Establishing the Maximum Collectivity in Highly Deformed N=Z Nuclei.

The lifetimes of the first excited 2^{+} states in the N=Z nuclei ^{80}Zr, ^{78}Y, and ^{76}Sr have been measured using the γ-ray line shape method following population via nucleon-knockout reactions from intermediate-energy rare-isotope beams. The extracted reduced electromagnetic transition strengths yield new information on where the collectivity is maximized and provide evidence for a significant, and as yet unexplained, odd-odd vs even-even staggering in the observed values. The experimental results are analyzed in the context of state-of-the-art nuclear density-functional model calculations.

First Direct Measurement of

Type-I x-ray bursts can reveal the properties of an accreting neutron star system when compared with astrophysics model calculations. However, model results are sensitive to a handful of uncertain nuclear reaction rates, such as ^{22}Mg(α,p). We report the first direct measurement of ^{22}Mg(α,p), performed with the Active Target Time Projection Chamber. The corresponding astrophysical reaction rate is orders of magnitude larger than determined from a previous indirect measurement in a broad temperature range. Our new measurement suggests a less-compact neutron star in the source GS1826-24.

Localizing the Shape Transition in Neutron-Deficient Selenium.

Neutron-deficient selenium isotopes are thought to undergo a rapid shape change from a prolate deformation near the line of beta stability towards oblate deformation around the line of N=Z. The point at which this shape change occurs is unknown, with inconsistent predictions from available theoretical models. A common feature in the models is the delicate nature of the point of transition, with the introduction of even a modest spin to the system sufficient to change the ordering of the prolate and oblate configurations. We present a measurement of the quadrupole moment of the first-excited state in radioactive ^{72}Se-a potential point of transition-by safe Coulomb excitation. This is the first low-energy Coulomb excitation to be performed with a rare-isotope beam at the reaccelerated beam facility at the National Superconducting Cyclotron Laboratory. By demonstrating a negative spectroscopic quadrupole moment for the first-excited 2^{+} state, it is found that any low-spin shape change in neutron-deficient selenium does not occur until ^{70}Se.

Lifetime Measurements and Triple Coexisting Band Structure in

Lifetime measurements of excited states in the neutron-rich nucleus ^{43}S were performed by applying the recoil-distance method on fast rare-isotope beams in conjunction with the Gamma-Ray Energy Tracking In-beam Nuclear Array. The new data based on γγ coincidences and lifetime measurements resolve a doublet of (3/2^{-}) and (5/2^{-}) states at low excitation energies. Results were compared to the π(sd)-ν(pf) shell model and antisymmetrized molecular dynamics calculations. The consistency with the theoretical calculations identifies a possible appearance of three coexisting bands near the ground state of ^{43}S: the K^{π}=1/2^{-} band built on a prolate-deformed ground state, a band built on an isomer with a 1f_{7/2}^{-1} character, and a suggested excited band built on a newly discovered doublet state. The latter further confirms the collapse of the N=28 shell closure in the neutron-rich region.

Fusion hindrance for a positive-q-value system (24)Mg+(30)Si.

Measurements of the excitation function for the fusion of (24)Mg+(30)Si (Q=17.89 MeV)have been extended toward lower energies with respect to previous experimental data. The S-factor maximum observed in this large, positive-Q-value system is the most pronounced among such systems studied thus far. The significance and the systematics of an S-factor maximum in systems with positive fusion Q values are discussed. This result would strongly impact the extrapolated cross sections and reaction rates in the carbon and oxygen burnings and, thus, the study of the history of stellar evolution.

Neutron pair transfer in (60)Ni+(116)Sn far below the Coulomb barrier.

An excitation function of one- and two-neutron transfer channels for the ^{60}Ni+^{116}Sn system has been measured with the magnetic spectrometer PRISMA in a wide energy range, from the Coulomb barrier to far below it. The experimental transfer probabilities are well reproduced, for the first time with heavy ions, in absolute values and in slope by microscopic calculations which incorporate nucleon-nucleon pairing correlations.

Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies.

Tumor necrosis factor-alpha production induced by viruses and by lipopolysaccharides in macrophages: similarities and differences.

Tumor necrosis factor (TNF)-a gene expression can be induced primarily in cells of the monocyte-macrophage lineage by a variety of inducers, including lipopolysaccharides (LPS), phorbol esters, ultraviolet (UV) light, and viruses. In this paper, we analyzed the regulatory mechanisms of TNF-alpha production induced by infection with the Sendai" virus in RAW 264.7 macrophages. We show that in these cells TNF-a synthesis results mainly from TNF-alpha mRNA translational activation. Using CAT reporter genes, we identified the UA- rich (UAR) sequences localized in the TNF-alpha mRNA 3' untranslated region (UTR) as the main sequence involved in this regulation. This sequence has been previously shown to be the essential regulatory element involved in LPS- induced translational activation of TNF mRNA. Activation of TNF gene expression by viral infection presents other similarities with those induced by LPS. First, TNF production in response to viral infection is inhibited by the protein-tyrosine kinase inhibitor herbimycin A as it is in response to LPS. More specifically, we show here that TNF mRNA translational activation induced by viral infection or by LPS is inhibited by pretreating the cells with herbimycin A. Second, TNF production in response to viruses is tissue-specific and is abrogated in RAW 264.7x NIH3T3 hybrid cells, which lack the ability to produce TNF in response to LPS, as a consequence of a defect in the LPS signaling pathway. However, viral infection induces TNF production in LPS- unresponsive C3H/HeJ mouse-derived peritoneal macro phages indicating that viruses and LPS signaling pathways differ for at least one intermediate which is the product of the Lps gene. Finally, we show that this regulatory mechanism can be triggered by different classes of viruses.

Cardiotonic steroids-mediated targeting of the Na(+)/K(+)-ATPase to combat chemoresistant cancers.

A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na(+)/K(+)-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.

The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers.

With an overall 5 year survival rate as low as 15% for non-small cell lung cancer (NSCLC), even with surgical intervention and the use of newer molecules in adjuvant chemotherapy, there is an urgent need for new biological targets and associated novel anti-cancer agents. The present study was undertaken to evaluate the potential of the Na(+)/K(+)-ATPase alpha1 subunit as a novel target in NSCLC and revealed that alpha1 expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in alpha1 expression in A549 NSCLC cells by anti-alpha1 siRNA resulted in markedly impaired proliferation and migration of these cancer cells. Finally, of three cardenolides investigated, UNBS1450, which is known to bind to Na(+)/K(+)-ATPase and displays potent anti-tumour activity in vivo in experimental models of human NSCLCs, is the most potent inhibitor of Na(+)/K(+)-ATPase isozymes (alpha1beta1, alpha2beta1 and alpha3beta1), most strikingly of alpha1beta1. This was reflected in the compound's more potent anti-proliferative activity in all NSCLC cell lines evaluated (A549, Cal-12T, NCI-H727 and A427); the first three of which over-express alpha1. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha1 siRNA or UNBS1450 treatment, was associated with features of abnormal cytokinesis, mediated in the case of UNBS1450 by disorganization of the actin cytoskeleton. Collectively these data strongly suggest that targeting the Na(+)/K(+)-ATPase alpha1 using specific cardenolides could represent a novel means to combat certain NSCLCs.

Co-expression/co-location of S100 proteins (S100B, S100A1 and S100A2) and protein kinase C (PKC-beta, -eta and -zeta) in a rat model of cerebral basilar artery vasospasm.

OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.

Tumor necrosis factor-alpha mRNA remains unstable and hypoadenylated upon stimulation of macrophages by lipopolysaccharides.

TNF-alpha gene expression is regulated at transcriptional and post-transcriptional levels in mouse macrophages. The post-transcriptional regulation is mediated by the AU-rich element (ARE) located in the TNF-alpha mRNA 3' untranslated region (UTR), which controls its translation and stability. In resting macrophages, the ARE represses TNF-alpha mRNA translation. Activation of macrophages with various agents [for example lipopolysaccharide (LPS), viruses] results in translational derepression, leading to the production of high levels of TNF-alpha. TNF-alpha ARE has also been shown to confer mRNA instability as its deletion from the mouse genome leads to an increase in the TNF-alpha mRNA half-life [Kontoyiannis, D., Pasparakis, M., Pizzaro, T., Cominelli, F. & Kollias, G. (1999) Immunity 10, 387-398]. In this study, we measured the half-life as well as the poly(A) tail length of TNF-alpha mRNA in the course of macrophage activation by LPS. We report that TNF-alpha mRNA is short lived even in conditions of maximal TNF-alpha synthesis. Moreover, TNF-alpha mRNA is hypoadenylated in a constitutive manner. These results reveal that TNF-alpha mRNA rapid turnover does not constitute a regulatory step of TNF-alpha biosynthesis in macrophages and that TNF-alpha mRNA translational activation upon LPS stimulation is not accompanied by a change of poly(A) tail length.

Interleukin-4 and -13 inhibit tumor necrosis factor-alpha mRNA translational activation in lipopolysaccharide-induced mouse macrophages.

The production of tumor necrosis factor-alpha (TNF-alpha) by lipopolysaccharide (LPS)-stimulated macrophages can be markedly inhibited by the two closely related cytokines, interleukin (IL)-4 and IL-13. To investigate the molecular mechanism of this inhibition, we analyzed the effect of the two cytokines on TNF-alpha production and TNF-alpha mRNA accumulation in the mouse macrophage cell lines RAW 264.7 and J774 stimulated by LPS. Whereas LPS-induced TNF-alpha production is strongly suppressed by both cytokines, TNF-alpha mRNA accumulation is not significantly affected, indicating that IL-4 and IL-13 induce a translational repression of TNF-alpha mRNA. Transfection of reporter gene constructs containing different regions of the TNF-alpha gene revealed that the inhibitory action of IL-4 and IL-13 is mediated by the UA-rich sequence present in the TNF-alpha mRNA 3'-untranslated region.

The infrared spectrum of human glioma cells is related to their in vitro and in vivo behavior.

The present research investigates whether infrared spectra can be related to the biological characteristics of glioma cell lines. We used nine human glioma cell lines for which a series of in vitro and in vivo biological features had already been established [Glia 36 (2001) 375] and were able to show that their characteristic infrared spectra reflect their in vitro migration (i.e., motility and invasiveness) properties and their in vivo aggressiveness. More particularly, the infrared data evidenced correlations at the level of the lipid/protein ratio. These relationships were found to be tissue-dependent when controlled on seven pancreatic carcinoma cell lines. We also showed that oligodendroglial and astrocytic tumor cells, whose identification remains difficult, can easily be identified by their infrared spectra in the lipid acyl chain region as well as in the nucleic acid region. We concluded that infrared spectroscopy could usefully complement information provided by more conventional diagnostic and prognostic (e.g., morphological and molecular) approaches.