A single-step cancer cell cytotoxic assay system for anticancer drug discovery has been developed which facilitates rapid screening of large combinatorial chemical libraries synthesized using the ...'one-bead-one-compound' (OBOC) methodology. Each OBOC library bead incorporates two orthogonally cleavable linkers that release the bead-bound compound at a different pH. The assay utilizes high concentrations of tumor cells mixed directly with OBOC beads and plated in soft agarose containing tissue culture medium. One of the orthogonal linkers is cleaved at neutral pH in tissue culture releasing an aliquot of compound to diffuse at a relatively high local concentration into the soft agarose immediately surrounding the bead. Active compounds are identified visually from a clear ring of tumor cell lysis which forms within 48 h around just the rare bead releasing a cytotoxic compound. The bead releasing a cytotoxin is then plucked from the agar and the remaining compound still linked to the bead can be released for structural analysis, followed by compound resynthesis and confirmatory testing. This assay system has been successfully applied to identification of lead cytotoxic compounds from model peptidic and non-peptidic combinatorial chemical libraries. Use of this methodology may facilitate anticancer drug discovery.
High quality single crystals of BaFe{sub 12}O{sub 19} were grown using the floating zone technique in 100 atm of flowing oxygen. Single crystal neutron diffraction was used to determine the nuclear ...and magnetic structures of BaFe{sub 12}O{sub 19} at 4 K and 295 K. At both temperatures, there exist local electric dipoles formed by the off-mirror-plane displacements of magnetic Fe{sup 3+} ions at the bipyramidal sites. The displacement at 4 K is about half of that at room temperature. The temperature dependence of the specific heat shows no anomaly associated with long range polar ordering in the temperature range from 1.90 to 300 K. The inverse dielectric permittivity, 1/ε, along the c-axis shows a T{sup 2} temperature dependence between 10 K and 20 K, with a significantly reduced temperature dependence displayed below 10 K. Moreover, as the sample is cooled below 1.4 K there is an anomalous sharp upturn in 1/ε. These features resemble those of classic quantum paraelectrics such as SrTiO{sub 3}. The presence of the upturn in 1/ε indicates that BaFe{sub 12}O{sub 19} is a critical quantum paraelectric system with Fe{sup 3+} ions involved in both magnetic and electric dipole formation.
To identify novel components of the TCR signaling pathway, a large-scale retroviral-based functional screen was performed using CD69 expression as a marker for T cell activation. In addition to known ...regulators, two truncated forms of p21-activated kinase 2 (PAK2), PAK2DeltaL(1-224) and PAK2DeltaS(1-113), both lacking the kinase domain, were isolated in the T cell screen. The PAK2 truncation, PAK2DeltaL, blocked Ag receptor-induced NFAT activation and TCR-mediated calcium flux in Jurkat T cells. However, it had minimal effect on PMA/ionomycin-induced CD69 up-regulation in Jurkat cells, on anti-IgM-mediated CD69 up-regulation in B cells, or on the migratory responses of resting T cells to chemoattractants. We show that PAK2 kinase activity is increased in response to TCR stimulation. Furthermore, a full-length kinase-inactive form of PAK2 blocked both TCR-induced CD69 up-regulation and NFAT activity in Jurkat cells, demonstrating that kinase activity is required for PAK2 function downstream of the TCR. We also generated a GFP-fused PAK2 truncation lacking the Cdc42/Rac interactive binding region domain, GFP-PAK2(83-149). We show that this construct binds directly to the kinase domain of PAK2 and inhibits anti-TCR-stimulated T cell activation. Finally, we demonstrate that, in primary T cells, dominant-negative PAK2 prevented anti-CD3/CD28-induced IL-2 production, and TCR-induced CD40 ligand expression, both key functions of activated T cells. Taken together, these results suggest a novel role for PAK2 as a positive regulator of T cell activation.
The structural relationship of 16 asiatic acid (AA) derivatives, including AA and asiaticoside (AS) to cytotoxicity and anti-hepatofibrotic activity in HSC-T6 cells, were investigated. Cytotoxicities ...of AA derivatives varied from 5.5 microM to over 2000 microM of IC50 depending on AA functional group modifications. Substituting the hydroxyl group at the C(2) to Ntriple bondC and substituting bulky groups for dihydroxyl groups at (3), (23) of the A-ring increased the cytotoxicity, but keto group at C(11) and benzoyl ester at C(2) were greatly reduced it. Modification of the carboxylic acid group at C28 also reduced the cytotoxicity. The collagen synthesis determined by hydroxyproline content in the cells was inhibited from a maximum of 48% (Zlx-i-85 and 87) to 15% (AS) by AA derivatives. The anti-hepatofibrotic effect of these compounds might be due to the reduced expression of prolyl 4-hydroxylase alpha and beta subunits and TIMP2. However, the inhibition of collagen by asiaticoside derivatives did not show any structural-activity relationship.
This paper reports for the first time the identification of a magnetic structure around a magnetic null in a magnetic reconnection region in the magnetotail. Magnetic reconnection is one of the ...fundamental processes in astrophysical and solar‐terrestrial plasmas. Though the concept of reconnection has been studied for many years, the process that really occurs has not been fully revealed by direct measurements. In particular, the lack of a description of three‐dimensional (3‐D) reconnecting magnetic field from observations makes the task more difficult. The Cluster spacecraft array provide an opportunity to reconstruct the 3‐D magnetic reconnection structure based on magnetic field vectors simultaneously measured at four positions. The identification of this structure comes from a new method of analysis of in situ measurements proposed here. Applying a fitting model of 10 spherical harmonic functions and a Harris current sheet function, plus a constant field, we reconstruct a 3‐D magnetic field configuration around the magnetic null in an reconnection event observed by Cluster in the geo‐magnetotail.
The KM2A is the largest sub-array of the Large High Altitude Air Shower Observatory (LHAASO). It consists of 5216 electromagnetic particle detectors (EDs) and 1188 muon detectors (MDs). The data ...recorded by the EDs and MDs are used to reconstruct primary information of cosmic ray and gamma-ray showers. This information is used for physical analysis in gamma-ray astronomy and cosmic ray physics. To ensure the reliability of the LHAASO-KM2A data, a three-level quality control system has been established. It is used to monitor the status of detector units, stability of reconstructed parameters and the performance of the array based on observations of the Crab Nebula and Moon shadow. This paper will introduce the control system and its application on the LHAASO-KM2A data collected from August 2021 to July 2023. During this period, the pointing and angular resolution of the array were stable. From the observations of the Moon shadow and Crab Nebula, the results achieved using the two methods are consistent with each other. According to the observation of the Crab Nebula at energies from 25 TeV to 100 TeV, the time averaged pointing errors are estimated to be \(-0.003^{\circ} \pm 0.005^{\circ}\) and \(0.001^{\circ} \pm 0.006^{\circ}\) in the R.A. and Dec directions, respectively.
We present measurements of the Cabibbo-suppressed decays Λc+→Λ0K+ and Λc+→Σ0K+ (both first observations), Λc+→Σ+K+π− (seen with large statistics for the first time), Λc+→pK+K− and Λc+→pφ (measured ...with improved accuracy). Improved branching ratio measurements for the decays Λc+→Σ+K+K− and Λc+→Σ+φ, which are attributed to W-exchange diagrams, are shown. We also present the first evidence for Λc+→Ξ(1690)0K+ and set an upper limit on the non-resonant decay Λc+→Σ+K+K−. This analysis was performed using 32.6 fb−1 of data collected by the Belle detector at the asymmetric e+e− collider KEKB.
Objectives This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis ...Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. Background During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)–lowering therapy did not reduce CV events compared with LDL-C–lowering therapy alone. Methods Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥198 mg/dl) and lowest HDL-C (<33 mg/dl) tertiles, ER niacin showed a trend toward benefit (hazard ratio: 0.74, p = 0.073). In-trial LDL-C levels, non–HDL-C levels, and the total cholesterol/HDL-C ratio were positively associated with CV events in the control group, but these relationships were absent in the ER niacin group. Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C–lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events AIM-HIGH; NCT00120289 )
To understand the genetic mechanisms underlying the progression of hepatocellular carcinoma (HCC) metastasis, differences of genomic alterations between 10 pairs of primary HCC tumors and their ...matched metastatic lesions were analyzed by comparative genomic hybridization. Several chromosomal alterations including loss of 8p, 4q, 17p, and 19p, gain of 5p and high-level amplification of 1q12-q22 were detected in two or more cases. The most significant finding is the loss of 8p which was detected in 8 metastatic tumors but only in 3 corresponding primary tumors (P = 0.03). This result suggests that the deletion of chromosome 8p might contribute to the development of HCC metastasis. Another interesting result is the detection of a minimum high-level amplification region at 1q12-q22 in HCC. This result provides a candidate amplification region in HCC for further study to identify amplified oncogenes related to the development or progression of HCC. Finally, this study provides a practicable model to detect specific genetic alterations related to the tumor metastasis through comparing the primary tumor and its corresponding metastatic lesion using comparative genomic hybridization technique.
Purpose Although the strength of a tendon repair is clearly important, the friction of the repair is also a relevant consideration. The purpose of this study was to characterize the frictional ...coefficient, gliding resistance, and breaking strength of suture materials and a suture construct commonly used for flexor tendon repair. Methods We measured the friction coefficients of 3-0 braided nylon enclosed in a smooth nylon outer shell (Supramid, S. Jackson, Alexandria, VA), 3-0 braided polyester coated with polybutilate (Ethibond, Ethicon, Somerville, NJ), and 3-0 braided polyester/monofilament polyethylene composite (FiberWire, Arthrex, Naples, FL) sutures. We also measured the gliding resistance, linear breaking strength, and resistance to gapping of zone 2 modified Pennington tendon repairs with the 2 lowest-friction sutures in 20 human cadaveric flexor digitorum profundus tendons. Results The braided polyester/monofilament polyethylene composite had a significantly lower friction coefficient (0.054) than either the coated polyester (0.076) or nylon (0.130) sutures. The gliding resistances of the repaired tendons with braided/monofilament polyethylene composite suture and those of coated, braided polyester were similar. The strength of the 2 repairs (force to produce a 2 mm gap) and resistance to gap formation were also not significantly different. Conclusions Braided polyester composite is a low-friction suture material. However, when this suture was used for tendon repair with a locking suture technique, it did not show a significant effect on the gliding resistance and repair strength compared with the same repair using a coated polyester suture.
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