YGR198w (YPP1) targets A30P α-synuclein to the vacuole for degradation

Using a genetic screen we discovered that YGR198w (named YPP1), which is an essential Saccharomyces cerevisiae gene of unknown function, suppresses the toxicity of an α-synuclein (α-syn) mutant (A30P) that is associated with early onset Parkinson's disease. Here, we show that YPP1 suppresses lethality of A30P, but not of wild-type α-syn or the A53T mutant. The Ypp1 protein, when overexpressed, drives each of the three α-syns into vesicles that bud off the plasma membrane, but only A30P-containing vesicles traffick to and merge with the vacuole, where A30P is proteolytically degraded. We show that Ypp1p binds to A30P but not the other two α-syns; that YPP1 interacts with genes involved in endocytosis/actin dynamics (SLA1, SLA2, and END3), protein sorting (class E vps), and vesicle-vacuole fusion (MON1 and CCZ1) to dispose of A30P; and that YPP1 also participates in pheromone-triggered receptor-mediated endocytosis. Our data reveal that YPP1 mediates the trafficking of A30P to the vacuole via the endocytic pathway

A map of OMC-1 in CO 9-8

The distribution of 12C16O J=9-8 (1.037 THz) emission has been mapped in OMC-1 at 35 points with 84" resolution. This is the first map of this source in this transition and only the second velocity-resolved ground-based observation of a line in the terahertz frequency band. There is emission present at all points in the map, a region roughly 4' by 6' in size, with peak antenna temperature dropping only near the edges. Away from the Orion KL outflow, the velocity structure suggests that most of the emission comes from the OMC-1 photon-dominated region, with a typical linewidthof 3-6 km/s. Large velocity gradient modeling of the emission in J=9-8 and six lower transitions suggests that the lines originate in regions with temperatures around 120 K and densities of at least 10^(3.5) cm^(-3) near theta^(1) C Ori and at the Orion Bar, and from 70 K gas at around 10^(4) cm^(-3) southeast and west of the bar. These observations are among the first made with the 0.8 m Smithsonian Astrophysical Observatory Receiver Lab Telescope, a new instrument designed to observe at frequencies above 1 THz from an extremely high and dry site in northern Chile.Comment: Minor changes to references, text to match ApJ versio

SMA CO(J=6-5) and 435 micron interferometric imaging of the nuclear region of Arp 220

We have used the Submillimeter Array (SMA) to make the first interferometric observations (beam size ~1") of the 12CO J=6-5 line and 435 micron (690 GHz) continuum emission toward the central region of the nearby ULIRG Arp 220. These observations resolve the eastern and western nuclei from each other, in both the molecular line and dust continuum emission. At 435 micron, the peak intensity of the western nucleus is stronger than the eastern nucleus, and the difference in peak intensities is less than at longer wavelengths. Fitting a simple model to the dust emission observed between 1.3 mm and 435 micron suggests that dust emissivity power law index in the western nucleus is near unity and steeper in the eastern nucleus, about 2, and that the dust emission is optically thick at the shorter wavelength. Comparison with single dish measurements indicate that the interferometer observations are missing ~60% of the dust emission, most likely from a spatially extended component to which these observations are not sensitive. The 12CO J=6-5 line observations clearly resolve kinematically the two nuclei. The distribution and kinematics of the 12CO J=6-5 line appear to be very similar to lower J CO lies observed at similar resolution. Analysis of multiple 12CO line intensities indicates that the molecular gas in both nuclei have similar excitation conditions, although the western nucleus is warmer and denser. The excitation conditions are similar to those found in other extreme environments, including M82, Mrk 231, and BR 1202-0725. Simultaneous lower resolution observations of the 12CO, 13CO, and C18O J=2-1 lines show that the 13CO and C18O lines have similar intensities, which suggests that both of these lines are optically thick, or possibly that extreme high mass star formation has produced in an overabundance of C18O.Comment: 13 pages (emulateapj), 10 figures, Accepted for publication in Ap

Novel suppressors of α-synuclein toxicity identified using yeast

The mechanism by which the Parkinson’s disease-related protein α-synuclein (α-syn) causes neurodegeneration has not been elucidated. To determine the genes that protect cells from α-syn, we used a genetic screen to identify suppressors of the super sensitivity of the yeast Saccharomyces cerevisiae expressing α-syn to killing by hydrogen peroxide. Forty genes in ubiquitin-dependent protein catabolism, protein biosynthesis, vesicle trafficking and the response to stress were identified. Five of the forty genes—ENT3, IDP3, JEM1, ARG2 and HSP82—ranked highest in their ability to block α-syn-induced reactive oxygen species accumulation, and these five genes were characterized in more detail. The deletion of any of these five genes enhanced the toxicity of α-syn as judged by growth defects compared with wild-type cells expressing α-syn, which indicates that these genes protect cells from α-syn. Strikingly, four of the five genes are specific for α-syn in that they fail to protect cells from the toxicity of the two inherited mutants A30P or A53T. This finding suggests that α-syn causes toxicity to cells through a different pathway than these two inherited mutants. Lastly, overexpression of Ent3p, which is a clathrin adapter protein involved in protein transport between the Golgi and the vacuole, causes α-syn to redistribute from the plasma membrane into cytoplasmic vesicular structures. Our interpretation is that Ent3p mediates the transport of α-syn to the vacuole for proteolytic degradation. A similar clathrin adaptor protein, epsinR, exists in humans

Network analysis of the Viking Age in Ireland as portrayed in Cogadh Gaedhel re Gallaibh

Cogadh Gaedhel re Gallaibh (‘The War of the Gaedhil with the Gaill’) is a medieval Irish text, telling how an army under the leadership of Brian Boru challenged Viking invaders and their allies in Ireland, culminating with the Battle of Clontarf in 1014. Brian’s victory is widely remembered for breaking Viking power in Ireland, although much modern scholarship disputes traditional perceptions. Instead of an international conflict between Irish and Viking, interpretations based on revisionist scholarship consider it a domestic feud or civil war. Counterrevisionists challenge this view and a long-standing and lively debate continues. Here, we introduce quantitative measures to the discussions.We present statistical analyses of network data embedded in the text to position its sets of interactions on a spectrum from the domestic to the international. This delivers a picture that lies between antipodal traditional and revisionist extremes; hostilities recorded in the text are mostly between Irish and Viking—but internal conflict forms a significant proportion of the negative interactions too

Deciphering the Preference and Predicting the Viability of Circular Permutations in Proteins

Circular permutation (CP) refers to situations in which the termini of a protein are relocated to other positions in the structure. CP occurs naturally and has been artificially created to study protein function, stability and folding. Recently CP is increasingly applied to engineer enzyme structure and function, and to create bifunctional fusion proteins unachievable by tandem fusion. CP is a complicated and expensive technique. An intrinsic difficulty in its application lies in the fact that not every position in a protein is amenable for creating a viable permutant. To examine the preferences of CP and develop CP viability prediction methods, we carried out comprehensive analyses of the sequence, structural, and dynamical properties of known CP sites using a variety of statistics and simulation methods, such as the bootstrap aggregating, permutation test and molecular dynamics simulations. CP particularly favors Gly, Pro, Asp and Asn. Positions preferred by CP lie within coils, loops, turns, and at residues that are exposed to solvent, weakly hydrogen-bonded, environmentally unpacked, or flexible. Disfavored positions include Cys, bulky hydrophobic residues, and residues located within helices or near the protein's core. These results fostered the development of an effective viable CP site prediction system, which combined four machine learning methods, e.g., artificial neural networks, the support vector machine, a random forest, and a hierarchical feature integration procedure developed in this work. As assessed by using the hydrofolate reductase dataset as the independent evaluation dataset, this prediction system achieved an AUC of 0.9. Large-scale predictions have been performed for nine thousand representative protein structures; several new potential applications of CP were thus identified. Many unreported preferences of CP are revealed in this study. The developed system is the best CP viability prediction method currently available. This work will facilitate the application of CP in research and biotechnology

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead