An engineered bacterial therapeutic lowers urinary oxalate in preclinical models and in silico simulations of enteric hyperoxaluria.

Enteric hyperoxaluria (EH) is a metabolic disease caused by excessive absorption of dietary oxalate leading to the formation of chronic kidney stones and kidney failure. There are no approved pharmaceutical treatments for EH. SYNB8802 is an engineered bacterial therapeutic designed to consume oxalate in the gut and lower urinary oxalate as a potential treatment for EH. Oral administration of SYNB8802 leads to significantly decreased urinary oxalate excretion in healthy mice and non-human primates, demonstrating the strain's ability to consume oxalate in vivo. A mathematical modeling framework was constructed that combines in vitro and in vivo preclinical data to predict the effects of SYNB8802 administration on urinary oxalate excretion in humans. Simulations of SYNB8802 administration predict a clinically meaningful lowering of urinary oxalate excretion in healthy volunteers and EH patients. Together, these findings suggest that SYNB8802 is a promising treatment for EH.

4.7 THz asymmetric beam multiplexer for GUSTO.

A full demonstration of the Fourier phase grating used as 4.7 THz local oscillator (LO) multiplexer for Galactic/Extragalactic ULDB Spectroscopic Terahertz Observatory (GUSTO) is presented in this paper, including its design, modeling, tolerance analysis, and experimental characterizations of the angular and intensity distributions among 2 × 4 output beams and the power efficiency. A quantum cascade laser (QCL) is used to generate the input beam for evaluation of the grating performance in its all relevant aspects with an accuracy level never reported before, where good agreements with modeling results are found. This is the first asymmetric-profile grating fully modelled and characterized at a THz frequency, that further confirms the versatility of this technology for providing an intermediate optical element for feeding multiple array detectors with a single radiation source at such a scientifically interesting frequency regime.

Multi-Step Crystallization of Self-Organized Spiral Eutectics.

A method for the solidification of metallic alloys involving spiral self-organization is presented as a new strategy for producing large-area chiral patterns with emergent structural and optical properties, with attention to the underlying mechanism and dynamics. This study reports the discovery of a new growth mode for metastable, two-phase spiral patterns from a liquid metal. Crystallization proceeds via a non-classical, two-step pathway consisting of the initial formation of a polytetrahedral seed crystal, followed by ordering of two solid phases that nucleate heterogeneously on the seed and grow in a strongly coupled fashion. Crystallographic defects within the seed provide a template for spiral self-organization. These observations demonstrate the ubiquity of defect-mediated growth in multi-phase materials and establish a pathway toward bottom-up synthesis of chiral materials with an inter-phase spacing comparable to the wavelength of infrared light. Given that liquids often possess polytetrahedral short-range order, our results are applicable to many systems undergoing multi-step crystallization.

3.9 THz spatial filter based on a back-to-back Si-lens system.

We present a terahertz spatial filter consisting of two back-to-back (B2B) mounted elliptical silicon lenses and an opening aperture defined on a thin gold layer between the lenses. The beam filtering efficiency of the B2B lens system is investigated by simulation and experiment. Using a unidirectional antenna coupled 3rd-order distributed feedback (DFB) quantum cascade laser (QCL) at 3.86 THz as the source, the B2B lens system shows 72% transmissivity experimentally with a fundamental Gaussian mode as the input, in reasonably good agreement with the simulated value of 80%. With a proper aperture size, the B2B lens system is capable of filtering the non-Gaussian beam from the QCL to a nearly fundamental Gaussian beam, where Gaussicity increases from 74% to 99%, and achieves a transmissivity larger than 30%. Thus, this approach is proven to be an effective beam shaping technique for QCLs, making them to be suitable local oscillators in the terahertz range with a Gaussian beam. Besides, the B2B lens system is applicable to a wide frequency range if the wavelength dependent part is properly scaled.

Ferulic acid confers protection on islet ß cells and placental tissues of rats with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) refers to glucose intolerance of variable degree with onset or first recognition during pregnancy. It causes polyhydramnios, ketoacidosis, fetal macrosomia, and neonatal respiratory distress syndrome. The incidence of GDM has greatly increased, hence the search for new interventions that can effectively treat it. The present study investigated the protective effect of ferulic acid on islet ß cells and placental tissues of rats with GDM. Female Sprague Dawley rats (n = 30) were used in this study. The rats were randomly assigned to three groups of 10 rats each: control group, GDM group and ferulic acid group. The rats were fed high-fat diet consecutively for 12 weeks, except those in control group. In addition, ferulic acid group rats received ferulic acid at a dose of 20 mg/kg body weight (bwt) intragastrically daily for 12 weeks. The expressions of insulin signal transduction proteins and inflammatory factors were determined in rat placental tissue. Apoptosis and levels of expression of apoptosis-related proteins were assessed in isolated islet ß cells. The results showed that the expressions of p-IRS1, p-IRS2, p-PI3K, GLUT1, GLUT3, and GLUT4 were significantly reduced by GDM, but were significantly upregulated after treatment with ferulic acid (p < 0.05). The levels of expression of NF-kB, ICAM-1, TNF-α and IL-ß in placental tissues were significantly higher in GDM group than in control group, but were significantly reduced by ferulic acid treatment (p < 0.05). However, the protein expression of visfatin was significantly reduced by GDM, but was significantly increased by ferulic acid treatment (p < 0.05). Apoptosis was significantly promoted by GDM in islet ß cells, but was significantly and concentration-dependently reduced after treatment with ferulic acid (p < 0.05). Gestational diabetes mellitus (GDM) also significantly down-regulated the expression of bcl-2, but markedly upregulated the expressions of bax and caspase-3 (p < 0.05). However, treatment with ferulic acid significantly and concentration-dependently upregulated the expression of bcl-2, but down-regulated bax and caspase-3 protein expressions (p < 0.05). These results indicate that ferulic acid protects ß cells from GDM-induced apoptosis and improves insulin signaling in placenta of female rats with GDM.

81 supra-THz beams generated by a Fourier grating and a quantum cascade laser.

Large heterodyne receiver arrays (~100 pixel) allow astronomical instrumentations to map more area within limited space mission lifetime. One challenge is to generate multiple local oscillator (LO) beams. Here, we succeeded in generating 81 beams at 3.86 THz by combining a reflective, metallic Fourier grating with an unidirectional antenna coupled 3rd-order distributed feedback (DFB) quantum cascade laser (QCL). We have measured the diffracted 81 beams by scanning a single pyroelectric detector at a plane, which is in the far field for the diffraction beams. The measured output beam pattern agrees well with a simulated result from COMSOL Multiphysics, with respect to the angular distribution and power distribution among the 81 beams. We also derived the diffraction efficiency to be 94 ± 3%, which is very close to what was simulated for a manufactured Fourier grating (97%). For an array of equal superconducting hot electron bolometer mixers, 64 out of 81 beams can pump the HEB mixers with similar power, resulting in receiver sensitivities within 10%. Such a combination of a Fourier grating and a QCL can create an LO with 100 beams or more, enabling a new generation of large heterodyne arrays for astronomical instrumentation.

Palladium-catalyzed allylation of aminophenol with alkynes to construct C-N bonds.

A method for the allylic alkylation of aminophenol with alkynes was developed using a palladium-catalysed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted allylamines were synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors.

A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.

Liquid phase separation in undercooled Cu-Co alloys under the influence of static magnetic fields.

Undercooling of Cu-based alloys often induces metastable liquid phase separation followed by rapid solidification of separated liquids. The rapid solidification can help freeze in the morphology of a higher-melting liquid and eases difficulties in studies of liquid phase separation kinetics. In the present work, the influence of static magnetic fields on liquid phase separation in bulk Cu84Co16 composition was investigated. Inductively melted samples were glass-fluxed, undercooled and solidified under uniform and non-uniform magnetic fields generated by a superconducting magnet. Solidification microstructure of the phase-separated samples was examined using an optical microscope. The imposition of the magnetic fields, both uniform and non-uniform, altered the morphology, segregation pattern and size distribution of Co-rich droplets due to liquid phase separation. The imposition of the non-uniform magnetic fields with positive and negative gradients brought about segregation of the Co-rich droplets at the top and the bottom side of the samples, respectively. Such influence of the static magnetic fields is interpreted by assuming intensification of convective flow and Kelvin force-controlled migration of the Co-rich droplets. This article is part of the theme issue 'Heterogeneous materials: metastable and non-ergodic internal structures'.

Novel indeno[2,1-b]carbazole donor-based organic dyes for dye-sensitized solar cells.

Four novel metal-free organic dyes (CFB1, CFB2, CFT1 and CFT2) based on indeno[2,1-b]carbazole donors were synthesized and their absorption spectra, photovoltaic performances, and electrochemical properties were evaluated. The differences in linking mode and the number of thiophene units led to variations in absorptivity, electron injection efficiency, and charge recombination. Among the four dyes, CFT1 with a π-bridge at the indeno[2,1-b]carbazole ring and a bridge of thiophene showed the best photovoltaic performance with a JSC of 12.34 mA cm-2, VOC of 0.71 V, and FF of 0.68, corresponding to an overall conversion efficiency η of 5.97% under standard AM 1.5 G irradiation.

A model for free growth of a lamellar eutectic dendrite with an incident flow.

A model for free growth of a lamellar eutectic dendrite with an incident flow was proposed for the breakdown of a planar solid/liquid interface into a dendritic contour due to a negative thermal gradient in an undercooled liquid. The model was used to predict the growth kinetics of an α-Ni/Ni3Sn eutectic dendrite with and without an incident flow in the growth direction. The modelling showed that free eutectic growth is not sensitive to the tip selection parameter of the eutectic dendrite, but is sensitive to incident flow of magnitude larger than eutectic growth velocities. While the larger incident flow increases the eutectic growth velocities generally, it has opposing effects on the interlamellar spacings depending on undercooling. The prediction of the model awaits experimental validation.This article is part of the theme issue 'From atomistic interfaces to dendritic patterns'.

3-(7-Azaindolyl)-4-indolylmaleimides as a novel class of mutant isocitrate dehydrogenase-1 inhibitors: Design, synthesis, and biological evaluation.

A series of 3-(7-azainodyl)-4-indolylmaleimides was designed, synthesized, and evaluated for their isocitrate dehydrogenase 1 (IDH1)/R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the wild-type IDH1. Evaluation of the biological activities at the cellular level showed that compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Preliminary structure-activity relationship (SAR) and molecular modeling studies were discussed based on the experimental data obtained. These findings may provide new insights into the development of novel IDH1/R132H inhibitors.

New D-D-π-A triphenylamine-coumarin sensitizers for dye-sensitized solar cells.

Three D-D-π-A triphenylamine-coumarin sensitizers were designed and synthesized with a triphenylamine and coumarin double donor and a cyanoacrylic acid acceptor. Thiophene, bithiophene and phenylthiophene were used as π-bridges, respectively, and the effects of different π-bridges on the photophysical properties and photovoltaic performance were investigated. With the incorporation of an additional thiophene unit, the bithiophene π-bridge contributes to better light absorption and hence superior JSC compared with the thiophene π-bridge. Although the dye with phenylthiophene π-bridge exhibits an inferior absorption spectrum to that with the thiophene π-bridge, it gives a photoelectrical conversion efficiency of 4.99% and exhibits the best photovoltaic performance of the three sensitizers, ascribed to its efficient photon-to-current conversion efficiency, slow charge recombination rate and good electron injection efficiency.

Spirooxindole synthesis via palladium-catalyzed dearomative reductive-Heck reaction.

Palladium-catalyzed intramolecular dearomative reductive-Heck reaction of C2-substituted indoles is developed, which provides access to structurally diverse 3,2'-spiropyrrolidine oxindoles. By changing the hydride source to AcONa base, direct C3-arylation products [2,3-b]quinolinones are achieved in good yields. The reaction of C2-substituted benzofuran is also realized, delivering the desired spiro-product.

Palladium-catalyzed allylation of tautomerizable heterocycles with alkynes.

A method for the allylic amidation of tautomerizable heterocycles was developed by a palladium catalyzed allylation reaction with 100% atom economy. A series of structurally diverse N-allylic substituted heterocycles can be synthesized in good yields with high chemo-, regio-, and stereoselectivities under mild conditions.

Synthesis and biological evaluation of novel 4,5-bisindolyl-1,2,4-triazol-3-ones as glycogen synthase kinase-3ß inhibitors and neuroprotective agents.

A series of novel 4,5-bisindolyl-1,2,4-triazol-3-ones were designed, prepared and evaluated for their glycogen synthase kinase (GSK)-3ß inhibitory activities. Compounds exhibited favorable inhibitory potency towards GSK-3ß kinase at the molecular level and in cells indicated by significantly reducing GSK-3ß substrate Tau phosphorylation at Ser396 in primary neurons showing the inhibition of cellular GSK-3ß. In an in vitro model of neuronal injury, compounds 6b, 6d and 6f prevented glutamate-induced neuronal death which was closely associated with cerebral ischemic stroke. Preliminary structure-activity relationship was examined and showed that different substituents on the indole ring had significant influences on the GSK-3ß inhibitory potency. These findings may provide new insights into the development of novel GSK-3ß inhibitors as neuroprotective agents.

Palladium/l-Proline-Catalyzed Enantioselective α-Arylative Desymmetrization of Cyclohexanones.

A highly enantioselective palladium/l-proline-catalyzed α-arylative desymmetrization of cyclohexanones was developed. The new strategy for α-arylation reaction led to a series of optically active morphan derivatives bearing α-carbonyl tertiary stereocenters in good yields with excellent enantioselectivities (up to 99% ee).

110 W 1678 nm laser based on high-efficiency optical parametric interactions pumped by high-power slab laser.

This Letter presents a high-efficiency optical parametric amplifier pumped by a high-power slab laser with approximate uniform rectangular distribution. By optimizing the overlapping, spectrum matching, and pulse synchronization for the pump and signal lasers, output power of 110.8 W at 1678 nm with corresponding conversion efficiency of 32.3% was achieved in addition to sufficient usage of the effective area in MgO doped periodically poled lithium niobate crystal. It could also provide a designable and tunable wavelength of the amplified laser in a wide infrared region.

Lewis Acid Catalyzed Friedel-Crafts Alkylation of Alkenes with Trifluoropyruvates.

A Friedel-Crafts alkylation reaction of styrenes with trifluoropyruvates has been developed, which delivered allylic alcohols in excellent yields (up to 98%) using the Ni(ClO4)2·6H2O/bipyridine complex as a catalyst. The asymmetric reaction was catalyzed by the chiral Cu(OTf)2/bisoxazoline complex to afford the corresponding chiral allylic alcohols bearing trifluoromethylated quaternary stereogenic centers in moderate enantioselectivities (up to 75% ee).

Enantioselective Friedel-Crafts Alkylation Reactions of 3-Substituted Indoles with Electron-Deficient Alkenes.

Highly enantioselective Friedel-Crafts C2-alkylation reactions of 3-substituted indoles with α,ß-unsaturated esters and nitroalkenes were developed using chiral Lewis acids as catalysts, which afforded chiral indole derivatives bearing C2-benzylic stereogenic centers in good to excellent yields (up to 99%) and enantioselectivities (up to 96% ee).