In Memoriam: Jean Luther Laffoon, 1922-1973

Jean L. Laffoon, Professor of Zoology and Entomology at Iowa State University, died January 19, 1973, in Ames, Iowa, after a brief illness. Dr. Laffoon was born in Sioux City Iowa on August 19 1922. He graduated from Central High School, Sioux Citv, in 1939 and was awarded a B.S. degree in biology from Morningside College in 1942. In the fall of that year he entered the University of Michigan, Ann Arbor, but withdrew to volunteer for service in the United States Navy. Upon his discharge, three years later, he enrolled in the Graduate College at Iowa State University, where he earned an M.S. degree in 1948 and a Ph.D. degree in 1953, both in entomology

Irreversible inhibitors of the 3C protease of Coxsackie virus through templated assembly of protein-binding fragments

Small-molecule fragments binding to biomacromolecules can be starting points for the development of drugs, but are often difficult to detect due to low affinities. Here we present a strategy that identifies protein-binding fragments through their potential to induce the target-guided formation of covalently bound, irreversible enzyme inhibitors. A protein-binding nucleophile reacts reversibly with a bis-electrophilic warhead, thereby positioning the second electrophile in close proximity of the active site of a viral protease, resulting in the covalent de-activation of the enzyme. The concept is implemented for Coxsackie virus B3 3C protease, a pharmacological target against enteroviral infections. Using an aldehyde-epoxide as bis- electrophile, active fragment combinations are validated through measuring the protein inactivation rate and by detecting covalent protein modification in mass spectrometry. The structure of one enzyme–inhibitor complex is determined by X-ray crystallography. The presented warhead activation assay provides potent non-peptidic, broad-spectrum inhibitors of enteroviral proteases

The future of human nature: a symposium on the promises and challenges of the revolutions in genomics and computer science, April 10, 11, and 12, 2003

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's Symposium on the Promises and Challenges of the Revolutions in Genomics and Computer Science took place during April 10, 11, and 12, 2003. Co-organized by Charles DeLisi and Kenneth Lewes; sponsored by Boston University, the Frederick S. Pardee Center for the Study of the Longer-Range Future.This conference focused on scientific and technological advances in genetics, computer science, and their convergence during the next 35 to 250 years. In particular, it focused on directed evolution, the futures it allows, the shape of society in those futures, and the robustness of human nature against technological change at the level of individuals, groups, and societies. It is taken as a premise that biotechnology and computer science will mature and will reinforce one another. During the period of interest, human cloning, germ-line genetic engineering, and an array of reproductive technologies will become feasible and safe. Early in this period, we can reasonably expect the processing power of a laptop computer to exceed the collective processing power of every human brain on the planet; later in the period human/machine interfaces will begin to emerge. Whether such technologies will take hold is not known. But if they do, human evolution is likely to proceed at a greatly accelerated rate; human nature as we know it may change markedly, if it does not disappear altogether, and new intelligent species may well be created

The future of human nature: a symposium on the promises and challenges of the revolutions in genomics and computer science, April 10, 11, and 12, 2003

This repository item contains a single issue of the Pardee Conference Series, a publication series that began publishing in 2006 by the Boston University Frederick S. Pardee Center for the Study of the Longer-Range Future. This was the Center's Symposium on the Promises and Challenges of the Revolutions in Genomics and Computer Science took place during April 10, 11, and 12, 2003. Co-organized by Charles DeLisi and Kenneth Lewes; sponsored by Boston University, the Frederick S. Pardee Center for the Study of the Longer-Range Future.This conference focused on scientific and technological advances in genetics, computer science, and their convergence during the next 35 to 250 years. In particular, it focused on directed evolution, the futures it allows, the shape of society in those futures, and the robustness of human nature against technological change at the level of individuals, groups, and societies. It is taken as a premise that biotechnology and computer science will mature and will reinforce one another. During the period of interest, human cloning, germ-line genetic engineering, and an array of reproductive technologies will become feasible and safe. Early in this period, we can reasonably expect the processing power of a laptop computer to exceed the collective processing power of every human brain on the planet; later in the period human/machine interfaces will begin to emerge. Whether such technologies will take hold is not known. But if they do, human evolution is likely to proceed at a greatly accelerated rate; human nature as we know it may change markedly, if it does not disappear altogether, and new intelligent species may well be created

Chemical Evolution of Antivirals Against Enterovirus D68 through Protein-Templated Knoevenagel Reactions

The generation of bioactive molecules from inactive precursors is a crucial step in the chemical evolution of life, however, mechanistic insights into this aspect of abiogenesis are scarce. Here, we investigate the protein-catalyzed formation of antivirals by the 3C-protease of enterovirus D68. The enzyme induces aldol condensations yielding inhibitors with antiviral activity in cells. Kinetic and thermodynamic analyses reveal that the bioactivity emerges from a dynamic reaction system including inhibitor formation, alkylation of the protein target by the inhibitors, and competitive addition of non-protein nucleophiles to the inhibitors. The most active antivirals are slowly reversible inhibitors with elongated target residence times. The study reveals first examples for the chemical evolution of bio-actives through protein-catalyzed, non-enzymatic C−C couplings. The discovered mechanism works under physiological conditions and might constitute a native process of drug development

Spitzer reveals what's behind Orion's Bar

We present Spitzer Space Telescope observations of 11 regions SE of the Bright Bar in the Orion Nebula, along a radial from the exciting star theta1OriC, extending from 2.6 to 12.1'. Our Cycle 5 programme obtained deep spectra with matching IRS short-high (SH) and long-high (LH) aperture grid patterns. Most previous IR missions observed only the inner few arcmin. Orion is the benchmark for studies of the ISM particularly for elemental abundances. Spitzer observations provide a unique perspective on the Ne and S abundances by virtue of observing the dominant ionization states of Ne (Ne+, Ne++) and S (S++, S3+) in Orion and H II regions in general. The Ne/H abundance ratio is especially well determined, with a value of (1.01+/-0.08)E-4. We obtained corresponding new ground-based spectra at CTIO. These optical data are used to estimate the electron temperature, electron density, optical extinction, and the S+/S++ ratio at each of our Spitzer positions. That permits an adjustment for the total gas-phase S abundance because no S+ line is observed by Spitzer. The gas-phase S/H abundance ratio is (7.68+/-0.30)E-6. The Ne/S abundance ratio may be determined even when the weaker hydrogen line, H(7-6) here, is not measured. The mean value, adjusted for the optical S+/S++ ratio, is Ne/S = 13.0+/-0.6. We derive the electron density versus distance from theta1OriC for [S III] and [S II]. Both distributions are for the most part decreasing with increasing distance. A dramatic find is the presence of high-ionization Ne++ all the way to the outer optical boundary ~12' from theta1OriC. This IR result is robust, whereas the optical evidence from observations of high-ionization species (e.g. O++) at the outer optical boundary suffers uncertainty because of scattering of emission from the much brighter inner Huygens Region.Comment: 60 pages, 16 figures, 10 tables. MNRAS accepte

TRPP2 and TRPV4 form a polymodal sensory channel complex

The primary cilium has evolved as a multifunctional cellular compartment that decorates most vertebrate cells. Cilia sense mechanical stimuli in various organs, but the molecular mechanisms that convert the deflection of cilia into intracellular calcium transients have remained elusive. Polycystin-2 (TRPP2), an ion channel mutated in polycystic kidney disease, is required for cilia-mediated calcium transients but lacks mechanosensitive properties. We find here that TRPP2 utilizes TRPV4 to form a mechano- and thermosensitive molecular sensor in the cilium. Depletion of TRPV4 in renal epithelial cells abolishes flow-induced calcium transients, demonstrating that TRPV4, like TRPP2, is an essential component of the ciliary mechanosensor. Because TRPV4-deficient zebrafish and mice lack renal cysts, our findings challenge the concept that defective ciliary flow sensing constitutes the fundamental mechanism of cystogenesis

Canny Algorithm, Cosmic Strings and the Cosmic Microwave Background

We describe a new code to search for signatures of cosmic strings in cosmic microwave anisotropy maps. The code implements the Canny Algorithm, an edge detection algorithm designed to search for the lines of large gradients in maps. Such a gradient signature which is coherent in position space is produced by cosmic strings via the Kaiser-Stebbins effect. We test the power of our new code to set limits on the tension of the cosmic strings by analyzing simulated data with and without cosmic strings. We compare maps with a pure Gaussian scale-invariant power spectrum with maps which have a contribution of a distribution of cosmic strings obeying a scaling solution. The maps have angular scale and angular resolution comparable to what current and future ground-based small-scale cosmic microwave anisotropy experiments will achieve. We present tests of the codes, indicate the limits on the string tension which could be set with the current code, and describe various ways to refine the analysis. Our results indicate that when applied to the data of ongoing cosmic microwave experiments such as the South Pole Telescope project, the sensitivity of our method to the presence of cosmic strings will be more than an order of magnitude better than the limits from existing analyses.Comment: 19 pp, 14 figures; v4. minor corrections, as appears in journa

High sensitivity measurements of the CMB power spectrum with the extended Very Small Array

We present deep Ka-band ($\nu \approx 33$ GHz) observations of the CMB made with the extended Very Small Array (VSA). This configuration produces a naturally weighted synthesized FWHM beamwidth of $\sim 11$ arcmin which covers an $\ell$-range of 300 to 1500. On these scales, foreground extragalactic sources can be a major source of contamination to the CMB anisotropy. This problem has been alleviated by identifying sources at 15 GHz with the Ryle Telescope and then monitoring these sources at 33 GHz using a single baseline interferometer co-located with the VSA. Sources with flux densities \gtsim 20 mJy at 33 GHz are subtracted from the data. In addition, we calculate a statistical correction for the small residual contribution from weaker sources that are below the detection limit of the survey. The CMB power spectrum corrected for Galactic foregrounds and extragalactic point sources is presented. A total $\ell$-range of 150-1500 is achieved by combining the complete extended array data with earlier VSA data in a compact configuration. Our resolution of $\Delta \ell \approx 60$ allows the first 3 acoustic peaks to be clearly delineated. The is achieved by using mosaiced observations in 7 regions covering a total area of 82 sq. degrees. There is good agreement with WMAP data up to $\ell=700$ where WMAP data run out of resolution. For higher $\ell$-values out to $\ell = 1500$, the agreement in power spectrum amplitudes with other experiments is also very good despite differences in frequency and observing technique.Comment: 16 pages. Accepted in MNRAS (minor revisions

Zero Botnets: An Observe-Pursue-Counter Approach

Adversarial Internet robots (botnets) represent a growing threat to the safe use and stability of the Internet. Botnets can play a role in launching adversary reconnaissance (scanning and phishing), influence operations (upvoting), and financing operations (ransomware, market manipulation, denial of service, spamming, and ad click fraud) while obfuscating tailored tactical operations. Reducing the presence of botnets on the Internet, with the aspirational target of zero, is a powerful vision for galvanizing policy action. Setting a global goal, encouraging international cooperation, creating incentives for improving networks, and supporting entities for botnet takedowns are among several policies that could advance this goal. These policies raise significant questions regarding proper authorities/access that cannot be answered in the abstract. Systems analysis has been widely used in other domains to achieve sufficient detail to enable these questions to be dealt with in concrete terms. Defeating botnets using an observe-pursue-counter architecture is analyzed, the technical feasibility is affirmed, and the authorities/access questions are significantly narrowed. Recommended next steps include: supporting the international botnet takedown community, expanding network observatories, enhancing the underlying network science at scale, conducting detailed systems analysis, and developing appropriate policy frameworks.Comment: 26 pages, 13 figures, 2 tables, 72 references, submitted to PlosOn