The Development of an Electron Transfer Initiated Cyclization Approach Toward the Total Synthesis of Mycalamide B. The Synthesis of the N7-C25 Fragment of Psymberin

The electron transfer initiated cyclization (ETIC) has been shown to be an efficient method for the generation of cyclic amido acetals. The tetrahydrofuranyloxy methyl ether was shown to be a stable nucleophilic hemiacetal surrogate allowing for the incorporation of a formaldehyde equivalent in the ETIC reaction. The ETIC reaction was employed in the stereoselective synthesis of amido trioxadecalin systems relevant to the synthesis of the mycalamides, onnamides and theopederins. The stereoselectivity resulting from these cyclizations was controlled by the substituents of the tetrahydropyran ring and the conformational bias of the developing trioxadecalin system. The epimerization of the N-acylaminal center of the amido trioxadecalin system was possible under mildly acidic conditions. An efficient and stereoselective synthetic route has been developed that intends to employ the ETIC reaction to selectively generate the N-acylaminal of mycalamide B. A linear approach to the generation of the right half of mycalamide B has been applied allowing for expedient access to the dimethyl tetrahydropyran core. The synthetic sequence employs an asymmetric Leighton allylation, selective boron mediated aldol, 1,3-syn-reduction, and selective epoxidation and syn-vinylation to establish the stereochemistry of the right hand fragment of mycalamide B. The stereoselective synthesis of the N7-C24 fragment of psymberin was developed. The synthesis is highlighted by the de novo generation of the C25-C17 pentasubstituted arene that allows for the expedient generation of multigram quantities of this intermediate. The stereochemistry of this fragment was established by an asymmetric Brown crotylation and Leighton allylation, selective Mukaiyama aldol addition, 1,3-syn-reduction, and a selective Lewis acid catalyzed TMSCN displacement of an acyl lactol

Naimark-Sacker Bifurcations in Linearly Coupled Quadratic Maps

We report exact analytical expressions locating the $0\to1$, $1\to2$ and $2\to4$ bifurcation curves for a prototypical system of two linearly coupled quadratic maps. Of interest is the precise location of the parameter sets where Naimark-Sacker bifurcations occur, starting from a non-diagonal period-2 orbit. This result is the key to understand the onset of synchronization in networks of quadratic maps.Comment: 6 pages, 3 figures (1 in color), submitted to Physica

Time-domain diffuse correlation spectroscopy

Physiological monitoring of oxygen delivery to the brain has great significance for improving the management of patients at risk for brain injury. Diffuse correlation spectroscopy (DCS) is a rapidly growing optical technology able to non-invasively assess the blood flow index (BFi) at the bedside. The current limitations of DCS are the contamination introduced by extracerebral tissue and the need to know the tissue's optical properties to correctly quantify the BFi. To overcome these limitations, we have developed a new technology for time-resolved diffuse correlation spectroscopy. By operating DCS in the time domain (TD-DCS), we are able to simultaneously acquire the temporal point-spread function to quantify tissue optical properties and the autocorrelation function to quantify the BFi. More importantly, by applying time-gated strategies to the DCS autocorrelation functions, we are able to differentiate between short and long photon paths through the tissue and determine the BFi for different depths. Here, we present the novel device and we report the first experiments in tissue-like phantoms and in rodents. The TD-DCS method opens many possibilities for improved non-invasive monitoring of oxygen delivery in humans

From proteomics to discovery of first-in-class ST2 inhibitors active in vivo

Soluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2

Desde el pacífico a la foresta tropical: redes de interacción social en el desierto de atacama durante el pleistoceno final

The social groups that initially inhabited the hyper arid core of the Atacama Desert of northern Chile during the late Pleistocene integrated a wide range of local, regional and supra regional goods and ideas for their social reproduction as suggested by the archaeological evidence contained in several open camps in Pampa del Tamarugal (PdT). Local resources for maintaining their every-day life, included stone raw material, wood, plant and animal fibers, game, and fresh water acquired within a radius of ∼30 km (ca. 1-2 days journey). At a regional scale, some goods were introduced from the Pacific coast (60-80 km to the west, ca. 3-4 days journey), including elongated rounded cobbles used as hammer stones in lithic production, and shells, especially from non-edible species of mollusks. From the Andes (ranging 80-150 km to the east, ca. 5-8 days of journey), they obtained camelid fiber, obsidian and a high-quality chalcedony, in addition to sharing knowledge on projectile point designs (Patapatane and Tuina type forms). Pieces of wood of a tropical forest tree species (Ceiba spp.) from the east Andean lowlands (600 km away, ca. 30 days of journey) were also brought to the PdT. While local goods were procured by the circulation of people within the PdT, the small number of foreign items would have been acquired through some sort of exchange networks that integrated dispersed local communities throughout several ecosystems. These networks may have been a key factor behind the success exhibited by these early huntergatherers in the hyper arid ecosystems of the Atacama Desert at the end of the Pleistocene. Different lines of archaeological evidence including open camps, workshop-quarries, lithic artifacts, archaeofaunal remains, plant and animal fibers and textiles, archaeobotanical remains, and paleoecological data show that people of the PdT managed a wide range of cultural items from the Pacific coast, the Andean highland and the tropical forest, that were integrated with resources gathered locally within the socio-cultural systems established by the end of the Pleistocene. These results are interpreted as material expressions of multi-scalar networking for resource management and other social material and immaterial requirements, which in other words, means that these people were actively connected to regional (coastal and highland), and supra-regional (trans-Andean) exchange networks from and out of the PdT.Los grupos sociales que inicialmente habitaban el núcleo hiperárido del Desierto de Atacama en el norte de Chile durante el Pleistoceno tardío integraron una amplia gama de bienes e ideas, locales, regionales y supra regionales, para su reproducción social, como lo sugieren las evidencias arqueológicas materiales recuperadas en varios campamentos al aire libre en Pampa del Tamarugal (PdT). Los recursos locales para mantener su vida diaria, incluían materias primas líticas, fibras de plantas y animales, presas de caza y agua dulce adquiridos en un radio de ̴30 km (ca. 1-2 días de viaje). A escala regional, se introdujeron algunos elementos desde la costa del Pacífico (60-80 km hacia el oeste, ca. 3 a 4 días de viaje), incluidos rodados redondeados alargados, utilizados como percutores en la producción lítica y conchas, especialmente de especies no comestibles de moluscos. Desde los Andes (80-150 km al este, ca. 5-8 días de viaje), obtuvieron fibra de camélido, obsidiana y una calcedonia de alta calidad, además de compartir conocimientos sobre diseños de puntas de proyectil (tipo Patapatane y Tuina). También se llevaron a la PdT trozos de madera de una especie de árbol de los bosques tropicales (Ceiba spp.) de las tierras bajas al este de los Andes (600 km de distancia, ca. 30 días de viaje). Mientras que los bienes locales fueron adquiridos por la circulación de personas dentro de la PdT, el pequeño número de artículos foráneos se adquirieron a través de redes de intercambio que integraron comunidades locales dispersas en varios ecosistemas; lo que debió ser un factor clave detrás del éxito demostrado por estos primeros cazadores-recolectores en los ecosistemas hiperáridos del Desierto de Atacama hacia el final del Pleistoceno. Diferentes líneas de evidencia arqueológica que incluyen campamentos al aire libre, talleres, canteras, artefactos líticos, restos arqueofaunales, fibras y textiles de plantas y animales, restos arqueobotánicos y datos paleoecológicos, muestran que la gente de la PdT manejaron una amplia gama de elementos culturales desde la costa del Pacífico, el altiplano andino y el bosque tropical, que se integraron a los recursos recolectados localmente dentro de los sistemas socioculturales establecidos al final del Pleistoceno. Estos resultados se interpretan como una expresión material de una red de múltiples escalas para la gestión de recursos y otros requisitos sociales e inmateriales, lo que en otras palabras, significaría que estos grupos sociales estaban conectados activamente con redes de interacción regionales (costa y tierras altas) y supra-regionales (transandinas) desde y hacia la PdT.Fil: Santoro, Calógero M.. Universidad de Tarapaca.; ChileFil: Gayo, Eugenia M.. Centro de Ciencia del Clima y la Resiliencia; Chile. Universidad de Concepción; ChileFil: Capriles Flores, Jose Mariano. State University of Pennsylvania; Estados UnidosFil: Rivadeneira Valenzuela, Marcelo Michel. Comisión Nacional de Investigación Científica y Tecnológica. Centro de Investigación Regional. Centro de Estudios en Zonas Áridas; Chile. Universidad Católica del Norte; Chile. Universidad de La Serena; ChileFil: Herrera, Katherine A.. Universite Paris Ouest Nanterre la Defense; Francia. Universidad de Tarapaca.; ChileFil: Mandakovic, Valentina. No especifíca;Fil: Rallo, Mónica. No especifíca;Fil: Rech, Jason A.. University of Miami; Estados UnidosFil: Cases, Bárbara. Universidad de Tarapaca.; ChileFil: Briones, Luis. Museo Municipalidad de Pica; ChileFil: Olguín, Laura. Universidad Católica del Norte, San Pedro de Atacama; ChileFil: Valenzuela, Daniela. Universidad de Tarapaca.; ChileFil: Borrero, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Ugalde, Paula C.. University of Arizona; Estados Unidos. Universidad de Tarapaca.; ChileFil: Rothhammer, Francisco. Universidad de Tarapaca.; ChileFil: Latorre, Claudio. Pontificia Universidad Católica de Chile; Chile. Instituto de Ecología y Biodiversidad; ChileFil: Szpak, Paul. Trent University; Canad

De novo Assembly of a 40 Mb Eukaryotic Genome from Short Sequence Reads: Sordaria macrospora, a Model Organism for Fungal Morphogenesis

Filamentous fungi are of great importance in ecology, agriculture, medicine, and biotechnology. Thus, it is not surprising that genomes for more than 100 filamentous fungi have been sequenced, most of them by Sanger sequencing. While next-generation sequencing techniques have revolutionized genome resequencing, e.g. for strain comparisons, genetic mapping, or transcriptome and ChIP analyses, de novo assembly of eukaryotic genomes still presents significant hurdles, because of their large size and stretches of repetitive sequences. Filamentous fungi contain few repetitive regions in their 30–90 Mb genomes and thus are suitable candidates to test de novo genome assembly from short sequence reads. Here, we present a high-quality draft sequence of the Sordaria macrospora genome that was obtained by a combination of Illumina/Solexa and Roche/454 sequencing. Paired-end Solexa sequencing of genomic DNA to 85-fold coverage and an additional 10-fold coverage by single-end 454 sequencing resulted in ∼4 Gb of DNA sequence. Reads were assembled to a 40 Mb draft version (N50 of 117 kb) with the Velvet assembler. Comparative analysis with Neurospora genomes increased the N50 to 498 kb. The S. macrospora genome contains even fewer repeat regions than its closest sequenced relative, Neurospora crassa. Comparison with genomes of other fungi showed that S. macrospora, a model organism for morphogenesis and meiosis, harbors duplications of several genes involved in self/nonself-recognition. Furthermore, S. macrospora contains more polyketide biosynthesis genes than N. crassa. Phylogenetic analyses suggest that some of these genes may have been acquired by horizontal gene transfer from a distantly related ascomycete group. Our study shows that, for typical filamentous fungi, de novo assembly of genomes from short sequence reads alone is feasible, that a mixture of Solexa and 454 sequencing substantially improves the assembly, and that the resulting data can be used for comparative studies to address basic questions of fungal biology

Bryophyte gas-exchange dynamics along varying hydration status reveal a significant carbonyl sulphide (COS) sink in the dark and COS source in the light

Carbonyl sulphide (COS) is a potential tracer of gross primary productivity (GPP), assuming a unidirectional COS flux into the vegetation that scales with GPP. However, carbonic anhydrase (CA), the enzyme that hydrolyses COS, is expected to be light independent, and thus plants without stomata should continue to take up COS in the dark. We measured net CO2 (A(C) ) and COS (A(S) ) uptake rates from two astomatous bryophytes at different relative water contents (RWCs), COS concentrations, temperatures and light intensities. We found large A(S) in the dark, indicating that CA activity continues without photosynthesis. More surprisingly, we found a nonzero COS compensation point in light and dark conditions, indicating a temperature-driven COS source with a Q10 (fractional change for a 10°C temperature increase) of 3.7. This resulted in greater A(S) in the dark than in the light at similar RWC. The processes underlying such COS emissions remain unknown. Our results suggest that ecosystems dominated by bryophytes might be strong atmospheric sinks of COS at night and weaker sinks or even sources of COS during daytime. Biotic COS production in bryophytes could result from symbiotic fungal and bacterial partners that could also be found on vascular plants.Funding was provided by the European Research Council (ERC) early career starting grant SOLCA (grant no. 338264) and the French Agence National de la Recherche (ANR) project ORCA. T.E.G. was funded by the IdEx post-doctoral programme of the Université de Bordeaux and by a Marie Skłodowska-Curie Intra-European fellowship (grant no. 653223). J.R. was funded by NERC grant NE/M00113X/1

Late Quaternary paleohydrology and surficial processes of the Atacama Desert, Chile: Evidence from wetland deposits and stable isotopes of soil salts

The origin of pedogenic salts in the Atacama Desert has long been debated. Possible salt sources include in situ weathering at the soil site, local sources such as aerosols from the adjacent Pacific Ocean or salt-encrusted playas, and extra-local atmospheric dust. To identify the origin of Ca and S in Atacama soil salts, we determined δ ³⁴S and ⁸⁷Sr/⁸⁶Sr values of soil gypsum/anhydrite and ⁸⁷Sr/⁸⁶Sr values of calcium carbonate along three east-west trending transects in the Atacama. Our results demonstrate the strong influence of marine aerosols on soil gypsum/anhydrite development in areas where marine fog penetrates inland. In areas where the Coastal Cordillera is >1200 m, however, coastal fog cannot penetrate inland and the contribution of marine aerosols to soils is greatly reduced. Salts in inland soils appear to originate from eolian redistribution of playa salts that are precipitated from evaporated ground water. This ground water has acquired its dissolved solids from water-rock interactions (both thermal and low-temperature) along flowpaths from recharge areas in the Andes. The spatial distribution of high-grade nitrate deposits appears to correspond with areas that receive the lowest fluxes of local dust, supporting arguments for an atmospheric source of nitrate. Ground water in the Atacama is derived from precipitation in the High Andes (>3500 m) that infiltrates soils and then flows down the Pacific slope of the Andes to feed aquifers within the hyperarid core of the Atacama Desert. At many locations, ground water surfaces and creates springs, marshes, and wetlands. In order to track late Quaternary fluctuations in ground-water recharge, paleowetland deposits at eight separate locations (between 18°-26°S) were mapped and dated. Over 200 AMS ¹⁴C dates on a variety of materials provide firm age control on these deposits. Replication of time-stratigraphic units from an assortment of hydrologic settings and varying distances from recharge areas in the Andes show that ground-water systems are responding to regional changes in climate and that response times are probably short (<1000 years). Results suggest that the wettest period represented by deposits was during the late Glacial/early Holocene (∼16-9.5 ka B.P.) and that a moderately wet period occurred during the mid-Holocene (8--3 ka B.P.). Major drops in Atacama water tables, due to regional drought, occurred between 9.5-8 and ∼3 ka B.P. The late Holocene was characterized by generally lower water tables than during the mid-Holocene and subject to more frequent water table drops. Fluctuations in tropical Pacific Sea Surface Temperatures, the Walker Circulation, and ENSO variability is thought to be the major control on precipitation over this region during the late Quaternary

Recovering parameters from self-similar structures in phase space of dissipative systems with constant Jacobian

Abstract We show that dissipative dynamical systems with constant Jacobian allow one to recover numerical values of control parameters under which the system is operating. This is done by performing measurements on self-similar (fractal) structures in phase space. We illustrate parameter recovery explicitly for the Ikeda laser ring-cavity map and the HÃ enon map. The ÿrst model involves transcendental equations of motion and can be solved only numerically. Analytical results are obtained for the HÃ enon map. In both cases, the dissipation rate is recovered from the speed at which fractal &quot;ÿngers&quot; making up basins of attraction accumulate towards basin boundaries. c 2000 Elsevier Science B.V. All rights reserved. This note reports equations deÿning interesting and generic paths (surfaces) in the parameter space of dissipative systems with constant Jacobian. The main characteristic of such paths is that under a suitable condition (existence of self-similar structures in phase space) they allow one to retrieve numerical values of model parameters under which the system is operating. Such paths are simple consequences of a standard linear PAC

Basin size evolution between dissipative and conservative limits

Recent methods for stabilizing systems like, e.g., loss-modulated CO2 lasers, involve inducing controlled monostability via slow parameter modulations. However, such stabilization methods presuppose detailed knowledge of the structure and size of basins of attraction. In this Brief Report, we numerically investigate basin size evolution when parameters are varied between dissipative and conservative limits. Basin volumes shrink fast as the conservative limit is approached, being well approximated by Gaussian profiles, independently of the period. Basin shrinkage and vanishing is due to the absence of bounded motions in the Hamiltonian limit. In addition, we find basin volume to remain essentially constant along a peculiar parameter path along which it is possible to recover the dissipation rate solely from metric properties of self-similar structures in phase-space