Transition of tumor-associated macrophages from MHC class IIhi to MHC class IIlow mediates tumor progression in mice

<p>Abstract</p> <p>Background</p> <p>Tumor-associated macrophages (TAMs) are the most abundant immune cells within the tumor stroma and play a crucial role in tumor development. Although clinical investigations indicate that high levels of macrophage (MΦ) infiltration into tumors are associated with a poor prognosis, the exact role played by TAMs during tumor development remains unclear. The present study aimed to investigate dynamic changes in TAM major histocompatibility complex (MHC) class II expression levels and to assess the effects of these changes on tumor progression.</p> <p>Results</p> <p>Significant inhibition of tumor growth in the murine hepatocellular carcinoma Hepa1-6 model was closely associated with partial TAM depletion. Strikingly, two distinct TAM subsets were found to coexist within the tumor microenvironment during Hepa1-6 tumor development. An MHC class II^hiTAM population appeared during the early phase of tumor development and was associated with tumor suppression; however, an MHC class II^lowTAM population became increasingly predominant as the tumor progressed.</p> <p>Conclusions</p> <p>Tumor progression was positively correlated with increasing infiltration of the tumor tissues by MHC class II^lowTAMs. Thus, targeting the transition of MΦ may be a novel strategy for drug development and immunotherapy.</p

Predicting pressure sore risk with the Braden(modified),Norton and WCUMS Scales

2003-2004 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

3D Mapping of the SPRY2 Domain of Ryanodine Receptor 1 by Single-Particle Cryo-EM

The type 1 skeletal muscle ryanodine receptor (RyR1) is principally responsible for Ca2+ release from the sarcoplasmic reticulum and for the subsequent muscle contraction. The RyR1 contains three SPRY domains. SPRY domains are generally known to mediate protein-protein interactions, however the location of the three SPRY domains in the 3D structure of the RyR1 is not known. Combining immunolabeling and single-particle cryo-electron microscopy we have mapped the SPRY2 domain (S1085-V1208) in the 3D structure of RyR1 using three different antibodies against the SPRY2 domain. Two obstacles for the image processing procedure; limited amount of data and signal dilution introduced by the multiple orientations of the antibody bound in the tetrameric RyR1, were overcome by modifying the 3D reconstruction scheme. This approach enabled us to ascertain that the three antibodies bind to the same region, to obtain a 3D reconstruction of RyR1 with the antibody bound, and to map SPRY2 to the periphery of the cytoplasmic domain of RyR1. We report here the first 3D localization of a SPRY2 domain in any known RyR isoform

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

The Homeobox Transcription Factor Barx2 Regulates Plasticity of Young Primary Myofibers

Adult mammalian muscle retains incredible plasticity. Muscle growth and repair involves the activation of undifferentiated myogenic precursors called satellite cells. In some circumstances, it has been proposed that existing myofibers may also cleave and produce a pool of proliferative cells that can re-differentiate into new fibers. Such myofiber dedifferentiation has been observed in the salamander blastema where it may occur in parallel with satellite cell activation. Moreover, ectopic expression of the homeodomain transcription factor Msx1 in differentiated C2C12 myotubes has been shown to induce their dedifferentiation. While it remains unclear whether dedifferentiation and redifferentiaton occurs endogenously in mammalian muscle, there is considerable interest in induced dedifferentiation as a possible regenerative tool.We previously showed that the homeobox protein Barx2 promotes myoblast differentiation. Here we report that ectopic expression of Barx2 in young immature myotubes derived from cell lines and primary mouse myoblasts, caused cleavage of the syncytium and downregulation of differentiation markers. Microinjection of Barx2 cDNA into immature myotubes derived from primary cells led to cleavage and formation of mononucleated cells that were able to proliferate. However, injection of Barx2 cDNA into mature myotubes did not cause cleavage. Barx2 expression in C2C12 myotubes increased the expression of cyclin D1, which may promote cell cycle re-entry. We also observed differential muscle gene regulation by Barx2 at early and late stages of muscle differentiation which may be due to differential recruitment of transcriptional activator or repressor complexes to muscle specific genes by Barx2.We show that Barx2 regulates plasticity of immature myofibers and might act as a molecular switch controlling cell differentiation and proliferation

Exploiting physico-chemical properties in string kernels

<p>Abstract</p> <p>Background</p> <p>String kernels are commonly used for the classification of biological sequences, nucleotide as well as amino acid sequences. Although string kernels are already very powerful, when it comes to amino acids they have a major short coming. They ignore an important piece of information when comparing amino acids: the physico-chemical properties such as size, hydrophobicity, or charge. This information is very valuable, especially when training data is less abundant. There have been only very few approaches so far that aim at combining these two ideas.</p> <p>Results</p> <p>We propose new string kernels that combine the benefits of physico-chemical descriptors for amino acids with the ones of string kernels. The benefits of the proposed kernels are assessed on two problems: MHC-peptide binding classification using position specific kernels and protein classification based on the substring spectrum of the sequences. Our experiments demonstrate that the incorporation of amino acid properties in string kernels yields improved performances compared to standard string kernels and to previously proposed non-substring kernels.</p> <p>Conclusions</p> <p>In summary, the proposed modifications, in particular the combination with the RBF substring kernel, consistently yield improvements without affecting the computational complexity. The proposed kernels therefore appear to be the kernels of choice for any protein sequence-based inference.</p> <p>Availability</p> <p>Data sets, code and additional information are available from <url>http://www.fml.tuebingen.mpg.de/raetsch/suppl/aask</url>. Implementations of the developed kernels are available as part of the Shogun toolbox.</p

Learning Control of Quantum Systems

This paper provides a brief introduction to learning control of quantum systems. In particular, the following aspects are outlined, including gradient-based learning for optimal control of quantum systems, evolutionary computation for learning control of quantum systems, learning-based quantum robust control, and reinforcement learning for quantum control.Comment: 9 page

Measurement of Beam-Spin Asymmetries for Deep Inelastic π+\pi^+ Electroproduction

We report the first evidence for a non-zero beam-spin azimuthal asymmetry in the electroproduction of positive pions in the deep-inelastic region. Data have been obtained using a polarized electron beam of 4.3 GeV with the CLAS detector at the Thomas Jefferson National Accelerator Facility (JLab). The amplitude of the $\sin\phi$ modulation increases with the momentum of the pion relative to the virtual photon, $z$, with an average amplitude of $0.038 \pm 0.005 \pm 0.003$ for $0.5 < z < 0.8$ range.Comment: 5 pages, RevTEX4, 3 figures, 2 table

Diseased muscles that lack dystrophin or laminin-α2 have altered compositions and proliferation of mononuclear cell populations

BACKGROUND: Multiple types of mononucleate cells reside among the multinucleate myofibers in skeletal muscles and these mononucleate cells function in muscle maintenance and repair. How neuromuscular disease might affect different types of muscle mononucleate cells had not been determined. In this study, therefore, we examined how two neuromuscular diseases, dystrophin-deficiency and laminin-α2-deficiency, altered the proliferation and composition of different subsets of muscle-derived mononucleate cells. METHODS: We used fluorescence-activated cell sorting combined with bromodeoxyuridine labeling to examine proliferation rates and compositions of mononuclear cells in diseased and healthy mouse skeletal muscle. We prepared mononucleate cells from muscles of mdx (dystrophin-deficient) or Lama2(-/- )(laminin-α2-deficient) mice and compared them to cells from healthy control muscles. We enumerated subsets of resident muscle cells based on Sca-1 and CD45 expression patterns and determined the proliferation of each cell subset in vivo by BrdU incorporation. RESULTS: We found that the proliferation and composition of the mononucleate cells in dystrophin-deficient and laminin-α2-deficient diseased muscles are different than in healthy muscle. The mdx and Lama2(-/- )muscles showed similar significant increases in CD45(+ )cells compared to healthy muscle. Changes in proliferation, however, differed between the two diseases with proliferation increased in mdx and decreased in Lama2(-/- )muscles compared to healthy muscles. In particular, the most abundant Sca-1(-)/CD45(- )subset, which contains muscle precursor cells, had increased proliferation in mdx muscle but decreased proliferation in Lama2(-/- )muscles. CONCLUSION: The similar increases in CD45(+ )cells, but opposite changes in proliferation of muscle precursor cells, may underlie aspects of the distinct pathologies in the two diseases

Measurement of the Polarized Structure Function σLT′\sigma_{LT^\prime} for p(e⃗,e′p)πop(\vec{e},e'p)\pi^o in the Δ(1232)\Delta(1232) Resonance Region

The polarized longitudinal-transverse structure function $\sigma_{LT^\prime}$ has been measured in the $\Delta(1232)$ resonance region at $Q^2=0.40$ and 0.65 GeV$^2$. Data for the $p(\vec e,e'p)\pi^o$ reaction were taken at Jefferson Lab with the CEBAF Large Acceptance Spectrometer (CLAS) using longitudinally polarized electrons at an energy of 1.515 GeV. For the first time a complete angular distribution was measured, permitting the separation of different non-resonant amplitudes using a partial wave analysis. Comparison with previous beam asymmetry measurements at MAMI indicate a deviation from the predicted $Q^2$ dependence of $\sigma_{LT^{\prime}}$ using recent phenomenological models.Comment: 5 pages, LaTex, 4 eps figures: to be published in PRC/Rapid Communications. Version 2 has revised Q^2 analysi