α-Tertiary Primary Amine Synthesis via Photocatalytic C(sp3)-H Aminoalkylation.

Facile access to sterically hindered α-tertiary primary amines via photocatalytic radical coupling of native C(sp3)-H substrates with N-unsubstituted ketimines is reported. LiBr was used as a hydrogen atom transfer reagent to cleave C(sp3)-H bonds to get alkyl radicals. The in situ-generated HBr can then serve as a Bronsted acid to activate N-unsubstituted ketimines readily for single-electron reduction to deliver α-amino radicals. As a consequence, radical-radical coupling affords primary amines with a congested α-tertiary substituent. This reaction is highlighted by simple and mild conditions, 100% atom-economy, and broad hydrocarbon substrate scope for benzyl ethers, cyclic ethers, benzyl alcohols, alkylarenes, and carbocycles.

Identification, evolution and expression analyses of the whole genome-wide PEBP gene family in Brassica napus L.

BACKGROUND: With the release of genomic data for B.rapa, B.oleracea, and B.napus, research on the genetic and molecular functions of Brassica spp. has entered a new stage. PEBP genes in plants play an important role in the transition to flowering as well as seed development and germination. Molecular evolutionary and functional analyses of the PEBP gene family in B.napus based on molecular biology methods can provide a theoretical basis for subsequent investigations of related regulators. RESULTS: In this paper, we identified a total of 29 PEBP genes from B.napus that were located on 14 chromosomes and 3 random locations. Most members contained 4 exons and 3 introns; motif 1 and motif 2 were the characteristic motifs of PEBP members. On the basis of intraspecific and interspecific collinearity analyses, it is speculated that fragment replication and genomic replication are the main drivers of for the amplification and evolution of the PEBP gene in the B.napus genome. The results of promoter cis-elements prediction suggest that BnPEBP family genes are inducible promoters, which may directly or indirectly participate in multiple regulatory pathways of plant growth cycle. Furthermore, the tissue-specific expression results show that the expression levels of BnPEBP family genes in different tissues were quite different, but the gene expression organization and patterns of the same subgroup were basically the same. qRT‒PCR revealed certain spatiotemporal patterns in the expression of the PEBP subgroups in roots, stems, leaves, buds, and siliques, was tissue-specific, and related to function. CONCLUSIONS: A systematic comparative analysis of the B.napus PEBP gene family was carried out at here. The results of gene identification, phylogenetic tree construction, structural analysis, gene duplication analysis, prediction of promoter cis-elements and interacting proteins, and expression analysis provide a reference for exploring the molecular mechanisms of BnPEBP family genes in future research.

Three-component reductive conjugate addition/aldol tandem reaction enabled by nickel/photoredox dual catalysis.

A three-component reductive cross-coupling of aryl halides, aldehydes, and alkenes by nickel/photoredox dual catalysis is disclosed. The key to success for this tandem transformation is to identify α-silylamine as a unique organic reductant, which releases silylium ions instead of protons to prevent unwanted protonation processes, and meanwhile serves as Lewis acid to activate aldehydes in situ. This dual catalytic protocol completes a traditional conjugate addition/aldol sequence that eliminates the requirement of organometallic reagents and metal-based reductants, thus providing a mild synthetic route to highly valuable ß-hydroxyl carbonyl compounds with contiguous 1,2-stereocenters.

Multi-functional topology optimization of Victoria cruziana veins.

The growth and development of biological tissues and organs strongly depend on the requirements of their multiple functions. Plant veins yield efficient nutrient transport and withstand various external loads. Victoria cruziana, a tropical species of the Nymphaeaceae family of water lilies, has evolved a network of three-dimensional and rugged veins, which yields a superior load-bearing capacity. However, it remains elusive how biological and mechanical factors affect their unique vein layout. In this paper, we propose a multi-functional and large-scale topology optimization method to investigate the morphomechanics of Victoria cruziana veins, which optimizes both the structural stiffness and nutrient transport efficiency. Our results suggest that increasing the branching order of radial veins improves the efficiency of nutrient delivery, and the gradient variation of circumferential vein sizes significantly contributes to the stiffness of the leaf. In the present method, we also consider the optimization of the wall thickness and the maximum layout distance of circumferential veins. Furthermore, biomimetic leaves are fabricated by using the three-dimensional printing technique to verify our theoretical findings. This work not only gains insights into the morphomechanics of Victoria cruziana veins, but also helps the design of, for example, rib-reinforced shells, slabs and dome skeletons.

From Esters to Ketones via a Photoredox-Assisted Reductive Acyl Cross-Coupling Strategy.

A method was developed for ketone synthesis via a photoredox-assisted reductive acyl cross-coupling (PARAC) using a nickel/photoredox dual-catalyzed cross-electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°-alkyl 2-pyridyl esters can act as acyl electrophiles while N-(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°-radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°-3°, 3°-2°, and aryl-3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0 /NiI /NiIII pathway for ketone formation.

Thermal Conductivity of ß-Phase Ga2O3 and (AlxGa1-x)2O3 Heteroepitaxial Thin Films.

Heteroepitaxy of ß-phase gallium oxide (ß-Ga2O3) thin films on foreign substrates shows promise for the development of next-generation deep ultraviolet solar blind photodetectors and power electronic devices. In this work, the influences of the film thickness and crystallinity on the thermal conductivity of (2̅01)-oriented ß-Ga2O3 heteroepitaxial thin films were investigated. Unintentionally doped ß-Ga2O3 thin films were grown on c-plane sapphire substrates with off-axis angles of 0° and 6° toward ⟨112̅0⟩ via metal-organic vapor phase epitaxy (MOVPE) and low-pressure chemical vapor deposition. The surface morphology and crystal quality of the ß-Ga2O3 thin films were characterized using scanning electron microscopy, X-ray diffraction, and Raman spectroscopy. The thermal conductivities of the ß-Ga2O3 films were measured via time-domain thermoreflectance. The interface quality was studied using scanning transmission electron microscopy. The measured thermal conductivities of the submicron-thick ß-Ga2O3 thin films were relatively low as compared to the intrinsic bulk value. The measured thin film thermal conductivities were compared with the Debye-Callaway model incorporating phononic parameters derived from first-principles calculations. The comparison suggests that the reduction in the thin film thermal conductivity can be partially attributed to the enhanced phonon-boundary scattering when the film thickness decreases. They were found to be a strong function of not only the layer thickness but also the film quality, resulting from growth on substrates with different offcut angles. Growth of ß-Ga2O3 films on 6° offcut sapphire substrates was found to result in higher crystallinity and thermal conductivity than films grown on on-axis c-plane sapphire. However, the ß-Ga2O3 films grown on 6° offcut sapphire exhibit a lower thermal boundary conductance at the ß-Ga2O3/sapphire heterointerface. In addition, the thermal conductivity of MOVPE-grown (2̅01)-oriented ß-(AlxGa1-x)2O3 thin films with Al compositions ranging from 2% to 43% was characterized. Because of phonon-alloy disorder scattering, the ß-(AlxGa1-x)2O3 films exhibit lower thermal conductivities (2.8-4.7 W/m·K) than the ß-Ga2O3 thin films. The dominance of the alloy disorder scattering in ß-(AlxGa1-x)2O3 is further evidenced by the weak temperature dependence of the thermal conductivity. This work provides fundamental insight into the physical interactions that govern phonon transport within heteroepitaxially grown ß-phase Ga2O3 and (AlxGa1-x)2O3 thin films and lays the groundwork for the thermal modeling and design of ß-Ga2O3 electronic and optoelectronic devices.

Iridoid compounds from the aerial parts of Swertia mussotii Franch. with cytotoxic activity.

One new secoiridoid compound swertiamarin B (1), along with a known compound lytanthosalin (2), were isolated from ethanol extract of the aerial parts of Swertia mussotii. Their structures were elucidated by the detailed analysis of comprehensive spectroscopic data. All compounds were first isolated from the Swertia genus. Their antitumor activities were evaluated for four human tumor cell lines (HCT-116, HepG2, MGC-803 and A549). Compounds 1 and 2 showed excellent cytotoxic activities toward the MGC-803 cell lines with IC50 values 3.61 and 12.04 µM, respectively.

Piezo1 regulates migration and invasion of breast cancer cells via modulating cell mechanobiological properties.

Cell migration and invasion are two essential processes during cancer metastasis. Increasing evidence has shown that the Piezo1 channel is involved in mediating cell migration and invasion in some types of cancers. However, the role of Piezo1 in the breast cancer and its underlying mechanisms have not been clarified yet. Here, we show that Piezo1 is high-expressed in breast cancer cell (BCC) lines, despite its complex expression in clinical patient database. Piezo1 knockdown (Piezo1-KD) promotes unconfined BCC migration, but impedes confined cell migration. Piezo1 may mediate BCC migration through the balances of cell adhesion, cell stiffness, and contractility. Furthermore, Piezo1-KD inhibits BCC invasion by impairing the invadopodium formation and suppressing the expression of metalloproteinases (MMPs) as well. However, the proliferation and cell cycle of BCCs are not significantly affected by Piezo1. Our study highlights a crucial role of Piezo1 in regulating migration and invasion of BCCs, indicating Piezo1 channel might be a new prognostic and therapeutic target in BCCs.

Quantitative defect analysis in MOCVD GaN-on-GaN using cathodoluminescence.

Cathodoluminescence (CL) is used as a quantitative characterization technique to probe impurities at the metal-organic chemical vapor deposition (MOCVD) grown GaN-on-GaN homoepitaxial interfaces. CL intensity contrast shows a strong correlation with the interfacial impurity concentrations. Based on the analysis of recombination mechanisms of electron beam induced non-equilibrium carriers, an analytical model is proposed to quantitatively determine the impurity concentrations from CL intensity. The extracted interfacial impurity concentrations from the analytical model show a good agreement with the compensation levels obtained from capacitance-voltage measurement, signifying the potential of CL for probing the quantitative impurity levels in GaN-on-GaN structures. This approach can also be extended to be applied in other material systems.

A function of fascin1 in the colony formation of mouse embryonic stem cells.

Fascin1 is known to participate in the migration of cancer cells by binding to actin filaments. Recent studies evidenced that fascin1 also modulates processes such as the tumorigenesis and maintenance of pluripotency genes in cancer stem cells. However, the function of fascin1 in embryonic stem cells remains unclear. In this article, we report that fascin1 is highly expressed and widely distributed in mouse embryonic stem cells (mESCs), which are regulated by JAK-STAT3 and ß-catenin. We found that the overexpression of fascin1 impairs the formation of mESC colonies via the downregulation of intercellular adhesion molecules, and that mimicking the dephosphorylated mutation of fascin1 or inhibiting phosphorylation with Gö6983 significantly enhances colony formation. Hyperphosphorylated fascin1 can promote the maintenance of pluripotency in mESCs via nuclear localization and suppressing DNA methyltransferase expression. Our findings demonstrate a novel function of fascin1, as a vital regulator, in the colony formation and pluripotency of mESCs and provide insights into the molecular mechanisms underlying embryonic stem cell self-organization and development in vitro.

Improved Prediction of Aqueous Solubility of Novel Compounds by Going Deeper With Deep Learning.

Aqueous solubility is an important physicochemical property of compounds in anti-cancer drug discovery. Artificial intelligence solubility prediction tools have scored impressive performances by employing regression, machine learning, and deep learning methods. The reported performances vary significantly partly because of the different datasets used. Solubility prediction on novel compounds needs to be improved, which may be achieved by going deeper with deep learning. We constructed deeper-net models of ~20-layer modified ResNet convolutional neural network architecture, which were trained and tested with 9,943 compounds encoded by molecular fingerprints. Retrospectively tested by 62 recently-published novel compounds, one deeper-net model outperformed four established tools, shallow-net models, and four human experts. Deeper-net models also outperformed others in predicting the solubility values of a series of novel compounds newly-synthesized for anti-cancer drug discovery. Solubility prediction may be improved by going deeper with deep learning. Our deeper-net models are accessible at http://www.npbdb.net/solubility/index.jsp.

Discontinued Drugs for the Treatment of Cardiovascular Disease from 2016 to 2018.

Cardiovascular drug research and development (R&D) has been in active state and continuously attracts attention from the pharmaceutical industry. However, only one individual drug can eventually reach the market from about the 10,000 compounds tested. It would be useful to learn from these failures when developing better strategies for the future. Discontinued drugs were identified from a search performed by Thomson Reuters Integrity. Additional information was sought through PubMed, ClinicalTrials.gov, and pharmaceutical companies search. Twelve compounds discontinued for cardiovascular disease treatment after reaching Phase I-III clinical trials from 2016 to 2018 are detailed in this manuscript, and the reasons for these failures are reported. Of these, six candidates (MDCO-216, TRV027, ubenimex, sodium nitrite, losmapimod, and bococizumab) were dropped for lack of clinical efficacy, the other six for strategic or unspecified reasons. In total, three candidates were discontinued in Phase I trials, six in Phase II, and three in Phase III. It was reported that the success rate of drug R&D utilizing selection biomarkers is higher. Four candidate developments (OPC-108459, ONO-4232, GSK-2798745, and TAK-536TCH) were run without biomarkers, which could be used as surrogate endpoints in the 12 cardiovascular drugs discontinued from 2016 to 2018. This review will be useful for those involved in the field of drug discovery and development, and for those interested in the treatment of cardiovascular disease.

Heat Stress-Induced Multiple Multipolar Divisions of Human Cancer Cells.

Multipolar divisions of heated cells has long been thought to stem from centrosome aberrations of cells directly caused by heat stress. In this paper, through long-term live-cell imaging, we provide direct cellular evidences to demonstrate that heat stress can promote multiple multipolar divisions of MGC-803 and MCF-7 cells. Our results show that, besides facilitating centrosome aberration, polyploidy induced by heat stress is another mechanism that causes multipolar cell divisions, in which polyploid cancer cells engendered by mitotic slippage, cytokinesis failure, and cell fusion. Furthermore, we also find that the fates of theses polyploid cells depend on their origins, in the sense that the polyploid cells generated by mitotic slippage experience bipolar divisions with a higher rate than multipolar divisions, while those polyploid cells induced by both cytokinesis failure and cell fusion have a higher frequency of multipolar divisions compared with bipolar divisions. This work indicates that heat stress-induced multiple multipolar divisions of cancer cells usually produce aneuploid daughter cells, and might lead to genetically unstable cancer cells and facilitate tumor heterogeneity.

Silk fibroin peptide suppresses proliferation and induces apoptosis and cell cycle arrest in human lung cancer cells.

Silkworm cocoon was recorded to cure carbuncle in the Compendium of Materia Medica. Previous studies have demonstrated that the supplemental silk protein sericin exhibits anticancer activity. In the present study, we investigated the effects of silk fibroin peptide (SFP) extracted from silkworm cocoons against human lung cancer cells in vitro and in vivo and its possible anticancer mechanisms. SFP that we prepared had high content of glycine (~ 30%) and showed a molecular weight of ~ 10 kDa. Intragastric administration of SFP (30 g/kg/d) for 14 days did not affect the weights, vital signs, routine blood indices, and blood biochemical parameters in mice. MTT assay showed that SFP dose-dependently inhibited the growth of human lung cancer A549 and H460 cells in vitro with IC50 values of 9.921 and 9.083 mg/mL, respectively. SFP also dose-dependently suppressed the clonogenic activity of the two cell lines. In lung cancer H460 xenograft mice, intraperitoneal injection of SFP (200 or 500 mg/kg/d) for 40 days significantly suppressed the tumor growth, but did not induce significant changes in the body weight. We further examined the effects of SFP on cell cycle and apoptosis in H460 cells using flow cytometry, which revealed that SFP-induced cell cycle arrest at the S phase, and then promoted cell apoptosis. We demonstrated that SFP (20-50 mg/mL) dose-dependently downregulates Bcl-2 protein expression and upregulates Bax protein in H460 cells during cell apoptosis. The results suggest that SFP should be studied further as a novel therapeutic agent for the treatment of lung cancer.

Effect of Different Additives in Diets on Secondary Structure, Thermal and Mechanical Properties of Silkworm Silk.

In this study, eight types of materials including nanoparticles (Cu and CaCO3), metallic ions (Ca2+ and Cu2+), and amino acid substances (serine, tyrosine, sericin amino acid, and fibroin amino acid) were used as additives in silkworm diets to obtain in-situ modified silk fiber composites. The results indicate that tyrosine and fibroin amino acids significantly increase potassium content in silk fibers and induce the transformation of α-helices and random coils to ß-sheet structures, resulting in higher crystallinities and better mechanical properties. However, the other additives-modified silk fibers show a decrease in ß-sheet contents and a slight increase or even decrease in tensile strengths. This finding provides a green and effective approach to produce mechanically enhanced silk fibers with high crystallinity on a large scale. Moreover, the modification mechanisms of these additives were discussed in this study, which could offer new insights into the design and regulation of modified fibers or composites with desirable properties and functions.

Formal [7 + 2] Cycloaddition of Arynes with N-Vinyl-α,ß-Unsaturated Nitrones: Synthesis of Benzoxazonines and Their N-O Bond Cleavage.

Various benzoxazonines were synthesized through a formal [7 + 2] cycloaddition of arynes with N-vinyl-α,ß-unsaturated nitrones under mild conditions. Controllable N-O bond cleavage of benzoxazonines afforded polysubstituted pyrrole-tethered benzopyrans and acyclic ketone-substituted phenols in moderate to good yields. Further transformations provided a facile approach to access useful building blocks with specific stereoselectivity.

Swertia mussotii extracts induce mitochondria-dependent apoptosis in gastric cancer cells.

Swertia mussotii (Gentianaceae) is a traditional Chinese medicinal plant grown in the Qinghai-Tibet Plateau. Three fractions from S. mussotii extract, named SWF50, SWF 70 and SWF100, were screened for in vitro anti-proliferative activity on two gastric cancer cell lines, MGC-803 and BGC-823 cells using MTT assay. Our results demonstrated that SMF70 showed an anti-proliferative effect in MGC-803 cells and SMF100 showed an anti-proliferative effect in BGC-823 cells in vitro. Moreover, both two fractions induced apoptosis via depolymerization of cytoskeletal filaments, increased cytoplasmic levels of ROS and Ca2+ and disrupted mitochondrial transmembrane potential. In addition, flow cytometry analysis indicated that both two fractions could induce cell apoptosis and arrest the cell cycle at S phase. Our results indicate that SMF70 induces apoptosis of MGC-803 cells and SMF100 induces apoptosis of BGC-823 cells via a mitochondrial-dependent pathway. Meanwhile, we also investigated antitumor effect of SMF70 in vivo, and exhibited effective tumor growth inhibition. Our findings demonstrate that S. mussotii extracts could be a potential new alternative therapeutic agent gastric cancer.

Synergistic adhesion mechanisms of spider capture silk.

It is well known that capture silk, the main sticky component of the orb web of a spider, plays an important role in the spider's ability to capture prey via adhesion. However, the detailed mechanism with which the spider achieves its unparalleled high-adhesion performance remains elusive. In this work, we combine experiments and theoretical analysis to investigate the adhesion mechanisms of spider silk. In addition to the widely recognized adhesion effect of the sticky glue, we reveal a synergistic enhancement mechanism due to the elasticity of silk fibres. A balance between silk stiffness, strength and glue stickiness is crucial to endow the silk with superior adhesion, as well as outstanding energy absorption capacity and structural robustness. The revealed mechanisms deepen our understanding of the working principles of spider silk and suggest guidelines for biomimetic designs of spider-inspired adhesion and capture devices.

Tuning charge carrier transport and optical birefringence in liquid-crystalline thin films: A new design space for organic light-emitting diodes.

Liquid-crystalline organic semiconductors exhibit unique properties that make them highly interesting for organic optoelectronic applications. Their optical and electrical anisotropies and the possibility to control the alignment of the liquid-crystalline semiconductor allow not only to optimize charge carrier transport, but to tune the optical property of organic thin-film devices as well. In this study, the molecular orientation in a liquid-crystalline semiconductor film is tuned by a novel blading process as well as by different annealing protocols. The altered alignment is verified by cross-polarized optical microscopy and spectroscopic ellipsometry. It is shown that a change in alignment of the liquid-crystalline semiconductor improves charge transport in single charge carrier devices profoundly. Comparing the current-voltage characteristics of single charge carrier devices with simulations shows an excellent agreement and from this an in-depth understanding of single charge carrier transport in two-terminal devices is obtained. Finally, p-i-n type organic light-emitting diodes (OLEDs) compatible with vacuum processing techniques used in state-of-the-art OLEDs are demonstrated employing liquid-crystalline host matrix in the emission layer.