Genomic and metagenomic approaches to natural product chemistry

For many years, natural products have been a primary source of new molecules for the treatment of disease, and microorganisms have been a prolific source of these molecules. Recent studies have indicated, however, that many biosynthetic pathways are present in organisms for which no natural product can be associated, and only a small fraction of the microbial life present in the environment can be grown in culture. This indicates that if methods could be developed for the isolation of these pathways and production of their target molecules in heterologous hosts, great numbers of potentially valuable compounds might be discovered. In these investigations, large insert libraries of two microorganisms were constructed, one a bacterial artificial chromosome (BAC) library, the other a fosmid library, and two large insert fosmid libraries were constructed with DNA isolated from marine environmental samples. A mathematical formula was derived to estimate probabilities of cloning intact biosynthetic pathways with large insert genomic libraries and tested with a computer simulation. This indicated that even large pathways could be cloned intact in large insert libraries, provided there was an adequate size difference between the target pathway and the library inserts, and there was a concomitant increase in the size of the library with the targeting of these larger pathways. In addition, an investigation into a mixed marine culture sample lead to the identification of an unusual relationship between two bacteria for which extended co-culture leads to the production of pyocyanin. However, no useful biosynthetic pathways were located within the genomic libraries. It is concluded that significant improvements would be required to make this approach feasible for larger scale investigations. It is further concluded, on the basis of recent developments in the field, including a reduction in the cost of sequencing, improvements in techniques of whole-genome shotgun sequencing, and the development of recombination based cloning, that the employment of mass sequencing efforts and sequence-driven, recombinationbased cloning, might prove to be a more fruitful and efficient alternative to large-insert library construction for the isolation and expression of these pathways. A possible paradigm for the cloning of pathways on the basis of this technology is proposed

Saddles in the energy landscape: extensivity and thermodynamic formalism

We formally extend the energy landscape approach for the thermodynamics of liquids to account for saddle points. By considering the extensive nature of macroscopic potential energies, we derive the scaling behavior of saddles with system size, as well as several approximations for the properties of low-order saddles (i.e., those with only a few unstable directions). We then cast the canonical partition function in a saddle-explicit form and develop, for the first time, a rigorous energy landscape approach capable of reproducing trends observed in simulations, in particular the temperature dependence of the energy and fractional order of sampled saddles.Comment: 4 pages, 1 figur

Molecular structural order and anomalies in liquid silica

The present investigation examines the relationship between structural order, diffusivity anomalies, and density anomalies in liquid silica by means of molecular dynamics simulations. We use previously defined orientational and translational order parameters to quantify local structural order in atomic configurations. Extensive simulations are performed at different state points to measure structural order, diffusivity, and thermodynamic properties. It is found that silica shares many trends recently reported for water [J. R. Errington and P. G. Debenedetti, Nature 409, 318 (2001)]. At intermediate densities, the distribution of local orientational order is bimodal. At fixed temperature, order parameter extrema occur upon compression: a maximum in orientational order followed by a minimum in translational order. Unlike water, however, silica's translational order parameter minimum is broad, and there is no range of thermodynamic conditions where both parameters are strictly coupled. Furthermore, the temperature-density regime where both structural order parameters decrease upon isothermal compression (the structurally anomalous regime) does not encompass the region of diffusivity anomalies, as was the case for water.Comment: 30 pages, 8 figure

Alien knowledge: Preparing student midwives for learning about infant feeding-Education practice at a UK university

Infant feeding education forms a key element in undergraduate midwifery education in the UK. Students must be prepared to provide women with support and information to make appropriate health choices for themselves and their infants. However, student midwives may already have developed opinions about infant feeding prior to commencing a midwifery education programme. The education literature suggests that existing attitudes may present a barrier to learning for some students. This particularly applies to learning in relation to sensitive or emotionally laden subjects. A review of the literature was undertaken to identify potential teaching approaches which might help students to overcome barriers to learning. Following this the evidence was utilised at a UK university to develop activities which prepare student midwives for effective learning around infant feeding. Students enrolled in the midwifery education programme were introduced to a number of activities aimed at encouraging them to accommodate unfamiliar ideas or 'alien knowledge'. These included placing students in situations which challenged their ideas, as well as engaging in group discussions and reflective exercises. The impact of these educational interventions was identified through formative and summative assessment, and through evaluation of the teaching strategy at the end of the programme. This demonstrated that, amongst those students with previously negative attitudes towards infant feeding, there was a move towards more positive attitudes and a greater confidence in providing evidence based information to parents

The effect of cross-linking on the molecular dynamics of the segmental and β Johari–Goldstein processes in polyvinylpyrrolidone-based copolymers

The effect of the cross-link density on the molecular dynamics of copolymers composed of vinylpyrrolidone (VP) and butyl acrylate (BA) was studied using differential scanning calorimetry (DSC) and dielectric relaxation spectroscopy (DRS). A single glass transition was detected by DSC measurements. The dielectric spectra exhibit conductive processes and three dipolar relaxations labeled as a, b and g in the decreasing order of temperatures. The cross-linker content affects both a and b processes, but the fastest g process is relatively unaffected. An increase of cross-linking produces a typical effect on the a process dynamics: (i) the glass transition temperature is increased, (ii) the dispersion is broadened, (iii) its strength is decreased and (iv) the relaxation times are increased. However, the b process, which possesses typical features of a pure Johari Goldstein relaxation, unexpectedly loses the intermolecular character for the highest cross-linker content.B.R.F., M.J.S., P.O.S. and M.C. gratefully acknowledge CICYT for grant MAT2012-33483. F.G. and J.M.G. acknowledge the Spanish Ministerio de Economia y Competitividad-FEDER (MAT2014-54137-R) and the Junta de Castilla y Leon (BU232U13).Redondo Foj, MB.; Sanchis Sánchez, MJ.; Ortiz Serna, MP.; Carsí Rosique, M.; García, JM.; García, FC. (2015). The effect of cross-linking on the molecular dynamics of the segmental and β Johari–Goldstein processes in polyvinylpyrrolidone-based copolymers. Soft Matter. 11:7171-7180. https://doi.org/10.1039/c5sm00714cS7171718011V. Bühler , Polyvinylpyrrolidone Excipients for Pharmaceuticals: Povidone, Crospovidone and Copovidone , Springer , Berlin , 2005Haaf, F., Sanner, A., & Straub, F. (1985). Polymers of N-Vinylpyrrolidone: Synthesis, Characterization and Uses. 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Preparation and electrical sensitive behavior of poly (N-vinylpyrrolidone-co-acrylic acid) hydrogel with flexible chain nature. European Polymer Journal, 49(7), 1871-1880. doi:10.1016/j.eurpolymj.2013.04.022Borns, M. A., Kalakkunnath, S., Kalika, D. S., Kusuma, V. A., & Freeman, B. D. (2007). Dynamic relaxation characteristics of crosslinked poly(ethylene oxide) copolymer networks: Influence of short chain pendant groups. Polymer, 48(25), 7316-7328. doi:10.1016/j.polymer.2007.10.020Qazvini, N. T., & Mohammadi, N. (2005). Dynamic mechanical analysis of segmental relaxation in unsaturated polyester resin networks: Effect of styrene content. Polymer, 46(21), 9088-9096. doi:10.1016/j.polymer.2005.06.118Cook, W. D., Scott, T. F., Quay-Thevenon, S., & Forsythe, J. S. (2004). Dynamic mechanical thermal analysis of thermally stable and thermally reactive network polymers. Journal of Applied Polymer Science, 93(3), 1348-1359. doi:10.1002/app.20569Viciosa, M. 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Journal of Physics D: Applied Physics, 46(29), 295304. doi:10.1088/0022-3727/46/29/295304Redondo-Foj, B., Carsí, M., Ortiz-Serna, P., Sanchis, M. J., Vallejos, S., García, F., & García, J. M. (2014). Effect of the Dipole–Dipole Interactions in the Molecular Dynamics of Poly(vinylpyrrolidone)-Based Copolymers. Macromolecules, 47(15), 5334-5346. doi:10.1021/ma500800aBershtein, V. A., Egorova, L. M., Yakushev, P. N., Pissis, P., Sysel, P., & Brozova, L. (2002). Molecular dynamics in nanostructured polyimide-silica hybrid materials and their thermal stability. Journal of Polymer Science Part B: Polymer Physics, 40(10), 1056-1069. doi:10.1002/polb.10162Alves, N. M., Gómez Ribelles, J. L., & Mano, J. F. (2005). Enthalpy relaxation studies in polymethyl methacrylate networks with different crosslinking degrees. Polymer, 46(2), 491-504. doi:10.1016/j.polymer.2004.11.016Scott, T. F., Cook, W. D., & Forsythe, J. S. (2002). Kinetics and network structure of thermally cured vinyl ester resins. 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Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

New Insights into Human Nondisjunction of Chromosome 21 in Oocytes

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors

Sulfur budget and global climate impact of the AD 1835 eruption of Cosigüina volcano, Nicaragua

Large explosive volcanic eruptions can inject massive amounts of sulfuric gases into the Earth's atmosphere and, in so doing, affect global climate. The January 1835 eruption of Cosigüina volcano, Nicaragua, ranks among the Americas’ largest and most explosive historical eruptions, but whether it had effects on global climate remains ambiguous. New petrologic analyses of the Cosigüina deposits reveal that the eruption released enough sulfur to explain a prominent ca. AD 1835 sulfate anomaly in ice cores from both the Arctic and Antarctic. A compilation of temperature-sensitive tree-ring chronologies indicates appreciable cooling of the Earth's surface in response to the eruption, consistent with instrumental temperature records. We conclude that this eruption represents one of the most important sulfur-producing events of the last few centuries and had a sizable climate impact rivaling that of the 1991 eruption of Mount Pinatubo

Assessment of a Program for SARS-CoV-2 Screening and Environmental Monitoring in an Urban Public School District

Importance: Scalable programs for school-based SARS-CoV-2 testing and surveillance are needed to guide in-person learning practices and inform risk assessments in kindergarten through 12th grade settings. Objectives: To characterize SARS-CoV-2 infections in staff and students in an urban public school setting and evaluate test-based strategies to support ongoing risk assessment and mitigation for kindergarten through 12th grade in-person learning. Design, Setting, and Participants: This pilot quality improvement program engaged 3 schools in Omaha, Nebraska, for weekly saliva polymerase chain reaction testing of staff and students participating in in-person learning over a 5-week period from November 9 to December 11, 2020. Wastewater, air, and surface samples were collected weekly and tested for SARS-CoV-2 RNA to evaluate surrogacy for case detection and interrogate transmission risk of in-building activities. Main Outcomes and Measures: SARS-CoV-2 detection in saliva and environmental samples and risk factors for SARS-CoV-2 infection. Results: A total of 2885 supervised, self-collected saliva samples were tested from 458 asymptomatic staff members (mean [SD] age, 42.9 [12.4] years; 303 women [66.2%]; 25 Black or African American [5.5%], 83 Hispanic [18.1%], 312 White [68.1%], and 35 other or not provided [7.6%]) and 315 students (mean age, 14.2 [0.7] years; 151 female students [48%]; 20 Black or African American [6.3%], 201 Hispanic [63.8%], 75 White [23.8%], and 19 other race or not provided [6.0%]). A total of 46 cases of SARS-CoV-2 (22 students and 24 staff members) were detected, representing an increase in cumulative case detection rates from 1.2% (12 of 1000) to 7.0% (70 of 1000) among students and from 2.1% (21 of 1000) to 5.3% (53 of 1000) among staff compared with conventional reporting mechanisms during the pilot period. SARS-CoV-2 RNA was detected in wastewater samples from all pilot schools as well as in air samples collected from 2 choir rooms. Sequencing of 21 viral genomes in saliva specimens demonstrated minimal clustering associated with 1 school. Geographical analysis of SARS-CoV-2 cases reported district-wide demonstrated higher community risk in zip codes proximal to the pilot schools. Conclusions and Relevance: In this study of staff and students in 3 urban public schools in Omaha, Nebraska, weekly screening of asymptomatic staff and students by saliva polymerase chain reaction testing was associated with increased SARS-CoV-2 case detection, exceeding infection rates reported at the county level. Experiences differed among schools, and virus sequencing and geographical analyses suggested a dynamic interplay of school-based and community-derived transmission risk. Collectively, these findings provide insight into the performance and community value of test-based SARS-CoV-2 screening and surveillance strategies in the kindergarten through 12th grade educational setting

When Institutional Work Backfires: Organizational Control Of Professional Work In The Pharmaceutical Industry

Integrating institutional and role theories, this paper develops a Logics–Roles– Action (LRA) framework for understanding how for-profit organizations structure institutional work to managerially control the work of professionals they employ. Structurally, this institutional work involves three elements: (1) internalizing pluralistic logics (logics); (2) institutionalizing distinct roles embedded in these logics (roles); and (3) scripting goal-oriented role enactment plans (action). An empirical examination of the LRA framework in the pharmaceutical industry evidences four distinct organizational strategies that script role enactments of sales professionals in their interactions with physicians. Each strategy is intended to reaffirm prevailing institutional logics, but eventually backfires by disrupting the very institutional structures that it seeks to maintain and replicate. We show that this disruptive effect is mediated by changes in the social knowledge of institutional work. We close with theoretical and managerial implications for organizational structuring of institutional work and dynamics of institutional change