Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder characterized by loss of cardiomyocytes and their replacement by adipose and fibrous tissue. It is considered a disease of cell adhesion because mutations in desmosomal genes, desmoplakin and plakoglobin, have been implicated in the pathogenesis of ARVC. In a recent report, mutations in plakophilin-2, a gene highly expressed in cardiac desmosomes, have been shown to cause ARVC.Methods and Results - We investigated 100 white patients with ARVC for mutations in plakophilin-2. Nine different mutations were identified by direct sequencing in 11 cases. Five of these mutations are novel (A733fsX740, L586fsX658, V570fsX576, R413X, and P533fsX561) and predicted to cause a premature truncation of the plakophilin-2 protein. Family studies showed incomplete disease expression in mutation carriers and identified a number of individuals who would be misdiagnosed with the existing International Task Force and modified diagnostic criteria for ARVC.Conclusions - In this study, we provide new evidence that mutations in the desmosomal plakophilin-2 gene can cause ARVC. A systematic clinical evaluation of mutation carriers within families demonstrated variable phenotypic expression, even among individuals with the same mutation, and highlighted the need for a more accurate set of diagnostic criteria for ARVC

The ortho-to-para ratio of ammonia in the L1157 outflow

We have measured the ortho-to-para ratio of ammonia in the blueshifted gas of the L1157 outflow by observing the six metastable inversion lines from (J, K) = (1, 1) to (6, 6). The highly excited (5, 5) and (6, 6) lines were first detected in the low-mass star forming regions. The rotational temperature derived from the ratio of four transition lines from (3, 3) to (6, 6) is 130-140 K, suggesting that the blueshifted gas is heated by a factor of ~10 as compared to the quiescent gas. The ortho-to-para ratio of the NH3 molecules in the blueshifted gas is estimated to be 1.3--1.7, which is higher than the statistical equilibrium value. This ratio provides us with evidence that the NH3 molecules have been evaporated from dust grains with the formation temperature between 18 and 25 K. It is most likely that the NH3 molecules on dust grains have been released into the gas phase through the passage of strong shock waves produced by the outflow. Such a scenario is supported by the fact that the ammonia abundance in the blueshifted gas is enhanced by a factor of ~5 with respect to the dense quiescent gas.Comment: 16 pages, including 3 PS figures. To appear in the ApJ (Letters). aastex macro

Biosynthesis-Assisted Structural Elucidation of the Bartolosides, Chlorinated Aromatic Glycolipids from Cyanobacteria

The isolation of the bartolosides, unprecedented cyanobacterial glycolipids featuring aliphatic chains with chlorine substituents and C-glycosyl moieties, is reported. Their chlorinated dialkylresorcinol (DAR) core presented a major structural-elucidation challenge. To overcome this, we discovered the bartoloside (brt) biosynthetic gene cluster and linked it to the natural products through in vitro characterization of the DAR-forming ketosynthase and aromatase. Bioinformatic analysis also revealed a novel potential halogenase. Knowledge of the bartoloside biosynthesis constrained the DAR core structure by defining key pathway intermediates, ultimately allowing us to determine the full structures of the bartolosides. This work illustrates the power of genomics to enable the use of biosynthetic information for structure elucidation

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

First Data Release of the Hyper Suprime-Cam Subaru Strategic Program

The Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP) is a three-layered imaging survey aimed at addressing some of the most outstanding questions in astronomy today, including the nature of dark matter and dark energy. The survey has been awarded 300 nights of observing time at the Subaru Telescope and it started in March 2014. This paper presents the first public data release of HSC-SSP. This release includes data taken in the first 1.7 years of observations (61.5 nights) and each of the Wide, Deep, and UltraDeep layers covers about 108, 26, and 4 square degrees down to depths of i~26.4, ~26.5, and ~27.0 mag, respectively (5sigma for point sources). All the layers are observed in five broad bands (grizy), and the Deep and UltraDeep layers are observed in narrow bands as well. We achieve an impressive image quality of 0.6 arcsec in the i-band in the Wide layer. We show that we achieve 1-2 per cent PSF photometry (rms) both internally and externally (against Pan-STARRS1), and ~10 mas and 40 mas internal and external astrometric accuracy, respectively. Both the calibrated images and catalogs are made available to the community through dedicated user interfaces and database servers. In addition to the pipeline products, we also provide value-added products such as photometric redshifts and a collection of public spectroscopic redshifts. Detailed descriptions of all the data can be found online. The data release website is https://hsc-release.mtk.nao.ac.jp/.Comment: 34 pages, 20 figures, 7 tables, moderate revision, accepted for publication in PAS

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death