The WD40 domain-containing protein Ehd5 positively regulates flowering in rice (Oryza sativa).

Heading date (flowering time), which greatly influences regional and seasonal adaptability in rice (Oryza sativa), is regulated by many genes in different photoperiod pathways. Here, we characterized a heading date gene, Early heading date 5 (Ehd5), using a modified bulked segregant analysis method. The ehd5 mutant showed late flowering under both short-day and long-day conditions, as well as reduced yield, compared to the wild type. Ehd5, which encodes a WD40 domain-containing protein, is induced by light and follows a circadian rhythm expression pattern. Transcriptome analysis revealed that Ehd5 acts upstream of the flowering genes Early heading date 1 (Ehd1), RICE FLOWERING LOCUS T 1 (RFT1), and Heading date 3a (Hd3a). Functional analysis showed that Ehd5 directly interacts with Rice outermost cell-specific gene 4 (Roc4) and Grain number, plant height, and heading date 8 (Ghd8), which might affect the formation of Ghd7-Ghd8 complexes, resulting in increased expression of Ehd1, Hd3a, and RFT1. In a nutshell, these results demonstrate that Ehd5 functions as a positive regulator of rice flowering and provide insight into the molecular mechanisms underlying heading date.

Rituximab plus cladribine versus R-CHOP in frontline management of marginal zone lymphoma in China: a propensity-score matched multicenter study.

Marginal zone lymphoma (MZL) is an uncommon subtype of non-Hodgkin lymphoma (NHL). Combination of rituximab and cladribine (R-2CdA) is a potential option for indolent NHL (iNHL) and mantle cell lymphoma (MCL) patients. The goal of this multicenter retrospective study was to assess the efficacy and safety of R-2CdA in MZL to support consensus-reaching in first-line therapy in advanced-stage patients. We searched electronic medical records databases of eight centers in China. Between November 2014 and December 2019, 183 symptomatic advanced MZL patients (42 treated with R-2CdA and 141 with rituximab plus cyclophosphamide, adriamycin, vincristine, and prednisone [R-CHOP]) were identified. After propensity score matching (PSM) (1:1) to adjust for clinical characteristics, 39 patients from each treatment arm were selected. The overall response rate (ORR) (84.6% vs. 94.9%, P = 0.263) and complete response rate (59.0% vs. 66.7%, P = 0.487) were comparable between two protocols. Neither progression-free survival (PFS), including the 5-year PFS (67.7% vs. 56.1%, P = 0.352), nor overall survival was improved by R-2CdA versus R-CHOP. However, R-2CdA was more tolerable than R-CHOP in MZL patients regarding grade 3/4 hematological adverse events (odds ratio [OR] 0.565, 95% confidence interval [CI] neutropenic fever (OR 0.795, 95% CI 0.678-0.932), and infections (OR 0.800, 95% CI 0.640-1.000). Overall, our study demonstrated that R-2CdA is potentially as effective as but safer than R-CHOP in advanced MZL.

Genomic architecture of heterosis for yield traits in rice.

Increasing grain yield is a long-term goal in crop breeding to meet the demand for global food security. Heterosis, when a hybrid shows higher performance for a trait than both parents, offers an important strategy for crop breeding. To examine the genetic basis of heterosis for yield in rice, here we generate, sequence and record the phenotypes of 10,074 F2 lines from 17 representative hybrid rice crosses. We classify modern hybrid rice varieties into three groups, representing different hybrid breeding systems. Although we do not find any heterosis-associated loci shared across all lines, within each group, a small number of genomic loci from female parents explain a large proportion of the yield advantage of hybrids over their male parents. For some of these loci, we find support for partial dominance of heterozygous locus for yield-related traits and better-parent heterosis for overall performance when all of the grain-yield traits are considered together. These results inform on the genomic architecture of heterosis and rice hybrid breeding.

A map of rice genome variation reveals the origin of cultivated rice.

Crop domestications are long-term selection experiments that have greatly advanced human civilization. The domestication of cultivated rice (Oryza sativa L.) ranks as one of the most important developments in history. However, its origins and domestication processes are controversial and have long been debated. Here we generate genome sequences from 446 geographically diverse accessions of the wild rice species Oryza rufipogon, the immediate ancestral progenitor of cultivated rice, and from 1,083 cultivated indica and japonica varieties to construct a comprehensive map of rice genome variation. In the search for signatures of selection, we identify 55 selective sweeps that have occurred during domestication. In-depth analyses of the domestication sweeps and genome-wide patterns reveal that Oryza sativa japonica rice was first domesticated from a specific population of O. rufipogon around the middle area of the Pearl River in southern China, and that Oryza sativa indica rice was subsequently developed from crosses between japonica rice and local wild rice as the initial cultivars spread into South East and South Asia. The domestication-associated traits are analysed through high-resolution genetic mapping. This study provides an important resource for rice breeding and an effective genomics approach for crop domestication research.

Structure and function of rice hybrid genomes reveal genetic basis and optimal performance of heterosis.

Exploitation of crop heterosis is crucial for increasing global agriculture production. However, the quantitative genomic analysis of heterosis was lacking, and there is currently no effective prediction tool to optimize cross-combinations. Here 2,839 rice hybrid cultivars and 9,839 segregation individuals were resequenced and phenotyped. Our findings demonstrated that indica-indica hybrid-improving breeding was a process that broadened genetic resources, pyramided breeding-favorable alleles through combinatorial selection and collaboratively improved both parents by eliminating the inferior alleles at negative dominant loci. Furthermore, we revealed that widespread genetic complementarity contributed to indica-japonica intersubspecific heterosis in yield traits, with dominance effect loci making a greater contribution to phenotypic variance than overdominance effect loci. On the basis of the comprehensive dataset, a genomic model applicable to diverse rice varieties was developed and optimized to predict the performance of hybrid combinations. Our data offer a valuable resource for advancing the understanding and facilitating the utilization of heterosis in rice.

Heparin therapy in COVID-19: Call for randomized controlled trials (RCTs).

Coronavirus disease 2019 (COVID-19) is associated with increases in abnormal coagulation, and particularly D-dimer (D-D) levels. Heparin therapy has been recommended as pharmacologic thromboprophylaxis in patients hospitalized with COVID-19; however, data on its efficacy are lacking. The current study retrospectively analyzed changes in blood coagulation and the impact of heparin therapy. Medical records of 593 patients with confirmed COVID-19 were collected. On admission, elevated fibrinogen (Fg) levels were noted in with 42.2% (250/593) of patients, followed by increases in D-D (28.5%) and a prolonged prothrombin time (PT) (23.9%). Patients with severe/critical COVID-19 had a higher proportion of abnormal coagulation parameters than patients with mild/ordinary COVID-19. Dynamic changes in coagulation parameters were plotted on timeline charts for 97 patients with COVID-19 after heparin treatment. These changes, when combined with Fg, PT, D-D, and other indicators, may provide a relatively comprehensive description of coagulation abnormalities. Heparin seems to be important in the treatment of patients with COVID-19 based on the current findings. The efficacy of heparin in the treatment of COVID-19 should be confirmed by randomized controlled trials (RCTs) as soon as possible.

LncRNAs as epigenetic regulators of epithelial to mesenchymal transition in pancreatic cancer.

Pancreatic cancer is the leading cause of cancer-related mortality because of tumor metastasis. Activation of the epithelial-to-mesenchymal transition (EMT) pathway has been confirmed to be an important driver of pancreatic cancer progression from initiation to metastasis. Long noncoding RNAs (lncRNAs) have been reported to exert essential physiological functions in pancreatic cancer progression by regulating the EMT program. In this review, we have summarized the role of EMT-related lncRNAs in human pancreatic cancer and the potential molecular mechanisms by which lncRNAs can be vital epigenetic regulators of epithelial to mesenchymal transition. Specifically, EMT-activating transcription factors (EMT-TFs) regulate EMT via TGF-ß/Smad, Wnt/ß-catenin, and JAK/STAT pathways. In addition, the interaction between lncRNAs and HIF-1α and m6A RNA methylation also have an impact on tumor metastasis and EMT in pancreatic cancer. This review will provide insights into lncRNAs as promising biomarkers for tumor metastasis and potential therapeutic strategies for pancreatic cancer.

Identification of prognostic immune-related lncRNAs in pancreatic cancer.

Long noncoding RNAs (lncRNAs) play a critical role in the immune regulation and tumor microenvironment of pancreatic cancer (PaCa). To construct a novel immune-related prognostic risk model for PaCa and evaluate the prognostic prediction of lncRNAs, essential immune-related lncRNAs (IRlncRNAs) were identified by Pearson correlation analysis of differentially expressed immune-related genes (IRGs) and IRlncRNAs in PaCa from The Cancer Genome Atlas (TCGA) and GTEx databases. Least absolute shrinkage and selection operator (LASSO) regression was also applied to construct a prognostic risk model of IRlncRNAs, and gene set enrichment analysis (GSEA) was further applied for functional annotation for these IRlncRNAs. A total of 148 IRlncRNAs were identified in PaCa to construct a prognostic risk model. Among them, lncRNA LINC02325, FNDC1-AS1, and ZEB2-AS1 were significantly upregulated in 69 pairs of PaCa tissues by qRT-PCR. ROC analyses showed that LINC02325 (AUC = 0.80), FNDC1-AS1 (AUC = 0.76), and ZEB2-AS1 (AUC = 0.75) had a good predictive effect on 5-year survival prognosis. We demonstrated that high expression levels of ZEB2-AS1 and LINC02325 were not only positively associated with tumor size and CA199, but elevated levels of ZEB2-AS1 and FNDC1-AS1 were also positively correlated with tumor stage. GSEA further revealed that immune-related pathways were mainly enriched in the high-risk groups. Several immune-related algorithms demonstrated that four IRlncRNAs were related to immune infiltration, immune checkpoints, and immune-related functions. Thus, the prognostic risk model based on IRlncRNAs in Paca indicates that the four IRlncRNA signatures may serve as predictors of survival and potential predictive biomarkers of the pancreatic tumor immune response.

Cytoplasmic and nuclear genome variations of rice hybrids and their parents inform the trajectory and strategy of hybrid rice breeding.

The male sterility (MS) line is a prerequisite for efficient production of hybrid seeds in rice, a self-pollinating species. MS line breeding is pivotal for hybrid rice improvement. Understanding the historical breeding trajectory will help to improve hybrid rice breeding strategies. Maternally inherited cytoplasm is an appropriate tool for phylogenetic reconstruction and pedigree tracing in rice hybrids. In this study, we analyzed the cytoplasmic genomes of 1495 elite hybrid rice varieties and identified five major types of cytoplasm, which correspond to different hybrid production systems. As the cytoplasm donors for hybrids, 461 MS lines were also divided into five major types based on cytoplasmic and nuclear genomic architecture. Specific core accessions cooperating with different fertility-associated genes drove the sequence divergence of MS lines. Dozens to hundreds of convergent and divergent selective sweeps spanning several agronomic trait-associated genes were identified among different types of MS lines. We further analyzed the cross patterns between different types of MS lines and their corresponding restorers. This study systematically analyzed the cytoplasmic genomes of rice hybrids revealed their relationships with nuclear genomes of MS lines, and illustrated the trajectory of hybrid rice breeding and the strategies for breeding different types of MS lines providing new insights for future improvement of hybrid rice.

Dissecting a heterotic gene through GradedPool-Seq mapping informs a rice-improvement strategy.

Hybrid rice breeding for exploiting hybrid vigor, heterosis, has greatly increased grain yield. However, the heterosis-related genes associated with rice grain production remain largely unknown, partly because comprehensive mapping of heterosis-related traits is still labor-intensive and time-consuming. Here, we present a quantitative trait locus (QTL) mapping method, GradedPool-Seq, for rapidly mapping QTLs by whole-genome sequencing of graded-pool samples from F2 progeny via bulked-segregant analysis. We implement this method and map-based cloning to dissect the heterotic QTL GW3p6 from the female line. We then generate the near isogenic line NIL-FH676::GW3p6 by introgressing the GW3p6 allele from the female line Guangzhan63-4S into the male inbred line Fuhui676. The NIL-FH676::GW3p6 exhibits grain yield highly increased compared to Fuhui676. This study demonstrates that it may be possible to achieve a high level of grain production in inbred rice lines without the need to construct hybrids.

Publisher Correction: Pan-genome analysis highlights the extent of genomic variation in cultivated and wild rice.

When published, this article did not initially appear open access. This error has been corrected, and the open access status of the paper is noted in all versions of the paper.

Pan-genome analysis highlights the extent of genomic variation in cultivated and wild rice.

The rich genetic diversity in Oryza sativa and Oryza rufipogon serves as the main sources in rice breeding. Large-scale resequencing has been undertaken to discover allelic variants in rice, but much of the information for genetic variation is often lost by direct mapping of short sequence reads onto the O. sativa japonica Nipponbare reference genome. Here we constructed a pan-genome dataset of the O. sativa-O. rufipogon species complex through deep sequencing and de novo assembly of 66 divergent accessions. Intergenomic comparisons identified 23 million sequence variants in the rice genome. This catalog of sequence variations includes many known quantitative trait nucleotides and will be helpful in pinpointing new causal variants that underlie complex traits. In particular, we systemically investigated the whole set of coding genes using this pan-genome data, which revealed extensive presence and absence of variation among rice accessions. This pan-genome resource will further promote evolutionary and functional studies in rice.

Autophagy as a target for hematological malignancy therapy.

Autophagy is an essential metabolic pathway by which the intracellular unwanted materials are digested within lysosomes for cellular homeostasis. It provides energy and building blocks upon starvation or other stresses. Autophagy even contributes to cell death especially under apoptosis incompetent conditions depending on the cellular contexts. Dysfunction of autophagy involves in the initiation and progression of multiple diseases and their treatments. But its principles and clinical applications have not been fully elucidated yet. Basal autophagy may serve as a tumor suppressive mechanism during tumorigenesis; nevertheless, excessive autophagy even works as a pro-survival pathway in already established cancers. Recently, mounting evidence highlighted its key roles in the genesis and therapy of various hematological malignancies. The combinations of autophagy inhibitors (such as chloroquine) with some first-line drugs, as well as novel autophagy-based manipulations, including Bcl-2 family regulation, caspase-dependent cleavage of ATG proteins and microRNA replacement are clinically or experimentally applied, representing promising approaches for their clinical treatments. This review is therefore to discuss the recent progress in autophagy machinery and its association with hematological malignancy therapy.

OsSPL13 controls grain size in cultivated rice.

Although genetic diversity has a cardinal role in domestication, abundant natural allelic variations across the rice genome that cause agronomically important differences between diverse varieties have not been fully explored. Here we implement an approach integrating genome-wide association testing with functional analysis on grain size in a diverse rice population. We report that a major quantitative trait locus, GLW7, encoding the plant-specific transcription factor OsSPL13, positively regulates cell size in the grain hull, resulting in enhanced rice grain length and yield. We determine that a tandem-repeat sequence in the 5' UTR of OsSPL13 alters its expression by affecting transcription and translation and that high expression of OsSPL13 is associated with large grains in tropical japonica rice. Further analysis indicates that the large-grain allele of GLW7 in tropical japonica rice was introgressed from indica varieties under artificial selection. Our study demonstrates that new genes can be effectively identified on the basis of genome-wide association data.

Genomic analysis of hybrid rice varieties reveals numerous superior alleles that contribute to heterosis.

Exploitation of heterosis is one of the most important applications of genetics in agriculture. However, the genetic mechanisms of heterosis are only partly understood, and a global view of heterosis from a representative number of hybrid combinations is lacking. Here we develop an integrated genomic approach to construct a genome map for 1,495 elite hybrid rice varieties and their inbred parental lines. We investigate 38 agronomic traits and identify 130 associated loci. In-depth analyses of the effects of heterozygous genotypes reveal that there are only a few loci with strong overdominance effects in hybrids, but a strong correlation is observed between the yield and the number of superior alleles. While most parental inbred lines have only a small number of superior alleles, high-yielding hybrid varieties have several. We conclude that the accumulation of numerous rare superior alleles with positive dominance is an important contributor to the heterotic phenomena.