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The Xenopus oocyte and the Human Embryonic Kidney (HEK) 293 cell expression systems are frequently used for functional characterization (deorphanization) of insect odorant receptors (ORs). However, the inherent characteristics of these heterologous systems differ in several aspects, which raises the question of whether the two systems provide comparable results, and how well the results correspond to the responses obtained from olfactory sensory neurons in vivo. Five candidate pheromone receptors were previously identified in the primitive moth Eriocrania semipurpurella (Esem) and their responses were characterized in HEK cells. We re-examined the responses of these five EsemORs in Xenopus oocytes. We showed that in both systems, EsemOR1 specifically responded to the plant volatile β-caryophyllene. EsemOR3 responded stronger to the pheromone component (S,Z)-6-nonen-2-ol than to its enantiomer (R,Z)-6-nonen-2-ol, the second pheromone component. However, EsemOR3 also responded secondarily to the plant volatile β-caryophyllene in the oocyte system, but not in the HEK cell system. EsemOR4 was unresponsive in the HEK cells, but responded primarily to (R,Z)-6-nonen-2-ol followed by (S,Z)-6-nonen-2-ol in the oocytes, representing a discovery of a new pheromone receptor in this species. EsemOR5 was broadly tuned in both systems, but the rank order among the most active pheromone compounds and antagonists was different. EsemOR6 showed no response to any compound in either system. We compared the results obtained in the two different heterologous systems with the activity previously recorded in vivo, and performed in situ hybridization to localize the expression of these OR genes in the antennae. In spite of similar results overall, differences in OR responses between heterologous expression systems suggest that conclusions about the function of individual ORs may differ depending on the system used for deorphanization.

This study compared three‐dimensional (3D) and two‐dimensional (2D) percentage gamma passing rates (%GPs) for detection sensitivity to IMRT delivery errors and investigated the correlation between two kinds of %GP. Eleven prostate IMRT cases were selected, and errors in multileaf collimator (MLC) bank sag, MLC leaf traveling, and machine output were simulated by recalculating the dose distributions in patients. 2D doses were extracted from the 3D doses at the isocenter position. The 3D and 2D %GPs with different gamma criteria were then obtained by comparing the recalculated and original doses in specific regions of interest (ROI), such as the whole body, the planning target volume (PTV), the bladder, and the rectum. The sensitivities to simulated errors of the two types of %GP were compared, and the correlation between the 2D and 3D %GPs for different ROIs were analyzed. For the whole‐body evaluation, both the 2D and 3D %GPs with the 3%/3 mm criterion were above 90% for all tested MLC errors and for MU deviations up to 4%, and the 3D %GP was higher than the 2D %GP. In organ‐specific evaluations, the PTV‐specific 2D and 3D %GP gradients were −4.70% and −5.14% per millimeter of the MLC traveling error, and −17.79% and −20.50% per percentage of MU error, respectively. However, a stricter criterion (2%/1 mm) was needed to detect the tested MLC sag error. The Pearson correlation analysis showed a significant strong correlation (r > 0.8 and P < 0.001) between the 2D and 3D %GPs in the whole body and PTV‐specific gamma evaluations. The whole‐body %GP with the 3%/3 mm criterion was inadequate to detect the tested MLC and MU errors, and a stricter criterion may be needed. The PTV‐specific gamma evaluation helped to improve the sensitivity of the error detection, especially using the 3D GP%.

Polyoxometalate [{a-PW11O39Zr(μ-OH)(H2O)}2]8– (POM1) is first prepared by sandwiching ZrIV among 2 mono-lacunary α-Keggin polyoxometalates, and then novel magnetic nanoparticles (NPs), Fe3O4@polyethyleneimine (PEI)@POM1, are fabricated by coating POM1 onto the surface of magnetic Fe3O4@PEI NPs under electrostatic interaction. The obtained Fe3O4@PEI@POM1 NPs are characterized by Fourier transform infrared, zeta potential, vibrating sample magnetometer, transmission electron microscopy, energy-dispersive X-ray spectroscopy, and X-ray diffraction. Ascribed to the hydrogen-bonding and electrostatic interactions, the NPs exhibit high adsorption selectivity toward IgG, and the adsorption capacity is high up to 304 mg g–1 under optimal adsorption conditions. By using 0.01% cetyl trimethylammonium bromide to strip the adsorbed protein species, an elution efficiency of 95% is achieved. The feasibility of Fe3O4@PEI@POM1 NPs in real-world sample assay has been demonstrated by the selective isolation of IgG heavy cha...

Proteins that mediate cellular and subcellular membrane fusion are key factors in vesicular trafficking in all eukaryotic cells, including the secretion and transport of plant pathogen virulence factors. In this study, we identified vesicle-fusion components that included 22 soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), four Sec1/Munc18 (SM) family proteins, and 10 Rab GTPases encoded in the genome of the vascular wilt pathogen Verticillium dahliae Vd991. Targeted deletion of two SNARE-encoding genes in V. dahliae, VdSec22 and VdSso1, significantly reduced virulence of both mutants on cotton, relative to the wild-type Vd991 strain. Comparative analyses of the secreted protein content (exoproteome) revealed that many enzymes involved in carbohydrate hydrolysis were regulated by VdSec22 or VdSso1. Consistent with a role of these enzymes in plant cell–wall degradation, pectin, cellulose, and xylan utilization were reduced in the VdSec22 or VdSso1 mutant strains along with a loss of exoproteome cytotoxic activity on cotton leaves. Comparisons with a pathogenicity-related exoproteome revealed that several known virulence factors were not regulated by VdSec22 or VdSso1, but some of the proteins regulated by VdSec22 or VdSso1 displayed different characteristics, including the lack of a typical signal peptide, suggesting that V. dahliae employs more than one secretory route to transport proteins to extracellular sites during infection.

Two new compounds, n-13,16-nonadecadienoic acid (1) and n-4,11-nonadecadienoic acid (2), and six other compounds, 7-nonadecenoic acid (3), 12-nonadecenoic acid (4), 14-methylstigmasta-7,24(28)-dien-3-ol (5), 21α-hydroxyserrat-14-en-3β-ol (6), longifloroside (7), and 1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-propane-1,3-diol (8), were isolated from soy germ. The structures were established using data from IR and NMR spectra.

Summary Wilt caused by Verticillium dahliae significantly reduces cotton yields, as host resistance in commercially cultivated Gossypium species is lacking. Understanding the molecular bases of disease resistance in non-commercial Gossypium species could galvanize the development of Verticillium wilt resistance in the cultivated species. Nucleotide binding site-leucine-rich repeat (NBS-LRR) proteins play a central role in plant defense against pathogens. In this study, we focused on the relationship between a locus enriched with eight NBS-LRR genes and Verticillium wilt resistance in G. barbadense. Independent virus-induced gene silencing of each of eight NBS-LRR genes in G. barbadense cultivar Hai 7124 revealed that silencing GbaNA1 alone compromised the resistance of G. barbadense to V. dahliae isolate Vd991. In cultivar Hai 7124, GbaNA1 could be induced by V. dahliae isolate Vd991 and by ethylene, jasmonic acid, and salicylic acid. Nuclear protein localization of GbaNA1 was demonstrated by transient expression. Sequencing the GbaNA1 ortholog in nine G. hirsutum accessions revealed that all carried a non-functional allele, due to a premature peptide truncation. In addition, all ten G. barbadense and nine G. hirsutum tested carried a full length (∼1140 amino acid) homolog of the V. dahliae race 1 resistance gene Gbve1, though some sequence polymorphisms were observed. V. dahliae Vd991 is a non-race 1 isolate that lacks the Ave1 gene. Thus, the resistance imparted by GbaNA1 appears to be mediated by a mechanism distinct from recognition of the fungal effector Ave1. This article is protected by copyright. All rights reserved.

Three Cd(II)-based coordination polymers (CPs) with unique structures and topologies, namely, [Cd2(L)2(bimb)2(H2O)2]n (1), {[Cd(L)(bmib)0.5(H2O)](CH3OH)0.5}n (2) and [Cd(L)(beib)0.5(H2O)]n (3) (H2L = methyl-3-hydroxy-5-carboxy-2-thiophenecarboxylate, bimb = 1,4-bis(imidazol-1′-yl)butane, bmib = 1,4-bis(2-methylimidazolyl)butane and beib = 1,4-bis(2-ethylimidazolyl)butane) have been successfully constructed and characterized by single crystal X-ray structure determination, IR spectra, elemental analyses and powder X-ray diffractions. X-ray results showed compound 1 features a new 2-nodal 5,6-connected 3D network with a point symbol of {45.5.63.7}2{42.54.69}. Compound 2 exhibits a rare 6-fold interpenetrating dia 3D network. Compound 3 bears a hydrogen bonded-extended 3D supramolecular structure based upon sql layers assembled from dinuclear Cd(II) units. Thermal stability and solid photoluminescence properties of compounds 1–3 were studied. Significantly, compound 1 can sense nitrobenzene through the luminescence quenching effect.

A porous hybrid, namely PW12@TiO2-Si(Et)Si/Pba, is fabricated by the modification of PW12@TiO2-Si(Et)Si with pyridine boronic acid via a solvothermal method. The covalent interactions between the boronic acid group of the hybrid and the glycosylated site of proteins provide the as-prepared hybrid with favorable adsorption performance towards glycoproteins. The adsorption behaviors of glycoproteins onto the hybrid fit well with the Langmuir model, and the adsorption capacities for glycoprotein IgG and Trf are high, up to 348.5 mg g-1 and 262.6 mg g-1, respectively. Thus, a protocol for the depletion of high abundant glycoproteins from human plasma is proposed. The percentage contents of Trf, IgG, haptoglobinis and IgM are reduced from 7.38%, 5.5%, 3.01% and 1.02% to 0.951%, 4.7%, 0.126% and 0.76%, respectively. 85 low abundant proteins are identified from the raw plasma after the depletion of the high abundance proteins, demonstrating the potential of PW12@TiO2-Si(Et)Si/Pba hybrid in proteomic studies.

A novel organic-inorganic hybrid was prepared by anchoring (3-aminopropyl)triethoxysilane (APTES) on the surface of monolayer titanate nanosheets and subsequent modification with hydrophilic polyethylene glycol (PEG). The PEGylated hydrophilic monolayer titanate nanosheets were abbreviated as PEG-APTES-TiNSs, and they exhibit a lateral dimension of dozens of nanometers and a thickness of ca. 1.9 nm. PEGylation of the titanate nanosheets significantly improved their selectivity toward the adsorption of glycoproteins through strong hydrophilic interaction, providing an adsorption capacity of 2540.9 mg g-1 for immunoglobulin G (IgG). The retained IgG is readily collected at a recovery rate of 83.4% with 0.5% (m/v) ammonium hydroxide (NH4OH) as the stripping reagent. PEG-APTES-TiNSs are applied for the selective adsorption of IgG from human serum, which is further confirmed by SDS-PAGE assay.

Protein disulfide isomerase (PDI), a principal endoplasmic reticulum resident oxidoreductase chaperone, is known to play a role in malignancies. This study aims to explore the molecular mechanism by which PDI regulates endoplasmic reticulum stress and the apoptosis signaling pathway in colorectal cancer (CRC). We determined the expression of PDI in CRC tissues and adjacent normal tissues. Gain- and loss- of function assays were conducted to evaluate the effects of PDI on oxidative stress, endoplasmic reticulum stress, and apoptosis in CRC cells, as reflected by hydrogen peroxide (H2O2) level and the expression of related proteins. PDI protein expression was upregulated in CRC tissues. Small molecule inhibitor of PDI or PDI knockdown reduced CRC cell viability and induced apoptosis. Overexpression of wild-type PDI augmented the viability of CRC cells and inhibited endoplasmic reticulum stress response and apoptosis. Small molecule inhibitor of PDI or PDI knockdown increased intracellular H2O2 level and activated apoptosis signaling pathway, which could be reversed by wild-type PDI restoration. Moreover, the catalytic active site of C-terminal of PDI was found to be indispensable for the regulatory effects of PDI on H2O2 levels, apoptosis and cell viability in CRC cells. Collectively, PDI inhibits endoplasmic reticulum stress and apoptosis of CRC cells through its oxidoreductase activity, thereby promoting the malignancy of CRC.

Two new Sulfur-containing Cadmium(II) coordination polymers {[Cd(HL)2](2H2O)}n (1) and {[Cd(L)(bmie)(H2O)](H2O)}n (2) (H2L = methyl-3-hydroxy-5-carboxy-2-thiophenecarboxylate, and bmie = 1,2-bis(imidazol-1′-yl)ethane) have been successfully constructed and structurally characterized by the single-crystal X-ray diffraction and other characterization techniques, such as elemental analysis, IR spectroscopy and thermogravimetric analysis. Structural analyses reveal that complex 1 exhibits a hydrogen bonded-extended 3D supramolecular structure based upon 4-connected sql layers assembled from single Cd(II) centers as nodes. Complex 2 features a 3D network which can be rationalized as a rare 4-connected cdl topology. It is shown that the H2L ligand is a suitable building block in constructing coordination polymers with structural diversities. Moreover, solid photoluminescent properties have been investigated.

Summary Verticillium dahliae isolates are most virulent on the host from which they were originally isolated. Mechanisms underlying these dominant host adaptations are currently unknown. We sequenced the genome of V. dahliae Vd991, which is highly virulent on its original host, cotton, and performed comparisons with the reference genomes of JR2 (from tomato) and VdLs.17 (from lettuce). Pathogenicity-related factor prediction, orthology and multigene family classification, transcriptome analyses, phylogenetic analyses, and pathogenicity experiments were performed. The Vd991 genome harbored several exclusive, lineage-specific (LS) genes within LS regions (LSRs). Deletion mutants of the seven genes within one LSR (G-LSR2) in Vd991 were less virulent only on cotton. Integration of G-LSR2 genes individually into JR2 and VdLs.17 resulted in significantly enhanced virulence on cotton but did not affect virulence on tomato or lettuce. Transcription levels of the seven LS genes in Vd991 were higher during the early stages of cotton infection, as compared with other hosts. Phylogenetic analyses suggested that G-LSR2 was acquired from Fusarium oxysporum f. sp. vasinfectum through horizontal gene transfer. Our results provide evidence that horizontal gene transfer from Fusarium to Vd991 contributed significantly to its adaptation to cotton and may represent a significant mechanism in the evolution of an asexual plant pathogen.

Objective— Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)–induced senescence of vascular smooth muscle cells (VSMCs). Approach and Results— We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment. Overexpression of SM22α promoted Ang II–induced VSMC senescence, whereas knockdown of SM22α suppressed this process. Moreover, this effect of SM22α was p53 dependent. Increased SM22α protein obstructed ubiquitination and degradation of p53 and subsequently improved its stability. Furthermore, SM22α inhibited phosphorylation of Mdm2 (mouse double minute 2 homolog), an E3 ubiquitin-protein ligase, accompanied by a decreased interaction between Mdm2 and p53. Using LY294002, a PI3K/Akt inhibitor, we found that PI3K/Akt-mediated Mdm2 phosphorylation and activation was inhibited in senescent or SM22α-overexpressed VSMCs, in parallel with decreased p53 ubiquitination. We further found that SM22α inhibited activation of PI3K/Akt/Mdm2 pathway via strengthening actin cytoskeleton. In the in vivo study, we showed that the disruption of SM22α reduced the increase of blood pressure induced by Ang II, associated with decreased VSMC senescence through a mechanism similar to that in VSMCs in vitro. Conclusions— In conclusion, these findings suggest that the accumulation of SM22α promotes Ang II–induced senescence via the suppression of Mdm2-mediated ubiquitination and degradation of p53 in VSMCs in vitro and in vivo.

As organ-specific three-dimensional cell clusters derived from cancer tissue or cancer-specific stem cells, cancer-derived organoids are organized in the same manner of the cell sorting and spatial lineage restriction in vivo, making them ideal for simulating the characteristics of cancer and the heterogeneity of cancer cells in vivo. Besides the applications as a new in vitro model to study the physiological characteristics of normal tissues and organs, organoids are also used for in vivo cancer cell characterization, anti-cancer drug screening, and precision medicine. However, organoid cultures are not without limitations, i.e., the lack of nerves, blood vessels, and immune cells. As a result, organoids could not fully replicate the characteristics of organs but partially simulate the disease process. This review attempts to provide insights into the organoid models for cancer precision medicine., Graphical abstract Image, graphical abstract

The rational design of electrochemical methods for chiral recognition is a focus of research in the detection fields of biomolecules and pharmaceuticals. In this work, electrochemical chiral interface based on chitosan (CS) and deoxyribonucleic acid (DNA) was constructed with self-assembly technology, and then characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), cyclic voltammetry, and electrochemical impedance spectroscopy. The FT-IR and SEM results showed the spatial structure of DNA and CS changed significantly and formed superhelix structure during the self-assembly process. Differential pulse voltammetry (DPV) results showed that the oxidation peak current ratio of D-Trp to L-Trp (ID/IL) was observed to be 4.02 at 25 °C due to the synergistic effects of CS and DNA, obviously higher than that on any individual CS or DNA modified electrode. In addition, there was a linear relationship between the peak current and Trp enantiomer concentration in the range of 0.005–0.15 mM, and the detection limits of D-Trp and L-Trp were 1.33 and 1.67 µM, respectively. More importantly, the chiral interface can also be used to identify the percentage of D-Trp in non-racemic Trp enantiomers mixture solutions, showing its effectiveness and promising potential in practical applications.

Spermiogenesis is a highly ordered and complex process in the male germ cell differentiation. The microtubule-based motor proteins KIF3A and KIF3B are required for the progression of the stages of spermiogenesis. In this study, the main goal was to determine whether KIF3A and KIF3B have a key role in spermiogenesis in Palaemon carincauda. The complete cDNA of KIF3A/3B from the testis of P. carincauda was cloned by using PCR and rapid amplification of cDNA ends (RACE). The predicted secondary and tertiary structures of KIF3A/3B contained three domains which were the: a) head region, b) stalk region, and c) tail region. Real-time quantitative PCR (qPCR) results revealed that KIF3A and KIF3B mRNAs were obtained for all the tissues examined, with the greatest gene expression in the testis. In situ hybridization indicated the KIF3A and KIF3B mRNAs were distributed in the periphery of the nuclear in the early spermatid of spermiogenesis. In the middle and late spermatid stages, KIF3A and KIF3B mRNAs were gradually upregulated and assembled to one side where acrosome biogenesis begins. In the mature sperm, KIF3A and KIF3B mRNAs were distributed in the acrosome cap and spike. Immunofluorescence studies indicated that KIF3A, tubulin, mitochondria, and Golgi were co-localized in different stages during spermiogenesis in P. carincauda. The temporal and spatial gene expression dynamics of KIF3A/3B indicate that KIF3A and KIF3B proteins may be involved in acrosome formation and nucleus shaping. Moreover, these proteins can transport the mitochondria and Golgi that facilitate acrosome formation in P. carincauda.

Fungal transcription factors (TFs) implicated in the regulation of virulence gene expression have been identified in a number of plant pathogens. In Verticillium dahliae, despite its agricultural importance, few regulators of transcription have been characterized. In this study, a T-DNA insertion mutant with significantly reduced virulence towards cotton was identified. The T-DNA was traced to VdFTF1, a gene encoding a TF containing a Fungal_trans domain. Transient expression in onion epidermal cells indicated that VdFTF1 is localized to the nucleus. The VdFTF1-deletion strains displayed normal vegetative growth, mycelial pigmentation and conidial morphology, but exhibited significantly reduced virulence on cotton, suggesting that VdFTF1 is required exclusively for pathogenesis. Comparisons of global transcription patterns of wild-type and VdFTF1-deletion strains indicated that VdFTF1 affected the expression of 802 genes, 233 of which were associated with catalytic processes. These genes encoded 69 potentially secreted proteins, 43 of which contained a carbohydrate enzyme domain known to participate in pathogenesis during infection of cotton. Targeted gene deletion of one VdFTF1-regulated gene resulted in significantly impaired vascular colonization, as measured by quantitative polymerase chain reaction, as well as aggressiveness and symptom severity in cotton. In conclusion, VdFTF1, which encodes a TF containing a Fungal_trans domain, regulates the gene expression of plant cell wall degradation enzymes in V. dahliae, which are required for full virulence on cotton.

A Gram-stain-negative, rod-shaped, strictly aerobic, motile bacterial strain, designated YM319T, was isolated from a seamount near the Yap Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YM319T was related to the genus Oceanisphaera and had highest 16S rRNA gene sequence similarities with the type strains Oceanisphaera profunda SM1222T (97.4 %), Oceanisphaera sediminis TW92T (97.3 %) and Oceanisphaera ostreae T-w6T (97.1 %). The predominant cellular fatty acids were summed feature 3 (composed of iso-C15 : 0 2-OH and/or C16 : 1 ω7c), C16 : 0 and C18 : 1ω7c. Strain YM319T had Q-8 as the predominant ubiquinone. The polar lipid profile contained diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid and four unidentified lipids. The genomic DNA G+C content of strain YM319T was 54.8 mol%. On the basis of the evidence presented in this study, strain YM319T represents a novel species of the genus Oceanisphaera , for which we propose the name Oceanisphaera marina sp. nov. (type strain YM319T=KACC 18564T=CGMCC 1.15923T).

Photodynamic therapy (PDT) represents a modern and noninvasive therapeutic approach, however, it relies on the development of photosensitizers. Here five new benzo[c,d]indole rhodamine complex merocyanines (BIRCM) D1-D5, displaying low dark toxicity and significant photo toxicity, were synthesized as PDT photosensitizers, and characterized by 1H NMR, IR, UV–Vis and HRMS. The investigation of their absorption spectra in different solvents showed that the absorption maxima and molar extinction coefficient were in the region 507–679 nm and 0.21 × 104–1.27 × 105 L · mol−1cm−1, respectively. The evaluation of PDT activity showed that only irradiation could not kill SMMC-7721 cells, and the cell survival rate and inhibition rate at the application dose and duration was 92%–87% and 78%–49%, respectively. Especially, using D2, absorbed in the red zone, as photosensitizer for PDT analyzed its effect on SMMC-7721 cells survival, it could be found that the cell survival rate was 92% without irradiating and the cell inhibited rate was 78% under irradiating at concentrations of 2.5 × 10−6 mol/L, displaying low dark toxicity and high photo toxicity, which was valuable for PDT of some microvascular diseases or other superficial diseases.

Spermatogenesis is a highly ordered process in the differentiation of male germ cells. Nuclear morphogenesis is one of the most fundamental cellular transformations to take place during spermatogenesis. These striking transformations from spermatogonia to spermatozoa are a result of phase-specific adaption of the cytoskeleton and its association with molecular motor proteins. KIFC1 is a C-terminal kinesin motor protein that plays an essential role in acrosome formation and nuclear reshaping during spermiogenesis in mammals. To explore its functions during the same process in Larimichthys crocea, we cloned and characterized the cDNA of a mammalian KIFC1 homolog (termed lc-KIFC1) from the total RNA of the testis. The 2481 bp complete lc-KIFC1 cDNA contained a 53 bp 5' untranslated region, a 535 bp 3' untranslated region, and a 1893 bp open reading frame that encoded a special protein of 630 amino acids. The predicted lc-KIFC1 protein possesses a divergent tail region, stalk region, and conserved carboxyl motor region. Protein alignment demonstrated that lc-KIFC1 had 73.2, 49.8, 49.3, 54.6, 56.5, 53.1, and 52.1% identity with its homologs in Danio rerio, Eriocheir sinensis, Octopus tankahkeei, Gallus gallus, Xenopus laevis, Mus musculus, and Homo sapiens, respectively. Tissue expression analysis revealed that lc-kifc1 mRNA was mainly expressed in the testis. The trend of lc-kifc1 mRNA expression at different growth stages of the testis showed that the expression increased first and then decreased, in the stage IV of testis, its expression quantity achieved the highest level. In situ hybridization and immunofluorescence results showed that KIFC1 was localized around the nucleus in early spermatids. As spermatid development progressed, the signals increased substantially. These signals peaked and were concentrated at one end of the nucleus when the spermatids began to undergo dramatic changes. In the mature sperm, the signal for KIFC1 gradually became weak and was mainly localized in the tail. In summary, evaluation of the expression pattern for lc-KIFC1 at specific stages of spermiogenesis has shed light on the potential functions of this motor protein in major cytological transformations. In addition, this study may provide a model for researching the molecular mechanisms involved in spermatogenesis in other teleost species, which will lead to a better understanding of the teleost fertilization process.

The global minimum structures of the carbon-doped Ben (n = 1-12) clusters are obtained at the B3PW91/6-311+G(d) level and compared with those of pure beryllium clusters. It is found that the carbon dopant prefers to locate on the periphery of the host Ben cluster and tends to be tetra-coordinated. The evolution of electronic and energetic properties of BenC with cluster size is studied using the QCISD(T) method. Results show that the introduction of carbon-doping in beryllium clusters strengthens intracluster interaction. Besides, Be3C and Be8C exhibit particular stability and are considered as magic number clusters in the BenC series. Molecular orbital (MO) analysis indicates that both clusters have fully-filled electron shells, whereas the contribution of carbon atomic orbital leads to MO energy level disorder relative to pure beryllium clusters.

Aims Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation. Methods and results The ligation injury model of Sirt1-Tg/Sm22α-/- mice displayed an increased level of the inflammatory molecules in the carotid arteries compared with Sirt1-Tg mice, accompanied with aggravating neointimal hyperplasia. In the in vitro study, on the one hand, we showed that TNF-α induced the epigenetic silencing of SM22α transcription via EZH2-mediated H3K27 methylation in the SM22α promoter region, contributing to inflammatory response. On the other hand, TNF-α simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22α transcription by inhibiting EZH2 activity. Increased SM22α in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1. Conclusion Our findings demonstrate that, in response to TNF-α stimulation, CKII-SIRT1-SM22α acts in a loop to reinforce the expression of SM22α, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22α to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.

Glycoside hydrolase 12 (GH12) proteins act as virulence factors and pathogen-associated molecular patterns (PAMPs) in oomycetes. However, the pathogenic mechanisms of fungal GH12 proteins have not been characterized. In this study, we demonstrated that two of the six GH12 proteins produced by the fungus Verticillium dahliae Vd991, VdEG1 and VdEG3 acted as PAMPs to trigger cell death and PAMP-triggered immunity (PTI) independent of their enzymatic activity in Nicotiana benthamiana. A 63-amino-acid peptide of VdEG3 was sufficient for cell death-inducing activity, but this was not the case for the corresponding peptide of VdEG1. Further study indicated that VdEG1 and VdEG3 trigger PTI in different ways: BAK1 is required for VdEG1- and VdEG3-triggered immunity, while SOBIR1 is specifically required for VdEG1-triggered immunity in N. benthamiana. Unlike oomycetes, which employ RXLR effectors to suppress host immunity, a carbohydrate-binding module family 1 (CBM1) protein domain suppressed GH12 protein-induced cell death. Furthermore, during infection of N. benthamiana and cotton, VdEG1 and VdEG3 acted as PAMPs and virulence factors, respectively indicative of host-dependent molecular functions. These results suggest that VdEG1 and VdEG3 associate differently with BAK1 and SOBIR1 receptor-like kinases to trigger immunity in N. benthamiana, and together with CBM1-containing proteins manipulate plant immunity.

Flexible quantum dot light emitting diodes (QLEDs) are highly desired due to their advantages of foldability, lightweight, and potential applications in lighting and displays. In this report, we successfully fabricated high performance red (R), green (G), and blue (B) three primary color QLEDs based on a poly(ethylene-terephthalate)/ITO/Ag/ITO (PET–IAI) cathode. The multilayer flexible IAI electrode shows outstanding stability even after bending over 2000 times with a critical bending radius of 5 mm; the sheet resistance of the IAI film only increases from 12.7 to 14.8 Ω □−1. The maximum current efficiencies are 16.3, 86.5, and 16.1 cd A−1 for RGB QLEDs, respectively, which is the best device performance for flexible RGB QLEDs reported to date. Moreover, to the best of our knowledge, these are also record efficiencies for the green and blue devices in all the reported QLEDs. Furthermore, all the devices show saturated electroluminescence (EL) with the corresponding emission peaks at 606, 530, and 478 nm for three primary color QLEDs. The superior performance is a result of high transmittance and stability of the PET–IAI film. These results signify remarkable progress in flexible QLEDs and suggest that the PET–IAI based flexible QLEDs can offer a practicable platform for foldable applications.

In spite of their widespread use as catalysts, 1,2,3,4,5-pentamethylcyclopentadienyl (Cp*) iridium complexes have been rarely employed in the synthesis of pyridine derivatives. Herein, we used density functional theory (DFT) calculations to predict the [Cp*Ir(OAc)]+-catalysed synthesis of 2,3-dihydropyridines, which are important starting materials for pharmaceuticals, from α,β-unsaturated oxime pivalates and alkenes. The corresponding Cp*Rh complex-catalysed processes were discussed in comparison. The simulated catalytic cycle consists of several elementary reactions, such as reversible acetate-assisted metalation–deprotonation, migratory insertion of the alkene, pivaloyl transfer, and reductive elimination. The migratory insertion of the alkene is identified as the rate-determining step, and the reductive elimination to furnish the product-ligated species makes the reaction irreversible (exergonic by about 48 kcal mol−1). The stabilities of the intermediates and the energy barrier of migratory insertion of the alkene can be affected by introducing substituent groups with different electronic characteristics into Cp* and the 2-position of α,β-unsaturated oxime pivalates, as well as by using polarised alkenes. The apparent activation energy of the reaction can be increased by increasing the electron-donating ability of the substituent group on Cp*, and by introducing electron-withdrawing groups into the terminus of alkenes. When a strong electron-donating group such as the amido group is introduced into the 2-position of α,β-unsaturated oxime pivalates, the apparent activation energy is greatly reduced so that the reaction can occur at room temperature. In contrast, changing phenyl into the highly electron-deficient p-CF3-phenyl makes the reaction more difficult. Diastereoselectivity of the reaction was examined using cyclohexylethylene as a substrate, and a method for enhancing diastereocontrol was suggested.

We report a ruthenium complex containing an N,N′-diimine ligand for the selective decomposition of formic acid to H2 and CO2 in water in the absence of any organic additives. A turnover frequency of 12 000 h–1 and a turnover number of 350 000 at 90 °C were achieved in the HCOOH/HCOONa aqueous solution. Efficient production of high-pressure H2 and CO2 (24.0 MPa (3480 psi)) was achieved through the decomposition of formic acid with no formation of CO. Mechanistic studies by NMR and DFT calculations indicate that there may be two competitive pathways for the key hydride transfer rate-determining step in the catalytic process.

A novel strategy for the preparation of magnetic nanospheres encapsulated by mesoporous copper oxide shell, shortly termed as Fe3O4@mCuO, is reported via the calcination of Cu(NH3)4(NO3)2 into continuous mesoporous CuO shell onto the surface of Fe3O4 nanoparticles. The magnetic nanospheres are characterized to possess stable core–shell structure with a crystalline mesoporous CuO layer, exhibiting a CuO loading content of 25.2 ± 1.1% along with a favorable magnetic susceptibility. Fe3O4@mCuO nanospheres exhibit favorable selectivity on the adsorption of hemoglobin with a high adsorption capacity of up to 1162.5 mg g–1. After adsorption, the high magnetic susceptibility allows convenient separation of the nanospheres by an external magnet. The retained hemoglobin could be readily recovered by using 0.5% (m/v) sodium dodecyl sulfate (SDS) as stripping reagent, providing a recovery of 78%. Circular dichroism spectra illustrate virtually no change in the conformation of hemoglobin after the process of adsorpti...

An alternative strategy, adopting the magnetic composite nanoparticles in the hole injection layer, is proposed in this Letter to obtain efficient organic light-emitting devices (OLEDs) by simultaneously integrating the localized surface plasmon (LSP), light-scattering, and magnetic field effects (MFE). A 90% increase in the current efficiency of Alq3-based fluorescent OLEDs is obtained by using the Fe3O4@Au nanoparticles (FOA NPs), compared with the device without NPs, arising from the LSP effect induced by Au NPs and the strong light-scattering effect related to FOA NPs. Meanwhile, the current efficiency can be further increased by ∼20% under an external magnetic field (EMF) of 0.5 T due to the increased singlet exciton induced by the spin injected holes via FOA NPs. Moreover, with an EMF, the current efficiency of Ir(ppy)2(acac)-based OLEDs is decreased slightly, implying that the emitting material system and mechanism have a great effect on the MFE. These results confirm the extensive use of FOA NPs in OLEDs and pave a new way to construct the FOA-NPs-based white OLEDs with both fluorescence and phosphorescence emitters, whose intensity and color can be modulated.

BACKGROUND: The basolateral potassium channel in the distal convoluted tubule (DCT), comprising the inwardly rectifying potassium channel Kir4.1/Kir5.1 heterotetramer, plays a key role in mediating the effect of dietary potassium intake on the thiazide-sensitive NaCl cotransporter (NCC). The role of Kir5.1 (encoded by Kcnj16) in mediating effects of dietary potassium intake on the NCC and renal potassium excretion is unknown. METHODS: We used electrophysiology, renal clearance, and immunoblotting to study Kir4.1 in the DCT and NCC in Kir5.1 knockout (Kcnj16(−/−)) and wild-type (Kcnj16(+/+)) mice fed with normal, high, or low potassium diets. RESULTS: We detected a 40-pS and 20-pS potassium channel in the basolateral membrane of the DCT in wild-type and knockout mice, respectively. Compared with wild-type, Kcnj16(−/−) mice fed a normal potassium diet had higher basolateral potassium conductance, a more negative DCT membrane potential, higher expression of phosphorylated NCC (pNCC) and total NCC (tNCC), and augmented thiazide-induced natriuresis. Neither high- nor low-potassium diets affected the basolateral DCT’s potassium conductance and membrane potential in Kcnj16(−/−) mice. Although high potassium reduced and low potassium increased the expression of pNCC and tNCC in wild-type mice, these effects were absent in Kcnj16(−/−) mice. High potassium intake inhibited and low intake augmented thiazide-induced natriuresis in wild-type but not in Kcnj16(−/−) mice. Compared with wild-type, Kcnj16(−/−) mice with normal potassium intake had slightly lower plasma potassium but were more hyperkalemic with prolonged high potassium intake and more hypokalemic during potassium restriction. CONCLUSIONS: Kir5.1 is essential for dietary potassium’s effect on NCC and for maintaining potassium homeostasis.

We have constructed a new approach to realize the light extraction enhancement in organic light-emitting diodes (OLEDs) by using Fe3O4@Au nanoparticles (FOA NPs). The current efficiency of 97.8 cd/A at a luminance of 500 cd/m2 can be obtained for the FOA-NP-based device, while it is only 61 cd/A for the control device without FOA NPs, corresponding a 60% enhancement in efficiency. The time-resolved photoluminescence and optical haze characterizations were performed to study the influence of FOA NPs on the lifetime of excitons and the light-scattering effect, respectively. These results reveal that the enhanced radical efficiency of an FOA-NP-based device is mainly ascribed to the localized surface plasmonic effects induced by Au NPs and the strong light-scattering effect related to FOA NPs, thereby achieving a double enhancement in light extraction, which paves a new way in realizing high-efficiency and controllable OLEDs.

High-responsivity phototransis-tors with a structure of perov-skite-WS2 nanosheet composite optical absorber and a reduced graphene oxide (rGO) channel layer is demonstrated via a facile and low-cost solution-processing method. The WS2 nanosheets are dispersed within the perovskite matrix, forming the perovskite-WS2 bulk heterojunction (BHJ). The hybrid phototransistor exhib-its excellent figures of merit in-cluding high photoresponsivity of 678.8 A/W, high specific de-tectivity of 4.99×1011 Jones, high EQE value of 2.04×105 % and rapid response to photoswitching. The high photoresponsivity could be attributed to the WS2 nanosheets induced photo-generated electron-hole separa-tion promotion effects due to the selective electron trapping effects in the WS2 nanosheets, as well as the high carrier mobility of the rGO channel layer. This work provides a promising platform for constructing high-responsivity photodetectors.

Verticillium dahliae is a broad host-range pathogen that causes vascular wilts in plants. Interactions between three hosts and specific V.dahliae genotypes result in severe defoliation. The underlying mechanisms of defoliation are unresolved. Genome resequencing, gene deletion and complementation, gene expression analysis, sequence divergence, defoliating phenotype identification, virulence analysis, and quantification of V.dahliae secondary metabolites were performed. Population genomics previously revealed that G-LSR2 was horizontally transferred from the fungus Fusarium oxysporum f. sp. vasinfectum to V.dahliae and is exclusively found in the genomes of defoliating (D) strains. Deletion of seven genes within G-LSR2, designated as VdDf genes, produced the nondefoliation phenotype on cotton, olive, and okra but complementation of two genes restored the defoliation phenotype. Genes VdDf5 and VdDf6 associated with defoliation shared homology with polyketide synthases involved in secondary metabolism, whereas VdDf7 shared homology with proteins involved in the biosynthesis of N-lauroylethanolamine (N-acylethanolamine (NAE) 12:0), a compound that induces defoliation. NAE overbiosynthesis by D strains also appears to disrupt NAE metabolism in cotton by inducing overexpression of fatty acid amide hydrolase. The VdDfs modulate the synthesis and overproduction of secondary metabolites, such as NAE 12:0, that cause defoliation either by altering abscisic acid sensitivity, hormone disruption, or sensitivity to the pathogen.

Chemical signaling is ubiquitous and employs a variety of receptor types to detect the cacophony of molecules relevant for each living organism. Insects, our most diverse taxon, have evolved unique olfactory receptors with as little as 10% sequence identity between receptor types. We have identified a promiscuous volatile, 2-methyltetrahydro-3-furanone (coffee furanone), that elicits chemosensory and behavioral activity across multiple insect orders and receptors. In vivo and in vitro physiology showed that coffee furanone was detected by roughly 80% of the recorded neurons expressing the insect-specific olfactory receptor complex in the antenna of Drosophila melanogaster, at concentrations similar to other known, and less promiscuous, ligands. Neurons expressing specialized receptors, other chemoreceptor types, or mutants lacking the complex entirely did not respond to this compound. This indicates that coffee furanone is a promiscuous ligand for the insect olfactory receptor complex itself and did not induce non-specific cellular responses. In addition, we present homology modeling and docking studies with selected olfactory receptors that suggest conserved interaction regions for both coffee furanone and known ligands. Apart from its physiological activity, this known food additive elicits a behavioral response for several insects, including mosquitoes, flies, and cockroaches. A broad-scale behaviorally active molecule non-toxic to humans thus has significant implications for health and agriculture. Coffee furanone serves as a unique tool to unlock molecular, physiological, and behavioral relationships across this diverse receptor family and animal taxa.

High-responsivity phototransistors with a structure of perovskite-WS2 nanosheet composite optical absorber and a reduced graphene oxide (rGO) channel layer is demonstrated via a facile and low-cost solution-processing method. The WS2 nanosheets are dispersed within the perovskite matrix, forming the perovskite-WS2 bulk heterojunction (BHJ). The hybrid phototransistor exhibits excellent figures of merit including high photoresponsivity of 678.8 A/W, high specific detectivity of 4.99 × 1011 Jones, high EQE value of 2.04 × 105% and rapid response to photoswitching. The high photoresponsivity could be attributed to the WS2 nanosheets induced photo-generated electron-hole separation promotion effects due to the selective electron trapping effects in the WS2 nanosheets, together with the high carrier mobility of the rGO channel. This work provides a promising platform for constructing high-responsivity photodetectors.

Objective To observe the effect of Qili Qiangxin Capsule (QQC) in improving lung struc- tural remodeling on heart failure (HF) rats after myocardial infarction (Ml) and to study its possible mecha- nism. Methods The proximal left anterior descending branch of coronary artery was ligated using a terylene suture to establish acute myocardial infarction (AMI) rat model. After successful AMI modeling rats were ran- domly divided into the model group (intragastrically administered with distilled water at 1 mL/100 g, n =13) and the QQC group (intragastrically administered with QQC at the daily dose of 1 g/kg, n =9). And the sham-opera- tion group (intragastrically administered with distilled water at 1 mL/100 g, n =10) was also set up. After four weeks intervention heart functions of rats were detected using echocardiography. The pathological changes of lung structures were observed by HE and Masson staining method. Protein expressions of lung α-SMA, Collagen I, TGF-β₁, and p-Smad3 of the lung tissue were detected by immunohistochemistry and Western blot. Re- sults Compared with the sham-operation group, ejection fraction (EF) and fraction shortening (FS) decreased (P0. 05) , protein expressions of lung left ventricular internal diastolic diameter (LVIDd), left ventric- ular internal systolic diameter (LVIDs), end diastolic volume (EDV), end systolic volume (ESV), α-smooth muscle actin (a-SMA), Collagen I, tumor growth factor-β₁ (TGF-β₁), and p-Smad3 increased (P0.05) in the model group. The muscularized small arteries ratio and collagen area of the lung tissue increased in the model group (P0. 05). Compared with the model group, EF and FS increased (P0. 05), protein expressions of LVIDs, ESV, α-SMA, Collagen I, TGF-β, , and p-Smad3 decreased (P0.05) in the QQC group. The muscular- ized small arteries ratio and collagen area of the lung tissue decreased in the QQC group (P0. 05). Conclusion QQC could improve lung structural remodeling degree of HF rats after MI, and its possible mechanism might be achieved by regulating TGF-beta,/Smad3 signaling pathways.

Aging as one of intrinsic biological processes is a risk factor for many chronic diseases. Kidney disease is a global problem and health care burden worldwide. The diagnosis of kidney disease is currently based on serum creatinine and urea levels. Novel biomarkers may improve diagnostic accuracy, thereby allowing early prevention and treatment. Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and could bind DNA, RNA and protein. Emerging evidence has demonstrated that lncRNAs played an important role in all stages of kidney disease. To date, only some lncRNAs were well identified and characterized, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains undefined. In this review, we summarized the lncRNA expression profiling of large-scale identified lncRNAs on kidney diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy and kidney transplantation. We further discussed a number of annotated lncRNAs linking with complex etiology of kidney diseases. Finally, several lncRNAs were highlighted as diagnostic biomarkers and therapeutic targets. Targeting lncRNAs may represent a precise therapeutic strategy for progressive renal fibrosis.

Infectious diseases are amongst the leading causes of morbidity and mortality. The Sophora flavescens root (traditional Chinese medicine “kushen”) is recognized as a strong anti-bacterial and anti-inflammatory Chinese herb, and widely used for clinical application. However, the ever-increasing demand for natural antibacterial agent is fostering the insufficient supply of “kushen”. This study was conducted for the first time to explore the feasibility of Sophora flavescens seed used as a supplement of Sophora flavescens root to alleviate the shortage of “kushen” resources. To accomplish this, the seed and root of Sophora flavescens were extracted by ultrasound-assisted extraction method. The antimicrobial activities of Sophora flavescens seed and root against Escherichia coli, Bacillus subtilis, Micrococcus tetragenus and Proteus species were compared by agar well diffusion method. And the phytochemical constituents from seed and root were analyzed by TLC, chromogenic reaction method, HPLC and GC/MS. The results revealed that different solvent fraction from Sophora flavescens root and seed exhibited different degrees of antibacterial activity. The chloroform fraction, ethyl acetate fraction and anhydrous ethanol fraction of Sophora flavescens root had obvious antibacterial activity. However, the best antibacterial activity of Sophora flavescens seed was achieved with the 80% ethanol extracts. Furthermore, the analysis of phytochemical compositions showed that the antibacterial-activity component profiles of Sophora flavescens seed were different from that of roots. This study clearly reveal that Sophora flavescens seed is unsuitable as a straight substitution of “kushen” due to the differences in their active component, but it has the potential to be used as a promising source of antibacterial agent, which could be utilized in clinical application and pharmaceutical industry, just as Sophora flavescens root.

Fibrosis is the excessive deposition of extracellular matrix components, which results in disruption of tissue architecture and loss of organ function. Fibrosis leads to high morbidity and mortality worldwide, mainly due to the lack of effective therapeutic strategies against fibrosis. It is generally accepted that fibrosis occurs during an aberrant wound healing process and shares a common pathogenesis across different organs such as the heart, liver, kidney, and lung. A better understanding of the fibrosis-related cellular and molecular mechanisms will be helpful for development of targeted drug therapies. Extensive studies revealed that numerous mediators contributed to fibrogenesis, suggesting that targeting these mediators may be an effective therapeutic strategy for antifibrosis. In this review, we describe a number of mediators involved in tissue fibrosis, including aryl hydrocarbon receptor, Yes-associated protein, cannabinoid receptors, angiopoietin-like protein 2, high mobility group box 1, angiotensin-converting enzyme 2, sphingosine 1-phosphate receptor-1, SH2 domain-containing phosphatase-2, and long non-coding RNAs, with the goal that drugs targeting these important mediators might exhibit a beneficial effect on antifibrosis. In addition, these mediators show profibrotic effects on multiple tissues, suggesting that targeting these mediators will exert antifibrotic effects on different organs. Furthermore, we present a variety of compounds that exhibit therapeutic effects against fibrosis. This review suggests therapeutic avenues for targeting organ fibrosis and concurrently identifies challenges and opportunities for designing new therapeutic strategies against fibrosis.

Metal organic frameworks (MOFs)-based catalysts are rising stars in advanced oxidation processes (AOPs) to generate reactive oxygen species (ROS). Nevertheless, constructing an affordable and recyclable MOFs-derived catalyst with high reactivity and stability is highly desirable but still challenging. Herein, we unprecedentedly designed a novel CoAl2O4@γ-Al2O3 pellet (CoAl2O4@AP) as a heterogeneous catalyst to activate peroxymonosulfate (PMS) toward ROS generation for metronidazole (MNZ) removal. A CoAl2O4 shell was formed on the pellet surface by direct calcination of the surface-nucleated ZIF-67 on γ-Al2O3 pellets. The strong and unique interactions between the Co species of ZIF-67 and γ-Al2O3 resulted in the formation of interfacial CoAl2O4. The CoAl2O4@AP exhibited a remarkably higher efficacy for PMS activation than ZIF-67-derived Co3O4 and commercial Co3O4. The effects of several reaction parameters (i.e., PMS dosage, reaction temperature, initial pH, and background inorganic ions) on MNZ removal were comprehensively investigated and the degradation pathways of MNZ were elucidated. The Co2+/Co3+ and oxygen vacancies of CoAl2O4@AP were the intrinsic active centers for PMS activation to simultaneously generate a diversity of ROS, among which SO4 − and 1O2 played the decisive roles in MNZ decomposition. After the reaction, CoAl2O4@AP can be easily separated from the bulk solution and regenerated via a PMS-assisted cleaning process, making the composites highly appealing for practical applications. This pioneering work on constructing microscopic CoAl2O4-based composites expands the application of MOFs-based catalysts in novel AOPs systems for the treatment of persistent emerging pollutants.

Development of novel nano-drug delivery systems (NDDS) that can transport anticancer drugs into cell nuclei is still a highly desirable strategy for reversing multi-drug resistance (MDR) in cancer therapy. Herein, we designed and prepared a novel NDDS, designated S@L NPs, in which several smaller nanoparticles are contained within a larger nanoparticle. Our S@L NPs (CS/PAA/VP-16@TPGS/PLGA NPs) possess a structure in which smaller nanoparticles (Chitosan-Poly(acrylic acid) nanoparticles, CS/PAA NPs) containing the drug etoposide (VP-16) are loaded within a larger nanoparticle (Vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate-modified poly(lactic-co-glycolic acid) nanoparticles, TPGS/PLGA NPs). The system utilizes intracellular pH gradients to achieve pH-sensitive sequential release within different intracellular domains of MDR cells. S@L NPs could be triggered to degrade and release CS/PAA/VP-16 NPs in the acid environment of the cytosol, endosomes or lysosomes, and CS/PAA/VP-16 NPs were capable of entering the nucleus through nucleopores. It is significant that CS/PAA/VP-16 NPs exhibit disaggregation in the alkaline environment of the nucleus and thereby release the contained anticancer drug. Further mechanistic studies showed that CS/PAA/VP-16 NPs escaped retention and degradation within lysosomes and protected the drug from P-glycoprotein-induced efflux. Simultaneously, S@L NPs enhanced the anticancer effect of the loaded drug by inducing autophagy and apoptosis of MDR cells. This novel NDDS may provide a promising platform for nuclear drug delivery for reversing MDR.