Direct evidence for thymic function in adult humans.

The understanding of human thymic function and evaluation of its contribution to T cell homeostasis are matters of great importance. Here we report the development of a novel assay to quantitate the frequency and diversity of recent thymic emigrants (RTEs) in the peripheral blood of humans. Such cells were defined by the presence of T cell receptor (TCR) rearrangement deletion circles (DCs), episomal byproducts of TCR-beta V(D)J rearrangement. DCs were detected in T cells in the thymus, cord blood, and adult peripheral blood. In the peripheral blood of adults aged 22 to 76 years, their frequency was highest in the CD4(+)CD45RA(+) CD62L(+) subpopulation of naive T cells. TCR DCs were also observed in other subpopulations of peripheral blood T cells, including those with the CD4(+)CD45RO(-)CD62L(+) and CD4(+)CD45RO(+)CD62L(+) phenotypes. RTEs were observed to have more than one Vbeta rearrangement, suggesting that replenishment of the repertoire in the adult is at least oligoclonal. These results demonstrate that the normal adult thymus continues to contribute, even in older individuals, a diverse set of new T cells to the peripheral circulation

The Bax/Bcl-2 Ratio Determines the Susceptibility of Human Melanoma Cells to CD95/Fas-Mediated Apoptosis

Defective cytochrome c release and the resulting loss of caspase-3 activation was recently shown to be essential for the susceptibility of human melanoma cells to CD95/Fas-induced apoptosis. Cytochrome c release from mitochondria is regulated by the relative amounts of apoptosis-promoting and apoptosis-inhibiting Bcl-2 proteins in the outer membrane of these organelles. The assignment of Bax/Bcl-2 ratios by quantitative Western blotting in 11 melanoma cell populations revealed a relation to the susceptibility to CD95-mediated apoptosis. We could show that a low Bax/Bcl-2 ratio was characteristic for resistant cells and a high Bax/Bcl-2 ratio was characteristic for sensitive cells. Low Bax expression was not a consequence of mutations in the p53 coding sequence. The Bax/Bcl-2 ratio was also in clear correlation with sensitivity to another cell death inducer, N-acetylsphingosine. Furthermore, Bcl-2 overexpression abolished apoptosis triggered by both apoptotic stimuli, confirming the critical role of the Bax/Bcl-2 ratio as a rheostat that determines the susceptibility to apoptosis in melanoma cells by regulating mitochondrial function. Interestingly, some chemotherapeutics lead to the activation of death pathways by CD95L upregulation, ceramide generation, direct activation of upstream caspases, or upregulation of proapoptotic genes. Taken together, these signals enter the apoptotic pathway upstream of mitochondria, resulting in activation of this central checkpoint. We therefore assumed that apoptosis deficiency of malignant melanoma can be circumvented by drugs directly influencing mitochondrial functions. For this purpose we used betulinic acid, a cytotoxic agent selective for melanoma, straightly perturbing mitochondrial functions. In fact, betulinic acid induced mitochondrial cytochrome c release and DNA fragmentation in both CD95-resistant and CD95-sensitive melanoma cell populations, independent of the Bax/Bcl-2 ratio

Bcl-2 antagonizes apoptotic cell death induced by two new ceramide analogues

AbstractCeramides which arise in part from the breakdown of sphingomyelin comprise a class of antiproliferative lipids and have been implicated in the regulation of programmed cell death better known as apoptosis. In the present study, two new synthetic ceramide analogues, N-thioacetylsphingosine and FS-5, were used in Molt4 cells to induce cell death. Besides their cytotoxic effects at concentrations ≥14 μM the data obtained clearly show that both analogues induced apoptosis at concentrations below this critical concentration as assessed by trypan blue exclusion and cleavage of the death substrate poly-(ADP-ribose) polymerase (PARP). Additional experiments in bcl-2-transfected Molt4 cells revealed that the apoptotic but not the lytic effects of the analogues were antagonized by the apoptosis inhibitor Bcl-2. Furthermore, neither N-thio-acetylsphingosine nor FS-5 induced PARP cleavage in bcl-2-transfected Molt4 cells indicating that the induction of apoptotic cell death by cell permeable ceramides is not due to unspecific disturbance of the cell membrane

Assessing Environmental Governance of the Hudson River Valley: Application of an IPPEP Model

The process of obtaining effective implementation of environmental laws is a process of “environmental governance.” Law, including environmental law and other fields of law related to environmental law, is essential to frame, facilitate, and foster the major parties to correctly play their roles. This thesis has been articulated through a Model of Interactions of Parties in the Process of Environmental Protection (IPPEP Model), which has been developed by Professor Wang Xi of Shanghai Jiao Tong University, in the context of the People’s Republic of China. The IPPEP Model is a tool for observing and accessing environmental governance at work. It is being tested by regional studies in various locations, such as the United States, the State of New York, and in this IPPEP case study of New York’s Hudson River Valley. The IPPEP model being examined, however, has universal applicability. Use of this model can predict that environmental standards will fail to be observed when necessary “Third Parties” are weak or absent. A nation with a commitment to the “rule of law” will enact and apply necessary legal procedures to ensure that each party can take part in the system and perform their role effectively. Part I of this paper describes the IPPEP Model. Part II is a brief introduction to the history of Hudson River Valley. Part III introduces the major parties or players in the process of protecting Hudson River Valley. Part IV consists of five case studies applying the IPPEP Model in cases of Hudson River Valley conservation. Part V concludes the paper

Anomalous f-electron Hall Effect in the Heavy-Fermion System CeTIn5_{5} (T = Co, Ir, or Rh)

The in-plane Hall coefficient $R_{H}(T)$ of CeRhIn$_{5}$, CeIrIn$_{5}$, and CeCoIn$_{5}$ and their respective non-magnetic lanthanum analogs are reported in fields to 90 kOe and at temperatures from 2 K to 325 K. $R_{H}(T)$ is negative, field-independent, and dominated by skew-scattering above $\sim$ 50 K in the Ce compounds. $R_{H}(H \to 0)$ becomes increasingly negative below 50 K and varies with temperature in a manner that is inconsistent with skew scattering. Field-dependent measurements show that the low-T anomaly is strongly suppressed when the applied field is increased to 90 kOe. Measurements on LaRhIn$_{5}$, LaIrIn$_{5}$, and LaCoIn$_{5}$ indicate that the same anomalous temperature dependence is present in the Hall coefficient of these non-magnetic analogs, albeit with a reduced amplitude and no field dependence. Hall angle ($\theta_{H}$) measurements find that the ratio $\rho_{xx}/\rho_{xy}=\cot(\theta_{H})$ varies as $T^{2}$ below 20 K for all three Ce-115 compounds. The Hall angle of the La-115 compounds follow this T-dependence as well. These data suggest that the electronic-structure contribution dominates the Hall effect in the 115 compounds, with $f$-electron and Kondo interactions acting to magnify the influence of the underlying complex band structure. This is in stark contrast to the situation in most $4f$ and $5f$ heavy-fermion compounds where the normal carrier contribution to the Hall effect provides only a small, T-independent background to $R_{H}.$Comment: 23 pages and 8 figure

First-principles theory of ferroelectric phase transitions for perovskites: The case of BaTiO3

We carry out a completely first-principles study of the ferroelectric phase transitions in BaTiO$_3$. Our approach takes advantage of two features of these transitions: the structural changes are small, and only low-energy distortions are important. Based on these observations, we make systematically improvable approximations which enable the parameterization of the complicated energy surface. The parameters are determined from first-principles total-energy calculations using ultra-soft pseudopotentials and a preconditioned conjugate-gradient scheme. The resulting effective Hamiltonian is then solved by Monte Carlo simulation. The calculated phase sequence, transition temperatures, latent heats, and spontaneous polarizations are all in good agreement with experiment. We find the transitions to be intermediate between order-disorder and displacive character. We find all three phase transitions to be of first order. The roles of different interactions are discussed.Comment: 33 pages latex file, 9 figure

Phase transitions in BaTiO3_3 from first principles

We develop a first-principles scheme to study ferroelectric phase transitions for perovskite compounds. We obtain an effective Hamiltonian which is fully specified by first-principles ultra-soft pseudopotential calculations. This approach is applied to BaTiO$_3$, and the resulting Hamiltonian is studied using Monte Carlo simulations. The calculated phase sequence, transition temperatures, latent heats, and spontaneous polarizations are all in good agreement with experiment. The order-disorder vs.\ displacive character of the transitions and the roles played by different interactions are discussed.Comment: 13 page

Low temperature growth technique for nanocrystalline cuprous oxide thin films using microwave plasma oxidation of copper

We report on the direct formation of phase pure nanocrystalline cuprous oxide (Cu2O) film with band gap ~ 2 eV by microwave plasma oxidation of pulsed dc magnetron sputtered Cu films and the highly controlled oxidation of Cu in to Cu2O and CuO phases by controlling the plasma exposure time. The structural, morphological and optoelectronic properties of the films were investigated. p-type Cu2O film with a grain size ~20-30 nm, resistivity of ~66 Ω cm and a hole concentration of ~2×1017 cm-3 is obtained for a plasma exposure time of 10 min without using any foreign dopants. The optical absorption coefficient (~105 cm-1) of the Cu2O film is also reported

Dasatinib inhibits the growth of molecularly heterogeneous myeloid leukemias.

PURPOSE: Dasatinib is a dual Src/Abl inhibitor recently approved for Bcr-Abl+ leukemias with resistance or intolerance to prior therapy. Because Src kinases contribute to multiple blood cell functions by triggering a variety of signaling pathways, we hypothesized that their molecular targeting might lead to growth inhibition in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We studied growth factor-dependent and growth factor-independent leukemic cell lines, including three cell lines expressing mutants of receptor tyrosine kinases (Flt3 or c-Kit) as well as primary AML blasts for responsiveness to dasatinib. RESULTS: Dasatinib resulted in the inhibition of Src family kinases in all cell lines and blast cells at approximately 1 x 10(-9) mol/L. It also inhibited mutant Flt3 or Kit tyrosine phosphorylation at approximately 1 x 10(-6) mol/L. Mo7e cells expressing the activating mutation (codon 816) of c-Kit were most sensitive to growth inhibition with a GI(50) of 5 x 10(-9) mol/L. Primary AML blast cells exhibited a growth inhibition of \u3c1 x\u3e10(-6) mol/L. Cell lines that showed growth inhibition at approximately 1 x 10(-6) mol/L showed a G(1) cell cycle arrest and correlated with accumulation of p21 and p27 protein. The addition of rapamycin or cytotoxic agents enhanced growth inhibition. Dasatinib also caused the apoptosis of Mo7e cells expressing oncogenic Kit. CONCLUSIONS: Although all of the precise targets for dasatinib are not known, this multikinase inhibitor causes either growth arrest or apoptosis in molecularly heterogeneous AML. The addition of cytotoxic or targeted agents can enhance its effects

Multiple models and experiments underscore large uncertainty in soil carbon dynamics

Soils contain more carbon than plants or the atmosphere, and sensitivities of soil organic carbon (SOC) stocks to changing climate and plant productivity are a major uncertainty in global carbon cycle projections. Despite a consensus that microbial degradation and mineral stabilization processes control SOC cycling, no systematic synthesis of long-term warming and litter addition experiments has been used to test process-based microbe-mineral SOC models. We explored SOC responses to warming and increased carbon inputs using a synthesis of 147 field manipulation experiments and five SOC models with different representations of microbial and mineral processes. Model projections diverged but encompassed a similar range of variability as the experimental results. Experimental measurements were insufficient to eliminate or validate individual model outcomes. While all models projected that CO efflux would increase and SOC stocks would decline under warming, nearly one-third of experiments observed decreases in CO flux and nearly half of experiments observed increases in SOC stocks under warming. Long-term measurements of C inputs to soil and their changes under warming are needed to reconcile modeled and observed patterns. Measurements separating the responses of mineral-protected and unprotected SOC fractions in manipulation experiments are needed to address key uncertainties in microbial degradation and mineral stabilization mechanisms. Integrating models with experimental design will allow targeting of these uncertainties and help to reconcile divergence among models to produce more confident projections of SOC responses to global changes. 2