Prevention and control of Zika fever as a mosquito-borne and sexually transmitted disease

The ongoing Zika virus (ZIKV) epidemic poses a major global public health emergency. It is known that ZIKV is spread by \textit{Aedes} mosquitoes, recent studies show that ZIKV can also be transmitted via sexual contact and cases of sexually transmitted ZIKV have been confirmed in the U.S., France, and Italy. How sexual transmission affects the spread and control of ZIKV infection is not well-understood. We presented a mathematical model to investigate the impact of mosquito-borne and sexual transmission on spread and control of ZIKV and used the model to fit the ZIKV data in Brazil, Colombia, and El Salvador. Based on the estimated parameter values, we calculated the median and confidence interval of the basic reproduction number R0=2.055 (95% CI: 0.523-6.300), in which the distribution of the percentage of contribution by sexual transmission is 3.044 (95% CI: 0.123-45.73). Our study indicates that R0 is most sensitive to the biting rate and mortality rate of mosquitoes while sexual transmission increases the risk of infection and epidemic size and prolongs the outbreak. In order to prevent and control the transmission of ZIKV, it must be treated as not only a mosquito-borne disease but also a sexually transmitted disease

Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis.

The use of photochemical transformations is a powerful strategy that allows for the formation of a high degree of molecular complexity from relatively simple building blocks in a single step. A central feature of all light-promoted transformations is the involvement of electronically excited states, generated upon absorption of photons. This produces transient reactive intermediates and significantly alters the reactivity of a chemical compound. The input of energy provided by light thus offers a means to produce strained and unique target compounds that cannot be assembled using thermal protocols. This review aims at highlighting photochemical transformations as a tool for rapidly accessing structurally and stereochemically diverse scaffolds. Synthetic designs based on photochemical transformations have the potential to afford complex polycyclic carbon skeletons with impressive efficiency, which are of high value in total synthesis.R01 GM073855 - NIGMS NIH HHS; R01 GM096129 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HH

Inhibition of oncogenic transcription factor REL by the natural product derivative calafianin monomer 101 induces proliferation arrest and apoptosis in human B-lymphoma cell lines

Increased activity of transcription factor NF-κB has been implicated in many B-cell lymphomas. We investigated effects of synthetic compound calafianin monomer (CM101) on biochemical and biological properties of NF-κB. In human 293 cells, CM101 selectively inhibited DNA binding by overexpressed NF-κB subunits REL (human c-Rel) and p65 as compared to NF-κB p50, and inhibition of REL and p65 DNA binding by CM101 required a conserved cysteine residue. CM101 also inhibited DNA binding by REL in human B-lymphoma cell lines, and the sensitivity of several B-lymphoma cell lines to CM101-induced proliferation arrest and apoptosis correlated with levels of cellular and nuclear REL. CM101 treatment induced both phosphorylation and decreased expression of anti-apoptotic protein Bcl-XL, a REL target gene product, in sensitive B-lymphoma cell lines. Ectopic expression of Bcl-XL protected SUDHL-2 B-lymphoma cells against CM101-induced apoptosis, and overexpression of a transforming mutant of REL decreased the sensitivity of BJAB B-lymphoma cells to CM101-induced apoptosis. Lipopolysaccharide-induced activation of NF-κB signaling upstream components occurred in RAW264.7 macrophages at CM101 concentrations that blocked NF-κB DNA binding. Direct inhibitors of REL may be useful for treating B-cell lymphomas in which REL is active, and may inhibit B-lymphoma cell growth at doses that do not affect some immune-related responses in normal cells.R01 GM094551 - NIGMS NIH HHS; P50 GM067041 - NIGMS NIH HHS; GM094551 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; GM067041 - NIGMS NIH HH

Asymmetric synthesis of gonytolide A: strategic use of an aryl halide blocking group for oxidative coupling

The first synthesis of the chromanone lactone dimer gonytolide A has been achieved employing vanadium(V)-mediated oxidative coupling of the monomer gonytolide C. An o-bromine blocking group strategy was employed to favor para- para coupling and to enable kinetic resolution of (±)-gonytolide C. Asymmetric conjugate reduction enabled practical kinetic resolution of a chiral, racemic precursor and the asymmetric synthesis of (+)-gonytolide A and its atropisomer.We thank the National Institutes of Health (R35 GM-118173) for research support. Work at the BU-CMD is supported by NIH R24 Grant GM-111625. We thank Prof. Scott Miller and Dr. Anthony Metrano (Yale University) for helpful discussions and preliminary experiments. We thank the Uehara Memorial Foundation for a postdoctoral fellowship to T.I., the American Cancer Society for a postdoctoral fellowship to K.D.R. (PF-16-235-01-CDD), Dr. Jeffrey Bacon (Boston University) for X-ray crystal structure analyses, and Prof. Haruhisa Kikuchi (Tohoku University) for providing a natural sample of gonytolide A. NMR (CHE-0619339) and MS (CHE-0443618) facilities at Boston University are supported by the NSF. (R35 GM-118173 - National Institutes of Health; GM-111625 - NIH; Uehara Memorial Foundation; PF-16-235-01-CDD - American Cancer Society; CHE-0619339 - NSF; CHE-0443618 - NSF

Identifying a sufficient core group for trachoma transmission.

BackgroundIn many infectious diseases, a core group of individuals plays a disproportionate role in transmission. If these individuals were effectively prevented from transmitting infection, for example with a perfect vaccine, then the disease would disappear in the remainder of the community. No vaccine has yet proven effective against the ocular strains of chlamydia that cause trachoma. However, repeated treatment with oral azithromycin may be able to prevent individuals from effectively transmitting trachoma.Methodology/principal findingsHere we assess several methods for identifying a core group for trachoma, assuming varying degrees of knowledge about the transmission process. We determine the minimal core group from a completely specified model, fitted to results from a large Ethiopian trial. We compare this benchmark to a core group that could actually be identified from information available to trachoma programs. For example, determined from the rate of return of infection in a community after mass treatments, or from the equilibrium prevalence of infection.Conclusions/significanceSufficient groups are relatively easy for programs to identify, but will likely be larger than the theoretical minimum

The discovery and dynamical evolution of an object at the outer edge of Saturn's A ring

This work was supported by the Science and Technology Facilities Council (Grant No. ST/F007566/1) and we are grateful to them for financial assistance. C.D.M. is also grateful to the Leverhulme Trust for the award of a Research Fellowshippublisher PDF not permitted, withdraw

Sensitization of renal carcinoma cells to TRAIL-induced apoptosis by rocaglamide and analogs

Rocaglamide has been reported to sensitize several cell types to TRAIL-induced apoptosis. In recent years, advances in synthetic techniques have led to generation of novel rocaglamide analogs. However, these have not been extensively analyzed as TRAIL sensitizers, particularly in TRAIL-resistant renal cell carcinoma cells. Evaluation of rocaglamide and analogs identified 29 compounds that are able to sensitize TRAIL-resistant ACHN cells to TRAIL-induced, caspase-dependent apoptosis with sub-µM potency which correlated with their potency as protein synthesis inhibitors and with loss of cFLIP protein in the same cells. Rocaglamide alone induced cell cycle arrest, but not apoptosis. Rocaglates averaged 4–5-fold higher potency as TRAIL sensitizers than as protein synthesis inhibitors suggesting a potential window for maximizing TRAIL sensitization while minimizing effects of general protein synthesis inhibition. A wide range of other rocaglate effects (e.g. on JNK or RAF-MEK-ERK signaling, death receptor levels, ROS, ER stress, eIF4E phosphorylation) were assessed, but did not contribute to TRAIL sensitization. Other than a rapid loss of MCL-1, rocaglates had minimal effects on mitochondrial apoptotic pathway proteins. The identification of structurally diverse/mechanistically similar TRAIL sensitizing rocaglates provides insights into both rocaglate structure and function and potential further development for use in RCC-directed combination therapy.This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research. Research performed at Boston University was supported in part by NIH R35 GM118173. Work at the BU-CMD is supported by R24 GM111625. (HHSN261200800001E - National Cancer Institute, National Institutes of Health; Intramural Research Program of NIH, Frederick. National Lab, Center for Cancer Research; R35 GM118173 - NIH; R24 GM111625)Published versio

Oxo-aglaiastatin-mediated inhibition of translation initiation

We thank Dr. Elias George (McGill University) for the kind gift of Pgp-1-expressing HeLa cells. RIM was supported by a doctoral fellowship from the Cole Foundation. This research was supported by a grant from the Canadian Institutes of Health Research (FDN-148366) to JP. J.A.P., Jr. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. (Cole Foundation; FDN-148366 - Canadian Institutes of Health Research; R35 GM118173 - NIH; R24 GM111625)Published versionSupporting documentatio

Phase light curves for extrasolar Jupiters and Saturns

We predict how a remote observer would see the brightness variations of giant planets similar to Jupiter and Saturn as they orbit their central stars. We model the geometry of Jupiter, Saturn and Saturn's rings for varying orbital and viewing parameters. Scattering properties for the planets and rings at wavelenghts 0.6-0.7 microns follow Pioneer and Voyager observations, namely, planets are forward scattering and rings are backward scattering. Images of the planet with or without rings are simulated and used to calculate the disk-averaged luminosity varying along the orbit, that is, a light curve is generated. We find that the different scattering properties of Jupiter and Saturn (without rings) make a substantial difference in the shape of their light curves. Saturn-size rings increase the apparent luminosity of the planet by a factor of 2-3 for a wide range of geometries. Rings produce asymmetric light curves that are distinct from the light curve of the planet without rings. If radial velocity data are available for the planet, the effect of the ring on the light curve can be distinguished from effects due to orbital eccentricity. Non-ringed planets on eccentric orbits produce light curves with maxima shifted relative to the position of the maximum planet's phase. Given radial velocity data, the amount of the shift restricts the planet's unknown orbital inclination and therefore its mass. Combination of radial velocity data and a light curve for a non-ringed planet on an eccentric orbit can also be used to constrain the surface scattering properties of the planet. To summarize our results for the detectability of exoplanets in reflected light, we present a chart of light curve amplitudes of non-ringed planets for different eccentricities, inclinations, and the viewing azimuthal angles of the observer.Comment: 40 pages, 13 figures, submitted to Ap.

A new perspective on the irregular satellites of Saturn - II Dynamical and physical origin

The origin of the irregular satellites of the giant planets has been long debated since their discovery. Their dynamical features argue against an in-situ formation suggesting they are captured bodies, yet there is no global consensus on the physical process at the basis of their capture. In this paper we explore the collisional capture scenario, where the actual satellites originated from impacts occurred within Saturn's influence sphere. By modeling the inverse capture problem, we estimated the families of orbits of the possible parent bodies and the specific impulse needed for their capture. The orbits of these putative parent bodies are compared to those of the minor bodies of the outer Solar System to outline their possible region of formation. Finally, we tested the collisional capture hypothesis on Phoebe by taking advantage of the data supplied by Cassini on its major crater, Jason. Our results presented a realistic range of solutions matching the observational and dynamical data.Comment: 26 Pages, 21 Figure