A novel N-heterocycles substituted oseltamivir derivatives as potent inhibitors of influenza virus neuraminidase: discovery, synthesis and biological evaluation.

Our previous studies have shown that the introduction of structurally diverse benzyl side chains at the C5-NH2 position of oseltamivir to occupy 150-cavity contributes to the binding affinity with neuraminidase and anti-influenza activity. To obtain broad-spectrum neuraminidase inhibitors, we designed and synthesised a series of novel oseltamivir derivatives bearing different N-heterocycles substituents that have been proved to induce opening of the 150-loop of group-2 neuraminidases. Among them, compound 6k bearing 4-((r)-2-methylpyrrolidin-1-yl) benzyl group exhibited antiviral activities similar to or weaker than those of oseltamivir carboxylate against H1N1, H3N2, H5N1, H5N6 and H5N1-H274Y mutant neuraminidases. More encouragingly, 6k displayed nearly 3-fold activity enhancement against H3N2 virus over oseltamivir carboxylate and 2-fold activity enhancement over zanamivir. Molecular docking studies provided insights into the explanation of its broad-spectrum potency against wild-type neuraminidases. Overall, as a promising lead compound, 6k deserves further optimisation by fully considering the ligand induced flexibility of the 150-loop.

Tailoring ultra-broadband vector beams via programming the electric field vector of light.

With spatially inhomogeneous polarization, vector beam (VB) has created substantial opportunities in both optics and photonics. However, the limited spectral bandwidth of VB generator hinders further advances for higher level of integration and functionality. Here, an innovative approach of programming the electric field vector of light is proposed to tailor arbitrary ultra-broadband VBs, in parallel among an unprecedented wavelength range over 1000 nm covering the visible and NIR band. We demonstrate the twisted nematic liquid crystals (TNLCs), specifically arranged in-situ by a dynamic programmable photopatterning, enable to directly manipulate the electric field vector of transmitted light into the VB as desired. Furthermore, the electrical responsiveness of TNLCs yields a dynamic multifunctionality between the VB and Gaussian beam. We anticipate this ultra-broadband VB generator would be promising for a variety of applications like optical manipulation, super-resolution imaging, and integrated optical communication system.

Low-voltage-driven smart glass based on micro-patterned liquid crystal Fresnel lenses.

We disclose a method of fabricating a low-voltage-driven smart glass based on micro-patterned liquid crystal (LC) Fresnel lenses and implement three proof-of-concept prototypes. Distinct from the conventional LC-based smart windows with the scattering state, the prominence of our proposed LC smart glass in blurry state under both normal and oblique observations stems from the image distortion caused by LC Fresnel lenses. In addition, the high transmittance (>90%) in clear state is obtained by applying a low voltage of 2 V to each prototype. Moreover, by elaborating the design of the LC smart glass, the reversed switching states [i.e., a clear (voltage OFF) state and a blurry (voltage ON) state] and fast switching time can be simultaneously achieved.

OsWRKY12 negatively regulates the drought-stress tolerance and secondary cell wall biosynthesis by targeting different downstream transcription factor genes in rice.

With the increasing occurrence of global warming, drought is becoming a major constraint for plant growth and crop yield. Plant cell walls experience continuous changes during the growth, development, and in responding to stressful conditions. The plant WRKYs play pivotal roles in regulating the secondary cell wall (SCW) biosynthesis and helping plant defend against abiotic stresses. qRT-PCR evidence showed that OsWRKY12 was affected by drought and ABA treatments. Over-expression of OsWRKY12 decreased the drought tolerance of the rice transgenics at the germination stage and the seedling stage. The transcription levels of drought-stress-associated genes as well as those genes participating in the ABA biosynthesis and signaling were significantly different compared to the wild type (WT). Our results also showed that less lignin and cellulose were deposited in the OsWRKY12-overexpressors, and heterogenous expression of OsWRKY12 in atwrky12 could lower the increased lignin and cellulose contents, as well as the improved PEG-stress tolerance, to a similar level as the WT. qRT-PCR results indicated that the transcription levels of all the genes related to lignin and cellulose biosynthesis were significantly decreased in the rice transgenics than the WT. Further evidence from yeast one-hybrid assay and the dual-luciferase reporter system suggested that OsWRKY12 could bind to promoters of OsABI5 (the critical component of the ABA signaling pathway) and OsSWN3/OsSWN7 (the key positive regulators in the rice SCW thickening), and hence repressing their expression. In conclusion, OsWRKY12 mediates the crosstalk between SCW biosynthesis and plant stress tolerance by binding to the promoters of different downstream genes.

Modification of lignin composition by ectopic expressing wheat TaF5H1 led to decreased salt tolerance in transgenic Arabidopsis plants.

Lignin is an important cell wall component that provides plants with mechanical support and improved tolerance to pathogen attacks. Previous studies have shown that plants rich in S-lignin content or with a higher S/G ratio always exhibit higher efficiency in the utilization of lignocellulosic biomass. Ferulate 5-hydroxylase, or coniferaldehyde 5-hydroxylase (F5H, or CAld5H), is the critical enzyme in syringyl lignin biosynthesis. Some F5Hs have been characterized in several plant species, e.g., Arabidopsis, rice, and poplar. However, information about F5Hs in wheat remains unclear. In this study, a wheat F5H gene, TaF5H1, together with its native promoter (pTaF5H1), was functionally characterized in transgenic Arabidopsis. Gus staining results showed that TaF5H1 could be expressed predominantly in the highly lignified tissues in transgenic Arabidopsis plants carrying pTaF5H1:Gus. qRT-PCR results showed that TaF5H1 was significantly inhibited by NaCl treatment. Ectopic expression of TaF5H1 driven by pTaF5H1 (i.e., pTaF5H1:TaF5H1) could increase the biomass yield, S-lignin content, and S/G ratio in transgenic Arabidopsis plants, which could also restore the traces of S-lignin in fah1-2, the Arabidopsis F5H mutant, to an even higher level than the wild type (WT), suggesting that TaF5H1 is a critical enzyme in S lignin biosynthesis, and pTaF5H1:TaF5H1 module has potential in the manipulation of S-lignin composition without any compromise on the biomass yield. However, expression of pTaF5H1:TaF5H1 also led to decreased salt tolerance compared with the WT. RNA-seq analysis showed that many stress-responsive genes and genes responsible for the biosynthesis of cell walls were differentially expressed between the seedlings harboring pTaF5H1:TaF5H1 and the WT, hinting that manipulation of the cell wall components targeting F5H may also affect the stress adaptability of the modified plants due to the interference to the cell wall integrity. In summary, this study demonstrated that the wheat pTaF5H1: TaF5H1 cassette has the potential to modulate S-lignin composition without any compromise in biomass yield in future engineering practice. Still, its negative effect on stress adaptability to transgenic plants should also be considered.

An F-box protein from wheat, TaFBA-2A, negatively regulates JA biosynthesis and confers improved salt tolerance and increased JA responsiveness to transgenic rice plants.

Soil salinity is a serious problem encountered by agriculture worldwide, which will lead to many harmful effects on plant growth, development, and even crop yield. F-box protein is the core subunit of the Skp1-Cullin-F-box (SCF) complex E3 ligase and plays crucial roles in regulating the growth, development, biotic & abiotic stresses, as well as hormone signaling pathway in plants. In this study, an FBA type F-box gene TaFBA-2A was isolated from wheat (Triticum aestivum L.). This study showed that TaFBA-2A could interact with TaSKP1, and TaOPR2, the crucial enzyme involving in jasmonic acid (JA) biosynthesis. TaFBA-2A negatively regulates JA biosynthesis, probably by mediating the degradation of TaOPR2 via the ubiquitin-26S proteasome pathway. Ectopic expression of TaFBA-2A improved the salt tolerance and increased the JA responsiveness of the transgenic rice lines. In addition, some agronomic traits closely related to crop yield were significantly enhanced in the rice lines ectopic expressing TaFBA-2A. The data obtained in this study shed light on the function and mechanisms of TaFBA-2A in JA biosynthesis and the responses to salt stress and JA treatment; this study also suggested that TaFBA-2A has the potential in improving the salt tolerance and crop yield of transgenic rice plants.

Growth-inhibitory and chemosensitizing effects of microRNA-31 in human glioblastoma multiforme cells.

The constitutive activation of signal transducer and activator of transcription 3 (STAT3) contributes to resistance to temozolomide (TMZ) in glioblastoma multiforme (GBM). The aim of this study was to explore the biological role of microRNA-31 (miR-31) in GBM, particularly its role in the regulation of TMZ chemosensitivity. For this purpose, the human GBM cell lines, U251 and U87, were transfected with a miR-31 precursor (pre-miR-31), and cell proliferation, apoptosis and STAT3 phosphorylation were then assessed. To evaluate the effects of miR-31 on TMZ cytotoxicity, the cells were transfected with pre-miR-31 and exposed to 100 µM TMZ for 72 h prior to cell proliferation and apoptosis analysis. A constitutively active STAT3 mutant was co-transfected with pre-miR-31 into the cells to confirm the mediating role of STAT3 signaling. The enforced expression of miR-31 significantly reduced cell proliferation and induced mitochondrial apoptosis, as manifested by the loss of mitochondrial membrane potential and the increase in caspase-9 and caspase-3 activity. The phosphorylation level of STAT3 was significantly decreased by the overexpression of miR-31. The co-delivery of the constitutively active STAT3 mutant blocked the tumor suppressive effects of miR-31. In addition, miR-31 overexpression significantly enhanced the cytotoxic effects of TMZ on the GBM cells, as evidenced by the accelerated suppression of cell proliferation and the induction of apoptosis. The chemosensitizing effects of miR-31 were significantly impaired by the expression of the constitutively active STAT3 mutant. Taken together, our results indicate that miR-31 triggers mitochondrial apoptosis and potentiates TMZ cytotoxicity in GBM cells largely through the suppression of STAT3 activation. Thus, the restoration of miR-31 expression may be of therapeutic beenefit in the treatment of GBM.