Condition on the Rényi Entanglement Entropy under Stochastic Local Manipulation.

The Rényi entanglement entropy (REE) is an entanglement quantifier considered as a natural generalization of the entanglement entropy. When it comes to stochastic local operations and classical communication (SLOCC), however, only a limited class of the REEs satisfy the monotonicity condition, while their statistical properties beyond mean values have not been fully investigated. Here, we establish a general condition that the probability distribution of the REE of any order obeys under SLOCC. The condition is obtained by introducing a family of entanglement monotones that contain the higher-order moments of the REEs. The contribution from the higher-order moments imposes a strict limitation on entanglement distillation via SLOCC. We find that the upper bound on success probabilities for entanglement distillation exponentially decreases as the amount of raised entanglement increases, which cannot be captured from the monotonicity of the REE. Based on the strong restriction on entanglement transformation under SLOCC, we design a new method to estimate entanglement in quantum many-body systems from experimentally observable quantities.

Classical and Nonclassical Time Dilation for Quantum Clocks.

Proper time, ideal clocks, and boosts are well understood classically, but subtleties arise in quantum physics. We show that quantum clocks set in motion via momentum boosts do not witness classical time dilation. However, using velocity boosts we find the ideal behavior in both cases, where the quantum clock and classical observer are set in motion. Without internal state-dependent forces additional effects arise. As such, we derive observed frequency shifts in ion trap atomic clocks, indicating a small additional shift, and also show the emergence of nonideal behavior in a theoretical clock model.

Quantum Delocalized Interactions.

Classical mechanics obeys the intuitive logic that a physical event happens at a definite spatial point. Entanglement, however, breaks this logic by enabling interactions without a specific location. In this work we study these delocalized interactions. These are quantum interactions that create less locational information than would be possible classically, as captured by the disturbance induced on some spatial superposition state. We introduce quantum games to capture the effect and demonstrate a direct operational use for quantum concurrence in that it bounds the nonclassical performance gain. We also find a connection with quantum teleportation, and demonstrate the games using an IBM quantum processor.

Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing.

Stromal derived factor-1 (SDF-1 or CXCL12) controls many aspects of stem cell function including trafficking and proliferation. Previously, it was demonstrated that DNA-damaging agents such as irradiation, cyclophosphamide or 5-fluorouracil increase the expression of SDF-1 by osteoblasts in murine marrow. Here, the production of SDF-1 by osteoblasts in vitro in response to cytokines known to be particularly important in bone physiology was examined using primary human osteoblasts (HOBs), mixed marrow stromal cells (BMSCs), and by, mouse, rat and human osteoblast-like cell lines. From these studies, it was determined that the expression of SDF-1 is an early feature of osteoblastic induction that may be modulated by IL-1beta, PDGF-BB, VEGF, TNF-alpha and PTH. Each of these factors increased SDF-1 synthesis, while TGF-beta1 decreased SDF-1 secretion. Of note, the biodistribution of SDF-1 in culture was equally distributed between the medium and detergent-soluble and -insoluble fractions of the cultures. Immunohistochemistry of developing bones demonstrated that SDF-1 was also a feature of early bone development first beginning in the perichondrium and moving into the marrow cavity of the developing bone analogue. As SDF-1 expression increases in response to PTH in vitro, animals were treated with an anabolic regime of PTH for 21 days. Under these conditions, significant increases in SDF-1 mRNA expression were observed near the growth plate and epiphysis regions of the long bones. Yet, in serum, immunodetectable SDF-1 levels were significantly reduced (24%) in the PTH-treated animals (Vehicle: 408 +/- 25 vs. PTH 308 +/- 20 SDF-1 pg/ml). Together, these data suggest a possible mechanism for localizing stem cells into a developing marrow where increased expression of SDF-1 in the local marrow environment along with decreased SDF-1 in the serum may create a homing gradient.

A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D.

We have identified a >600-kb region at 16q23.2 that is homozygously deleted from malignant ovarian ascites using representational difference analysis. Overlapping homozygous deletions were also observed in the colon carcinoma cell line HCT116 and a xenograft established from the small cell lung cancer cell line WX330. This region coincides with that described previously by others as showing loss of heterozygosity in prostate and breast cancers (C. Li et al., Genes Chromosomes Cancer, 24: 175-182, 1999; A. Latil et al., Cancer Res., 57: 1058-1062, 1997; K. Driouch et al., Genes Chromosomes Cancer, 19: 185-191, 1997; A. Iida et al., Br. J. Cancer, 75: 264-267, 1997). In addition, the minimally deleted region spans the common fragile site FRA16D. We have constructed a 700-kb physical map encompassing the deleted region. By fluorescence in situ hybridization of aphidicolin-induced metaphase chromosomes, we have preliminary data to suggest that P1-derived bacterial artificial chromosome clones from the contig lie on both sides of FRA16D. This is confirmed by extensive fluorescence in situ hybridization analysis of the region reported in the accompanying article (M. Mangelsdorf et al., Cancer Res., 60: 1683-1689, 2000) and is consistent with an involvement of this common fragile site in the loss of 16q23.2 material in various cancer types. The minimally deleted region of approximately 210 kb has been characterized using our own markers and public domain markers. Eleven distinct expressed sequences mapped to the region, providing a basis for identifying the predicted tumor suppressor gene in this region.

WWOX mRNA expression profile in epithelial ovarian cancer supports the role of WWOX variant 1 as a tumour suppressor, although the role of variant 4 remains unclear.

WWOX is a candidate tumour suppressor gene that exhibits LOH or homozygous deletion in several tumour types. As well as the predominant full-length transcript (variant 1) there also exist alternatively spliced transcripts found previously only in malignant tissue. It has been suggested that proteins encoded by these variants may interfere with normal WWOX function in a dominant negative fashion. The most prevalent alternate transcript demonstrated in ovarian cancer is variant 4, which lacks exons 6-8. Here, we report the first comparison of the mRNA expression of WWOX variants 1 and 4 in human ovarian tumours and normal ovaries, and correlate expression with clinical data. We demonstrate significantly lower WWOX variant 1 expression in tumours than in normal ovaries. This reduction was not associated with any specific clinical subgroup. Variant 4 was expressed at low levels, and significantly associated with high grade and advanced stage ovarian cancer. Furthermore, tumours co-expressing variant 4 and relatively high levels of variant 1 showed significantly worse survival than tumours expressing variant 1 alone. However, variant 4 was also frequently identified in non-malignant ovarian tissue. These results support the role of WWOX variant 1 as a suppressor of ovarian tumourigenesis, but the role of variant 4 remains speculative.

Preserved global histone H4 acetylation linked to ETV6-RUNX1 fusion and PAX5 deletions is associated with favorable outcome in pediatric B-cell progenitor acute lymphoblastic leukemia.

Epigenetic dysregulation is a hallmark of cancer executed by a number of complex processes the most important of which converge on DNA methylation and histone protein modifications. Epigenetic marks are potentially reversible and thus promising drug targets. In the setting of acute lymphoblastic leukemia (ALL) they have been associated with clinicopathological features including risk of relapse or molecular subgroups of the disease. Here, using immunocytochemistry of bone marrow smears from diagnosis, we studied global histone H4 acetylation, whose loss was previously linked to treatment failure in adults with ALL, in pediatric patients. We demonstrate that preserved global histone H4 acetylation is significantly associated with favorable outcome (RFS, EFS, OS) in children with B cell progenitor (BCP) ALL, recapitulating the findings from adult populations. Further, for the first time we demonstrate differential histone H4 acetylation in molecular subclasses of BCP-ALL including cases with ETV6-RUNX1 fusion gene or PAX5 deletion or deletions in genes linked to B cell development. We conclude global histone H4 acetylation is a prognostic marker and a potential therapeutic target in ALL.

Parathyroid hormone stimulates fra-2 expression in osteoblastic cells in vitro and in vivo.

PTH and PTH-related protein (PTHrP) are key mediators of skeletal development and homeostasis through their activation of the PTH-1 receptor. Previous studies have found that several AP-1 family members are regulated by PTH, such as c-fos, fra-1, and c-jun. There are numerous genes in the bone microenvironment that contain AP-1 sites, and different Fos family members are reported to have opposing transcriptional activities at AP-1 sites. The purpose of this study was to identify the effects of PTH on expression of the AP-1 protein complex member, fra-2, to extend our understanding of transcriptional regulators of PTH action. PTH induction of fra-2 messenger RNA (mRNA) levels in MC3T3-E1 preosteoblastic cells was maximal with 0.1 microM PTH (1-34). The expression in vitro was greatest 1 h after treatment and was present with N-terminal PTH but not PTH (7-34) or (53-84). Cycloheximide treatment induced fra-2 expression, and actinomycin D inhibited basal and PTHrP-induced expression. AP-1 protein in nuclear extracts of MC3T3-E1 cells was increased with PTH treatment at 3 h and consisted of high levels of Fra-2 protein, as evidenced by a supershift in an electrophoretic mobility shift assay and Western blot analysis. Up-regulation of steady-state fra-2 mRNA was also noted in vivo, where injection of PTH (1-34) (20 microgram) resulted in a more-than-7-fold maximal increase in fra-2 mRNA expression in the calvaria of mice, after 1 h of treatment. These data add to the transcriptional mediators induced by PTH and suggest that the interplay of AP-1 family members will provide insight into regulatory pathways of PTH and PTHrP for their anabolic and catabolic actions in bone.

TLR5 is not required for flagellin-mediated exacerbation of DSS colitis.

BACKGROUND: The two forms of human inflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T-cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll-like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murine colitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. METHODS: We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5-independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. RESULTS: We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5(-/-) mice than wildtype C57BL/6 mice. CONCLUSIONS: Together, these results suggest that flagellin-mediated exacerbation of colitis is independent of TLR5.

Redefining tumour suppressor genes: exceptions to the two-hit hypothesis.

Knudson's two-hit model of tumour suppressor genes supposes that two mutations are required to cause a tumour, one occurring in each of the two alleles of the gene. Many such cancer genes exhibiting biallelic disruption and truncating point mutations have been identified, revealing the success of the model. Despite changes in our concept of cancer genes, two inactivating point mutations are still considered the hallmark of tumour suppressor genes. Recently, however, more and more reports describe candidate tumour suppressors that do not conform to this standard definition, including haploinsufficient genes requiring inactivation of only one allele, and genes inactivated not by mutation but rather epigenetic hypermethylation. This review describes some of these exceptions and proposes a revised tumour suppressor gene definition to facilitate the identification of this new generation of tumour suppressor loci.

A deletion on chromosome 4 cosegregates with the whirler deafness mutation: exclusion of Orm1 as a candidate.

Whirler (wi) mice display profound deafness and a head-tossing and circling phenotype, showing an autosomal recessive mode of inheritance. The wi mutation has been shown to map close to the Orm gene cluster on mouse Chromosome (Chr) 4. We have, therefore, investigated the Orm loci as candidates for the whirler gene. Detailed mapping and analysis of the Orm gene cluster in both normal and whirler mice indicates the presence of a <48-kb deletion in whirler mice that disrupts the Orm1 locus. The Orm1 locus is also deleted in the CE/J mouse strain, and we discuss the candidature of Orm1 for the whirler gene.

WWOX: a candidate tumor suppressor gene involved in multiple tumor types.

We previously reported the construction of a P1-derived artificial chromosome (PAC) contig encompassing a set of homozygous deletions of chromosome 16q23-24.1 found in primary ovarian tumor material and several tumor cell lines. Using these PAC clones in a cDNA selection experiment, we have isolated a Sau3A fragment homologous to the WWOX transcript (GenBank accession no. ) from normal human ovarian surface epithelial (HOSE) cells. We demonstrate the homozygous deletion of WWOX exons from ovarian cancer cells and three different tumor cell lines. We also identify an internally deleted WWOX transcript from a further primary ovarian tumor. In three of these samples the deletions result in frameshifts, and in each case the resulting WWOX transcripts lack part, or all, of the short chain dehydrogenase domain and the putative mitochondrial localization signal. Sequencing revealed several missense polymorphisms in tumor cell lines and identified a high level of single nucleotide polymorphism (SNP) within the WWOX gene. This evidence strengthens the case for WWOX as a tumor suppressor gene in ovarian cancer and other tumor types.

Effects of sex steroid receptor specificity in the regulation of skeletal metabolism.

The interaction between estrogens and androgens, with their protective effects in bone, and parathyroid hormone (PTH), a calcitropic peptide hormone, is complex but may be better understood with murine models. The purpose of this study was to characterize skeletal phenotypes of mice deficient in estrogen receptor alpha (ERalpha), androgen receptor (AR, mutant tfm), or both, and determine if ERalpha and AR alter osteoblast differentiation and/or PTH response in vitro. Loss of ERalpha resulted in increased long bone length in females, but reduced length in males, suggesting loss of ERalpha reversed sex steroid-dependent skeletal dimorphism. The AR deficient tfm mice (genetically male but phenotypically female) had the longest bones and, similar to males, lengths were reduced with loss of ERalpha. Loss of AR and/or ERalpha resulted in a reduction in femoral bone mineral density (BMD) compared to male wildtype (WT) mice, suggesting tfm mice follow the female sex for BMD. In males or tfm mice, but not females, loss of AR and/or ERalpha caused a reduction in cortical width of the tibia compared to male WT mice. Reduced trabecular bone was found in tibiae of female and tfm mice versus male littermates, suggesting that tfm mice follow the female sex for trabecular bone but loss of ERalpha did not alter trabecular bone levels. Primary calvarial osteoblasts of male WT mice were less responsive to PTH stimulation of cAMP than all other genotypes, suggesting the female chromosomal sex and/ or loss of ERalpha or AR results in increased sensitivity to PTH. In conclusion, tfm mice follow the male pattern of long bone development, but imitate females in bone density and trabecular bone. Loss of ERalpha and/or AR results in increased osteoblast sensitivity to PTH and may explain actions of PTH noted in hypogonadal humans.

Transgenic models of metabolic bone disease: impact of estrogen receptor deficiency on skeletal metabolism.

Estrogen has protective effects on the skeleton via its inhibition of bone resorption. Mechanisms for these effects and the selectivity to the estrogen receptor alpha (ER alpha) or ER beta are unclear. The purpose of our study was to determine the impact of the ER alpha on skeletal metabolism using murine models with targeted disruption of the ER alpha and beta. Mice generated by homologous recombination and Cre/loxP technology yielding a deletion of the ER alpha exon 3 were evaluated and also crossed with mice with a disruption of the exon 3 of the ER beta to result in double ER alpha and ER beta knockout mice. Skeletal analysis of long bone length and width, radiographs, dual X-ray absorptiometry, bone histomorphometry, micro computerized tomography, biomechanical analysis, serum biochemistry, and osteoblast differentiation were evaluated. Male ER alpha knockout mice had the most dramatic phenotype consisting of reduced bone mineral density (BMD), and bone mineral content (BMC) of femurs at 10 and 16 weeks and 8-9 months of age. Female ER alpha knockout mice also had reduced density of long bones but to a lesser degree than male mice. The reduction of trabecular and cortical bone in male ER alpha knockout mice was statistically significant. Male double ER alpha and ER beta knockouts had similar reductions in bone density versus the single ER alpha knockout mice suggesting that the ER alpha is more protective than the ER beta in bone. In vitro analysis revealed no differences in osteoblast differentiation or mineralized nodule formation among cells from ER alpha genotypes. These data suggest that estrogens are important in skeletal metabolism in males; the ER alpha plays an important role in estrogen protective effects; osteoblast differentiation is not altered with loss of the ER alpha; and compensatory mechanisms are present in the absence of the ER alpha and/or another receptor for estrogen exists that mediates further effects of estrogen on the skeleton.