Deficiency of Capicua disrupts bile acid homeostasis

Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type 1 and cancer in mammals; however, the in vivo physiological functions of CIC remain largely unknown. Here we show that Cic hypomorphic (Cic-L-/-) mice have impaired bile acid (BA) homeostasis associated with induction of proinflammatory cytokines. We discovered that several drug metabolism and BA transporter genes were down-regulated in Cic-L-/- liver, and that BA was increased in the liver and serum whereas bile was decreased within the gallbladder of Cic-L-/- mice. We also found that levels of proinflammatory cytokine genes were up-regulated in Cic-L-/- liver. Consistent with this finding, levels of hepatic transcriptional regulators, such as hepatic nuclear factor 1 alpha (HNF1 alpha), CCAAT/enhancer-binding protein beta (C/EBP beta), forkhead box protein A2 (FOXA2), and retinoid X receptor alpha (RXR alpha), were markedly decreased in Cic-L-/- mice. Moreover, induction of tumor necrosis factor alpha (Tnf alpha) expression and decrease in the levels of FOXA2, C/EBP beta, and RXRa were found in Cic-L-/- liver before BA was accumulated, suggesting that inflammation might be the cause for the cholestasis in Cic-L-/- mice. Our findings indicate that CIC is a critical regulator of BA homeostasis, and that its dysfunction might be associated with chronic liver disease and metabolic disorders.open11810Ysciescopu

Integrated Effects of Urban Morphology

The aim of this study is to determine how to increase birdsong loudness and the visibility of green areas in low-density residential areas by controlling urban morphological parameters. The spatial sound level distributions of birdsong at 12 sites sampled from a GIS database of Assen, the Netherlands, were simulated by noise mapping techniques and calculated using a MATLAB program on spatial sound level matrices. The visibilities of green areas are analysed and calculated by Visibility Analysis Graph in Space Syntax. Correlation analyses were conducted between the obtained data on spatial sound level indices, the mean visibility and urban morphological parameters. The results show that birdsong loudness has significant positive linear relationships with urban morphological parameters, including Building Plan Area Fraction (R2 = 0.491), Green Area Perimeters (R2 = 0.491) and Green Area Dispersion Index (R2 = 0.618), while the visibility of green area has negative linear relationships with morphological parameters, including Building Plan Area Fraction (R2 = 0.431) and Green Area Perimeters (R2 = 0.799). It has also been found that in the proximity of green areas, the visibility of green areas has a positive relationship with birdsong loudness, whereas in most areas further from green areas, the visibility of green areas has a negative relationship with birdsong loudness. Either increasing birdsong loudness or enhancing visibility of the green areas by controlling urban morphological parameters is helpful for the optimisation of soundscape design with masking effects. Bird habitats and vegetation are important ecological issues to consider for the enhancement of the roles of urban morphology

Classes of Multiple Decision Functions Strongly Controlling FWER and FDR

This paper provides two general classes of multiple decision functions where each member of the first class strongly controls the family-wise error rate (FWER), while each member of the second class strongly controls the false discovery rate (FDR). These classes offer the possibility that an optimal multiple decision function with respect to a pre-specified criterion, such as the missed discovery rate (MDR), could be found within these classes. Such multiple decision functions can be utilized in multiple testing, specifically, but not limited to, the analysis of high-dimensional microarray data sets.Comment: 19 page

The Multifunctional Sorting Protein PACS-2 Regulates SIRT1-Mediated Deacetylation of p53 to Modulate p21-Dependent Cell-Cycle Arrest

SIRT1 regulates the DNA damage response by deacetylating p53, thereby repressing p53 transcriptional output. Here, we demonstrate that the sortingprotein PACS-2 regulates SIRT1-mediated deacetylation of p53 to modulate the DNA damage response. PACS-2 knockdown cells failed to efficiently undergo p53-induced cell-cycle arrest in response to DNA damage. Accordingly, p53 acetylation was reduced both in PACS-2 knockdown cells and thymocytes from Pacs-2-/- mice, thereby blunting induction of the cyclin-dependent kinase inhibitor p21 (CDKN1A). The SIRT1 inhibitor EX-527 or SIRT1 knockdown restored p53 acetylation and p21 induction as well as p21-dependent cell-cycle arrest in PACS-2 knockdown cells. Traffickingstudies revealed that cytoplasmic PACS-2 shuttled to the nucleus, where it interacted with SIRT1 andrepressed SIRT1-mediated p53 deacetylation. Correspondingly, invitro assays demonstrated that PACS-2 directly inhibited SIRT1-catalyzed p53 deacetylation. Together, these findings identify PACS-2 as an invivo mediator of the SIRT1-p53-p21 axis that modulates the DNA damage response

Visualizing landscapes of the superconducting gap in heterogeneous superconductor thin films: geometric influences on proximity effects

The proximity effect is a central feature of superconducting junctions as it underlies many important applications in devices and can be exploited in the design of new systems with novel quantum functionality. Recently, exotic proximity effects have been observed in various systems, such as superconductor-metallic nanowires and graphene-superconductor structures. However, it is still not clear how superconducting order propagates spatially in a heterogeneous superconductor system. Here we report intriguing influences of junction geometry on the proximity effect for a 2D heterogeneous superconductor system comprised of 2D superconducting islands on top of a surface metal. Depending on the local geometry, the superconducting gap induced in the surface metal region can either be confined to the boundary of the superconductor, in which the gap decays within a short distance (~ 15 nm), or can be observed nearly uniformly over a distance of many coherence lengths due to non-local proximity effects.Comment: 17 pages, 4 figure

Discovery of a potent deubiquitinase (DUB) small molecule activity‐based probe enables broad spectrum DUB activity profiling in living cells

Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates. This leads to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many diseases, including cancer, neurodegeneration and auto-inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin-derived covalent activity-based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling, we identify cyanopyrrolidine (CNPy) probe IMP-2373 (12) as a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cells. Through proteomics and targeted assays, we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs across a range of non-toxic concentrations in diverse cell lines. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition and during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes

The most dangerous hospital or the most dangerous equation?

<p>Abstract</p> <p>Background</p> <p>Hospital mortality rates are one of the most frequently selected indicators for measuring the performance of NHS Trusts. A recent article in a national newspaper named the hospital with the highest or lowest mortality in the 2005/6 financial year; a report by the organization Dr Foster Intelligence provided information with regard to the performance of all NHS Trusts in England.</p> <p>Methods</p> <p>Basic statistical theory and computer simulations were used to explore the relationship between the variations in the performance of NHS Trusts and the sizes of the Trusts. Data of hospital standardised mortality ratio (HSMR) of 152 English NHS Trusts for 2005/6 were re-analysed.</p> <p>Results</p> <p>A close examination of the information reveals a pattern which is consistent with a statistical phenomenon, discovered by the French mathematician de Moivre nearly 300 years ago, described in every introductory statistics textbook: namely that variation in performance indicators is expected to be greater in small Trusts and smaller in large Trusts. From a statistical viewpoint, the number of deaths in a hospital is not in proportion to the size of the hospital, but is proportional to the square root of its size. Therefore, it is not surprising to note that small hospitals are more likely to occur at the top and the bottom of league tables, whilst mortality rates are independent of hospital sizes.</p> <p>Conclusion</p> <p>This statistical phenomenon needs to be taken into account in the comparison of hospital Trusts performance, especially with regard to policy decisions.</p

Vectorlike Confinement at the LHC

We argue for the plausibility of a broad class of vectorlike confining gauge theories at the TeV scale which interact with the Standard Model predominantly via gauge interactions. These theories have a rich phenomenology at the LHC if confinement occurs at the TeV scale, while ensuring negligible impact on precision electroweak and flavor observables. Spin-1 bound states can be resonantly produced via their mixing with Standard Model gauge bosons. The resonances promptly decay to pseudo-Goldstone bosons, some of which promptly decay to a pair of Standard Model gauge bosons, while others are charged and stable on collider time scales. The diverse set of final states with little background include multiple photons and leptons, missing energy, massive stable charged particles and the possibility of highly displaced vertices in dilepton, leptoquark or diquark decays. Among others, a novel experimental signature of resonance reconstruction out of massive stable charged particles is highlighted. Some of the long-lived states also constitute Dark Matter candidates.Comment: 33 pages, 6 figures. v4: expanded discussion of Z_2 symmetry for stability, one reference adde

Coherent optical wavelength conversion via cavity-optomechanics

We theoretically propose and experimentally demonstrate coherent wavelength conversion of optical photons using photon-phonon translation in a cavity-optomechanical system. For an engineered silicon optomechanical crystal nanocavity supporting a 4 GHz localized phonon mode, optical signals in a 1.5 MHz bandwidth are coherently converted over a 11.2 THz frequency span between one cavity mode at wavelength 1460 nm and a second cavity mode at 1545 nm with a 93% internal (2% external) peak efficiency. The thermal and quantum limiting noise involved in the conversion process is also analyzed, and in terms of an equivalent photon number signal level are found to correspond to an internal noise level of only 6 and 4x10-3 quanta, respectively.Comment: 11 pages, 7 figures, appendi