Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of A beta Toxicity and Stroke

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer\u27s disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain\u27s response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (A beta) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model A beta toxicity, rats received intracerebralventricular (icv) injections of the toxic 25-35 fragment of the A beta peptide (A beta alone group). To model the combination of A beta toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of A beta(25-35) (combined A beta/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without A beta. By 21 d, GM2 levels only remained elevated in the combined A beta/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined A beta/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and A beta/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke

Ratios of BB and DD Meson Decay Constants in Relativistic Quark Model

We calculate the ratios of $B$ and $D$ meson decay constants by applying the variational method to the relativistic hamiltonian of the heavy meson. We adopt the Gaussian and hydrogen-type trial wave functions, and use six different potentials of the potential model. We obtain reliable results for the ratios, which are similar for different trial wave functions and different potentials. The obtained ratios show the deviation from the nonrelativistic scaling law, and they are in a pretty good agreement with the results of the Lattice calculations.Comment: 13 pages, 1 Postscript figur

Magnetic Field Dependence of Macroscopic Quantum Tunneling and Coherence of Ferromagnetic Particle

We calculate the quantum tunneling rate of a ferromagnetic particle of $\sim 100 \AA$ diameter in a magnetic field of arbitrary angle. We consider the magnetocrystalline anisotropy with the biaxial symmetry and that with the tetragonal symmetry. Using the spin-coherent-state path integral, we obtain approximate analytic formulas of the tunneling rates in the small $\epsilon (=1- H/H_c)$-limit for the magnetic field normal to the easy axis ($\theta_H = \pi/2$), for the field opposite to the initial easy axis ($\theta_H = \pi$), and for the field at an angle between these two orientations ($\pi/2 << \theta_H << \pi$). In addition, we obtain numerically the tunneling rates for the biaxial symmetry in the full range of the angle $\theta_H$ of the magnetic field ($\pi/2 < \theta_H \leq \pi$), for the values of \epsilon =0.01 and 0.001.Comment: 25 pages of text (RevTex) and 4 figures (PostScript files), to be published in Phys. Rev.

Expression of TLR2, TLR4, and TLR9 in dermatomyositis and polymyositis

The aim of this study was to investigate the expressions of Toll-like receptor (TLR) 2, TLR4, TLR9, and their correlations with the expression of cytokines that are associated with activation of CD4+ T cells and inflammation including interferon γ (IFNγ), interleukin 4 (IL4), interleukin 17 (IL17), and tumor necrosis factor α (TNFα) in muscle tissues of patients with dermatomyositis (DM) and polymyositis (PM). The expressions of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were measured by real-time reverse transcription–polymerase chain reaction in muscle tissues from 14 patients with DM and PM (nine patients with DM, five patients with PM) and three controls. The expressions of TLR2, TLR4, and TLR9 were also localized with immunohistochemistry. The expression levels of TLR2, TLR4, TLR9, IFNγ, IL4, IL17, and TNFα were significantly high in patients with DM and PM compared with those in the controls, and the expression levels of TLR4 and TLR9 had significant positive correlations with the expressions of IFNγ, IL4, IL17, and TNFα. Immunohistochemistry showed that TLR2, TLR4, and TLR9 were expressed by infiltrating cells of perimysium in DM, whereas they were expressed by infiltrating cells of endomysium in PM. These results suggest that the involvement of TLR4 and TLR9 in immunopathogenesis of DM and PM might be connected with activation of CD4+ T cells

Mammalian Ste20-Like Kinase and SAV1 Promote 3T3-L1 Adipocyte Differentiation by Activation of PPARγ

The mammalian ste20 kinase (MST) signaling pathway plays an important role in the regulation of apoptosis and cell cycle control. We sought to understand the role of MST2 kinase and Salvador homolog 1 (SAV1), a scaffolding protein that functions in the MST pathway, in adipocyte differentiation. MST2 and MST1 stimulated the binding of SAV1 to peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor that plays a key role in adipogenesis. The interaction of endogenous SAV1 and PPARγ was detected in differentiating 3T3-L1 adipocytes. This binding required the kinase activity of MST2 and was mediated by the WW domains of SAV1 and the PPYY motif of PPARγ. Overexpression of MST2 and SAV1 increased PPARγ levels by stabilizing the protein, and the knockdown of SAV1 resulted in a decrease of endogenous PPARγ protein in 3T3-L1 adipocytes. During the differentiation of 3T3-L1 cells into adipocytes, MST2 and SAV1 expression began to increase at 2 days when PPARγ expression also begins to increase. MST2 and SAV1 significantly increased PPARγ transactivation, and SAV1 was shown to be required for the activation of PPARγ by rosiglitazone. Finally, differentiation of 3T3-L1 cells was augmented by MST2 and SAV1 expression and inhibited by knockdown of MST1/2 or SAV1. These results suggest that PPARγ activation by the MST signaling pathway may be a novel regulatory mechanism of adipogenesis

HIV Reservoirs and Immune Surveillance Evasion Cause the Failure of Structured Treatment Interruptions: A Computational Study

Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models

Decay Constants of BB, B∗B^* and DD, D∗D^* Mesons in Relativistic Mock Meson Model

We derive formulas for the decay constants $f_P$ and $f_V$ of pseudoscalar and vector mesons in the relativistic mock meson model. Using these formulas, we obtain $f_P$ and $f_V$ of $B_s$, $B_d$, $D_s$, and $D_d$ mesons as functions of the mock meson parameter $\beta$. Then by using the values of $\beta$ which are obtained by the variational method in the relativistic quark model, we obtain the decay constants $f_P$ and $f_V$ of the heavy mesons, and the corresponding ratios $f_V/f_P$. The results are compared with other calculations and existing experimental results.Comment: 12 pages, 3 Postscript figure

Methylsulfonylmethane Suppresses Breast Cancer Growth by Down-Regulating STAT3 and STAT5b Pathways

Breast cancer is the most aggressive form of all cancers, with high incidence and mortality rates. The purpose of the present study was to investigate the molecular mechanism by which methylsulfonylmethane (MSM) inhibits breast cancer growth in mice xenografts. MSM is an organic sulfur-containing natural compound without any toxicity. In this study, we demonstrated that MSM substantially decreased the viability of human breast cancer cells in a dose-dependent manner. MSM also suppressed the phosphorylation of STAT3, STAT5b, expression of IGF-1R, HIF-1α, VEGF, BrK, and p-IGF-1R and inhibited triple-negative receptor expression in receptor-positive cell lines. Moreover, MSM decreased the DNA-binding activities of STAT5b and STAT3, to the target gene promoters in MDA-MB 231 or co-transfected COS-7 cells. We confirmed that MSM significantly decreased the relative luciferase activities indicating crosstalk between STAT5b/IGF-1R, STAT5b/HSP90α, and STAT3/VEGF. To confirm these findings in vivo, xenografts were established in Balb/c athymic nude mice with MDA-MB 231 cells and MSM was administered for 30 days. Concurring to our in vitro analysis, these xenografts showed decreased expression of STAT3, STAT5b, IGF-1R and VEGF. Through in vitro and in vivo analysis, we confirmed that MSM can effectively regulate multiple targets including STAT3/VEGF and STAT5b/IGF-1R. These are the major molecules involved in tumor development, progression, and metastasis. Thus, we strongly recommend the use of MSM as a trial drug for treating all types of breast cancers including triple-negative cancers