Advancing Meta-Selective C-H Amination through Non-Covalent Interactions.

Regioselective C-H amination of simple arenes is highly desirable, but accessing meta-sites of ubiquitous arenes has proven challenging due to the lack of both electronic and spatial preference. This study demonstrates the successful use of various privileged nitrogen-containing functionalities found in pharmaceutical compounds to direct meta-C-H amination of arenes, overcoming the long-standing requirement for a redundant directing group. The remarkable advancements in functional group accommodation for precise regiochemical control were achieved through the discovery of an unprecedented organo-initiator and the strategic utilization of non-covalent interactions. This protocol has been successfully applied in the concise synthesis and late-stage derivatization of drug molecules, which would have been otherwise challenging to achieve.

Cyclic nucleotide gated channel genes (CNGCs) in Rosaceae: genome-wide annotation, evolution and the roles on Valsa canker resistance.

KEY MESSAGE: In Rosaceae, tandem duplication caused the drastic expansion of CNGC gene family Group I. The members MdCN11 and MdCN19 negatively regulate Valsa canker resistance. Apple (Malus domestica) and pear (Pyrus bretschneideri and P. communis) are important fruit crops in Rosaceae family but are suffering from threats of Valsa canker. Cyclic nucleotide-gated ion channels (CNGCs) take crucial roles in plant immune responses. In the present study, a total of 355 CNGCs was identified from 8 Rosaceae plants. Based on phylogenetic analysis, 540 CNGCs from 18 plants (8 in Rosaceae and 10 others) could be divided into four groups. Group I was greatly expanded in Rosaceae resulted from tandem duplications. A large number of cis-acting regulatory elements (cis-elements) responsive to signals from multiple stresses and hormones were identified in the promoter regions of CNGCs in Malus spp. and Pyrus spp. Expressions of most Group I members were obviously up-regulated in Valsa canker susceptible varieties but not in the resistant ones. Furthermore, overexpression of the MdCN11 and MdCN19 in both apple fruits and 'Duli' (P. betulifolia) suspension cells compromised Valsa canker resistance. Overexpression of MdCN11 induced expression of hypersensitive response (HR)-related genes. In conclusion, tandem duplication resulted in a drastic expansion of CNGC Group I members in Rosaceae. Among these, MdCN11 and MdCN19 negatively regulate the Valsa canker resistance via inducting HR.

Sekgranaticin, a SEK34b-Granaticin Hybrid Polyketide from Streptomyces sp. 166.

Sekgranaticin (1), a novel hybrid polyketide with a complex 6/6/6/6/6/6/6 7-ring system, was isolated together with granaticins A (2) and B (3) and methyl granaticinate (4) from the culture broth of Streptomyces sp. 166#. Its structure was elucidated by spectroscopic analysis. The absolute configuration was determined on the basis of the calculated 13C NMR and electronic circular dichroism data. Compounds 1-4 exhibited potent cytotoxicity against cancer cell lines MCF-7, A549, P6C, and HCT-116 with IC50 values of 0.02-6.77 µM. The biosynthetic pathway of sekgranaticin (1) was proposed.

Pressure-Stabilized Superconductive Ionic Tantalum Hydrides.

High-pressure structures of tantalum hydrides were investigated over a wide pressure range of 0-300 GPa by utilizing evolutionary structure searches. TaH and TaH2 were found to be thermodynamically stable over this entire pressure range, whereas TaH3, TaH4, and TaH6 become thermodynamically stable at pressures greater than 50 GPa. The dense Pnma (TaH2), R3̅m (TaH4), and Fdd2 (TaH6) compounds possess metallic character with a strong ionic feature. For the highly hydrogen-rich phase of Fdd2 (TaH6), a calculation of electron-phonon coupling reveals the potential high-Tc superconductivity with an estimated value of 124.2-135.8 K.

Investigation of superconductivity in compressed vanadium hydrides.

Aiming at finding new superconducting materials, we performed systematical simulations on phase diagrams, crystal structures, and electronic properties of vanadium hydrides under high pressures. The VH, VH2, VH3, and VH5 species were found to be stable under high pressures; among these, VH2 had previously been investigated. Moreover, all three novel stoichiometries showed a strong ionic character as a result of the charge transfer from V to H. The electron-phonon coupling calculations revealed the potentially superconductive nature of these vanadium hydrides, with estimated superconducting critical temperature (Tc) values of 6.5-10.7 K for R3[combining overline]m (VH), 8.0-1.6 K for Fm3[combining overline]m (VH3), and 30.6-22.2 K for P6/mmm (VH5) within the pressure range from 150 GPa to 250 GPa.

Investigation of stable germane structures under high-pressure.

The evolutionary structure-searching method discovers that the energetically preferred compounds of germane can be synthesized at a pressure of 190 GPa. New structures with the space groups Ama2 and C2/c proposed here contain semimolecular H2 and V-type H3 units, respectively. Electronic structure analysis shows the metallic character and charge transfer from Ge to H. The conductivity of the two structures originates from the electrons around the hydrogen atoms. Further electron-phonon coupling calculations predict that the two phases are superconductors with a high Tc of 47-57 K for Ama2 at 250 GPa and 70-84 K for C2/c at 500 GPa from quasi-harmonic approximation calculations, which may be higher than under actual conditions.

Design, synthesis and mechanism study of coumarin-sulfonamide derivatives as carbonic anhydrase IX inhibitors with anticancer activity.

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC50 value of 6.01 ± 0.81 µM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

Phaeochromycins I-K, Three Methylene-Bridged Dimeric Polyketides from Streptomyces sp. 166.

Three new dimeric polyketides, i.e., phaeochromycins I-K (1-3, respectively) and a known polyketide phaeochromycin F (4), were isolated from the culture broth of a saline Qinghai-Tibet Plateau permafrost soil-derived Streptomyces sp. 166#. The structures were determined by analyzing one-dimensional and two-dimensional NMR as well as HRESIMS data. Compounds 2 and 3 exhibited a selective antiproliferative activity against H1299 and HUCCT1 cell lines, exhibiting IC50 values ranging from 8.83 to 10.52 µM.

Integrated supercapacitor with self-healing, arbitrary deformability and anti-freezing based on gradient interface structure from electrode to electrolyte.

Flexible supercapacitors have attracted more and more attention because of their promising applications in wearable electronics, however, it is still important to harmonize their mechanical and electrochemical properties for practical applications. In the present work, a seamless transition between polyaniline (PANI) electrode and NH4VO3_FeSO4 dual redox-mediated gel polymer electrolyte (GPE) is presented through in situ formation of gradient interface structure. Multiple physical interactions make the GPE excellent mechanical and self-healing properties. Meanwhile, double role functions of Fe2+ ions greatly relieve the traditional contradiction between mechanical and electrochemical properties of GPE. Moreover, benefiting from the structure and reversible redox reactions of VO3- and Fe2+, the integrated supercapacitor delivers an exceptional specific capacitance of 441.8 mF/cm2, a high energy density of 63.1 µWh/cm2, remarkable cyclic stability. Simultaneously, the gradient structure from PANI electrode to GPE greatly improves the electrode/electrolyte interface compatibility and ion transport, which endows the supercapacitor with stable electrochemical performance. Furthermore, the supercapacitor well-maintains the specific capacitance even at -20 °C with over 89.19 % retention after 6 cutting/healing cycles. The gradient interface structure design will promote the development of high-performance supercapacitor.

Forced degradation studies of elagolix sodium with the implementation of high resolution LC-UV-PDA-MSn (n = 1,2,3 ) and NMR structural elucidation.

Elagolix sodium (ELS) is a marketed product using to release moderate to severe endometriosis-associated pain. It contains functional groups such as carboxyl group, secondary amino group, 2,4-dioxo pyrimidinyl and several benzyl or benzyl-like position hydrogen atom that are susceptive to occur stress degradation. Forced degradation studies of ELS reveal different degradation profiles of the drug substance which are conducted under photo, thermal, acidic, neutral, alkaline and hydrogen peroxide oxidative conditions in the direction of the ICH guidances. With structural elucidation of LC-PDA/UV-MSn and NMR, the degradants were identified, and seven new degradants are reported in this study. It is confirmed that most of the degradation behaviors of ELS are related to the carboxyl group and secondary amino group in the 3-carboxyl propylamine side chain. Under the oxidative condition using hydrogen peroxide as the oxidant, the secondary amine was oxidized to form an N-hydrogen amine degradant and two further degradants of amine and carbonyl analogs were generated. Under the alkaline degradation condition, the ELS is proven to be stable and no obvious degradants are produced. On the other hand, under the acidic and neutral degradation condition, the 2,4-dioxo pyrimidinyl core of elagolix sodium is stable but the carboxyl group and secondary amine will occur ring cyclization to form the δ-lactam analogs of elagolix sodium. The plausible mechanisms for the degradation of acidic, thermal, photo-degradative and hydrogen peroxide mediated oxidative of elagolix sodium are proposed. It is worth to note that DP-3-4 are the potential degradants which are only found in the solution degradation and are not the real impurities of elagolix sodium.

Design, synthesis and anticancer activity studies of 3-(coumarin-3-yl)-acrolein derivatives: Evidenced by integrating network pharmacology and vitro assay.

Coumarin derivatives have diverse structures and show various significant biological activities. Aiming to develop more potent coumarin derivatives for cancer treatment, a series of coumarin acrolein hybrids were designed and synthesized by using molecular hybridization approach, and investigated for their antiproliferative activity against A549, KB, Hela and MCF-7 cancer cells as well as HUVEC and LO2 human normal cells. The results indicated that most of the synthesized compounds displayed remarkable inhibitory activity towards cancer cells but low cytotoxicity on normal cells. Among all the compounds, 5d and 6e were the most promising compounds against different cancer cell lines, especially for A549 and KB cells. The preliminary action mechanism studies suggested that compound 6e, the representative compound, was capable of dose-dependently suppressing migration, invasion and inducing significant apoptosis. Furthermore, the combined results of network pharmacology and validation experiments revealed that compound 6e induced mitochondria dependent apoptosis via the PI3K/AKT-mediated Bcl-2 signaling pathway. In summary, our study indicated compound 6e could inhibit cell proliferation, migration, invasion and promote cell apoptosis through inhibition of PI3K/AKT signaling pathway in human oral epidermoid carcinoma cells. These findings demonstrated the potential of 3-(coumarin-3-yl)-acrolein derivatives as novel anticancer chemotherapeutic candidates, providing ideas for further development of drugs for clinical use.

Human RSPO1 Mutation Represses Beige Adipocyte Thermogenesis and Contributes to Diet-Induced Adiposity.

Recent genetic evidence has linked WNT downstream mutations to fat distribution. However, the roles of WNTs in human obesity remain unclear. Here, the authors screen all Wnt-related paracrine factors in 1994 obese cases and 2161 controls using whole-exome sequencing (WES) and identify that 12 obese patients harbor the same mutations in RSPO1 (p.R219W/Q) predisposing to human obesity. RSPO1 is predominantly expressed in visceral fat, primarily in the fibroblast cluster, and is increased with adiposity. Mice overexpressing human RSPO1 in adipose tissues develop obesity under a high-fat diet (HFD) due to reduced brown/beige fat thermogenesis. In contrast, Rspo1 ablation resists HFD-induced adiposity by increasing thermogenesis. Mechanistically, RSPO1 overexpression or administration significantly inhibits adipocyte mitochondrial respiration and thermogenesis via LGR4-Wnt/ß-catenin signaling pathway. Importantly, humanized knockin mice carrying the hotspot mutation (p.R219W) display suppressed thermogenesis and recapitulate the adiposity feature of obese carriers. The mutation disrupts RSPO1's electrostatic interaction with the extracellular matrix, leading to excessive RSPO1 release that activates LGR4-Wnt/ß-catenin signaling and attenuates thermogenic capacity in differentiated beige adipocytes. Therefore, these findings identify that gain-of-function mutations and excessive expression of RSPO1, acting as a paracrine Wnt activator, suppress fat thermogenesis and contribute to obesity in humans.

Two-dimensional antiferromagnetic nodal-line semimetal and quantum anomalous Hall state in the van der Waals heterostructure germanene/Mn2S2.

Materials with interactions between the topology and magnetism are triggering increasing interest. We constructed a two-dimensional (2D) van der Waals heterostructure germanene/Mn2S2, where the germanene is a quantum spin Hall insulator and Mn2S2provides antiferromagnetic (AFM) interactions. In this structure, a 2D AFM nodal-line semimetal (NLSM) phase is expected without the spin-orbit coupling (SOC), which is of a high density of states around the Fermi level. The band touching rings originate from the intersection between different spin components ofporbitals of germanene. This result provides a possible 2D realization of NLSMs, which are usually realized in three-dimensional systems. When the SOC is present, a quantum anomalous Hall (QAH) state emerges with the annihilation of the band-touching rings. The nontrivial topology is determined by calculating the Chern number and Wannier charge centers. This provides an alternative platform to realize QAH states. These results could also provide the possibility of further understanding the topological states in NLSM and electronic applications.

Long-term effects of maize straw return and manure on the microbial community in cinnamon soil in Northern China using 16S rRNA sequencing.

Excessive use of chemical fertilizers in agricultural practices have demonstrated a significant impact on microbial diversity and community in soil by altering soil physical and chemical properties, thereby leading to a certain degree of soil salinization and nutritional imbalances. As an organic amendment, maize straw has been widely used to improve soil quality; however, its effect on the soil bacterial community remains limited in Calcarie-Fluvie Cambisols soil in semi-humid arid plateau of North China. In the present experiment, we investigated the effects of continuous straw utilization and fertilization on bacterial communities in Shouyang, Shanxi province, China. Soil samples were collected from 5 different straw utilization and fertilization modes in the following ways: straw mulching (SM), straw crushing (SC), cattle manure (CM), in which way straw is firstly used as silage and then organic fertilizer, control with no straw return (NSR), and control without fertilizers (CK), same amount of N+P fertilizer was applied to the regimes except CK. High-throughput sequencing approaches were applied to the V3-V4 regions of the 16S ribosomal RNA for analysis of the bacterial abundance and community structures. Different long-term straw returning regimes significantly altered the physicochemical properties and bacterial communities of soil, among which CM had the most significant effects on soil fertility and bacterial diversity. Proteobacteria, Actinobacteria, Chloroflexi, Acidobacteria, and Gemmatimonadetes were consistently dominant in all soil samples, and Redundancy analysis (RDA) showed significant association of total nitrogen (TN), total phosphorus (TP) and available potassium (AK) with alternation of the bacterial community. Cattle manure had the most beneficial effects on soil fertility and bacterial diversity among different straw utilization and fertilization modes.

Electrically controlled spin polarized current in Dirac semimetals.

We propose a highly tunable [Formula: see text] spin-polarized current generated in a spintronic device based on a Dirac semimetal (DSM) under a magnetic field, which can be achieved merely by controlling electrical parameters, i.e. the gate voltage, the chemical potential in the lead and the coupling strength between the leads and the DSM. These parameters are all related to the special properties of a semimetal. The spin polarized current generated by gate voltage is guaranteed by its semimetallic feature, because of which the density of state vanishes near Dirac nodes. The barrier controlled current results from the different distance of Weyl nodes generated by the Zeeman field. And the coupling strength controlled spin polarized current originates from the surface Fermi arcs. This DSM-based spintronic device is expected to be realized in [Formula: see text] experimentally.

The generation of switchable polarized currents in nodal ring semimetals using high-frequency periodic driving.

A nodal ring semimetal (NRSM) can be driven to a spin-polarized NRSM or a spin-polarized Weyl semimetal (WSM) by a high-frequency electromagnetic field. We investigate the conditions in realizing these phases and propose a switchable spin-polarized currents generator based on periodically driven NRSMs. Both bulk and surface polarized currents are investigated. The polarization of bulk current is sensitive to the amplitude of the driving field and robust against the direction and polarization of the driving, the opaqueness of the lead-device interface and the misalignment between the nodal ring and the interface, which provides sufficient flexibility in manipulating the devices. Similar switchable polarized surface currents are also expected, which is contributed by the Fermi arc surface state associated with the WSM phases. The generation of polarized currents and the polarization switching effect offer opportunities to design periodic driving controlled topological spintronics devices based on NRSMs.

Acyl-carnitine, C5DC, and C26 as potential biomarkers for diagnosis of autism spectrum disorder in children.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders that shown a close association with impaired lipid metabolism. The acyl-carnitine spectrum status in Chinese children with ASD has not been reported. In this study, we assessed the levels of blood acyl-carnitines in Chinese children with ASD and examined the relation between acyl-carnitine profiles and the intelligence levels. Blood levels of acyl-carnitines were determined by tandem mass spectrometry in 60 children with ASD and 30 typically developing children. Chinese Wechsler Young Children Scale of Intelligence (C-WYCSI) was used in ASD group. Blood levels of free carnitine, glutaricyl carnitine, octyl carnitine, twenty four carbonyl carnitine and carnosyl carnitine in the ASD group were significantly lower than those in the control group. Glutaryl carnitine and carnosyl carnitine might be potential biomarkers for diagnosis of ASD. The changes in the acyl-carnitine spectrum indicate potential mitochondrial dysfunction and abnormal fatty acid metabolism in preschool ASD children.

Identification of toxic substances in phenol-acetone wastewater on activated sludge and selective toxicity removal performance with ferrous pretreatment.

We investigated the effects of toxic wastewater generated during the production of phenol-acetone on activated sludge and tested pretreatment methods to selectively remove the toxicity. We found that the microbial activity in the activated sludge was inhibited by the wastewater, in which cumene hydroperoxide (CHP) with a medium effective concentration (EC50) of 225 mg L-1 was the main toxic substance. We tested one pretreatment method with ferrous iron to selectively remove the CHP. The CHP decomposition process, which mainly produced acetophenone, was very quick. The CHP was selectively transformed into low-toxicity organics, and a maximum of 92% was removed when 1.08 mmol L-1 of ferrous iron was added, for a reaction time of 10 min, a pH of 5, and a temperature of 25 °C, and the resulting wastewater only slightly inhibited the oxygen uptake rate of activated sludge. The acclimation of activated sludge was accelerated, and a COD removal rate of more than 85% was achieved within a week. Our results confirm that ferrous iron provides a cost-effective method to selectively remove toxins from wastewater.

Metabolic profiling of dehydrodiisoeugenol using xenobiotic metabolomics.

Dehydrodiisoeugenol (DDIE), a representative and major benzofuran-type neolignan in Myristica fragrans Houtt., shows anti-inflammatory and anti-bacterial actions. In order to better understand its pharmacological properties, xenobiotic metabolomics was used to determine the metabolic map of DDIE and its influence on endogenous metabolites. Total thirteen metabolites of DDIE were identified through in vivo and in vitro metabolism, and seven of them were reported for the first time in the present study. The identity of DDIE metabolites was achieved by comparison of the MS/MS fragmentation pattern with DDIE using ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI- QTOFMS). Demethylation and ring-opening reaction were the major metabolic pathways for in vivo metabolism of DDIE. Recombinant cytochrome P450s (CYPs) screening revealed that CYP1A1 is a primary enzyme contributing to the formation of metabolites D1-D4. More importantly, the levels of two endogenous metabolites 2,8-dihydroxyquinoline and its glucuronide were significantly elevated in mouse urine after DDIE exposure, which explains in part its modulatory effects on gut microbiota. Taken together, these data contribute to the understanding of the disposition and pharmacological activities of DDIE in vivo.

High levels of chorionic gonadotrophin attenuate insulin sensitivity and promote inflammation in adipocytes.

Gestational diabetes mellitus (GDM) presents with moderate inflammation, insulin resistance and impaired glucose uptake, which may result from increased maternal fat mass and increased circulation of placental hormones and adipokines. In this study, we set out to test whether the surge in chorionic gonadotrophin (CG) secretion is a cause of inflammation and impaired insulin sensitivity in GDM. We first found that LH/chorionic gonadotrophin receptors (CG/LHR) were expressed at low levels in insulin-sensitive murine 3T3-L1 adipocytes and murine C2C12 myocytes. CG treatment not only directly reduced insulin-responsive gene expression, including that of glucose transporter 4 (GLUT4), but also impaired insulin-stimulated glucose uptake in 3T3-L1 cells. Moreover, CG treatment increased the expression of the proinflammatory cytokine monocyte chemotactic protein 1 (MCP1) and upregulated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in 3T3-L1 cells. Clinically, pregnant women who had higher CG levels and elevated MCP1 developed GDM. Above all, apart from prepregnancy BMI and MCP1 level, CG level was associated with abnormal glucose tolerance. In summary, our findings confirmed that higher CG levels in pregnancy possibly played a role in GDM development partly by impairing the functions of insulin, such those involved in as glucose uptake, while promoting inflammation in adipocyte.