Two soybean homologues of TERMINAL FLOWER 1 control flowering time under long day conditions

Flowering time is a key agronomic trait that directly affect the adaptation and yield of soybean.After whole genome duplications,about 75%of genes being represented by multiple copies in soybean.There are four TERMINAL FLOWER 1(TFL1)genes in soybean,and the TFL1b(Dt1)has been characterized as the determinant of stem growth habit.The function of other TFL1 homologs in soybean is still unclear.Here,we generated knockout mutants by CRISPR/Cas9 genome editing technology and found that the tfl1c/tfl1d double mutants flowered significantly earlier than wild-type plants.We investigated that TFL1c and TFL1d could physically interact with the b ZIP transcription factor FDc1 and bind to the promoter of APETALA1a(AP1a).RNA-seq and q RT-PCR analyses indicated that TFL1c and TFL1d repressed the expressions of the four AP1 homologs and delayed the flowering time in soybean.The two genes play important roles in the regulation of flowering time in soybean and mainly act as the flowering inhibitors under long-day conditions.Our results identify novel components in the flowering-time regulation network of soybean and will be invaluable for molecular breeding of improved soybean yield.

复发性胸腺瘤PD-L1和p53表达的临床意义

目的:分析复发性胸腺瘤PD-L1和p53的表达及与世界卫生组织(WHO)分型的关系。方法:回顾性分析2008年1月至2015年12月于浙江大学医学院附属第二医院行胸腺瘤完整切除术并行组织病理学检查的患者资料,对电话随访有效的患者标本行免疫组织化学标记物PD-L1和p53检测。对复发组和未复发组的WHO分型及免疫组织化学标记物PD-L1和p53的检测结果差异进行统计学分析。结果:纳入20例复发性胸腺瘤(男性13例,女性7例)和61例未复发胸腺瘤(男性27例,女性34例),两组间在WHO分型构成方面差异有统计学意义(P=0.001)。81例胸腺瘤总体复发率为24.69%。各WHO分型复发率中,A型复发率最低(0),C型复发率最高(57.14%),不同分型间复发率差异有统计学意义(P=0.017)。复发组PD-L1表达分值和p53的表达等级分别较未复发组更高(P=0.02和P=0.019)。在所有标本中,PD-L1分值和WHO分型呈显著正相关(r=0.358,P=0.001);PD-L1分值和p53等级呈显著正相关(r=0.317,P=0.004)。结论:WHO分型、PD-L1和p53的表达对预测胸腺瘤复发的不良行为具有重要的临床价值。

Cancer incidence in Beijing, 2014

Objective： To analyze cancer incidence data in Beijing in 2014 and temporal trends for selected common cancers during 2005 and 2014.Methods： A total of 144 secondary and tertiary hospitals reported newly diagnosed cancer cases to Beijing Cancer Registry, which covers 13 million residents in Beijing. The cancer incidence rate was calculated in strata by cancer type, sex, age group and area. The population composition of China in 1982 and Segi＇s population structure were used to calculate age-standardized rates. Extensive procedures were used to assure the quality of the data.Results： The overall data quality indicators of the percentage of morphology verification（MV）（%）, the percentage of death certificate-only（DCO）（%） and the mortality to incidence ratio（M/I） were 72.15%, 0.94% and0.54 respectively. A total of 45,300 new cancer cases were diagnosed in Beijing in 2014. The incidence rate was341.92/100,000（343.50/100,000 in males, 340.33/100,000 in females）, and the age-standardized incidence rates by Chinese standard population（ASIRC） and by world standard population（ASIRW） were 143.48/100,000 and182.99/100,000, respectively. The cumulative incidence rate for cancer before 75 years was 20.61%. Cancers of lung, colorectum, liver, stomach and prostate were the top five common cancer types for males, while cancers of breast, lung, thyroid, colorectum and uterus were the top five common cancer types for females. The different patterns were also observed between rural and urban areas. Regarding temporal trends, the incidence of thyroid cancer has the fastest growth between 2005 and 2014. The incidence of liver cancer decreased, and stomach and esophageal cancer also decreased significantly for males in the last decade. Incidence rate for lung cancer was relatively stable during that period of time.Conclusions： With more than 45,000 new cases in Beijing in 2014, cancer remains an important public health problem. Actions should be taken to diminish total cancer incidence in Beijing.

Development and validation of InDel markers for identification of QTL underlying flowering time in soybean

Soybean [Glycine max(L.) Merrill] is a major plant source of protein and oil. An accurate and well-saturated molecular linkage map is a prerequisite for forward genetic studies of gene function and for modern breeding for many useful agronomic traits. Next-generation sequence data available in public databases provides valuable information and offers new insights for rapid and efficient development of molecular markers. In this study, we attempted to show the feasibility and facility of using genomic resequencing data as raw material for identifying putative In Del markers. First, we identified 17,613 In Del sites among 56 soybean accessions and obtained 12,619 primer pairs. Second, we constructed a genetic map with a random subset of 2841 primer pairs and aligned 300 polymorphic markers with the 20 consensus linkage groups(LG). The total genetic distance was 2347.3 c M and the number of mapped markers per LG ranged from 10 to 23 with an average of 15 markers. The largest and smallest genetic distances between adjacent markers were 52.3 c M and 0.1 cM, respectively. Finally, we validated the genetic map constructed by newly developed In Del markers by QTL analysis of days to flowering(DTF) under different environments. One major QTL(qDTF4) and four minor QTL(qDTF20, qDTF13, qDTF12,and q DTF11) on 5 LGs were detected. These results demonstrate the utility of the In Del markers developed in this work for map-based cloning and molecular breeding in soybean.

Advances in the pathogenesis of Rett syndrome using cell models

Rett syndrome(RTT)is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders.MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity.As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models,cell models cultured in vitro play indispensable roles.Here we reviewed the research progress in the pathogenesis of RTT at the cellular level,summarized the preclinical-research-related applications,and prospected potential future development.

Multiplex CRISPR/Cas9-mediated knockout of soybean LNK2 advances flowering time

Flowering time is an important agronomic trait for soybean yield and adaptation. However, the genetic basis of soybean adaptation to diverse latitudes is still not clear. Four NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED 2(LNK2) homeologs of Arabidopsis thaliana LNK2 were identified in soybean. Three single-guide RNAs were designed for editing the four LNK2 genes. A transgene-free homozygous quadruple mutant of the LNK2 genes was developed using the CRISPR(clustered regularly interspaced short palindromic repeats)/Cas9(CRISPR-associated protein 9). Under long-day(LD) conditions, the quadruple mutant flowered significantly earlier than the wild-type(WT). Quantitative real-time PCR(q RT-PCR)revealed that transcript levels of LNK2 were significantly lower in the quadruple mutant than in the WT under LD conditions. LNK2 promoted the expression of the legume-specific E1 gene and repressed the expression of FT2 a. Genetic markers were developed to identify LNK2 mutants for soybean breeding.These results indicate that CRISPR/Cas9-mediated targeted mutagenesis of four LNK2 genes shortens flowering time in soybean. Our findings identify novel components in flowering-time control in soybean and may be beneficial for further soybean breeding in high-latitude environments.

Comments on‘Downregulation of hepatic ceruloplasmin ameliorates NAFLD via SCO1–AMPK–LKB1 complex’

Human health requires macronutrients,such as amino acids,glucose,and lipids,as well as micronutrients,including copper and iron.Copper is required for the assembly of various enzymes,such as copper/zinc superoxide dismutase and cytochrome c oxidase(Kim et al.,2008).It has been well documented that adenosine monophosphate-activated protein kinase(AMPK)senses intracellular glucose concentrations(Li et al.,2019),mTOR is responsible for monitoring intracellular amino acid levels(Liu and Sabatini,2020),and CD36 functions as a sensor for intracellular lipid amounts(Hao et al.,2020).However,it is still unclear how intracellular copper dynamic changes are sensed and whether copper plays a crucial messenger role in the regulation of metabolism of macronutrients.

Parallel selection of distinct Tof5 alleles drove the adaptation of cultivated and wild soybean to high latitudes

Photoperiod responsiveness is a key factor limiting the geographic distribution of cultivated soybean and its wild ancestor.In particular,the genetic basis of the adaptation in wild soybean remains poorly understood.In this study,by combining whole-genome resequencing and genome-wide association studies we identified a novel locus,Time of Flowering 5(Tof5),which promotes flowering and enhances adaptation to high latitudes in both wild and cultivated soybean.By genomic,genetic and transgenic analyses we showed that Tof5 en-codes a homolog of Arabidopsis thaliana FRUITFULL(FUL).Importantly,further analyses suggested that different alleles of Tof5 have undergone parallel selection.The Tof5H1 allele was strongly selected by humans after the early domestication of cultivated soybean,while Tof5H2 allele was naturally selected in wild soybean,and in each case facilitating adaptation to high latitudes.Moreover,we found that the key flowering repressor E1 suppresses the transcription of Tof5 by binding to its promoter.In turn,Tof5 physically associates with the promoters of two important FLOWERING LOCUS T(FT),FT2a and FT5a,to upregulate their transcription and promote flowering under long photoperiods.Collectively,ourfindings provide insights into how wild soybean adapted to high latitudes through natural selection and indicate that cultivated soybean underwent changes in the same gene but evolved a distinct allele that was artificially selected after domestication.

Soybean AP1 homologs control flowering time and plant height

Flowering time and plant height are key agronomic traits that directly affect soybean(Glycine max)yield.APETALA1(AP1)functions as a class A gene in the ABCE model for floral organ development,helping to specify carpel,stamen,petal,and sepal identities.There are four AP1 homologs in soybean,all of which are mainly expressed in the shoot apex.Here,we used clustered regularly interspaced short palindromic repeats(CRISPR)–CRISPR-associated protein 9 technology to generate a homozygous quadruple mutant,gmap1,with loss-of-function mutations in all four GmAP1 genes.Under short-day(SD)conditions,the gmap1 quadruple mutant exhibited delayed flowering,changes in flower morphology,and increased node number and internode length,resulting in plants that were taller than the wild type.Conversely,overexpression of GmAP1a resulted in early flowering and reduced plant height compared to the wild type under SD conditions.The gmap1 mutant and the overexpression lines also exhibited altered expression of several genes related to flowering and gibberellic acid metabolism,thereby providing insight into the role of GmAP1 in the regulatory networks controlling flowering time and plant height in soybean.Increased node number is the trait with the most promise for enhancing soybean pod number and grain yield.Therefore,the mutant alleles of the four AP1 homologs described here will be invaluable for molecular breeding of improved soybean yield.

Tumor necrosis factor-α signaling in nonalcoholic steatohepatitis and targeted therapies

Nonalcoholic steatohepatitis(NASH),an inflammatory subtype of nonalcoholic fatty liver disease,is featured by significantly elevated levels of various proinflammatory cytokines.Among numerous proinflammatory factors that contribute to NASH pathogenesis,the secreted protein,tumor necrosis factoralpha(TNF-α),plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target.In this review,we will first systematically describe the preclinical studies on the biochemical function of TNF-αand its intracellular downstream signaling mechanisms through its receptors.Moreover,we extensively discuss its functions in regulating inflammation,cell death,and fibrosis of liver cells in the pathogenesis of NASH,and the molecular mechanism that TNF-αexpression is regulated by NF-κB and other upstream master regulators during NASH progression.As TNF-αis one of the causal factors that remarkably contributes to NASH progression,combination of therapeutic modalities,including TNF-α-based therapies may lead to the resolution of NASH via multiple pathways and thus generate clinical benefits.For translational studies,we summarize recent advances in strategies targeting TNF-αand its signaling pathway,which paves the way for potential therapeutic treatments for NASH in the future.

A New Next-Generation Sequencing-Based Assay for Concurrent Preimplantation Genetic Diagnosis of Charcot-Marie-Tooth Disease Type 1A and Aneuploidy Screening

Charcot-Marie-Tooth （CMT） disease is the most common hereditary neuropathy, with a population prevalence of 1 in 2500. CMT disease type 1A （CMT1A）, accounting for ~70% of CMT1 cases and ~ 50% of all CMT cases, is transmitted in an autosomal dominant manner. CMT1A maps to chromo- some 17pl 1.2 and is caused, in the majority of cases, by a 1.4- Mb tandem duplication that includes the peripheral myelin protein22 （PMP22） gene （Li et al., 2013）. The disease usually presents in the first 20 years of age, causing difficulty in walking or running, distal symmetrical muscle weakness and wasting, and sensory loss （van Paassen et al., 2014）.

A recent retrotransposon insertion of J caused E6 locus facilitating soybean adaptation into low latitude

Soybean(Glycine max) is an important legume crop that was domesticated in temperate regions.Soybean varieties from these regions generally mature early and exhibit extremely low yield when grown under inductive short-day(SD) conditions at low latitudes. The long-juvenile(LJ) trait, which is characterized by delayed flowering and maturity,and improved yield under SD conditions, allowed the cultivation of soybean to expand to lower latitudes. Two major loci control the LJ trait: J and E6. In the current study, positional cloning, sequence analysis, and transgenic complementation confirmed that E6 is a novel allele of J, the ortholog of Arabidopsis thaliana EARLY FLOWERING 3(ELF3). The mutant allele e6^(PG), which carries a Ty1/Copia-like retrotransposon insertion, does not suppress the legume-specific flowering repressor E1, allowing E1 to inhibit Flowering Locus T(FT) expression and thus delaying flowering and increasing yields under SD conditions. The e6^(PG)allele is a rare allele that has not been incorporated into modern breeding programs.The dysfunction of J might have greatly facilitated the adaptation of soybean to low latitudes. Our findings increase our understanding of the molecular mechanisms underlying the LJ trait and provide valuable resources for soybean breeding.

Current overview on the genetic basis of key genes involved in soybean domestication

Modern crops were created through the domestication and genetic introgression of wild relatives and adaptive differentiation in new environments.Identifying the domestication-related genes and unveiling their molecular diversity provide clues for understanding how the domesticated variants were selected by ancient people,elucidating how and where these crops were domesticated.Molecular genetics and genomics have explored some domestication-related genes in soybean(Glycine max).Here,we summarize recent studies about the quantitative trait locus(QTL)and genes involved in the domestication traits,introduce the functions of these genes,clarify which alleles of domesticated genes were selected during domestication.A deeper understanding of soybean domestication could help to break the bottleneck of modern breeding by highlighting unused genetic diversity not selected in the original domestication process,as well as highlighting promising new avenues for the identification and research of important agronomic traits among different crop species.