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The sulfide solid electrolytes have the characteristics of high ionic conductivity and low grain boundary resistance, which make them suitable for bulk-type all-solid-state batteries. However, most of them suffer from poor stability in air. Here, we explore the air stable sulfide solid electrolytes in Li4SnS4-Li3SbS4 system. The solid solutions of Li4–xSbxSn1–xS4 (0 ≤ x ≤ 0.5) can be formed in Li4SnS4-Li3SbS4 system. Li3.8Sb0.2Sn0.8S4 achieves the highest ionic conductivity of 3.5 × 10−4 S cm−1 in this system, which is 5 times as that of Li4SnS4 and 3 orders of magnitude higher than that of Li3SbS4, respectively. Li3.8Sb0.2Sn0.8S4 crystallizes into the same structure with high ionic conductivity phase of β-Li3PS4. Moreover, Li3.8Sb0.2Sn0.8S4 owns good stability in humid air. Matching with LiCoO2 and Li4Ti5O12, Li3.8Sb0.2Sn0.8S4 exhibits the potential to be applied in all-solid-state batteries.

We demonstrate an electrically pumped light emitting device by integrating a monolayer MoTe2 directly on doped Silicon to form a Si-MoTe2 double heterostructure. An external quantum efficiency of ~0.65% was achieved.

Doped zirconia is a promising electrolyte candidate for Solid Oxide Fuel Cells (SOFCs). The effects of dopants and their interactions with oxygen vacancies on the conduction properties have been systematically investigated by density functional theory (DFT) calculations and experiments. The influences of dopants' valences and radii on the defect formation energies and defect binding energies are discussed. Our results show that, for Scandia stabilized zirconia (ScSZ) co-doped with In3+, Yb3+, or Bi3+, the defect formation energy differences and binding energy differences of different sites are low, which indicates that for these co-doping cases the oxygen vacancies distribute more randomly, and are more beneficial for improving the oxygen vacancy diffusing efficiency. The inner influence mechanisms of the co-dopants are discussed from the aspects of elastic and electrostatic effects. Oxygen diffusion barriers in ScSZ co-doped with various elements are also calculated by the saddle point method. The calculated results indicate that the diffusion barrier orders for different edges are ESc-Zr RZr and ESc-Zr ≈ ESc-M

The objective of this study was to investigate the effect of dietary Tartary buckwheat extract (TBE) supplementation on animal growth performance, meat quality and antioxidative activity in the Longissimus thoracis et lumborum muscle of lambs. The results showed that dietary TBE increased body weight, average daily gain, carcass weight, dry matter intake, and digestive organ weight. Dietary TBE had no effect on the pH, color, shear force or intramuscular fat of Longissimus muscle examined, whereas the cooking loss was decreased. The total antioxidative capacity and glutathione peroxidase 4 (GPx4) activity of Longissimus muscle were increased in lambs fed TBE. The mRNA contents of superoxide dismutase, catalase, GPx4 and nuclear factor-like-2 factor (Nrf2) did not vary among the groups, and greater protein levels of GPx4 and Nrf2 were observed. Taken together, these results suggest that TBE can be used as a feed ingredient in lamb production to improve its growth performance, and relieve oxidative stress and increase water holding capacity of meat.

It is unanimously accepted that non-ferromagnetic inclusions in a ferromagnetic system will lower down total saturation magnetization in unit of emu/g. In this study, “lattice strain” was found to be another key factor to have critical impact on magnetic saturation behavior of the system. The lattice strain determined assembling patterns of primary nanoparticles in hierarchical structures and was intimately related with the formation process of these architectures. Therefore, flower-necklace-like and cauliflower-like nickel hierarchical structures were used as prototype systems to evidence the relationship between assembling patterns of primary nanoparticles and magnetic saturation behaviors of these architectures. It was found that the influence of lattice strain on saturation magnetization outperformed that of non-ferromagnetic inclusions in these hierarchical structures. This will enable new insights into fundamental understanding of related magnetic effects.

In orthodontic treatment with fixed appliances, the use of nickel alloy for archwire may cause nickel allergy suffered from the release of nickel ions. In addition, esthetic concerns are a problem for many people. Shape memory polymer (SMP), as a functional material with the ability of thermo-driven shape change to produce force and with good biocompatible properties, possesses the potential to be used in orthodontic appliances. To investigate the feasibility of using polyurethane (PU) as orthodontic archwire, a kind of SMP, namely shape memory polyurethane (SMPU), a simulation via finite element method was conducted, based on a new three dimensional (3D) thermo-mechanical constitutive model and data acquired from some mechanics experiments related to temperature. Finally, a tooth-moving simulation with SMPU archwire on a wax model was performed. The results illustrated that SMPU wire shows good prospects in orthodontic application: the archwire with a 0.5 mm diameter can supply recovery force with magnitude 0.588–1.176 N (60–120 g), which is within the required range 0.49–2.94 N (50–300 g) for tooth movement. However, the force is smaller than that produced from metal wire, and more work related to material strengthening, such as filling SMPU with reinforcement material, is required in the future.

High performance solid electrolytes have been widely used in many devices, such as intermediate temperature (650–850 °C) solid oxide fuel cells, oxygen sensors, super capacitors, etc. In order to solve the problem of phase stability and high grain boundary resistance during the working process, the novel core/shell structure ScSZ nanocomposites were successfully prepared by fractional-precipated method. Non core/shell composites were also prepared by co-precipitation at the same Sc/Zr ratio for comparison. high-resolution transmission electron microscopy (HRTEM), X-ray photoelectron spectroscopy (XPS), Raman characterization were performed to identify the microstructure and phase configuration of the obtained composites. According to HRTEM, clear rich scandia shell layer of 2–4 nm existed at the edge of each core/shell particle. The HRTEM figures of non core/shell composites were homogeneous without the shell structure. XPS element analysis for core/shell composite indicated that scandium ratio increased and zirconium ratio decreased when heat treatment temperature fell. When the heating temperature fell down to 450 °C, scandium ratio reached nearly 35 mol.%. EIS and DC measurement were taken for both kinds of electrolytes to study the electrochemical properties. The ionic conductivity were 178.2 and 154.4 mS/cm at 850 °C for core/shell and non core/shell electrolytes, respectively. The mechanism of conductivity improvement was also studied. It was predicted that the core/shell interface could improve ionic conductivity by modifying the space-charge regions. This result outlines a novel and potential direction for high-end electrolytes to enhance ionic conductivity.

As a critical solid electrolyte material, 5 mol% yttrium stabilized tetragonal zirconia (5YSTZ) is commonly synthesized by hydrothermal . In this work, in order to explore the crystallization mechanism and achieve controllable preparation, six precursors with different zirconium coordination and yttrium/zirconium mixing state were used to hydrothermally synthesize nanostructured 5YSTZ. By analyzing elemental distribution, phase structure and microstructure of obtained samples, we have found that 5YSTZ follows different crystallization mechanisms under different preparation conditions: dissolution-crystallization is the major mechanism when using negatively charged zirconium coordination as precursor, while in-situ mechanism dominates when using positively charged zirconium coordination as precursor. This means the crystallization and phase structure of 5YSTZ can be adjusted by controlling the zirconium coordination in precursor. Significantly, 5YSTZ produced by precursor with uniformly mixed yttrium and negatively charged zirconium coordination has the highest densification (>99%) and ionic conductivity (34.09 mS/cm) measured at 850 °C, with the lowest activation energy (0.93eV).

Integrated photonics requires high gain optical materials in the telecom wavelength range for optical amplifiers and coherent light sources. Erbium (Er) containing materials are ideal candidates due to the 1.5 μm emission from Er3+ ions. However, the Er density in typical Er-doped materials is less than 1020 cm–3, thus limiting the maximum optical gain to a few dB/cm, too small to be useful for integrated photonic applications. Er compounds could potentially solve this problem since they contain much higher Er3+ density. So far the existing Er compounds suffer from short lifetime and strong upconversion effects, mainly due to poor crystal qualities. Recently, we explore a new Er compound: erbium chloride silicate (ECS, Er3(SiO4)2Cl) in the form of nanowire, which facilitates the growth of high quality single crystal with relatively large Er3+ density (1.62 × 1022 cm–3). Previous optical results show that the high crystal quality of ECS material leads to a long lifetime up to 1 ms. The Er lifetime-density product was found to be the largest among all the Er containing materials. Pump-probe experiments demonstrated a 644 dB/cm signal enhancement and 30 dB/cm net gain per unit length from a single ECS wire. As a result, such high-gain ECS nanowires can be potentially fabricated into ultra-compact lasers. Even though a single ECS nanowire naturally serves as good waveguide, additional feedback mechanism is needed to form an ultra-compact laser. In this work, we demonstrate the direct fabrication of 1D photonic crystal (PhC) air hole array structure on a single ECS nanowire using focused ion beam (FIB). Transmission measurement shows polarization-dependent stop-band behavior. For transverse electric (TE) polarization, we observed stop-band suppression as much as 12 dB with a 9 μm long airholed structure. Through numerical simulation, we showed that Q-factor as high as 11000 can be achieved at 1.53 μm for a 1D PhC micro-cavity on an ECS nanowire. Such a high Q cavity combined with the high material gain of ECS nanowires provides an attractive solution for ultra-compact lasers, an important goal of this research.

Purpose The purpose of this study was to analyze mechanical behaviors of a topologically optimized and 3D-printed mandibular bone block with polyetherketoneketone (PEKK) for surgical mandibular reconstruction. Materials and methods 3D virtual mandibular models were reconstructed from cone beam computed tomography images. A proposed mandibular resection of the mandibular body (40 mm anterior-posteriorly) was segmented. Internal structure of the resected bone was designed with topological optimization. Dental implants and implant-supported crowns were integrated into the design. A second 3D virtual model was created with the same size and location of the defect but was reconstructed with a fibular graft and implant-supported crowns. The biomechanical behaviors of the two models were compared by finite element method (FEM) under the same boundary constraints and three loading locations, namely, central incisors, lower left and right side first molar areas. Results The FEM results showed the maximum stresses and displacements of the topology optimized model were much lower than those of the model with fibular bone graft. The highest stress of the optimized mandibular model was located on the lower edge of the posterior border of bone analog, and fixation screws. The maximum displacement occurred at the lower edge of the proximal mandibular stump or the lower edge of the distal mandibular body on the contralateral site. Under the same three loading locations, the maximum stress of the optimized model significantly decreased by 67.9%, 71.9% and 68.6% compared to the fibular graft model. Conclusions The 3D printed bone analog with topological optimization is patient-specific and has advantages over the conventional fibular bone graft for surgical mandibular reconstruction. The optimized PEKK bone analog model creates more normal stress-strain trajectories than the fibular graft model and likely provides better functional and cosmetic outcomes.

The variations of structure and thermal properties in iron phosphate glasses and boron-doped iron phosphate glasses due to MoO3 addition up to 50 mol% were investigated and compared in detail. The results show that MoO3 depolymerizes the phosphate networks resulting in a higher connectivity of the networks through [MoO4] units and the formation of Mo–O–P bonds diversifies the cross-linking of the glass networks, leading to the conversion of long phosphate chains to pyrophosphate units and/or orthophosphate units. These structure variations cause the decrease of glass transition temperature, thermal stability and glass formation ability of iron phosphate glasses. Moreover, the MoO3 loading, thermal stability and glass formation ability of iron phosphate glasses were improved by boron. The reasons on the improved properties are also explained and analyzed. The obtained conclusions provide researchers with the role of Mo in structure and properties of phosphate glasses for Mo containing nuclear waste immobilization.

The demand for batteries with high safety and high energy density produces considerable efforts toward the development of all-solid-batteries and solid state electrolytes. Halogen-substituted lithium argyrodites, Li6PS5X (X = Cl, Br), represent a class of promising and suitable sulfide-based solid electrolytes with high conductivity and good processability. To further extend the scope and better understand the structure-property relationship, we systematically explore the effect of partial substitution of Li+ by other cations in Li6PS5X (X = Cl, Br). The X-ray diffraction (XRD) analysis shows the possibility of successful substitution at Li+ position by various cations. Among them, substitution with a small amount of Al3+ in Li6PS5Br is confirmed by Rietveld refinements. The ionic conductivity is improved by almost three times to 2.4 × 10−3 S cm−1. This improvement is attributed to the shortened distances of inter-cage jumps. In addition, the substituted sample shows better electrochemical performance in all-solid-state batteries. This work demonstrates the feasibility of performance improvement by manipulating the position of Li+ in the structure of lithium argyrodites, which provides a versatile approach toward designing better performing solid electrolytes.

Dexmedetomidine (DEX) is a widely used clinical anesthetic with proven anti-inflammatory effects. Both high mobility group box 1 (HMGB1) and pyroptosis play an important role in the inflammatory response to infection and trauma. Thus far, there have been no studies published addressing the effect of DEX on HMGB1 and pyroptosis. In order to fill this gap in the literature, bone marrow-derived macrophages (BMDMs) were exposed to HMGB1 (4 µg/mL) with or without DEX (50 μM) pretreatment. The production of pro-inflammatory cytokines [such as tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-18], phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and P38, and the activation of caspase-1 were measured by enzyme immunosorbent assay, western blot analysis, confocal microscope, and flow cytometry, respectively. We found that DEX protected against HMGB1-induced cell death of BMDMs. In addition, DEX suppressed the generation of TNF-α, IL-1β, and IL-18 as well as the phosphorylation of ERK1/2 and P38. Moreover, DEX inhibited caspase-1 activation and decreased pyroptosis. Taken together, these findings demonstrate the protective effect of DEX in mediating HMGB1-induced cellular injury, thus indicating that DEX may be a potential therapeutic candidate for the management of infection and trauma-derived inflammation.

Transition metal dichalcogenides (TMDs) have attracted a great deal of attention for potential applications in a variety of areas including integrated optoelectronic devices. Most of TMDs transform from indirect to direct band-gap semiconductors when their thickness is reduced to a monolayer. Therefore, monolayer TMDs could serve as efficient optical gain materials, especially for making nanolasers with the smallest possible volume of active medium. Such lasers with small gain media could be important as light sources for integrated photonics for future on-chip interconnects, where extreme low energy consumption is required. Furthermore, the large exciton binding energy in monolayer TMDs exceeding 0.5 eV makes them important as potential candidate for exciton lasers at room temperature. So far, lasers based on monolayer TMDs have been reported at cryogenic temperatures, employing a monolayer WSe2 coupled onto a GaP photonic-crystal cavity, or a monolayer WS2 with a Si3N4 micro-disk. One of the possible reasons for the low temperature operation is the low Q-cavity as a result of the choices of cavity materials and structures and the associated fabrication precision. Here, we demonstrate the first room-temperature operation of a nanolaser using a monolayer molybdenum ditelluride nanolaser combined with a silicon nanobeam cavity. Lasing operation at 1132 nm is supported by the exciton emission with a linewidth of 0.202 nm and a Q factor of 5605. The room temperature operation shows the feasibility of TMDs nanolaser towards practical application. In addition, the silicon nanobeam cavity would make such 2D-based lasers more attractive for silicon photonics integration.

Photodynamic therapy with toluidine blue O (TBO) hydrogel exhibits antibacterial activity against Staphylococcus aureus and Escherichia coli in this paper. The response surface methodology is employed to optimize formulations for antibacterial activity. The optimal formulations are carbomer concentration of 3% (w/v), TBO concentration of 0.1mg/mL and the quality ratio of NaOH and carbomer of 0.4 (w/w). Under the optimized formulations, the log-transformed of CFUmL-1 on the Staphylococcus aureus and Escherichia coli are 0.84 and 1.26 (the log-transformed of CFUmL-1 of negative control groups on the Staphylococcus aureus and Escherichia coli are 8.21 and 8.47), respectively. In comparison with photodynamic therapy with TBO aqueous solution, the proposed formulations provide a much stronger antibacterial activity against Staphylococcus aureus and Escherichia coli. TBO hydrogels are stable during 6weeks at three different temperatures (4, 25 and 40°C) with respect to no change of color, transparency, pH and viscosity. 50% and 68.26% of TBO are released from carbomer hydrogel after 4h and 24h, respectively. TBO hydrogel alone or light alone (630nm) treatment is incapable of showing antibacterial activity against Staphylococcus aureus and Escherichia coli. Therefore, photodynamic therapy with the novel optimized TBO hydrogel formulations is a promising treatment strategy for periodontitis.

Monolayer transition metal dichalcogenides (TMDs) provide the most efficient optical gain materials and have potential for making nanolasers with the smallest gain media with lowest energy consumption. But lasing demonstrations based on TMDs have so far been limited to low temperatures. Here, we demonstrate the first room-temperature laser operation in the infrared wavelengths from a monolayer of molybdenum ditelluride on a silicon photonic-crystal nanobeam cavity. Our demonstration is made possible by a unique choice of TMD material with emission wavelength below silicon absorption, combined with the high Q-cavity design by silicon nanobeam. Lasing at 1132 nm is demonstrated at room-temperature pumped by a continuous-wave laser, with a threshold density at 6.6 W/cm2. The room-temperature linewidth of 0.202 nm is the narrowest with the corresponding Q of 5603, the largest observed for a TMD laser. This demonstration establishes TMDs as practical nanolaser materials. The silicon structures provide additional benefits for silicon-compatible nanophotonic applications in the important infrared wavelengths.

We review the recent progress in studying and utilizing 2D monolayer transition metal dichalcogenides as gain materials to be integrated with various micro and nano-cavities for the realization of low energy lasers including room-temperature operation.

Genetic analysis of wood chemical composition is often limited by the cost and throughput of direct analytical methods. The speed and low cost of Fourier transform near infrared (FT-NIR) overcomes many of these limitations, but it is an indirect method relying on calibration models that are typically developed and validated with small sample sets. In this study, we used &gt, 1500 young greenhouse grown trees from a clonally propagated single Populus family, grown at low and high nitrogen, and compared FT-NIR calibration sample sizes of 150, 250, 500 and 750 on calibration and prediction model statistics, and heritability estimates developed with pyrolysis molecular beam mass spectrometry (pyMBMS) wood chemical composition. As calibration sample size increased from 150 to 750, predictive model statistics improved slightly. Overall, stronger calibration and prediction statistics were obtained with lignin, S-lignin, S/G ratio, and m/z 144 (an ion from cellulose), than with C5 and C6 carbohydrates, and m/z 114 (an ion from xylan). Although small differences in model statistics were observed between the 250 and 500 sample calibration sets, when predicted values were used for calculating genetic control, the 500 sample set gave substantially more similar results to those obtained with the pyMBMS data. With the 500 sample calibration models, genetic correlations obtained with FT-NIR and pyMBMS methods were similar. Quantitative trait loci (QTL) analysis with pyMBMS and FT-NIR predictions identified only three common loci for lignin traits. FT-NIR identified four QTLs that were not found with pyMBMS data, and these QTLs were for the less well predicted carbohydrate traits.

A record level of spatial-averaged internal net gain larger than 300 dB/cm is demonstrated at 1532 nm from a single-crystal Erbium Chloride Silicate nanowire. Signal enhancement at small signal regime was resolved along the entire nanowire. Pump power dependence of gain saturation are studied.

Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices.

We demonstrate a record level of optical gain at 189 dB/cm and a spatial-averaged signal enhancement of ∼ 902 dB/cm at 1532 nm from a single-crystal erbium chloride silicate nanowire by performing systematic optical characterizations.

Bioprinting by the codeposition of cells and biomaterials is constrained by the availability of printable materials. Herein we describe a novel macromonomer, a new two-step photocrosslinking strategy, and the use of a simple rapid prototyping system to print a proof-of-concept tubular construct. First, we synthesized the methacrylated ethanolamide derivative of gelatin (GE-MA). Second, partial photochemical cocrosslinking of GE-MA with methacrylated hyaluronic acid (HA-MA) gave an extrudable gel-like fluid. Third, the new HA-MA:GE-MA hydrogels were biocompatible, supporting cell attachment and proliferation of HepG2 C3A, Int-407, and NIH 3T3 cells in vitro. Moreover, hydrogels injected subcutaneously in nude mice produced no inflammatory response. Fourth, using the Fab@Home printing system, we printed a tubular tissue construct. The partially crosslinked hydrogels were extruded from a syringe into a designed base layer, and irradiated again to create a firmer structure. The computer-driven protocol was iterated to complete a cellularized tubular construct with a cell-free core and a cell-free structural halo. Cells encapsulated within this printed construct were viable in culture, and gradually remodeled the synthetic extracellular matrix environment to a naturally secreted extracellular matrix. This two-step photocrosslinkable biomaterial addresses an unmet need for printable hydrogels useful in tissue engineering.

Bioprinting enables deposition of cells and biomaterials into spatial orientations and complexities that mirror physiologically relevant geometries. To facilitate the development of bioartificial vessel-like grafts, two four-armed polyethylene glycol (PEG) derivatives with different PEG chain lengths, TetraPEG8 and TetraPEG13, were synthesized from tetrahedral pentaerythritol derivatives. The TetraPEGs are unique multi-armed PEGs with a compact and symmetrical core. The TetraPEGs were converted to tetra-acrylate derivatives (TetraPAcs) which were used in turn to co-crosslink thiolated hyaluronic acid and gelatin derivatives into extrudable hydrogels for printing tissue constructs. First, the hydrogels produced by TetraPAc crosslinking showed significantly higher shear storage moduli when compared to PEG diacrylate (PEGDA)-crosslinked synthetic extracellular matrices (sECMs) of similar composition. These stiffer hydrogels have rheological properties more suited to bioprinting high-density cell suspensions. Second, TetraPAc-crosslinked sECMs were equivalent or superior to PEGDA-crosslinked gels in supporting cell growth and proliferation. Third, the TetraPac sECMs were employed in a proof-of-concept experiment by encapsulation of NIH 3T3 cells in sausage-like hydrogel macrofilaments. These macrofilaments were then printed into tubular tissue constructs by layer-by-layer deposition using the Fab@Home printing system. LIVE/DEAD viability/cytotoxicity-stained cross-sectional images showed the bioprinted cell structures to be viable in culture for up to 4 weeks with little evidence of cell death. Thus, biofabrication of cell suspensions in TetraPAc sECMs demonstrates the feasibility of building bioartificial blood vessel-like constructs for research and potentially clinical uses.

An unmet need for expansion of primary cells and progenitor cells in three dimensions (3-D) is a synthetic mimic of the extracellular matrix (ECM) with user-controllable composition that would permit rapid recovery of viable cells under mild, non-enzymatic conditions. Three block copolymers based on disulfide-containing polyethylene glycol diacrylate crosslinkers were synthesized, and were used to crosslink thiol-modified hyaluronan and gelatin macromonomers in the presence of cells. The triblock PEGSSDA contained a single disulfide-containing block, the pentablock PEG(SS)(2)DA contained two disulfide blocks, and the heptablock PEG(SS)(3)DA contained three disulfide blocks. For each hydrogel composition, four cell types were encapsulated in 3-D, and growth and proliferation were evaluated. Murine NIH 3T3 fibroblasts, human HepG2 C3A hepatocytes, human bone marrow-derived mesenchymal stem cells (MSCs), and human umbilical vein endothelial cells (HUVECs) all showed excellent viability and growth during expansion in 3-D in the three disulfide block copolymer crosslinkers. After cell expansion, the hydrogels were dissociated using the thiol-disulfide exchange reaction in the presence of N-acetyl-cysteine or glutathione, which dissolved the hydrogel network. After dissolution, cells were recovered in high yield and with high viability by gentle centrifugation.

Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.

Titanium (Ti) is a widely used material for surgical implants; total joint replacements (TJRs), screws and plates for fixing bones and dental implants are forged from Ti. Whilst Ti integrates well into host tissue approximately 10% of TJRs will fail in the lifetime of the patient through a process known as aseptic loosening. These failures necessitate revision arthroplasties which are more complicated and costly than the initial procedure. Finding ways of enhancing early (osseo)integration of TJRs is therefore highly desirable and continues to represent a research priority in current biomaterial design. One way of realising improvements in implant quality is to coat the Ti surface with small biological agents known to support human osteoblast formation and maturation at Ti surfaces. Lysophosphatidic acid (LPA) and certain LPA analogues offer potential solutions as Ti coatings in reducing aseptic loosening. Herein we present evidence for the successful bio-functionalisation of Ti using LPA. This modified Ti surface heightened the maturation of human osteoblasts, as supported by increased expression of alkaline phosphatase. These functionalised surfaces also deterred the attachment and growth of Staphylococcus aureus, a bacterium often associated with implant failures through sepsis. Collectively we provide evidence for the fabrication of a dual-action Ti surface finish, a highly desirable feature towards the development of next-generation implantable devices.

The combretastatin A-4 analogue cis-1-(3′-N,N-dimethylthiocarbamoyl-4′-methoxy)-2-(3″,4″, 5″-trimethoxyphenyl) ethene (1) and its trans stereoisomer (2) were synthesized. The molecular structures of these compounds were obtained by single-crystal X-ray diffraction. Crystallization of 1 occurs in the centrosymmetric monoclinic space group C2/c (No. 15) with a = 21.468(5), b = 7.932(1), c = 23.949(3); and β = 100.75(1)∘ and Z = 8. Crystallization of 2 occurs in the centrosymmetric monoclinic space group P21/n (No. 14) with a = 11.7825(7), b = 11.562(1), c = 14.911(1) and β = 93.294(6); and Z = 4. Details of the synthesis and the structural characterization of the title compounds are presented and discussed.

4-Alkylamino-1,8-naphthalimides have been previously demonstrated to photochemically crosslink proteins and bond tissues. In order to gain a greater understanding of protein crosslinking by these agents, and in hopes of developing improved protein crosslinking and tissue bonding agents, we have studied the effect of changing the C4 substituent on the naphthalimide chromaphore. In that regard, five compounds (compounds 5-9; Figure 2) have been synthesized and characterized as protein crosslinking agents. Substituents that stabilize a positive charge by resonance were found to reduce protein crosslinking. However, these substituents also move the absorbance of the compounds further into the visible, which is desirable for the clinical application of these compounds to tissue binding. Further work is underway to better delineate the characteristics of an optimized photochemical tissue bonding agent.

Carboxymethyl hyaluronic acid (CMHA) is a semisynthetic derivative of HA that is recognized by HA binding proteins but contains an additional carboxylic acid on some of the 6-hydroxyl groups of the N-acetyl glucosamine sugar units. These studies tested the ability of CMHA to stabilize the formation of calcium phosphate nanoparticles and evaluated their potential to target therapy resistant, CD44+/CD24−/lowhuman breast cancer cells (BT-474EMT). CMHA stabilized particles (nCaPCMHA) were loaded with the chemotherapy drugcis-diamminedichloroplatinum(II) (CDDP) to form nCaPCMHACDDP. nCaPCMHACDDP was determined to be poorly crystalline hydroxyapatite, 200 nm in diameter with a −43 mV zeta potential. nCaPCMHACDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days. Surface plasmon resonance showed that nCaPCMHACDDP binds to CD44, but less effectively than CMHA or hyaluronan. nCaPCMHA-AF488was taken up by CD44+/CD24−BT-474EMTbreast cancer cells within 18 hours. nCaPCMHACDDP was as cytotoxic as free CDDP against the BT-474EMTcells. Subcutaneous BT-474EMTtumors were more reproducibly inhibited by a near tumor dose of 2.8 mg/kg CDDP than a 7 mg/kg dose nCaPCMHACDDP. This was likely due to a lack of distribution of nCaPCMHACDDP throughout the dense tumor tissue that limited drug diffusion.

We established the physiological relevance of LL-37 induced bladder inflammation. We hypothesized that 1) human urinary LL-37 is increased in pediatric patients with spina bifida, 2) LL-37 induced inflammation occurs in our mouse model via urothelial binding and is dose dependent and 3) LL-37 induced inflammation involves mast cells.To test our first hypothesis, we obtained urine samples from 56 pediatric patients with spina bifida and 22 normal patients. LL-37 was measured by enzyme-linked immunosorbent assay. Our second hypothesis was tested in C57Bl/6 mice challenged with 7 LL-37 concentrations intravesically for 1 hour. At 24 hours tissues were examined histologically and myeloperoxidase assay was done to quantitate inflammation. In separate experiments fluorescent LL-37 was instilled and tissues were obtained immediately (time = 0) and at 24 hours (time = 24). To test our final hypothesis, we performed immunohistochemistry for mast cell tryptase and evaluated 5 high power fields per bladder to determine the mean number of mast cells per mm(2).Urinary LL-37 was 89-fold higher in patients with spina bifida. Mouse LL-37 dose escalation experiments revealed increased inflammation at higher LL-37 concentrations. Fluorescent LL-37 demonstrated global urothelial binding at time = 0 but was not visible at time = 24. Immunohistochemistry for tryptase revealed mast cell infiltration in all tissue layers. At higher concentrations the LL-37 challenge led to significantly greater mast cell infiltration.Urinary LL-37 was significantly increased in pediatric patients with spina bifida. To our knowledge we report for the first time that LL-37 can elicit profound, dose dependent bladder inflammation involving the urothelium. Finally, inflammation propagation involves mast cells.

(1-x)Pb(Zn 1/3 Nb 2/3 )O 3- xPbTiO 3 nano-grade films were produced by using both an normally liquid phase epitaxy and an improved vertically dipping liquid phase epitaxy system developed by ourselves. Utilizing a specially heating device, the improved liquid phase epitaxy system can offer a controllable time-lag before the melt adhered on the bottom of the substrate crystallized into film. In the time-lag moment, the force of the rolling substrate driven by the rolling seed role would throw out some melt adhered on the bottom of the substrate and reduce the quantity of the melt. And the surface of the film can be smoothed. By adjusting the quality of the melt left on the bottom of the substrate, nanograde thin films of (1-x)Pb(Zn 1/3 Nb 2/3 )O 3- xPbTiO 3 were grown up on the substrates of SrTiO 3 (001). The morphology of the both films produced by normal LPE method and our improved LPE method were investigated by OM. The results show that the films produced by using this improved LPE method have uniform morphology without powders adhered in it. The farther investigation of the morphology of the PZNT film produced by our improved LPE method was done by using AFM show that the grains of the films have column-shaped morphology with similar size. For the films produced by using normal LPE method, the farther investigation of their morphology were done by SEM method. The results show that there are square-shaped grains with different size for the grains of the film, and there are many stuff material in the space among the grains. The study of XRD reveals that the films produced by using both normal LPE method and improved method had good alignment on the SrTiO 3 (001) substrate.

The first synthesis of dolastatin 11, a potent antineoplastic agent from the sea hare Dolabella auricularia, confirmed the proposed structure and established the last configuration in this natural ...

Certain substituted naphthalimides have been shown to produce, on photochemical activation, mechanically viable bonds between a variety of tissue surfaces. It is believed that these compounds act as photochemically activated oxidants, catalyzing the formation of reactive intermediates in the extracellular matrices of approximated tissue surfaces. The condensation of these intermediates results in the formation of crosslinks between the intimate surfaces. Of particular interest is the application of this technique to the repair of tears in the typically unrepairable avascular zone of menisci. The menisci are collagen-rich fibrocartilaginous tissues that support up to 90% of the load across the knee joint and participate in important functions including shock absorption, joint stabilization, hyperextension prevention, and lubrication of the knee. Preliminary ex vivo and in vivo work in our laboratories has demonstrated that photochemically activated naphthalimides have significant potential for the repair of meniscal lesions. We describe preliminary ex vivo studies assessing the relative abilities of a variety of water-soluble monomeric 4-amino-1,8-naphthalimides to bond bovine knee meniscal tissue on visible light irradiation.

Combretastatin A-4 disodiumphosphate (CA4P), a prodrug formulation of the natural product combretastatin A-4 (CA4), is currently in clinical investigation for the treatment of cancer. In vivo, CA4P is rapidly enzymatically converted to CA4, a potent inhibitor of tubulin polymerization (IC50 = 1-2 muM), and rapidly causes bloodflow shutdown in tumor tissues. A variety of alkyl and aryl di- and triesters of CA4P have been synthesized and evaluated as potential CA4 prodrugs and/or stable CAV analogues. (C) 2003 Elsevier Science Ltd. All rights reserved.

A mixture of 4-alkylamino-1,8-naphthalimides has previously been reported to exhibit potential utility as a photochemical tissue-bonding reagent. In order to determine which constituents of the mixture were responsible for the observed tissue bonding and to facilitate study of the mechanism, we have synthesized each of the primary constituents of the mixture. Each naphthalimide synthesized has been demonstrated to photochemically crosslink proteins.

Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Since ATX inhibitors may have broad implications for therapy, we sought to create a novel series of inhibitors for use against cancer, especially melanoma. Herein we report on the synthesis and biological activity of a targeted affinity label for the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of vinyl sulfone analogs of ATX that function as irreversible inhibitors of ATX and inactivate the enzyme. We commenced biological testing of this compound with viability assays against multiple cancer cell lines whereby the IC50 values ranged from 6.74 - 0.39 μM, which was consistent with the Ki of the vinyl sulfone (3.50 μM). In addition, this compound was also able to significantly inhibit melanoma cell wound closure and pore migration. Most importantly, the vinyl sulfone significantly inhibited melanoma progression using an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that the vinyl sulfone is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo. Note: This abstract was not presented at the meeting. Citation Format: Mandi M. Murph, Molly Altman, Wei Jia, Duy Nguyen, Jada Fambrough, William J. Hardman, Guowei Jiang, Damian Madan, Jianxing Zhang, Glenn D. Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2672. doi:10.1158/1538-7445.AM2014-2672

Background Rosacea is a common disfiguring skin disease of primarily Caucasians characterized by central erythema of the face, with telangiectatic blood vessels, papules and pustules, and can produce skin thickening, especially on the nose of men, creating rhinophyma. Rosacea can also produce dry, itchy eyes with irritation of the lids, keratitis and corneal scarring. The cause of rosacea has been proposed as over-production of the cationic cathelicidin peptide LL-37. Methodology/Principal Findings We tested a new class of non-anticoagulant sulfated anionic polysaccharides, semi-synthetic glycosaminoglycan ethers (SAGEs) on key elements of the pathogenic pathway leading to rosacea. SAGEs were anti-inflammatory at ng/ml, including inhibition of polymorphonuclear leukocyte (PMN) proteases, P-selectin, and interaction of the receptor for advanced glycation end-products (RAGE) with four representative ligands. SAGEs bound LL-37 and inhibited interleukin-8 production induced by LL-37 in cultured human keratinocytes. When mixed with LL-37 before injection, SAGEs prevented the erythema and PMN infiltration produced by direct intradermal injection of LL-37 into mouse skin. Topical application of a 1% (w/w) SAGE emollient to overlying injected skin also reduced erythema and PMN infiltration from intradermal LL-37. Conclusions Anionic polysaccharides, exemplified by SAGEs, offer potential as novel mechanism-based therapies for rosacea and by extension other LL-37-mediated and RAGE-ligand driven skin diseases.

Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF-7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1.