Genomic heterogeneity of multiple synchronous lung cancer

Multiple synchronous lung cancers (MSLCs) present a clinical dilemma as to whether individual tumours represent intrapulmonary metastases or independent tumours. In this study we analyse genomic profiles of 15 lung adenocarcinomas and one regional lymph node metastasis from 6 patients with MSLC. All 15 lung tumours demonstrate distinct genomic profiles, suggesting all are independent primary tumours, which are consistent with comprehensive histopathological assessment in 5 of the 6 patients. Lung tumours of the same individuals are no more similar to each other than are lung adenocarcinomas of different patients from TCGA cohort matched for tumour size and smoking status. Several known cancer-associated genes have different mutations in different tumours from the same patients. These findings suggest that in the context of identical constitutional genetic background and environmental exposure, different lung cancers in the same individual may have distinct genomic profiles and can be driven by distinct molecular events

Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5

A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS

Role of miR-17 Family in the Negative Feedback Loop of Bone Morphogenetic Protein Signaling in Neuron

<div><p>Bone morphogenetic protein (BMP) signaling is active in many tissues including the central nervous system, in which it regulates cell proliferation, differentiation and maturation. The modulation of BMP pathway is crucial since abnormality of BMP signaling may cause cellular malfunction such as apoptosis. There are evidences indicating that miR-17 family is involved in the BMP signaling. In the present study, we demonstrated that BMP2 stimulation directly increased the transcription of miR-17-92 and miR-106b-25 cluster via Smad activation, which leads to the up-regulation of mature miR-17/20a/93. In addition, we provided evidence that BMP2 activation repressed BMPRII expression through modulating miR-17 family in primary neurons. Furthermore, we proved that such negative regulation protected neurons from apoptosis induced by abnormal BMP signaling. Taken together, these results suggest a regulatory pathway of BMP-miR-17 family-BMPRII, which consist a negative feedback loop that balances BMP signaling and maintains cell homeostasis in neurons.</p> </div

Additional file 1: Figures S1–S5. of miR-17-92 facilitates neuronal differentiation of transplanted neural stem/precursor cells under neuroinflammatory conditions

Figure S1. Characterization of the NSCs. Figure S2. Effect of LIF and CNTF on differentiation of NSCs. Figure S3. miR-17-92 members directly target the 3′UTR of CNTFR or GP130. Figure S4. Bioinformatics analysis of miR-17-92 cluster members binding sites within CNTFR, GP130, JAK2, and STAT3. Figure S5. Traumatic brain injury. (PDF 558 kb

Analysis of the Postharvest Storage Characteristics of Two New Pear Cultivars ‘Shannongsu’ and ‘Xincixiang’

‘Shannongsu’ and ‘Xincixiang’ were two new late-ripening pear cultivars with high quality, that were bred by our team. In order to clear the postharvest storage characteristics, mature pears were collected and stored at room temperature. Several fruit characteristics were evaluated over time, such as firmness, ethylene release rate, content of aroma components, softening-related enzyme activity, and gene expression. Both ‘Shannongsu’ and ‘Xincixiang’ were crisp and juicy stored after 60 d at room temperature, which exhibited excellent storage characteristics. The storability may be comprehensive result of low levels of ethylene production, aroma synthesis, softening-related activities, and gene expression. The research cleared the storage characteristics of ‘Shannongsu’ and ‘Xincixiang’ at room temperature for the first time, which will provide scientific theoretical guidance for fruit production and marketing

Association of Serum Bile Acid and Unsaturated Fatty Acid Profiles with the Risk of Diabetic Retinopathy in Type 2 Diabetic Patients.

AIM: We aimed to identify the ability of serum bile acids (BAs) and unsaturated fatty acids (UFAs) profiles to predict the development of diabetic retinopathy (DR) in type 2 diabetes mellitus (T2DM) patients. METHODS: We first used univariate and multivariate analysis to compare 15 serum BA and 11 UFA levels in healthy control (HC) group (n = 82), T2DM patients with DR (n = 58) and T2DM patients without DR (n = 60). Forty T2DM patients were considered for validation. Then, the receiver operating characteristic curve (ROC) and decision curve analysis were used to assess the diagnostic value and clinical benefit of serum biomarkers alone, clinical variables alone or in combination, and the area under the curve (AUC), integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were used to further assess whether the addition of biomarkers significantly improved the predictive ability of the model. RESULTS: Orthogonal partial least squares-discriminant analysis (OPLS-DA) of serum BAs and UFAs separated the three cohorts including HC, T2DM patients with or without DR. The difference in serum BA and UFA profiles of T2DM patients with or without DR was mainly manifested in the three metabolites of taurolithocholic acid (TLCA), tauroursodeoxycholic acid (TUDCA) and arachidonic acid (AA). Together, they had an AUC of 0.785 (0.918 for validation cohort) for predicting DR in T2DM patients. After adjusting for numerous confounding factors, TLCA, TUDCA, and AA were independent predictors that differentiated T2DM with or without DR. The results of AUC, IDI, and NRI demonstrated that adding these three biomarkers to a model with clinical variables statistically increased their predictive value and were replicated in our independent validation cohort. CONCLUSION: These findings highlight the association of three metabolites, TLCA, TUDCA and AA, with DR and may indicate their potential value in the pathogenesis of DR

Functional analysis of BMP-miR-17 family-BMPRII negative feedback loop in neuron apoptosis.

<p>(<b>A</b>) TUNEL assay and quantification in different groups of primary cortical neurons. Cells were transfected with miR-17 family sponge or miR-17 mimics for 12 h, followed with or without BMP2 (50 ng/ml) treatment for 5 days (left panels, scale bar = 20 μm, arrows: TUNEL positive cells). Quantitative analysis of apoptotic cell ratios is shown (right panels). *p< 0.05, **p < 0.01, vs Mock. (<b>B</b>) Western blot of BMPRII, PTEN, p-AKT and cleaved-caspase 3 levels in primary cortical neuron tranfected with miR-17 family sponge or miR-17 mimics followed with BMP2 (50ng/ml) treatment for 6h. (<b>C</b>-<b>D</b>) Quantitative analysis of BMPRII, PTEN, p-AKT and cleaved-caspase 3 levels in differently treated neurons. *p< 0.05, **p < 0.01, vs Control/Scramble. Data shown are the mean ± SD for three independent experiments.</p

BMP2 negatively regulates BMPRII protein level through induction of miR-17 family.

<p>(<b>A</b>) Time course of BMPRII protein levels in primary cortical neurons under BMP2 (10 ng/ml) treatment: representative Western blot (upper panel) and quantitative analysis of BMPRII level (bottom panel). **p < 0.01, vs 0 h BMP2. (<b>B</b>) Time course of miRNA expression in primary cortical neurons under the treatment of BMP2 (10ng/ml). *p< 0.05, **p < 0.01, vs 0 h BMP2. (<b>C</b>) Time course of BMPRII mRNA levels in primary cortical neurons under BMP2 (10ng/ml) treatment. (<b>D</b>) Luciferase reporter activity of different groups of SH-SY5Y cells. **p < 0.01, vs Control. (<b>E</b>) Protein analysis of BMPRII in different groups of primary culture: representative Western blot (upper panel) and quantitative analysis of BMPRII level (bottom panel). **p < 0.01, vs Control. Data shown are the mean ± SD for three independent experiments.</p

miR-17/93 represses BMPRII expression.

<p>(<b>A</b>) Phylogenetic sequence alignment of miR-17 family seed sequence in wild-type (wt) and mutant (mut) BMPRII 3’-UTR. Luciferase reporters carrying wild-type or mutant BMPRII 3’-UTR were co-transfected into SH-SY5Y cells along with the indicated oligonucleotides. Cells were maintained for 48 hours before luciferase activity was determined. (<b>B</b>) Mature miRNA sequences of miR-17 family with seed sequence capital highlighted. (<b>C</b>-<b>D</b>) RNA analysis (left) and luciferase reporter activity (right) of different groups of SH-SY5Y cells transfected with miR-17/93 mimics or/and miR-17/93 inhibitors. *p< 0.05, **p < 0.01, vs Scramble. (<b>E</b>-<b>I</b>) Protein analysis of BMPRII (left) and miRNA levels (right) in primary neuron transfected with miR-17/93 mimics, miR-17/93 inhibitors or miR-17 family sponge. *p< 0.05, **p < 0.01, vs Scramble/Control. Data shown are the mean ± SD for three independent experiments.</p