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Additional file 3: Table S3. Position and effect of the blast resistance-associated region identified from the LTH��SA0169 F2 population

Additional file 11: Figure S2. Blast resistance responses of the gene-edited plants obtained by the CRISPR/Cas9 technique

Additional file 8: Table S8. Molecular markers of the Xa genes, Pi169-6(t), and Pi169-11(t) for marker-assisted backcrossing

Additional file 14: Figure S5. Plant morphology of the newly developed blast and bacterial blight double resistant lines

Additional file 7: Table S7. The origin and composition of mixed rice blast isolates

Additional file 2: Table S2. Segregation of rice blast resistance in the F2 populations

Additional file 5: Table S5. Summary of sequencing depth and coverage

Additional file 1: Table S1. Response of 22 rice varieties/lines to 187 blast isolates challenge (2019)

Additional file 1. Table S1. Definition of Codes for theChang Gung Memorial Hospital Examination Code Systems. Table S2. Definition of Codes for Different Coding System.

Additional file 13: Figure S4. Disease resistance study against rice bacterial blight (BB) pathogen Xanthomonas oryzae pv. oryzae (Xoo) XF-89b strain

Additional file 6: Table S6. List of the gene-edited plants of the NBS-LRR2 in TNG67 and SA0169 through the CRISPR/Cas9 technique

Additional file 10: Figure S1. Two genomic regions responsible for the blast resistance in SA0169 were identified

Additional file 12: Figure S3. The breeding scheme of the lines with blast and bacterial blight double resistance

Supplementary Information

Interferon-induced transmembrane protein3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. Here we studied clinical cohorts of patients with Bcell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting Bcells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the Bcell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In Bcell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3-/- naive Bcells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3-/- Bcells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant Bcells. Mechanistic experiments revealed that IFITM3 functions as a PIP3scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3-/- Bcells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after Bcells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of Bcells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P=2.2×10-16). Single-cell mutation and phospho-proteinanalyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene occur in ∼10% of B-cell acute lymphoblastic leukemia (B-ALL) and define a group of patients with dismal outcomes. Immunohistochemical staining of bone marrow biopsies from most of these patients revealed aberrant expression of BCL6, a transcription factor that promotes oncogenic B-cell transformation and drug resistance in B-ALL. Our genetic and ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analyses showed that MLL-AF4 and MLL-ENL fusions directly bound to the BCL6 promoter and up-regulated BCL6 expression. While oncogenic MLL fusions strongly induced aberrant BCL6 expression in B-ALL cells, germline MLL was required to up-regulate Bcl6 in response to physiological stimuli during normal B-cell development. Inducible expression of Bcl6 increased MLL mRNA levels, which was reversed by genetic deletion and pharmacological inhibition of Bcl6, suggesting a positive feedback loop between MLL and BCL6. Highlighting the central role of BCL6 in MLL-rearranged B-ALL, conditional deletion and pharmacological inhibition of BCL6 compromised leukemogenesis in transplant recipient mice and restored sensitivity to vincristine chemotherapy in MLL-rearranged B-ALL patient samples. Oncogenic MLL fusions strongly induced transcriptional activation of the proapoptotic BH3-only molecule BIM, while BCL6 was required to curb MLL-induced expression of BIM. Notably, peptide (RI-BPI) and small molecule (FX1) BCL6 inhibitors derepressed BIM and synergized with the BH3-mimetic ABT-199 in eradicating MLL-rearranged B-ALL cells. These findings uncover MLL-dependent transcriptional activation of BCL6 as a previously unrecognized requirement of malignant transformation by oncogenic MLL fusions and identified BCL6 as a novel target for the treatment of MLL-rearranged B-ALL.

Supplemental material, Supplementary_Tables_1_and_2_042819 for The irreversible HCV-associated risk of gastric cancer following interferon-based therapy: a joint study of hospital-based cases and nationwide population-based cohorts by Chun-Wei Chen, Jur-Shan Cheng, Tai-Di Chen, Puo-Hsien Le, Hsin-Ping Ku and Ming-Ling Chang in Therapeutic Advances in Gastroenterology

We report semiconducting behavior of monolayer graphene enabled through plasma activation of substrate surfaces. The graphene devices are fabricated by mechanical exfoliation onto pre-processed SiO2/Si substrates. Contrary to pristine graphene, these graphene samples exhibit a transport gap as well as nonlinear transfer characteristics, a large on/off ratio of 600 at cryogenic temperatures, and an insulating-like temperature dependence. Raman spectroscopic characterization shows evidence of sp3 hybridization of C atoms in the samples of graphene on activated SiO2/Si substrates. We analyze the hopping transport at low temperatures, and weak localization observed from magnetotransport measurements, suggesting a correlation between carrier localization and the sp3-type defects in the functionalized graphene. The present study demonstrates the functionalization of graphene using a novel substrate surface-activation method for future graphene-based applications.

Fluorescent organic compounds are of significant importance to the development of low-cost opto-electronic devices. Blue fluorescence from aromatic or olefinic molecules and their derivatives is particularly important for display and lighting applications. Thin film deposition of low-molecular-weight fluorescent organic compounds typically requires costly vacuum evaporation systems. On the other hand, solution-processable polymeric counterparts generally luminesce at longer wavelengths due to larger delocalization in the chain. Blue light emission from solution-processed materials is therefore of unique technological significance. Here we report near-UV to blue photoluminescence (PL) from solution-processed graphene oxide (GO). The characteristics of the PL and its dependence on the reduction of GO indicates that it originates from the recombination of electron-hole (e-h) pairs localized within small sp2 carbon clusters embedded within an sp3 matrix. These results suggest that a sheet of graphene provides a parent structure on which fluorescent components can be chemically engineered without losing the macroscopic structural integrity. Our findings offer a unique route towards solution-processable opto-electronics devices with graphene., Comment: Accepted for publication in Adv. Mater