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Extracellular vesicles (EVs) are present in blood at much lower concentrations (5-6 orders of magnitude) compared to lipoprotein particles (LP). Because LP and EV overlap in size and density, isolating high-purity EVs is a significant challenge. While the current two-step sequential EV isolation process using size-expression chromatography (SEC) followed by a density gradient (DG) achieves high purity, the time-consuming ultracentrifugation (UC) step in DG hinders workflow efficiency. This paper introduces an optimized magnetic bead reagent, LipoMin, functionalized with glycosaminoglycans (GAGs), as a rapid alternative for LP removal during the second-step process in about 10 minutes. We evaluated LipoMin's efficacy on two sample types: (a) EV fractions isolated by size exclusion chromatography (SEC + LipoMin) and (b) the pellet obtained from ultracentrifugation (UC + LipoMin). The workflow is remarkably simple, involving a 10 min incubation with LipoMin followed by magnetic separation of the LP-depleted EV-containing supernatant. Results from enzyme-linked immunosorbent assay (ELISA) revealed that LipoMin removes 98.2% ApoB from SEC EV fractions, comparable to the LP removal ability of DG in the SEC + DG two-step process. Importantly, the EV yield (CD81 ELISA) remained at 93.0% and Western blot analysis confirmed that key EV markers, flotillin and CD81, were not compromised. Recombinant EV (rEV), an EV reference standard, was spiked into SEC EV fractions and recovered 89% of CD81 protein. For UC + LipoMin, ApoA1 decreased by 76.5% while retaining 90.7% of CD81. Notably, both colorectal cancer (CRC) and Alzheimer's disease (AD) samples processed by SEC + LipoMin and UC + LipoMin displayed clear expression of relevant EV and clinical markers. With a 10 min workflow (resulting in a 96% time saving compared to the traditional method), the LipoMin reagent offers a rapid and efficient alternative to DG for LP depletion, paving the way for a streamlined SEC + LipoMin two-step EV isolation process.

Various approaches have been developed to enhance the solubility or dissolution rate for the delivery of poorly water-soluble molecules. In this work, guided by an in silico solubility sensitivity analysis for oral absorption, a comparative assessment of the biopharmaceutical performance of a jet-milled free base, a tosylate salt, and a 50:50 (w/w) amorphous solid dispersion (ASD) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) of a weak base drug candidate, GDC-3280, was conducted. Successful particle size reduction without amorphization or form change was confirmed for the jet-milled free base. The potential of solubility enhancement and desupersaturation risk were identified for tosylate salt and ASD formulation by measurements of tosylate salt solubility product constant ( K sp ) and amorphous solubility of GDC-3280. In vitro dissolution testing demonstrated dissolution rate improvement for the jet-milled free base when compared with the unmilled free base and confirmed solubility enhancement followed by desupersaturation for GDC-3280 tosylate salt and ASD formulation. A crystallization inhibitor, hydroxypropyl methylcellulose (HPMC), was found to slow down the desupersaturation of tosylate salt solution, providing general insights for the development of pharmaceutical salts with disproportionation risks. Finally, a pharmacokinetic study in dogs showed that the in vivo exposure increased by 1.7- to 2-fold for the tosylate salt and ASD formulation compared with the jet-milled free base, consistent with the in silico solubility sensitivity analysis for the fraction of drug absorbed. Overall, this work provides insights into the evaluation of multiple formulation approaches for enhancing the biopharmaceutical performance of poorly water-soluble drugs.

Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.

NF-κB-inducing kinase (NIK) is a protein kinase central to the noncanonical NF-κB pathway downstream from multiple TNF receptor family members, including BAFF, which has been associated with B cell survival and maturation, dendritic cell activation, secondary lymphoid organ development, and bone metabolism. We report herein the discovery of lead chemical series of NIK inhibitors that were identified through a scaffold-hopping strategy using structure-based design. Electronic and steric properties of lead compounds were modified to address glutathione conjugation and amide hydrolysis. These highly potent compounds exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes. Compound 4f is shown to have a favorable pharmacokinetic profile across species and to inhibit BAFF-induced B cell survival in vitro and reduce splenic marginal zone B cells in vivo.

A high-gravity carbonation process was deployed at a petrochemical plant using petroleum coke fly ash and blowdown wastewater to simultaneously mineralized CO 2 and remove nitrogen oxides and particulate matters from the flue gas. With a high-gravity carbonation process, the CO 2 removal efficiency was found to be 95.6%, corresponding to a capture capacity of 600 kg CO 2 per day, at a gas flow rate of 1.47 m 3 /min under ambient temperature and pressure. Moreover, the removal efficiency of nitrogen oxides and particulate matters was 99.1% and 83.2%, respectively. After carbonation, the reacted fly ash was further utilized as supplementary cementitious materials in the blended cement mortar. The results indicated that cement with carbonated fly ash exhibited superior compressive strength (38.1 ± 2.5 MPa at 28 days in 5% substitution ratio) compared to the cement with fresh fly ash. Furthermore, the environmental benefits for the high-gravity carbonation process using fly ash were critically assessed. The energy consumption of the entire high-gravity carbonation ranged from 80 to 169 kWh/t-CO 2 (0.29-0.61 GJ/t-CO 2 ). Compared with the scenarios of business-as-usual and conventional carbon capture and storage plant, the economic benefit from the high-gravity carbonation process was approximately 90 and 74 USD per ton of CO 2 fixation, respectively.

Most anaplastic lymphoma kinase (ALK) inhibitors adopt a type I binding mode, but only limited type II ALK structural studies are available. Herein, we present the structure of ALK in complex with N1-(3-4-[([5-(tert-butyl)-3-isoxazolyl]aminocarbonyl)amino]-3-methylphenyl-1H-5-pyrazolyl)-4-[(4-methylpiperazino)methyl]benzamide (5a), a novel ALK inhibitor adopting a type II binding mode. It revealed binding of 5a resulted in the conformational change and reposition of the activation loop, αC-helix, and juxtamembrane domain, which are all important domains for the autoinhibition mechanism and downstream signal pathway regulation of ALK. A structure-activity relationship study revealed that modifications to the structure of 5a led to significant differences in the ALK potency and altered the protein structure of ALK. To the best of our knowledge, this is the first structural biology study to directly observe how changes in the structure of a small molecule can regulate the switch between the type I and type II binding modes and induce dramatic conformational changes.

The high-gravity carbonation process for CO2 mineralization and product utilization as a green cement was evaluated using field operation data from the steelmaking industry. The effect of key operating factors, including rotation speed, liquid-to-solid ratio, gas flow rate, and slurry flow rate, on CO2 removal efficiency was studied. The results indicated that a maximal CO2 removal of 97.3% was achieved using basic oxygen furnace slag at a gas-to-slurry ratio of 40, with a capture capacity of 165 kg of CO2 per day. In addition, the product with different carbonation conversions (i.e., 0%, 17%, and 48%) was used as supplementary cementitious materials in blended cement at various substitution ratios (i.e., 0%, 10%, and 20%). The performance of the blended cement mortar, including physicochemical properties, morphology, mineralogy, compressive strength, and autoclave soundness, was evaluated. The results indicated that the mortar with a high carbonation conversion of slag exhibited a higher mechanical strength in the early stage than pure portland cement mortar, suggesting its suitability for use as a high early strength cement. It also possessed superior soundness compared to the mortar using fresh slag. Furthermore, the optimal operating conditions of the high-gravity carbonation were determined by response surface models for maximizing CO2 removal efficiency and minimizing energy consumption.

The β-selective phenylation of benzyl and boronate protected 1,6-anhydroglucose and the direct phenylation of unprotected 1,6-anhydroglucose (10), pretreated with i-Bu2AlH, i-Bu3Al, Et3Al, Me3Al, or n-octyl3Al, with triphenylalane or aryl(chloro)alanes is reported. The utility of the unprotected version of the method is demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin (1a), from commercially available 10 in one C-C bond-forming step. This approach circumvents the need for conventional protecting groups, and therefore no formal protection and deprotection steps are required.

Forming fluid supported lipid bilayers (SLBs) on a gold surface can enable various lipid-membrane-associated biomolecular interactions to be investigated by several surface sensing techniques, such as surface plasmon resonance and scanning tunneling microscopy. However, forming fluid SLBs on a gold surface through lipid vesicle deposition continues to pose a challenge. In this study, we constructed nanograting structures on a gold surface to induce lipid vesicle rupture for forming a mobile layer of SLBs. Observations based on fluorescence recovery after photobleaching showed that SLBs on the prepared grating supports had some fluidity, while SLBs on the planar support had no fluidity. The anisotropic fluorescence intensity recovery shape changes observed in the SLBs on the grating support suggested that a second layer of SLBs partially formed on top of the first layer in contact with the gold surface and extended along the grating structure. Comparisons of the relative amounts of second bilayer and the fluorescence recovery fractions on supports with various grating edge densities suggested that the second layer formed at the edge regions and that the coverage ratio was directly proportional to the grating edge density. All of these results showed that the grating edges could serve as vesicle-rupture-inducing sites for the formation of a mobile second SLB on a gold surface. The formation of the second layer of SLBs at the edge regions but not in the flat regions enabled us to determine the second layer locations and provided us with an opportunity to pattern mobile lipid bilayers on gold surfaces by controlling the edge locations.

The stereoselective arylation of hydroxy protected 1,6-anhydro-β-d-glucose with arylalanes to provide β-C-arylglucosides is reported. Modification of triarylalanes, Ar3Al, with strong Brønsted acids (HX) or AlCl3 produced more reactive arylating agents, Ar2AlX, while the incorporation of alkyl dummy ligands into the arylating agents was also viable. Me3Al and i-Bu2AlH were found useful in the in situ blocking of the C3-hydroxyl group of 2,4-di-O-TBDPS protected 1,6-anhydroglucose. The utility of the method was demonstrated by the synthesis of the SGLT2 inhibitor, canagliflozin.

Supported lipid bilayers (SLBs) have been widely used to study protein-lipid membrane interactions because their planar geometry is suitable for many surface analysis tools. However, the friction coupling between the support and the membrane can influence the properties of biomolecules in the membrane. Many studies have attempted to span SLBs over nanostructured supports to create free-standing regions in SLBs for biosensor applications. However, membranes following the support surface contour are more frequently observed than are free-standing membranes on structured supports, indicating that the parameter range suitable for formation of free-standing SLBs might be narrow and more information is necessary to understand the required conditions. The objective of this study was to estimate the system energies of free-standing and contour-following membrane states and determine which state is the most energetically favorable under various conditions. For a lipid membrane preferring to stay close to the support, an energy reward occurs when they are in close proximity; however, increasing the contact area on a structured surface can result in an energy penalty because of the bending of the lipid bilayer. Whether the energy reward or the energy penalty dominates could determine the membrane state. We used the extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory and the Helfrich bending theory to relate the energy sizes to experimentally controllable parameters. We experimentally examined whether the membrane state followed the model prediction when we used various buffer ionic strengths, various lipid types, and nanograting supports with three different geometries. Because it is difficult to observe the experimental membrane state directly at the nanoscale, we developed a method to use the fluorescence recovery shape change after photobleaching to distinguish experimental membrane states at the micrometer scale. Our experimental results closely matched the theoretical predictions, suggesting that the developed model can be used to predict suitable conditions for formation of free-standing bilayers on nanostructured solid supports.

In the early drug discovery environment, poorly soluble compounds with suboptimal potency are often used in efficacy studies to demonstrate in vivo preclinical proof-of-concept for new drug discovery targets and in preclinical toxicity studies to assess chemical scaffold safety. These compounds present a challenge to formulation scientists who are tasked with improving their oral bioavailability because high systemic concentrations are required. Despite the use of enabling formulations, increases in systemic exposure following oral delivery are often not achieved. We hypothesize that in some cases non-sink intestinal permeation can occur for poorly soluble compounds where their high systemic concentrations can act to inhibit their own oral absorption. Rats were given a 30 mg/kg oral dose of 1,3-dicyclohexyl urea (DCU) alone or concurrently with deuterated DCU (D8-DCU) intravenous infusions at rates of 13, 17, and 22 mg/kg/h. D8-DCU infusions dose dependently inhibited DCU oral absorption up to a maximum of 92%. Physiologically based pharmacokinetic modeling was utilized to understand the complex interaction between high DCU systemic concentrations and its effect on its own oral absorption. We show that high systemic concentrations of DCU act to suppress its own absorption by creating a condition where intestinal permeation occurs under non-sink conditions. More importantly, we identify relevant DCU concentrations that create the concentration gradient driving the intestinal permeation process. A new parameter, the maximum permeation extraction ratio, is proposed and provides a simple means to assess the extent of non-sink permeation.

The Asp-Phe-Gly (DFG) motif plays an important role in the regulation of kinase activity. Structure-based drug design was performed to design compounds able to interact with the DFG motif; epidermal growth factor receptor (EGFR) was selected as an example. Structural insights obtained from the EGFR/2a complex suggested that an extension from the meta-position on the phenyl group (ring-5) would improve interactions with the DFG motif. Indeed, introduction of an N,N-dimethylamino tail resulted in 4b, which showed almost 50-fold improvement in inhibition compared to 2a. Structural studies confirmed this N,N-dimethylamino tail moved toward the DFG motif to form a salt bridge with the side chain of Asp831. That the interactions with the DFG motif greatly contribute to the potency of 4b is strongly evidenced by synthesizing and testing compounds 2a, 3g, and 4f: when the charge interactions are absent, the inhibitory activity decreased significantly.

Both basic oxygen furnace (BOF) slag and cold-rolling wastewater (CRW) exhibiting highly alkaline characteristics require stabilization and neutralization prior to utilization and/or final disposal. Using CO2 from flue gases as the stabilizing and neutralizing agents could also diminish CO2 emissions. In this investigation, ex situ hot stove gas containing 30 vol% CO2 in the steelmaking process was captured by accelerated carbonation of BOF slag coupled with CRW in a rotating packed bed (RPB). The developed RPB process exhibits superior results, with significant CO2 removal efficiency (η) of 96-99% in flue gas achieved within a short reaction time of 1 min at 25 °C and 1 atm. Calcite (CaCO3) was identified as the main product according to XRD and SEM-XEDS observations. In addition, the elimination of lime and Ca(OH)2 in the BOF slag during carbonation is beneficial to its further use as construction material. Consequently, the developed RPB process could capture the CO2 from the flue gas, neutralize the CRW, and demonstrate the utilization potential for BOF slag. It was also concluded that carbonation of BOF slag coupled with CRW in an RPB is a viable method for CO2 capture due to its higher mass transfer rate and CO2 removal efficiency in a short reaction time.

Accelerated carbonation of basic oxygen furnace slag (BOFS) coupled with cold-rolling wastewater (CRW) was performed in a rotating packed bed (RPB) as a promising process for both CO2 fixation and wastewater treatment. The maximum achievable capture capacity (MACC) via leaching and carbonation processes for BOFS in an RPB was systematically determined throughout this study. The leaching behavior of various metal ions from the BOFS into the CRW was investigated by a kinetic model. In addition, quantitative X-ray diffraction (QXRD) using the Rietveld method was carried out to determine the process chemistry of carbonation of BOFS with CRW in an RPB. According to the QXRD results, the major mineral phases reacting with CO2 in BOFS were Ca(OH)2, Ca2(HSiO4)(OH), CaSiO3, and Ca2Fe1.04Al0.986O5. Meanwhile, the carbonation product was identified as calcite according to the observations of SEM, XEDS, and mappings. Furthermore, the MACC of the lab-scale RPB process was determined by balancing the carbonation conversion and energy consumption. In that case, the overall energy consumption, including grinding, pumping, stirring, and rotating processes, was estimated to be 707 kWh/t-CO2. It was thus concluded that CO2 capture by accelerated carbonation of BOFS could be effectively and efficiently performed by coutilizing with CRW in an RPB.

Successful synthesis and characterization of the six-coordinated complex [Ru(STTP)(CO)Cl] (1; STTP = 5,10,15,20-tetratolyl-21-thiaporphyrinato) allowed the development of the coordination chemistry of ruthenium-thiaporphyrin through dechlorination and metathesis reactions. Accordingly, [Ru(II)(STTP)(CO)X] (X = NO(3)(-) (2), NO(2)(-) (3), and N(3)(-) (4)) was synthesized and analyzed by single-crystal X-ray structural determination and NMR, UV-vis, and FT-IR spectroscopic methods. An independent reaction of STPPH and [Ru(COD)Cl(2)] led to [Ru(III)(STTP)Cl(2)] (5), which possessed a higher-valent Ru(III) center and exhibited good stability in the solution state. This stability allowed reversible redox processes in a cyclic voltammetric study. Reactions of [Ru(S(2)TTP)Cl(2)] (S(2)TTP = 5,10,15,20-tetratolyl-21,23-dithiaporphyrinato) with AgNO(3) and NaSePh, also via the metathesis strategy, resulted in novel dithiaporphyrin complexes [Ru(II)(S(2)TTP)(NO(3))(2)] (6) and [Ru(0)(S(2)TTP)(PhSeCH(2)SePh)(2)] (7), respectively. The structures of 6 and 7 were corroborated by X-ray crystallographic analyses. Complex 7 is an unprecedented ruthenium(0)-dithiaporphyrin with two bis(phenylseleno)methanes as axial ligands. A comparison of the analyses of the crude products from reactions of NaSePh and CH(2)Cl(2) with or without [Ru(S(2)TTP)Cl(2)], further supported by UV-vis spectral changes under stoichiometric reactions between [Ru(S(2)TTP)Cl(2)] and NaSePh, suggested a reaction sequence in the order of (1) formation of a putative [Ru(II)(S(2)TTP)(SePh)(2)] intermediate, followed by (2) the concerted formation of PhSe-CH(2)Cl and simultaneously a reduction of Ru(II) to Ru(0) and finally (3) nucleophilic substitution of PhSeCH(2)Cl by excess PhSe(-), resulting in PhSeCH(2)SePh, which readily coordinated to the Ru(0) and completed the formation of bis(phenylseleno)methane complex 7.

Active matrix organic light-emitting diode (AMOLED) display holds great potential for the next generation visual technologies due to its high light efficiency, flexibility, lightweight, and low-temperature processing. However, suitable thin-film transistors (TFTs) are required to realize the advantages of AMOLED. Preseparated, semiconducting enriched carbon nanotubes are excellent candidates for this purpose because of their excellent mobility, high percentage of semiconducting nanotubes, and room-temperature processing compatibility. Here we report, for the first time, the demonstration of AMOLED displays driven by separated nanotube thin-film transistors (SN-TFTs) including key technology components, such as large-scale high-yield fabrication of devices with superior performance, carbon nanotube film density optimization, bilayer gate dielectric for improved substrate adhesion to the deposited nanotube film, and the demonstration of monolithically integrated AMOLED display elements with 500 pixels driven by 1000 SN-TFTs. Our approach can serve as the critical foundation for future nanotube-based thin-film display electronics.

Silicon nanowires (NWs) have stimulated significant interest and found numerous applications; however, many applications will require a bulk quantity of nanowires to be synthesized in a reliable way. In this paper, we report the bulk synthesis of silicon nanowires on millimeter scale Al(2)O(3) spheres with a thermal chemical vapor deposition system (CVD) via the vapor-liquid-solid (VLS) growth mechanism. The spherical substrates enable the realization of Si nanowire synthesis on three-dimensional surfaces in comparison with the synthesis on a planar, two-dimensional wafer substrate. By modifying temperature in the recipe of synthesis, both single-crystalline and crystalline core/amorphous shell Si nanowires were obtained with this nanowire-on-spherical-support method. Conspicuous distinction in crystallinity of the nanowires was revealed by transmission electron microscopy characterization. The crystalline core/amorphous shell Si nanowires were utilized to form the anode of Li-ion battery half-cells with the traditional slurry method. Galvanostatic measurement demonstrated that the maximum power capacity achievable by the electrodes was 3500 mAh/g and capacity sustained at 1100 mAh/g after 60 cycles of charging and discharging.

NHC-catalyzed oxidations using carbon dioxide as the stoichiometric oxidant have been carefully investigated. These studies support a secondary role of CO(2) in suppressing side reactions and exogenous oxygen as the actual oxidant.

Helical inorganic nanostructures have received great attention due to their unique structures that could be interesting for both fundamental research and nanodevice applications. Using a tube-in-tube laser ablation chemical vapor deposition (CVD) method with gold nanoparticles as the catalysts, we reported the synthesis of self-assembled kinked In2O3 nanospirals and multikinked nanowires. As-synthesized nanostructures showed ultrafast photoinduced reversible wettability switching behavior from hydrophobic (132.7°) to superhydrophilic (0°) within 14 min. Single kinked In2O3 nanostructure-based field-effect transistors were fabricated, and mobilities higher than 200 cm2/(V·s) were obtained, revealing good opportunity in fabricating high-performance electronic and optoelectronic devices.

We present a quantitative design methodology for optimizing insulator gap width, gap resistivity, and collector to needle height for the alignment of sub-100 nm electrospun nanofibers at insulator gaps of metal collectors. Enhancement of the spatial extent of alignment forces at insulator gaps, due to the concerted action of attractive stretching forces from the modified electric fields and repulsive forces from residual charges on undischarged fibers in the gap, is studied. At gap widths considerably smaller than the collector to needle height (<2%), the spatial extent of stretching forces is large as evidenced by successive reduction in nanofiber size with gap width; however, the low magnitude of repulsive forces limits the degree of nanofiber alignment. At successively larger gap widths less than the needle height, the spatial extent of the stretching forces is gradually restricted toward the metal-insulator edges, while the influence of repulsive forces is gradually extended across the rest of the spatial extent of the gap, to cause enhanced nanofiber alignment through the concerted action of these forces. At gap widths greater than the needle height, the limited spatial extent and lowered maximum value of the stretching forces at the metal-insulator edge reduces their influence on fiber stretching and alignment. The collection of sub-100 nm electrospun poly(lactic acid-co-glycolic acid) nanofibers with a good degree of alignment (≤10° deviation) is found to require intermediate size gaps (∼2% of needle height) of high resistivity (≥10(12) ohm-cm), to enhance the spatial extent of stretching forces while maintaining the dominance of repulsive forces due to residual charge across a majority of the spatial extent of the gap.

In the work described in this paper, we have successfully fabricated flexible asymmetric supercapacitors (ASCs) based on transition-metal-oxide nanowire/single-walled carbon nanotube (SWNT) hybrid thin-film electrodes. These hybrid nanostructured films, with advantages of mechanical flexibility, uniform layered structures, and mesoporous surface morphology, were produced by using a filtration method. Here, manganese dioxide nanowire/SWNT hybrid films worked as the positive electrode, and indium oxide nanowire/SWNT hybrid films served as the negative electrode in a designed ASC. In our design, charges can be stored not only via electrochemical double-layer capacitance from SWNT films but also through a reversible faradic process from transition-metal-oxide nanowires. In addition, to obtain stable electrochemical behavior during charging/discharging cycles in a 2 V potential window, the mass balance between two electrodes has been optimized. Our optimized hybrid nanostructured ASCs exhibited a superior device performance with specific capacitance of 184 F/g, energy density of 25.5 Wh/kg, and columbic efficiency of approximately 90%. In addition, our ASCs exhibited a power density of 50.3 kW/kg, which is 10-fold higher than obtained in early reported ASC work. The high-performance hybrid nanostructured ASCs can find applications in conformal electrics, portable electronics, and electrical vehicles.

A series of small molecules bearing an alpha-ketoamide warhead were synthesized and evaluated for their ability to inhibit cathepsin S, a key proteolytic enzyme upregulated in many cancers during tumor progression and metastasis. Most of the synthetic compounds were noncytotoxic, but several robustly inhibited cathepsin S (IC(50) < 10 nM) and potently suppressed cell migration, invasion, and capillary tube formation. These results highlight the potential of alpha-ketoamide therapy for preventing or delaying cancer spread.

Nanowire/nanotube biosensors have stimulated significant interest; however, the inevitable device-to-device variation in the biosensor performance remains a great challenge. We have developed an analytical method to calibrate nanowire biosensor responses that can suppress the device-to-device variation in sensing response significantly. The method is based on our discovery of a strong correlation between the biosensor gate dependence (dI(ds)/dV(g)) and the absolute response (absolute change in current, DeltaI). In(2)O(3) nanowire-based biosensors for streptavidin detection were used as the model system. Studying the liquid gate effect and ionic concentration dependence of strepavidin sensing indicates that electrostatic interaction is the dominant mechanism for sensing response. Based on this sensing mechanism and transistor physics, a linear correlation between the absolute sensor response (DeltaI) and the gate dependence (dI(ds)/dV(g)) is predicted and confirmed experimentally. Using this correlation, a calibration method was developed where the absolute response is divided by dI(ds)/dV(g) for each device, and the calibrated responses from different devices behaved almost identically. Compared to the common normalization method (normalization of the conductance/resistance/current by the initial value), this calibration method was proven advantageous using a conventional transistor model. The method presented here substantially suppresses device-to-device variation, allowing the use of nanosensors in large arrays.

We report high-performance arsenic (As)-doped indium oxide (In(2)O(3)) nanowires for transparent electronics, including their implementation in transparent thin-film transistors (TTFTs) and transparent active-matrix organic light-emitting diode (AMOLED) displays. The As-doped In(2)O(3) nanowires were synthesized using a laser ablation process and then fabricated into TTFTs with indium-tin oxide (ITO) as the source, drain, and gate electrodes. The nanowire TTFTs on glass substrates exhibit very high device mobilities (approximately 1490 cm(2) V(-1) s(-1)), current on/off ratios (5.7 x 10(6)), steep subthreshold slopes (88 mV/dec), and a saturation current of 60 microA for a single nanowire. By using a self-assembled nanodielectric (SAND) as the gate dielectric, the device mobilities and saturation current can be further improved up to 2560 cm(2) V(-1) s(-1) and 160 microA, respectively. All devices exhibit good optical transparency (approximately 81% on average) in the visible spectral range. In addition, the nanowire TTFTs were utilized to control green OLEDs with varied intensities. Furthermore, a fully integrated seven-segment AMOLED display was fabricated with a good transparency of 40% and with each pixel controlled by two nanowire transistors. This work demonstrates that the performance enhancement possible by combining nanowire doping and self-assembled nanodielectrics enables silicon-free electronic circuitry for low power consumption, optically transparent, high-frequency devices assembled near room temperature.

A pharmacophore model, Hypo1, was built on the basis of 21 training-set indole compounds with varying levels of antiproliferative activity. Hypo1 possessed important chemical features required for the inhibitors and demonstrated good predictive ability for biological activity, with high correlation coefficients of 0.96 and 0.89 for the training-set and test-set compounds, respectively. Further utilization of the Hypo1 pharmacophore model to screen chemical database in silico led to the identification of four compounds with antiproliferative activity. Among these four compounds, 43 showed potent antiproliferative activity against various cancer cell lines with the strongest inhibition on the proliferation of KB cells (IC(50) = 187 nM). Further biological characterization revealed that 43 effectively inhibited tubulin polymerization and significantly induced cell cycle arrest in G(2)-M phase. In addition, 43 also showed the in vivo-like anticancer effects. To our knowledge, 43 is the most potent antiproliferative compound with antitubulin activity discovered by computer-aided drug design. The chemical novelty of 43 and its anticancer activities make this compound worthy of further lead optimization.

N-heterocyclic carbene-catalyzed reactions of alpha,beta-unsaturated aldehydes and a variety of electrophiles allow the facile preparation of a diverse array of annulation products including trisubstituted cyclopentenes, gamma-lactams, and bicyclic beta-lactams. The substrate scope of these reactions, however, is limited by the difficulties of preparing the starting alpha,beta-unsaturated aldehydes. We now report that alpha'-hydroxyenones, which can be prepared in a single convenient step from aromatic and heteroaromatic aldehydes, can serve as efficient surrogates for enals in the annulation reactions. This protocol allows the facile preparation and use of substrates bearing nitrogen heterocycles. These reagents have also allowed us to demonstrate that, in contrast to other classes of aldehydes, the formation of the Breslow intermediate from enals and N-heterocyclic carbenes is irreversible under the reaction conditions.

Gallium sulfide (GaS) is a wide direct bandgap semiconductor with uniform layered structure used in photoelectric devices, electrical sensors, and nonlinear optical applications. We report here the controlled synthesis of various high-quality one-dimensional GaS nanostructures (thin nanowires, nanobelts, and zigzag nanobelts) as well as other kinds of GaS products (microbelts, hexagonal microplates, and GaS/Ga(2)O(3) heterostructured nanobelts) via a simple vapor-solid method. The morphology and structures of the products can be easily controlled by substrate temperature and evaporation source. Optical properties of GaS thin nanowires and nanobelts were investigated and both show an emission band centered at 580 nm.

Antibody mimic proteins (AMPs) are polypeptides that bind to their target analytes with high affinity and specificity, just like conventional antibodies, but are much smaller in size (2-5 nm, less than 10 kDa). In this report, we describe the first application of AMP in the field of nanobiosensors. In(2)O(3) nanowire based biosensors have been configured with an AMP (Fibronectin, Fn) to detect nucleocapsid (N) protein, a biomarker for severe acute respiratory syndrome (SARS). Using these devices, N protein was detected at subnanomolar concentration in the presence of 44 microM bovine serum albumin as a background. Furthermore, the binding constant of the AMP to Fn was determined from the concentration dependence of the response of our biosensors.

Utilizing medicinal chemistry design strategies such as benzo splitting and ring expansion, we converted PPARalpha/gamma dual agonist 1 to selective PPARgamma agonists 19 and 20. Compounds 19 and 20 were 2- to 4-fold better than rosiglitazone at PPARgamma receptor, with 80- to 100-fold PPARgamma selectivity over PPARalpha receptor. X-ray cocrystal studies in PPARgamma and modeling studies in PPARalpha give molecular insights for the improved PPARgamma potency and selectivity for 19 when compared to 1.

We report high-performance fully transparent thin-film transistors (TTFTs) on both rigid and flexible substrates with transfer printed aligned nanotubes as the active channel and indium-tin oxide as the source, drain, and gate electrodes. Such transistors have been fabricated through low-temperature processing, which allowed device fabrication even on flexible substrates. Transparent transistors with high effective mobilities (approximately 1300 cm(2) V(-1) s(-1)) were first demonstrated on glass substrates via engineering of the source and drain contacts, and high on/off ratio (3 x 10(4)) was achieved using electrical breakdown. In addition, flexible TTFTs with good transparency were also fabricated and successfully operated under bending up to 120 degrees . All of the devices showed good transparency (approximately 80% on average). The transparent transistors were further utilized to construct a fully transparent and flexible logic inverter on a plastic substrate and also used to control commercial GaN light-emitting diodes (LEDs) with light intensity modulation of 10(3). Our results suggest that aligned nanotubes have great potential to work as building blocks for future transparent electronics.

Optically transparent, mechanically flexible displays are attractive for next-generation visual technologies and portable electronics. In principle, organic light-emitting diodes (OLEDs) satisfy key requirements for this application-transparency, lightweight, flexibility, and low-temperature fabrication. However, to realize transparent, flexible active-matrix OLED (AMOLED) displays requires suitable thin-film transistor (TFT) drive electronics. Nanowire transistors (NWTs) are ideal candidates for this role due to their outstanding electrical characteristics, potential for compact size, fast switching, low-temperature fabrication, and transparency. Here we report the first demonstration of AMOLED displays driven exclusively by NW electronics and show that such displays can be optically transparent. The displays use pixel dimensions suitable for hand-held applications, exhibit 300 cd/m2 brightness, and are fabricated at temperatures suitable for integration on plastic substrates.

The prediction of transmembrane (TM) helix and topology provides important information about the structure and function of a membrane protein. Due to the experimental difficulties in obtaining a high-resolution model, computational methods are highly desirable. In this paper, we present a hierarchical classification method using support vector machines (SVMs) that integrates selected features by capturing the sequence-to-structure relationship and developing a new scoring function based on membrane protein folding. The proposed approach is evaluated on low- and high-resolution data sets with cross-validation, and the topology (sidedness) prediction accuracy reaches as high as 90%. Our method is also found to correctly predict both the location of TM helices and the topology for 69% of the low-resolution benchmark set. We also test our method for discrimination between soluble and membrane proteins and achieve very low overall false positive (0.5%) and false negative rates (0 to approximately 1.2%). Lastly, the analysis of the scoring function suggests that the topogeneses of single-spanning and multispanning TM proteins have different levels of complexity, and the consideration of interloop topogenic interactions for the latter is the key to achieving better predictions. This method can facilitate the annotation of membrane proteomes to extract useful structural and functional information. It is publicly available at http://bio-cluster.iis.sinica.edu.tw/~bioapp/SVMtop.

Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds. The results would be helpful in designing novel PPAR agonists.

We report a new efficient intramolecular [3 + 2]-cycloaddition of unactivated arenyne (or enyne)-yne functionalities, catalyzed mainly by the AuPPh3SbF6 complex (2 mol %) under ambient conditions. The value of this cyclization is reflected by its applicability to a wide range of diyne substrates bearing various functional groups.

This work investigates the feasibility of thermal and catalytic cyclization of 6,6-disubstituted 3,5-dien-1-ynes via a 1,7-hydrogen shift. Our strategy began with an understanding of a structural correlation of 3,5-dien-1-ynes with their thermal cyclization efficiency. Thermal cyclization proceeded only with 3,5-dien-1-ynes bearing an electron-withdrawing C(1)-phenyl or C(6)-carbonyl substituent, but the efficiencies were generally low (20-40% yields). On the basis of this structure-activity relationship, we conclude that such a [1,7]-hydrogen shift is characterized by a "protonic" hydrogen shift, which should be catalyzed by pi-alkyne activators. We prepared various 6,6-disubstituted 3,5-dien-1-ynes bearing either a phenyl or a carbonyl group, and we found their thermal cyclizations to be greatly enhanced by RuCl(3), PtCl(2), and TpRuPPh(3)(CH(3)CN)(2)PF(6) catalysts to confirm our hypothesis: the C(7)-H acidity of 3,5-dien-1-ynes is crucial for thermal cyclization. To achieve the atom economy, we have developed a tandem aldol condensation-dehydration and aromatization catalysis between cycloalkanones and special 3-en-1-yn-5-als using the weakly acidic catalyst CpRu(PPh(3))(2)Cl, which provided complex 1-indanones and alpha-tetralones with yields exceeding 65% in most cases. The deuterium-labeling experiments reveal two operable pathways for the metal-catalyzed [1,7]-hydrogen shift of 3,5-dien-1-ynes. Formation of alpha-tetralones d(4)-56 arises from a concerted [1,7]-hydrogen shift, whereas benzene derivative d(4)-9 proceeds through a proton dissociation and reprotonation process.

Allophycocyanin (APC) is one of the phycobiliproteins expressed in cyanobacteria. Phycobiliproteins contain a covalently bound chromophore, and thus, they are valuable as fluorescent probes. Biosynthesis of a functional phycobiliprotein is achieved by a bilin attachment process between the chromophore and apoprotein. Chromophore lyases are necessary to catalyze the chromophorylation of cyanobacterial phycobiliproteins, such as C-phycocyanin, and phycoerythrocyanin. To identify the lyase that catalyzes the chromophorylation of the APC alpha-subunit (ApcA), we searched the entire genomes of two cyanobacteria, Synechocystis sp. PCC6803 and Anabaena sp. PCC 7120; however, these genomes do not appear to encode an APC-specific chromophore lyase. In this study, chromophorylated ApcA (chromo-ApcA) was obtained via a spontaneous bilin attachment reaction. The absorption and fluorescence characteristics of chromo-ApcA were similar to those of the native APC alpha-subunit. The extent of chromophore attachment to apo-ApcA was comparable to that of the lyase-catalyzed reactions for other phycobiliproteins. These results indicate that ApcA has autocatalytic bilin:biliprotein lyase activity.

A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity.

Manganese oxide electrodes composed of interconnected nanowires are electrochemically synthesized in manganous acetate solution at room temperature without any template and catalyst. Annealing temperature affects the electrode morphology, crystallization, and electrochemical performance. Scanning electron microscope (SEM) results show that nanowires are uniformly distributed and sizes are about 12-18 nm in diameter; the diameter decreases to about 8-12 nm after annealing at 300 degrees C. X-ray diffraction (XRD) and transmission electron microscope (TEM) images indicate that nanowires have poor crystalline characteristics. The higher the annealing temperature, the higher the crystalline degree is in manganese oxide. The synthesized anode material shows a much larger capacity than the traditional graphite materials for lithium storage. After annealing at 300 degrees C, the electrode's reversible capacity reaches 800 mAhg(-1), and the specific capacity retention remains nearly constant after 100 cycles.

Plant nonspecific lipid transfer proteins (nsLTPs) are thermal stable proteins that are capable of transferring lipid molecules between bilayers in vitro. This family of proteins, abundant in plants, is proposed to be involved in defense, pollination, and germination; the in vivo biological function remains, however, elusive. Here we report the purification and sequencing of an nsLTP1 from mung bean sprouts. We have also determined the solution structure of this nsLTP1, which represents the first 3D structure of the dicotyledonous nsLTP1 family. The global fold of mung bean nsLTP1 is similar to those of the monocotyledonous nsLTP1 structures and consists of four alpha-helices stabilized by four disulfide bonds. There are, however, some notable differences in the C-terminal tails and internal hydrophobic cavities. Circular dichroism and fluorescence spectroscopy were used to compare the thermodynamics and lipid transfer properties of mung bean nsLTP1 with those of rice nsLTP1. Docking of a lipid molecule into the solution structure of mung bean nsLTP1 reveals similar binding cavities and hydrophobic interactions as in rice nsLTP1, consistent with their comparable lipid transfer properties measured experimentally.

Plant nonspecific lipid transfer proteins (nsLTPs) are small basic proteins that transport phospholipids between membranes. On the basis of molecular mass, nsLTPs are subdivided into nsLTP1 and nsLTP2. NsLTPs are all helical proteins stabilized by four conserved disulfide bonds. The existence of an internal hydrophobic cavity, running through the molecule, is a typical characteristic of nsLTPs that serves as the binding site for lipid-like substrates. NsLTPs are known to participate in plant defense, but the exact mechanism of their antimicrobial action against fungi or bacteria is still unclear. To trigger plant defense responses, a receptor at the plant surface needs to recognize the complex of a fungal protein (elicitin) and ergosterol. NsLTPs share high structural similarities with elicitin and need to be associated with a hydrophobic ligand to stimulate a defense response. In this study, binding of sterol molecules with rice nsLTPs is analyzed using various biophysical methods. NsLTP2 can accommodate a planar sterol molecule, but nsLTP1 binds only linear lipid molecules. Although the hydrophobic cavity of rice nsLTP2 is smaller than that of rice nsLTP1, it is flexible enough to accommodate the voluminous sterol molecule. The dissociation constant for the nsLTP2/cholesterol complex is approximately 71.21 microM as measured by H/D exchange and mass spectroscopic detection. Schematic models of the nsLTP complex structure give interesting clues about the reason for differential binding modes. Comparisons of NMR spectra of the sterol/rice nsLTP2 complex and free nsLTP2 revealed the residues involved in binding.

A unique class of proteins, containing high-mobility group (HMG) domain(s), recognizes unusual DNA structures and/or bends specific to AT-rich linear double-stranded DNA. The DNA binding feature of these proteins is exhibited in the HMG domain(s). Although the sequence specific and non-sequence specific HMG domains exhibit very high degrees of sequence similarity, the reasons for the difference between their DNA recognition mechanisms are unclear. A series of zebra fish SOX9 HMG domain mutants was prepared in an effort to elucidate the importance of various residues on protein stability and DNA binding. This study is the first of a comprehensive mutagenesis study on a sequence specific HMG domain. Comparing how various residues influence sequence specific and non-sequence specific HMG domains helps us to rationalize their mode of action. Positively charged amino acids concentrated at the surface of sequence specific HMG domains recognize specific, linear AT-rich DNA segments. After the negative charges at the surface of the DNA are neutralized, the hydrophobic residues of the protein may intercalate DNA. Phenylalanine at position 12 plays a crucial role in the sequence specific HMG domain. The differences in pI values, the instability index, and DNA contact regions between sequence and non-sequence specific HMG domains are associated with their functional modes.