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The limited availability of high-cost nucleotide sugars is a significant constraint on the application of their downstream products (glycosides and prebiotics) in the food or pharmaceutical industry. To better solve the problem, this study presented a one-pot approach for the biosynthesis of UDP-Gal using a thermophilic multienzyme system consisting of GalK, UGPase, and PPase. Under optimal conditions, a 2 h reaction resulted in a UTP conversion rate of 87.4%. In a fed-batch reaction with Gal/ATP = 20 mM:10 mM, UDP-Gal accumulated to 33.76 mM with a space-time yield ( STY ) of 6.36 g/L·h -1 after the second feeding. In repetitive batch synthesis, the average yield of UDP-Gal over 8 cycles reached 10.80 g/L with a very low biocatalyst loading of 0.002 g enzymes /g product . Interestingly, Galk (Tth0595) could synthesize Gal-1P using ADP as a donor of phosphate groups, which had never been reported before. This approach possessed the benefits of high synthesis efficiency, low cost, and superior reaction system stability, and it provided new insights into the rapid one-pot synthesis of UDP-Gal and high-value glycosidic compounds.

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor ( 1 ) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc 1 gene. However, 1 showed the risk of genotoxicity in vitro . Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc 1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds 31 and 48 stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7 , a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.

To illustrate the synthetic significance of C-C activation methods, here we describe an efficient strategy for the enantioselective total syntheses of (-)-cycloclavine and (-)-5- epi-cycloclavine, which is enabled by an asymmetric Rh-catalyzed "cut-and-sew" transformation between benzocyclobutenones and olefins. Despite the compact structure of cycloclavine with five-fused rings, the total synthesis was accomplished in 10 steps with a 30% overall yield. Key features of the synthesis include (1) a Pd-catalyzed tandem C-N bond coupling/allylic alkylation sequence to construct the nitrogen-tethered benzocyclobutenone, (2) a highly enantioselective Rh-catalyzed carboacylation of alkenes to forge the indoline-fused tricyclic structure, and (3) a diastereoselective cyclopropanation for preparing the tetrasubstituted cyclopropane ring. Notably, an improved catalytic condition has been developed for the nitrogen-tethered cut-and-sew transformation, which uses a low catalyst loading and allows for a broad substrate scope with high enantioselectivity (94-99% e.e.). The C-C activation-based strategy employed here is anticipated to have further implications for syntheses of other natural products that contain complex fused or bridged rings.

To meet the growing demands in flexible and wearable electronics, various sensors have been designed for detecting and monitoring the physical quantity changes. However, most of these sensors can only detect one certain kind of physical quantity based on a single mechanism. In this paper, we have fabricated a multifunctional sensor made from carbonized electrospun polyacrylonitrile/barium titanate (PAN-C/BTO) nanofiber film. It can detect two physical quantities (pressure and curvature), independently and simultaneously, by integrating piezoresistive, piezoelectric, and triboelectric effects. For flex sensing with the impedance change of PAN-C/BTO nanofiber films during bending, it had a sensitivity of 1.12 deg -1 from 58.9° to 120.2° and a working range of 28°-150°. For self-powered force sensing, it had a gauge factor of 1.44 V·N -1 within the range of 0.15-25 N. The sensor had a long stability over 60 000 cycles at both sensing modes. The inclusion of barium titanate nanoparticles (BTO NPs) into the nanofiber film had an over 2.4 times enhancement of sensitivity for pressure sensing because of the synergy of piezoelectric and triboelectric effects. On the basis of multifunction and modularity, a series of potential applications of the sensor were demonstrated, including sensing human's swallowing, walking gaits, finger flexure, and finger-tapping. The self-powered flexible dual-mode sensor has great application potential in human-computer interactive and smart wearable sensing systems.

In this Communication, we develop a two-step acyclic diene metathesis in situ polymerization/cross-linking method to synthesize uniaxially aligned main-chain liquid crystal elastomers with chemically bonded near-infrared absorbing four-alkenyl-tailed croconaine-core cross-linkers. Because of the extraordinary photothermal conversion property, such a soft actuator material can raise its local temperature from 18 to 260 °C in 8 s, and lift up burdens 5600 times heavier than its own weight, under 808 nm near-infrared irradiation.

Crystal structures and magnetic properties of three one-dimensional (1D) azido-bridged cobalt(II) chains with different amide ligands (L), [Co 2 (N 3 ) 4 (DMF) 3 ] (1), [Co 4 (N 3 ) 8 (DEF) 5 ] (2), and [Co 2 (N 3 ) 4 (DIPF) 2 ] (3) (DMF = N,N-dimethylformamide, DEF = N,N-diethylformamide, and DIPF = N,N-diisopropylformamide), are reported to investigate the influence of L on their structures and magnetic properties. Single-crystal X-ray crystallographic analysis revealed that, although 1-3 all consist of cobalt chains bridged by end-on (EO) azides, the coordination geometry of the Co II ions and the repeating units of the 1D structures are quite different. As the size of L increases, the ratio of L to Co II decreases from 6:4 in 1 to 5:4 and 4:4 in 2 and 3, respectively. In 1, two [CoN 5 O 1 ] and two [CoN 4 O 2 ] distorted octahedra form the {[CoN 5 O 1 ][CoN 4 O 2 ] 2 [CoN 5 O 1 ]} tetramers (denoted as Co 4 A), which are linked to each other by sharing the N-N edge to form the chain. Similarly, the chain structure of 3 is constructed from a similar tetramer unit {[CoN 5 ][CoN 4 O 2 ] 2 [CoN 5 ]} (denoted as Co 4 B), where half of the Co II centers are in the [CoN 5 ] trigonal bipyramid because of the larger steric effect of the DIPF ligand, while, for compound 2 of the medium-sized amide, it has the transition structure between those of 1 and 3. The chain is composed of two different repeating units: Co 4 A unit similar to that in 1 and Co 4 B unit similar to that in 3. Because of their similar structures, compounds 1-3 exhibit analogical magnetic properties. Direct-current magnetic measurements demonstrated that all compounds show intrachain ferromagnetic coupling through the EO azides and interchain anti-ferromagnetic interactions. Alternating-current data revealed the slow magnetic relaxation in the anti-ferromagnetic ordered phases. While compound 1 exhibits spin glass behavior, compounds 2 and 3 behave as the single-chain magnets. This difference might come from the interference of the anti-ferromagnetic ordering on the magnetic dynamic of the magnetic chain.

Two cyanide-bridged compounds based on the Fe II cation and the anisotropic [Mo III (CN) 7 ] 4- anion, namely, {Fe 2 (H 2 O) 5 [Mo(CN) 7 ]·5H 2 O} n (1) and {[NH 2 (CH 3 ) 2 ] 2 Fe 5 (H 2 O) 10 [Mo(CN) 7 ] 3 ·8H 2 O} n (2), have been prepared. Single crystal X-ray analyses revealed that their structures exhibit different three-dimensional topologies as a result of the addition of [NH 2 (CH 3 ) 2 ] + during the synthesis of 2. For both 1 and 2, the geometry of the [Mo(CN) 7 ] 4- unit is a slightly distorted capped trigonal prism; all Fe II centers are hexacoordinate and adopt a distorted octahedral configuration. Compound 1 is a three-nodal 3,4,7-connected net with the point symbol of {4.6 2 }{4 5 .6}{4 6 .6 12 .8 3 }, while compound 2 is a five-nodal 4,4,4,6,7-connected net with the point symbol of {4 4 .6 2 }{4 5 .6} 4 {4 6 .6 7 .8 2 }{4 9 .6 11 .8} 2 . Magnetic studies revealed that both compounds exhibit magnetic ordering below 65 K. Apart from the plethora of Mn II -[Mo(CN) 7 ] 4- compounds documented in the literature, these two Fe II -[Mo(CN) 7 ] 4- compounds are the only other [Mo(CN) 7 ] 4- extended structures to be characterized by single crystal structures to date.

Perovskite solar cells (PSCs) with TiO2 materials have attracted much attention due to their high photovoltaic performance. Aligned TiO2 nanorods have long been used for potential application in highly efficient perovskite solar cells, but the previously reported efficiencies of perovskite solar cells based on TiO2 nanorod arrays were underrated. Here we show a solvothermal method based on a modified ketone-HCl system with the addition of organic acids suitable for modulation of the TiO2 nanorod array films to fabricate highly efficient perovskite solar cells. Photovoltaic measurements indicated that efficient nanorod-structured perovskite solar cells can be achieved with the length of the nanorods as long as approximately 200 nm. A record efficiency of 18.22% under the reverse scan direction has been optimized by avoiding direct contact between the TiO2 nanorods and the hole transport materials, eliminating the organic residues on the nanorod surfaces using UV-ozone treatment and tuning the nanorod array morphologies through addition of different organic acids in the solvothermal process.

Metallic nanotubes represent a class of hollow nanostructures with unique catalytic properties. However, the wet-chemical synthesis of metallic nanotubes remains a substantial challenge, especially for those with dimensions below 50 nm. This communication describes a simultaneous alloying-etching strategy for the synthesis of Pt nanotubes with open ends by selective etching Au core from coaxial Au/Pt nanorods. This approach can be extended for the preparation of Pt nanorings when Saturn-like Au core/Pt shell nanoparticles are used. The diameter and wall thickness of both nanotubes and nanorings can be readily controlled in the range of 14-37 nm and 2-32 nm, respectively. We further demonstrated that the nanotubes with ultrathin side walls showed superior catalytic performance in oxygen reduction reaction.

Premature drug release is a common drawback in stimuli-responsive drug delivery systems (DDS), especially if it depends on internal triggers, which are hard to control, or a single external stimulus, which can only have one function. Thus, many DDS systems have been reported that combined different triggers; however, limited success has been established in fine-tuning the release process, mainly due to the poor bioavailability and complexity of the reported designs. This paper reports the design of a hybrid microcapsule (h-MC) by a simple layer-by-layer technique comprising polysaccharides (sodium alginate, chitosan, and hyaluronic acid), iron oxide, and graphene oxide (GO). Electrostatic assembly of the oppositely charged polysaccharides and graphene sheets provided a robust structure in which to load drugs through pH control. The polysaccharide component ensured high biocompatibility, bioavailability, and tumor cells targeting. The alternative magnetic field and near-infrared laser triggerable Fe3O4@GO component provided for dual high-energy and high-penetration hyperthermia therapy. On-demand drug release from h-MC can be achieved by synchronizing these external triggers, making the release highly controllable. The synergistic effect of hyperthermia and chemotherapy was successfully confirmed in vitro and in vivo.

Herein we describe the first enantioselective Rh-catalyzed carboacylation of oximes (imines) via C-C activation. In this transformation, the benzocyclobutenone C1-C2 bond is selectively activated by a low valent rhodium catalyst and subsequently the resulting two Rh-C bonds add across a C═N bond, which provides a unique approach to access chiral lactams. A range of polycyclic nitrogen-containing scaffolds were obtained in good yields with excellent enantioselectivity. Further derivatization of the lactam products led to a rapid entry to various novel fused heterocycles.

Uranyl (UO2(2+)) is a form of uranium in aqueous solution that represents the greatest risk to human health because of its bioavailability. Different sensing techniques have been used with very sensitive detection limits especially the recently reported uranyl-specific DNAzymes systems. However, to the best of our knowledge, few efficient detection methods have been reported for uranyl sensing in seawater. Herein, gold nanoclusters (AuNCs) are employed in an efficient spectroscopic method to detect uranyl ion (UO2(2+)) with a detection limit of 1.86 μM. In the absence of UO2(2+), the BSA-stabilized AuNCs (BSA-AuNCs) showed an intrinsic peroxidase-like activity. In the presence of UO2(2+), this activity can be efficiently restrained. The preliminary quenching mechanism and selectivity of UO2(2+) was also investigated and compared with other ions. This design strategy could be useful in understanding the binding affinity of protein-stabilized AuNCs to UO2(2+) and consequently prompt the recycling of UO2(2+) from seawater.

Depletion of intracellular antioxidants is linked to major cytotoxic events and cellular disorders, such as oxidative stress and multiple sclerosis. In addition to medical diagnosis, determining the concentration of antioxidants in foodstuffs, food preservatives, and cosmetics has proved to be very vital. Gold nanoclusters (Au-NCs) have a core size below 2 nm and contain several metal atoms. They have interesting photophysical properties, are readily functionalized, and are safe to use in various biomedical applications. Herein, a simple and quantitative spectroscopic method based on Au-NCs is developed to detect and image antioxidants such as ascorbic acid. The sensing mechanism is based on the fact that antioxidants can protect the fluorescence of Au-NCs against quenching by highly reactive oxygen species. Our method shows great accuracy when employed to detect the total antioxidant capacity in commercial fruit juice. Moreover, confocal fluorescence microscopy images of HeLa cells show that this approach can be successfully used to image antioxidant levels in living cells. Finally, the potential application of this "light-on" detection method in multiple logic gate fabrication was discussed using the fluorescence intensity of Au-NCs as output.

The objective of this study was to investigate the effects of combined low-pressure ultraviolet (LPUV) irradiation and free chlorination on the formation of trichloronitromethane (TCNM) byproduct from amine precursors, including a commonly used polyamine coagulant aid (poly(epichlorohydrin dimethylamine)) and simple alkylamines dimethylamine (DMA) and methylamine (MA). Results showed that TCNM formation can increase up to 15 fold by combined UV/chlorine under disinfection to advanced oxidation conditions. The enhancement effect is influenced by UV irradiance, chlorine dose, and water pH. Extended reaction time leads to the decay of TCNM by direct photolysis. The combined UV/chlorine conditions significantly promoted degradation of polyamine to generate intermediates, including DMA and MA, which are better TCNM precursors than polyamine, and also facilitated transformation of these amine precursors to TCNM. Under combined UV/chlorine, polyamine degradation was likely promoted by radical oxidation, photodecay of chlorinated polyamine, and chlorine oxidation/substitution. Promoted TCNM formation from primary amine MA was primarily due to radicals' involvement. Promoted TCNM formation from secondary amine DMA likely involved a combination of radical oxidation, photoenhanced chlorination reactions, and other unknown mechanisms. Insights obtained in this study are useful for reducing TCNM formation during water treatment when both UV and chlorine will be encountered.

Polyetherimide (PEI) nanocomposites comprising bucky gels of industrial-grade multiwalled carbon nanotubes (MWCNTs) and ionic liquid (IL, 1-butyl-3-methyl imidazolium hexafluorophosphate ([BMIM][PF6])) were prepared. The processing framework for this nanocomposite is simple, reproducible, and easily scalable. The strong interaction between IL and MWCNTs caused the latter to uniformly disperse in the PEI matrix while IL flowed into the gaps between the nanotubes' walls. The nanocomposite exhibited an enhanced conductivity of 2.01 × 10(4) Ω·cm volume resistivity at room temperature; the value decreased dramatically by 12 orders of magnitude, compared to pristine PEI. The IL free ions and MWCNTs networks provided excellent channels for electron transfer. PEI/bucky gels nanocomposites also showed improved thermal stability and high tensile strength. Other than having antiwear properties, this material can have numerous applications in the aerospace and electronics industries. Moreover, our work presents a "green" method toward modified nanocomposites industrial production as IL is environmentally safe and is easily recyclable.

The competitive adsorption of methylene blue (MB) and β-casein on hydrophilic glass from an aqueous mixed solution was directly detected at the solution pH smaller than the protein isoelectric point (pI) by means of the waveguide-based broadband time-resolved evanescent wave absorption spectroscopy. The competitive adsorption causes the MB coverage to exponentially decrease with time from its peak value and prevents MB aggregation at the interface. The kinetic equation for the competitive adsorption of binary adsorbates was theoretically deduced based on the Langmuir model, and was used for creating the best fit to the experimental data. In the case of a fixed concentration of MB in the mixed solution, the best-fit parameter τ(-1) increases with the protein concentration at a specific pH and decreases with the solution pH at a given concentration of protein. The findings suggest that the β-casein concentration in sub-μM level can be rapidly determined by the time-resolved waveguide absorptiometry based on the competitive adsorption of MB and protein.