BackgroundGene presence/absence (P/A) polymorphisms are commonly observed in plants and are important in individual adaptation and species differentiation. Detecting their abundance, distribution and variation among individuals would help to understand the role played by these polymorphisms in a given species. The recently sequenced 80 Arabidopsis genomes provide an opportunity to address these questions.ResultsBy systematically investigating these accessions, we identified 2,407 P/A genes (or 8.9%) absent in one or more genomes, averaging 444 absent genes per accession. 50.6% of P/A genes belonged to multi-copy gene families, or 31.0% to clustered genes. However, the highest proportion of P/A genes, outnumbered in singleton genes, was observed in the regions near centromeres. In addition, a significant correlation was observed between the P/A gene frequency among the 80 accessions and the diversity level at P/A loci. Furthermore, the proportion of P/A genes was different among functional gene categories. Finally, a P/A gene tree showed a diversified population structure in the worldwide Arabidopsis accessions.ConclusionsAn estimate of P/A genes and their frequency distribution in the worldwide Arabidopsis accessions was obtained. Our results suggest that there are diverse mechanisms to generate or maintain P/A genes, by which individuals and functionally different genes can selectively maintain P/A polymorphisms for a specific adaptation.

Photothermal therapy (PTT) combined with chemotherapy, a promising strategy for breast cancer treatment, has a high potential to control drug release, reduce multidrug resistance, and improve therapeutic efficacy. The challenge is how to realize tumor ablation in deeper tissue and NIR‐controlled drug delivery. Herein, tumor acidity and near‐infrared light (NIR) responsive folic acid (FA) functionalized polydopamine (DPA) nanoparticles (NPs) are developed for doxorubicin (DOX) and epigallocatechin‐3‐gallate (EGCG) dual delivery. With the assistance of NIR, the cellular uptake of DOX‐EGCG/DPA‐FA NPs is about three‐ to sixfold higher when compared with the free DOX group and the control group without NIR irradiation. Moreover, biodistribution study in vivo indicates that DPA‐FA NPs can enhance tumoral accumulation, penetration, retention of drugs, and display a ≈4‐ and 19‐fold higher intra‐tumoral distribution than that of the DPA NPs and free drug groups at 24 h postinjection. Furthermore, 60% of breast cancer‐bearing mice survive over 70 days in the DOX‐EGCG/DPA‐FA NPs group. Additionally, DOX‐EGCG/DPA‐FA NPs can effectively boost therapeutic efficacy by inducing significant suppression of tumor growth and angiogenesis, and enhancement of apoptosis and necrosis of breast cancer cells. Taken together, DOX‐EGCG/DPA‐FA NPs may have potential applications as a useful nanoscale vector for enhanced cancer therapy.

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.

Down syndrome (DS), or trisomy 21, is one of the critical risk factors for early-onset Alzheimer’s disease (AD), implicating key roles for chromosome 21–encoded genes in the pathogenesis of AD. We previously identified a role for the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in the AD brain; however, whether USP25 affects amyloid pathology remains unknown. Here, by crossing 5×FAD AD and Dp16 DS mice, we observed that trisomy 21 exacerbated amyloid pathology in the 5×FAD brain. Moreover, bacterial artificial chromosome (BAC) transgene–mediated USP25 overexpression increased amyloid deposition in the 5×FAD mouse brain, whereas genetic deletion of Usp25 reduced amyloid deposition. Furthermore, our results demonstrate that USP25 promoted β cleavage of APP and A β generation by reducing the ubiquitination and lysosomal degradation of both APP and BACE1. Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the 5×FAD mouse brain. In summary, we identified the DS-related gene USP25 as a critical regulator of AD pathology, and our data suggest that USP25 serves as a potential pharmacological target for AD drug development.

Atherosclerosis (AS) is the primary cause of various cardiovascular and cerebrovascular diseases and has high morbidity and mortality rates. Oxidative stress-induced endothelial cells (ECs) dysfunction is the pathological basis of AS. In addition, sphingomyelin (SM) and the Wnt/β-catenin signaling pathway are considered to be closely associated with AS; however, the specific mechanism is not clear. Therefore, the present study investigated whether SM may induce ECs dysfunction through the Wnt/β-catenin signaling pathway. Firstly, a sphingomyelin synthase 2 (SMS2) overexpression cell model was constructed. It was identified that the expression of SMS2 was increased when ECs were treated with H2O2. In addition, these results demonstrated that SMS2 overexpression promoted apoptosis and macrophage adhesion of H2O2-induced ECs, thereby increasing the expression of β-catenin. Furthermore, SMS activity was inhibited with Dy105, combined with simultaneous treatment with LiCl or H2O2. This additionally confirmed that Dy105 significantly inhibited SMS activity and decreased the level of ECs dysfunction and β-catenin content; however, LiCl served a key role in activating the Wnt/β-catenin signaling pathway to promote ECs dysfunction. Collectively, these results suggested that SMS2 overexpression may promote ECs dysfunction by activating the Wnt/β-catenin signaling pathway, while Dy105 may inhibit the evolution of oxidative stress-induced dysfunction.