Geochemistry on Yangla copper deposit, China

The Yangla copper deposit, situated in the middle section of Jinshajiang tectonic belt between Zhongza-Zhongdian block and Changdu-Simao block, is a representative and giant copper deposit that has been discovered in Jinshajiang-Lancangjiang-Nujiang region in recent years. There are coupled relationship between Yangla granodiorite and copper mineralization in the Yangla copper deposit. Five molybdenite samples yielded a well-constrained 187Re-187Os isochron age of 233.3±3 Ma, the metallogenesis is therefore slightly younger than the crystallization age of the granodiorite. S, Pb isotopic compositions of the Yangla copper deposit indicate that the ore-forming materials were derived from the mixture of upper crust and mantle, also with the magmatic contributions. In the late Early Permian, the Jinshajiang Oceanic plate was subducted to the west, resulting in the formation of a series of gently dipping thrust faults in the Jinshajiang tectonic belt, meanwhile, accompanied magmatic activities. In the early Late Triassic, which was a time of transition from collision-related compression to extension in the Jinshajiang tectonic belt, the thrust faults were tensional; it would have been a favorable environment for forming ore fluids. The ascending magma provided a channel for the ore-forming fluid from the mantle wedge. After the magma arrived at the base of the early-stage Yangla granodiorite, the platy granodiorite at the base of the body would have shielded the late-stage magma from the fluid. The magma would have cooled slowly, and some of the ore-forming fluid in the magma would have entered the gently dipping thrust faults near the Yangla granodiorite, resulting in mineralization.

Composition and age of igneous rocks from the Vityaz Ridge

Results of geological research carried out by V.I. Il'ichev Pacific Oceanological Institute (Far East Division of the Russian Academy of Sciences) and P.P. Shirshov Institute of Oceanology (Russian Academy of Sciences) on the submarine Vityaz Ridge during Cruise 37 of R/V Akademik Lavrentyev in 2005 are discussed. Various rocks composing the basement and the sedimentary cover of the ridge were dredged in three areas. Based on isotope geochronology, petrogeochemical, petrographic, and paleontological data and comparison with similar rocks available from the adjacent land and the Sea of Okhotsk, they are subdivided into several age complexes. Late Cretaceous, Eocene, Late Oligocene, Miocene, and Pliocene-Pleistocene complexes are defined among igneous rocks, while volcanogenic-sedimentary rocks are united into Late Cretaceous - Early Paleocene (Late Campanian - Danian), undivided Paleogene (Paleocene-Eocene?), Oligocene - Early Miocene, and Pliocene-Pleistocene complexes. Obtained data on age and formation settings of the defined complexes allowed to reconstruct geological evolution of the central Pacific slope of the Kurile Island arc.

On the Extension of the Analytic Nodal Diffusion Solver ANDES to Sodium Fast Reactors

Within the framework of the Collaborative Project for a European Sodium Fast Reactor, the reactor physics group at UPM is working on the extension of its in-house multi-scale advanced deterministic code COBAYA3 to Sodium Fast Reactors (SFR). COBAYA3 is a 3D multigroup neutron kinetics diffusion code that can be used either as a pin-by-pin code or as a stand-alone nodal code by using the analytic nodal diffusion solver ANDES. It is coupled with thermalhydraulics codes such as COBRA-TF and FLICA, allowing transient analysis of LWR at both fine-mesh and coarse-mesh scales. In order to enable also 3D pin-by-pin and nodal coupled NK-TH simulations of SFR, different developments are in progress. This paper presents the first steps towards the application of COBAYA3 to this type of reactors. ANDES solver, already extended to triangular-Z geometry, has been applied to fast reactor steady-state calculations. The required cross section libraries were generated with ERANOS code for several configurations. The limitations encountered in the application of the Analytic Coarse Mesh Finite Difference (ACMFD) method –implemented inside ANDES– to fast reactors are presented and the sensitivity of the method when using a high number of energy groups is studied. ANDES performance is assessed by comparison with the results provided by ERANOS, using a mini-core model in 33 energy groups. Furthermore, a benchmark from the NEA for a small 3D FBR in hexagonal-Z geometry and 4 energy groups is also employed to verify the behavior of the code with few energy groups.

Crystal structure of the HLA-Cw3 allotype-specific killer cell inhibitory receptor KIR2DL2

Killer cell inhibitory receptors (KIR) protect class I HLAs expressing target cells from natural killer (NK) cell-mediated lysis. To understand the molecular basis of this receptor-ligand recognition, we have crystallized the extracellular ligand-binding domains of KIR2DL2, a member of the Ig superfamily receptors that recognize HLA-Cw1, 3, 7, and 8 allotypes. The structure was determined in two different crystal forms, an orthorhombic P212121 and a trigonal P3221 space group, to resolutions of 3.0 and 2.9 Å, respectively. The overall fold of this structure, like KIR2DL1, exhibits K-type Ig topology with cis-proline residues in both domains that define β-strand switching, which sets KIR apart from the C2-type hematopoietic growth hormone receptor fold. The hinge angle of KIR2DL2 is approximately 80°, 14° larger than that observed in KIR2DL1 despite the existence of conserved hydrophobic residues near the hinge region. There is also a 5° difference in the observed hinge angles in two crystal forms of 2DL2, suggesting that the interdomain hinge angle is not fixed. The putative ligand-binding site is formed by residues from several variable loops with charge distribution apparently complementary to that of HLA-C. The packing of the receptors in the orthorhombic crystal form offers an intriguing model for receptor aggregation on the cell surface.

Characterization of inhibitory and stimulatory forms of the murine natural killer cell receptor 2B4

The receptor 2B4 belongs to the Ig superfamily and is found on the surface of all murine natural killer (NK) cells as well as T cells displaying non-MHC-restricted cytotoxicity. Previous studies have suggested that 2B4 is an activating molecule because cross-linking of this receptor results in increased cytotoxicity and γ-interferon secretion as well as granule exocytosis. However, it was recently shown that the gene for 2B4 encodes two different products that arise by alternative splicing. These gene products differ solely in their cytoplasmic domains. One form has a cytoplasmic tail of 150 amino acids (2B4L) and the other has a tail of 93 amino acids (2B4S). To determine the function of each receptor, cDNAs for 2B4S and 2B4L were transfected into the rat NK cell line RNK-16. Interestingly, the two forms of 2B4 had opposing functions. 2B4S was able to mediate redirected lysis of P815 tumor targets, suggesting that this form represents an activating receptor. However, 2B4L expression led to an inhibition of redirected lysis of P815 targets when the mAb 3.2.3 (specific for rat NKRP1) was used. In addition, 2B4L constitutively inhibits lysis of YAC-1 tumor targets. 2B4L is a tyrosine phosphoprotein, and removal of domains containing these residues abrogates its inhibitory function. Like other inhibitory receptors, 2B4L associates with the tyrosine phosphatase SHP-2. Thus, 2B4L is an inhibitory receptor belonging to the Ig superfamily.

HLA-G expression in melanoma: A way for tumor cells to escape from immunosurveillance

Considering the well established role of nonclassical HLA-G class I molecules in inhibiting natural killer (NK) cell function, the consequence of abnormal HLA-G expression in malignant cells should be the escape of tumors from immunosurveillance. To examine this hypothesis, we analyzed HLA-G expression and NK sensitivity in human malignant melanoma cells. Our analysis of three melanoma cell lines and ex vivo biopsy demonstrated that (i) IGR and M74 human melanoma cell lines exhibit a high level of HLA-G transcription with differential HLA-G isoform transcription and protein expression patterns, (ii) a higher level of HLA-G transcription ex vivo is detected in a skin melanoma metastasis biopsy compared with a healthy skin fragment from the same individual, and (iii) HLA-G protein isoforms other than membrane-bound HLA-G1 protect IGR from NK lysis. It thus appears of critical importance to consider the specific role of HLA-G expression in tumors in the design of future cancer immunotherapies.

The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one mechanism that tumor cells use to escape death induced by chemotherapeutic agents. However, the mechanism by which P-gp confers resistance to a large variety of structurally diverse molecules has remained elusive. In this study, classical multidrug resistant human CEM and K562 tumor cell lines expressing high levels of P-gp were less sensitive to multiple forms of caspase-dependent cell death, including that mediated by cytotoxic drugs and ligation of Fas. The DNA fragmentation and membrane damage inflicted by these stimuli were defined as caspase dependent by various soluble peptide fluoromethylketone caspase inhibitors. Inhibition of P-gp function by the anti-P-gp mAb MRK-16 or verapamil could reverse resistance to these forms of cell death. Inhibition of P-gp function also enhanced drug or Fas-mediated activation of caspase-3 in drug-resistant CEM cells. By contrast, caspase-independent cell death events in the same cells, including those mediated by pore-forming proteins or intact NK cells, were not affected by P-gp expression. These observations suggest that, in addition to effluxing drugs, P-gp may play a specific role in regulating some caspase-dependent apoptotic pathways.

Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization

Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund’s adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund’s adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund’s adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.

An interleukin 4 (IL-4)-independent pathway for CD4+ T cell IL-4 production is revealed in IL-4 receptor-deficient mice

IL-4 receptor α chain (IL-4Rα)-deficient mice were generated by gene-targeting in BALB/c embryonic stem cells. Mutant mice showed a loss of IL-4 signal transduction and functional activity. The lack of IL-4Rα resulted in markedly diminished, but not absent, TH2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis. CD4+, CD62L-high, and CD62L-low T cell populations from uninfected IL-4Rα−/− mice were isolated by cell sorting. Upon primary stimulation by T cell receptor cross-linkage, the CD62L-low, but not the CD62L-high, cells secreted considerable amounts of IL-4, which was strikingly enhanced upon 4-day culture with anti-CD3 in the presence or absence of IL-4. CD62L-low cells isolated from IL-4Rα−/−, β2-microglobulin−/− double homozygous mice produced less IL-4 than did either IL-4Rα−/− or wild-type mice. These results indicate that an IL-4-independent, β2-microglobulin-dependent pathway exists through which the CD62L-low CD4+ population has acquired IL-4-producing capacity in vivo, strongly suggesting that these cells are NK T cells.

Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis

HLA-G is a nonclassical major histocompatibility complex class I molecule selectively expressed on cytotrophoblasts at the feto–maternal interface, where it may play an important role in maternal tolerance of the fetus. We provide direct evidence under physiological conditions that supports the role of HLA-G in protecting cytotrophoblasts against natural killer (NK) cytolysis in 6 semiallogenic combinations of maternal uterine NK cells and their own trophoblast counterparts, as well as in 20 allogenic combinations of maternal uterine NK cells and trophoblasts from different mothers. We show that, in all cases studied, this HLA-G-mediated protection was abolished by treatment of cytotrophoblasts with an HLA-G-specific mAb. The HLA class I-negative K562 cell line transfected with the predominant HLA-G1 isoform results in similar protection and abolition from maternal uterine NK lysis. Because maternal uterine NK cells express killer inhibitory receptors for HLA-G, we conclude that their interactions contribute to the survival of the fetal semiallograft by confering immunological tolerance to its tissues.

Natural killer cell lines kill autologous β2-microglobulin-deficient melanoma cells: Implications for cancer immunotherapy

Cancer vaccines used to generate specific cytotoxic T lymphocytes are not effective against tumor cells that have lost or suppressed expression of their class I major histocompatibility complex proteins. This loss is common in some cancers and particularly in metastatic lesions. We show that β2-microglobulin-deficient class I-negative melanoma variants derived from patients undergoing specific T cell therapy are lysed by heterologous as well as autologous natural killer (NK) lines and clones, but not by specific T cells. Moreover, the minor NK cell fraction but not the major T cell fraction derived from heterologous lymphokine activated killer cells kills those tumor cell lines. ICAM-1 expression by the different class I protein deficient tumors was correlated with their sensitivity to lysis by NK cells. Adoptive autologous NK therapy may be an important supplement to consider in the design of new cancer immunotherapies.