Heterosis is a fundamental biological phenomenon characterized by the superior performance of a hybrid compared with its parents. The underlying molecular basis for heterosis, particularly for allopolyploids, remains elusive. In this study we analyzed the transcriptomes of Brassica napus parental lines and their F hybrids at three stages of early flower development. Phenotypically, the F hybrids show remarkable heterosis in silique number and grain yield. Transcriptome analysis revealed that various phytohormone (auxin and salicylic acid) response genes are significantly altered in the F hybrids relative to the parental lines. We also found evidence for decreased expression divergence of the homoeologous gene pairs in the allopolyploid F hybrids and suggest that high-parental expression-level dominance plays an important role in heterosis. Small RNA and methylation studies aimed at examining the epigenetic effect of the changes in gene expression level in the F hybrids showed that the majority of the small interfering RNA (siRNA) clusters had a higher expression level in the F hybrids than in the parents, and that there was an increase in genome-wide DNA methylation in the F hybrid. Transposable elements associated with siRNA clusters had a higher level of methylation and a lower expression level in the F hybrid, implying that the non-additively expressed siRNA clusters resulted in lower activity of the transposable elements through DNA methylation in the hybrid. Our data provide insights into the role that changes in gene expression pattern and epigenetic mechanisms contribute to heterosis during early flower development in allopolyploid B. napus.

Immune checkpoint therapy has resulted in remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with fourth generation 'armored' chimeric antigen receptor (CAR-IL-15) engineering of cord blood (CB) derived natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that targeting a cytokine checkpoint further enhances the antitumor activity of IL-15 secreting armored CAR-NK cells by promoting their metabolic fitness and anti-tumor activity. This combined approach represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.

Targeting the αv integrin-TGF-β axis improves natural killer cell function against glioblastoma stem cells Running title-GBM induce NK cell dysfunction via integrin-TGF- axis

Electronic cigarettes (e-cigarettes) generate an aerosol vapor (e-vapor) thought to represent a less risky alternative to main stream smoke (MSS) of conventional tobacco cigarettes. RNA-seq analysis was used to examine the transcriptomes of differentiated human bronchial epithelial (HBE) cells exposed to air, MSS from 1R5F tobacco reference cigarettes, and e-vapor with and without added nicotine in an in vitro air-liquid interface model for cellular exposure. Our results indicate that while e-vapor does not elicit many of the cell toxicity responses observed in MSS-exposed HBE cells, e-vapor exposure is not benign, but elicits discrete transcriptomic signatures with and without added nicotine. Among the cellular pathways with the most significantly enriched gene expression following e-vapor exposure are the phospholipid and fatty acid triacylglycerol metabolism pathways. Our data suggest that alterations in cellular glycerophopholipid biosynthesis are an important consequences of e-vapor exposure. Moreover, the presence of nicotine in e-vapor elicits a cellular response distinct from e-vapor alone including alterations of cytochrome P450 function, retinoid metabolism, and nicotine catabolism. These studies establish a baseline for future analysis of e-vapor and e-vapor additives that will better inform the FDA and other governmental bodies in discussions of the risks and future regulation of these products.

Obesity is usually considered to predispose to atherosclerotic cardiovascular disease (ASCVD) but milder degrees of obesity or overweight may be protective in some elderly populations. We examined the relationships between general and abdominal obesity indices with ASCVD and its risk factors in elderly (aged ≥65 years) Shanghai community residents Among the 3950 participants, 21.5% had ASCVD, 56.2% had body mass index (BMI) ≥24 kg/m2, 50.1% had high waist circumference (WC) and 77.1% had waist-to-height ratio (WHtR) ≥0.50. WHtR increased with age in both men and women whereas WC increased with age only in women and BMI decreased with age only in men. The optimal WHtR cut-off value to predict the risk of ASCVD determined by receiver operating characteristic analysis was WHtR ≥0.53 with a prevalence of 55.8%. Having abdominal obesity was significantly associated with prevalent ASCVD with WHtR ≥0.53 having a higher value for the odds ratio than high WC, whereas high BMI was not associated. All three indices predicted high glucose, triglycerides and hsCRP levels but only the WHtR ≥0.53 showed a significant association with physical activity. Abdominal obesity indices, but not BMI, predicted prevalent ASCVD and its risk factors in this elderly Chinese population.

Purpose: Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation. Experimental Design: We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood–derived NK cells was investigated in vitro and in vivo. Results: We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30+ lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and ex vivo expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13–NK complex cells exhibited enhanced responses to CD30+ lymphomas in vitro and in vivo. Conclusions: We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.

Summary Brassica napus (AACC, 2n = 38) is an important oilseed crop grown worldwide. However, little is known about the population evolution of this species, the genomic difference between its major genetic groups, such as European and Asian rapeseed, and the impacts of historical large‐scale introgression events on this young tetraploid. In this study, we reported the de novo assembly of the genome sequences of an Asian rapeseed (B. napus), Ningyou 7, and its four progenitors and compared these genomes with other available genomic data from diverse European and Asian cultivars. Our results showed that Asian rapeseed originally derived from European rapeseed but subsequently significantly diverged, with rapid genome differentiation after hybridization and intensive local selective breeding. The first historical introgression of B. rapa dramatically broadened the allelic pool but decreased the deleterious variations of Asian rapeseed. The second historical introgression of the double‐low traits of European rapeseed (canola) has reshaped Asian rapeseed into two groups (double‐low and double‐high), accompanied by an increase in genetic load in the double‐low group. This study demonstrates distinctive genomic footprints and deleterious SNP (single nucleotide polymorphism) variants for local adaptation by recent intra‐ and interspecies introgression events and provides novel insights for understanding the rapid genome evolution of a young allopolyploid crop.

BackgroundAlthough Helicobacter pylori (H.pylori) is the dominant gastrointestinal pathogen, the genetic and molecular mechanisms underlying H.pylori-related diseases have not been fully elucidated. Long non-coding RNAs (lncRNAs) have been identified in eukaryotic cells, many of which play important roles in regulating biological processes and pathogenesis. However, the expression changes of lncRNAs in human infected by H.pylori have been rarely reported. This study aimed to identify the dysregulated lncRNAs in human gastric epithelial cells and tissues infected with H.pylori.MethodsThe aberrant expression profiles of lncRNAs and mRNAs in GES-1 cells with or without H.pylori infection were explored by microarray analysis. LncRNA-mRNA co-expression network was constructed based on Pearson correlation analysis. Gene Ontology (GO) and KEGG Pathway analyses of aberrantly expressed mRNAs were performed to identify the related biological functions and pathologic pathways. The expression changes of target lncRNAs were validated by qRT-PCR to confirm the microarray data in both cells and clinical specimens.ResultsThree hundred three lncRNAs and 565 mRNAs were identified as aberrantly expressed transcripts (≥2 or ≤0.5-fold change, P < 0.05) in cells with H.pylori infection compared to controls. LncRNA-mRNA co-expression network showed the core lncRNAs/mRNAs which might play important roles in H.pylori-related pathogenesis. GO and KEGG analyses have indicated that the functions of aberrantly expressed mRNAs in H.pylori infection were related closely with inflammation and carcinogenesis. QRT-PCR data confirmed the expression pattern of 8 (n345630, XLOC_004787, n378726, LINC00473, XLOC_005517, LINC00152, XLOC_13370, and n408024) lncRNAs in infected cells. Additionally, four down-regulated (n345630, XLOC_004787, n378726, and LINC00473) lncRNAs were verified in H.pylori-positive gastric samples.ConclusionOur study provided a preliminary exploration of lncRNAs expression profiles in H.pylori-infected cells by microarray. These dysregulated lncRNAs might contribute to the pathological processes during H.pylori infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0159-0) contains supplementary material, which is available to authorized users.