Low expression of the putative tumour suppressor spinophilin is associated with higher proliferative activity and poor prognosis in patients with hepatocellular carcinoma

BACKGROUND: Spinophilin, a multifunctional intracellular scaffold protein, is reduced in certain types of cancer and is regarded as a novel putative tumour suppressor protein. However, the role of spinophilin in hepatocellular carcinoma (HCC) has never been explored before. METHODS: In this study, we determined for the first time the expression pattern of spinophilin in human HCC by immunohistochemistry and quantitative reverse transcriptase–PCR analysis. In addition, we performed immunohistochemical analysis of p53, p14(ARF) and the proliferation marker Ki-67. Kaplan–Meier curves and multivariate Cox proportional models were used to study the impact on clinical outcome. Small interfering RNA (siRNA) was used to silence spinophilin and to explore the effects of reduced spinophilin expression on cellular growth. RESULTS: In our study, complete loss of spinophilin immunoreactivity was found in 44 of 104 HCCs (42.3%) and reduced levels were found in an additional 37 (35.6%) cases. After adjusting for other prognostic factors, multivariate Cox regression analysis identified low expression of spinophilin as an independent prognostic factor with respect to disease-free (hazard ratio (HR)=1.8; 95% confidence interval (CI)=1.04–3.40; P=0.043) and cancer-specific survival (HR=2.0; CI=1.1–3.8; P=0.025). Reduced spinophilin expression significantly correlated with higher Ki-67 index in HCC (P=0.014). Reducing spinophilin levels by siRNA induced a higher cellular growth rate and increased cyclin D2 expression in tumour cells (P<0.05). CONCLUSION: This is the first study of the expression pattern and distribution of spinophilin in HCC. According to our data, the loss of spinophilin is associated with higher proliferation and might be useful as a prognostic marker in patients with HCC

A stochastic model for heart rate fluctuations

Normal human heart rate shows complex fluctuations in time, which is natural, since heart rate is controlled by a large number of different feedback control loops. These unpredictable fluctuations have been shown to display fractal dynamics, long-term correlations, and 1/f noise. These characterizations are statistical and they have been widely studied and used, but much less is known about the detailed time evolution (dynamics) of the heart rate control mechanism. Here we show that a simple one-dimensional Langevin-type stochastic difference equation can accurately model the heart rate fluctuations in a time scale from minutes to hours. The model consists of a deterministic nonlinear part and a stochastic part typical to Gaussian noise, and both parts can be directly determined from the measured heart rate data. Studies of 27 healthy subjects reveal that in most cases the deterministic part has a form typically seen in bistable systems: there are two stable fixed points and one unstable one.Comment: 8 pages in PDF, Revtex style. Added more dat

How close to the O (6) symmetry is the nucleus 124Xe?

Excited states in 124Xe have been studied via the 12C(124Xe, 124Xe*) Coulomb excitation reaction. Their population cross-sections relative to the 21+ state have been determined from the γ-ray yields observed with Gammasphere. More than twenty absolute E2 strengths for seven off-yrast, low-spin states of 124Xe have been deduced for the first time. The absolute B (E 2) values indicate pronounced O (5) symmetry, even for the off-yrast states with high O (5) quantum number τ, while the O (6) symmetry is substantially broken

Evolution of the mixed-symmetry 21,ms+ quadrupole-phonon excitation from spherical to γ-soft Xe nuclei

Low-lying collective states of Xe130,132 have been investigated by γ-ray spectroscopy following C12(Xe,Xe*)C12 projectile Coulomb excitation. The one-phonon 21,ms+ states have been identified: the 24+ state at 2150 keV with B(M1;24+→21+)=0.15(4)μN2 in Xe130 and the 23+ state at 1985 keV with B(M1;23+→21+)=0.22(6)μN2 in Xe132. The evolution of the one-phonon 21,ms+ states in the even-even stable xenon isotopic chain from the vibrators near N=82 to the γ-soft nuclei toward midshell is discussed

Robust test of E(5) symmetry in Xe128

Low-lying collectively excited states of Xe128 were investigated by γ-ray spectroscopy following the C12(Xe128,Xe128*)C12 projectile Coulomb excitation reaction. Nineteen absolute E2 transition strengths were obtained including the first measurement of the critical B(E2) decays from the second and third Jπ=0+ states. These data are compared with the theoretical predictions of the critical point symmetry E(5) and allow us to conclude that Xe128 is not an E(5) nucleus as previously suggested, leaving Xe130 as the most likely candidate among the Xe isotopes

O(6)-symmetry breaking in the γ-soft nucleus Xe126 and its evolution in the light stable xenon isotopes

Low-lying collective states in Xe126 have been investigated via the C12(Xe126,Xe126*) projectile Coulomb excitation reaction at 399 MeV. The γ decays were detected with the Gammasphere array. Coulomb excitation cross sections relative to the 21+ state were obtained. Twenty-two absolute E2 transition strengths have been deduced. An sd- interacting boson model (IBM-1) fit agrees well with the new experimental data. This makes a quantitative test of O(6)-symmetry breaking in Xe126 possible. The measured absolute B(E2) values indicate a preservation of O(5) symmetry, while the O(6) symmetry is broken. The evolution of O(6)-symmetry breaking and of O(5)-symmetry conservation in the Xe124,126,128 isotopic chain is discussed

Cardiac and Respiratory Patterns Synchronize between Persons during Choir Singing

Dyadic and collective activities requiring temporally coordinated action are likely to be associated with cardiac and respiratory patterns that synchronize within and between people. However, the extent and functional significance of cardiac and respiratory between-person couplings have not been investigated thus far. Here, we report interpersonal oscillatory couplings among eleven singers and one conductor engaged in choir singing. We find that: (a) phase synchronization both in respiration and heart rate variability increase significantly during singing relative to a rest condition; (b) phase synchronization is higher when singing in unison than when singing pieces with multiple voice parts; (c) directed coupling measures are consistent with the presence of causal effects of the conductor on the singers at high modulation frequencies; (d) the different voices of the choir are reflected in network analyses of cardiac and respiratory activity based on graph theory. Our results suggest that oscillatory coupling of cardiac and respiratory patterns provide a physiological basis for interpersonal action coordination

The Prevalence of TNFα-Induced Necrosis over Apoptosis Is Determined by TAK1-RIP1 Interplay

Death receptor-induced programmed necrosis is regarded as a secondary death mechanism dominating only in cells that cannot properly induce caspase-dependent apoptosis. Here, we show that in cells lacking TGFβ-activated Kinase-1 (TAK1) expression, catalytically active Receptor Interacting Protein 1 (RIP1)-dependent programmed necrosis overrides apoptotic processes following Tumor Necrosis Factor-α (TNFα) stimulation and results in rapid cell death. Importantly, the activation of the caspase cascade and caspase-8-mediated RIP1 cleavage in TNFα-stimulated TAK1 deficient cells is not sufficient to prevent RIP1-dependent necrosome formation and subsequent programmed necrosis. Our results demonstrate that TAK1 acts independently of its kinase activity to prevent the premature dissociation of ubiquitinated-RIP1 from TNFα-stimulated TNF-receptor I and also to inhibit the formation of TNFα-induced necrosome complex consisting of RIP1, RIP3, FADD, caspase-8 and cFLIPL. The surprising prevalence of catalytically active RIP1-dependent programmed necrosis over apoptosis despite ongoing caspase activity implicates a complex regulatory mechanism governing the decision between both cell death pathways following death receptor stimulation