Abstract Poly(ethylene glycol) (PEG) is usually used to protect nanoparticles from rapid clearance in blood. The effects are highly dependent on the surface PEG density of nanoparticles. However, ...there lacks a detailed and informative study in PEG density and in vivo drug delivery due to the critical techniques to precisely control the surface PEG density when maintaining other nano-properties. Here, we regulated the polymeric nanoparticles' size and surface PEG density by incorporating poly(ε-caprolactone) (PCL) homopolymer into poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG–PCL) and adjusting the mass ratio of PCL to PEG–PCL during the nanoparticles preparation. We further developed a library of polymeric nanoparticles with different but controllable sizes and surface PEG densities by changing the molecular weight of the PCL block in PEG–PCL and tuning the molar ratio of repeating units of PCL (CL) to that of PEG (EG). We thus obtained a group of nanoparticles with variable surface PEG densities but with other nano-properties identical, and investigated the effects of surface PEG densities on the biological behaviors of nanoparticles in mice. We found that, high surface PEG density made the nanoparticles resistant to absorption of serum protein and uptake by macrophages, leading to a greater accumulation of nanoparticles in tumor tissue, which recuperated the defects of decreased internalization by tumor cells, resulting in superior antitumor efficacy when carrying docetaxel.
The first reversible photoisomerization between a borepin and a borirane was reported in the photo‐induced reactions of B(npy)Ar2 (npy=2‐(naphthalen‐1‐yl) pyridine, Ar=phenyl or electron rich aryl; ...S. Wang, et al. Angew. Chem. Int. Ed. 2019, 58, 6683–6687). In this work, the detailed mechanisms of the unprecedented reversible photoisomerization between the borepin (compound a) and the borirane (compound b) of B(npy)Ph2 in the first excited singlet (S1) state and the ground (S0) state were studied by carrying out calculations with the complete active space self‐consistent field (CASSCF) and its second‐order perturbation (CASPT2) methods combined with time‐dependent density functional theory (TD‐DFT). The calculation results show that photoexcitation of a‐S0 at 365 nm and b‐S0 at 450 nm populate their S1 state with evident charge transfer characteristics. The photoisomerization is triggered in the S1 state and ends in the S0 state, at which the intersection points in a (S1/S0)x intersection seam participate in and promote phenyl migration and ring‐closure processes. Furthermore, we reveal that the not large energy difference (less than 0.6 eV) and similar conjugation properties of π electrons between a‐S0 and b‐S0 are responsible for their unique photo‐reversible reactivity, compared with those of the isomers of the thermally reversible compound B(ppy)Mes2. Our results contribute to an understanding of the excited‐state reactivity of organoboron compounds and will be useful to support the design of new boron‐based photo‐responsive materials.
Multi‐reference calculations with the CASPT2//CASSCF method have established detailed mechanisms for the photo‐induced reversible isomerization between a borepin and a borirane, in which the (S1/S0)x intersection seam plays crucial roles.
Mesenchymal stromal/stem cell (MSC) transplantation is a promising therapy for tissue regeneration. Extracellular vesicles (EVs) released by MSCs act as their paracrine effectors by delivering ...proteins and genetic material to recipient cells. To assess how their cargo mediates biological processes that drive their therapeutic effects, we integrated miRNA, mRNA, and protein expression data of EVs from porcine adipose tissue-derived MSCs.
Simultaneous expression profiles of miRNAs, mRNAs, and proteins were obtained by high-throughput sequencing and LC-MS/MS proteomic analysis in porcine MSCs and their daughter EVs (n = 3 each). TargetScan and ComiR were used to predict miRNA target genes. Functional annotation analysis was performed using DAVID 6.7 database to rank primary gene ontology categories for the enriched mRNAs, miRNA target genes, and proteins. STRING was used to predict associations between mRNA and miRNA target genes.
Differential expression analysis revealed 4 miRNAs, 255 mRNAs, and 277 proteins enriched in EVs versus MSCs (fold change >2, p<0.05). EV-enriched miRNAs target transcription factors (TFs) and EV-enriched mRNAs encode TFs, but TF proteins are not enriched in EVs. Rather, EVs are enriched for proteins that support extracellular matrix remodeling, blood coagulation, inflammation, and angiogenesis.
Porcine MSC-derived EVs contain a genetic cargo of miRNAs and mRNAs that collectively control TF activity in EVs and recipient cells, as well as proteins capable of modulating cellular pathways linked to tissue repair. These properties provide the fundamental basis for considering therapeutic use of EVs in tissue regeneration.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Systemic delivery of small interfering RNA (siRNA) into cancer cells remains the major obstacle to siRNA drug development. An ideal siRNA delivery vehicle for systemic administration should ...have long circulation time in blood, accumulate at tumor site, and sufficiently internalize into cancer cells for high-efficiency of gene silence. Herein, we report a core–shell Micelleplex delivery system that made from block copolymer bearing poly(ethylene glycol) (PEG), matrix metalloproteinase 2 (MMP-2)-degradable peptide PLG*LAG, cationic cell penetrating peptide polyarginine r9 and poly(ε-caprolactone) (PCL) for siRNA delivery. We show clear evidences in vitro and in vivo to prove that the micelle carrying siRNA can circulate enough time in blood, enrich accumulation at tumor sites, shed the PEG layer when triggered by tumor overexpressing MMP-2, and then the exposing cell penetrating peptide r9 enhanced cellular uptake of siRNA. Accordingly, this design strategy enhances the inhibition of breast tumor growth following systemic injection of this system carrying siRNA against Polo-like kinase 1, which demonstrating this Micelleplex can be a potential delivery system for systemic siRNA delivery in cancer therapy.
Plants monitor seasonal cues to optimize reproductive success by tuning onset of reproduction and inflorescence architecture. TERMINAL FLOWER 1 (TFL1) and FLOWERING LOCUS T (FT) and their orthologs ...antagonistically regulate these life history traits, yet their mechanism of action, antagonism and targets remain poorly understood. Here, we show that TFL1 is recruited to thousands of loci by the bZIP transcription factor FD. We identify the master regulator of floral fate, LEAFY (LFY) as a target under dual opposite regulation by TFL1 and FT and uncover a pivotal role of FT in promoting flower fate via LFY upregulation. We provide evidence that the antagonism between FT and TFL1 relies on competition for chromatin-bound FD at shared target loci. Direct TFL1-FD regulated target genes identify this complex as a hub for repressing both master regulators of reproductive development and endogenous signalling pathways. Our data provide mechanistic insight into how TFL1-FD sculpt inflorescence architecture, a trait important for reproductive success, plant architecture and yield.
Summary
We aimed to identify genomic traits of transitions to ectomycorrhizal ecology within the Boletales by comparing the genomes of 21 symbiotrophic species with their saprotrophic brown‐rot ...relatives.
Gene duplication rate is constant along the backbone of Boletales phylogeny with large loss events in several lineages, while gene family expansion sharply increased in the late Miocene, mostly in the Boletaceae.
Ectomycorrhizal Boletales have a reduced set of plant cell‐wall‐degrading enzymes (PCWDEs) compared with their brown‐rot relatives. However, the various lineages retain distinct sets of PCWDEs, suggesting that, over their evolutionary history, symbiotic Boletales have become functionally diverse. A smaller PCWDE repertoire was found in Sclerodermatineae. The gene repertoire of several lignocellulose oxidoreductases (e.g. laccases) is similar in brown‐rot and ectomycorrhizal species, suggesting that symbiotic Boletales are capable of mild lignocellulose decomposition. Transposable element (TE) proliferation contributed to the higher evolutionary rate of genes encoding effector‐like small secreted proteins, proteases, and lipases. On the other hand, we showed that the loss of secreted CAZymes was not related to TE activity but to DNA decay.
This study provides novel insights on our understanding of the mechanisms influencing the evolutionary diversification of symbiotic boletes.
Lethal Amanita species in China Cai, Qing; Cui, Yang-Yang; Yang, Zhu L.
Mycologia,
09/2016, Letnik:
108, Številka:
5
Journal Article
Recenzirano
Lethal amanitas (Amanita sect. Phalloideae) cause many casualties worldwide. Recent molecular phylogenetic studies revealed diverse lethal Amanita spp. in China. Here a 5-gene phylogeny (nuc rDNA ...region encompassing the internal transcribed spacers 1 and 2 with the 5.8S rDNA, the D1-D3 domains of nuc 28S rDNA, and partial RNA polymerase II second largest subunit, translation elongation factor 1-α and β-tubulin genes) is used to investigate the phylogenetic lineages and species delimitation in this section. Thirteen species are recognized, including four new species, namely A. griseorosea, A. molliuscula, A. parviexitialis, and A. subfuliginea. They are documented with morphological, multigene phylogenetic, and ecological evidence, line drawings, and photographs and compared with similar species. A key to the Chinese lethal Amanita species is provided.
The CRISPR/Cas9 gene editing technology holds promise for the treatment of multiple diseases. However, the inability to perform specific gene editing in targeted tissues and cells, which may cause ...off-target effects, is one of the critical bottlenecks for therapeutic application of CRISPR/Cas9. Herein, macrophage-specific promoter-driven Cas9 expression plasmids (pM458 and pM330) were constructed and encapsulated in cationic lipid-assisted PEG-b-PLGA nanoparticles (CLAN). The obtained nanoparticles encapsulating the CRISPR/Cas9 plasmids were able to specifically express Cas9 in macrophages as well as their precursor monocytes both in vitro and in vivo. More importantly, after further encoding a guide RNA targeting Ntn1 (sgNtn1) into the plasmid, the resultant CLANpM330/sgNtn1 successfully disrupted the Ntn1 gene in macrophages and their precursor monocytes in vivo, which reduced expression of netrin-1 (encoded by Ntn1) and subsequently improved type 2 diabetes (T2D) symptoms. Meanwhile, the Ntn1 gene was not disrupted in other cells due to specific expression of Cas9 by the CD68 promoter. This strategy provides alternative avenues for specific in vivo gene editing with the CRISPR/Cas9 system.
K‐rich adakite‐like rocks (KARs) in post‐collisional settings, such as in Tibet, have been widely linked with the melting of pre‐existing thickened crust. Here, we investigate geochemical data of the ...Late Eocene (38–34 Ma) volcanic rocks including KARs from the southern Qiangtang terrane (SQT) of central Tibet. The data reveal that: (a) the volcanic rocks define a fractionation trend from high‐K alkaline basalt to high‐K calc‐alkaline rhyolite, with a continuous compositional range and (b) they are characterized by a narrow range of depleted Sr–Nd isotopic compositions relative to the pre‐Eocene SQT crust. We contend that the KARs in the SQT resulted from fractional crystallization of hydrous, alkaline melts derived from the lithospheric mantle where fractionation was dominated by amphibole and plagioclase. Partial melting of the lithospheric mantle beneath the SQT was possibly triggered by thermal perturbations owing to the north‐directed subduction of the Indian continental lithosphere beneath southern Tibet.
Plain Language Summary
Adakites were originally defined as silica‐rich magmas produced by melting of basalts in subducting oceanic crust. They are Na‐rich with low K2O and K2O/Na2O, and are characterized by high Sr/Y and La/Yb and low Y and Yb. In post‐collisional settings, such as in Tibet, silica‐rich magmatic rocks with high Sr/Y and La/Yb have been identified, but they are not sodic as true adakites, and are rich in K2O, forming K‐rich adakite‐like rocks (KARs). They have been linked with the melting of pre‐existing crustal rocks at high pressures where garnet is present. We investigate geochemical data of the Late Eocene (38–34 Ma) volcanic rocks that include KARs from the southern Qiangtang terrane (SQT) of central Tibet. We conclude that these KARs were not products of crustal melting at high pressures, but resulted from extreme fractional crystallization of lithospheric mantle‐derived, hydrous, primitive alkaline melts. Given that extreme fractional crystallization commonly occurs in a compressive regime, we argue that the lithospheric mantle underneath the SQT underwent melting during a compressive regime possibly due to thermal perturbations, driven by north‐directed subduction of the Indian continental lithosphere beneath southern Tibet.
Key Points
Late Eocene K‐rich adakite‐like rocks (KARs) in the S. Qiangtang terrane resulted from fractional crystallization of a primitive alkaline melt
Fractionation was dominated by amphibole and plagioclase
KARs from the S. Qiantang terrane have a different origin from those of the Lhasa terrane
Polymerase Chain Reaction (PCR) is one of the most common technologies used to produce millions of copies of targeted nucleic acid in vitro and has become an indispensable technique in molecular ...biology. However, it suffers from low efficiency and specificity problems, false positive results, and so on. Although many conditions can be optimized to increase PCR yield, such as the magnesium ion concentration, the DNA polymerases, the number of cycles, and so on, they are not all-purpose and the optimization can be case dependent. Nano-sized materials offer a possible solution to improve both the quality and productivity of PCR. In the last two decades, nanoparticles (NPs) have attracted significant attention and gradually penetrated the field of life sciences because of their unique chemical and physical properties, such as their large surface area and small size effect, which have greatly promoted developments in life science and technology. Additionally, PCR technology assisted by NPs (NanoPCR) such as gold NPs (Au NPs), quantum dots (QDs), and carbon nanotubes (CNTs), etc., have been developed to significantly improve the specificity, efficiency, and sensitivity of PCR and to accelerate the PCR reaction process. This review discusses the roles of different types of NPs used to enhance PCR and summarizes their possible mechanisms.
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