Search

Herein, we report a catalyst-free reaction of cyclobutanone oximes with chlorophosphines (R2PCl), which forms a fragile C═N–O–PR2species that undergoes N–O homolysis, fragmentation, and radical–radical coupling, leading to the formation of cyano-containing phosphine oxides in good yields. The reaction features an in situactivation of cyclobutanone oximes for radical generation, in which R2PCl plays a dual role as both an activator and a reactant.

Processor and communication link failures are inevitable in a large multiprocessor system, and so the fault tolerance of its underlying interconnection network has become a key scientific issue. Connectivity is an important parameter to characterize network fault tolerance, and there are many novel variants of classical connectivity to measure the fault tolerance of interconnection networks. However, these new strategies only consider a single faulty vertex. Structure connectivity and substructure connectivity make up for this deficiency, which underline the fault situation with certain specific structures. H-structure-connectivity $ \kappa (G;H) $ κ(G;H)(resp. H-substructure-connectivity $ \kappa ^s(G;H) $ κs(G;H)) of Gis the minimum cardinality of H-structure-cuts (resp. H-substructure-cuts). For the n-dimensional Bicube network $ BQ_n $ BQn, we establish the structure and substructure connectivity of Bicube networks, i.e. $ \kappa {(BQ_n;K_{1,1})}=\kappa ^s{(BQ_n;K_{1,1})}= n $ κ(BQn;K1,1)=κs(BQn;K1,1)=nfor odd $ n\geq 5 $ n≥5; $ \kappa {(BQ_n;K_{1,1})}=\kappa ^s{(BQ_n;K_{1,1})}= n-1 $ κ(BQn;K1,1)=κs(BQn;K1,1)=n−1for even $ n\geq 4 $ n≥4and $ \kappa {(BQ_n;K_{1,r})}=\kappa ^s{(BQ_n;K_{1,r})}=\lceil \frac {n}{2}\rceil $ κ(BQn;K1,r)=κs(BQn;K1,r)=⌈n2⌉for $ n\geq 6 $ n≥6and $ 2\leq r\leq n-1 $ 2≤r≤n−1.

Luminescent gold nanoparticles (L-AuNPs) with diameters exceeding 2 nm hold great promise for biomedical imaging due to their unique optical properties and excellent biocompatibility. However, they typically exhibit weak photoluminescence (PL) because of surface plasmon resonance (SPR) effects. Moreover, conventional synthesis of L-AuNPs, often through thermal or chemical reduction, tends to be complex and labor-intensive. It is crucial, therefore, to develop more straightforward synthesis methods that enhance PL emission efficiency. Herein, we introduce a facile photochemical method for synthesizing highly luminescent AuNPs coated with 2-n-hexylthio-1,3,4-thiadiazole-5-thiol (L-AuNP@HTT). These nanoparticles, with a diameter of 3.19 nm, exhibit outstanding optical properties, including a high quantum yield (φ~ 12%), an extremely long luminescence lifetime (~ 1 µs), a symmetric PL spectrum, and a narrow full width at half maximum (FWHM ≤ 49 nm). They also feature an exceptionally large two-photon absorption cross-section (σ), reaching up to 8.0 × 104GM (1 GM = 10−50cm4s photon−1). Upon encapsulation in a polymer matrix (p-AuNPs), the TPA cross-sections were further enhanced to 1.1 × 108GM. These p-AuNPs demonstrated high photostability and efficient targeting to mitochondria, making them highly effective for mitochondrial-targeted two-photon excited luminescence (TPEL) imaging. Deep-tissue time-gated TPEL imaging and in vivo computed tomography (CT) imaging have also been achieved with p-AuNPs. This work establishes a straightforward synthesis route for highly luminescent gold nanoparticles larger than 2 nm, significantly broadening their potential in various bioimaging applications.

Battery thermal management is very crucial for the safe and long-term operation of electric vehicles or hybrid electric vehicles. In this study, numerical simulation method is adopted to simulate the temperature field of Li-ion battery cell and module. It is proved that the maximum temperature and maximum temperature difference of battery cell and module increase with the increase of charge/discharge rate (C-rate) of the battery. For battery module, it can reach a maximum temperature of 61.1°C at a C-rate of 2 under natural convection condition with the ambient temperature of 20.0°C. A battery thermal management system based on micro heat pipe array (BTMS-MHPA) is deeply investigated. Experiments are conducted to compare the cooling effect on the battery module with different cooling methods, which include natural cooling, only MHPA, MHPA with fan. The maximum temperature of battery module which is cooled by MHPA with a fan is 43.4°C at a C-rate of 2, which is lower than that in the condition of natural cooling. Meanwhile, the maximum temperature difference was also greatly reduced by the application of MHPA cooling. The experimental results confirm that the feasibility and superiority of the BTMS-MHPA for guaranteeing the working temperature range and temperature uniformity of the battery.

Emerging nanotechnologies demonstrate unparalleled benefits in expediting cancer treatment. Despite the widespread use of nanocomposites in tumor therapy, particularly in the treatment of osteosarcoma, there is a lack of review articles specifically focusing on their application in osteosarcoma immunotherapy. Nanocomposites have demonstrated exceptional performance in improving the effectiveness of osteosarcoma treatments, with multiple metal ions playing a pivotal role in modulating innate immune stimulation and overcoming acquired immune tolerance. The rational design of functional materials can efficiently induce immunogenic cell death in tumors or directly activate antigen-presenting cells, thereby initiating specific anti-tumor immune responses. This comprehensive review focuses on the most recent progress of the immune microenvironment in osteosarcoma, followed by an introduction to the characteristics of various metal ions (iron-based, bismuth-based, copper-based, and other metal-based nanocomposites) in osteosarcoma immunotherapy, as well as their forms and mechanisms of action in anti-tumor immune regulation: serving as an efficient cancer vaccine or nanodrugs to induce a strong tumor-specific immune response; acting as a biocompatible nanocarrier to provide immunotherapeutic agents for tumor immunotherapy. Finally, the main challenges and possible development directions in this field are highlighted, providing reference and guidance for the subsequent research on metal-based nanoparticles in the treatment of malignant bone tumors.

To use probe oscillation shear wave elastography (PROSE) with two vibration sources to generate two shear waves in the imaging plane to quantitatively assess the shear wave speeds (SWSs) of muscles with and without the diagnosis of taut bands (TB) and/or myofascial trigger points (MTrPs). Thirty‐three patients were scanned with the PROSE technique. Shear waves were generated through continuous vibration of the ultrasound probe, while the shear wave motions were detected using the same probe. SWSs for the sides with and without TBs and/or MTrPs were computed and compared. The pressure pain thresholds (PPTs) were measured as an indicator of maximum pain tolerance of patients. The statisticaldifferences between the SWSs with and without TBs and/or MTrPs with different PPT values were analyzed using the nonparametric Wilcoxon rank‐sum test. The mean SWSs for the sides with TBs and/or MTrPs are faster than that of the contralateral side without TBs and/or MTrPs. A significant difference was observed between mean SWSs with and without TBs and/or MTrPs without any information of PPT, with rank‐sum test P<  .005. Additionally, with the information of PPT, a significant difference was observed between mean SWSs for the sides with and without TBs and/or MTrPs, for PPT values between 0 and 50 N/cm2(P<  .005), but for PPT values between 50 and 90 N/cm2, it was difficult to differentiate mean SWSs with and without TBs and/or MTrPs. Our preliminary results show that SWSs measured from patients had a significant difference between the mean SWSs with and without TBs and/or MTrPs.

Methanobactins (Mbns) are a family of copper-binding peptides involved in copper uptake by methanotrophs, and are potential therapeutic agents for treating diseases characterized by disordered copper accumulation. Mbns are produced via modification of MbnA precursor peptides at cysteine residues catalyzed by the core biosynthetic machinery containing MbnB, an iron-dependent enzyme, and MbnC. However, mechanistic details underlying the catalysis of the MbnBC holoenzyme remain unclear. Here, we present crystal structures of MbnABC complexes from two distinct species, revealing that the leader peptide of the substrate MbnA binds MbnC for recruitment of the MbnBC holoenzyme, while the core peptide of MbnA resides in the catalytic cavity created by the MbnB–MbnC interaction which harbors a unique tri-iron cluster. Ligation of the substrate sulfhydryl group to the tri-iron center achieves a dioxygen-dependent reaction for oxazolone-thioamide installation. Structural analysis of the MbnABC complexes together with functional investigation of MbnB variants identified a conserved catalytic aspartate residue as a general base required for MbnBC-mediated MbnA modification. Together, our study reveals the similar architecture and function of MbnBC complexes from different species, demonstrating an evolutionarily conserved catalytic mechanism of the MbnBC holoenzymes.

Background: Mounting evidence has shown that Cyclin E1 (CCNE1) facilitates various carcinoma progression, but its function in lung adenocarcinoma (LUAD) remains unclear. Objective: Our study aims to explore the significance of CCNE1 in clinical progression and study its biological functions in LUAD. Methods: CCNE1 expressions in LUAD specimens and cells were detected through quantitative realtimepolymerase chain reaction (qRT-RCR) and western blot. An immunohistochemistry technique wasused to detect CCNE1 expression to explore its association with clinical parameters. The LUAD cellswith stable knockdown of CCNE1 were constructed by small interfering RNA. The effect of CCNE1on LUAD cells proliferation and apoptosis was evaluated through Cell Counting Kit-8 (CCK-8), colonyformation, and Annexin V/propidium iodide (AV-PI) assays, respectively. The cell migration andinvasion were evaluated by Wound-healing and Transwell assays, respectively. The xenograft and lungmetastasis mouse models were introduced to analyze how CCNE1 knockdown affects tumor growthand tumor metastasis. Results: CCNE1 expression was upregulated in LUAD tissue and cells. CCNE1 knockdown inhibited LUAD cellular malignant behavior in vitro and reduced tumor growth and metastasis in vivo. High expression of CCNE1 was correlated with big tumor size, cancer stage, lymph node metastasis, and poor prognosis. Conclusion: CCNE1 overexpression promotes LUAD growth, metastasis, and forebode poor prognosis: it can serve as a new prognostic marker of LUAD.

Acute febrile illness is one of the main reasons for outpatient hospital visits worldwide. However, differential diagnosis between bacterial and viral causes is challenging and misdiagnosis can result in antimicrobial overuse and hinder prompt treatment. We aimed to build and validate a diagnostic model to discriminate bacterial from viral infection in acute febrile illness by evaluating the expression of potential classifier host genes.

On the basis of the unprecedented one-dimensional {Cu2(tetrazole)(SO4)(OH)}ncluster, a novel two-dimensional layered copper(II) organic framework, {[Cu2(TTB)(SO4)(OH)]·H2O·MeCN}n(1), is constructed from 1-(tetrazo-5-yl)-4-(triazo-1-yl) benzene (HTTB) and CuSO4under hydrothermal conditions. Photocatalytic experiments revealed that 1is an outstanding semiconducting material (Eg= 2.21 eV) for the degradation of methyl blue under UV light irradiation. Besides, electrocatalytic research showed that the 1@NF electrode shows better oxygen evolution reaction (OER) performance than RuO2@NF, reaching a current density of 10 mA·cm–2when the overpotential of OER is 377 mV in 1.0 M KOH electrolyte and the Tafel slope of 1@NF is 15.6 mV·dec–1. Meanwhile, the overpotential of the hydrogen evolution reaction (HER) is 242 mV at a current density of 10 mA·cm–2, with the Tafel slope being 23.1 mV·dec–1, also suggesting the HER performance of 1@NF is better than that of Pt/C@NF. The durability test showed the electrocatalytic activity of 1@NF was maintained at 90% after 12 h. Photocatalytic and electrocatalytic properties show that 1is an excellent candidate as a multifunctional material to solve environmental pollution and energy shortages.

Menthais a commonly used spice worldwide, which possesses medicinal properties and fragrance. These characteristics are conferred, at least partially, by essential oils such as menthol. In this study, a gap-free assembly with a genome size of 414.3 Mb and 31,251 coding genes was obtained for Mentha suaveolens‘Variegata’. Based on its high heterozygosity (1.5%), two complete haplotypic assemblies were resolved, with genome sizes of 401.9 and 405.7 Mb, respectively. The telomeres and centromeres of each haplotype were almost fully annotated. In addition, we detected a total of 41,135 structural variations. Enrichment analysis demonstrated that genes involved in terpenoid biosynthesis were affected by these structural variations. Analysis of volatile metabolites showed that M. suaveolensmainly produces piperitenone oxide rather than menthol. We identified three genes in the M. suaveolensgenome which encode isopiperitenone reductase (ISPR), a key rate-limiting enzyme in menthol biosynthesis. However, the transcription levels of ISPRwere low. Given that other terpenoid biosynthesis genes were expressed, M. suaveolens ISPRsmay account for the accumulation of piperitenone oxide in this species. The findings of this study may provide a valuable resource for improving the detection rate and accuracy of genetic variants, thereby enhancing our understanding of their impact on gene function and expression. Moreover, our haplotype-resolved gap-free genome assembly offers novel insights into molecular marker-assisted breeding of Mentha.

In this work, an original Si/SiGe heterojunction tunneling field‐effect transistor which has a double‐stacked heterogeneous oxide gate (HfO2/Al2O3) structure (DSG–HJ–TFET) is designed and investigated by Sentaurus technology computer aided design (TCAD) simulation software. To ensure good interface quality, a stacked oxide gate dielectric of Al2O3and HfO2is proposed. The on‐state current (Ion) is increased though improving the carrier mobility degradation caused by the poor quality of interface between the high‐κdielectric and semiconductor. Moreover, a heterojunction with SiGe (source)/Si (channel) and pocket layer which is inserted between the source region and the channel is adopted to reduce the tunneling barrier and improve the Ion. Therefore, the higher Ionis obtained by the proposed DSG–HJ–TFET. In the simulation results, it is shown that Ionof DSG–HJ–TFET is increased by three orders of magnitude compared with that of the conventional high‐κgate dielectric TFET structure. In addition, the off‐state current (Ioff) of 4.91 × 10−11 μA μm−1, the minimum subthreshold swing of 14 mV dec−1, the Ion/Ioffratio of 1.13 × 1012, transconductance of 260 μS μm−1, fTof 49.8 GHz, and gain bandwidth product (GBW) of 7.2 GHz are obtained. The propose DSG–HJ–TFET is favored in ultralow‐power applications for the rather good performance. To ensure good interface quality, a stacked oxide gate dielectric of Al2O3and HfO2is proposed. Moreover, a heterojunction with SiGe (source)/Si (channel) and pocket layer which is inserted between the source region and the channel is adopted to reduce the tunneling barrier and improve the on‐state current.

Soft actuators and microrobots that can move spontaneously and continuously without artificial energy supply and intervention have great potential in industrial, environmental, and military applications, but still remain a challenge. Here, a bioinspired MXene-based bimorph actuator with an asymmetric layered microstructure is reported, which can harness natural sunlight to achieve directional self-locomotion. We fabricate a freestanding MXene film with an increased and asymmetric layered microstructure through the graft of coupling agents into the MXene nanosheets. Owing to the excellent photothermal effect of MXene nanosheets, increased interlayer spacing favoring intercalation/deintercalation of water molecules and its caused reversible volume change, and the asymmetric microstructure, this film exhibits light-driven deformation with a macroscopic and fast response. Based on it, a soft bimorph actuator with ultrahigh response to solar energy is fabricated, showing natural sunlight-driven actuation with ultralarge amplitude and fast response (346° in 1 s). By utilizing continuous bending deformation of the bimorph actuator in response to the change of natural sunlight intensity and biomimetic design of an inchworm to rectify the repeated bending deformation, an inchwormlike soft robot is constructed, achieving directional self-locomotion without any artificial energy and control. Moreover, soft arms for lifting objects driven by natural sunlight and wearable smart ornaments that are combined with clothing and produce three-dimensional deformation under natural sunlight are also developed. These results provide a strategy for developing natural sunlight-driven soft actuators and reveal great application prospects of this photoactuator in sunlight-driven soft biomimetic robots, intelligent solar-energy-driven devices in space, and wearable clothing.

Dynamic and real-time monitoring of the motion state of soft actuators is of great significance for optimizing their performance. However, present noncontact measurement approaches based on diffractive groove arrays fabricated by imprinting have some limitation, e.g., the grooves should be processed before the solidification of soft materials or the depth and period of grooves cannot be flexibly adjusted. Here, a flexible and high-efficiency fabrication approach carbon-assisted laser interference lithography (CLIL) for periodical groove structures with structural color is proposed. This technique is to irradiate the interference laser on the PDMS surface coated by a carbon layer, which is used for enhanced laser absorption. The processing parameters are systematically studied and optimized to achieve a bright structural color. Benefiting from the advantages of CLIL, the structural color can be processed on a solidified transparent surface with controllable characteristics such as groove period and depth. Lastly, the motion of an electric-driven actuator can be real-time quantified by calibrating the relationship between the observation angle and the observed structural color.

Redwood trees (Sequoioideae), including Metasequoia glyptostroboides(dawn redwood), Sequoiadendron giganteum(giant sequoia), and Sequoia sempervirens(coast redwood), are threatened and widely recognized iconic tree species. Genomic resources for redwood trees could provide clues to their evolutionary relationships. Here, we report the 8-Gb reference genome of M. glyptostroboidesand a comparative analysis with two related species. More than 62% of the M. glyptostroboidesgenome is composed of repetitive sequences. Clade-specific bursts of long terminal repeat retrotransposons may have contributed to genomic differentiation in the three species. The chromosomal synteny between M. glyptostroboidesand S. giganteumis extremely high, whereas there has been significant chromosome reorganization in S. sempervirens. Phylogenetic analysis of marker genes indicates that S. sempervirensis an autopolyploid, and more than 48% of the gene trees are incongruent with the species tree. Results of multiple analyses suggest that incomplete lineage sorting (ILS) rather than hybridization explains the inconsistent phylogeny, indicating that genetic variation among redwoods may be due to random retention of polymorphisms in ancestral populations. Functional analysis of ortholog groups indicates that gene families of ion channels, tannin biosynthesis enzymes, and transcription factors for meristem maintenance have expanded in S. giganteumand S. sempervirens, which is consistent with their extreme height. As a wetland-tolerant species, M. glyptostroboidesshows a transcriptional response to flooding stress that is conserved with that of analyzed angiosperm species. Our study offers insights into redwood evolution and adaptation and provides genomic resources to aid in their conservation and management.

Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are a class of toxic environmental pollutants that are persistent, bioaccumulative, and difficult to degrade. Their structure is very similar to the thyroid hormone (T4) and uses the body’s thyroid transporter (TTR) binding to interfere with the endocrine balance, disrupting the body’s normal physiological activity. According to Fourier transform infrared spectroscopy and dynamics simulation of do_dsspmodule analysis, there are three kinds of OH-PBDEs that can induce TTR secondary structural changes. Fluorescence spectra and UV–Vis spectra show that for the three kinds of OH-PBDEs for TTR, the main methods of quenching are static quenching and non-radiative energy transfer. According to thermodynamic analysis, ΔG < 0, ΔH > 0, and ΔS > 0 combine to show that the hydrophobic interaction is the main driving force of the combination. From the molecular docking analysis, it was found that 4′-hydroxy-2,2′,4,5′- tetrabromodiphenyl ether (4′-OH-BDE49) and 4 hydroxy-2,2′,3,4′,5,6,6′- heptabromodiphenyl ether (4-OH-BDE188) had a cationic–π interaction with TTR, whereas 4 hydroxy-2,2′,3,4,5,5′,6- heptabromodiphenyl ether (4-OH-BDE187) was bonded to TTR by hydrogen bonds to form stable complexes. In this paper, we highlight the consistency of spectroscopic experiments and computer simulations so as to provide a reliable analytical method for the toxicological properties of small molecule contaminants.

•Two ejection-compression refrigeration cycles (EC and ES) are compared.•The impact of various operating parameters on the performance parameters is explored.•EC is recommended when low-grade heat is free and ejection system cost is low.•COPelefor ES is 2.24 higher than that of EC at the cost of low-grade heat consumption is only 20%.•The PBP for EC and ES range from 25.33 to 9.24 years and 12.06 to 2.85 years, respectively.

Allopolyploid oilseed rape (Brassica napus) is an important oil crop and vegetable. However, the latest version of its reference genome, with collapsed duplications, gaps, and other issues, prevents comprehensive genomic analysis. Herein, we report a gap-free assembly of the rapeseed cv. Xiang5A genome using a combination of ONT (Oxford Nanopore Technologies) ultra-long reads, PacBio high-fidelity reads, and Hi-C datasets. It includes gap-free assemblies of all 19 chromosomes and telomere-to-telomere assemblies of eight chromosomes. Compared with previously published genomes of B. napus, our gap-free genome, with a contig N50 length of 50.70 Mb, has complete assemblies of 9 of 19 chromosomes without manual intervention, and greatly improves contiguity and completeness, thereby representing the highest quality genome assembly to date. Our results revealed that B. napusXiang5A underwent nearly complete triplication and allotetraploidy relative to Arabidopsis thaliana. Using the gap-free assembly, we found that 917 flowering-related genes were affected by structural variation, including BnaA03.VERNALIZATION INSENSITIVE 3and BnaC04.HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1. These genes may play crucial roles in regulating flowering time and facilitating the adaptation of Xiang5A in the Yangtze River Basin of China. This reference genome provides a valuable genetic resource for rapeseed functional genomic studies and breeding.

The physical and chemical properties of polybrominated diphenyl ethers (PBDEs) are important for modeling their transport. The primary objective of this study was to evaluate the interaction of transthyretin (TTR) with BDE-100, 3-OH-BDE-100 and 3-MeO-BDE-100 using fluorescence spectroscopy, three-dimensional fluorescence, circular dichroism (CD), molecular docking and molecular dynamics methods. These PBDEs significantly quench the intrinsic fluorescence of TTR viastatic mode and non-radiation energy transfer. Then, the secondary structure and kinetic parameters of the protein were analyzed by three-dimension fluorescence spectra, CD spectra and molecular dynamics simulations. The results suggest that the binding of BDE-100, 3-OH-BDE-100 and 3-MeO-BDE-100 to TTR can induce conformational changes. According to molecular docking and thermodynamic method, hydrogen and van der Waals force driven BDE-100 binding with TTR and hydrophobic attractions may be the key factors for the stability of the TTR-3-OH-BDE-100 and TTR-3-MeO-BDE-100 complex. Moreover, docking studies and free energy calculations demonstrated that Lys15, Leu110 and Thr119 are crucial and important for the binding of TTR with BDE-100, 3-OH-BDE-100, 3-MeO-BDE-100.

A phosphine-catalyzed ring-opening addition reaction of cyclopropenones with a variety of nucleophiles (NuH), including oxygen-, nitrogen-, sulfur-, and carbon-based ones, has been investigated, which produces potentially useful α,β-unsaturated carbonyl derivatives in high yields (up to 99%), high regioselectivity, and exclusive E-selectivity. The reaction proceeds in high efficiency under very mild conditions using only 1 mol % PPh3as the catalyst at room temperature. The method is also amenable for the synthesis of deuterated alkenes when deuterated nucleophiles (NuD) are employed. The mechanism is investigated by experiments and DFT calculations, which suggests an α-ketenyl phosphorus ylide as a key intermediate in the catalytic cycle that captures the nucleophiles in a stereoselective manner.

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease affecting predominantly females. To discover additional genetic risk variants for SLE on the X chromosome, we performed a follow-up study of our previously published genome-wide association study (GWAS) data set in this study. Twelve single nucleotide polymorphisms (SNPs) within novel or unpublished loci with P-value < 1.00 × 10−02were selected for genotype with a total of 2,442 cases and 2,798 controls(including 1,156 cases and 2,330 controls from central China, 1,012 cases and 335 controls from southern China and 274 cases and 133 controls from northern China) using Sequenom Massarry system. Associaton analyses were performed using logistic regression with sample region as a covariate through PLINK 1.07 software. Combined analysis in discovery and central validation dataset discovered a novel locus rs5914778 within LINC01420associated with SLE at genome-wide significance (P= 1.00 × 10−08; odds ratio (OR) = 1.32). We also confirmed rs5914778 in the southern Chinese sample cohort (P= 5.31 × 10−05; OR = 1.51), and meta-analysis of the samples from the discovery, central and southern validations regions provided robust evidence for the association of rs5914778 (P= 5.26 × 10−12; OR = 1.35). However, this SNP did not show association with SLE in the northern sample (P= 0.33). Further analysis represent the association of northern was significantly heterogeneous compared to central and southern respectively. Our study increases the number of established susceptibility loci for SLE in Han Chinese population and has further demonstrated the important role of X-linked genetic risk variants in the pathogenesis of SLE in Chinese Han population.

Magnetic carbon spheres have been successfully prepared by the synchronous carbonation and activation of the 8-quinoliolato Fe(III) complexe with sphere morphology, which has been synthesized by solovthermal method. The obtained composite possesses relatively even pore diameter of 3.8 nm, high surface area of 335.59 m 2 /g with 52.67 wt.% Fe 3 O 4 coated, and a saturation magnetization (Ms) of 35.27 emu/g. Dye separation performance of the magnetic carbon spheres is investigated using methylene orange and methylene blue as modle. The resluts show that the maxium adsorption capacity for methylene orange and methylene blue is 128.70 mg g −1 and 151.29 mg g −1 , respectively, and the process can rapidly reach adsorption equilibrium within 5 min, which is important for the application of the as-prepared magnetic carbon spheres. [ABSTRACT FROM AUTHOR]

Cobimetinib is a MEK inhibitor currently in clinical trials as an anticancer agent. The objectives of this study were to determine in vitro and in vivo if cobimetinib is a substrate of P-glycoprotein (P-gp) and/or breast cancer resistance protein (Bcrp1) and to assess the implications of efflux on cobimetinib pharmacokinetics (PK), brain penetration, and target modulation. Cell lines transfected with P-gp or Bcrp1 established that cobimetinib was a substrate of P-gp but not a substrate of Bcrp1. In vivo, after intravenous and oral administration of cobimetinib to FVB (wild-type; WT), Mdr1a/b(−/−),Bcrp1 (−/−), and Mdr1a/b(−/−)/Bcrp(−/−)knockout (KO) mice, clearance was similar in WT (35.5 ± 16.7 mL/min/kg) and KO animals (22.0 ± 3.6 to 27.6 ± 5.2 mL/min/kg); oral exposure was also similar between WT and KO animals. After an oral 10 mg/kg dose of cobimetinib, the mean total brain to plasma ratio (Kp) at 6 h postdose was 0.3 and 0.2 in WT and Bcrp1(−/−)mice, respectively. In Mdr1a/b(−/−)and Mdr1a/1b/Bcrp1(−/−)KO mice and WT mice treated with elacridar (a P-gp and BCRP inhibitor), Kp increased to 11, 6, and 7, respectively. Increased brain exposure in Mdr1a/b(−/−)and Mdr1a/1b/Bcrp1(−/−)KO and elacridar treated mice was accompanied by up to ∼65% suppression of the target (pErk) in brain tissue, compared to WT mice. By MALDI imaging, the cobimetinib signal intensity was relatively high and was dispersed throughout the brain of Mdr1a/1b/Bcrp1(−/−)KO mice compared to low/undetectable signal intensity in WT mice. The efflux of cobimetinib by P-gp may have implications for the treatment of patients with brain tumors/metastases.

This review summarizes the background and updated progress of pharmacophore based drug design and provides the fundamental approach strategies on both structure based and ligand based pharmacophore approaches. The different programs and methodologies enable the implementation of more accurate and sophisticated pharmacophore model generation and application in drug discovery. This review will discuss and illustrate their advantages in pharmacophore based virtual screening and exemplify the detailed application workflow, which can be easily utilized by pharmaceutical bench work medicinal chemists. Pharmacophore based drug design process includes pharmacophore modeling and validation; pharmacophore based virtual screening, virtual hits profiling and lead identification. Strategies and proven methodologies for pharmacophore modeling are described including common feature and 3D QSAR based pharmacophore generation as well as structure based pharmacophore development. Different virtual screening strategies will be described in this review with detailed case studies for supporting practical applications. Representative success examples of pharmacophore based virtual screening for lead generation will be collected to demonstrate capabilities.

•This is the first time to study and find out that sinomenine hydrochloride and iodine-131 synergic enhance the apoptosis and regulate DNA repair and cell cycle checkpoint on papillary thyroid carcinoma cells.•This is the first time to study and find out that sinomenine hydrochloride increased the radiosensitivity of papillary thyroid carcinoma cells and normal thyroid cells.•This is the first time to study and find out that sinomenine hydrochloride could be a potential therapeutic radiosensitizer in papillary thyroid carcinoma radiotherapy after total thyroidectomy .