Programmable Tetrahedral DNA-RNA Nanocages Woven with Stimuli-Responsive siRNA for Enhancing Therapeutic Efficacy of Multidrug-Resistant Tumors.

Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA targeting drug efflux has emerged as an effective cancer treatment to overcome MDR. Herein, stimuli-responsive programmable tetrahedral DNA-RNA nanocages (TDRN) have been rationally designed and developed for dynamic co-delivery of the chemotherapeutic drug doxorubicin and P-glycoprotein (P-gp) siRNA. Specifically, the sense and antisense strand sequences of the P-gp siRNA, which are programmable bricks with terminal disulfide bond conjugation, are precisely embedded in one edge of the DNA tetrahedron. TDRN provides a stimuli-responsive release element for dynamic control of functional cargo P-gp siRNA that is significantly more stable than the "tail-like" TDN nanostructures. The stable and highly rigid 3D nanostructure of the siRNA-organized TDRN nanocages demonstrated a notable improvement in the stability of RNase A and mouse serum, as well as long-term storage stability for up to 4 weeks, as evidenced by this study. These biocompatible and multifunctional TDRN nanocarriers with gold nanocluster-assisted delivery (TDRN@Dox@AuNCp) are successfully used to achieve synergistic RNAi/Chemo-therapy in vitro and in vivo. This programmable TDRN drug delivery system, which integrates RNAi therapy and chemotherapy, offers a promising approach for treating multidrug-resistant tumors.

Research on the preparation and performance of Ni2P@MOF composite nanomaterials.

The present study employed a solvothermal method utilizing triphenylphosphine and nickel acetylacetonate as precursors for phosphide preparation, followed by analysis and characterization. The Ni-MOF precursor was prepared using benzene diacid, triethylenediamine, and nickel sulfate as raw materials. Ni2P was introduced into the Ni-MOF precursor during its preparation while maintaining the synthesis conditions, allowing for the adsorption of Ni2P nanoparticles during Ni-MOF synthesis to produce Ni2P@MOF composite materials. The materials underwent individual testing for UV, magnetic, and microwave absorption properties. Magnetic testing results demonstrated that the incorporation of Ni2P led to an increase in the saturation magnetization (Ms) of Ni2P@MOFs compared to the Ni-MOF, thereby enhancing its electromagnetic loss capability. Microwave absorption property testing indicated that the Ni2P@MOFs exhibited enhanced dielectric and electromagnetic loss capabilities compared to the Ni-MOF, optimizing impedance matching properties and increasing effective absorption bandwidth compared to pure Ni2P materials.

Microstructure and Properties of Aluminum-Graphene-SiC Matrix Composites after Friction Stir Processing.

Enhancing the mechanical properties of conventional ceramic particles-reinforced aluminum (Al 1060) metal matrix composites (AMCs) with lower detrimental phases is difficult. In this research work, AMCs are reinforced with graphene nanosheet (GNS) and hybrid reinforcement (GNS combined with 20% SiC, synthesized by shift-speed ball milling (SSBM), and further fabricated by two-pass friction stir processing (FSP). The effect of GNS content and the addition of SiC on the microstructure and mechanical properties of AMCs are studied. The microstructure, elemental, and phase composition of the developed composite are examined using SEM, EDS, and XRD techniques, respectively. Mechanical properties such as hardness, wear, and tensile strength are analyzed. The experimental results show that the GNS and the SiC are fairly distributed in the Al matrix via SSBM, which is beneficial for the mechanical properties of the composites. The maximum tensile strength of the composites is approximately 171.3 MPa in AMCs reinforced by hybrid reinforcements. The tensile strength of the GNS/Al composites increases when the GNS content increases from 0 to 1%, but then reduces with the further increase in GNS content. The hardness increases by 2.3%, 24.9%, 28.9%, and 41.8% when the Al 1060 is reinforced with 0.5, 1, 2% GNS, and a hybrid of SiC and GNS, respectively. The SiC provides further enhancement of the hardness of AMCs reinforced by GNS. The coefficient of friction decreases by about 7%, 13%, and 17% with the reinforcement of 0.5, 1, and 2% GNS, respectively. Hybrid reinforcement has the lowest friction coefficient (0.41). The decreasing friction coefficient contributes to the self-lubrication of GNSs, the reduction in the contact area with the substrate, and the load-bearing ability of ceramic particles. According to this study, the strengthening mechanisms of the composites may be due to thermal mismatch, grain refinement, and Orowan looping. In summary, such hybrid reinforcements effectively improve the mechanical and tribological properties of the composites.

A novel single domain bispecific antibody targeting VEGF and TNF-α ameliorates rheumatoid arthritis.

Anti-TNF-α therapy fails in 30% of patients, where TNF-α may not be the key causative factor in these patients. We developed a bispecific single-domain antibody block TNF-α and VEGF (V5-3).The experiments showed that V5-3 effectively activated proliferation and migration of RA-FLS and HUVEC, tube-forming role of HUVEC, and expression of inflammatory factors in vitro. Besides, the experiments indicated that the anti-RA activity of V5-3 was superior to Anbainuo in vivo. Application of V5-3 reduced the expression of inflammatory factors, extent of synovial inflammation and angiogenesis and attenuated the severity of autoimmune arthritis in collagen-induced arthritis (CIA) mice. Mechanistically, V5-3 suppressed p65, AKT and VEGFR2 phosphorylation, as well as production of TNF-α and VEGF in joint tissues. These results demonstrated that V5-3 displayed a superior effect of anti-RA, may be a new therapy to overcome the limitations of anti-TNF-α monoclonal antibody.

DHHC2 regulates fear memory formation, LTP, and AKAP150 signaling in the hippocampus.

Palmitoyl acyltransferases (PATs) have been suggested to be involved in learning and memory. However, the underlying mechanisms have not yet been fully elucidated. Here, we found that the activity of DHHC2 was upregulated in the hippocampus after fear conditioning, and DHHC2 knockdown impaired fear induced memory and long-term potentiation (LTP). Additionally, the activity of DHHC2 and its synaptic expression were increased after high frequency stimulation (HFS) or glycine treatment. Importantly, fear learning selectively augmented the palmitoylation level of AKAP150, not PSD-95, and this effect was abolished by DHHC2 knockdown. Furthermore, 2-bromopalmitic acid (2-BP), a palmitoylation inhibitor, attenuated the increased palmitoylation level of AKAP150 and the interaction between AKAP150 and PSD-95 induced by HFS. Lastly, DHHC2 knockdown reduced the phosphorylation level of GluA1 at Ser845, and also induced an impairment of LTP in the hippocampus. Our results suggest that DHHC2 plays a critical role in regulating fear memory via AKAP150 signaling.

Improving the Mechanical Properties of a Lattice Structure Composed of Struts with a Tri-Directional Elliptical Cylindrical Section via Selective Laser Melting.

In recent years, lattice structures produced via additive manufacturing have been increasingly investigated for their unique mechanical properties and the flexible and diverse approaches available to design them. The design of a strut with variable cross-sections in a lattice structure is required to improve the mechanical properties. In this study, a lattice structure design method based on a strut cross-section composed of a mixture of three ellipses named a tri-directional elliptical cylindrical section (TEC) is proposed. The lattice structures were fabricated via the selective laser melting of 316L alloy. The finite element analysis results show that the TEC strut possessed the high mechanical properties of lattice structures. Compression experiments confirmed that the novel lattice structure with the TEC strut exhibited increases in the elastic modulus, compressive yield strength, and energy absorption capacity of 24.99%, 21.66%, and 20.50%, respectively, compared with the conventional lattice structure at an equal level of porosity.

Effect of Nanofiller on the Mechanical Properties of Carbon Fiber/Epoxy Composites under Different Aging Conditions.

In this study, carbon fiber-reinforced epoxy composites (CFRPs) containing multi-walled carbon nanotube (MWCNT) and halloysite nanoclay were fabricated. The effects of these nanofillers (MWCNT and nanoclay) on the tensile and flexural properties of the CFRPs under different aging conditions were studied. These aging conditions included water soaking, acid soaking, alkali soaking, and thermal shock cycling. The experimental results showed that, after accelerated aging, the mechanical performance of the CFRPs decreased. The performance degradation in the soaking environment depends on the immersion temperature and immersion medium. High-temperature accelerated the aging behavior of the CFRPs, resulting in low strength and modulus. The CFRPs were more vulnerable to acid soaking and alkali soaking than water soaking. The MWCNT and halloysite nanoclay are beneficial to improve the immersion aging resistance of the CFRPs, and the additions of nanofillers delayed the performance degradation under immersion aging conditions. However, nanofillers hardly improve the aging resistance of the CFRPs under thermal shock cycling condition. The fracture morphologies were observed by scanning electron microscopy (SEM) to reflect the failure modes of the CFRPs under various aging conditions. Differential scanning calorimeter (DSC) and fourier transform infrared (FTIR) spectroscopy tests were used to estimate the changes in the chemical structures and properties of epoxy resin and its composites under different conditions.

Design, synthesis and biological activity of novel 2,3,4,5-tetra-substituted thiophene derivatives as PI3Kα inhibitors with potent antitumor activity.

Using a rational design strategy for isoform-selective inhibition of PI3Kα, two series of novel 2,3,4,5-tetra-substituted thiophene derivatives containing either diaryl urea or N-Acylarylhydrazone scaffold were designed and synthesized. The most promising compound 12k was demonstrated to bear nanomolar PI3Kα inhibitory potency with 12, 28, 30, 196-fold selectivity against isoforms ß, γ, δ and mTOR. Besides, it also showed good developability profiles in cell-based proliferation against a panel of human tumor cells as well as ADME assays. We herein report on their design, synthesis, SAR and potential developability properties.

Synthesis of Branched Triubiquitin Active-Site Directed Probes.

Active-site directed probes are powerful tools for studying the ubiquitin conjugation and deconjugation machinery. Branched ubiquitin chains have emerged as important proteasome-targeting signals for aggregation-prone proteins and cell cycle regulators. By implementing a new synthetic strategy for the electrophilic warhead, we herein report on the generation and reactivity of a series of branched triubiquitin active-site directed probes. These new tools can be used to dissect the molecular basis of branched chain assembly and disassembly.

Identification and biological evaluation of novel benzothiazole derivatives bearing a pyridine-semicarbazone moiety as apoptosis inducers via activation of procaspase-3 to caspase-3.

Three series of compounds were designed, synthesized and evaluated for their in vitro anticancer activity against a procaspase-3 over-expression cancer cell line (U937) and a procaspase-3 no-expression cancer cell line (MCF-7) to rule out off-target effects. Biological evaluation led to the identification of a series of benzothiazole derivatives bearing a pyridine-semicarbazone moiety, 8j and 8k, with promising anticancer activity and remarkable selectivity. Further mechanism studies revealed that compounds 8j and 8k could induce apoptosis of cancer cells by activating procaspase-3 to caspase-3, and compound 8k exhibited the strongest procaspase-3 activation activity. Structure-activity relationships (SARs) revealed that the presence of benzothiazole and an N,N,O-donor set is crucial for the anticancer activity and selectivity, and reducing the electron density of the N,N,O-donor set results in a dramatic decline in the anticancer activity and selectivity. Furthermore, toxicity evaluation (zebrafish) in vivo and metabolic stability studies (human, rat and mouse liver microsomes) were performed to provide reliable guidance for further PK/PD studies in vivo.

Semicarbazone Derivatives Bearing Phenyl Moiety: Synthesis, Anticancer Activity, Cell Cycle, Apoptosis-Inducing and Metabolic Stability Study.

A series of semicarbazone derivatives bearing phenyl moiety were synthesized and evaluated for the vitro anticancer activities in four human cancer cell lines (human colon cancer (HT29), human neuro-blastoma (SK-N-SH), human breast cancer (MDA-MB-231), and human gastric cancer (MKN45)). Biological evaluation led to the identification of 11q and 11s, which showed excellent anticancer activities against tested cancer cell lines with IC50 values ranging from 0.32 to 1.57 µM, respectively, while exhibiting weak cytotoxicity on the normal cells (human umbilical vein endothelial cell (HUVEC)). Flow cytometric assay for cell cycle and apoptosis revealed that 11q and 11s caused an arrest in the Sub-G1 cell cycle and inhibited proliferation of cancer cells by inducing apoptosis in a dose-dependent manner. Further enzymatic assay suggested that 11q and 11s could significantly activated procaspase-3 to caspase-3. Metabolic stability study indicated that 11q and 11s showed moderate stability in vitro in human and rat liver microsomes. In view of promising pharmacological activities of 11q and 11s, which had emerged as the valuable lead for further development in the treatment for cancer.

Kinetic analyses and structure-activity relationship studies of synthetic lysine acetylation catalysts.

Lysine acylation of proteins is a crucial chemical reaction, both as a post-translational modification and as a method for bioconjugation. We previously developed a chemical catalyst, DSH, which activates a chemically stable thioester including acyl-CoA, allowing the site-selective lysine acylation of histones under physiological conditions. However, a more active catalyst is required for efficient lysine acylation in more complex biological milieu, such as in living cells, but there are no rational guidelines for developing efficient lysine acylation catalysts for use under physiological conditions as opposed to in organic solvents. We, herein, conducted a kinetic analysis of the ability of DSH and several derivatives to mediate lysine acetylation to better understand the structural elements essential for high acetylation activity under physiological conditions. Interestingly, the obtained trend in reactivity was different from that observed in organic solvents, suggesting that a different principle is necessary for designing chemical catalysts specifically for use under physiological conditions compared to catalysts for use in organic solvents. Based on the obtained information, we identified a new catalyst scaffold with high activity and structural flexibility for further modification to improve this catalyst system.

An exploration of an integrated stochastic-fuzzy pollution assessment for heavy metals in urban topsoil based on metal enrichment and bioaccessibility.

An integrated stochastic-fuzzy pollution assessment method (ISFPAM) for soil heavy metal was established based on geo-accumulation index (Igeo), stochastic-fuzzy theory and double weight system under synthetical consideration of metal ecotoxicity and bioaccessibility. The pollution characteristics of the topsoil heavy metals (Cu, Zn, Cd, Pb and Cr) in Xiangjiang New District were evaluated by the widely-used Single factor index (SF), Nemerow index (NI), Igeo, Potential ecological index (PERI), Risk assessment code (RAC) and the ISFPAM. The results of SF, NI, Igeo, RI and RAC of the studied metals revealed the following orders: Cd > Zn > Cr > Cu > Pb, Cd > Zn > Pb > Cr > Cu, Cd > Cr > Cu > Zn > Pb, Cd > Cu > Pb > Cr > Zn, and Cd > Pb > Cr > Zn > Cu, respectively. The different pollution assessment methods outputted the differentiated conclusions to some extent except the judgment for Cd. Results based on ISFPAM indicated that metal pollution degrees decreased in the order of Cd (5.91, Grade 6) > Cu (2.81, Grade 3) > Pb (2.66, Grade 3) > Cr (1.58, Grade 2) > Zn (0.69, Grade 1). By detailed comparison analysis, the double weight system and stochastic-fuzzy theory made ISFPAM better resolving ability to find out priority heavy metals and areas with relatively higher enrichment, ecotoxicity and bioaccessibility under efficient parameter uncertainty control. Cd, Cu and Pb were regarded as the priority control metals, especially Cd. Simultaneously, the reliabilities of heavy metal pollution corresponding to adjacent pollution grades were quite close in some sites, which recommend recheck for avoid misleading the decision-makers.

LC-MS/MS-based quantitative study of the acyl group- and site-selectivity of human sirtuins to acylated nucleosomes.

Chromatin structure and gene expression are dynamically regulated by posttranslational modifications of histones. Recent advance in mass spectrometry has identified novel types of lysine acylations, such as butyrylation and malonylation, whose functions and regulations are likely different from those of acetylation. Sirtuins, nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, catalyze various deacylations. However, it is poorly understood how distinct sirtuins regulate the histone acylation states of nucleosomes that have many lysine residues. Here, we provide mass spectrometry-based quantitative information about the acyl group- and site-selectivity of all human sirtuins on acylated nucleosomes. The acyl group- and site-selectivity of each sirtuin is unique to its subtype. Sirt5 exclusively removes negatively-charged acyl groups, while Sirt1/2/3/6/7 preferentially remove hydrophobic acyl groups; Sirt1 and Sirt3 selectively remove acetyl group more than butyryl group, whereas Sirt2 and Sirt6 showed the opposite selectivity. Investigating site-selectivity for active sirtuins revealed acylated lysines on H4 tails to be poor substrates and acylated H3K18 to be a good substrate. Furthermore, we found Sirt7 to be a robust deacylase of H3K36/37, and its activity reliant on nucleosome-binding at its C-terminal basic region. All together, our quantitative dataset provides a useful resource in understanding chromatin regulations by histone acylations.

Compressive Properties of Open-Cell Al Hybrid Foams at Different Temperatures.

Hybrid Ni/Al foams were fabricated by depositing electroless Ni-P (EN) coatings on open-cell Al foam substrate to obtain enhanced mechanical properties. The microstructure, chemical components and phases of the hybrid foams were observed and analyzed by scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD), respectively. The mechanical properties of the foams were studied by compressive tests at different temperatures. The experiment results show that the coating is mainly composed of Ni and P elements. There was neither defect at the interface nor crack in the coatings, indicating that the EN coatings had fine adhesion to the Al substrate. The compressive strengths and energy absorption capacities of the as-received foam and hybrid foams decrease with the increasing testing temperatures, but the hybrid foams exhibit a lower decrement rate than the as-received foam. This might be attributed to the different failure mechanisms at different testing temperatures, which is conformed by fractography observation.

Supramolecular Ligands for Histone Tails by Employing a Multivalent Display of Trisulfonated Calix[4]arenes.

Post-translational modification of histone tails plays critical roles in gene regulation. Thus, molecules recognizing histone tails and controlling their epigenetic modification are desirable as biochemical tools to elucidate regulatory mechanisms. There are, however, only a few synthetic ligands that bind to histone tails with substantial affinity. We report CA2 and CA3, which exhibited sub-micromolar affinity to histone tails (especially tails with a trimethylated lysine). Multivalent display of trisulfonated calix[4]arene was important for strong binding. CA2 was applicable not only to synthetic tail peptides but also to endogenous histone proteins, and was successfully used to pull-down endogenous histones from nuclear extract. These findings indicate the utility of these supramolecular ligands as biochemical tools for studying chromatin regulator protein and as a targeting motif in ligand-directed catalysis to control epigenetic modifications.

Sound Absorption Characteristics of Aluminum Foams Treated by Plasma Electrolytic Oxidation.

Open-celled aluminum foams with different pore sizes were fabricated. A plasma electrolytic oxidation (PEO) treatment was applied on the aluminum foams to create a layer of ceramic coating. The sound absorption coefficients of the foams were measured by an impedance tube and they were calculated by a transfer function method. The experimental results show that the sound absorption coefficient of the foam increases gradually with the decrease of pore size. Additionally, when the porosity of the foam increases, the sound absorption coefficient also increases. The PEO coating surface is rough and porous, which is beneficial for improvement in sound absorption. After PEO treatment, the maximum sound absorption of the foam is improved to some extent.

Influence of Sulfate-Reducing Bacteria on the Corrosion Residual Strength of an AZ91D Magnesium Alloy.

In this paper, the corrosion residual strength of the AZ91D magnesium alloy in the presence of sulfate-reducing bacteria is studied. In the experiments, the chemical composition of corrosion film was analyzed by a scanning electron microscope with energy dispersive X-ray spectroscopy. In addition, a series of instruments, such as scanning electronic microscope, pH-meter and an AG-10TA materials test machine, were applied to test and record the morphology of the corrosion product, fracture texture and mechanical properties of the AZ91D magnesium alloy. The experiments show that the sulfate-reducing bacteria (SRB) play an important role in the corrosion process of the AZ91D magnesium alloy. Pitting corrosion was enhanced by sulfate-reducing bacteria. Corrosion pits are important defects that could lead to a significant stress concentration in the tensile process. As a result, sulfate-reducing bacteria influence the corrosion residual strength of the AZ91D magnesium alloy by accelerating pitting corrosion.

Biomimetic superhydrophobic surface of high adhesion fabricated with micronano binary structure on aluminum alloy.

Triggered by the microstructure characteristics of the surfaces of typical plant leaves such as the petals of red roses, a biomimetic superhydrophobic surface with high adhesion is successfully fabricated on aluminum alloy. The essential procedure is that samples were processed by a laser, then immersed and etched in nitric acid and copper nitrate, and finally modified by DTS (CH3(CH2)11Si(OCH3)3). The obtained surfaces exhibit a binary structure consisting of microscale crater-like pits and nanoscale reticula. The superhydrophobicity can be simultaneously affected by the micronano binary structure and chemical composition of the surface. The contact angle of the superhydrophobic surface reaches up to 158.8 ± 2°. Especially, the surface with micronano binary structure is revealed to be an excellent adhesive property with petal-effect. Moreover, the superhydrophobic surfaces show excellent stability in aqueous solution with a large pH range and after being exposed long-term in air. In this way, the multifunctional biomimetic structural surface of the aluminum alloy is fabricated. Furthermore, the preparation technology in this article provides a new route for other metal materials.