Ferritin Heavy-like subunit is involved in the innate immune defense of the red swamp crayfish Procambarus clarkii.

Iron-binding proteins, known as ferritins, play pivotal roles in immunological response, detoxification, and iron storage. Despite their significance to organisms, little is known about how they affect the immunological system of the red swamp crayfish (Procambarus clarkii). In our previous research, one ferritin subunit was completely discovered as an H-like subunit (PcFeH) from P. clarkii. The full-length cDNA of PcFerH is 1779 bp, including a 5'-UTR (untranslated region, UTR) of 89 bp, 3'-UTR (untranslated region, UTR) of 1180 bp and an ORF (open reading frame, ORF) of 510 bp encoding a polypeptide of 169 amino acids that contains a signal peptide and a Ferritin domain. The deduced PcFerH protein sequence has highly identity with other crayfish. PcFerH protein's estimated tertiary structure is quite comparable to animal structure. The PcFerH is close to Cherax quadricarinatus, according to phylogenetic analysis. All the organs examined showed widespread expression of PcFerH mRNA, with the ovary exhibiting the highest levels of expression. Additionally, in crayfish muscles, intestines, and gills, the mRNA transcript of PcFerH was noticeably up-regulated, after LPS and Poly I:C challenge. The expression of downstream genes in the immunological signaling system was suppressed when the PcFerH gene was knocked down. All of these findings suggested that PcFerH played a vital role in regulating the expression of downstream effectors in the immunological signaling pathway of crayfish.

Complete mitochondrial genome of Parasa sinica: New insights into the phylogeny of Limacodidae.

In this study, the whole mitochondrial genome (mitogenome) of Parasa sinica was sequenced. It contains 15,306 base pairs (bp), 13 protein-coding genes (PCGs), two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs), and one non-coding regulatory area (CR), all of which are shared by other lepidopterans. It follows the same gene order as ordinary lepidopterans. Further, out of these 37 genes, 23 are present on the heavy strand whereas the remaining 14 are located on the light strand. The A + T composition of the mitogenome is relatively high. Although P. sinica has a negative AT-skew and GC-skew, the GC-skew value is significantly lower than the AT-skew value. All PCGs, with the exception of CO1, carry the same start codon (ATN). All tRNAs exhibit the usual cloverleaf secondary structure. We identified the conserved motif "ATAGA + poly-T″ found in other lepidopteran insects at the beginning of the CR. We collected the concatenated PCGs sequences in the mitochondrial genome of 15 species of Zygaenoidea, with the sequences of Geometridae as outgroups, including P. sinica, and constructed phylogenetic trees using Bayesian inference (BI) and maximum likelihood (ML) methods. The monolineage of each superfamily is usually well supported. Based on phylogenetic analysis, P. sinica is a member of family Limacodidae, strongly supporting the monophyly of the Zygaenoidea groups.

SETD1A-mediated H3K4me3 methylation upregulates lncRNA HOXC-AS3 and the binding of HOXC-AS3 to EP300 and increases EP300 stability to suppress the ferroptosis of NSCLC cells.

BACKGROUND: Histone methyltransferases are crucial regulators in non-small cell lung cancer (NSCLC) development. This study explored the mechanism of histone methyltransferase SET domain containing 1A (SETD1A)-mediated H3K4me2 methylation in NSCLC cell ferroptosis and provides novel targets for NSCLC treatment. METHODS: Upon downregulation of SETD1A in NSCLC cell lines, cell proliferation potential, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) activities, iron content, and SETD1A, long noncoding RNA HOXC cluster antisense RNA 3 (lncRNA HOXC-AS3), E1A binding protein p300 (EP300), glutathione peroxidase 4 (GPX4) expressions were determined via cell counting kit-8, ELISA, iron assay kits, RT-qPCR, and western blot. Enrichment levels of SETD1A and H3K4me3 in the HOXC-AS3 promotor were measured via chromatin immunoprecipitation, and the binding of HOXC-AS3 and EP300 was analyzed via RNA immunoprecipitation. Rescue experiments were performed to confirm their roles in NSCLC cell ferroptosis. Xenograft tumor models were established to validate the role of SETD1A in vivo. RESULTS: SETD1A, H3K4me3, HOXC-AS3, and EP300 were highly-expressed in NSCLC cells. Silencing SETD1A inhibited NSCLC cell proliferation, increased MDA and iron levels, and decreased SOD, GSH, and GPX4 levels. SETD1A downregulation reduced H3K4me3 level, HOXC-AS3 expression, the binding of HOXC-AS3 to EP300, and EP300 stability. Overexpression of HOXC-AS3 or EP300 reversed the promotion of silencing SETD1A on NSCLC cell ferroptosis. Silencing SETD1A reduced tumor volume and weight and positive rate of ki67 and increased ferroptosis through the HOXC-AS3/EP300 axis. CONCLUSION: SETD1A-mediated H3K4me2 methylation promoted HOXC-AS3 expression, binding of HOXC-AS3 to EP300, and EP300 stability, thereby suppressing NSCLC cell ferroptosis.

Efficacy of PD-1/PD-L1 plus CTLA-4 inhibitors in solid tumors based on clinical characteristics: a meta-analysis.

Aims: To clarify the relationship between the potency of dual blockade of PD-1 or its ligand (PD-L1) plus CTLA-4 and patients with different clinical characteristics with solid tumors, the authors performed this meta-analysis. Patients & methods: 12 randomized clinical trials containing 7056 patients were included after the literature was filtered. Results: Dual blockade substantially enhanced overall survival and progression-free survival compared with standard of care, especially in patients aged <65 years old, those 65-74 years old, those with a smoking history, members of the White population and those with a high tumor mutation burden. Conclusion: Dual blockade therapy significantly improved patient survival outcomes. Age, smoking history, race and tumor mutation burden might be used to predict the potency of dual blockade therapy in solid tumors.

PD-1/PD-L1 plus CTLA-4 inhibitors therapy has been shown to be effective in many cancers. This meta-analysis found a correlation between efficacy and the characteristics of patients. Several datasets were used to screen the articles. Review Manager 5.3 was used for statistical analysis. A total of 7056 patients from 12 randomized, controlled trials were included. It was found that significant benefits were obtained by dual inhibitors. Their efficacy was correlated with patient age, smoking history, race and tumor mutation burden. These findings are important for clinical medication decisions.

Downregulation of Hotair or LSD1 Impaired Heart Regeneration in the Neonatal Mouse.

Previous studies have shown that lysine-specific demethylase 1 (LSD1) could regulate cell cycle progression through demethylation. The 3'domain of HOX transcript antisense RNA (Hotair) combined with the LSD1/CoREST/REST complex helps LSD1 target the corresponding gene. However, its role in mice's myocardial regeneration is still unclear. The heart from neonatal mice shows strong myocardial regeneration ability, but this ability disappears 7 days after birth. Our study shows that the myocardial tissue highly expresses Hotair and Lsd1 within 1 week after birth, consistent with the myocardial regeneration time window. Knockdown Lsd1 or Hotair expression by RNA interference could inhibit myocardial regeneration and cardiomyocyte proliferation. Our results suggest that Hotair-mediated demethylation of LSD1 may play an important role in myocardial regeneration in neonatal mice.

Transcriptome analysis of immune-related genes in Sesarmops sinensis hepatopancreas in reaction to peptidoglycan challenge.

Sesarmops sinensis is a dominant omnivorous crab species, which plays an important ecological function in salt marsh ecosystems. To better understand its immune system and immune related genes under pathogen infection, the transcriptome was analyzed by comparing the data of S. sinensis hepatopancreas stimulated by PBS and PGN. A set of assembly and annotation identified 39,039 unigenes with an average length of 1105 bp, obtaining 1300 differentially expressed genes (DEGs) in all, which included 466 remarkably up-regulated unigenes and 834 remarkably down-regulated unigenes. In addition, based on mensurable real time-polymerase chain reaction and high-throughput sequencing, several immune responsive genes were found to be markedly up-regulated under PGN stimulation. In conclusion, in addition to enriching the existing transcriptome data of S. sinensis, this study also clarified the immune response of S. sinensis to PGN stimulation, which will help us to further understand the crustacean's immune system.

pH and redox dual-responsive nanoparticles based on disulfide-containing poly(ß-amino ester) for combining chemotherapy and COX-2 inhibitor to overcome drug resistance in breast cancer.

BACKGROUND: Multidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. Celecoxib (CXB), a selective COX-2 inhibitor, can dramatically enhance the cytotoxicity of doxorubicin (DOX) in breast cancer cells overexpressing P-gp. Thus it can be seen that the combination of DOX and CXB maybe obtain synergistic effects against breast cancer by overcoming drug resistance. RESULTS: In this study, we designed a pH and redox dual-responsive nanocarrier system to combine synergistic effects of DOX and CXB against drug resistant breast cancer. This nanocarrier system denoted as HPPDC nanoparticles showed good in vitro stability and significantly accelerated drug releases under the acidic and redox conditions. In drug-resistant human breast cancer MCF-7/ADR cells, HPPDC nanoparticles significantly enhanced the cellular uptake of DOX through the endocytosis mediated by CD44/HA specific binding and the down-regulated P-gp expression induced by COX-2 inhibition, and thus notably increased the cytotoxicity and apoptosis-inducing activity of DOX. In MCF-7/ADR tumor-bearing nude mice, HPPDC nanoparticles showed excellent tumor-targeting ability, remarkably enhanced tumor chemosensitivity and reduced COX-2 and P-gp expressions in tumor tissues. CONCLUSION: All results demonstrated that HPPDC nanoparticles can efficiently overcome drug resistance in breast cancer both in vitro and in vivo by combining chemotherapy and COX-2 inhibitor. In a summary, HPPDC nanoparticles show a great potential for combination treatment of drug resistant breast cancer.

pH- and redox-responsive nanoparticles composed of charge-reversible pullulan-based shells and disulfide-containing poly(ß-amino ester) cores for co-delivery of a gene and chemotherapeutic agent.

A novel pH- and redox-responsive nanoparticle system was designed based on a charge-reversible pullulan derivative (CAPL) and disulfide-containing poly(ß-amino ester) (ssPBAE) for the co-delivery of a gene and chemotherapeutic agent targeting hepatoma. The end-alkene groups of ssPBAE were reacted with diethylenetriamine to form amino-modified ssPBAE (NH-ssPBAE). Methotrexate (MTX), a chemotherapy agent, was then conjugated to NH-ssPBAE via an amide bond to obtain the polymeric prodrug ssPBAE-MTX. ssPBAE-MTX exhibited a good capability for condensing genes, including plasmid DNA (pDNA) and tetramethyl rhodamine-labeled DNA (TAMRA-DNA), and almost completely condensed pDNA at the weight ratio of 5/1 to form spherical nanocomplexes with a uniform size. In a D,L-dithiothreitol solution, the ssPBAE-MTX/pDNA nanocomplexes showed rapid release of pDNA and MTX, indicating their redox-responsive capability. CAPL, a pullulan derivative containing ß-carboxylic amide bond, was efficiently coated on the surfaces of ssPBAE-MTX/pDNA nanocomplexes to form polysaccharide shells, thus realizing co-loading of the gene and chemotherapeutic agent. CAPL/ssPBAE-MTX/pDNA nanoparticles displayed an obvious pH-responsive charge reversal ability due to the rupture of the ß-carboxylic amide bond under the weakly acidic condition. In human hepatoma HepG2 cells, CAPL/ssPBAE-MTX/TAMRA-DNA nanoparticles were efficiently internalized via endocytosis and successfully escaped from the endo/lysosomes into the cytoplasm, and CAPL/ssPBAE-MTX/pDNA nanoparticles remarkably inhibited the cell growth. In summary, this nanoparticle system based on CAPL and ssPBAE showed great potential for combined gene/chemotherapy on hepatomas.

Dual pH-responsive multifunctional nanoparticles for targeted treatment of breast cancer by combining immunotherapy and chemotherapy.

In the present study, a dual pH-responsive multifunctional nanoparticle system was designed for combining immunotherapy and chemotherapy to treat breast cancer through targeting immune cells and cancer cells. A proven anti-tumor immune regulator, R848, was encapsulated with poly(L-histidine) (PHIS) to form PHIS/R848 nanocores. Doxorubicin (DOX) was conjugated to hyaluronic acid (HA) through an acid-cleavable hydrazone bond linkage to synthesize polymeric prodrug HA-DOX, which was subsequently coated outside PHIS/R848 nanocores to form HA-DOX/PHIS/R848 nanoparticles. Ionization of PHIS around pH 6.5 (a pH value close to that of tumor microenvironment) switched the nature of this material from hydrophobic to hydrophilic, and thus triggered the release of R848 to exert immunoregulatory action. The rupture of hydrazone bond in HA-DOX at about pH 5.5 (pH of endo/lysosomes) accelerated the release of DOX to exert cytotoxic effects. In immune cells, PHIS/R848 nanocores exhibited strong immunoregulatory activities similar to those induced by free R848. In breast cancer cells overexpressing CD44, HA-DOX was specially internalized by CD44-mediated endocytosis and significantly inhibited the cell growth. In 4T1 tumor-bearing mice, HA-DOX/PHIS/R848 nanoparticles showed excellent tumor-targeting ability and remarkably inhibited the tumor growth by regulating tumor immunity and killing tumor cells. In summary, this multifunctional nanoparticle system could deliver R848 and DOX respectively to tumor microenvironment and breast cancer cells to achieve synergistic effects of immunotherapy and chemotherapy against breast cancer. STATEMENT OF SIGNIFICANCE: Combination of immunotherapy and chemotherapy is becoming a promising new treatment for cancer. The major challenge is to target cancer and immune cells simultaneously and specifically. In this study, a dual pH-responsive multifunctional nanoparticle system based on poly(L-histidine) and hyaluronic acid was designed for co-loading R848 (immune-regulator) and doxorubicin (chemotherapeutic drug) through different encapsulation modes. By responding to the acidic pHs of tumor microenvironment and intracellular organelles, this multifunctional nanoparticle system could release R848 extracellularly and deliver DOX targetedly to breast cancer cells, thus achieving synergistic effects of immunotherapy and chemotherapy against breast cancer.

Pullulan-coated phospholipid and Pluronic F68 complex nanoparticles for carrying IR780 and paclitaxel to treat hepatocellular carcinoma by combining photothermal therapy/photodynamic therapy and chemotherapy.

IR780, a near-infrared dye, can also be used as a photosensitizer both for photothermal therapy (PTT) and photodynamic therapy (PDT). In this study, we designed a simple but effective nanoparticle system for carrying IR780 and paclitaxel, thus hoping to combine PTT/PDT and chemotherapy to treat hepatocellular carcinoma (HCC). This nanosystem, named PDF nanoparticles, consisted of phospholipid/Pluronic F68 complex nanocores and pullulan shells. IR780 and paclitaxel were loaded separately into PDF nanoparticles to form PDFI and PDFP nanoparticles, which had regular sphere shapes and relatively small sizes. Upon near-infrared laser irradiation at 808 nm, PDFI nanoparticles showed strong PTT/PDT efficacy both in vitro and in vivo. In MHCC-97H cells, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles exhibited significant synergistic effects on inhibiting cell proliferation and inducing cell apoptosis and cell cycle arrest at G2/M phase. In MHCC-97H tumor-bearing mice, PDFI nanoparticles exhibited excellent HCC-targeting and accumulating capability after intravenous injection. Furthermore, the combined treatment of PDFI nanoparticles/laser irradiation and PDFP nanoparticles also effectively inhibited the tumor growth and the tumor angiogenesis in MHCC-97H tumor-bearing mice. In summary, we put forward a therapeutic strategy for HCC treatment by combining PTT/PDT and chemotherapy.

Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(ß-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma.

Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(ß-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of ß-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis. In conclusion, this novel nanoparticle system is a promising candidate as carrier for drugs against HCC.

Functionalized Graphene Oxide with Hepatocyte Targeting as Anti-Tumor Drug and Gene Intracellular Transporters.

In order to realize the hepatocyte-specific targeted delivery of anti-tumor drug and gene, lactosylated chitosan oligosaccharide (LCO) functionalized graphene oxides (GO-LCO) containing quaternary ammonium groups (GO-LCO+) were prepared. The formation and composition of GO-LCO+ were confirmed by FTIR, AFM, TGA and zeta-potential. The in vitro cells uptakes of this functionalized GO were investigated and the results showed that GO-LCO+ can deliver fluorescein FAM-labeled DNA sequence (FAM-DNA) into human hepatic carcinoma cells (QGY-7703) with higher efficiency than positively charged chitosan oligosaccharide (CO) functionalized graphene oxides (GO-CO+) without Lactose acid modification. The loading efficiency of doxorubicin chloride (Dox) on GO-LCO+ with 477 µg/mg was obtained at the initial Dox concentration of 0.45 mg/ml and release of Dox on GO-LCO+ showed strong pH dependence. The toxicity of GO-LCO+ before and after loading with Dox toward QGY-7703 cells was further investigated. Our results suggest the functionalized GO to be used as a nanocarrier for hepatocyte targeted co-delivery of anti-tumor drugs and genes with low cytotoxicity, promising for future applications in anticancer drug and gene combined therapy.

Transfer printing of thermoreversible ion gels for flexible electronics.

Thermally assisted transfer printing was employed to pattern thin films of high capacitance ion gels on polyimide, poly(ethylene terephthalate), and SiO2 substrates. The ion gels consisted of 20 wt % block copolymer poly(styrene-b-ethylene oxide-b-styrene and 80 wt % ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethyl sulfonyl)amide. Patterning resolution was on the order of 10 µm. Importantly, ion gels containing the block polymer with short PS end blocks (3.4 kg/mol) could be transfer-printed because of thermoreversible gelation that enabled intimate gel-substrate contact at 100 °C, while gels with long PS blocks (11 kg/mol) were not printable at the same temperature due to poor wetting contact between the gel and substrates. By using printed ion gels as high-capacitance gate insulators, electrolyte-gated thin-film transistors were fabricated that operated at low voltages (<1 V) with high on/off current ratios (∼10(5)). Statistical analysis of carrier mobility, turn-on voltage, and on/off ratio for an array of printed transistors demonstrated the excellent reproducibility of the printing technique. The results show that transfer printing is an attractive route to pattern high-capacitance ion gels for flexible thin-film devices.

High toughness, high conductivity ion gels by sequential triblock copolymer self-assembly and chemical cross-linking.

Self-assembly of ABA triblocks in ionic liquids provides a versatile route to highly functional physical ion gels, with promise in applications ranging from plastic electronics to gas separation. However, the reversibility of network formation, so favorable for processing, restricts the ultimate mechanical strength of the material. Here, we describe a novel ABA system that can be chemically cross-linked in a second annealing step, thereby providing greatly enhanced toughness. The ABA triblock is a poly(styrene-b-ethylene oxide-b-styrene) polymer in which about 25 mol % of the styrene units have a pendant azide functionality. After self-assembly of 10 wt % triblock in the ionic liquid [EMI][TFSA], the styrene domains are cross-linked by annealing at elevated temperature for ca. 20 min. The high ionic conductivity (ca. 10 mS/cm) of the physical ion gels is preserved in the final product, while the tensile strength is increased by a factor of 5.

Electrolyte-gated transistors for organic and printed electronics.

Here we summarize recent progress in the development of electrolyte-gated transistors (EGTs) for organic and printed electronics. EGTs employ a high capacitance electrolyte as the gate insulator; the high capacitance increases drive current, lowers operating voltages, and enables new transistor architectures. Although the use of electrolytes in electronics is an old concept going back to the early days of the silicon transistor, new printable, fast-response polymer electrolytes are expanding the potential applications of EGTs in flexible, printed digital circuits, rollable displays, and conformal bioelectronic sensors. This report introduces the structure and operation mechanisms of EGTs and reviews key developments in electrolyte materials for use in printed electronics. The bulk of the article is devoted to electrical characterization of EGTs and emerging applications.

"Cut and stick" rubbery ion gels as high capacitance gate dielectrics.

A free-standing polymer electrolyte called an ion gel is employed in both organic and inorganic thin-film transistors as a high capacitance gate dielectric. To prepare a transistor, the free-standing ion gel is simply laid over a semiconductor channel and a side-gate electrode, which is possible because of the gel's high mechanical strength.

Electrical impedance of spin-coatable ion gel films.

The electrical properties (capacitance, resistance, and conductivity) of ion gel films were examined as a function of film geometry and temperature by using electrical impedance spectroscopy. Ion gel films, which consist of a triblock copolymer, poly (styrene-b-methyl methacrylate-b-styrene) [SMS], and an ionic liquid, 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, [EMI][TFSI], were deposited by spin coating from ethyl acetate solution. The thickness (2.2-13.4 µm) and the area (0.01-0.06 cm(2)) of the film sandwiched between two gold electrodes were varied systematically to investigate the relation between the electrical properties and the geometry of the film. The resistance (R) was directly proportional to the thickness and the reciprocal area, as expected, whereas the specific capacitance (C') was insensitive to the film geometry. Importantly, the gel polarization time constants (RC, where C = C' × area) were as small as 2.8 µs for 2.2 µm thick ion gel films. Conductivity and capacitance of the film both increase with increasing temperature, with conductivity following the Vogel-Fulcher-Tamman equation, indicating entropically activated behavior, and capacitance at 10 Hz showing Arrhenius-type activation.

Electrolyte gate-controlled Kondo effect in SrTiO3.

We report low-temperature, high-field magnetotransport measurements of SrTiO(3) gated by an ionic gel electrolyte. A saturating resistance upturn and negative magnetoresistance that signal the emergence of the Kondo effect appear for higher applied gate voltages. This observation, enabled by the wide tunability of the ionic gel-applied electric field, promotes the interpretation of the electric field-effect-induced 2D electron system in SrTiO(3) as an admixture of magnetic Ti(3+) ions, i.e., localized and unpaired electrons, and delocalized electrons that partially fill the Ti 3d conduction band.