Bulk Fermi surface and momentum density in heavily doped La2−x_{2-x}Srx_xCuO4_4 using high resolution Compton scattering and positron annihilation spectroscopies

We have observed the bulk Fermi surface (FS) in an overdoped ($x$=0.3) single crystal of La$_{2-x}$Sr$_x$CuO$_4$ by using Compton scattering. A two-dimensional (2D) momentum density reconstruction from measured Compton profiles yields a clear FS signature in the third Brillouin zone along [100]. The quantitative agreement between density functional theory (DFT) calculations and momentum density experiment suggests that Fermi-liquid physics is restored in the overdoped regime. In particular the predicted FS topology is found to be in good accord with the corresponding experimental data. We find similar quantitative agreement between the measured 2D angular correlation of positron annihilation radiation (2D-ACAR) spectra and the DFT based computations. However, 2D-ACAR does not give such a clear signature of the FS in the extended momentum space in either the theory or the experiment.Comment: 9 pages, 8 figure

High resolution Compton scattering as a Probe of the Fermi surface in the Iron-based superconductor LaO1−xFxFeAsLaO_{1-x}F_xFeAs

We have carried out first principles all-electron calculations of the (001)-projected 2D electron momentum density and the directional Compton profiles along the [100], [001] and [110] directions in the Fe-based superconductor LaOFeAs within the framework of the local density approximation. We identify Fermi surface features in the 2D electron momentum density and the directional Compton profiles, and discuss issues related to the observation of these features via Compton scattering experiments.Comment: 4 pages, 3 figure

Anaplasma phagocytophilum Ats-1 Is Imported into Host Cell Mitochondria and Interferes with Apoptosis Induction

Anaplasma phagocytophilum, the causative agent of human granulocytic anaplasmosis, infects human neutrophils and inhibits mitochondria-mediated apoptosis. Bacterial factors involved in this process are unknown. In the present study, we screened a genomic DNA library of A. phagocytophilum for effectors of the type IV secretion system by a bacterial two-hybrid system, using A. phagocytophilum VirD4 as bait. A hypothetical protein was identified as a putative effector, hereby named Anaplasma translocated substrate 1 (Ats-1). Using triple immunofluorescence labeling and Western blot analysis of infected cells, including human neutrophils, we determined that Ats-1 is abundantly expressed by A. phagocytophilum, translocated across the inclusion membrane, localized in the host cell mitochondria, and cleaved. Ectopically expressed Ats-1 targeted mitochondria in an N-terminal 17 residue-dependent manner, localized in matrix or at the inner membrane, and was cleaved as native protein, which required residues 55–57. In vitro-translated Ats-1 was imported in a receptor-dependent manner into isolated mitochondria. Ats-1 inhibited etoposide-induced cytochrome c release from mitochondria, PARP cleavage, and apoptosis in mammalian cells, as well as Bax-induced yeast apoptosis. Ats-1(55–57) had significantly reduced anti-apoptotic activity. Bax redistribution was inhibited in both etoposide-induced and Bax-induced apoptosis by Ats-1. Taken together, Ats-1 is the first example of a bacterial protein that traverses five membranes and prevents apoptosis at the mitochondria

Using death to one's advantage: HIV modulation of apoptosis

Infection by human immunodeficiency virus (HIV) is associated with an early immune dysfunction and progressive destruction of CD4+ T lymphocytes. This progressive disappearance of T cells leads to a lack of immune control of HIV replication and to the development of immune deficiency resulting in the increased occurrence of opportunistic infections associated with acquired immune deficiency syndrome (AIDS). The HIV-induced, premature destruction of lymphocytes is associated with the continuous production of HIV viral proteins that modulate apoptotic pathways. The viral proteins, such as Tat, Env, and Nef, are associated with chronic immune activation and the continuous induction of apoptotic factors. Viral protein expression predisposes lymphocytes, particularly CD4+ T cells, CD8+ T cells, and antigen-presenting cells, to evolve into effectors of apoptosis and as a result, to lead to the destruction of healthy, non-infected T cells. Tat and Nef, along with Vpu, can also protect HIV-infected cells from apoptosis by increasing anti-apoptotic proteins and down- regulating cell surface receptors recognized by immune system cells. This review will discuss the validity of the apoptosis hypothesis in HIV disease and the potential mechanism(s) that HIV proteins perform in the progressive T cell depletion observed in AIDS pathogenesis. Originally published Leukemia, Vol. 15, No. 3, Mar 200

Suppression of Her2/neu expression through ILK inhibition is regulated by a pathway involving TWIST and YB-1

In a previous study it was found that the therapeutic effects of QLT0267, a small molecule inhibitor of integrin-linked kinase (ILK), were influenced by Her2/neu expression. To understand how inhibition or silencing of ILK influences Her2/neu expression, Her2/neu signaling was evaluated in six Her2/neu-positive breast cancer cell lines (LCC6Her2, MCF7Her2, SKBR3, BT474, JIMT-1 and KPL-4). Treatment with QLT0267 engendered suppression (32–87%) of total Her2/neu protein in these cells. Suppression of Her2/neu was also observed following small interfering RNA-mediated silencing of ILK expression. Time course studies suggest that ILK inhibition or silencing caused transient decreases in P-AKTser473, which were not temporally related to Her2/neu downregulation. Attenuation of ILK activity or expression was, however, associated with decreases in YB-1 (Y-box binding protein-1) protein and transcript levels. YB-1 is a known transcriptional regulator of Her2/neu expression, and in this study it is demonstrated that inhibition of ILK activity using QLT0267 decreased YB-1 promoter activity by 50.6%. ILK inhibition was associated with changes in YB-1 localization, as reflected by localization of cytoplasmic YB-1 into stress granules. ILK inhibition also suppressed TWIST (a regulator of YB-1 expression) protein expression. To confirm the role of ILK on YB-1 and TWIST, cells were engineered to overexpress ILK. This was associated with a fourfold increase in the level of YB-1 in the nucleus, and a 2- and 1.5-fold increase in TWIST and Her2/neu protein levels, respectively. Taken together, these data indicate that ILK regulates the expression of Her2/neu through TWIST and YB-1, lending support to the use of ILK inhibitors in the treatment of aggressive Her2/neu-positive tumors

Lymphocyte recruitment and homing to the liver in primary biliary cirrhosis and primary sclerosing cholangitis

The mechanisms operating in lymphocyte recruitment and homing to liver are reviewed. A literature review was performed on primary biliary cirrhosis (PBC), progressive sclerosing cholangitis (PSC), and homing mechanisms; a total of 130 papers were selected for discussion. Available data suggest that in addition to a specific role for CCL25 in PSC, the CC chemokines CCL21 and CCL28 and the CXC chemokines CXCL9 and CXCL10 are involved in the recruitment of T lymphocytes into the portal tract in PBC and PSC. Once entering the liver, lymphocytes localize to bile duct and retain by the combinatorial or sequential action of CXCL12, CXCL16, CX3CL1, and CCL28 and possibly CXCL9 and CXCL10. The relative importance of these chemokines in the recruitment or the retention of lymphocytes around the bile ducts remains unclear. The available data remain limited but underscore the importance of recruitment and homing

7th Drug hypersensitivity meeting: part two

No abstract availabl

Carbon-Ion Beam Irradiation Kills X-Ray-Resistant p53-Null Cancer Cells by Inducing Mitotic Catastrophe

Background and Purpose: To understand the mechanisms involved in the strong killing effect of carbon-ion beam irradiation on cancer cells with TP53 tumor suppressor gene deficiencies.Copyright:Materials and Methods: DNA damage responses after carbon-ion beam or X-ray irradiation in isogenic HCT116 colorectal cancer cell lines with and without TP53 (p53+/ + and p53-/-, respectively) were analyzed as follows: cell survival by clonogenic assay, cell death modes by morphologic observation of DAPI-stained nuclei, DNA doublestrand breaks (DSBs) by immunostaining of phosphorylated H2AX (γH2AX), and cell cycle by flow cytometry and immunostaining of Ser10-phosphorylated histone H3.Results: The p53-/- cells were more resistant than the p53+/+ cells to X-ray irradiation, while the sensitivities of the p53+/+ and p53-/- cells to carbon-ion beam irradiation were comparable. X-ray and carbon-ion beam irradiations predominantly induced apoptosis of the p53+/+ cells but not the p53-/- cells. In the p53-/- cells, carbon-ion beam irradiation, but not X-ray irradiation, markedly induced mitotic catastrophe that was associated with premature mitotic entry with harboring longretained DSBs at 24 h post-irradiation.Conclusions: Efficient induction of mitotic catastrophe in apoptosis-resistant p53- deficient cells implies a strong cancer cell-killing effect of carbon-ion beam irradiation that is independent of the p53 status, suggesting its biological advantage over X-ray treatment