rainstorm events due to raindrop energy. The crust, which is a result of physical segregation and rearrangement of soil particles, affects some of the soil's physical properties, such as infiltration, run-off and soil erosion. A set of soil samples was subjected in the laboratory to increased levels of cumulative energy from a simulated rainstorm, while measuring the infiltration rate. The result was a set of soil samples with increased levels of crusting and correspondingly reduced infiltration rates. After drying the soil samples, their spectral parameters across the SWIR region (1.2 w m-2.4 w m) were studied in the laboratory. Empirical relations were found between the infiltration rate and reflectance values (either in raw or in first derivative domains). A spectral ratio manipulation, using a fog type rain treatment (characterized as having no rain energy) as reference, confirmed that, within the spectrum, changes in both albedo and absorption enabled the crust to be detected using reflectance radiation. This is basically because fine (mostly clay) mineral enrichment processes occurred at the surface of the crusted soil. These minerals (montmorillonite, calcite) are spectrally active across the selected spectral region. Although further study is required to fully account for other soils, rainstorm energies and water qualities, this technique suggests great potential as a tool for rapid, non-destructive, in situ assessment of crusted soil properties. 相似文献
75.
OBJECTIVE: The authors examined the efficacy of intramuscular flunitrazepam compared with intramuscular haloperidol for the immediate control of agitated or aggressive behavior in acutely psychotic patients. METHOD: Twenty-eight actively psychotic inpatients, aged 20-60 years, who were under treatment with neuroleptic agents were selected for the study. Each was randomly assigned on a double-blind basis to receive either 5 mg i.m. of haloperidol (N=13) or 1 mg i.m. of flunitrazepam (N=15) during an aggressive event. Verbal and physical aggression was measured over time with the Overt Aggression Scale. Patients were also rated with the Brief Psychiatric Rating Scale and the Clinical Global Impression scale. RESULTS: Both flunitrazepam and haloperidol exhibited acute antiaggressive activity. This beneficial effect, as assessed by the Overt Aggression Scale, was obtained within 30 minutes. CONCLUSIONS: Intramuscular flunitrazepam may serve as a convenient, rapid, safe, and effective adjunct to neuroleptics in reducing aggressive behavior in emergency psychiatric settings. 相似文献
76.
W. Blumberg 《化学,工程师,技术》1998,70(9):1077-1078
77.
PURPOSE: To evaluate the efficacy of topical mitomycin C in treating conjunctival and corneal epithelial dysplasia and neoplasia. METHODS: Seven eyes of seven patients with conjunctival and corneal epithelial dysplasia and neoplasia were treated with one drop of topical mitomycin C 0.04% four times a day for 7 days in alternate weeks. The patients' charts were reviewed retrospectively. Patients with either multiple recurrences or extensive ocular surface involvement were treated. In all eyes, the diagnosis of epithelial dysplasia or neoplasia was confirmed by histopathology before the onset of therapy. Patients were examined at least every 14 days during treatment and examined at intervals after completion of treatment. RESULTS: With topical mitomycin C, six eyes of seven patients had complete clinical regression of their conjunctival and corneal epithelial dysplasia and neoplasia. One eye of one patient had partial clinical regression of conjunctival and corneal epithelial dysplasia. Follow-up after completion of topical mitomycin C therapy and excision of residual disease ranged from 2 to 16 months (mean, 9 months; SD, 4.3 months) and was without clinical sign of recurrence. Topical mitomycin C therapy was associated with transitory ocular discomfort, conjunctival injection, tearing, photophobia, and punctate epithelial keratopathy. CONCLUSION: In this small series of eyes, topical mitomycin C was effective as a treatment for conjunctival and corneal epithelial dysplasia and neoplasia. 相似文献
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Or Raifman Dr. Sofiya Kolusheva Dr. Said El Kazzouli Dr. Dina M. Sigano Dr. Noemi Kedei Dr. Nancy E. Lewin Ruben Lopez‐Nicolas Ana Ortiz‐Espin Juan C. Gomez‐Fernandez Dr. Peter M. Blumberg Dr. Victor E. Marquez Prof. Senena Corbalan‐Garcia Prof. Raz Jelinek 《Chembiochem : a European journal of chemical biology》2010,11(14):2003-2009
Synthetic diacylglycerol‐lactones (DAG‐lactones) are effective modulators of critical cellular signaling pathways, downstream of the lipophilic second messenger diacylglycerol, that activate a host of protein kinase C (PKC) isozymes and other nonkinase proteins that share similar C1 membrane‐targeting domains with PKC. A fundamental determinant of the biological activity of these amphiphilic molecules is the nature of their interactions with cellular membranes. This study examines the biological properties of charged DAG‐lactones exhibiting different alkyl groups attached to the heterocyclic nitrogen of an α‐pyridylalkylidene chain, and particularly the relationship between membrane interactions of the substituted DAG‐lactones and their respective biological activities. Our results suggest that bilayer interface localization of the N‐alkyl chain in the R2 position of the DAG‐lactones inhibits translocation of PKC isoenzymes onto the cellular membrane. However, the orientation of a branched alkyl chain at the bilayer surface facilitates PKC binding and translocation. This investigation emphasizes that bilayer localization of the aromatic side residues of positively charged DAG‐lactone derivatives play a central role in determining biological activity, and that this factor contributes to the diversity of biological actions of these synthetic biomimetic ligands. 相似文献