Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Unraveling the role of polycystin-2/inositol 1,4,5-trisphosphate receptor interaction in Ca2+ signaling

Autosomal dominant polycystic kidney disease (ADPKD) arises as a consequence of mutations of the genes PKD1 and PKD2, encoding respectively the integral membrane proteins polycystin-1 and polycystin-2 (TRPP2), resulting in a disturbance in intracellular Ca2+ signaling. Previously we investigated the interaction between TRPP2 and the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), an intracellular Ca2+ channel in the endoplasmic reticulum (ER). We identified the molecular determinants of this interaction and observed an enhanced IP3-induced Ca2+ release (IICR). Since we found that TRPP2 strongly bound to a cluster of positively charged amino acids in the N-terminal ligand-binding domain (LBD) of the IP3R, we now investigated whether TRPP2 would interfere with the binding of IP3 to the IP3R. In in vitro experiments we observed that TRPP2 partially inhibited the binding of IP3 to the LBD of the IP3R with an IC50 of ~350 nM. The suppressor domain, i.e. the N-terminal 225 amino acids of the LBD of the IP3R, mediated this inhibitory effect of TRPP2 on IP3 binding. The observation that the interaction between the IP3R and TRPP2 decreased IP3 binding is in apparent contrast to the increased IICR. The data can be explained however by a subsequent activation of Ca2+-induced Ca2+ release (CICR) via TRPP2. Implications of this mechanism for cellular Ca2+ signaling are discussed in this addendum

New Insights in the IP3 Receptor and Its Regulation

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) is a Ca2+-release channel mainly located in the endoplasmic reticulum (ER). Three IP3R isoforms are responsible for the generation of intracellular Ca2+ signals that may spread across the entire cell or occur locally in so-called microdomains. Because of their ubiquitous expression, these channels are involved in the regulation of a plethora of cellular processes, including cell survival and cell death. To exert their proper function a fine regulation of their activity is of paramount importance. In this review, we will highlight the recent advances in the structural analysis of the IP3R and try to link these data with the newest information concerning IP3R activation and regulation. A special focus of this review will be directed towards the regulation of the IP3R by protein-protein interaction. Especially the protein family formed by calmodulin and related Ca2+-binding proteins and the pro- and anti-apoptotic/autophagic Bcl-2-family members will be highlighted. Finally, recently identified and novel IP3R regulatory proteins will be discussed. A number of these interactions are involved in cancer development, illustrating the potential importance of modulating IP3R-mediated Ca2+ signaling in cancer treatment.status: publishe

Alterations in Ca2+ Signalling via ER-mitochondria contact site remodelling in cancer

Inter-organellar contact sites establish microdomains for localised Ca2+-signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca2+-transport systems, mediating efficient Ca2+ transfer from the ER to the mitochondria. These Ca2+ signals critically control several mitochondrial functions, thereby impacting cell metabolism, cell death and survival, proliferation and migration. Hence, the MAMs have emerged as critical signalling hubs in physiology, while their dysregulation is an important factor that drives or at least contributes to oncogenesis and tumour progression. In this book chapter, we will provide an overview of the role of the MAMs in cell function and how alterations in the MAM composition contribute to oncogenic features and behaviours