The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia.

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

COIMMR: a computational framework to reveal the contribution of herbal ingredients against human cancer via immune microenvironment and metabolic reprogramming.

Immune evasion and metabolism reprogramming have been regarded as two vital hallmarks of the mechanism of carcinogenesis. Thus, targeting the immune microenvironment and the reprogrammed metabolic processes will aid in developing novel anti-cancer drugs. In recent decades, herbal medicine has been widely utilized to treat cancer through the modulation of the immune microenvironment and reprogrammed metabolic processes. However, labor-based herbal ingredient screening is time consuming, laborious and costly. Luckily, some computational approaches have been proposed to screen candidates for drug discovery rapidly. Yet, it has been challenging to develop methods to screen drug candidates exclusively targeting specific pathways, especially for herbal ingredients which exert anti-cancer effects by multiple targets, multiple pathways and synergistic ways. Meanwhile, currently employed approaches cannot quantify the contribution of the specific pathway to the overall curative effect of herbal ingredients. Hence, to address this problem, this study proposes a new computational framework to infer the contribution of the immune microenvironment and metabolic reprogramming (COIMMR) in herbal ingredients against human cancer and specifically screen herbal ingredients targeting the immune microenvironment and metabolic reprogramming. Finally, COIMMR was applied to identify isoliquiritigenin that specifically regulates the T cells in stomach adenocarcinoma and cephaelin hydrochloride that specifically targets metabolic reprogramming in low-grade glioma. The in silico results were further verified using in vitro experiments. Taken together, our approach opens new possibilities for repositioning drugs targeting immune and metabolic dysfunction in human cancer and provides new insights for drug development in other diseases. COIMMR is available at https://github.com/LYN2323/COIMMR.

Engineering exosomes derived from subcutaneous fat MSCs specially promote cartilage repair as miR-199a-3p delivery vehicles in Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease involving cartilage. Exosomes derived from Mesenchymal stem cells (MSCs) therapy improves articular cartilage repair, but subcutaneous fat (SC) stromal cells derived exosomes (MSCsSC-Exos), especially engineering MSCsSC-Exos for drug delivery have been rarely reported in OA therapy. This objective of this study was to clarify the underlying mechanism of MSCsSC-Exos on cartilage repair and therapy of engineering MSCsSC-Exos for drug delivery in OA. MSCsSC-Exos could ameliorate the pathological severity degree of cartilage via miR-199a-3p, a novel molecular highly enriched in MSCsSC-Exos, which could mediate the mTOR-autophagy pathway in OA rat model. Intra-articular injection of antagomiR-199a-3p dramatically attenuated the protective effect of MSCsSC-Exos-mediated on articular cartilage in vivo. Furthermore, to achieve the superior therapeutic effects of MSCsSC-Exos on injured cartilage, engineering exosomes derived from MSCsSC as the chondrocyte-targeting miR-199a-3p delivery vehicles were investigated in vitro and in vivo. The chondrocyte-binding peptide (CAP) binding MSCsSC-Exos could particularly deliver miR-199a-3p into the chondrocytes in vitro and into deep articular tissues in vivo, then exert the excellent protective effect on injured cartilage in DMM-induced OA mice. As it is feasible to obtain human subcutaneous fat from healthy donors by liposuction operation in clinic, meanwhile engineering MSCsSC-Exos to realize targeted delivery of miR-199a-3p into chondrocytes exerted excellent therapeutic effects in OA animal model in vivo. Through combining MSCsSC-Exos therapy and miRNA therapy via an engineering approach, we develop an efficient MSCsSC-Exos-based strategy for OA therapy and promote the application of targeted-MSCsSC-Exos for drug delivery in the future.

Simultaneous determination of multiple constituents, serum composition, and tissue distribution of Qingshen granule using ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry.

Qingshen granule, composed of 14 herbal drugs, is primarily used as the assistant therapy for chronic kidney disease. Qingshen granule chemical composition was complex, but its chemical constituents and the pharmacodynamic material basis remain unreported. Ultra-high-performance liquid chromatography (UHPLC)-quadrupole-orbitrap high-resolution mass spectrometry was applied to recognize the chemical constituents of Qingshen granule. The analysis was performed using the ACQUITY UHPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) with acetonitrile-0.1% formic acid as the mobile phase for gradient elution. The data were collected using heated electrospray ionization in positive and negative ion modes. This study successfully applied the UPHLC-quadrupole-orbitrap high-resolution mass spectrometry technique with the Compound Discoverer 3.3 platform to analyze Qingshen granule chemical composition. A total of 127 and 42 chemical components were identified in Qingshen granule in vitro and in vivo, respectively. In the tissue distribution of Qingshen granule, 9, 10, 11, 10, and 18 prototype components were detected in the heart, liver, spleen, lungs, and kidneys, respectively. Qingshen granule chemical constituents were characterized rapidly for the first time in this study, laying a foundation for further research on the substance basis and quality control of Qingshen granule in treating chronic kidney disease.

Ultra-purification of heavy metals and robustness of calcium silicate hydrate (C-S-H) nanocomposites.

For the sake of remediating the contamination of heavy metal ions (HMs) that poses high risk to the global environment, a novel inorganic nanocomposite with excellent robustness, calcium silicate hydrate (C-S-H), is synthesized at extremely low cost yet presents rapid adsorption rate and superhigh adsorption capacity. High concentrations of Cu(Ⅱ), Cd(Ⅱ), Co(Ⅱ) and Cr(Ⅲ) in wastewater can be purified to ultra-low level (∼0.008 mg L-1) within 60 min at low C-S-H dosage, the concentration and pH indexes of which meet the standard for direct discharge in China. The adsorption processes are spontaneous, following the Langmuir adsorption isotherm model, and its kinetics conforms to pseudo-second order model. Meanwhile, C-S-H presents excellent anti-interference performance during the ultra-purification of HMs when exposed to the acid environments, solutions with various HMs as well as high salinity. The ultra-purification of HMs and robustness of C-S-H is realized through multiple mechanisms based on adsorption, involving hydrolysis of HMs, electrostatic interaction, chemical microprecipitation, surface complexation and interlayer complexation, among which interlayer complexation is dominant. All these verify the robust performance and broad applicability of C-S-H to complex aqueous systems.

Deformation and Cracking Resistance of MgO-Incorporated Cementitious Material: A Review.

In China, MgO-based expansive agent (MEA) has been used for concrete shrinkage compensation and cracking control for over 40 years. The expansive behavior of MEA in cementitious materials could be manipulated to some extent by adjusting the calcination process of MEA and influenced by the restraint condition of the matrix. It is key to investigate the factors related to deformation and cracking resistance so that the desired performance of MEA in certain concrete structures could be achieved. This paper reviews the influence of key parameters such as hydration reactivity, dosage, and calcination conditions of MEA, the water-to-binder ratio, supplementary cementitious material, aggregates, and curing conditions on the deformation and cracking resistivity of cement paste, mortar, and concrete with an MEA addition. The numerical simulation methods and deformation prediction models are then summarized and analyzed for more reasonable estimations.

Pangenomic analysis of Chinese gastric cancer.

Pangenomic study might improve the completeness of human reference genome (GRCh38) and promote precision medicine. Here, we use an automated pipeline of human pangenomic analysis to build gastric cancer pan-genome for 185 paired deep sequencing data (370 samples), and characterize the gene presence-absence variations (PAVs) at whole genome level. Genes ACOT1, GSTM1, SIGLEC14 and UGT2B17 are identified as highly absent genes in gastric cancer population. A set of genes from unaligned sequences with GRCh38 are predicted. We successfully locate one of predicted genes GC0643 on chromosome 9q34.2. Overexpression of GC0643 significantly inhibits cell growth, cell migration and invasion, cell cycle progression, and induces cell apoptosis in cancer cells. The tumor suppressor functions can be reversed by shGC0643 knockdown. The GC0643 is approved by NCBI database (GenBank: MW194843.1). Collectively, the robust pan-genome strategy provides a deeper understanding of the gene PAVs in the human cancer genome.

[Corrigendum] Integrated transcriptomic and epigenetic data analysis identifies aberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Following the publication of this paper, the authors have realized that the final article did not indicate in the Authors' Contribution section that Fangce Wang and Zheng Li made equal contributions to this work (FW and ZL performed most of the statistical analyses and drafted the initial version of the manuscript). Therefore, the affiliations for this paper should have been written as follows (changes are highlighted in bold): FANGCE WANG1*, ZHENG LI1*, GUANGMING WANG1, XIAOXUE TIAN1, JIE ZHOU1, WENLEI YU1, ZHUOYI FAN1, LIN DONG1, JINYUAN LU1, JUN XU2, WENJUN ZHANG1 and AIBIN LIANG1. 1Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200092; 2Medical Center for Stem Cell Engineering and Transformation, East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China. *Contributed equally. The authors confirm that there are no further errors in the paper, and all the authors agree to this correction. The authors and the Editor apologize for any inconvenience caused. [the original article was published in Molecular Medicine Reports 21: 883­893, 2020, DOI: 10.3892/mmr.2019.10849].

Tied Infections: How Social Connectedness to Other COVID-19 Patients Influences Illness Severity.

Expanding on recent research on the transmission of COVID-19 via social networks, this article argues that exposure to familial and other close contacts who already have the disease may increase the severity of one's subsequent illness. We hypothesize that having family members or close contacts who were diagnosed with COVID-19 before one's own diagnosis exacerbates illness severity due to several potential mechanisms including changes in available social support access, increased stress and strain, and increased viral load due to the nature of one's exposure to the novel coronavirus. We analyze administrative data of all 417 patients who were diagnosed with COVID-19 in the Chinese city of Shenzhen between January 8 and February 25, 2020. Our analyses show that, when patients had family members or close ties diagnosed with COVID-19, they experienced more severe illness. We also find that patients with infected family members or close contacts did not have significantly extended total illness duration, due to their reduced time to diagnosis. The implications of both findings are discussed.

Predictive value of serological factors, maximal standardized uptake value and ratio of Ki67 in patients diagnosed with non-Hodgkin's lymphoma.

The present study aimed to determine the prognostic value of serological factors, positron emission tomography/computed tomography maximal standardized uptake value (SUVmax) and the immunohistochemical index ratio of Ki67 (Ki67%) for patients diagnosed with non-Hodgkin's lymphoma (NHL). A total of 120 patients with NHL who received regular chemotherapy and underwent serological, radiological and pathological examinations at Shanghai Tongji Hospital between July 2015 and March 2019 were retrospectively analyzed. Spearman's correlation analysis was preformed to describe the associations between different categories of indicators. Kaplan-Meier analysis and log-rank test were used to compare the survival of different subgroups. Receiver operating characteristic curves were generated to assess the predictive value of prominent indicators derived from Cox regression analysis. The results indicated that inflammatory cytokines were strongly associated with tumor burden indicators. The correlation between SUVmax and Ki67% was significant, and SUVmax of the biopsy site exhibited a stronger association with Ki67% (Ρ=0.529, P<0.001) compared with SUVmax of the whole body (Ρ=0.395, P=0.017). C-reactive protein (CRP), lactate dehydrogenase (LDH) and interleukin-6 could differentiate the survival status of patients with NHL, whereas no statistical significance in the estimation of overall survival (OS) was obtained for SUVmax and Ki67%. SUVmax of the biopsy site had only a limited value in the estimation of progression-free survival (PFS), whereas LDH, ß2-microglobulin (ß2-mg) and CRP were independent predictors of both OS and PFS with high sensitivity and specificity. Among all indicators, CRP and ß2-mg could predict both survival status and complete remission of patients with NHL, whereas the prognostic value of SUVmax and Ki67% requires further study and discussion.

Integrated transcriptomic and epigenetic data analysis identifiesaberrant expression of genes in acute myeloid leukemia with MLL­AF9 translocation.

Rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (AML). MLLT3, super elongation complex subunit (AF9) is one of the most common MLL fusion partners in AML. The present study aimed to explore the aberrant expression of genes associated with the MLL­AF9 translocation and identified potential new targets for the therapy of AML with MLL­AF9 translocation. The transcriptomic and epigenetic datasets were downloaded from National Center of Biotechnology Information Gene Expression Omnibus (GEO) database. Differentially expressed genes were obtained from two independent datasets (GSE68643 and GSE73457). Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the Database for Annotation, Visualization and Integrated Discovery. MLL­AF9­associated chromatin immunoprecipitation sequencing (ChIP­Seq) data was analyzed and identified binding sites for MLL­AF9 and wild type MLL (MLL WT). The ChIP­Seq of histone modification data was downloaded from the GEO database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the MLL­AF9 leukemia cells and normal hematopoietic cells at MLL­AF9 and MLL WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL­AF9 direct target genes. Upon validation using RNA­Seq data from the Therapeutically Applicable Research to Generate Effective Treatments AML project, eight potential direct target genes of MLL­AF9 were identified and further confirmed in MLL­AF9 mouse model using reverse transcription­quantitative polymerase chain reaction. These genes may have a critical role in AML with MLL­AF9 translocation.

HUPAN: a pan-genome analysis pipeline for human genomes.

The human reference genome is still incomplete, especially for those population-specific or individual-specific regions, which may have important functions. Here, we developed a HUman Pan-genome ANalysis (HUPAN) system to build the human pan-genome. We applied it to 185 deep sequencing and 90 assembled Han Chinese genomes and detected 29.5 Mb novel genomic sequences and at least 188 novel protein-coding genes missing in the human reference genome (GRCh38). It can be an important resource for the human genome-related biomedical studies, such as cancer genome analysis. HUPAN is freely available at http://cgm.sjtu.edu.cn/hupan/ and https://github.com/SJTU-CGM/HUPAN .

Discovery and characterization of the evolution, variation and functions of diversity-generating retroelements using thousands of genomes and metagenomes.

BACKGROUND: Diversity-generating retroelements (DGRs) are a unique family of retroelements that generate sequence diversity of DNA to benefit their hosts by introducing variations and accelerating the evolution of target proteins. They exist widely in bacteria, archaea, phage and plasmid. However, our understanding about DGRs in natural environments was still very limited. RESULTS: We developed an efficient computational algorithm to identify DGRs, and applied it to characterize DGRs in more than 80,000 sequenced bacterial genomes as well as more than 4,000 human metagenome datasets. In total, we identified 948 non-redundant DGRs, which expanded the number of known DGRs in bacterial genomes and human microbiomes by about 55%, and provided a much more comprehensive reference for the study of DGRs. Phylogenetic analysis was done for identified DGRs. The putative target genes of DGRs were searched, and the functions of these target genes were investigated with a comprehensive alignment against the nr database. CONCLUSIONS: DGR system is a powerful and universal mechanism to generate diversity. DGR evolution is closely associated with the living environment and their cassette structures. Furthermore, it may impact a wide range of functional processes in addition to receptor-binding. These results significantly improved our understanding about DGRs.

Novel sequences, structural variations and gene presence variations of Asian cultivated rice.

Genomic diversity within a species genome is the genetic basis of its phenotypic diversity essential for its adaptation to environments. The big picture of the total genetic diversity within Asian cultivated rice has been uncovered since the sequencing of 3,000 rice genomes, including the SNP data publicly available in the SNP-Seek database. Here we report other aspects of the genetic diversity, including rice sequences assembled from over 3,000 accessions but absent in the Nipponbare reference genome, structural variations (SVs) and gene presence/absence variations (PAVs) in 453 accessions with sequencing depth over 20x. Using either SVs or gene PAVs, we were able to reconstruct the population structure of O. sativa, which was consistent with previous result based on SNPs. Moreover, we demonstrated the usefulness of the new data sets by successfully detecting the strong association of the "Green Revolution gene", sd1, with plant height. Our data provide a more comprehensive view of the genetic diversity within rice, as well as additional genomic resources for research in rice breeding and plant biology.

Genomic variation in 3,010 diverse accessions of Asian cultivated rice.

Here we analyse genetic variation, population structure and diversity among 3,010 diverse Asian cultivated rice (Oryza sativa L.) genomes from the 3,000 Rice Genomes Project. Our results are consistent with the five major groups previously recognized, but also suggest several unreported subpopulations that correlate with geographic location. We identified 29 million single nucleotide polymorphisms, 2.4 million small indels and over 90,000 structural variations that contribute to within- and between-population variation. Using pan-genome analyses, we identified more than 10,000 novel full-length protein-coding genes and a high number of presence-absence variations. The complex patterns of introgression observed in domestication genes are consistent with multiple independent rice domestication events. The public availability of data from the 3,000 Rice Genomes Project provides a resource for rice genomics research and breeding.

EUPAN enables pan-genome studies of a large number of eukaryotic genomes.

SUMMARY: Pan-genome analyses are routinely carried out for bacteria to interpret the within-species gene presence/absence variations (PAVs). However, pan-genome analyses are rare for eukaryotes due to the large sizes and higher complexities of their genomes. Here we proposed EUPAN, a eukaryotic pan-genome analysis toolkit, enabling automatic large-scale eukaryotic pan-genome analyses and detection of gene PAVs at a relatively low sequencing depth. In the previous studies, we demonstrated the effectiveness and high accuracy of EUPAN in the pan-genome analysis of 453 rice genomes, in which we also revealed widespread gene PAVs among individual rice genomes. Moreover, EUPAN can be directly applied to the current re-sequencing projects primarily focusing on single nucleotide polymorphisms. AVAILABILITY AND IMPLEMENTATION: EUPAN is implemented in Perl, R and C ++. It is supported under Linux and preferred for a computer cluster with LSF and SLURM job scheduling system. EUPAN together with its standard operating procedure (SOP) is freely available for non-commercial use (CC BY-NC 4.0) at http://cgm.sjtu.edu.cn/eupan/index.html . CONTACT: ccwei@sjtu.edu.cn or jianxin.shi@sjtu.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

RPAN: rice pan-genome browser for ∼3000 rice genomes.

A pan-genome is the union of the gene sets of all the individuals of a clade or a species and it provides a new dimension of genome complexity with the presence/absence variations (PAVs) of genes among these genomes. With the progress of sequencing technologies, pan-genome study is becoming affordable for eukaryotes with large-sized genomes. The Asian cultivated rice, Oryza sativa L., is one of the major food sources for the world and a model organism in plant biology. Recently, the 3000 Rice Genome Project (3K RGP) sequenced more than 3000 rice genomes with a mean sequencing depth of 14.3×, which provided a tremendous resource for rice research. In this paper, we present a genome browser, Rice Pan-genome Browser (RPAN), as a tool to search and visualize the rice pan-genome derived from 3K RGP. RPAN contains a database of the basic information of 3010 rice accessions, including genomic sequences, gene annotations, PAV information and gene expression data of the rice pan-genome. At least 12 000 novel genes absent in the reference genome were included. RPAN also provides multiple search and visualization functions. RPAN can be a rich resource for rice biology and rice breeding. It is available at http://cgm.sjtu.edu.cn/3kricedb/ or http://www.rmbreeding.cn/pan3k.