Zika Virus Attenuation by Codon Pair Deoptimization Induces Sterilizing Immunity in Mouse Models.

Zika virus (ZIKV) infection during the large epidemics in the Americas is related to congenital abnormities or fetal demise. To date, there is no vaccine, antiviral drug, or other modality available to prevent or treat Zika virus infection. Here we designed novel live attenuated ZIKV vaccine candidates using a codon pair deoptimization strategy. Three codon pair-deoptimized ZIKVs (Min E, Min NS1, and Min E+NS1) were de novo synthesized and recovered by reverse genetics and contained large amounts of underrepresented codon pairs in the E gene and/or NS1 gene. The amino acid sequence was 100% unchanged. The codon pair-deoptimized variants had decreased replication fitness in Vero cells (Min NS1 ≫ Min E > Min E+NS1), replicated more efficiently in insect cells than in mammalian cells, and demonstrated diminished virulence in a mouse model. In particular, Min E+NS1, the most restrictive variant, induced sterilizing immunity with a robust neutralizing antibody titer, and a single immunization achieved complete protection against lethal challenge and vertical ZIKV transmission during pregnancy. More importantly, due to the numerous synonymous substitutions in the codon pair-deoptimized strains, reversion to wild-type virulence through gradual nucleotide sequence mutations is unlikely. Our results collectively demonstrate that ZIKV can be effectively attenuated by codon pair deoptimization, highlighting the potential of Min E+NS1 as a safe vaccine candidate to prevent ZIKV infections.IMPORTANCE Due to unprecedented epidemics of Zika virus (ZIKV) across the Americas and the unexpected clinical symptoms, including Guillain-Barré syndrome, microcephaly, and other birth defects in humans, there is an urgent need for ZIKV vaccine development. Here we provided the first attenuated versions of ZIKV with two important genes (E and/or NS1) that were subjected to codon pair deoptimization. Compared to parental ZIKV, the codon pair-deoptimized ZIKVs were mammal attenuated and preferred insect to mammalian cells. Min E+NS1, the most restrictive variant, induced sterilizing immunity with a robust neutralizing antibody titer and achieved complete protection against lethal challenge and vertical virus transmission during pregnancy. More importantly, the massive synonymous mutational approach made it impossible for the variant to revert to wild-type virulence. Our results have proven the feasibility of codon pair deoptimization as a strategy to develop live attenuated vaccine candidates against flaviviruses such as ZIKV, Japanese encephalitis virus, and West Nile virus

In vivo imaging of Zika virus reveals dynamics of viral invasion in immune-sheltered tissues and vertical propagation during pregnancy

Rationale: Zika virus (ZIKV) is a pathogenic virus known to cause a wide range of congenital abnormalities, including microcephaly, Guillain-Barre syndrome, meningoencephalitis, and other neurological complications, in humans. This study investigated the noninvasive detection of ZIKV infection in vivo, which is necessary for elucidating the virus's mechanisms of viral replication and pathogenesis, as well as to accelerate the development of anti-ZIKV therapeutic strategies. Methods: In this study, a recombinant ZIKV harbouring Nluc gene (ZIKV-Nluc) was designed, recovered, and purified. The levels of bioluminescence were directly correlated with viral loads in vitro and in vivo. The dynamics of ZIKV infection in A129 (interferon (IFN)-α/β receptor deficient), AG6 (IFN-α/β and IFN-γ receptor deficient), and C57BL/6 mice were characterized. Pregnant dams were infected with ZIKV-Nluc at E10 via intra footpad injection. Then, the pooled immune sera (anti-ZIKV neutralizing antibodies) #22-1 in ZIKV-Nluc virus-infected mice were visualized. Results: ZIKV-Nluc showed a high genetic stability and replicated well in cells with similar properties to the wild-type ZIKV (ZIKVwt). Striking bioluminescence signals were consistently observed in animal organs, including spleen, intestine, testis, uterus/ovary, and kidney. The ileocecal junction was found to be the crucial visceral target. Infection of pregnant dams with ZIKV-Nluc showed that ZIKV was capable of crossing the maternal-fetal barrier to infect the fetuses via vertical transmission. Furthermore, it was visualized that treatment with the pooled immune sera was found to greatly restrict the spread of the ZIKV-Nluc virus in mice. Conclusions: This study is the first to report the real-time noninvasive tracking of the progression of ZIKV invading immune-sheltered tissues and propagating vertically during pregnancy. The results demonstrate that ZIKV-Nluc represents a powerful tool for the study of the replication, dissemination, pathogenesis, and treatment of ZIKV in vitro and in vivo

Simulation of sound propagation over porous barriers of arbitrary shapes

A time-domain solver using an immersed boundary method is investigated for simulating sound propagation over porous and rigid barriers of arbitrary shapes. In this study, acoustic propagation in the air from an impulse source over the ground is considered as a model problem. The linearized Euler equations are solved for sound propagation in the air and the Zwikker-Kosten equations for propagation in barriers as well as in the ground. In comparison to the analytical solutions, the numerical scheme is validated for the cases of a single rigid barrier with different shapes and for two rigid triangular barriers. Sound propagations around barriers with different porous materials are then simulated and discussed. The results show that the simulation is able to capture the sound propagation behaviors accurately around both rigid and porous barriers

Possible DDˉD\bar{D} and BBˉB\bar{B} Molecular states in a chiral quark model

We perform a systematic study of the bound state problem of $D\bar{D}$ and $B\bar{B}$ systems by using effective interaction in our chiral quark model. Our results show that both the interactions of $D\bar{D}$ and $B\bar{B}$ states are attractive, which consequently result in $I^G(J^{PC})=0^+(0^{++})$ $D\bar{D}$ and $B\bar{B}$ bound states.Comment: arXiv admin note: substantial text overlap with arXiv:1204.395

Radio variability of 1st 3-months Fermi blazars at 5 GHz: affected by interstellar scintillation?

Blazars from the first-three-months Fermi-AGN list were observed with the Urumqi 25m radio telescope at 5GHz in IDV (Intra-Day Variability) mode and inter-month observation mode. A significant correlation between the flux density at 5GHz and the gamma-ray intensity for the Fermi-LAT detected blazars is seen. There is a higher IDV detection rate in Fermi detected blazars than those reported for other samples. Stronger variability appears at lower Galactic latitudes; IDV appears to be stronger in weaker sources, indicating that the variability is affected by interstellar scintillation.Comment: 4 pages, 4 figures, in proceedings of 'Multiwavelength Variability of Blazars' in Guangzhou Uni. of China, 22-24, Sep. 2010, to appear in JA

Recent breakthroughs in carrier depletion based silicon optical modulators

The majority of the most successful optical modulators in silicon demonstrated in recent years operate via the plasma dispersion effect and are more specifically based upon free carrier depletion in a silicon rib waveguide. In this work we overview the different types of free carrier depletion type optical modulators in silicon. A summary of some recent example devices for each configuration is then presented together with the performance that they have achieved. Finally an insight into some current research trends involving silicon based optical modulators is provided including integration, operation in the mid-infrared wavelength range and application in short and long haul data transmission link

The signal of Z±(4430)Z^\pm(4430) in nucleon-antinucleon scattering

We study the production of $Z^\pm(4430)$ at a nucleon-antinucleon scattering experiment. Considering the PANDA experiment to be an ideal platform to explore the production of the charmonium and charmonim-like states, we suggest the forthcoming PANDA experiment to pay attention to the production of $Z^\pm(4430)$.Comment: 6 pages, 15 figures. Published version in EPJ

Charge carrier localization induced by excess Fe in the Fe1+y(Te,Se) superconductor system

We have investigated the effect of Fe nonstoichiometry on properties of the Fe1+y(Te, Se) superconductor system by means of resistivity, Hall coefficient, magnetic susceptibility, and specific heat measurements. We find that the excess Fe at interstitial sites of the (Te, Se) layers not only suppresses superconductivity, but also results in a weakly localized electronic state. We argue that these effects originate from the magnetic coupling between the excess Fe and the adjacent Fe square planar sheets, which favors a short-range magnetic order.Comment: 15 pages, 6 figures accepted for publication in PR

TEDD: a database of temporal gene expression patterns during multiple developmental periods in human and model organisms

Characterization of the specific expression and chromatin profiles of genes enables understanding how they contribute to tissue/organ development and the mechanisms leading to diseases. Whilst the number of single-cell sequencing studies is increasing dramatically; however, data mining and reanalysis remains challenging. Herein, we systematically curated the up-to-date and most comprehensive datasets of sequencing data originating from 2760 bulk samples and over 5.1 million single-cells from multiple developmental periods from humans and multiple model organisms. With unified and systematic analysis, we profiled the gene expression and chromatin accessibility among 481 cell-types, 79 tissue-types and 92 timepoints, and pinpointed cells with the co-expression of target genes. We also enabled the detection of gene(s) with a temporal and cell-type specific expression profile that is similar to or distinct from that of a target gene. Additionally, we illustrated the potential upstream and downstream gene−gene regulation interactions, particularly under the same biological process(es) or KEGG pathway(s). Thus, TEDD (Temporal Expression during Development Database), a value-added database with a user-friendly interface, not only enables researchers to identify cell-type/tissue-type specific and temporal gene expression and chromatin profiles but also facilitates the association of genes with undefined biological functions in development and diseases. The database URL is https://TEDD.obg.cuhk.edu.hk/