New Observations of the Interstellar Medium in the Lyman Break Galaxy MS 1512-cB58

We present the results of a detailed study of the interstellar medium of MS 1512-cB58, an L* Lyman break galaxy at z = 2.7276, based on new spectral observations obtained with the Echelle Spectrograph and Imager on the Keck II telescope at 58 km/s resolution. We focus in particular on the chemical abundances and kinematics of the interstellar gas and our main findings are as follows. Even at this relatively early epoch, the ISM of this galaxy is already highly enriched in elements released by Type II supernovae; the abundances of O, Mg, Si, P, and S are all about 2/5 of their solar values. In contrast, N and the Fe-peak elements Mn, Fe, and Ni are underabundant by a factor of about 3. Based on current ideas of stellar nucleosynthesis, these results can be understood if most of the metal enrichment in cB58 has taken place within the last 300 million years, the timescale for the release of N from intermediate mass stars. cB58 appears to be an example of a galaxy in the process of converting its gas into stars on a few dynamical timescales; quite possibly we are witnessing the formation of a galactic bulge or an elliptical galaxy. The energetic star formation activity has stirred the interstellar medium to high velocities of up to 1000 km/s. The net effect is a bulk outflow of the ISM at a speed of 255 km/s and at a rate which exceeds the star formation rate. It is unclear whether this gas will be lost or retained by the galaxy. We point out that the chemical and kinematic properties of cB58 are markedly different from those of most damped Lyman alpha systems at the same redshift.Comment: 38 pages, LaTeX, 9 Postscript Figures. Accepted for publication in the Astrophysical Journal. Sections 3.3 and 5.3 expanded, and two additional figures included, following referee's repor

The loss and gain of functional amino acid residues is a common mechanism causing human inherited disease

Elucidating the precise molecular events altered by disease-causing genetic variants represents a major challenge in translational bioinformatics. To this end, many studies have investigated the structural and functional impact of amino acid substitutions. Most of these studies were however limited in scope to either individual molecular functions or were concerned with functional effects (e.g. deleterious vs. neutral) without specifically considering possible molecular alterations. The recent growth of structural, molecular and genetic data presents an opportunity for more comprehensive studies to consider the structural environment of a residue of interest, to hypothesize specific molecular effects of sequence variants and to statistically associate these effects with genetic disease. In this study, we analyzed data sets of disease-causing and putatively neutral human variants mapped to protein 3D structures as part of a systematic study of the loss and gain of various types of functional attribute potentially underlying pathogenic molecular alterations. We first propose a formal model to assess probabilistically function-impacting variants. We then develop an array of structure-based functional residue predictors, evaluate their performance, and use them to quantify the impact of disease-causing amino acid substitutions on catalytic activity, metal binding, macromolecular binding, ligand binding, allosteric regulation and post-translational modifications. We show that our methodology generates actionable biological hypotheses for up to 41% of disease-causing genetic variants mapped to protein structures suggesting that it can be reliably used to guide experimental validation. Our results suggest that a significant fraction of disease-causing human variants mapping to protein structures are function-altering both in the presence and absence of stability disruption

Inferring the molecular and phenotypic impact of amino acid variants with MutPred2

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants

Selection against Spurious Promoter Motifs Correlates with Translational Efficiency across Bacteria

Because binding of RNAP to misplaced sites could compromise the efficiency of transcription, natural selection for the optimization of gene expression should regulate the distribution of DNA motifs capable of RNAP-binding across the genome. Here we analyze the distribution of the −10 promoter motifs that bind the σ70 subunit of RNAP in 42 bacterial genomes. We show that selection on these motifs operates across the genome, maintaining an over-representation of −10 motifs in regulatory sequences while eliminating them from the nonfunctional and, in most cases, from the protein coding regions. In some genomes, however, −10 sites are over-represented in the coding sequences; these sites could induce pauses effecting regulatory roles throughout the length of a transcriptional unit. For nonfunctional sequences, the extent of motif under-representation varies across genomes in a manner that broadly correlates with the number of tRNA genes, a good indicator of translational speed and growth rate. This suggests that minimizing the time invested in gene transcription is an important selective pressure against spurious binding. However, selection against spurious binding is detectable in the reduced genomes of host-restricted bacteria that grow at slow rates, indicating that components of efficiency other than speed may also be important. Minimizing the number of RNAP molecules per cell required for transcription, and the corresponding energetic expense, may be most relevant in slow growers. These results indicate that genome-level properties affecting the efficiency of transcription and translation can respond in an integrated manner to optimize gene expression. The detection of selection against promoter motifs in nonfunctional regions also confirms previous results indicating that no sequence may evolve free of selective constraints, at least in the relatively small and unstructured genomes of bacteria

CHEMICAL CARTOGRAPHY with APOGEE: METALLICITY DISTRIBUTION FUNCTIONS and the CHEMICAL STRUCTURE of the MILKY WAY DISK

Using a sample of 69,919 red giants from the SDSS-III/APOGEE Data Release 12, we measure the distribution of stars in the [/Fe] versus [Fe/H] plane and the metallicity distribution functions (MDFs) across an unprecedented volume of the Milky Way disk, with radius 3 < R < 15 kpc and height kpc. Stars in the inner disk (R < 5 kpc) lie along a single track in [/Fe] versus [Fe/H], starting with -enhanced, metal-poor stars and ending at [/Fe] ∼ 0 and [Fe/H] ∼ +0.4. At larger radii we find two distinct sequences in [/Fe] versus [Fe/H] space, with a roughly solar- sequence that spans a decade in metallicity and a high- sequence that merges with the low- sequence at super-solar [Fe/H]. The location of the high- sequence is nearly constant across the disk

The James Webb Space Telescope

The James Webb Space Telescope (JWST) is a large (6.6m), cold (50K), infrared-optimized space observatory that will be launched early in the next decade. The observatory will have four instruments: a near-infrared camera, a near-infrared multi-object spectrograph, and a tunable filter imager will cover the wavelength range, 0.6 to 5.0 microns, while the mid-infrared instrument will do both imaging and spectroscopy from 5.0 to 29 microns. The JWST science goals are divided into four themes. The End of the Dark Ages: First Light and Reionization theme seeks to identify the first luminous sources to form and to determine the ionization history of the early universe. The Assembly of Galaxies theme seeks to determine how galaxies and the dark matter, gas, stars, metals, morphological structures, and active nuclei within them evolved from the epoch of reionization to the present day. The Birth of Stars and Protoplanetary Systems theme seeks to unravel the birth and early evolution of stars, from infall on to dust-enshrouded protostars to the genesis of planetary systems. The Planetary Systems and the Origins of Life theme seeks to determine the physical and chemical properties of planetary systems including our own, and investigate the potential for the origins of life in those systems. To enable these observations, JWST consists of a telescope, an instrument package, a spacecraft and a sunshield. The telescope consists of 18 beryllium segments, some of which are deployed. The segments will be brought into optical alignment on-orbit through a process of periodic wavefront sensing and control. The JWST operations plan is based on that used for previous space observatories, and the majority of JWST observing time will be allocated to the international astronomical community through annual peer-reviewed proposal opportunities.Comment: 96 pages, including 48 figures and 15 tables, accepted by Space Science Review

Real-time nodes permit adaptive management of endangered species of fishes

Abstract Background Currently acoustic tag-detecting autonomous receivers must be visited periodically to download the files of tag detections. Hence, the information about the whereabouts of tagged fishes is not available to make prompt regulatory decisions to reduce entrainment. In contrast, real-time receivers can detect the signal from a transmitter on a passing fish and immediately transmit its identity and time of detection to a website, where they can be viewed on either a computer or cellular telephone. Real-time nodes can aid regulatory biologists in making important decisions. This is a powerful new tool for resource managers and conservation biologists. Results We describe a network of real-time, fish-tracking nodes on the Sacramento River, California. Two case studies illustrate the value of the nodes. The first entails detecting the arrival of migrating winter-run Chinook salmon near a water diversion and alerting regulatory biologists to keep the diversion closed to increase the migratory success. The second study involves the detection of green sturgeon at potential stranding sites, alerting biologists of the need to transport them from that site to the main channel of the river so they can continue their upstream migration to their spawning sites

The structure of the prokaryotic cyclic nucleotide-modulated potassium channel MIoK1 at 16 angstrom resolution

The gating ring of cyclic nucleotide-modulated channels is proposed to be either a two-fold symmetric dimer of dinners or a four-fold symmetric tetramer based on high-resolution structure data of soluble cyclic nucleotide-binding domains and functional data on intact channels. We addressed this controversy by obtaining structural data on an intact, full-length, cyclic nucleotide-modulated potassium channel, MloK1, from Mesorhizobium loti, which also features a putative voltage-sensor. We present here the 3D single-particle structure by transmission electron microscopy and the projection map of membrane-reconstituted 2D crystals of MloK1 in the presence of cAMP. Our data show a four-fold symmetric arrangement of the CNBDs, separated by discrete gaps. A homology model for full-length MloK1 suggests a vertical orientation for the CNBDs. The 2D crystal packing in the membrane-embedded state is compatible with the S1-S4 domains in the vertical "up" state