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Cardiovascular diseases (CVDs) are the leading causes of death and disability worldwide, despite the wide diversity of molecular targets identified and the development of therapeutic methods. MicroRNAs (miRNAs) are a class of small (about 22 nucleotides) non-coding RNAs (ncRNAs) that negatively regulate gene expression at the post-transcriptional level in the cytoplasm and play complicated roles in different CVDs. While miRNA overexpression in one type of cell protects against heart disease, it promotes cardiac dysfunction in another type of cardiac cell. Moreover, recent studies have shown that, apart from cytosolic miRNAs, subcellular miRNAs such as mitochondria- and nucleus-localized miRNAs are dysregulated in CVDs. However, the functional properties of cellular- and subcellular-localized miRNAs have not been well characterized. In this review article, by carefully revisiting animal-based miRNA studies in CVDs, we will address the regulation and functional properties of miRNAs in various CVDs. Specifically, the cell–cell crosstalk and subcellular perspective of miRNAs are highlighted. We will provide the background for attractive molecular targets that might be useful in preventing the progression of CVDs and heart failure (HF) as well as insights for future studies.

Supplementary Figure 3 from Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Supplementary Figure 1 from Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Histone deacetylase inhibitors (HDACi) show promise as a novel class of antitumoral agents and have shown the ability to induce apoptosis of tumor cells. To gain a better understanding of the action of HDACi, we conducted a functional gene screen approach named suppression of mortality by antisense rescue technique to identify the key genes responsible for the tumor-selective killing trichostatin A. Over 20 genes associated with HDACi-induced mortality were identified. One of the confirmed positive hits is LIV1, a putative zinc transporter. LIV1 is significantly induced by treatment with HDACi in a number of tumor cells, but not in normal cells. Knockdown of LIV1 suppressed apoptosis induced by HDACi in tumor cells. Although HDACi induced a slight increase in the free intracellular zinc concentration, knockdown of LIV1 significantly enhanced the intracellular zinc level, which was associated with resistance to apoptosis. On the other hand, pretreatment of the cells with a specific zinc chelator TPEN reversed the apoptosis resistance conferred by knockdown of LIV1. However, the biological effects of TPEN were abolished by addition of physiologic concentrations of zinc. Taken together, the present study identifies LIV1 as a critical mediator responsible for HDACi-induced apoptosis. The effect of LIV1 is, at least in part, mediated by affecting intracellular zinc homeostasis, which may be related to alteration of the catalytic activity of the Caspase 3 and expression of some BCL-2 family genes. As such, these findings highlight a novel mechanism underlying the action of HDACi that could be potentially useful in the clinical setting. [Mol Cancer Ther 2009;8(11):3108–16]

Supplementary Figure 5 from Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Supplementary Figure 2 from Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Supplementary Figure 4 from Identification of LIV1, a Putative Zinc Transporter Gene Responsible for HDACi-Induced Apoptosis, Using a Functional Gene Screen Approach

Rust fungi (Pucciniales) are the largest group of plant pathogens. Adaptive radiation is a predominant feature in Pucciniales evolution.

The objective of the present study was to evaluate the difference in net clinical benefit of clopidogrel plus aspirin compared with ticagrelor plus aspirin after 12 months in patients in mainland China with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) with newer-generation drug-eluting stents (DESs).In this multicenter, retrospective, real-world study, the data were sourced from three databases: BRIC-ACS(I) study, COSTIC study, and 301 Hospital PCI patient database from January 2014 to October 2017. The primary endpoint of the study was net adverse clinical and cerebral events (NACCE) comprised of all-cause death, non-fatal myocardial infarction (MI), non-fatal stroke or Bleeding Academic Research Consortium (BARC) type ≥ 2 (excluding BARC type = 4) bleeding, whereas the secondary end point was evaluation of major adverse cardiovascular events (MACE) and BARC type ≥ 2 bleeding events.A total of 7862 ACS patients were included in the final analysis, of whom propensity score matching (PSM) analysis yielded 2165 patients in each cohort. After PSM analysis, cumulative incidence of NACCE was significantly lower with clopidogrel and aspirin than with ticagrelor and aspirin [117 (5.4%) vs. 180 (8.3%), P 0.001] at 12 months. Effect estimates showed reduced risk of NACCE occurrence in patients treated with clopidogrel and aspirin [adjusted hazard ratio (aHR): 0.61, 95% CI 0.48-0.77, P 0.001]. Incidence of bleeding was significantly lower in the clopidogrel cohort than in the ticagrelor cohort (aHR: 0.48, 95% CI 0.35-0.66, P 0.001). Clopidogrel and aspirin therapy was comparable to ticagrelor and aspirin in reducing the incidence of MACE after PSM analysis.In Chinese ACS patients who underwent PCI with second-generation DESs, outpatient use of clopidogrel dual antiplatelet therapy (DAPT) was associated with reduction in NACCE and bleeding.

Summary Efficient phosphate (Pi) uptake and utilisation are essential for promoting crop yield. However, the underlying molecular mechanism is still poorly understood in complex crop species such as hexaploid wheat. Here we report that TaPHT1;9‐4B and its transcriptional regulator TaMYB4‐7D function in Pi acquisition, translocation and plant growth in bread wheat.TaPHT1;9‐4B, a high‐affinity Pi transporter highly upregulated in roots by Pi deficiency, was identified using quantitative proteomics. Disruption of TaPHT1;9‐4B function by BSMV‐VIGS or CRISPR editing impaired wheat tolerance to Pi deprivation, whereas transgenic expression of TaPHT1;9‐4B in rice improved Pi uptake and plant growth. Using yeast‐one‐hybrid assay, we isolated TaMYB4‐7D, a R2R3 MYB transcription factor that could activate TaPHT1;9‐4B expression by binding to its promoter. Silencing TaMYB4‐7D decreased TaPHT1;9‐4B expression, Pi uptake and plant growth.Four promoter haplotypes were identified for TaPHT1;9‐4B, with Hap3 showing significant positive associations with TaPHT1;9‐4B transcript level, growth performance and phosphorus (P) content in wheat plants. A functional marker was therefore developed for tagging Hap3.Collectively, our data shed new light on the molecular mechanism controlling Pi acquisition and utilisation in bread wheat. TaPHT1;9‐4B and TaMYB4‐7D may aid further research towards the development of P efficient crop cultivars.

Viruses often usurp host machineries for their amplification, but it remains unclear if hosts may subvert virus proteins to regulate viral proliferation. Here, we show that the 17K protein, an important virulence factor conserved in barley yellow dwarf viruses (BYDVs) and related poleroviruses, is phosphorylated by host GRIK1-SnRK1 kinases, with the phosphorylated 17K (P17K) capable of enhancing the abundance of virus-derived small interfering RNAs (vsiRNAs) and thus antiviral RNAi. Furthermore, P17K interacts with barley small RNA-degrading nuclease 1 (HvSDN1) and impedes HvSDN1-catalyzed vsiRNA degradation. Additionally, P17K weakens the HvSDN1-HvAGO1 interaction, thus hindering HvSDN1 from accessing and degrading HvAGO1-carried vsiRNAs. Importantly, transgenic expression of 17K phosphomimetics (17K

Rongping Fan,1,2,&ast; Lei Xie,1,2,&ast; Xuemin Peng,1,2 Bo Yu,3 Huajie Zou,1,2,4 Jiaojiao Huang,1,2 Xuefeng Yu,1,2 Daowen Wang,3 Yan Yang1,2 1Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 2Branch of National Clinical Research Center for Metabolic Diseases, Wuhan, 430030, People’s Republic of China; 3Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China; 4Division of Endocrinology, Department of Internal Medicine, The Affiliated Hospital of Qinghai University, Xining, Qinghai, 810001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Yang; Daowen Wang, Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, People’s Republic of China, Tel +86-27-83665513, Fax +86-27-83662883, Email yangyan6910@163.com; dwwang@tjh.tjmu.edu.cnAim: To explore the clinical outcomes among preadmission insulin-treated type 2 diabetes mellitus (T2DM) in intensive care units (ICU).Patients and Methods: In this retrospective observational study, 578 T2DM patients admitted to ICU were recruited from March 2011 to February 2021, which were composed of 528 patients treated with insulin after ICU admission (including 300 preadmission non-insulin-treated and 228 preadmission insulin-treated patients) and 50 patients treated without insulin before and after ICU admission. Clinical outcomes were compared between the groups. Variables of age (± 10 years), gender, blood glucose > 10 mmol/l on ICU admission, and original comorbidities were used for matching to get the 1:1 matched cohort. The Kaplan–Meier survival curves were graphed to describe the survival trend and Cox regression analysis was performed to get adjusted hazard ratio (HR).Results: Compared with the preadmission non-insulin-treated T2DM patients, preadmission insulin-treated T2DM patients had higher incidence of hypoglycemia [14.5% (33/228) vs 8.7% (26/300); p = 0.036]. In the 1:1 matched cohort, the preadmission insulin-treated T2DM patients had significantly increased mortality rate [30.0% (45/150) vs (16.0% (24/150)); adjusted HR, 1.68 (1.01– 2.80)] than preadmission non-insulin-treated T2DM patients. Compared with T2DM patients treated without insulin before and after ICU admission, preadmission insulin-treated T2DM patients had higher mortality and longer length of ICU stay (all p < 0.05).Conclusion: Preadmission insulin treatment was associated with increased mortality rate and longer length of ICU stay among T2DM patients in ICU. Preadmission insulin-treated T2DM patients might have worse clinical outcomes when they are critically ill.Keywords: insulin treatment, intensive care units, type 2 diabetes mellitus, mortality, ICU stay

Summary Certain obligate parasites induce complex and substantial phenotypic changes in their hosts in ways that favor their transmission to other trophic levels. However, the mechanisms underlying these changes remain largely unknown. Here we demonstrate how SAP05 protein effectors from insect-vectored plant pathogenic phytoplasmas take control of several plant developmental processes. These effectors simultaneously prolong the host lifespan and induce witches’ broom-like proliferations of leaf and sterile shoots, organs colonized by phytoplasmas and vectors. SAP05 acts by mediating the concurrent degradation of SPL and GATA developmental regulators via a process that relies on hijacking the plant ubiquitin receptor RPN10 independent of substrate ubiquitination. RPN10 is highly conserved among eukaryotes, but SAP05 does not bind insect vector RPN10. A two-amino-acid substitution within plant RPN10 generates a functional variant that is resistant to SAP05 activities. Therefore, one effector protein enables obligate parasitic phytoplasmas to induce a plethora of developmental phenotypes in their hosts., Graphical abstract, Highlights • Phytoplasma SAP05 proteins bind plant SPL and GATA transcription factors and RPN10 • SAP05 mediates degradation of SPLs and GATAs in a ubiquitin-independent manner • SAP05 decouples plant developmental transitions and induces witches’ broom symptoms • Engineering of plant RPN10 confers resistance to SAP05 activities, A virulence factor from an insect-vectored parasitic phytoplasma induces ubiquitin receptor-mediated developmental changes in the plant host that favor pathogenesis. This effector-receptor interaction can be modulated to engineer plants resistant to parasitic infection.

Bread wheat (Triticum aestivum L.) is a major crop that feeds 40% of the world's population. Over the past several decades, advances in genomics have led to tremendous achievements in understanding the origin and domestication of wheat, and the genetic basis of agronomically important traits, which promote the breeding of elite varieties. In this review, we focus on progress that has been made in genomic research and genetic improvement of traits such as grain yield, end-use traits, flowering regulation, nutrient use efficiency, and biotic and abiotic stress responses, and various breeding strategies that contributed mainly by Chinese scientists. Functional genomic research in wheat is entering a new era with the availability of multiple reference wheat genome assemblies and the development of cutting-edge technologies such as precise genome editing tools, high-throughput phenotyping platforms, sequencing-based cloning strategies, high-efficiency genetic transformation systems, and speed-breeding facilities. These insights will further extend our understanding of the molecular mechanisms and regulatory networks underlying agronomic traits and facilitate the breeding process, ultimately contributing to more sustainable agriculture in China and throughout the world.

Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (

Summary Heat stress (HS) causes substantial damages to worldwide crop production. As a cool season crop, wheat (Triticum aestivum) is sensitive to HS‐induced damages. To support the genetic improvement of wheat HS tolerance (HST), we conducted fine mapping of TaHST1, a locus required for maintaining wheat vegetative and reproductive growth under elevated temperatures. TaHST1 was mapped to the distal terminus of 4AL chromosome arm using genetic populations derived from two BC6F6 breeding lines showing tolerance (E6015‐4T) or sensitivity (E6015‐3S) to HS. The 4AL region carrying TaHST1 locus was approximately 0.949 Mbp and contained the last 19 high confidence genes of 4AL according to wheat reference genome sequence. Resequencing of E6015‐3S and E6015‐4T and haplotype analysis of 3087 worldwide wheat accessions revealed heightened deletion polymorphisms in the distal 0.949 Mbp region of 4AL, which was confirmed by the finding of frequent gene losses in this region in eight genome‐sequenced hexaploid wheat cultivars. The great majority (86.36%) of the 3087 lines displayed different degrees of nucleotide sequence deletions, with only 13.64% of them resembling E6015‐4T in this region. These deletions can impair the presence and/or function of TaHST1 and surrounding genes, thus rendering global wheat germplasm vulnerable to HS or other environmental adversities. Therefore, conscientious and urgent efforts are needed in global wheat breeding programmes to optimize the structure and function of 4AL distal terminus by ensuring the presence of TaHST1 and surrounding genes. The new information reported here will help to accelerate the ongoing global efforts in improving wheat HST.

BackgroundPolyploidization and introgression are major events driving plant genome evolution and influencing crop breeding. However, the mechanisms underlying the higher-order chromatin organization of subgenomes and alien chromosomes are largely unknown.ResultsWe probe the three-dimensional chromatin architecture of Aikang 58 (AK58), a widely cultivated allohexaploid wheat variety in China carrying the 1RS/1BL translocation chromosome. The regions involved in inter-chromosomal interactions, both within and between subgenomes, have highly similar sequences. Subgenome-specific territories tend to be connected by subgenome-dominant homologous transposable elements (TEs). The alien 1RS chromosomal arm, which was introgressed from rye and differs from its wheat counterpart, has relatively few inter-chromosome interactions with wheat chromosomes. An analysis of local chromatin structures reveals topologically associating domain (TAD)-like regions covering 52% of the AK58 genome, the boundaries of which are enriched with active genes, zinc-finger factor-binding motifs, CHH methylation, and 24-nt small RNAs. The chromatin loops are mostly localized around TAD boundaries, and the number of gene loops is positively associated with gene activity.ConclusionsThe present study reveals the impact of the genetic sequence context on the higher-order chromatin structure and subgenome stability in hexaploid wheat. Specifically, we characterized the sequence homology-mediated inter-chromosome interactions and the non-canonical role of subgenome-biased TEs. Our findings may have profound implications for future investigations of the interplay between genetic sequences and higher-order structures and their consequences on polyploid genome evolution and introgression-based breeding of crop plants.

Summary The LRK10‐like receptor kinases (LRK10L‐RLKs) are ubiquitously present in higher plants, but knowledge of their expression and function is still limited. Here, we report expression and functional analysis of TtdLRK10L‐1, a typical LRK10L‐RLK in durum wheat (Triticum turgidum L. ssp. durum). The introns of TtdLRK10L‐1 contained multiple kinds of predicted cis‐elements. To investigate the potential effect of these cis‐elements on TtdLRK10L‐1 expression and function, two types of transgenic wheat lines were prepared, which expressed a GFP‐tagged TtdLRK10L‐1 protein (TtdLRK10L‐1:GFP) from the cDNA or genomic DNA (gDNA) sequence of TtdLRK10L‐1 under the native promoter. TtdLRK10L‐1:GFP expression was up‐regulated by the powdery mildew pathogen Blumeria graminis f. sp. tritici (Bgt) in both types of transgenic plants, with the scale of the elevation being much stronger in the gDNA lines. Both types of transgenic plants exhibited enhanced resistance to Bgt infection relative to wild type control. Notably, the Bgt defence activated in the gDNA lines was significantly stronger than that in the cDNA lines. Further analysis revealed that a putative MYB transcription factor binding site (MYB‐BS, CAGTTA) located in TtdLRK10L‐1 intron I was critical for the efficient expression and function of TtdLRK10L‐1 in Bgt defence. This MYB‐BS could also increase the activity of a superpromoter widely used in ectopic gene expression studies in plants. Together, our results deepen the understanding of the expression and functional characteristics of LRK10L‐RLKs. TtdLRK10L‐1 is likely useful for further dissecting the molecular processes underlying wheat defence against Bgt and for developing Bgt resistant wheat crops.

Despite its critical role in repelling damaging insects, our understanding of nonhost resistance against herbivores remains very limited. Recently, Bai et al. identified a novel caffeoylputrescine-green leaf volatile (GLV) compound in wild tobacco plants that confers nonhost resistance to Empoasca leafhoppers through high-throughput multi-omics analyses.

Hydrogen sulfide (H2S) serves as an important gaseous signaling molecule that is involved in intra- and intercellular signal transduction in plant–environment interactions. In plants, H2S is formed in sulfate/cysteine reduction pathways. The activation of endogenous H2S and its exogenous application has been found to be highly effective in ameliorating a wide variety of stress conditions in plants. The H2S interferes with the cellular redox regulatory network and prevents the degradation of proteins from oxidative stress via post-translational modifications (PTMs). H2S-mediated persulfidation allows the rapid response of proteins in signaling networks to environmental stimuli. In addition, regulatory crosstalk of H2S with other gaseous signals and plant growth regulators enable the activation of multiple signaling cascades that drive cellular adaptation. In this review, we summarize and discuss the current understanding of the molecular mechanisms of H2S-induced cellular adjustments and the interactions between H2S and various signaling pathways in plants, emphasizing the recent progress in our understanding of the effects of H2S on the PTMs of proteins. We also discuss future directions that would advance our understanding of H2S interactions to ultimately mitigate the impacts of environmental stresses in the plants.

Mitochondria regulate energy production, cell cycle, and immune signaling. Li et al. recently reported that Toxoplasma gondii induces the shedding of mitochondrial outer membrane to promote its growth. Intriguingly, the hijacking of host mitochondria has been shown to play an essential role in the pathogenesis of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Background: Genetic variants in Scavenger receptor Class B Type 1 (SCARB1) influencing high-density lipoprotein cholesterol (HDL-C) and coronary heart disease (CHD) risk were identified by recent genome-wide association studies. Further study of potential functional variants in SCARB1 may provide new ideas of the complicated relationship between HDL-C and CHD.Methods: 2000 bp in SCARB1 promoter region was re-sequenced in 168 participants with extremely high plasma HDL-C and 400 control subjects. Putative risk alleles were identified using bioinformatics analysis and reporter-gene assays. Two indel variants, rs144334493 and rs557348251, respectively, were genotyped in 5,002 CHD patients and 5,175 control subjects. The underlying mechanisms were investigated.Results: Through resequencing, 27 genetic variants were identified. Results of genotyping in 5,002 CHD patients and 5,175 control subjects revealed that rs144334493 and rs557348251 were significantly associated with increased risk of CHD [odds ratio (OR): 1.28, 95% confidence interval (CI): 1.09 to 1.52, p = 0.003; OR: 2.65, 95% CI: 1.66–4.24, p = 4.4 × 10−5). Subsequent mechanism experiments demonstrated that rs144334493 deletion allele attenuated forkhead box A1 (FOXA1) binding to the promoter region of SCARB1, while FOXA1 overexpression reversely increased SR-BI expression.Conclusion: Genetic variants in SCARB1 promoter region significantly associated with the plasma lipid levels by affecting SR-BI expression and contribute to the susceptibility of CHD.

As a plant hormone, salicylic acid (SA) plays essential roles in plant defense against biotrophic and hemibiotrophic pathogens. Significant progress has been made in understanding the SA biosynthesis pathways and SA-mediated defense signaling networks in the past two decades. Plant defense responses involve rapid and massive transcriptional reprogramming upon the recognition of pathogens. Plant transcription factors and their co-regulators are critical players in establishing a transcription regulatory network and boosting plant immunity. A multitude of transcription factors and epigenetic regulators have been discovered, and their roles in SA-mediated defense responses have been reported. However, our understanding of plant transcriptional networks is still limited. As such, novel genomic tools and bioinformatic techniques will be necessary if we are to fully understand the mechanisms behind plant immunity. Here, we discuss current knowledge, provide an update on the SA biosynthesis pathway, and describe the transcriptional and epigenetic regulation of SA-mediated plant immune responses.

Key message Recent genomic and functional genomics analyses have substantially improved the understanding on gluten proteins, which are important determinants of wheat grain quality traits. The new insights obtained and the availability of precise, versatile and high-throughput genome editing technologies will accelerate simultaneous improvement of wheat end-use and health-related traits. Abstract Being a major staple food crop in the world, wheat provides an indispensable source of dietary energy and nutrients to the human population. As worldwide population grows and living standards rise in both developed and developing countries, the demand for wheat with high quality attributes increases globally. However, efficient breeding of high-quality wheat depends on critically the knowledge on gluten proteins, which mainly include several families of prolamin proteins specifically accumulated in the endospermic tissues of grains. Although gluten proteins have been studied for many decades, efficient manipulation of these proteins for simultaneous enhancement of end-use and health-related traits has been difficult because of high complexities in their expression, function and genetic variation. However, recent genomic and functional genomics analyses have substantially improved the understanding on gluten proteins. Therefore, the main objective of this review is to summarize the genomic and functional genomics information obtained in the last 10 years on gluten protein chromosome loci and genes and the cis- and trans-factors regulating their expression in the grains, as well as the efforts in elucidating the involvement of gluten proteins in several wheat sensitivities affecting genetically susceptible human individuals. The new insights gathered, plus the availability of precise, versatile and high-throughput genome editing technologies, promise to speed up the concurrent improvement of wheat end-use and health-related traits and the development of high-quality cultivars for different consumption needs.

Summary Powdery mildew disease, elicited by the obligate fungal pathogen Blumeria graminis f.sp. tritici (Bgt), causes widespread yield losses in global wheat crop. However, the molecular mechanisms governing wheat defense to Bgt are still not well understood.Here we found that TuACO3, encoding the 1‐aminocyclopropane‐1‐carboxylic acid (ACC) oxidase functioning in ethylene (ET) biosynthesis, was induced by Bgt infection of the einkorn wheat Triticum urartu, which was accompanied by increased ET content. Silencing TuACO3 decreased ET production and compromised wheat defense to Bgt, whereas both processes were enhanced in the transgenic wheat overexpressing TuACO3.TuMYB46L, phylogenetically related to Arabidopsis MYB transcription factor AtMYB46, was found to bind to the TuACO3 promoter region in yeast‐one‐hybrid and EMSA experiments. TuMYB46L expression decreased rapidly following Bgt infection. Silencing TuMYB46L promoted ET content and Bgt defense, but the reverse was observed when TuMYB46L was overexpressed.Hence, decreased expression of TuMYB46L permits elevated function of TuACO3 in ET biosynthesis in Bgt‐infected wheat. The TuMYB46L‐TuACO3 module regulates ET biosynthesis to promote einkorn wheat defense against Bgt. Furthermore, we found four chitinase genes acting downstream of the TuMYB46L‐TuACO3 module. Collectively, our data shed a new light on the molecular mechanisms underlying wheat defense to Bgt.

Grain yield in cereal crops is a complex trait controlled by multiple genes and influenced by developmental processes and environment. Here we report the effects of alleles Rht8 and Ppd-D1a on plant height, time to heading, and grain yield and its component traits. Association analysis and quantitative trait locus mapping using phenotypic data from 15 environments led to the following conclusions. First, both Rht8 and Ppd-D1a reduce plant height. However, Ppd-D1a but not Rht8 causes earlier heading. Second, both Rht8 and Ppd-D1a promote grain yield and affect component traits. Their combined effects are substantially larger than those conferred by either allele alone. Third, promotion of grain yield by Rht8 and Ppd-D1a is through increasing fertile spikelet number. We speculate that Rht8 and Ppd-D1a act independently and additively in control of plant height, grain yield and yield component. Combination of the two alleles is desirable for adjusting plant height and enhancing grain yield and abiotic stress tolerance. Keywords: Association analysis, QTL mapping, Grain number, Grain yield, Triticum aestivum

Salicylic acid (SA) is a plant defense signal that mediates local and systemic immune responses against pathogen invasion. However, the underlying mechanism of SA-mediated defense is very complex due to the involvement of various positive and negative regulators to fine-tune its signaling in diverse pathosystems. Upon pathogen infections, elevated level of SA promotes massive transcriptional reprogramming in which Non-expresser of PR genes 1 (NPR1) acts as a central hub and transcriptional coactivator in defense responses. Recent findings show that Enhanced Disease Susceptibility 1 (EDS1) also functions as a transcriptional coactivator and stimulates the expression of PR1 in the presence of NPR1 and SA. Furthermore, EDS1 stabilizes NPR1 protein level, while NPR1 sustains EDS1 expression during pathogenic infection. The interaction of NPR1 and EDS1 coactivators initiates transcriptional reprogramming by recruiting cyclin-dependent kinase 8 in the Mediator complex to control immune responses. In this review, we highlight the recent breakthroughs that considerably advance our understanding on how transcriptional coactivators interact with their functional partners to trigger distinct pathways to facilitate immune responses, and how SA accumulation induces dynamic changes in NPR1 structure for transcriptional reprogramming. In addition, the functions of different Mediator subunits in SA-mediated plant immunity are also discussed in light of recent discoveries. Taken together, the available evidence suggests that transcriptional coactivators are essential and potent regulators of plant defense pathways and play crucial roles in coordinating plant immune responses during plant–pathogen interactions.

Description, EDS1 acts as a transcriptional coactivator that interacts with NPR1 and Mediator to promote plant defense., The phytohormone salicylic acid (SA) plays a pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. NPR1 and EDS1 function as two central hubs in plant local and systemic immunity. However, it is unclear how NPR1 orchestrates gene regulation and whether EDS1 directly participates in transcriptional reprogramming. Here, we show that NPR1 and EDS1 synergistically activate pathogenesis-related (PR) genes and plant defenses by forming a protein complex and recruiting Mediator. We discover that EDS1 functions as an autonomous transcriptional coactivator with intrinsic transactivation domains and physically interacts with the CDK8 subunit of Mediator. Upon SA induction, EDS1 is directly recruited by NPR1 onto the PR1 promoter via physical NPR1-EDS1 interactions, thereby potentiating PR1 activation. We further demonstrate that EDS1 stabilizes NPR1 protein and NPR1 transcriptionally up-regulates EDS1. Our results reveal an elegant interplay of key coactivators with Mediator and elucidate important molecular mechanisms for activating transcription during immune responses.

Review Role of Sodium Glucose Cotransporter 2 Inhibitor in Hypertension Zhitong Zhou, Dao Wen Wang, Junfang Wu * Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan 430030, China. * Correspondence: Junfang.wu@tjh.tjmu.edu.cn Received: 17 October 2022 Accepted: 15 November 2022 Published: 21 December 2022 Abstract: Sodium glucose cotransporter 2 inhibitors (SGLT-2i) are a new class of antidiabetic drugs that act by inhibiting the reabsorption of glucose in the proximal renal tubule, which results in lowering the level of blood and urinary glucose. Besides the glucose-lowing effect, some clinical trials found the benefits of SGLT2i in treating heart failure with or without diabetes. In 2021, SGLT2i were recommended by the European Society of Cardiology in treating of heart failure. Compared to heart failure, hypertension is a common cardiovascular disease with an increasing prevalence globally. There is also clinical evidence indicating that SGLT2i can lower blood pressure. Here we focused on addressing the role of SGLT-2i in treating hypertension and its possible mechanism in this review.

MiR396s play important roles in regulating plant growth and stress response, and great potential for crop yield promotion was anticipated. For more comprehensive and precise understanding of miR396s in Poaceae, we analyzed the phylogenetic linkage, gene expression, and chromosomal distribution of miR396s in this study. Although the mature miR396s' sequences were mostly conserved, differential expression patterns and chromosomal distribution were found among Poaceae species including the major cereal crops rice, wheat, and maize. Consistently, in comparison with rice, wheat and maize plants transformed with the target mimicry construct of miR396 (MIM396) exhibited differential effects on grain size and disease resistance. While the TaMIM396 plants showed increased grain size, panicle length and sensitivity to B. graminis, the ZmMIM396 plants didn't show obvious changes in grain size and disease resistance. In Addition, several GROWTH-REGULATING FACTOR (GRF) genes in wheat and maize were repressed by miR396s, which could be reversed by MIM396, confirming the conserved regulatory roles of miR396 on GRFs. While providing new solution to enhance grain yield in wheat and revealing potential regulatory variations of miR396s in controlling grain size and disease resistance in different crops, this study gives clues to further explore miR396s' functions in other Poaceae species.

ATP11p and ATP12p are two nuclear-encoded mitochondrial chaperone proteins required for assembling the F1Fo-ATP synthase F1 sector. ATPAF1 and ATPAF2 are the mammalian homologs of ATP11p and ATP12p. However, the biochemical and physiological relevance of ATPAF1 and ATPAF2 in animal tissues with high energy-dependence remains unclear. To explore the in vivo role of ATP assembly and the effects of ATP synthase deficiency in animals, we have generated knockout (KO) mouse models of these assembly factors using CRISPR/Cas9 technology. While the Atpaf2-KO mice were embryonically lethal, Atpaf1-KO mice grew to adulthood but with smaller body sizes and elevated blood lactate later in life. We specifically investigated how ATPAF1 deficiency may affect ATP synthase biogenesis and mitochondrial respiration in the mouse heart, an organ highly energy-dependent. Western blots and Blue-Native electrophoresis (BN-PAGE) demonstrated a decreased F1 content and ATP synthase dimers in the Atpaf1-KO heart. Mitochondria from ATPAF1-deficient hearts showed ultrastructural abnormalities with condensed degenerated mitochondria, loss of cristae, and impaired respiratory capacity. ATP synthase deficiency also leads to impaired autophagy and mitochondrial dynamic. Consequently, decreased cardiac function was exhibited in adult Atpaf1-KO mice. The results provide strong support that ATPAF1 is essential for ATP synthase assembly and mitochondrial oxidative phosphorylation, thus playing a crucial role in maintaining cardiac structure and function in animals.

Aims: Although insulin treatment is widely used in critically ill patients with type 2 diabetes mellitus in the intensive care unit (ICU), the clinical outcomes of insulin treatment remain unclear. This retrospective study aimed to explore the impact of insulin treatment on mortality and ICU stay among patients with type 2 diabetes. Methods: We consecutively recruited 578 ICU patients with type 2 diabetes, from 2011 to 2021. According to their medication history regarding insulin use before and after ICU admission, these patients were categorized into three groups: N-N (treated without insulin before and after ICU admission), N-I (treated without insulin before and with insulin after ICU admission) and I-I (treated with insulin before and after ICU admission). Clinical characteristics were analyzed, and clinical outcomes including mortality and the length of ICU stay were compared between the groups. Propensity score matching was performed to obtain comparable subpopulation and the Kaplan-Meier survival curves were graphed to describe the survival trend of different groups. Results: Compared with the N-N group, the N-I and I-I groups had significantly higher ICU mortality rates [20.0% (N-I) and 24.6% (I-I) vs. 0.0% (N-N); p < 0.001; respectively] and longer lengths of ICU stay [ 8.5 (N-I), 9 (I-I) vs. 6 (N-N), p < 0.05, respectively]. After propensity score matching, the N-I group had a significantly higher ICU mortality (15.4% vs. 0.0%, p = 0.025) and poorer survival rates (log-rank p = 0.040) than the N-N group. The length of ICU stay was significantly longer in the I-I group than in the N-N group (10 vs. 7, p = 0.026). Conclusions: Insulin treatment was associated with increased ICU mortality rate and longer length of ICU stay among critically ill patients with type 2 diabetes. Caution is warranted for the regular application of insulin in critical patients with type 2 diabetes.

Summary Development of marker‐free and transgene insertion site‐defined (MFTID) transgenic plants is essential for safe application of transgenic crops. However, MFTID plants have not been reported for wheat (Triticum aestivum). Here, we prepared a RNAi cassette for suppressing lipoxygenase (LOX) gene expression in wheat grains using a double right border T‐DNA vector. The resultant construct was introduced into wheat genome via Agrobacterium‐mediated transformation, with four homozygous marker‐free transgenic lines (namely GLRW‐1, ‐3, ‐5 and ‐8) developed. Aided by the newly published wheat genome sequence, the T‐DNA insertion sites in GLRW‐3 and GLRW‐8 were elucidated at base‐pair resolution. While the T‐DNA in GLRW‐3 inserted in an intergenic region, that of GLRW‐8 inactivated an endogenous gene, which was thus excluded from further analysis. Compared to wild ‐type (WT) control, GLRW‐1, ‐3 and ‐5 showed decreased LOX gene expression, lower LOX activity and less lipid peroxidation in the grains; they also exhibited significantly higher germination rates and better seedling growth after artificial ageing treatment. Interestingly, the three GLRW lines also had substantially increased contents of several fatty acids (e.g., linoleic acid and linolenic acid) in their grain and flour samples than WT control. Collectively, our data suggest that suppression of grain LOX activity can be employed to improve the storability and fatty acid content of wheat seeds and that the MFTID line GLRW‐3 is likely of commercial value. Our approach may also be useful for developing the MFTID transgenic lines of other crops with enhanced grain storability and fatty acid content.

NPR1 (NONEXPRESSER OF PR GENES1) functions as a master regulator of the plant hormone salicylic acid (SA) signaling and plays an essential role in plant immunity. In the nucleus, NPR1 interacts with transcription factors to induce the expression of PR (PATHOGENESIS-RELATED) genes and thereby promote defense responses. However, the underlying molecular mechanism of PR gene activation is poorly understood. Furthermore, despite the importance of NPR1 in plant immunity, the regulation of NPR1 expression has not been extensively studied. Here, we show that SA promotes the interaction of NPR1 with both CDK8 (CYCLIN-DEPENDENT KINASE8) and WRKY18 (WRKY DNA-BINDING PROTEIN18) in Arabidopsis (Arabidopsis thaliana). NPR1 recruits CDK8 and WRKY18 to the NPR1 promoter, facilitating its own expression. Intriguingly, CDK8 and its associated Mediator subunits positively regulate NPR1 and PR1 expression and play a pivotal role in local and systemic immunity. Moreover, CDK8 interacts with WRKY6, WRKY18, and TGA transcription factors and brings RNA polymerase II to NPR1 and PR1 promoters and coding regions to facilitate their expression. Our studies reveal a mechanism in which NPR1 recruits CDK8, WRKY18, and TGA transcription factors along with RNA polymerase II in the presence of SA and thereby facilitates its own and target gene expression for the establishment of plant immunity.

Spotting off-targets from gene editing Unintended genomic modifications limit the potential therapeutic use of gene-editing tools. Available methods to find off-targets generally do not work in vivo or detect single-nucleotide changes. Three papers in this issue report new methods for monitoring gene-editing tools in vivo (see the Perspective by Kempton and Qi). Wienert et al. followed the recruitment of a DNA repair protein to DNA breaks induced by CRISPR-Cas9, enabling unbiased detection of off-target editing in cellular and animal models. Zuo et al. identified off-targets without the interference of natural genetic heterogeneity by injecting base editors into one blastomere of a two-cell mouse embryo and leaving the other genetically identical blastomere unedited. Jin et al. performed whole-genome sequencing on individual, genome-edited rice plants to identify unintended mutations. Cytosine, but not adenine, base editors induced numerous single-nucleotide variants in both mouse and rice. Science , this issue p. 286 , p. 289 , p. 292 ; see also p. 234

East Asians are the most populous race in the world and their health status is an important global issue. Compared with Caucasian populations, East Asian patients have a different benefit/risk ratio when using antithrombotic treatment. Despite this observation, treatment strategies in East Asian patients are mostly based on the American and European guidelines. Despite a lower platelet inhibitory response to clopidogrel, East Asian patients show a similar or even a lower rate of ischemic event occurrence and higher bleeding risk compared with Caucasian patients. For potent P2Y12 inhibitors (ticagrelor and prasugrel), East Asian patients have shown less favorable net clinical benefits compared with Caucasian patients, which may be related to differences in pharmacokinetic/pharmacodynamic profiles and therapeutic zone of antiplatelet effect. This updated consensus mainly focuses on state-of-the-art and current controversies in the East Asian population. In addition, when East Asian patients are administered potent P2Y12 receptor inhibitors, the strategies and ongoing trials to overcome the related hurdles are discussed.

Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, ABCA1 facilitates the efflux of excess intracellular cholesterol and phospholipids and controls the rate-limiting step of reverse cholesterol transport. In addition, ABCA1 interacts with the apolipoprotein receptor and suppresses inflammation through a series of signaling pathways. Thus, ABCA1 may prevent cardiovascular disease by inhibiting inflammation and maintaining lipid homeostasis. Several studies have indicated that post-transcriptional modifications play a critical role in the regulation of ABCA1 transportation and plasma membrane localization, which affects its biological function. Meanwhile, carriers of the loss-of-function ABCA1 gene are often accompanied by decreased expression of ABCA1 and an increased risk of cardiovascular diseases. We summarized the ABCA1 transcription regulation mechanism, mutations, post-translational modifications, and their roles in the development of dyslipidemia, atherosclerosis, ischemia/reperfusion, myocardial infarction, and coronary heart disease.

Translational regulation by upstream open reading frames (uORFs) is becoming established as a general mechanism for controlling the amount of protein that is synthesized from downstream primary ORFs (pORFs). We found that genome editing of endogenous uORFs in plants enabled the modulation of translation of mRNAs from four pORFs that are involved in either development or antioxidant biosynthesis. A single-guide RNA that targeted the region harboring a uORF initiation codon can produce multiple mutations. Following uORF editing, we observed varying amounts of mRNA translation in four pORFs. Notably, editing the uORF of LsGGP2, which encodes a key enzyme in vitamin C biosynthesis in lettuce, not only increased oxidation stress tolerance, but also increased ascorbate content by ∼150%. These data indicate that editing plant uORFs provides a generalizable, efficient method for manipulating translation of mRNA that could be applied to dissect biological mechanisms and improve crops.

Triticum urartu (AA, 2n = 2x = 14), a wild grass endemic to the Fertile Crescent (FC), is the progenitor of the A subgenome in common wheat. It belongs to the primary gene pool for wheat improvement. Here, we evaluated the yellow rust (caused by Puccinia striiformis f. sp. tritici, Pst) reactions of 147 T. urartu accessions collected from different parts of the FC. The reactions varied from susceptibility to strong resistance. In general, there were more accessions with stronger resistance to race CYR33 than to CYR 32. In most cases the main form of defense was a moderate resistance characterized by the presence of necrotic/chlorotic lesions with fewer Pst uredinia on the leaves. Forty two accessions displayed resistance to both races. Histological analysis showed that Pst growth was abundant in the compatible interaction but significantly suppressed by the resistant response. Gene silencing mediated by Barley stripe mosaic virus was effective in two T. urartu accessions with different resistance responses, indicating that this method can expedite future functional analysis of resistance genes. Our data suggest that T. urartu is a valuable source of resistance to yellow rust, and represents a model for studying the genetic, genomic and molecular basis underlying interaction between wheat and Pst. Keywords: Common wheat, Disease resistance, Gene silencing, Puccinia striiformis

The phytohormone salicylic acid (SA) plays a pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. Genetic studies have identified NPR1 and EDS1 as two central hubs in plant local and systemic immunity. However, it is unclear how NPR1 orchestrates gene regulation and whether EDS1 directly participates in transcriptional reprogramming. Here we show that NPR1 and EDS1 synergistically activatePathogenesis-Related(PR) genes and plant defenses by forming a protein complex and co-opting with Mediator. In particular, we discover that EDS1 functions as an autonomous transcriptional coactivator with intrinsic transactivation domains and physically interacts with the CDK8 subunit of Mediator. Upon SA induction, EDS1 is directly recruited by NPR1 onto thePR1promoter via physical NPR1-EDS1 interactions, thereby potentiatingPR1activation. We further demonstrate that EDS1 stabilizes NPR1 protein and NPR1 transcriptionally upregulatesEDS1in plant-pathogen interactions. Our results reveal an elegant interplay of key coactivators with Mediator and elucidate novel molecular mechanisms for activating transcription during immune responses.