Discreteness and entropic fluctuations in GREM-like systems

Within generalized random energy models, we study the effects of energy discreteness and of entropy extensivity in the low temperature phase. At zero temperature, discreteness of the energy induces replica symmetry breaking, in contrast to the continuous case where the ground state is unique. However, when the ground state energy has an extensive entropy, the distribution of overlaps P(q) instead tends towards a single delta function in the large volume limit. Considering now the whole frozen phase, we find that P(q) varies continuously with temperature, and that state-to-state fluctuations of entropy wash out the differences between the discrete and continuous energy models.Comment: 7 pages, 3 figure, 2 figures are added, the volume changes from 4 pages to 7 page

Evidence for the double degeneracy of the ground-state in the 3D ±J\pm J spin glass

A bivariate version of the multicanonical Monte Carlo method and its application to the simulation of the three-dimensional $\pm J$ Ising spin glass are described. We found the autocorrelation time associated with this particular multicanonical method was approximately proportional to the system volume, which is a great improvement over previous methods applied to spin-glass simulations. The principal advantage of this version of the multicanonical method, however, was its ability to access information predictive of low-temperature behavior. At low temperatures we found results on the three-dimensional $\pm J$ Ising spin glass consistent with a double degeneracy of the ground-state: the order-parameter distribution function $P(q)$ converged to two delta-function peaks and the Binder parameter approached unity as the system size was increased. With the same density of states used to compute these properties at low temperature, we found their behavior changing as the temperature is increased towards the spin glass transition temperature. Just below this temperature, the behavior is consistent with the standard mean-field picture that has an infinitely degenerate ground state. Using the concept of zero-energy droplets, we also discuss the structure of the ground-state degeneracy. The size distribution of the zero-energy droplets was found to produce the two delta-function peaks of $P(q)$.Comment: 33 pages with 31 eps figures include

Direct sampling of complex landscapes at low temperatures: the three-dimensional +/-J Ising spin glass

A method is presented, which allows to sample directly low-temperature configurations of glassy systems, like spin glasses. The basic idea is to generate ground states and low lying excited configurations using a heuristic algorithm. Then, with the help of microcanonical Monte Carlo simulations, more configurations are found, clusters of configurations are determined and entropies evaluated. Finally equilibrium configuration are randomly sampled with proper Gibbs-Boltzmann weights. The method is applied to three-dimensional Ising spin glasses with +- J interactions and temperatures T<=0.5. The low-temperature behavior of this model is characterized by evaluating different overlap quantities, exhibiting a complex low-energy landscape for T>0, while the T=0 behavior appears to be less complex.Comment: 9 pages, 7 figures, revtex (one sentence changed compared to v2

酸化物ガラスの塩基度と XPS による O1s 化学シフトの相関に関する考察

O1s binding energy measured by X-ray photoelectron spectroscopy (XPS) is candidate as a new tool to determine a new scale of Lewis basicity of oxide ions in glass. Some mathematical expressions for the basicity or XPS chemical shift, such as charge parameter and optical basicity, were compared with the experimental O1s binding energy in binary alkali oxide glasses. The expressions so far in use needed some modification in parameters. A new empirical expression introduced in this paper gives a new concept and universal scale of basicity

Effect of splenectomy on type-1/type-2 cytokine gene expression in a patient with adult idiopathic thrombocytopenic purpura (ITP)

BACKGROUND: In view of clinical observations and laboratory results that support a central role of the spleen in idiopathic thrombocytopenic purpura (ITP) pathophysiology, we studied the effect of splenectomy on type-1 and type-2 cytokine gene expression in an adult ITP case, refractory to conservative treatment. CASE PRESENTATION: The patient was subjected to splenectomy 9 months after the diagnosis with complete response, attaining platelet counts over 150 × 10(6)/L within 10 days after the operation. Two consecutive blood samples were obtained from the patient, 3 and 7 months after the splenectomy for the purposes of this study. A control group consisted of 11 healthy adults. Peripheral blood mononuclear cells were prepared from each blood sample and cultured in vitro for 8 h with the addition of the mitogens phorbol myristate acetate and ionomycin. Total cellular RNA extracted from 10(6 )cells was submitted to semiquantitave reverse transcriptase-polymerase chain reaction (RT-PCR) for the amplification of IL-2, IFN-γ, IL-4, IL-5, and IL-10 metagraphs. The PCR products were run on ethidium-stained agarose gels, photographed and quantified by densitometry. A steep decrease of type-1 cytokine expression (IL-2, IFN-γ) and their calculated sum expressing Th1 activity was observed at 7 months post-splenectomy compared to 3 months post-splenectomy, in parallel with a rise of platelet count from 190 × 10(6)/L to 265 × 10(6)/L. The change of type-2 cytokine expression (IL-4, IL-5, IL-10) was slight and the Th2 activity (IL-4+IL-5) remained largely unchanged. The Th1/Th2 ratio, that reflects the pathogenic disease-specific T-cell immune deviation, was accordingly reduced 7 months post-splenectomy (Th1/Th2 = 1.3) compared to 3 months (Th1/Th2 = 3.5). CONCLUSIONS: The reduction of the Th1/Th2 cytokine ratio that was observed over time after splenectomy was accompanied by full clinical remission. Nevertheless, the persistence of a type-1 polarization, even after several months following spleen removal, is suggestive of a more basic abnormality of the immune function in these patients

Small nucleoli are a cellular hallmark of longevity

Animal lifespan is regulated by conserved metabolic signalling pathways and specific transcription factors, but whether these pathways affect common downstream mechanisms remains largely elusive. Here we show that NCL-1/TRIM2/Brat tumour suppressor extends lifespan and limits nucleolar size in the major C. elegans longevity pathways, as part of a convergent mechanism focused on the nucleolus. Long-lived animals representing distinct longevity pathways exhibit small nucleoli, and decreased expression of rRNA, ribosomal proteins, and the nucleolar protein fibrillarin, dependent on NCL-1. Knockdown of fibrillarin also reduces nucleolar size and extends lifespan. Among wildtype C. elegans, individual nucleolar size varies, but is highly predictive for longevity. Long-lived dietary restricted fruit flies and insulin-like-peptide mutants exhibit small nucleoli and fibrillarin expression, as do long-lived dietary restricted and IRS1 knockout mice. Furthermore, human muscle biopsies from individuals who underwent modest dietary restriction coupled with exercise also display small nucleoli. We suggest that small nucleoli are a cellular hallmark of longevity and metabolic health conserved across taxa

Ribonucleotide reductase inhibitors suppress SAMHD1 ara‐CTPase activity enhancing cytarabine efficacy

The deoxycytidine analogue cytarabine (ara‐C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara‐C efficacy by hydrolysing the active triphosphate metabolite ara‐CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1‐mediated barrier to ara‐C efficacy in primary blasts and mouse models of AML, displaying SAMHD1‐dependent synergy with ara‐C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara‐CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara‐C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML

Development of an In Vitro Model for the Multi-Parametric Quantification of the Cellular Interactions between Candida Yeasts and Phagocytes

We developed a new in vitro model for a multi-parameter characterization of the time course interaction of Candida fungal cells with J774 murine macrophages and human neutrophils, based on the use of combined microscopy, fluorometry, flow cytometry and viability assays. Using fluorochromes specific to phagocytes and yeasts, we could accurately quantify various parameters simultaneously in a single infection experiment: at the individual cell level, we measured the association of phagocytes to fungal cells and phagocyte survival, and monitored in parallel the overall phagocytosis process by measuring the part of ingested fungal cells among the total fungal biomass that changed over time. Candida albicans, C. glabrata, and C. lusitaniae were used as a proof of concept: they exhibited species-specific differences in their association rate with phagocytes. The fungal biomass uptaken by the phagocytes differed significantly according to the Candida species. The measure of the survival of fungal and immune cells during the interaction showed that C. albicans was the more aggressive yeast in vitro, destroying the vast majority of the phagocytes within five hours. All three species of Candida were able to survive and to escape macrophage phagocytosis either by the intraphagocytic yeast-to-hyphae transition (C. albicans) and the fungal cell multiplication until phagocytes burst (C. glabrata, C. lusitaniae), or by the avoidance of phagocytosis (C. lusitaniae). We demonstrated that our model was sensitive enough to quantify small variations of the parameters of the interaction. The method has been conceived to be amenable to the high-throughput screening of mutants in order to unravel the molecular mechanisms involved in the interaction between yeasts and host phagocytes

Qualitative prediction of blood–brain barrier permeability on a large and refined dataset

The prediction of blood–brain barrier permeation is vitally important for the optimization of drugs targeting the central nervous system as well as for avoiding side effects of peripheral drugs. Following a previously proposed model on blood–brain barrier penetration, we calculated the cross-sectional area perpendicular to the amphiphilic axis. We obtained a high correlation between calculated and experimental cross-sectional area (r = 0.898, n = 32). Based on these results, we examined a correlation of the calculated cross-sectional area with blood–brain barrier penetration given by logBB values. We combined various literature data sets to form a large-scale logBB dataset with 362 experimental logBB values. Quantitative models were calculated using bootstrap validated multiple linear regression. Qualitative models were built by a bootstrapped random forest algorithm. Both methods found similar descriptors such as polar surface area, pKa, logP, charges and number of positive ionisable groups to be predictive for logBB. In contrast to our initial assumption, we were not able to obtain models with the cross-sectional area chosen as relevant parameter for both approaches. Comparing those two different techniques, qualitative random forest models are better suited for blood-brain barrier permeability prediction, especially when reducing the number of descriptors and using a large dataset. A random forest prediction system (ntrees = 5) based on only four descriptors yields a validated accuracy of 88%