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.

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.

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.

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.

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.

Surface antireflection properties of GaN nanostructures with various effective refractive index profiles.

GaN nanostructures with various effective refractive index profiles (Linear, Cubic, and Quintic functions) were numerically studied as broadband omnidirectional antireflection structures for concentrator photovoltaics by using three-dimensional finite difference time domain (3D-FDTD) method. Effective medium theory was used to design the surface structures corresponding to different refractive index profiles. Surface antireflection properties were calculated and analyzed for incident light with wavelength, polarization and angle dependences. The surface antireflection properties of GaN nanostructures based on six-sided pyramid with both uniform and non-uniform patterns were also investigated. Results indicate a significant dependence of the surface antireflection on the refractive index profiles of surface nanostructures as well as their pattern uniformity. The GaN nanostructures with linear refractive index profile show the best performance to be used as broadband omnidirectional antireflection structures.

Weighted gene coexpression network analysis and machine learning for the determination of tfh cell and B cell infiltrating biomarkers in thymoma-associated myasthenia gravis.

Patients with thymoma (THYM)-associated myasthenia gravis (MG) typically have a poor prognosis and recurring illness. This study aimed to discover important biomarkers associated with immune cell infiltration and THYM-associated MG (THYM-MG) development. Gene expression microarray data were downloaded from The Cancer Genome Atlas website (TCGA) and Gene Expression Omnibus (GEO). A total of 102 differentially expressed genes were investigated. According to the immune infiltration data, the distribution of Tfh cells, B cells, and CD4 T cells differed significantly between the THYM-MG and THYM-NMG groups. WGCNA derived 25 coexpression modules; one hub module (the blue module) strongly correlated with Tfh cells. Combining differential genes revealed 21 intersecting genes. LASSO analysis subsequently revealed 16 hub genes as potential THYM-MG biomarkers. ROC curve analysis of the predictive model revealed moderate diagnostic value. The association between the 16 hub genes and infiltrating immune cells was further evaluated in TIMER2.0 and the validation dataset. Draggability analysis identified the therapeutic target genes PTGS2 and ALB, along with significant drugs including Firocoxib, Alclofenac, Pyridostigmine, and Stavudine. This was validated through MD simulation, PCA, and MM-GBSA analyses. The interaction between numerous activated B cells and follicular helper T cells is closely associated with THYM-MG pathogenesis from a bioinformatics perspective. Hub genes (including SP6, SCUBE3, B3GNT7, and MAGEL2) may be downregulated in immune cells in THYM-MG and associated with progression.

Relationship between serum prealbumin level and prognosis of community-acquired bacterial meningitis in adults: a retrospective cohort study.

Background: Low serum prealbumin levels have been identified as a predictor of infectious complication in critically ill patients. However, the association in patients with Community-acquired bacterial meningitis (CABM) remains unclear. The aim of this study is to investigate the relationship of prealbumin and the poor outcome of CABM through a retrospective cohort study. Methods: A total of 77 patients of CABM were enrolled. They were divided into good outcome group (GOS: 5) and a bad outcome group (GOS: 1-4). Serum prealbumin and other clinical records were measured within 24 h after admission. Results: Among the included patients, 38(65.52%) had a bad outcome (the GOS score between 1 and 4). The mean age of the overall cohort was 45.3 ± 15.9 years, and 58.6% of patients were male. The mean prealbumin level in the bad outcome group was 115.4 ± 49.4 mmol/L, while the mean level in the good outcome group was 199.1 ± 49.3 mmol/L (p < 0.001). Individuals with plasma prealbumin level ≤180 mmol/L had a 3.32-fold higher risk of CABM than those with normal plasma prealbumin level [OR = 4.32 (1.02 ~ 18.24), p < 0.05]. Conclusion: Reduced plasma prealbumin level is independently associated with the poor outcome of CABM. Plasma prealbumin level might help to identify patients at high risk of bad outcome.

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.

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.

Analysis of light extraction efficiency enhancement for thin-film-flip-chip InGaN quantum wells light-emitting diodes with GaN micro-domes.

The enhancement of light extraction efficiency for thin-film flip-chip (TFFC) InGaN quantum wells (QWs) light-emitting diodes (LEDs) with GaN micro-domes on n-GaN layer was studied. The light extraction efficiency of TFFC InGaN QWs LEDs with GaN micro-domes were calculated and compared to that of the conventional TFFC InGaN QWs LEDs with flat surface. The three dimensional finite difference time domain (3D-FDTD) method was used to calculate the light extraction efficiency for the InGaN QWs LEDs emitting at 460nm and 550 nm, respectively. The effects of the GaN micro-dome feature size and the p-GaN layer thickness on the light extraction efficiency were studied systematically. Studies indicate that the p-GaN layer thickness is critical for optimizing the TFFC LED light extraction efficiency. Significant enhancement of the light extraction efficiency (2.5-2.7 times for λ(peak) = 460nm and 2.7-2.8 times for λ(peak) = 550nm) is achievable from TFFC InGaN QWs LEDs with optimized GaN micro-dome diameter and height.

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.

Approaches for high internal quantum efficiency green InGaN light-emitting diodes with large overlap quantum wells.

Optimization of internal quantum efficiency (IQE) for InGaN quantum wells (QWs) light-emitting diodes (LEDs) is investigated. Staggered InGaN QWs with large electron-hole wavefunction overlap and improved radiative recombination rate are investigated for nitride LEDs application. The effect of interface abruptness in staggered InGaN QWs on radiative recombination rate is studied. Studies show that the less interface abruptness between the InGaN sub-layers will not affect the performance of the staggered InGaN QWs detrimentally. The growths of linearly-shaped staggered InGaN QWs by employing graded growth temperature grading are presented. The effect of current injection efficiency on IQE of InGaN QWs LEDs and other approaches to reduce dislocation in InGaN QWs LEDs are also discussed. The optimization of both radiative efficiency and current injection efficiency in InGaN QWs LEDs are required for achieving high IQE devices emitting in the green spectral regime and longer.

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.

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.

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.

Theoretical study of the competition between cell-cell and cell-matrix adhesions.

Adhesions between neighboring cells or between cells and their surrounding tissue/matrix play a crucial role in a wide range of biological processes. In order to investigate the competitive mechanisms between cell-cell and cell-matrix adhesions, we here develop a theoretical framework for multiple interacting cells lying on a planar matrix coated with distributed ligands. This model allows us to study, from the viewpoints of energy and statistics, the effects of such physical mechanisms as binding energy of bonds, nonspecific interactions, elastic deformation of cell membranes, and mixing entropy. Our calculations show that cell-matrix adhesion cannot occur when the ligand density on the matrix is lower than a threshold value, and cell-cell adhesion does not happen for a high ligand density. Glycocalyx repulsion plays a more important role in cell-matrix adhesion than in cell-cell adhesion. In addition, it is found that the cell-cell adhesion density decreases as the number of cells increases.

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.