Fold Improvement Research Articles

Optimizing MRF-ASL scan design for precise quantification of brain hemodynamics using neural network regression.

Arterial Spin Labeling (ASL) is a quantitative, non-invasive alternative for perfusion imaging that does not use contrast agents. The magnetic resonance fingerprinting (MRF) framework can be adapted to ASL to estimate multiple physiological parameters simultaneously. In this work, we introduce an optimization scheme to increase the sensitivity of the ASL fingerprint. We also propose a regression based estimation framework for MRF-ASL. To improve the sensitivity of MRF-ASL signals to underlying parameters, we optimized ASL labeling durations using the Cramer-Rao Lower Bound (CRLB). This paper also proposes a neural network regression based estimation framework trained using noisy synthetic signals generated from our ASL signal model. We tested our methods in silico and in vivo, and compared with multiple post labeling delay (multi-PLD) ASL and unoptimized MRF-ASL. We present comparisons of estimated maps for the six parameters of our signal model. The scan design process facilitated precise estimates of multiple hemodynamic parameters and tissue properties from a single scan, in regions of normal gray and white matter, as well as regions with anomalous perfusion activity in the brain. In particular, there was a 86.7% correlation of perfusion estimates with the ground truth in silico, using our proposed techniques. In vivo, there was roughly a 7 fold improvement in the Coefficient of Variation (CoV) for white matter perfusion, and 2 fold improvement in gray matter perfusion CoV in comparison to a reference Multi PLD method. The regression based estimation approach provided perfusion estimates rapidly, with estimation times of around 1s per map. Scan design optimization, coupled with regression-based estimation is a powerful tool for improving precision in MRF-ASL.

Brief Normothermic Machine Perfusion Rejuvenates Discarded Human Kidneys.

Discarded deceased donor kidneys (n = 15) underwent 1-hour NMP following CS. Renal perfusion, biochemical, and histologic parameters were recorded. NMP was directly compared with CS in paired donor kidneys using simulated transplantation with allogeneic whole blood, followed by assessment of the aforementioned parameters, in addition to RNA sequencing. Kidneys were successfully perfused, with improved renal blood flows and resistance over the course of perfusion, and evidence of urine output (median 21 mL), in all but one kidney. NMP completely resolved nonperfused regions in discarded donation after circulatory death kidneys. In paired kidneys (n = 4 pairs), transcriptomic analyses showed induction of stress and inflammatory pathways in NMP kidneys, with upregulation of pathways promoting cell survival and proliferation. Furthermore, the NMP pairs had significantly better renal perfusion (1.5-2 fold improvement) and functional parameters, and amelioration of cell death, oxidative stress, and complement activation. In this pilot preclinical study using simulated transplantation of paired kidneys, NMP of discarded marginal kidneys demonstrated some significant mechanistic benefits in comparison to CS alone. NMP may have potential to reduce organ discards and enhance early graft function in such kidneys.

Enhanced Interferometric Weak Value Amplification With Multiple Reflection

A multiple-reflection scheme was proposed to improve the sensitivity and resolution of interferometric weak measurement by introducing a cuboid prism device in the optical path. Increasing the number of reflection in a total internal reflection weak value amplification (WVA) system resulted in a 3.8 fold improvement in the sensitivity of the central wavelength shift to refractive index unit (RIU) (from 1788 nm/RIU to 6821 nm/RIU). Using the multiple reflection device, a RIU resolution of $2.7\times 10$ -7 RIU was obtained. The real-time deposition process of dopamine is monitored.

Designing quantum experiments with a genetic algorithm

We introduce a genetic algorithm that designs quantum optics experiments for engineering quantum states with specific properties. Our algorithm is powerful and flexible, and can easily be modified to find methods of engineering states for a range of applications. Here we focus on quantum metrology. First, we consider the noise-free case, and use the algorithm to find quantum states with a large quantum Fisher information (QFI). We find methods, which only involve experimental elements that are available with current or near-future technology, for engineering quantum states with up to a 100 fold improvement over the best classical state, and a 20 fold improvement over the optimal Gaussian state. Such states are a superposition of the vacuum with a large number of photons (around 80), and can hence be seen as Schrödinger-cat-like states. We then apply the two most dominant noise sources in our setting—photon loss and imperfect heralding—and use the algorithm to find quantum states that still improve over the optimal Gaussian state with realistic levels of noise. This will open up experimental and technological work in using exotic non-Gaussian states for quantum-enhanced phase measurements. Finally, we use the Bayesian mean square error to look beyond the regime of validity of the QFI, finding quantum states with precision enhancements over the alternatives even when the experiment operates in the regime of limited data.

503P - EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer

BackgroundThe androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (eg. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in mCRPC patients. EPI-7386 is a more potent and stable NTD inhibitor (Anitens) that is advancing to clinical trials. The compounds’ characteristics and the initial clinical study plans including potential biomarkers will be reviewed. MethodsChemical structure activity relationships were developed to increase molecule potency using a wide variety of CRPC models in vivo and in vitro. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. Biomarkers were also explored. ResultsEPI-7386 demonstrated a 20 fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostante cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to control tumor growth and induce tumor regressions in several CRPC xenografts, including enzalutamide resistant models. In addition, the combination of enzalutamide with EPI-7386 demonstrated a more robust and more homogeneuous antitumor response. Pharmacodynamic markers specific to NTD inhibitors will be presented. ConclusionsThe next generation aniten compound EPI-7386 is more active and more metabolically stable than EPI-002. It demonstrated potential as single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of Aniten will be discussed. Legal entity responsible for the studyESSA Pharmaceuticals. FundingESSA Pharmaceuticals. DisclosureR. Le Moigne: Full / Part-time employment: ESSA pharma. C.A. Banuelos: Shareholder / Stockholder / Stock options: ESSA pharma. N.R. Mawji: Shareholder / Stockholder / Stock options: ESSA pharma. R.J. Andersen: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma. A. Cesano: Advisory / Consultancy: ESSA pharma; Full / Part-time employment: Nanostring. M.D. Sadar: Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma; Speaker Bureau / Expert testimony: Pfizer. H. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. P. Virsik: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. All other authors have declared no conflicts of interest.

InAs/InP core/shell nanowire gas sensor: Effects of InP shell on sensitivity and long-term stability

Long-term stability is an issue for semiconductor gas sensors, because the sensing material normally needs to be exposed to ambient air (oxygen and water molecules). InAs nanowires (NWs) feature good gas sensing properties at room temperature, but the NWs can be oxidized in air. In this paper, the gas sensing properties of InAs/InP core/shell NWs were investigated for the first time. It was demonstrated that the InP shell thicker than 3.3 nm can effectively retard the oxidation of InAs NWs in air for about 6 years. Moreover, the sensitivity can also be improved by introducing an InP shell. In comparison with the bare InAs NWs, ~1000 fold improvement on detection limit (i.e., 0.8 ppb NO2 at room temperature) was realized with an InP shell thicker than 3.3 nm. Related sensing mechanism is discussed.

Subminute micro-isolation of pharmaceuticals with ultra-high pressure liquid chromatography

The drive for faster separations while maintaining quality and yield remains an important consideration for enhanced productivity as well as cost reduction for drug discovery laboratories in the pharmaceutical industry. High-throughput experimentation (HTE) and high-throughput screening (HTS) techniques can benefit from rapid and efficient isolation of product at high purity and recovery from microgram-scale crude reaction mixtures. In this study we describe the isolation of small molecule and biomolecule crude mixtures at the microgram-scale (100–2500 μg) in single or library format with methods as fast as 1.0 min and system pressures averaging 10,000 psi with an ultra-high pressure liquid chromatography (UHPLC) setup. UHPLC technology provides several advantages for rapid (<1.0 min) separations with small-particle (1.8–3.5 μm) size 4.6 × 50 mm C18 columns such as minimal extra column and delay volume, fast detector response time, and higher linear velocities for improved speed and resolution. We typically see a 5–10 fold improvement in purification time and overall sample processing time with low fraction volumes and same-day drying when compared with traditional semi-preparative techniques. There is a significant 50-fold reduction in solvent usage per run, resulting in a much lower cost of solvent and waste handling. Fluidic pathways have been optimized for collection into tared high-density 96 or 384 well 2D barcoded storage tubes in a microtiter plate (MTP) layout. Coupling the system to robotics has enabled us to implement a fully integrated automation platform with additional capabilities for small-scale purification at high speed and reduced cost of materials. The resulting arrays of small-quantity, high-purity compounds enable synthetic route scouting for HTE and HTS for biological target validation.

Implementation of Metallic Vertical Interconnect Access in Hybrid Intercalated Graphene/Quantum Dot Photodetector for Improved Charge Collection

Colloidal quantum dots (QDs) are of great interest in optoelectronic and photovoltaic devices with low-cost processing, strong light absorption, and size tunable direct band gap. However, their limited carrier mobility and short diffusion length limit efficient charge collection and transport. The short diffusion length in QD solid films, 100–200 nm, limits their thickness to t≈200–300 nm, resulting in poor absorption in the near-infrared, lambda>800 nm, wasting part of sunlight and reducing power conversion efficiency. Recently, a novel architecture based on multiple graphene monolayers (Gr) intercalated inside QD films was reported to improve charge extraction beyond QDs diffusion length. The intercalated graphene layers ensure efficient charge collected in QD films thicker than the diffusion length. However, this architecture still fails to collect carriers from the QDs when the thickness is >200 nm due to the poor vertical conductivity of the devices. Herein, we present the fabrication, optimization and implementation of intercalated devices with vertical interconnecting contacts, increasing carrier collection and photocurrent, aiming to develop a novel architecture for improved photodetection and photovoltaics with QDs. First, we analyze the individual roles of Gr and QDs, studying the evolution of light absorption, photocurrent, and conductivity as successive QD and Gr layers are added. We find the optimal interspacing between graphene layers in the intercalated system, aiming for the best compromise between light absorption and efficient charge collection. Our main contribution is the implementation of vertical interconnect access (VIAs) to each graphene layer to ensuring efficient charge transfer from Gr to the gold electrical contacts for efficient current collection. We show that for 850 nm wavelength illumination, photocurrent of intercalated devices show a 10 fold improvement over devices without VIAs. We also use a back-gate voltage to monitor Fermi level shift in Gr and charge transfer from QDs to Gr. The intercalated configuration with VIAs contacts herein presented is a significant improvement in charge collection for QD optoelectronic applications as well as a promising architecture to enhance the power conversion efficiency for QD solar cells.

Abstract 2642: Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer cells

Abstract The signal transducer and activator of transcription 3 (STAT3) is linked to multiple cancers, including breast and lung adenocarcinomas, where it is known to activate multiple oncogenic pathways and serve as a bypass mechanism in drug resistance. For example, STAT3 is known to be a driver in some basal-like Triple-negative breast cancers (TNBC) and a resistance mechanism to EGFR inhibitors in non-small cell lung cancer (NSCLC). Thus STAT3 has become an attractive target in cancer therapeutics. A naturally occurring alternative splicing variant, STAT3-beta, is truncated and lacks the C-terminal trans-activation domain. Stat3-beta can act in a dominant negative fashion. We recently demonstrated that splice-switching oligonucleotides (SSOs) can be used to induce a shift in endogenous expression from the abundant, oncogenic STAT3-alpha to the truncated dominant-negative STAT3-beta isoform. This leads to decreased cell viability in triple-negative breast cancer cells and to tumor regression in mice, as compared to full STAT3 knock-down or controls. Our aim was to test a panel of next-generation SSOs in order to evaluate their efficacy in basal-like breast cancer cells, which are typically refractory to tyrosine kinase inhibitors. Based on our previous studies, we generated a panel of optimized SSOs targeting STAT3, and assayed the extent of the STAT3 alpha-to-beta switch, at the RNA and protein level, and at their efficacy at eliciting cell apoptosis in MDA-MB-468 TNBC cells, and identified one which show a 5-10 fold improvement of activity in vitro, compared to our previous leading published compound. The optimized STAT3 SSO sequence was also tested in RTK inhibitor-resistant H1975 non-small cell lung cancer cells and was found to be effective in killing the cancer cells as compared to Stat3 knockdown. We also used a similar antisense approach to induce the expression of a dominant-negative variant of the EGFR and tested in combination with our STAT3 SSO. While both the SSO-induced dominant negative variants of EGFR or STAT3 were able to effectively kill lung cancer cells individually, we observed a marked synergistic increase in inhibition when the two compounds where used in combination. Citation Format: Prasad Subramaniam, Luca Cartegni. Antisense oligonucleotide-based induction of dominant-negative variants of STAT3 and EGFR in breast and lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2642.

A STATISTICAL STRATEGY FOR THE PRODUCTION OF CELLULASE, XYLANASE AND -AMYLASE BY CLADOSPORIUM CLADOSPORIOIDES.

Agro wastes such as carrot peels are economical abundantly and naturally available easily. The present study was aimed for the production of cellulase, xylanase and a-amylase simultaneously using carrot peels. Cladosporium cladosporioides was isolated from soil. It was observed that the fungi displayed high production of cellulase, xylanase and a-amylase using economical substrate such as carrot peel. Cellulase increased up to 1.74U/mL with an approximate of 2.8 fold improvement over the previous production of 0.62 U/mL and xylanase increased up to 19.2 U/mL with an approximate of 2.2 fold over the previous production of 8.43 U/mL. The optimization of media led to 2.5 fold increased in a-amylase activity up to 0.639U/mL over the previous production 0.24 U/mL.

A biorefinery for valorization of industrial waste-water and flue gas by microalgae for waste mitigation, carbon-dioxide sequestration and algal biomass production

Massive industrialization all over the globe is the main cause for the generation of huge quantity of wastes such as flue gas and wastewaters. Mindless release of these hazardous wastes into the environment is threatening the health and survival of the mankind. Judicious use of these wastes for microalgal biomass cultivation is recognized as a plausible approach for the creation of a renewable and sustainable process chain for biofuel production. This study was designed to cultivate microalgae utilizing the organic and inorganic nutrients from the industrial wastewater (IWW) and coal-fired flue gas (FG) for simultaneous waste bio-remediation and biomass production for biorefinery application in closed photobioreactors. The two microalgae, Chlorella sp. and Chlorococcum sp. were cultivated in industrial wastewater where varying concentrations of coal-fired FG from 1 to 10% CO2, volume/volume percent (v/v) was supplied to stimulate the mixotrophic growth. Performance of the two microalgae was evaluated in terms of nutrient removal (ammonium, nitrate, phosphate and COD), CO2 fixation, total lipid and carbohydrate content obtained in the integrated mode of process development. The IWW with flue gas (5% CO2 (v/v)) resulted in maximum growth and CO2 fixation. The highest biomass growth (1.52 g L−1) and CO2 fixation (187.65 mg L−1 d−1) of Chlorella sp. with nutrient removal of >70% was observed by 5th day of batch cultivation. Nearly 90% removal of nitrogen resulted in nutrient limitation condition that steered the accumulation of lipid (17–34%) and carbohydrate (21.5–23.1%) in Chlorella and Chlorococcum sp. An overall 1.7 fold improvement in biomass was observed in this process integration compared with control culture. The present study presents a green process for waste remediation, CO2 fixation and production of biomass rich in lipid & carbohydrate content for the development of a green microalgal biorefinery.

Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and &gt; 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s &lt; 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with &gt; 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.

Discovery of deshydroxy bicalutamide derivatives as androgen receptor antagonists

Deshydroxy propioanilides were synthesised by Michael addition reaction between substituted thiophenols onto four different phenylacrylamide derivatives to give twenty-three novel deshydroxy bicalutamide derivatives lacking the central hydroxyl group. The antiproliferative activities of these compounds were evaluated against human prostate cancer cell lines and thirteen compounds showed better inhibitory activities (IC50 = 2.67–13.19 μM) compared to bicalutamide (IC50 = 20.44 μM) in LNCaP. Remarkably, novel double branched bicalutamide analogues (27 and 28) were isolated as major by-products and found to have the best activity across three human prostate cancer cell lines (LNCaP, VCaP and PC3). The most active compound 28 shows sub-micromolar activity (IC50 = 0.43 μM in LNCaP), which represents more than 40-fold improvement over the clinical anti-androgen bicalutamide (IC50 = 20.44 μM) and a more than 3 fold improvement over enzalutamide (IC50 = 1.36 μM). Moreover, strong reduction of PSA expression in LNCaP cells upon treatment with compounds 27, 28 and 33 was observed during qPCR analysis, confirming their AR antagonist activity. Molecular modelling studies revealed a novel binding mode of these structurally distinct double branched analogues within the ligand binding domain (LBD) of the androgen receptor.

Precision spectra of AΣ+2 , v′=0←XΠ3/22 , v″=0 , J″=3/2 transitions in OH16 and OD16

We report absolute optical frequencies of electronic transitions from the $X\phantom{\rule{0.16em}{0ex}}^{2}\mathrm{\ensuremath{\Pi}}_{3/2},\phantom{\rule{0.28em}{0ex}}{v}^{\ensuremath{''}}=0,\phantom{\rule{0.28em}{0ex}}{J}^{\ensuremath{''}}=3/2$ rovibronic ground state to the 12 lowest levels of the $A\phantom{\rule{0.16em}{0ex}}^{2}\mathrm{\ensuremath{\Sigma}}^{+},\phantom{\rule{0.28em}{0ex}}{v}^{\ensuremath{'}}=0$ vibronic state in $^{16}\mathrm{OH}$, as well as to the 16 lowest levels of the same vibronic state in $^{16}\mathrm{OD}$. The absolute frequencies of these transitions have been determined with a relative uncertainty of a few parts in ${10}^{11}$, representing a $\ensuremath{\sim}1000$-fold improvement over previous measurements. To reach this level of precision, an optical frequency comb has been used to transfer the stability of a narrow-linewidth ${\mathrm{I}}_{2}$-stabilized reference laser onto the 308-nm spectroscopy laser. The comb is also used to compare the optical frequency of the spectroscopy laser to an atomic clock reference, providing absolute accuracy. Measurements have been carried out on OH and OD molecules in a highly collimated molecular beam, reducing possible pressure shifts and minimizing Doppler broadening. Systematic shifts due to retroreflection quality, the Zeeman effect, and the ac Stark effect have been considered during the analysis of the measured spectra; particularly in the case of the OD isotopologue, these effects can result in shifts of the fitted line positions of as much as 300 kHz. The transition frequencies extracted in the analysis were also used to determine spectroscopic constants for the $A\phantom{\rule{0.16em}{0ex}}^{2}\mathrm{\ensuremath{\Sigma}}^{+},\phantom{\rule{0.28em}{0ex}}{v}^{\ensuremath{'}}=0$ vibronic state. The constants fitted in this work differ significantly from those reported in previous works that measured the $A\text{\ensuremath{-}}X$ transitions, resulting in typical deviations of the predicted optical transition frequencies of $\ensuremath{\sim}150\phantom{\rule{0.28em}{0ex}}\mathrm{MHz}$, but they generally agree quite well with the constants determined using hyperfine-resolved measurements of splittings within the $A$ state.

Improving the sensitivity of X-ray microanalysis in the analytical electron microscope

A study of the influence of experimental parameters on the sensitivity of x-ray energy dispersive spectroscopy in the analytical electron microscope from 20–200 kV is conducted. Optimization of conditions in the next generation of aberration corrected AEM instrument coupled with an array configuration of SDD detectors can potentially yield a 10–20 fold improvement over older Si(Li) systems still in use today.

Enhanced Visible‐Light‐Driven Activity of Sodium‐, Calcium‐ and Aluminium‐Inserted g‐C3N4

Abstractg‐C3N4 has emerged as a promising low‐cost metal free photocatalyst with ideal optical‐electronic properties; however, high recombination rate is one of the barriers associated with its low photocatalytic activity. Al and Ca intercalated g‐C3N4 photocatalysts with superior visible‐light utilization and charge‐carrier have been synthesized using one‐step thermal condensation method. An enhanced visible‐light harvesting capacity due to a red shift in the optical band gap of inserted g‐C3N4 photocatalysts was observed. The charge‐transfer, its kinetics across the interface and electron‐hole pairs separations were systematically investigated using photoelectrochemical measurements. The evaluation of photocatalytic activity of Al and Ca intercalated g‐C3N4 through degradation of RhB dye revealed 4.6 and 2.5 fold improvement in performance of g‐C3N4. Al intercalated g‐C3N4 shows highest photocurrent density, lowest Tafel slope and highest exchange‐current density due to least recombination rate of photo generated charge‐carriers, facile kinetics and least charge‐transfer resistance without use of any noble metal co‐catalyst towards oxygen evolution reaction (OER) with excellent stability.

Bioactive Heterometallic CuII–ZnII Complexes with Potential Biomedical Applications

A series of multinuclear heterometallic Cu–Zn complexes of molecular formula [(CuL)2Zn(dca)2] (1), [(CuL)2Zn(NO3)2] (2), [(CuL)2Zn2(Cl)4] (3), and [(CuL)2Zn2(NO2)4] (4) have been synthesized by reacting [CuL] as a “metalloligand (ML)” (where HL = N,N′-bis(5-chloro-2-hydroxybenzylidene)-2,2-dimethylpropane-1,3-diamine) and by varying the anions or coligands using the same molar ratios of the reactants. All of the four products including the ML have been characterized by infrared and UV–vis spectroscopies and elemental and single-crystal X-ray diffraction analyses. By varying the anions, different structures and topologies are obtained which we have tried to rationalize by means of thorough density functional theory calculations. All of the complexes (1–4) have now been applied for several biological investigations to verify their therapeutic worth. First, their cytotoxicity properties were assessed against HeLa human cervical carcinoma along with the determination of IC50 values. The study was extended with extensive DNA and protein binding experiments followed by detailed fluorescence quenching study with suitable reagents to comprehend the mechanistic pathway. From all of these biological studies, it has been found that all of these heterometallic complexes show more than a few fold improvement of their therapeutic values as compared to the similar homometallic ones probably because of the simultaneous synergic effect of copper and zinc. Among all of the four heterometallic complexes, complex 3 exhibits highest binding constants and IC50 values suggest for their better interaction toward the biological targets and hence have better clinical importance.

Upgrading of Biomass Monosaccharides by Immobilized Glucose Dehydrogenase and Xylose Dehydrogenase

AbstractDirect upgrading and separation of the monosaccharides from biomass liquors is an overlooked area. In this work we demonstrate enzymatic production of gluconic acid and xylonic acid from glucose and xylose present in pretreated birchwood liquor by glucose dehydrogenase (GDH, EC 1.1.1.47) and xylose dehydrogenase (XDH, EC 1.1.1.175), respectively. The biocatalytic conversions were compared using two different kinds of silica support materials (silica nanoparticles (nanoSiO2) and porous silica particles with hexagonal pores (SBA 15 silica) for enzyme immobilization. Upon immobilization, both enzymes showed significant improvement in their thermal stability and robustness at alkaline pH and exhibited over 50 % activity even at pH 10 and 60 °C on both immobilization matrices. When compared to free enzymes at 45 °C, GDH immobilized on nanoSiO2 and SBA silica displayed a 4.5 and 7.25 fold increase in half‐life, respectively, whilst XDH immobilized on nanoSiO2 and SBA showed a 4.7 and 9.5 fold improvement in half‐life, respectively. Additionally, after five reaction cycles both nanoSiO2GDH and nanoSiO2XDH retained more than 40 % activity and GDH and XDH immobilized on SBA silica maintained around 50 % of their initial activity resulting in about 1.5–1.6 fold increase in biocatalytic productivity compared to the free enzymes.

Urban Walkability Design Using Virtual Population Simulation

AbstractWe present a system to generate a procedural environment that produces a desired crowd behaviour. Instead of altering the behavioural parameters of the crowd itself, we automatically alter the environment to yield such desired crowd behaviour. This novel inverse approach is useful both to crowd simulation in virtual environments and to urban crowd planning applications. Our approach tightly integrates and extends a space discretization crowd simulator with inverse procedural modelling. We extend crowd simulation by goal exploration (i.e. agents are initially unaware of the goal locations), variable‐appealing sign usage and several acceleration schemes. We use Markov chain Monte Carlo to quickly explore the solution space and yield interactive design. We have applied our method to a variety of virtual and real‐world locations, yielding one order of magnitude faster crowd simulation performance over related methods and several fold improvement of crowd indicators.

Picoanalysis of Drugs in Biofluids with Quantitative Label-Free Surface-Enhanced Raman Spectroscopy.

The enormous increase of Raman signal in the vicinity of metal nanoparticles allows surface-enhanced Raman spectroscopy (SERS) to be employed for label-free detection of substances at extremely low concentrations. However, the ultimate potential of label-free SERS to identify pharmaceutical compounds at low concentrations, especially in relation to biofluid sensing, is far from being fully realized. Opioids are a particular challenge for rapid clinical identification because their molecular structural similarities prevent their differentiation with immunolabeling approaches. In this paper, a new method called quantitative label-free SERS (QLF-SERS) which involves the formation of halide-conjugated gold nanoclusters trapping the analyte of interest near the SERS hot spots is reported, and it is demonstrated that it yields a 105 fold improvement in the detection limit over previously reported results for the entire class of clinically relevant opioids and their metabolites. Measurements of opioid concentrations in multicomponent mixtures are also demonstrated. QLF-SERS has comparable detection limits as currently existing laboratory urine drug testing techniques but is significantly faster and inexpensive and, therefore, can be easily adapted as part of a rapid clinical laboratory routine.