Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia

This work was supported by the grants from British Council China (Sino-UK higher Education for PhD studies) to Y.D. and C.D.M., and also from the following funding resources: Tenovus Scotland (G12/05, B.L.), The Carnegie Trust (RG13060-10, B.L.) and National Natural Science Foundation of China (91232724, Y.D.; 31100788, L.Z.; 81200933, N.N.S.; 31528011, B.L. and Y.D.).Peer reviewedPublisher PD

Why do models overestimate surface ozone in the Southeast United States

Ozone pollution in the Southeast US involves complex chemistry driven by emissions of anthropogenic nitrogen oxide radicals (NOx  ≡  NO + NO2) and biogenic isoprene. Model estimates of surface ozone concentrations tend to be biased high in the region and this is of concern for designing effective emission control strategies to meet air quality standards. We use detailed chemical observations from the SEAC4RS aircraft campaign in August and September 2013, interpreted with the GEOS-Chem chemical transport model at 0.25°  ×  0.3125° horizontal resolution, to better understand the factors controlling surface ozone in the Southeast US. We find that the National Emission Inventory (NEI) for NOx from the US Environmental Protection Agency (EPA) is too high. This finding is based on SEAC4RS observations of NOx and its oxidation products, surface network observations of nitrate wet deposition fluxes, and OMI satellite observations of tropospheric NO2 columns. Our results indicate that NEI NOx emissions from mobile and industrial sources must be reduced by 30–60 %, dependent on the assumption of the contribution by soil NOx emissions. Upper-tropospheric NO2 from lightning makes a large contribution to satellite observations of tropospheric NO2 that must be accounted for when using these data to estimate surface NOx emissions. We find that only half of isoprene oxidation proceeds by the high-NOx pathway to produce ozone; this fraction is only moderately sensitive to changes in NOx emissions because isoprene and NOx emissions are spatially segregated. GEOS-Chem with reduced NOx emissions provides an unbiased simulation of ozone observations from the aircraft and reproduces the observed ozone production efficiency in the boundary layer as derived from a regression of ozone and NOx oxidation products. However, the model is still biased high by 6 ± 14 ppb relative to observed surface ozone in the Southeast US. Ozonesondes launched during midday hours show a 7 ppb ozone decrease from 1.5 km to the surface that GEOS-Chem does not capture. This bias may reflect a combination of excessive vertical mixing and net ozone production in the model boundary layer

Structural Analysis of Heparin-Derived 3- O -Sulfated Tetrasaccharides: Antithrombin Binding Site Variants

Heparin is a polysaccharide that is widely used as an anticoagulant drug. The mechanism for heparin’s anticoagulant activity is primarily through its interaction with a serine protease inhibitor, antithrombin III (AT), that enhances its ability to inactivate blood coagulation serine proteases, including thrombin (factor IIa) and factor Xa. The AT-binding site in the heparin is one of the most well-studied carbohydrate-protein binding sites and its structure is the basis for the synthesis of the heparin pentasaccharide drug, fondaparinux. Despite our understanding of the structural requirements for the heparin pentasaccharide AT-binding site, there is a lack of data on the natural variability of these binding sites in heparins extracted from animal tissues. The present work provides a detailed study on the structural variants of the tetrasaccharide fragments of this binding site afforded following treatment of a heparin with heparin lyase II. The 5 most commonly observed tetrasaccharide fragments of the AT-binding site are fully characterized, and a method for their quantification in heparin and low-molecular-weight heparin products is described

Mitigating the effect of shipping on freshwater megafauna: the case study of the Yangtze finless porpoise

Shipping has increasingly become a major threat to cetaceans due to its direct effect (e.g. ship strikes) and indirect effects (e.g. noise and habitat displacement). Most previous studies have focused on the deleterious effects of shipping traffic on marine species, while the effect of shipping on freshwater cetaceans has received little attention. The Yangtze River is a major trade artery in China, and shipping traffic there caused deaths of the now-extinct Yangtze river dolphin or baiji (Lipotes vexillifer). Here, we examine the distributional overlap of another cetacean species, the critically endangered Yangtze finless porpoise (Neophocoena asiaorientalis asiaorientalis) and cargo ships in a busy section of Yangtze River from Ezhou to Zhenjiang City. We use vessel-based survey data from 2006, 2012, and 2017 to quantify the distribution of porpoise. We use satellite images to quantify the distribution of cargo vessels travelling upstream. Most porpoise were concentrated within 300 m of the river banks. Shipping increased by 65% from 2006 to 2017, and ~ 60% of the upstream vessels was also within 300 m of the banks. This increase in shipping may have caused an observed shift in porpoise distribution away from the banks after 2006. Enhanced enforcement of existing shipping regulations that limit vessels to established shipping lane and set refuges in the side channels could help reduce the distributional overlap of porpoise and ships and aid in porpoise conservation. This could be applied and benefit the cetacean conservation under continued growth of shipping in rivers

A particle swarm optimization-based algorithm for finding gapped motifs

<p>Abstract</p> <p>Background</p> <p>Identifying approximately repeated patterns, or motifs, in DNA sequences from a set of co-regulated genes is an important step towards deciphering the complex gene regulatory networks and understanding gene functions.</p> <p>Results</p> <p>In this work, we develop a novel motif finding algorithm (PSO+) using a population-based stochastic optimization technique called Particle Swarm Optimization (PSO), which has been shown to be effective in optimizing difficult multidimensional problems in continuous domains. We propose a modification of the standard PSO algorithm to handle discrete values, such as characters in DNA sequences. The algorithm provides several features. First, we use both consensus and position-specific weight matrix representations in our algorithm, taking advantage of the efficiency of the former and the accuracy of the latter. Furthermore, many real motifs contain gaps, but the existing methods usually ignore them or assume a user know their exact locations and lengths, which is usually impractical for real applications. In comparison, our method models gaps explicitly, and provides an easy solution to find gapped motifs without any detailed knowledge of gaps. Our method allows the presence of input sequences containing zero or multiple binding sites.</p> <p>Conclusion</p> <p>Experimental results on synthetic challenge problems as well as real biological sequences show that our method is both more efficient and more accurate than several existing algorithms, especially when gaps are present in the motifs.</p

Electro-Magnetic Earthquake Bursts and Critical Rupture of Peroxy Bond Networks in Rocks

We propose a mechanism for the low frequency electromagnetic emissions and other electromagnetic phenomena which have been associated with earthquakes. The mechanism combines the critical earthquake concept and the concept of crust acting as a charging electric battery under increasing stress. The electric charges are released by activation of dormant charge carriers in the oxygen anion sublattice, called peroxy bonds or positive hole pairs (PHP), where a PHP represents an $O_3X/^{OO}\backslash YO_3$ with $X,Y = Si^{4+}, Al^{3+}...$, i.e. an $O^-$ in a matrix of $O^{2-}$ of silicates. We propose that PHP are activated by plastic deformations during the slow cooperative build-up of stress and the increasingly correlated damage culminating in a large ``critical'' earthquake. Recent laboratory experiments indeed show that stressed rocks form electric batteries which can release their charge when a conducting path closes the equivalent electric circuit. We conjecture that the intermittent and erratic occurrences of EM signals are a consequence of the progressive build-up of the battery charges in the Earth crust and their erratic release when crack networks are percolating throughout the stressed rock volumes, providing a conductive pathway for the battery currents to discharge. EM signals are thus expected close to the rupture, either slightly before or after, that is, when percolation is most favored.Comment: 17 pages with 3 figures, extended discussion with 1 added figure and 162 references. The new version provides both a synthesis of two theories and a review of the fiel

Spectral Line-by-Line Pulse Shaping of an On-Chip Microresonator Frequency Comb

We report, for the first time to the best of our knowledge, spectral phase characterization and line-by-line pulse shaping of an optical frequency comb generated by nonlinear wave mixing in a microring resonator. Through programmable pulse shaping the comb is compressed into a train of near-transform-limited pulses of \approx 300 fs duration (intensity full width half maximum) at 595 GHz repetition rate. An additional, simple example of optical arbitrary waveform generation is presented. The ability to characterize and then stably compress the frequency comb provides new data on the stability of the spectral phase and suggests that random relative frequency shifts due to uncorrelated variations of frequency dependent phase are at or below the 100 microHertz level.Comment: 18 pages, 4 figure

Infection and genotype remodel the entire soybean transcriptome

<p>Abstract</p> <p>Background</p> <p>High throughput methods, such as high density oligonucleotide microarray measurements of mRNA levels, are popular and critical to genome scale analysis and systems biology. However understanding the results of these analyses and in particular understanding the very wide range of levels of transcriptional changes observed is still a significant challenge. Many researchers still use an arbitrary cut off such as two-fold in order to identify changes that may be biologically significant. We have used a very large-scale microarray experiment involving 72 biological replicates to analyze the response of soybean plants to infection by the pathogen <it>Phytophthora sojae </it>and to analyze transcriptional modulation as a result of genotypic variation.</p> <p>Results</p> <p>With the unprecedented level of statistical sensitivity provided by the high degree of replication, we show unambiguously that almost the entire plant genome (97 to 99% of all detectable genes) undergoes transcriptional modulation in response to infection and genetic variation. The majority of the transcriptional differences are less than two-fold in magnitude. We show that low amplitude modulation of gene expression (less than two-fold changes) is highly statistically significant and consistent across biological replicates, even for modulations of less than 20%. Our results are consistent through two different normalization methods and two different statistical analysis procedures.</p> <p>Conclusion</p> <p>Our findings demonstrate that the entire plant genome undergoes transcriptional modulation in response to infection and genetic variation. The pervasive low-magnitude remodeling of the transcriptome may be an integral component of physiological adaptation in soybean, and in all eukaryotes.</p

Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease.

OBJECTIVE: To identify rare coding variants segregating with late-onset Alzheimer disease (LOAD) in Caribbean Hispanic families. METHODS: Whole-exome sequencing (WES) was completed in 110 individuals from 31 Caribbean Hispanic families without APOE ε4 homozygous carriers. Rare coding mutations segregating in families were subsequently genotyped in additional families and in an independent cohort of Caribbean Hispanic patients and controls. SRCAP messenger RNA (mRNA) expression was assessed in whole blood from mutation carriers with LOAD, noncarriers with LOAD, and healthy elderly controls, and also from autopsied brains in 2 clinical neuropathologic cohort studies of aging and dementia. RESULTS: Ten ultra-rare missense mutations in the Snf2-related CREBBP, activator protein (SRCAP), were found in 12 unrelated families. Compared with the frequency in Caribbean Hispanic controls and the Latino population in the Exome Aggregation Consortium, the frequency of SRCAP mutations among Caribbean Hispanic patients with LOAD was significantly enriched (p = 1.19e-16). mRNA expression of SRCAP in whole blood was significantly lower in mutation carriers with LOAD, while the expression in whole blood and in the brain was significantly higher in nonmutation carriers with LOAD. Brain expression also correlated with clinical and neuropathologic endophenotypes. CONCLUSIONS: WES in Caribbean Hispanic families with LOAD revealed ultra-rare missense mutations in SRCAP, a gene expressed in the brain and mutated in Floating-Harbor syndrome. SRCAP is a potent coactivator of the CREB-binding protein and a regulator of DNA damage response involving ATP-dependent chromatin remodeling. We hypothesize that increased expression in LOAD suggests a compensatory mechanism altered in mutation carriers