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Tyrosine phosphorylation is tightly regulated by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), and has a critical role in malignant transformation and progression. Although PTKs have a well-established role in regulating breast cancer growth, contribution of PTPs remains mostly unknown. Here, we report that the tyrosine phosphatase PTPH1 stimulates breast cancer growth through regulating vitamin D receptor (VDR) expression. PTPH1 was shown to be overexpressed in 49% of primary breast cancer and levels of its protein expression positively correlate with the clinic metastasis, suggesting its oncogenic activity. Indeed, PTPH1 promotes breast cancer growth by a mechanism independent of its phosphatase activity, but dependent of its stimulatory effect on the nuclear receptor VDR protein expression and depletion of induced VDR abolishes the PTPH1 oncogenic activity. Additional analyses showed that PTPH1 binds VDR and increases its cytoplasmic accumulation, leading to their mutual stabilization and stable expression of a nuclear localization-deficient VDR abolishes the growth-inhibitory activity of the receptor independent of 1,25-dihydroxyvitamin D3. These results reveal a new paradigm in which a PTP may stimulate breast cancer growth through increasing cytoplasmic translocation of a nuclear receptor, leading to their mutual stabilization.

Owing to the loss of subcarrier orthogonalities in high-speed applications, the use of conventional frequency-domain-based channel estimation in high mobility orthogonal frequency division multiple access (OFDMA) systems such as mobile WiMax may give rise to an unacceptable high channel estimation error floor. To alleviate this problem, the authors develop some basis expansion model (BEM)-based estimation schemes for the OFDMA uplink. Specifically, the authors express the time-varying channel as a superposition of a small number of complex exponential basis functions spanning the entire Doppler range, and then formulate least square and linear minimum mean square error algorithms to estimate the basis coefficients for two different types of pilot patterns. The authors also derive the respective Cramer-Rao lower bounds for these estimators. It has been shown that the time domain BEM using a pilot scheme where pilots are placed over time axis will give better performance under a high Doppler scenario.

A bstract We report a search for B decays to selected final states with the η c meson: B ± → K ± η c π + π − , B ± → K ± η c ω , B ± → K ± η c η and B ± → K ± η c π 0 . The analysis is based on 772 × 10 6 B B ¯ pairs collected at the Υ(4 S ) resonance with the Belle detector at the KEKB asymmetric-energy e + e − collider. We set 90% confidence level upper limits on the branching fractions of the studied B decay modes, independent of intermediate resonances, in the range (0 . 6–5 . 3) × 10 −4 . We also search for molecular-state candidates in the D 0 D ¯ ∗ 0 − D ¯ 0 D ∗ 0 , D 0 D ¯ 0 + D ¯ 0 D 0 and D ∗ 0 D ¯ ∗ 0 + D ¯ ∗ 0 D ∗ 0 combinations, neutral partners of the Z (3900) ± and Z (4020) ± , and a poorly understood state X (3915) as possible intermediate states in the decay chain, and set 90% confidence level upper limits on the product of branching fractions to the mentioned intermediate states and decay branching fractions of these states in the range (0 . 6–6 . 9) × 10 −5 .

The rare osteosclerotic disease, pycnodysostosis, is characterized by decreased osteoclastic bone collagen degradation due to the absence of active cathepsin K. Although this enzyme is primarily expressed by osteoclasts, there is increasing evidence that it may also be present in other cells, including fibroblasts. Since fibroblasts are known to degrade collagen intracellularly following phagocytosis, we analyzed various soft connective tissues (periosteum, perichondrium, tendon, and synovial membrane) from a 13-week-old human fetus with pycnodysostosis for changes in this collagen digestion pathway. In addition, the same tissues from cathepsin K-deficient and control mice were analyzed. Microscopic examination of the human fetal tissues showed that cross-banded collagen fibrils had accumulated in lysosomal vacuoles of fibroblasts. Morphometric analysis of periosteal fibroblasts revealed that the volume density of collagen-containing vacuoles was 18 times higher than in fibroblasts of control patients. A similar accumulation was seen in periosteal fibroblasts of three children with pycnodysostosis. In contrast to the findings in humans, an accumulation of internalized collagen was not apparent in fibroblasts of mice with cathepsin K deficiency. Our observations indicate that the intracellular digestion of phagocytosed collagen by fibroblasts is inhibited in humans with pycnodysostosis, but probably not in the mouse model mimicking this disease. The data strongly suggest that cathepsin K is a crucial protease for this process in human fibroblasts. Murine fibroblasts may have other proteolytic activities that are expressed constitutively or up regulated in response to a deficiency of cathepsin K. This may explain why cathepsin K-deficient mice lack the dysostotic features that are prominent in patients with pycnodysostosis.

Synovial fibroblasts (SFs) play a critical role in the pathogenesis of rheumatoid arthritis (RA) and are directly involved in joint destruction. Both SF-resident matrix metalloproteases and cathepsins have been implicated in cartilage degradation although their identities and individual contributions remain unclear. The aims of this study were to investigate the expression of cathepsin K in SFs, the correlation between cathepsin K expression and disease severity, and the contribution of cathepsin K to fibroblast-mediated collagen degradation. Immunostaining of joint specimens of 21 patients revealed high expression of cathepsin K in SFs in the synovial lining and the stroma of synovial villi, and to a lesser extent in CD68-positive cells of the synovial lining. Cathepsin K-positive SFs were consistently observed at sites of cartilage and bone degradation. Expression levels of cathepsin K in the sublining and vascularized areas of inflamed synovia showed a highly significant negative correlation with results derived from the Hannover Functional Capacity Questionnaire ( r = 0.78, P = 0.003; and r = 0.70, P = 0.012, respectively) as a measure of the severity of RA in individual patients. For comparison, there was no correlation between Hannover Functional Capacity Questionnaire and cathepsin S whose expression is limited to CD-68-positive macrophage-like synoviocytes. The expression of cathepsin K was also demonstrated in primary cell cultures of RA-SFs. Co-cultures of SFs on cartilage disks revealed the ability of fibroblast-like cells to phagocytose collagen fibrils whose intralysosomal hydrolysis was prevented in the presence of a potent cathepsin K inhibitor but not by an inhibitor effective against cathepsins L, B, and S. The selective and critical role of cathepsin K in articular cartilage and subchondral bone erosion was further corroborated by the finding that cathepsin K has a potent aggrecan-degrading activity and that cathepsin K-generated aggrecan cleavage products specifically potentiate the collagenolytic activity of cathepsin K toward type I and II collagens. This study demonstrates for the first time a critical role of cathepsin K in cartilage degradation by SFs in RA that is comparable to its well-known activity in osteoclasts.

We present the first model-independent measurement of the CKM unitarity triangle angle ϕ3 using B±→ D(KS0\\[ {K}_{\\mathrm{S}}^0 \\]π+π−π0) K± decays, where D indicates either a D0 or D¯\\[ \\overline{D} \\]0 meson. Measurements of the strong-phase difference of the D →KS0\\[ {K}_{\\mathrm{S}}^0 \\]π+π−π0 amplitude obtained from CLEO-c data are used as input. This analysis is based on the full Belle data set of 772 × 106BB¯\\[ \\overline{B} \\] events collected at the Υ(4S) resonance. We obtain ϕ3 = (5.7−8.8+10.2\\[ {5.7}_{-8.8}^{+10.2} \\]±3.5±5.7)° and the suppressed amplitude ratio rB = 0.323±0.147±0.023±0.051. Here the first uncertainty is statistical, the second is the experimental systematic, and the third is due to the precision of the strong-phase parameters measured from CLEO-c data. The 95% confidence interval on ϕ3 is (−29.7, 109.5)°, which is consistent with the current world average.

High-precision analyses of supersymmetry parameters aim at reconstructing the fundamental supersymmetric theory and its breaking mechanism. A well defined theoretical framework is needed when higher-order corrections are included. We propose such a scheme, Supersymmetry Parameter Analysis SPA, based on a consistent set of conventions and input parameters. A repository for computer programs is provided which connect parameters in different schemes and relate the Lagrangian parameters to physical observables at LHC and high energy e + e- linear collider experiments, i.e., masses, mixings, decay widths and production cross sections for supersymmetric particles. In addition, programs for calculating high-precision low energy observables, the density of cold dark matter (CDM) in the universe as well as the cross sections for CDM search experiments are included. The SPA scheme still requires extended efforts on both the theoretical and experimental side before data can be evaluated in the future at the level of the desired precision. We take here an initial step of testing the SPA scheme by applying the techniques involved to a specific supersymmetry reference point.

Discoveries at the LHC will soon set the physics agenda for future colliders. This report of a CERN Theory Institute includes the summaries of Working Groups that reviewed the physics goals and prospects of LHC running with 10 to 300 fb−1 of integrated luminosity, of the proposed sLHC luminosity upgrade, of the ILC, of CLIC, of the LHeC and of a muon collider. The four Working Groups considered possible scenarios for the first 10 fb−1 of data at the LHC in which (i) a state with properties that are compatible with a Higgs boson is discovered, (ii) no such state is discovered either because the Higgs properties are such that it is difficult to detect or because no Higgs boson exists, (iii) a missing-energy signal beyond the Standard Model is discovered as in some supersymmetric models, and (iv) some other exotic signature of new physics is discovered. In the contexts of these scenarios, the Working Groups reviewed the capabilities of the future colliders to study in more detail whatever new physics may be discovered by the LHC. Their reports provide the particle physics community with some tools for reviewing the scientific priorities for future colliders after the LHC produces its first harvest of new physics from multi-TeV collisions.

We study B meson decays to two charmless baryons in the diquark model, including strong and electroweak penguins as well as the tree operators. It is shown that penguin operators can enhance \\(\\bar{B} \\rightarrow{\\vec B}_s \\bar{{\\vec B}}\\) considerably, but affect \\(\\bar{B} \\rightarrow{\\vec B}_1 \\bar{{\\vec B}}_2\\) only slightly, where \\({\\vec B}_{(1,2)}\\) and \\({\\vec B}_s\\) are non-strange and strange baryons, respectively. The \\(\\gamma\\) dependence of the decay rates due to tree–penguin interference is illustrated. In principle, some of the \\({\\vec B}_s \\bar{{\\vec B}}\\) modes could dominate over \\({\\vec B}_1 \\bar{{\\vec B}}_2\\) for \\(\\gamma > 90^\\circ\\), but in general the effect is milder than their mesonic counterparts. This is because the \\(O_6\\) operator can only produce vector but not scalar diquarks, while the opposite is true for \\(O_1\\) and \\(O_4\\). Predictions from the diquark model are compared to those from the sum rule calculation. The decays \\(\\bar{B} \\rightarrow{\\vec B}_s \\bar{{\\vec B}}_s\\) and inclusive baryonic decays are also discussed.