Efficacy and safety of infliximab in the treatment of Kawasaki disease: A systematic review and meta-analysis.

Infliximab is a monoclonal antibody specifically binding tumor necrosis factor-alpha and has been approved for the treatment of several inflammatory disorders. However, the efficacy of infliximab in primary treatment of Kawasaki disease (KD) or retreatment of intravenous immunoglobulin (IVIG)-resistant KD in children is controversial. Therefore, we conducted a meta-analysis to compare the efficacy of infliximab alone or in combination with IVIG to IVIG. Eligible randomized and non-randomized trials were retrieved by searching literature databases prior to May 31, 2023. Pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated for dichotomous variables, and mean difference (MD) with 95% CI was estimated for continuous variables. A total of 14 eligible studies comprising 1257 participants were included. In refractory KD, infliximab alone was associated with a higher effectiveness rate (OR = 4.48, 95% CI 2.67-7.52) and defervescence rate (OR = 5.01, 95% CI 2.99-8.37) and resulted in a 1.08-day-shorter duration of fever (95% CI 0.61-1.55, P < 0.001) and 1.36-day-shorter length of hospital stay (95% CI 0.65-2.08) compared with IVIG. Incidences of coronary artery lesions (CALs), newly developing CALs, and CAL regression did not differ between both groups. For initial treatment of KD, infliximab in addition to IVIG led to a nominally significant higher effectiveness rate (OR = 2.26, 95% CI 1.02-5.01) and a larger reduction of right coronary artery Z score (MD = -0.24, 95% CI -0.27 to -0.21) but did not show additional efficacy in improving other outcomes. The safety profile was similar between both groups.   Conclusion: The meta-analysis demonstrates that infliximab alone is a well-tolerated and effective treatment for IVIG-resistant KD. The additional efficacy of infliximab to IVIG for initial treatment of KD is limited. More large and high-quality trials are needed to confirm the efficacy of infliximab, especially for intensification of primary treatment for KD. What is Known: • Infliximab is a novel monoclonal antibody specifically blocking tumor necrosis factor-alpha and is approved for treatment of several immune-mediated inflammatory disorders. • The efficacy of infliximab in treating children with Kawasaki disease is controversial. What is New: • Infliximab is an effective and safe treatment for children with refractory Kawasaki disease but adds limited efficacy to intravenous immunoglobulin for initial treatment of Kawasaki disease.

The AP2/ERF transcription factor TOE4b regulates photoperiodic flowering and grain yield per plant in soybean.

Photoperiod-mediated flowering determines the phenological adaptability of crops including soybean (Glycine max). A genome-wide association study (GWAS) identified a new flowering time locus, Time of flowering 13 (Tof13), which defined a gene encoding an AP2/ERF transcription factor. This new transcription factor, which we named TOE4b, is localized in the nucleus. TOE4b has been selected for soybean latitude adaptability. The existing natural variant TOE4bH4 was rare in wild soybean accessions but occurred more frequently in landraces and cultivars. Notably, TOE4bH4 improved high-latitude adaptation of soybean to some extent. The gene-edited TOE4b knockout mutant exhibited earlier flowering, conversely, TOE4b overexpression delayed flowering time. TOE4b is directly bound to the promoters and gene bodies of the key flowering integration factor genes FT2a and FT5a to inhibit their transcription. Importantly, TOE4b overexpression lines in field trials not only showed late flowering but also altered plant architecture, including shorter internode length, more internodes, more branches and pod number per plant, and finally boosted grain yield per plant by 60% in Guangzhou and 87% in Shijiazhuang. Our findings therefore identified TOE4b as a pleiotropic gene to increase yield potential per plant in soybean, and these results provide a promising option for breeding a soybean variety with an idealized plant architecture that promotes high yields.

Natural variation of FKF1 controls flowering and adaptation during soybean domestication and improvement.

Soybean (Glycine max) is a major source of protein and edible oil world-wide and is cultivated in a wide range of latitudes. However, it is extremely sensitive to photoperiod, which influences flowering time, maturity, and yield, and severely limits soybean latitude adaptation. In this study, a genome-wide association study (GWAS) identified a novel locus in accessions harboring the E1 allele, called Time of flowering 8 (Tof8), which promotes flowering and enhances adaptation to high latitude in cultivated soybean. Gene functional analyses showed that Tof8 is an ortholog of Arabidopsis FKF1. We identified two FKF1 homologs in the soybean genome. Both FKF1 homologs are genetically dependent on E1 by binding to E1 promoter to activate E1 transcription, thus repressing FLOWERING LOCUS T 2a (FT2a) and FT5a transcription, which modulate flowering and maturity through the E1 pathway. We also demonstrate that the natural allele FKF1bH3 facilitated adaptation of soybean to high-latitude environments and was selected during domestication and improvement, leading to its rapid expansion in cultivated soybean. These findings provide novel insights into the roles of FKF1 in controlling flowering time and maturity in soybean and offer new means to fine-tune adaptation to high latitudes and increase grain yield.

Genome-wide identification and functional prediction of BYPASS1-related (BPS1) homologs in soybean.

The BYPASS1-related gene (BPS1) encodes a protein with an unknown functional domain that regulates plant organ growth and development by inhibiting the continuous production of a root-derived long-distance signaling molecule called bypass (bps). We conducted a comprehensive study to investigate the BPS gene family in soybean and identified twenty-three BPS genes in Glycine max and twenty BPS genes in Glycine soja (wild soybean). Collinearity analysis revealied the existence of multiple orthologs of soybean BPS genes in wild soybean, indicating incomplete conservation between the BPS genes of soybean and wild soybean. Phylogenetic analysis successfully categorized all BPS genes into five distinct groups. We further scrutinized their chromosomal locations, gene structures, conserved motifs, cis-acting elements, and expression patterns. Leveraging publicly available data on genetic variation, phenotypic variation, and single-cell transcriptome sequencing of root nodules, we discovered a potential association between BPS genes and multiple soybean traits, particularly those related to the root nodule phenotype. This pioneering study provides a systematic and comprehensive examination of the BPS gene family in soybean. The findings establish a robust foundation for future investigations into the functional roles of BPS genes in plant growth and development. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01403-2.

GIGANTEA orthologs, E2 members, redundantly determine photoperiodic flowering and yield in soybean.

Soybean (Glycine max L.) is a typical photoperiod-sensitive crop, such that photoperiod determines its flowering time, maturity, grain yield, and phenological adaptability. During evolution, the soybean genome has undergone two duplication events, resulting in about 75% of all genes being represented by multiple copies, which is associated with rampant gene redundancy. Among duplicated genes, the important soybean maturity gene E2 has two homologs, E2-Like a (E2La) and E2-Like b (E2Lb), which encode orthologs of Arabidopsis GIGANTEA (GI). Although E2 was cloned a decade ago, we still know very little about its contribution to flowering time and even less about the function of its homologs. Here, we generated single and double mutants in E2, E2La, and E2Lb by genome editing and determined that E2 plays major roles in the regulation of flowering time and yield, with the two E2 homologs depending on E2 function. At high latitude regions, e2 single mutants showed earlier flowering and high grain yield. Remarkably, in terms of genetic relationship, genes from the legume-specific transcription factor family E1 were epistatic to E2. We established that E2 and E2-like proteins form homodimers or heterodimers to regulate the transcription of E1 family genes, with the homodimer exerting a greater function than the heterodimers. In addition, we established that the H3 haplotype of E2 is the ancestral allele and is mainly restricted to low latitude regions, from which the loss-of-function alleles of the H1 and H2 haplotypes were derived. Furthermore, we demonstrated that the function of the H3 allele is stronger than that of the H1 haplotype in the regulation of flowering time, which has not been shown before. Our findings provide excellent allelic combinations for classical breeding and targeted gene disruption or editing.

Agronomical selection on loss-of-function of GIGANTEA simultaneously facilitates soybean salt tolerance and early maturity.

Salt stress and flowering time are major factors limiting geographic adaptation and yield productivity in soybean (Glycine max). Although improving crop salt tolerance and latitude adaptation are essential for efficient agricultural production, whether and how these two traits are integrated remains largely unknown. Here, we used a genome-wide association study to identify a major salt-tolerance locus controlled by E2, an ortholog of Arabidopsis thaliana GIGANTEA (GI). Loss of E2 function not only shortened flowering time and maturity, but also enhanced salt-tolerance in soybean. E2 delayed soybean flowering by enhancing the transcription of the core flowering suppressor gene E1, thereby repressing Flowering Locus T (FT) expression. An E2 knockout mutant e2CR displayed reduced accumulation of reactive oxygen species (ROS) during the response to salt stress by releasing peroxidase, which functions in ROS scavenging to avoid cytotoxicity. Evolutionary and population genetic analyses also suggested that loss-of-function e2 alleles have been artificially selected during breeding for soybean adaptation to high-latitude regions with greater salt stress. Our findings provide insights into the coupled selection for adaptation to both latitude and salt stress in soybean; and offer an ideal target for molecular breeding of early-maturing and salt-tolerant cultivars.

The legume-specific transcription factor E1 controls leaf morphology in soybean.

BACKGROUND: The leaf is a determinate organ essential for photosynthesis, whose size and shape determine plant architecture and strongly affect agronomic traits. In soybean, the molecular mechanism of leaf development is not well understood. The flowering repressor gene E1, which encodes a legume-specific B3-like protein, is known to be the gene with the largest influence on soybean flowering and maturity. However, knowledge of its potential other functions remains poor. RESULTS: Here, we identified a novel function of E1 protein in leaf development. Unifoliolate leaves of E1-overexpression (E1-OE) lines were smaller and curlier than those of wild type DongNong 50 (DN50) and Williams 82 (W82). Transverse histological sections showed disorganized cells and significantly elevated palisade tissue number, spongy tissue number, and bulliform cell number in E1-OE lines. Our results indicate that E1 binds to the promoters of the leaf- development-related CINCINNATA (CIN)-like TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR (TCP) transcription factor genes to negatively regulate their expression. CONCLUSIONS: Our findings identify E1 as an important new factor in soybean leaf development.

Natural variation of the Dt2 promoter controls plant height and node number in semi-determinant soybean.

Soybean (Glycine max (L.) Merrill) is an important legume crop worldwide. Plant height (PH) is a quantitative trait that is closely related to node number (NN) and internode length (IL) on the main stem, which together affect soybean yield. To identify candidate genes controlling these three traits in soybean, we examined a recombinant inbred line (RIL) population derived from a cross between two soybean varieties with semi-determinate stems (Dt1Dt1Dt2Dt2), JKK378 and HXW. A quantitative trait locus (QTL) named qPH18 was identified that simultaneously controls PH, NN, and IL; this region harbors the semi-determinant gene Dt2. Sequencing of the Dt2 promoter from JKK378 identified three polymorphisms relative to HXW, including two single nucleotide polymorphism (SNPs) and an 18-bp insertion/deletion polymorphism (Indel). Dt2 expression was lower in the qPH18JKK378 group than in the qPH18HXW group, whereas the expression level of the downstream gene Dt1 showed the opposite tendency. A transient transfection assay confirmed that Dt2 promoter activity is lower in JKK378 compared to HXW. We propose that the polymorphisms in the dominant Dt2 promoter underlie the differences in Dt2 expression and its downstream gene Dt1 in the two parents, thereby affecting PH, NN, IL, and grain weight per plant without altering stem growth habit. Compared to the PH18HXW allele, the qPH18JKK378 allele suppresses Dt2 expression, which releases the inhibition of Dt1 expression, thus enhancing NN and grain yield. Our findings shed light on the mechanism underlying NN and PH in soybean and provide a molecular marker to facilitate breeding. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01235-y.

A critical suppression feedback loop determines soybean photoperiod sensitivity.

Photoperiod sensitivity is crucial for soybean flowering, adaptation, and yield. In soybean, photoperiod sensitivity centers around the evening complex (EC) that regulates the transcriptional level of the core transcription factor E1, thereby regulating flowering. However, little is known about the regulation of the activity of EC. Our study identifies how E2/GIGANTEA (GI) and its homologs modulate photoperiod sensitivity through interactions with the EC. During long days, E2 interacts with the blue-light receptor flavin-binding, kelch repeat, F box 1 (FKF1), leading to the degradation of J/ELF3, an EC component. EC also suppresses E2 expression by binding to its promoter. This interplay forms a photoperiod regulatory loop, maintaining sensitivity to photoperiod. Disruption of this loop leads to losing sensitivity, affecting soybean's adaptability and yield. Understanding this loop's dynamics is vital for molecular breeding to reduce soybean's photoperiod sensitivity and develop cultivars with better adaptability and higher yields, potentially leading to the creation of photoperiod-insensitive varieties for broader agricultural applications.

Epigenetic regulation of photoperiodic flowering in plants.

In response to changeable season, plants precisely control the initiation of flowering in appropriate time of the year to ensure reproductive success. Day length (photoperiod) acts as the most important external cue to determine flowering time. Epigenetics regulates many major developmental stages in plant life, and emerging molecular genetics and genomics researches reveal their essential roles in floral transition. Here, we summarize the recent advances in epigenetic regulation of photoperiod-mediated flowering in Arabidopsis and rice, and discuss the potential of epigenetic regulation in crops improvement, and give the brief prospect for future study trends.

Soybean reduced internode 1 determines internode length and improves grain yield at dense planting.

Major cereal crops have benefitted from Green Revolution traits such as shorter and more compact plants that permit high-density planting, but soybean has remained relatively overlooked. To balance ideal soybean yield with plant height under dense planting, shortening of internodes without reducing the number of nodes and pods is desired. Here, we characterized a short-internode soybean mutant, reduced internode 1 (rin1). Partial loss of SUPPRESSOR OF PHYA 105 3a (SPA3a) underlies rin1. RIN1 physically interacts with two homologs of ELONGATED HYPOCOTYL 5 (HY5), STF1 and STF2, to promote their degradation. RIN1 regulates gibberellin metabolism to control internode development through a STF1/STF2-GA2ox7 regulatory module. In field trials, rin1 significantly enhances grain yield under high-density planting conditions comparing to its wild type of elite cultivar. rin1 mutants therefore could serve as valuable resources for improving grain yield under high-density cultivation and in soybean-maize intercropping systems.