Tyrosine phosphatase SHP-2 regulates IL-1 signaling in fibroblasts through focal adhesions

Interleukin-1beta (IL-1beta) mediates destruction of matrix collagens in diverse inflammatory diseases including arthritis, periodontitis, and pulmonary fibrosis by activating fibroblasts, cells that interact with matrix proteins through integrin-based adhesions. In vitro, IL-1beta signaling is modulated by focal adhesions, supramolecular protein complexes that are enriched with tyrosine kinases and phosphatases. We assessed the importance of tyrosine phosphatases in regulating cell-matrix interactions and IL-1beta signaling. In human gingival fibroblasts plated on fibronectin, IL-1beta enhanced the maturation of focal adhesions as defined by morphology and enrichment with paxillin and alpha-actinin. IL-1beta also induced activation of ERK and recruitment of phospho-ERK to focal complexes/adhesions. Treatment with the potent tyrosine phosphatase inhibitor pervanadate, in the absence of IL-1beta, recapitulated many of these responses indicating the importance of tyrosine phosphatases. Immunoblotting of collagen bead-associated complexes revealed that the tyrosine phosphatase, SHP-2, was also enriched in focal complexes/adhesions. Depletion of SHP-2 by siRNA or by homologous recombination markedly altered IL-1beta-induced ERK activation and maturation of focal adhesions. IL-1beta-induced tyrosine phosphorylation of SHP-2 on residue Y542 promoted focal adhesion maturation. Association of Gab1 with SHP-2 in focal adhesions correlated temporally with activation of ERK and was abrogated in cells expressing mutant (Y542F) SHP-2. We conclude that IL-1beta mediated maturation of focal adhesions is dependent on tyrosine phosphorylation of SHP-2 at Y542, leading to recruitment of Gab1, a process that may influence the downstream activation of ERK.     

DNA binding properties of novel cytotoxic gold(III) complexes of terpyridine ligands: the impact of steric and electrostatic effects

Four gold(III) complexes of terpyridine derivatives 1–4 have been synthesized and characterized by spectroscopic methods. In vitro data demonstrated that all of them showed higher cytotoxicity than cisplatin against the human non-small-cell lung cancer cell line (A-549), the human stomach carcinoma cell line (SGC-7901), the human cervix carcinoma cell line (HELA), the human colon carcinoma cell line (HCT-116), the human liver carcinoma cell line (BEL-7402), the murine leukemia cell line (P-388) and the human acute promyelocytic leukemia cell line (HL-60). Complex 3 exhibits the highest activity, with growth inhibition rates of over 80% at 10⁻⁸ mol L⁻¹ against the A-549, HCT-116 and HELA tumor cell lines. Interestingly, ligands L1–L4 are also very cytotoxic against the cell lines tested. Complexes 1–4 are stable in aqueous solution for 2 days in the presence of the biological reducing agent glutathione. The inductively coupled plasma mass spectrometry data showed that DNA isolated from cells treated with complexes 1 and 3 contained gold with gold-to-nucleotide ratios of approximately 1:6,400 and 1:4,900, respectively. Fluorescence titration, UV and circular dichroism analyses proved that the steric and electrostatic effects of the ligand remarkably influence the interactions of their gold(III) complexes with DNA. The DNA binding ability of the complexes has been correlated with their cytotoxicity, which could potentially provide a new rationale for the future design of terpyridine-based metal complexes with antitumor potential.Electronic Supplementary Material Supplementary material is available to authorized users in the online version of this article at .     

Importance of assemblage‐level thinning: A field experiment in an alpine meadow on the Tibet plateau

Question: Which fraction of the decrease in species richness under fertilization can be explained by assemblage‐level thinning? Location: An alpine meadow on the eastern Tibet plateau. Methods: 60‐m² plots were randomly assigned to a control or one of four levels of ammonium phosphate fertilizer. Treatments were repeated for three years. The effect of as semblage‐level thinning was decided based on similarity in quadrats within and between fertilizing levels, bootstrap simulation based on random thinning of the high density (low production, low fertility) quadrats and correlation of species’ biomass in low fertility and high fertility. Results: Fertilization increased production, reduced species richness and reduced density of individuals. Heavily fertilized quadrats are more similar in species composition in 2000 but less similar in 2001 and 2002. Rarefaction showed that a decrease in density can account for 32.3‐42.9% decrease of species richness, but the simulated species richness is always significantly higher than the observed one. When production and species richness are similar at two levels of fertilization, species biomass in the higher fertility treatment is positively correlated with biomass at lower fertility. When the two fertilizer levels differed in production and species richness, there was no evidence of correlation in species biomass, suggesting that assemblage level thinning cannot explain all the loss of species. Conclusion: Although a decrease in density could explain much of the decrease (up to 42.9%) in species richness when this alpine meadow was fertilized, other important mechanisms such as interspecific competition cannot be ignored. Future studies should investigate the effect of assemblage level thinning on species diversity, and search for mechanisms responsible for a decrease in diversity.     

An efficient comprehensive search algorithm for tagSNP selection using linkage disequilibrium criteria

MOTIVATION: Selecting SNP markers for genome-wide association studies is an important and challenging task. The goal is to minimize the number of markers selected for genotyping in a particular platform and therefore reduce genotyping cost while simultaneously maximizing the information content provided by selected markers. RESULTS: We devised an improved algorithm for tagSNP selection using the pairwise r(2) criterion. We first break down large marker sets into disjoint pieces, where more exhaustive searches can replace the greedy algorithm for tagSNP selection. These exhaustive searches lead to smaller tagSNP sets being generated. In addition, our method evaluates multiple solutions that are equivalent according to the linkage disequilibrium criteria to accommodate additional constraints. Its performance was assessed using HapMap data. AVAILABILITY: A computer program named FESTA has been developed based on this algorithm. The program is freely available and can be downloaded at http://www.sph.umich.edu/csg/qin/FESTA/     

Exploiting redundancy to boost performance in a RAID-10 style cluster-based file system

While aggregating the throughput of existing disks on cluster nodes is a cost-effective approach to alleviate the I/O bottleneck in cluster computing, this approach suffers from potential performance degradations due to contentions for shared resources on the same node between storage data processing and user task computation. This paper proposes to judiciously utilize the storage redundancy in the form of mirroring existed in a RAID-10 style file system to alleviate this performance degradation. More specifically, a heuristic scheduling algorithm is developed, motivated from the observations of a simple cluster configuration, to spatially schedule write operations on the nodes with less load among each mirroring pair. The duplication of modified data to the mirroring nodes is performed asynchronously in the background. The read performance is improved by two techniques: doubling the degree of parallelism and hot-spot skipping. A synthetic benchmark is used to evaluate these algorithms in a real cluster environment and the proposed algorithms are shown to be very effective in performance enhancement. Yifeng Zhu received his B.Sc. degree in Electrical Engineering in 1998 from Huazhong University of Science and Technology, Wuhan, China; the M.S. and Ph.D. degree in Computer Science from University of Nebraska – Lincoln in 2002 and 2005 respectively. He is an assistant professor in the Electrical and Computer Engineering department at University of Maine. His main research interests are cluster computing, grid computing, computer architecture and systems, and parallel I/O storage systems. Dr. Zhu is a Member of ACM, IEEE, the IEEE Computer Society, and the Francis Crowe Society. Hong Jiang received the B.Sc. degree in Computer Engineering in 1982 from Huazhong University of Science and Technology, Wuhan, China; the M.A.Sc. degree in Computer Engineering in 1987 from the University of Toronto, Toronto, Canada; and the PhD degree in Computer Science in 1991 from the Texas A&M University, College Station, Texas, USA. Since August 1991 he has been at the University of Nebraska-Lincoln, Lincoln, Nebraska, USA, where he is Professor and Vice Chair in the Department of Computer Science and Engineering. His present research interests are computer architecture, parallel/distributed computing, cluster and Grid computing, computer storage systems and parallel I/O, performance evaluation, real-time systems, middleware, and distributed systems for distance education. He has over 100 publications in major journals and international Conferences in these areas and his research has been supported by NSF, DOD and the State of Nebraska. Dr. Jiang is a Member of ACM, the IEEE Computer Society, and the ACM SIGARCH. Xiao Qin received the BS and MS degrees in computer science from Huazhong University of Science and Technology in 1992 and 1999, respectively. He received the PhD degree in computer science from the University of Nebraska-Lincoln in 2004. Currently, he is an assistant professor in the department of computer science at the New Mexico Institute of Mining and Technology. He had served as a subject area editor of IEEE Distributed System Online (2000–2001). His research interests are in parallel and distributed systems, storage systems, real-time computing, performance evaluation, and fault-tolerance. He is a member of the IEEE. Dan Feng received the Ph.D degree from Huazhong University of Science and Technology, Wuhan, China, in 1997. She is currently a professor of School of Computer, Huazhong University of Science and Technology, Wuhan, China. She is the principal scientist of the the National Grand Fundamental Research 973 Program of China “Research on the organization and key technologies of the Storage System on the next generation Internet.” Her research interests include computer architecture, storage system, parallel I/O, massive storage and performance evaluation. David Swanson received a Ph.D. in physical (computational) chemistry at the University of Nebraska-Lincoln (UNL) in 1995, after which he worked as an NSF-NATO postdoctoral fellow at the Technical University of Wroclaw, Poland, in 1996, and subsequently as a National Research Council Research Associate at the Naval Research Laboratory in Washington, DC, from 1997–1998. In 1999 he returned to UNL where he directs the Research Computing Facility and currently serves as an Assistant Research Professor in the Department of Computer Science and Engineering. The Office of Naval Research, the National Science Foundation, and the State of Nebraska have supported his research in areas such as large-scale scientific simulation and distributed systems.     

Determination of ultrasound phase velocity in trabecular bone using time dependent phase tracking technique

Ultrasound velocity is one of the key acoustic parameters for noninvasive diagnosis of osteoporosis. Ultrasound phase velocity can be uniquely measured from the phase of the ultrasound signal at a specified frequency. Many previous studies used fast Fourier transform (FFT) to determine the phase velocity, which may cause errors due to the limitations of FFT. The new phase tracking technique applied an adaptive tracking algorithm to detect the time dependent phase and amplitude of the ultrasound signal at a specified frequency. This overcame the disadvantages of FFT to ensure the accuracy of the ultrasound phase velocity. As a result, the new method exhibited high accuracy in the measurement of ultrasound phase velocity of two phantom blocks with the error less than 0.4%. 41 cubic trabecular samples from sheep femoral condyles were used in the study. The phase velocity of the samples using the new method had significantly high correlation to the bulk stiffness of the samples (r = 0.84) compared to the phase velocity measured using fast Fourier transform FFT (r = 0.14). In conclusion, the new method provided an accurate measurement of the ultrasound phase velocity in bone.     

Gold(III) compounds of 1,4,7-triazacyclononane showing high cytotoxicity against A-549 and HCT-116 tumor cell lines

Two gold(III) compounds [Au(TACN)Cl(2)]Cl (1) and [Au(TACN)Cl(2)][AuCl(4)] (2) (where TACN=1,4,7-triazacyclononane), have been synthesized and characterized by electrospray ionization mass spectrometry (ESI-MS), (1)H NMR spectroscopy and elemental analyses. The structure of compound 2 was determined by X-ray crystallography, in which TACN coordinates to the gold(III) center in a bidentate mode and the unbound amine group forms a very short intramolecular Au-H(-N) contact (1.91A). Biological activity data showed that compound 1 is more cytotoxic than cisplatin against A-549 and HCT-116 tumor cell lines. The interactions of compound 1 with CT-DNA were studied by UV-Vis, fluorescence and CD spectroscopy, which suggests that compound 1 can induce the distortion of DNA double helix.     

Stimulation effect of lithium on the metabolic activity of liver tissue mitochondria measured by microcalorimetry

The effect of Li(I) on the metabolism of mitochondria isolated from Carassius auratus liver tissue was investigated by microcalorimetric method to provide evidence for mitochondria hypothesis of biporlar disorder (BPD) and to explore therapeutic mechanism of drug for treatment of BPD. Obvious stimulation induced by Li(I) on mitochondria metabolism was reflected by power-time (P-t) curves. The power-time curves of hepatic mitochondria metabolism without Li(I) could be divided into four parts: lag phase, active recovery phase, stationary phase, and decline phase. When Li(I) was added, the second heat peak occurred in a concentration-dependent sequence. Considering the first heat peak on the p-t curves, Li(I) in the range of therapeutic and lower concentration induced slight alterations in comparison with the characteristic heat peak observed in the control. However, Li(I) above the therapeutic concentration resulted in significant changes. Heat output increased with the concentration of Li(I), but the rate constant (k ₂) and the maximum heat power (P _max2) for the second heat peak reached maximum value in the range of therapeutic concentration. Mechanism of activation of mitoKatp was suggested and discussed.