Invariant Distribution of Promoter Activities in Escherichia coli

Cells need to allocate their limited resources to express a wide range of genes. To understand how Escherichia coli partitions its transcriptional resources between its different promoters, we employ a robotic assay using a comprehensive reporter strain library for E. coli to measure promoter activity on a genomic scale at high-temporal resolution and accuracy. This allows continuous tracking of promoter activity as cells change their growth rate from exponential to stationary phase in different media. We find a heavy-tailed distribution of promoter activities, with promoter activities spanning several orders of magnitude. While the shape of the distribution is almost completely independent of the growth conditions, the identity of the promoters expressed at different levels does depend on them. Translation machinery genes, however, keep the same relative expression levels in the distribution across conditions, and their fractional promoter activity tracks growth rate tightly. We present a simple optimization model for resource allocation which suggests that the observed invariant distributions might maximize growth rate. These invariant features of the distribution of promoter activities may suggest design constraints that shape the allocation of transcriptional resources

Finite element analysis of the effect of cementing concepts on implant stability and cement fatigue failure

Background and purpose Two contradictory cementing techniques (using an undersized stem versus a canal-filling stem) can both lead to excellent survival rates, a phenomenon known as the “French paradox”. Furthermore, previous studies have indicated that the type of bone supporting the cement mantle may affect implant survival. To further evaluate the mechanical consequences of variations in cementing technique, we studied the effect of implant size and type of bone supporting the cement mantle on the mechanical performance of cemented total hip arthroplasty, using finite element analysis

A Survey of Honey Bee Colony Losses in the U.S., Fall 2007 to Spring 2008

Honey bees are an essential component of modern agriculture. A recently recognized ailment, Colony Collapse Disorder (CCD), devastates colonies, leaving hives with a complete lack of bees, dead or alive. Up to now, estimates of honey bee population decline have not included losses occurring during the wintering period, thus underestimating actual colony mortality. Our survey quantifies the extent of colony losses in the United States over the winter of 2007–2008.Surveys were conducted to quantify and identify management factors (e.g. operation size, hive migration) that contribute to high colony losses in general and CCD symptoms in particular. Over 19% of the country's estimated 2.44 million colonies were surveyed. A total loss of 35.8% of colonies was recorded; an increase of 11.4% compared to last year. Operations that pollinated almonds lost, on average, the same number of colonies as those that did not. The 37.9% of operations that reported having at least some of their colonies die with a complete lack of bees had a total loss of 40.8% of colonies compared to the 17.1% loss reported by beekeepers without this symptom. Large operations were more likely to have this symptom suggesting that a contagious condition may be a causal factor. Sixty percent of all colonies that were reported dead in this survey died without dead bees, and thus possibly suffered from CCD. In PA, losses varied with region, indicating that ambient temperature over winter may be an important factor.Of utmost importance to understanding the recent losses and CCD is keeping track of losses over time and on a large geographic scale. Given that our surveys are representative of the losses across all beekeeping operations, between 0.75 and 1.00 million honey bee colonies are estimated to have died in the United States over the winter of 2007–2008. This article is an extensive survey of U.S. beekeepers across the continent, serving as a reference for comparison with future losses as well as providing guidance to future hypothesis-driven research on the causes of colony mortality

Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms

CRISPR transcriptional repression devices and layered circuits in mammalian cells

A key obstacle to creating sophisticated genetic circuits has been the lack of scalable device libraries. Here we present a modular transcriptional repression architecture based on clustered regularly interspaced palindromic repeats (CRISPR) system and examine approaches for regulated expression of guide RNAs in human cells. Subsequently we demonstrate that CRISPR regulatory devices can be layered to create functional cascaded circuits, which provide a valuable toolbox for engineering purposes.National Institutes of Health (U.S.) (Grant 5R01CA155320-04)National Institutes of Health (U.S.) (Grant P50 GM098792)Korea (South). Ministry of Science, Information and Communication Technolgy. Intelligent Synthetic Biology Center of Global Frontier Project (2013M3A6A8073557

Hyperon Photoproduction in the Nucleon Resonance Region

Cross-sections and recoil polarizations for the reactions gamma + p --> K^+ + Lambda and gamma + p --> K^+ + Sigma^0 have been measured with high statistics and with good angular coverage for center-of-mass energies between 1.6 and 2.3 GeV. In the K^+Lambda channel we confirm a structure near W=1.9 GeV at backward kaon angles, but our data shows a more complex s- and u- channel resonance structure than previously seen. This structure is present at forward and backward angles but not central angles, and its position and width change with angle, indicating that more than one resonance is playing a role. Rising back-angle cross sections at higher energies and large positive polarization at backward angles are consistent with sizable s- or u-channel contributions. None of the model calculations we present can consistently explain these aspects of the data.Comment: 5 pages, 3 figures, submitted to Physical Review Letter

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

First Measurement of Beam-Recoil Observables Cx and Cz in Hyperon Photoproduction

Spin transfer from circularly polarized real photons to recoiling hyperons has been measured for the reactions $\vec\gamma + p \to K^+ + \vec\Lambda$ and $\vec\gamma + p \to K^+ + \vec\Sigma^0$. The data were obtained using the CLAS detector at Jefferson Lab for center-of-mass energies $W$ between 1.6 and 2.53 GeV, and for $-0.85<\cos\theta_{K^+}^{c.m.}< +0.95$. For the $\Lambda$, the polarization transfer coefficient along the photon momentum axis, $C_z$, was found to be near unity for a wide range of energy and kaon production angles. The associated transverse polarization coefficient, $C_x$, is smaller than $C_z$ by a roughly constant difference of unity. Most significantly, the {\it total} $\Lambda$ polarization vector, including the induced polarization $P$, has magnitude consistent with unity at all measured energies and production angles when the beam is fully polarized. For the $\Sigma^0$ this simple phenomenology does not hold. All existing hadrodynamic models are in poor agreement with these results.Comment: 28 pages, 18 figures, Submitted to Physical Review

Identifier mapping performance for integrating transcriptomics and proteomics experimental results

Background\ud Studies integrating transcriptomic data with proteomic data can illuminate the proteome more clearly than either separately. Integromic studies can deepen understanding of the dynamic complex regulatory relationship between the transcriptome and the proteome. Integrating these data dictates a reliable mapping between the identifier nomenclature resultant from the two high-throughput platforms. However, this kind of analysis is well known to be hampered by lack of standardization of identifier nomenclature among proteins, genes, and microarray probe sets. Therefore data integration may also play a role in critiquing the fallible gene identifications that both platforms emit.\ud \ud Results\ud We compared three freely available internet-based identifier mapping resources for mapping UniProt accessions (ACCs) to Affymetrix probesets identifications (IDs): DAVID, EnVision, and NetAffx. Liquid chromatography-tandem mass spectrometry analyses of 91 endometrial cancer and 7 noncancer samples generated 11,879 distinct ACCs. For each ACC, we compared the retrieval sets of probeset IDs from each mapping resource. We confirmed a high level of discrepancy among the mapping resources. On the same samples, mRNA expression was available. Therefore, to evaluate the quality of each ACC-to-probeset match, we calculated proteome-transcriptome correlations, and compared the resources presuming that better mapping of identifiers should generate a higher proportion of mapped pairs with strong inter-platform correlations. A mixture model for the correlations fitted well and supported regression analysis, providing a window into the performance of the mapping resources. The resources have added and dropped matches over two years, but their overall performance has not changed.\ud \ud Conclusions\ud The methods presented here serve to achieve concrete context-specific insight, to support well-informed decisions in choosing an ID mapping strategy for "omic" data merging

Genome-Wide Analysis of Natural Selection on Human Cis-Elements

Background: It has been speculated that the polymorphisms in the non-coding portion of the human genome underlie much of the phenotypic variability among humans and between humans and other primates. If so, these genomic regions may be undergoing rapid evolutionary change, due in part to natural selection. However, the non-coding region is a heterogeneous mix of functional and non-functional regions. Furthermore, the functional regions are comprised of a variety of different types of elements, each under potentially different selection regimes. Findings and Conclusions: Using the HapMap and Perlegen polymorphism data that map to a stringent set of putative binding sites in human proximal promoters, we apply the Derived Allele Frequency distribution test of neutrality to provide evidence that many human-specific and primate-specific binding sites are likely evolving under positive selection. We also discuss inherent limitations of publicly available human SNP datasets that complicate the inference of selection pressures. Finally, we show that the genes whose proximal binding sites contain high frequency derived alleles are enriched for positive regulation of protein metabolism and developmental processes. Thus our genome-scale investigation provide