Low viscosity and low temperature curing reactive POSS/epoxy hybrid resin with enhanced toughness and comprehensive thermal performance.

The mechanical and high-temperature resistance properties of epoxy resins cured at low temperatures (Tcuring ≤ 100 °C) are often inferior, and the most toughening modification methods for epoxy resins tend to compromise thermal resistance, which significantly limit the practical applications of it. Therefore, this work reported a low viscosity and low-temperature curing epoxy hybrid resin system (OPEP), adopting E-51 as a resin matrix, liquid anhydride (MHHPA) as a curing agent, tertiary amine (DMBA) as a curing accelerator, and reactive octa-epoxy terminated polyhedral oligomeric silsesquioxane (OG-POSS) as a toughening modifier. Results demonstrated that the OPEP system has excellent processability with low viscosity and long processing window period and satisfies the practical requirements of low-temperature curing. The OG-POSS exhibits superior compatibility and reactivity with the resin matrix, and its addition slightly reduces the Eα of the curing reaction and has a certain promotive effect on the curing of epoxy resin. In addition, the curing reaction rate of the OPEP resin complies with the Sesták-Berggren autocatalytic kinetics model. The impact strength, flexural strength, tensile strength, and elongation at break of the OPEP resin reached a maximum of 15.55 kJ m-2, 121.65 MPa, 90.36 MPa, and 2.48%, representing increases of 55.97%, 3.1%, 64.68%, and 26.51% compared to those of the pure resin, respectively. Notably, due to the heat-resistant inorganic silicon cage structure of OG-POSS, the thermal decomposition temperature (Td5), glass transition temperature (Tg), and heat distortion temperature (THDT) of the OPEP0.02 resin were 313.2 °C, 123.7 °C, and 102.0 °C, showing increases of 13.0 °C, 2.3 °C, and 6.8 °C compared to the pure resin, respectively, which is difficult to achieve for the general thermosetting resin toughening modification method. This research utilized organic-inorganic nanohybrid materials (POSS) to optimize the toughness and thermal stability of the resin in a coordinated manner, providing guidance for the preparation of high-performance epoxy resins that cure at low temperatures.

Polypeptides inhibit HIV-1 replication by interfering viral Vpu-mediated tetherin degradation.

Background: HIV-1 Vpu acts by counteracting the tethering function of tetherin and resulting in the release of HIV-1 virion. Disrupting Vpu-tetherin interactions may provide a promising new target for antiretroviral therapy. Methods: Polypeptides that covered the amino acid sequence on the interface of Vpu-tetherin complex were designed. Phenotypic susceptibilities and cellular toxicities to the polypeptides were measured. The mechanisms of the anti-HIV-1 polypeptides were determined by the Western blot analysis and laser confocal scanning. Seven 20-mer polypeptides from wild-type Vpu amino acid sequence were designed. Results: We report the design and identification of 3 novel anti-HIV-1 polypeptides that derived from Vpu sequence which can efficiently inhibit HIV-1 infection. A pilot mechanism study showed that the active polypeptide could counteract Vpu-mediated tetherin downregulation. Laser confocal image scanning study showed that the polypeptides bound on the cell surface with a receptor specific binding manner, which may target tetherin that expressed on cell surface. Conclusion: Our work provided first evidence that counteracting Vpu-mediated tetherin downregulation could be a target for novel anti-HIV-1 drug design. Future works to provide direct evidence of inhibitors interact with tetherin at atomic resolution and the development of small molecules inhibitors targeting Vpu-tetherin interactions may open a new avenue for novel antiretroviral therapy.

Compact and high Q-factor multimode racetrack ring resonator based on transformation optics.

The ring resonator is a versatile and functional component in the silicon-based integrated optical circuit. Most of the previously reported ring resonators work in the single-mode case. With the rapid development of mode division multiplexing technology, a multimode ring resonator (MMRR) has been proposed and the usage beyond the limit of a conventional single mode ring resonator has been explored. However, the reported MMRRs are either large in size or low in quality factor. In this paper, we designed a compact silicon MMRR with a small bending radius of 15µm, in which the three lowest TE modes all have high Q-factors. For suppressing the mode loss and inter-mode crosstalk in MMRR, a multimode waveguide bend (MWB) with mode adiabatic evolution was designed based on transformation optics and waveguide shape optimization. The independent excitation of each order mode of the MMRR is realized by using bending directional coupler and asymmetric directional coupler. We successfully fabricated the device on a silicon-on-insulator (SOI) platform using simple one-step lithography. The measured loaded Q-factors of the three lowest TE modes are 5.9 × 104, 4.5 × 104, and 4.7 × 104, respectively.

Structural control of a novel hierarchical porous carbon material and its adsorption properties.

Novel hierarchical porous carbon materials (HPCs) were fabricated via a reactive template-induced in situ hypercrosslinking procedure. The effects of carbonization conditions on the microstructure and morphology of HPCs were investigated, and the adsorption of methylene blue (MB) on HPCs was explored. The as-prepared HPCs has a hierarchical micro-, meso- and macropore structure, which results from the overlap of hollow nanospheres possessing microporous shells and macroporous cavities. The carbonization temperature, carbonization time and carbonization heating rate played important roles in tailoring the nanostructures of HPCs. The BET specific surface area and micropore specific surface area can reach 2388 m2 g-1 and 1892 m2 g-1, respectively. Benefitting from the well-developed pore structure, the MB removal efficiency can exceed 99% under optimized conditions. The adsorption kinetics and thermodynamics can be well described by a pseudo-second-order model and Langmuir model, respectively. Furthermore, such adsorption was characterized by a spontaneous endothermic process.

Deterministic design of focusing apodized subwavelength grating coupler based on weak form and transformation optics.

The focusing apodized subwavelength grating coupler (F-ASGC) has advantages of high coupling efficiency, small footprint and simple fabrication process, which make it a popular component for chip-scale coupling and testing of integrated optical circuit. However, the design of F-ASGC based on effective medium theory lacks accuracy, causing the drawbacks of peak wavelength deviation and performance degradation. In this work, we propose a deterministic design method of F-ASGC. Our grating coupler is formed by assembling various subwavelength grating units according to their complex effective indexes. The complex effective indexes of these grating units are accurately obtained by the weak form calculation. Then combining with transformation optics, we strictly analyze the F-ASGC for the first time. The simulation results show that the deterministically designed F-ASGC has high coupling efficiency of -2.51 dB, 3 dB bandwidth of 51 nm, and accurate central wavelength of 1553.1 nm. And we also fabricated it on the commercial SOI wafer. The measured maximum efficiency is -3.10 dB, the 3 dB bandwidth is 55 nm, and the central wavelength is 1551.5 nm.

Characterization of the complete mitochondrial genome of Lepus comus, the endemic Lepus in China.

Lepus comus is the endemic species in China and has been listed on the IUCN Red List in 2013. In this study, we undertook and obtained the complete Lepus comus mitochondrial genome. The circular mitochondrial genome sequence is 17,534 bp in size, containing 13 protein-coding genes (PCGs), 21 transfer RNA (tRNA) genes, 2 ribosome RNA (rRNA) genes and a longer D-loop region of 2,610 bp in length. The base composition of the mtDNA is as follows: 31.5% of A, 29.8% of T, 29.8% of C and 13.3% of G, with a total G + C content of the mtDNA 38.7% and A + T of 61.3%. The phylogenetic Maximum-Likelihood (ML) tree was constructed to validate the taxonomic status of Lepus comus, exhibiting the closest relationship with Lepus tibetanus. The study of the complete Lepus comus mitochondrial genome can provide a reference taxonomic relationships and more basic data for future.

CASC2/miR-24/miR-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3.

Hepatocellular carcinoma is one of the most common solid tumors in the digestive system. The prognosis of patients with hepatocellular carcinoma is still poor due to the acquisition of multi-drug resistance. TNF Related Apoptosis Inducing Ligand (TRAIL), an attractive anticancer agent, exerts its effect of selectively inducing apoptosis in tumor cells through death receptors and the formation of the downstream death-inducing signaling complex, which activates apical caspases 3/8 and leads to apoptosis. However, hepatocellular carcinoma cells are resistant to TRAIL. Non-coding RNAs, including long non-coding RNAs (lncRNAs) and miRNAs have been regarded as major regulators of normal development and diseases, including cancers. Moreover, lncRNAs and miRNAs have been reported to be associated with multi-drug resistance. In the present study, we investigated the mechanism by which TRAIL resistance of hepatocellular carcinoma is affected from the view of non-coding RNA regulation. We selected and validated candidate miRNAs, miR-24 and miR-221, that regulated caspase 3/8 expression through direct targeting, and thereby affecting TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. In addition, we revealed that CASC2, a well-established tumor suppressive long non-coding RNA, could serve as a "Sponge" of miR-24 and miR-221, thus modulating TRAIL-induced tumor cell apoptosis TRAIL resistance of hepatocellular carcinoma. Taken together, we demonstrated a CASC2/miR-24/miR-221 axis, which can affect the TRAIL resistance of hepatocellular carcinoma through regulating caspase 3/8; through acting as a "Sponge" of miR-24 and miR-221, CASC2 may contribute to improving hepatocellular carcinoma TRAIL resistance, and finally promoting the treatment efficiency of TRAIL-based therapies.

A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41.

HIV-1 fusion with the target cell is initiated by the insertion of the gp41 fusion peptide (FP) into the target cell membrane and the interaction between the gp41 N- and C-terminal heptad repeats (NHR and CHR), followed by the formation of the six-helix bundle (6-HB) fusion core. Therefore, both FP and NHR are important targets for HIV-1 fusion inhibitors. Here, we designed and synthesized a dual-target peptidic HIV-1 fusion inhibitor, 4HR-LBD-VIRIP, in which 4HR-LBD is able to bind to the gp41 NHR domain, while VIRIP is able to interact with gp41 FP. We found that 4HR-LBD-VIRIP is about tenfold more potent than 4HR-LBD and VIRIP in inhibiting HIV-1IIIB infection and HIV-1 envelope glycoprotein (Env)-mediated cell-cell fusion, suggesting that this dual-target HIV-1 fusion inhibitor possesses a strong synergistic antiviral effect. A biophysical analysis indicates that 4HR-LBD-VIRIP can interact with N70 peptide that contains the gp41 NHR and FP domains and binds with lipid membrane. This study provides a new approach for designing novel viral fusion inhibitors against HIV and other enveloped viruses with class I membrane fusion proteins.

Strong contribution of pore morphology to the high-rate electrochemical performance of lithium-ion batteries.

The interconnected ordered pore channels facilitate faster permeation of Li(+) ions during the charge-discharge process than the isolated ordered pore channels, resulting in significantly enhanced capacities, better rate capabilities and more remarkable cycling stability.

Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41.

Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development.

Silica nanonetwork confined in nitrogen-doped ordered mesoporous carbon framework for high-performance lithium-ion battery anodes.

A new class of nitrogen-doped ordered mesoporous carbon/silica (N-OMC/SiO2) nanocomposites was successfully fabricated via a multi-constituent co-assembly strategy. The N-OMC/SiO2 nanocomposite presented a unique interpenetrating carbon/silica structure whose carbon/silica interface is highly uniform, and thus demonstrated high capacity, good cycling and excellent rate properties.

Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion inhibitor: a promising strategy for discovering new antiviral therapeutics.

Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins.

The use of hairpin DNA duplexes as HIV-1 fusion inhibitors: synthesis, characterization, and activity evaluation.

Discovery of new drugs for the treatment of AIDS that possess unique structures associated with novel mechanisms of action are of great importance due the rapidity with which drug-resistant HIV-1 strains evolve. Recently we reported on a novel class of DNA duplex-based HIV-1 fusion inhibitors modified with hydrophobic groups. The present study describes a new category of hairpin fusion inhibitor DNA duplexes bearing a 3 nucleotide loop located at either the hydrophobic or hydrophilic end. The new loop structures were designed to link 2 separate duplex-forming oligodeoxynucleotides (ODNs) to make helix-assembly easier and more thermally stable resulting in a more compact form of DNA duplex based HIV-1 fusion inhibitors. A series of new hairpin duplexes were tested for anti-HIV-1 cell-cell membrane fusion activity. In addition, Tm, CD, fluorescent resonance energy transfer assays, and molecular modeling analyses were carried out to define their structural activity relationships and possible mechanisms of action.

Hydrophobic mutations in buried polar residues enhance HIV-1 gp41 N-terminal heptad repeat-C-terminal heptad repeat interactions and C-peptides' anti-HIV activity.

OBJECTIVE: To investigate the effect of mutations in a highly conserved buried polar area on the function of HIV-1 gp41. DESIGN: During HIV-1 entry, a six helical bundle (6-HB) formation between the C-terminal and N-terminal heptad repeat (CHR and NHR) of gp41 provides energy for virus cell membrane fusion. In 6-HB, residues at a and d (a-d) positions of CHR directly interact with NHR and are buried. They are considered critical residues for 6-HB stability and for anti-HIV-1 activity of CHR-derived peptides (C-peptides). Most of a-d residues in CHR are hydrophobic, as buried hydrophobic residues facilitate protein stability. However, HIV-1 gp41 CHR contains a highly conserved polar area with four successive buried a-d polar residues: S649/Q652/N656/E659. We mutated these buried polar residues to hydrophobic residues, either Leu or Ile, and studied its effect on the gp41 NHR-CHR interactions and anti-HIV activities of the C-peptides. METHODS: We measured the C-peptide mutants' ability to form 6-HB with NHR, thermal stability of the 6-HBs and C-peptides' inhibitory activity against both T20-sensitive and resistant HIV-1 strains. RESULTS: All the mutated C-peptides retained their ability to form stable 6-HB with NHR and strongly inhibited HIV-1 replication. Strikingly, S649L and E659I mutations endow C-peptide with a significantly enhanced activity against T20-resistant HIV-1 strains. CONCLUSION: The highly conserved buried a-d polar residues in HIV-1 gp41 CHR can be mutated as a means of developing new fusion inhibitors against drug-resistant HIV-1 strains. The concept can also be utilized to design fusion inhibitors against other viruses with similar mechanisms.

Artificial peptides conjugated with cholesterol and pocket-specific small molecules potently inhibit infection by laboratory-adapted and primary HIV-1 isolates and enfuvirtide-resistant HIV-1 strains.

OBJECTIVES: To develop new HIV-1 fusion inhibitors with improved antiviral activities and resistance profiles, we designed two categories of artificial peptides, each containing four heptad repeats (m4HR) conjugated with a pocket-specific small molecule (pssm) or pssm and cholesterol (chol), designated pssm-m4HR or pssm-m4HR-chol, respectively, and tested their anti-HIV-1 activity. METHODS: We synthesized the artificial peptides and conjugated these peptides with pssm and chol using a standard solid-phase Fmoc protocol and a chemoselective thioether conjugation method, respectively. We tested the inhibitory activities of the peptide conjugates against HIV-1 Env-mediated cell-cell fusion and infection by laboratory-adapted and primary HIV-1 isolates, and enfuvirtide-resistant HIV-1 strains using cell-cell fusion and p24 production assays, respectively. We assessed their cytotoxicity towards MT-2 cells using the XTT assay. RESULTS: We found that pssm-m4HR conjugates exhibited promising inhibitory activity against HIV-1 Env-mediated cell-cell fusion and laboratory-adapted HIV-1 replication with IC50 values at the low micromolar level, whereas the pssm-m4HR-chol conjugates exhibited dramatically increased anti-HIV-1 activities with IC50 values at the low nanomolar level. Some of the pssm-m4HR-chol conjugates (e.g. 5a and 5b) showed highly potent antiviral activity against infection by primary HIV-1 isolates and enfuvirtide-resistant HIV-1 strains. All the conjugates displayed no or low cytotoxicity towards MT-2 cells. The result of a prime/wash assay indicated pssm-m4HR-chol conjugates were strongly anchored to the membrane and sustained a potent inhibitory effect after washing. CONCLUSIONS: These results suggest this scaffold design is a promising strategy for developing novel peptide conjugates with improved antiviral activity against a broad spectrum of HIV-1 strains, including those highly resistant to enfuvirtide.

Exchangeability of amino acid residues with similar physicochemical properties in coiled-coil interactions.

Systematic exchange of amino acid residues of similar physicochemical properties maintains specific coiled-coil interaction between two heptad repeats of HIV-1 gp41, as well as the biological activity of related peptide fusion inhibitors. This exchangeability can greatly degenerate sequence space of peptides thus making ab initio design of coiled-coil interaction feasible.

Increase of anti-HIV activity of C-peptide fusion inhibitors using a bivalent drug design approach.

We reported the design of fusion inhibitors with improved activity using a multivalent inhibitor design strategy. First, we chose C29 as the template sequence, which is a 29-mer peptide derived from HIV-1 gp41 CHR domain and has anti-HIV activity of IC50 118 nM in a cell-cell fusion assay. We optimized the crosslink sites and linkers of the template peptide. We found that N-terminal crosslink caused activity improvement based on the multivalent co-operative effect. Especially, the IC50 of peptide (CAcaC29)2 was improved from 49.02 (monomeric form) to 5.71 nM. Compared with long peptides, short peptides may be more suitable to analyze the co-operative effect. So we selected a shorter peptide C22 to synthesize the bivalent inhibitors. Due its weak helicity, no co-operative effect appeared. Therefore, we chose SC22EK, which were introduced salt bridges to consolidate the helicity based on the natural sequence C22. The cross-linked (CAcaSC22EK)2 was four times more potent than the monomer SC22EK in anti-HIV activity, with an IC50 value of 4.92 nM close to the high active peptide fusion inhibitor C34. The strategy used in this study may be used to design new fusion inhibitors to interfere similar processes.

DNA duplexes with hydrophobic modifications inhibit fusion between HIV-1 and cell membranes.

Discovery of new drugs for the treatment of AIDS typically possessing unique structures associated with novel mechanisms of action has been of great importance due to the quick drug-resistant mutations of HIV-1 strains. The work presented in this report describes a novel class of DNA duplex-based HIV-1 fusion inhibitors. Hydrophobic groups were introduced into a DNA duplex skeleton either at one end, at both ends, or in the middle. These modified DNA duplexes inhibited fusion between HIV-1 and human cell membranes at micro- or submicromolar concentrations. Respective inhibitors adopted an aptamer pattern instead of a base-pairing interaction pattern. Structure-activity relationship studies of the respective DNA duplexes showed that the rigid and negatively charged DNA skeletons, in addition to the presence of hydrophobic groups, were crucial to the anti-HIV-1 activity of these compounds. A fluorescent resonance energy transfer (FRET)-based inhibitory assay showed that these duplex inhibitors interacted with the primary pocket in the gp41 N-terminal heptad repeat (NHR) instead of interacting with the lipid bilayers.

Design, synthesis, and biological evaluation of highly potent small molecule-peptide conjugates as new HIV-1 fusion inhibitors.

The small molecule fusion inhibitors N-(4-carboxy-3-hydroxyphenyl)-2,5-dimethylpyrrole (NB-2) and N-(3-carboxy-4-hydroxyphenyl)-2,5-dimethylpyrrole (A12) target a hydrophobic pocket of HIV-1 gp41 and have moderate anti-HIV-1 activity. In this paper, we report the design, synthesis, and structure-activity relationship of a group of hybrid molecules in which the pocket-binding domain segment of the C34 peptide was replaced with NB-2 and A12 derivatives. In addition, the synergistic effect between the small molecule and peptide moieties was analyzed, and lead compounds with a novel scaffold were discovered. We found that either the nonpeptide or peptide part alone showed weak activity against HIV-1-mediated cell-cell fusion, but the conjugates properly generated a strong synergistic effect. Among them, conjugates Aoc-ßAla-P26 and Noc-ßAla-P26 exhibited a low nanomolar IC50 in the cell-cell fusion assay and effectively inhibited T20-sensitive and -resistant HIV-1 strains. Furthermore, the new molecules exhibited better stability against proteinase K digestion than T20 and C34.

Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket.

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.