Eigenvector sensitivity under general and structured perturbations of tridiagonal Toeplitz-type matrices

The sensitivity of eigenvalues of structured matrices under general or structured perturbations of the matrix entries has been thoroughly studied in the literature. Error bounds are available and the pseudospectrum can be computed to gain insight. Few investigations have focused on analyzing the sensitivity of eigenvectors under general or structured perturbations. The present paper discusses this sensitivity for tridiagonal Toeplitz and Toeplitz-type matrices.Comment: 21 pages, 4 figure

Triclosan Disrupts SKN-1/Nrf2- Mediated Oxidative Stress Response in C. elegans and Human Mesenchymal Stem Cells

Triclosan (TCS), an antimicrobial chemical with potential endocrine-disrupting properties, may pose a risk to early embryonic development and cellular homeostasis during adulthood. Here, we show that TCS induces toxicity in both the nematode C. elegans and human mesenchymal stem cells (hMSCs) by disrupting the SKN-1/Nrf2-mediated oxidative stress response. Specifically, TCS exposure affected C. elegans survival and hMSC proliferation in a dose-dependent manner. Cellular analysis showed that TCS inhibited the nuclear localization of SKN-1/Nrf2 and the expression of its target genes, which were associated with oxidative stress response. Notably, TCS-induced toxicity was significantly reduced by either antioxidant treatment or constitutive SKN-1/Nrf2 activation. As Nrf2 is strongly associated with aging and chemoresistance, these findings will provide a novel approach to the identification of therapeutic targets and disease treatment

Effect of P to A Mutation of the N-Terminal Residue Adjacent to the Rgd Motif on Rhodostomin: Importance of Dynamics in Integrin Recognition

Rhodostomin (Rho) is an RGD protein that specifically inhibits integrins. We found that Rho mutants with the P48A mutation 4.4–11.5 times more actively inhibited integrin α5β1. Structural analysis showed that they have a similar 3D conformation for the RGD loop. Docking analysis also showed no difference between their interactions with integrin α5β1. However, the backbone dynamics of RGD residues were different. The values of the R2 relaxation parameter for Rho residues R49 and D51 were 39% and 54% higher than those of the P48A mutant, which caused differences in S2, Rex, and τe. The S2 values of the P48A mutant residues R49, G50, and D51 were 29%, 14%, and 28% lower than those of Rho. The Rex values of Rho residues R49 and D51 were 0.91 s−1 and 1.42 s−1; however, no Rex was found for those of the P48A mutant. The τe values of Rho residues R49 and D51 were 9.5 and 5.1 times lower than those of P48A mutant. Mutational study showed that integrin α5β1 prefers its ligands to contain (G/A)RGD but not PRGD sequences for binding. These results demonstrate that the N-terminal proline residue adjacent to the RGD motif affect its function and dynamics, which suggests that the dynamic properties of the RGD motif may be important in Rho's interaction with integrin α5β1

The Gag Cleavage Product, p12, is a Functional Constituent of the Murine Leukemia Virus Pre-Integration Complex

The p12 protein is a cleavage product of the Gag precursor of the murine leukemia virus (MLV). Specific mutations in p12 have been described that affect early stages of infection, rendering the virus replication-defective. Such mutants showed normal generation of genomic DNA but no formation of circular forms, which are markers of nuclear entry by the viral DNA. This suggested that p12 may function in early stages of infection but the precise mechanism of p12 action is not known. To address the function and follow the intracellular localization of the wt p12 protein, we generated tagged p12 proteins in the context of a replication-competent virus, which allowed for the detection of p12 at early stages of infection by immunofluorescence. p12 was found to be distributed to discrete puncta, indicative of macromolecular complexes. These complexes were localized to the cytoplasm early after infection, and thereafter accumulated adjacent to mitotic chromosomes. This chromosomal accumulation was impaired for p12 proteins with a mutation that rendered the virus integration-defective. Immunofluorescence demonstrated that intracellular p12 complexes co-localized with capsid, a known constituent of the MLV pre-integration complex (PIC), and immunofluorescence combined with fluorescent in situ hybridization (FISH) revealed co-localization of the p12 proteins with the incoming reverse transcribed viral DNA. Interactions of p12 with the capsid and with the viral DNA were also demonstrated by co-immunoprecipitation. These results imply that p12 proteins are components of the MLV PIC. Furthermore, a large excess of wt PICs did not rescue the defect in integration of PICs derived from mutant p12 particles, demonstrating that p12 exerts its function as part of this complex. Altogether, these results imply that p12 proteins are constituent of the MLV PIC and function in directing the PIC from the cytoplasm towards integration

HIV infection of non-dividing cells: a divisive problem

Understanding how lentiviruses can infect terminally differentiated, non-dividing cells has proven a very complex and controversial problem. It is, however, a problem worth investigating, for it is central to HIV-1 transmission and AIDS pathogenesis. Here I shall attempt to summarise what is our current understanding for HIV-1 infection of non-dividing cells. In some cases I shall also attempt to make sense of controversies in the field and advance one or two modest proposals

Evaluation of an automated method for arterial input function detection for first-pass myocardial perfusion cardiovascular magnetic resonance

ABSTRACT: Background: Quantitative assessment of myocardial blood flow (MBF) with first-pass perfusion cardiovascular magnetic resonance (CMR) requires a measurement of the arterial input function (AIF). This study presents an automated method to improve the objectivity and reduce processing time for measuring the AIF from first-pass perfusion CMR images. This automated method is used to compare the impact of different AIF measurements on MBF quantification.Methods: Gadolinium-enhanced perfusion CMR was performed on a 1.5 T scanner using a saturation recovery dual-sequence technique. Rest and stress perfusion series from 270 clinical studies were analyzed. Automated image processing steps included motion correction, intensity correction, detection of the left ventricle (LV), independent component analysis, and LV pixel thresholding to calculate the AIF signal. The results were compared with manual reference measurements using several quality metrics based on the contrast enhancement and timing characteristics of the AIF. The median and 95 % confidence interval (CI) of the median were reported. Finally, MBF was calculated and compared in a subset of 21 clinical studies using the automated and manual AIF measurements.Results: Two clinical studies were excluded from the comparison due to a congenital heart defect present in one and a contrast administration issue in the other. The proposed method successfully processed 99.63 % of the remaining image series. Manual and automatic AIF time-signal intensity curves were strongly correlated with median correlation coefficient of 0.999 (95 % CI [0.999, 0.999]). The automated method effectively selected bright LV pixels, excluded papillary muscles, and required less processing time than the manual approach. There was no significant difference in MBF estimates between manually and automatically measured AIFs (p = NS). However, different sizes of regions of interest selection in the LV cavity could change the AIF measurement and affect MBF calculation (p = NS to p = 0.03).Conclusion: The proposed automatic method produced AIFs similar to the reference manual method but required less processing time and was more objective. The automated algorithm may improve AIF measurement from the first-pass perfusion CMR images and make quantitative myocardial perfusion analysis more robust and readily available