Publications by authors named "Nian Wang"

279 Publications

Inflammasome-Dependent Coagulation Activation in Sepsis.

Front Immunol 2021 16;12:641750. Epub 2021 Mar 16.

Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States.

Sepsis is a potentially life-threatening, pathological condition caused by a dysregulated host response to infection. Pathologically, systemic inflammation can initiate coagulation activation, leading to organ dysfunction, and ultimately to multiple organ failure and septic death. The inflammasomes are cytosolic multiprotein signaling complexes that control the host response to diverse pathogen-associated molecular patterns (PAMPs) from microorganisms as well as damage-associated molecular patterns (DAMPs) from dead or dying host cells. Recent studies highlight that the activation of canonical and non-canonical inflammasomes not only mediate the maturation and secretion of interleukin-1 (IL1) family cytokines, but also trigger the release of coagulation factor III, tissue factor (F3, best known as TF) in activated macrophages and monocytes. These emerging functions of inflammasomes in immunocoagulation are further positively regulated by stimulator of interferon response cGAMP interactor 1 (STING1, also known as STING or TMEM173, a hub of the innate immune signaling network) and high mobility group box 1 (HMGB1, a nuclear DAMP). This mini-review will discuss the regulation and function of inflammasome-dependent coagulation activation in sepsis.
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http://dx.doi.org/10.3389/fimmu.2021.641750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007875PMC
March 2021

Pharmacological Modulation of BET Family in Sepsis.

Front Pharmacol 2021 11;12:642294. Epub 2021 Mar 11.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, United States.

The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis 3.0) recommended defining sepsis as a life-threatening organ dysfunction caused by the host's uncontrolled response to infection. The bromodomain and extra-terminal (BET) protein family (such as BRD2, BRD3, and BRD4), an epigenetic regulator of gene transcription, has recently been recognized as a significant septic regulator of inflammation and immune response, including cytokine and chemokine production. Mechanistically, the two N-terminal conserved tandem bromodomains (namely the first bromodomain [BD1] and the second bromodomain [BD2]) favor the binding of BETs to acetylated histones or transcription factors, thereby initiating gene transcription machinery after CycT1 and CDK9 (also known as P-TEFb) are recruited to gene promoters to phosphorylate RNA pol II. Notably, BD1 and BD2 are not functionally redundant because they have different target genes in innate immune cells. Small-molecule BET inhibitors (BETis) for different BDs, such as I-BET, JQ1, I-BET151, apabetalone, RVX-297, and dBET1 have shown promising therapeutic effects in experimental sepsis models. This mini-review summarizes the emerging roles of BETs and the applications of BETis in sepsis, discusses the existing shortcomings of BETis, and introduces possible future research directions in this area.
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http://dx.doi.org/10.3389/fphar.2021.642294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990776PMC
March 2021

Resolving phylogeny and polyploid parentage using genus-wide genome-wide sequence data from birch trees.

Mol Phylogenet Evol 2021 Feb 27;160:107126. Epub 2021 Feb 27.

School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK; Royal Botanic Gardens Kew, Richmond, Surrey TW9 3AB, UK. Electronic address:

Numerous plant genera have a history including frequent hybridisation and polyploidisation (allopolyploidisation), which means that their phylogeny is a network of reticulate evolution that cannot be accurately depicted as a bifurcating tree with a single tip per species. The genus Betula, which contains many ecologically important tree species, is a case in point. We generated genome-wide sequence reads for 27 diploid and 36 polyploid Betula species or subspecies using restriction site associated DNA (RAD) sequences. These reads were assembled into contigs with a mean length of 675 bp. We reconstructed the evolutionary relationships among diploid Betula species using both supermatrix (concatenation) and species tree methods. We identified the closest diploid relatives of the polyploids according to the relative rates at which reads from polyploids mapped to contigs from different diploid species within a concatenated reference sequence. By mapping reads from allopolyploids to their different putative diploid relatives we assembled contigs from the putative sub-genomes of allopolyploid taxa. We used these to build new phylogenies that included allopolyploid sub-genomes as separate tips. This approach yielded a highly evidenced phylogenetic hypothesis for the genus Betula, including the complex reticulate origins of the majority of its polyploid taxa. Our phylogeny divides the genus into two well supported clades, which, interestingly, differ in their seed-wing morphology. We therefore propose to split Betula into two subgenera.
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http://dx.doi.org/10.1016/j.ympev.2021.107126DOI Listing
February 2021

How do corruption and energy efficiency affect the carbon emission performance of China's industrial sectors?

Environ Sci Pollut Res Int 2021 Feb 19. Epub 2021 Feb 19.

School of Economics and Management, Nanjing University of Science and Technology, Xuanwu District, Xiaolingwei Street 200, Nanjing, 210094, China.

Existing research on the relationship among corruption, energy efficiency, and industrial carbon emissions is limited, while incorporating them into one analytical framework might provide new insights for the mechanism between corruption and industrial carbon emissions. Using the provincial panel data in China's industry from 2005 to 2015, this study applies the System Generalized Method of Moments (SYS-GMM) to explore the impacts of corruption and energy efficiency on industrial carbon emissions. The results indicate that under current economic development status, the effects of corruption and energy efficiency on industrial carbon emissions are divergent; i.e., corruption can enhance carbon emissions, whereas energy efficiency facilitates carbon emission reduction. Energy efficiency plays a mediating role in the relationship between corruption and carbon emissions for both the whole sample and the sub-samples. In other words, corruption aggravates industrial carbon emissions through lowering energy efficiency. Additionally, for the eastern region in China, there is an inverted U-shaped curve relationship between corruption and carbon emissions, as well as a U-shaped curve relationship between energy efficiency and carbon emissions. For the other regions, there is little sign of nonlinearity. Based on the results, policy implications regarding carbon emissions curbing are proposed.
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http://dx.doi.org/10.1007/s11356-021-13032-3DOI Listing
February 2021

A promising plant defense peptide against citrus Huanglongbing disease.

Authors:
Nian Wang

Proc Natl Acad Sci U S A 2021 Feb;118(6)

Citrus Research and Education Center, Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Lake Alfred, FL 33850

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http://dx.doi.org/10.1073/pnas.2026483118DOI Listing
February 2021

The HrpG/HrpX Regulon of Xanthomonads-An Insight to the Complexity of Regulation of Virulence Traits in Phytopathogenic Bacteria.

Microorganisms 2021 Jan 16;9(1). Epub 2021 Jan 16.

Citrus Research and Education Center, Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Lake Alfred, FL 33850, USA.

Bacteria of the genus cause a wide variety of economically important diseases in most crops. The virulence of the majority of spp. is dependent on secretion and translocation of effectors by the type 3 secretion system (T3SS) that is controlled by two master transcriptional regulators HrpG and HrpX. Since their discovery in the 1990s, the two regulators were the focal point of many studies aiming to decipher the regulatory network that controls pathogenicity in bacteria. HrpG controls the expression of HrpX, which subsequently controls the expression of T3SS apparatus genes and effectors. The HrpG/HrpX regulon is activated and subjected to tight metabolic and genetic regulation. In this review, we cover the advances made in understanding the regulatory networks that control and are controlled by the HrpG/HrpX regulon and their conservation between different spp.
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http://dx.doi.org/10.3390/microorganisms9010187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831014PMC
January 2021

Consequences of adaptation of TAL effectors on host susceptibility to Xanthomonas.

PLoS Genet 2021 Jan 19;17(1):e1009310. Epub 2021 Jan 19.

Citrus Research and Education Center, Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Lake Alfred, Florida, United States of America.

Transcription activator-like effectors (TALEs) are virulence factors of Xanthomonas that induce the expression of host susceptibility (S) genes by specifically binding to effector binding elements (EBEs) in their promoter regions. The DNA binding specificity of TALEs is dictated by their tandem repeat regions, which are highly variable between different TALEs. Mutation of the EBEs of S genes is being utilized as a key strategy to generate resistant crops against TALE-dependent pathogens. However, TALE adaptations through rearrangement of their repeat regions is a potential obstacle for successful implementation of this strategy. We investigated the consequences of TALE adaptations in the citrus pathogen Xanthomonas citri subsp. citri (Xcc), in which PthA4 is the TALE required for pathogenicity, whereas CsLOB1 is the corresponding susceptibility gene, on host resistance. Seven TALEs, containing two-to-nine mismatching-repeats to the EBEPthA4 that were unable to induce CsLOB1 expression, were introduced into Xcc pthA4:Tn5 and adaptation was simulated by repeated inoculations into and isolations from sweet orange for a duration of 30 cycles. While initially all strains failed to promote disease, symptoms started to appear between 9-28 passages in four TALEs, which originally harbored two-to-five mismatches. Sequence analysis of adapted TALEs identified deletions and mutations within the TALE repeat regions which enhanced putative affinity to the CsLOB1 promoter. Sequence analyses suggest that TALEs adaptations result from recombinations between repeats of the TALEs. Reintroduction of these adapted TALEs into Xcc pthA4:Tn5 restored the ability to induce the expression of CsLOB1, promote disease symptoms and colonize host plants. TALEs harboring seven-to-nine mismatches were unable to adapt to overcome the incompatible interaction. Our study experimentally documented TALE adaptations to incompatible EBE and provided strategic guidance for generation of disease resistant crops against TALE-dependent pathogens.
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http://dx.doi.org/10.1371/journal.pgen.1009310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845958PMC
January 2021

The BET family in immunity and disease.

Signal Transduct Target Ther 2021 Jan 19;6(1):23. Epub 2021 Jan 19.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Innate immunity serves as the rapid and first-line defense against invading pathogens, and this process can be regulated at various levels, including epigenetic mechanisms. The bromodomain and extraterminal domain (BET) family of proteins consists of four conserved mammalian members (BRD2, BRD3, BRD4, and BRDT) that regulate the expression of many immunity-associated genes and pathways. In particular, in response to infection and sterile inflammation, abnormally expressed or dysfunctional BETs are involved in the activation of pattern recognition receptor (e.g., TLR, NLR, and CGAS) pathways, thereby linking chromatin machinery to innate immunity under disease or pathological conditions. Mechanistically, the BET family controls the transcription of a wide range of proinflammatory and immunoregulatory genes by recognizing acetylated histones (mainly H3 and H4) and recruiting transcription factors (e.g., RELA) and transcription elongation complex (e.g., P-TEFb) to the chromatin, thereby promoting the phosphorylation of RNA polymerase II and subsequent transcription initiation and elongation. This review covers the accumulating data about the roles of the BET family in innate immunity, and discusses the attractive prospect of manipulating the BET family as a new treatment for disease.
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http://dx.doi.org/10.1038/s41392-020-00384-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813845PMC
January 2021

Time-Resolved Acetaldehyde-Based Accessibility Profiling Maps Ligand-Target Interactions.

J Am Soc Mass Spectrom 2021 Feb 31;32(2):519-530. Epub 2020 Dec 31.

Jiangsu Provincial Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Tongjiaxiang #24, Nanjing, Jiangsu 210009, China.

Elucidating ligand-protein interactions is important in understanding the biochemical machinery for given proteins. Previously, formaldehyde (FH)-based labeling has been employed to obtain such structural knowledge, since reactive residues that participate in ligand-target interactions display reduced accessibility to FH-labeling reagents, and thus can be identified by quantitative proteomics. Although being rapid and efficient for probing proteinaceous lysine accessibility, here, we report an acetaldehyde (AcH)-labeling approach that complements with FH for probing ligand-target interactions. AcH labeling examines lysine accessibility at a more moderate reaction speed and hence delivers a cleaner reaction when compared to that of FH. The subsequent application of AcH to label RNase A without and with ligands has assisted to assign lysines involved in ligand-RNase A binding by detecting the time-dependent changes in accessibility profiles. We further employed multiple reaction monitoring (MRM) to quantify these ligand-binding-responsive sites when a variety of potential ligands were queried. We noted that the time-resolved abundance changes of these peptides can sensitively determine the ligand-binding sites and differentiate binding affinities among these ligands, which was confirmed by native mass spectrometry (MS) and molecular docking. Lastly, we demonstrated that the binding sites can be recognized by monitoring the chemical accessibility of these responsive peptides in cell lysates. Together, we believe that the proposed combined use of AcH-based lysine accessibility profiling, native MS, and MRM screening is a powerful toolbox in characterizing ligand-target interactions, mapping topography, and interrogating affinities and holds promise for future applications in a complex cellular environment.
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http://dx.doi.org/10.1021/jasms.0c00382DOI Listing
February 2021

Region-wide comprehensive implementation of roguing infected trees, tree replacement, and insecticide applications successfully controls citrus HLB.

Phytopathology 2020 Dec 23. Epub 2020 Dec 23.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Huanglongbing (HLB) is a devastating citrus disease worldwide. A three-pronged approach to controlling HLB has been suggested, namely, removal of HLB-symptomatic trees, psyllid control, and replacement with HLB-free trees. However, such a strategy did not lead to successful HLB control in many citrus producing regions. We hypothesize this is because of the small-scale or incomprehensive implementation of the program, conversely, a comprehensive implementation of such a strategy at regional level can successfully control HLB. Here we investigated the effects of region-wide comprehensive implementation of this scheme to control HLB in Gannan region, China, with a total planted citrus acreage of over 110,000 ha from 2013-2019. With the region-wide implementation of comprehensive HLB management, overall HLB incidence in Gannan decreased from 19.71% in 2014 to 3.86% in 2019. A partial implementation of such a program (without a comprehensive inoculum removal) at the regional level in Brazil resulted in HLB incidence increasing from 1.89% in 2010 to 19.02% in 2019. A dynamic regression model analyses predicated that in a region-wide comprehensive implementation of such a program, HLB incidence would be controlled to a level of less than 1%. Economic feasibility analyses showed that average net profits were positive for groves that implemented the comprehensive strategy, but negative for groves without such a program over a ten-year period. Overall, the key for the three-pronged program to successfully control HLB control is the large scale (region-wide) and comprehensiveness in implementation. This study provides valuable information to control HLB and other endemic diseases worldwide.
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http://dx.doi.org/10.1094/PHYTO-09-20-0436-RDOI Listing
December 2020

Rhizosphere bacterial and fungal communities succession patterns related to growth of poplar fine roots.

Sci Total Environ 2021 Feb 20;756:143839. Epub 2020 Nov 20.

Taishan Forest Ecosystem Research Station of State Forestry Administration, College of Forestry, Shandong Agricultural University, Tai'an 271018, PR China. Electronic address:

Understanding the succession patterns of microbial community along root growth provides deep insights into interaction between fine roots and microbes. In the study, we investigated this issue using fine roots from poplar trees and grouped these fine roots into three growth stages: newborn white roots (WR), mature yellow roots (YR) and aging brown roots (BR). Root surface traits were observed under a scanning electron microscopy (SEM). Adhered soils on roots of the three growth stages were grouped into the three soil compartments, correspondingly. The 16S rRNA and ITS1 region were sequenced for bacteria and fungi inhabiting rhizosphere soils, respectively. Phospholipid fatty acid (PLFA) technology was employed to examine the biomass of bacterial and fungal communities. The anatomical traits of fine roots show apparent differences among the WR, YR and BR. Both bacteria and fungi have 25 dominant genera with a relative abundance over 1%, of which, four genera of the bacteria (Bacillus, Burkholderia, Ralstonia and Dyella) differ in abundance among the WR, YR and BR soil compartments and four genera of the fungi (Fusarium, Chaetomium, Penicillium and Scleroderma) differ in abundance among these soil compartments. The operational taxonomic units (OTUs) showed the highest richness in the WR soil compartment for bacteria and in the YR soil compartment for fungi, indicating a different succession pattern between the bacterial and fungal communities. Furthermore, the biomass of bacterial community is larger than the fungal community according to PLFAs, and both decreased along fine root growth. The total carbon (TC) in the soil increases along root growth while the dissolved organic carbon (DOC) decreases. Redundancy analysis (RDA) shows a close correlation between twelve dominant bacteria genera and the total organic carbon (TOC), the readily oxidizable organic carbon (ROC) and DOC and ten dominant fungi genera with the TOC and ROC. In conclusion, our results indicate that fine roots growth has shaped the composition and structure of root associated bacterial and fungal communities.
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http://dx.doi.org/10.1016/j.scitotenv.2020.143839DOI Listing
February 2021

Residue dynamics of streptomycin in citrus delivered by foliar spray and trunk injection and effect on 'Candidatus Liberibacter asiaticus' titer.

Phytopathology 2020 Dec 2. Epub 2020 Dec 2.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Streptomycin (STR) has been used to control citrus huanglongbing (HLB) caused by 'Candidatus Liberibacter asiaticus' (CLas) via foliar spray. Here, we studied the residue dynamics of STR and its effect on CLas titers in planta applied by foliar spray and trunk injection of 3-year-old citrus trees. Following foliar spray, STR levels in leaves peaked at 2 to 7 days post-application (DPA) and gradually declined thereafter. The STR spray did not significantly affect CLas titers in leaves of treated plants. Following trunk injection, peak levels of STR were observed 7 to 14 DPA in the leaf and root tissues, and near-peak levels were sustained for another 14 days before significantly declining. At 12 months after injection, moderate to low or undetectable levels of STR were observed in the leaf, root, and fruit, depending on the doses of STR injected, with a residue level of 0.28 μg/g in harvested fruit at the highest injection concentration of 2.0 g/tree. CLas titers in leaves were significantly reduced by trunk injection of STR at 1.0 or 2.0 g/tree, starting from 7 DPA and throughout the experimental period. The reduction of CLas titers was positively correlated with STR residue levels in leaves. The in planta minimum effective concentration of STR required to suppress the CLas titer to an undetectable level (Ct ≥ 36.0) was 1.92 µg/g fresh weight. Determination of the in planta minimum effective concentration of STR against CLas and its spatiotemporal residue levels in planta provides the guidance to use STR for HLB management.
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http://dx.doi.org/10.1094/PHYTO-09-20-0427-RDOI Listing
December 2020

Spatiotemporal dynamics of Candidatus Liberibacter asiaticus colonization inside citrus plant and Huanglongbing disease development.

Phytopathology 2020 Nov 11. Epub 2020 Nov 11.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Candidatus Liberibacter asiaticus (CLas), the causal agent of citrus huanglongbing, colonizes inside the phloem and is naturally transmitted by the Asian citrus psyllid (ACP). Here, we investigated the spatiotemporal CLas colonization in different tissues post ACP transmission. At 75 day-post-ACP-removal (DPR), CLas was detected in roots of all trees, but in the mature leaf of only one tree, of the nine plants that were successfully infected via ACP transmission, consistent with the model that CLas moves passively from the source to sink. CLas was detected in 11.1%, and 43.1% mature leaves, which were unfed by ACPs during transmission, at 75, and 365 DPR, respectively, unveiling active movement to the source tissue. The difference in colonization timing of sink and source tissues indicates CLas is capable of both passive and active movement with passive movement being dominant. At 225 DPR, leaves fed by ACPs during the young stage showed the highest ratio of HLB symptomatic leaves and highest CLas titer, followed by that of leaves emerged post ACP removal, and mature leaves not fed by ACPs. Importantly, our data showed that ACPs were unable to transmit CLas via feeding on mature leaves. It is estimated that it takes at most three years for CLas to infect the whole tree. Overall, the spatiotemporal detection of CLas in different tissues after ACP transmission helps visualize the infection process of CLas in planta and subsequent HLB symptom development, and provides the knowledge supporting that young leaves should be the focus of HLB management.
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http://dx.doi.org/10.1094/PHYTO-09-20-0407-RDOI Listing
November 2020

Standard Operating Procedures for Chinese Medicine Data Monitoring Committees of Clinical Studies.

Chin J Integr Med 2020 Nov 10. Epub 2020 Nov 10.

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Although there is guidance from different regulatory agencies, there are opportunities to bring greater consistency and stronger applicability to address the practical issues of establishing and operating a data monitoring committee (DMC) for clinical studies of Chinese medicine. We names it as a Chinese Medicine Data Monitoring Committee (CMDMC). A panel composed of clinical and statistical experts shared their experience and thoughts on the important aspects of CMDMCs. Subsequently, a community standard on CMDMCs (T/CACM 1323-2019) was issued by the China Association of Chinese Medicine on September 12, 2019. This paper summarizes the key content of this standard to help the sponsors of clinical studies establish and operate CMDMCs, which will further develop the scientific integrity and quality of clinical studies.
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http://dx.doi.org/10.1007/s11655-020-3439-2DOI Listing
November 2020

HSF1 functions as a key defender against palmitic acid-induced ferroptosis in cardiomyocytes.

J Mol Cell Cardiol 2021 01 22;150:65-76. Epub 2020 Oct 22.

Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410008, China; Key Laboratory of Sepsis Translational Medicine of Hunan, Central South University, Changsha, Hunan 410008, China. Electronic address:

Palmitic acid (PA)-induced myocardial injury is considered a critical contributor to the development of obesity and type 2 diabetes mellitus (T2DM)-related cardiomyopathy. However, the underlying mechanism has not been fully understood. Here, we demonstrated that PA induced the cell death of H9c2 cardiomyoblasts in a dose- and time-dependent manner, while different ferroptosis inhibitors significantly abrogated the cell death of H9c2 cardiomyoblasts and primary neonatal rat cardiomyocytes exposed to PA. Mechanistically, PA decreased the protein expression levels of both heat shock factor 1 (HSF1) and glutathione peroxidase 4 (GPX4) in a dose- and time-dependent manner, which were restored by different ferroptosis inhibitors. Overexpression of HSF1 not only alleviated PA-induced cell death and lipid peroxidation but also improved disturbed iron homeostasis by regulating the transcription of iron metabolism-related genes (e.g., Fth1, Tfrc, Slc40a1). Additionally, PA-blocked GPX4 protein expression was evidently restored by HSF1 overexpression. Inhibition of endoplasmic reticulum (ER) stress rather than autophagy contributed to HSF1-mediated GPX4 expression. Moreover, GPX4 overexpression protected against PA-induced ferroptosis, whereas knockdown of GPX4 reversed the anti-ferroptotic effect of HSF1. Consistent with the in vitro findings, PA-challenged Hsf1 mice exhibited more serious ferroptosis, increased Slc40a1 and Fth1 mRNA expression, decreased GPX4 and TFRC expression and enhanced ER stress in the heart compared with Hsf1 mice. Altogether, HSF1 may function as a key defender against PA-induced ferroptosis in cardiomyocytes by maintaining cellular iron homeostasis and GPX4 expression.
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http://dx.doi.org/10.1016/j.yjmcc.2020.10.010DOI Listing
January 2021

Census of Candidatus Liberibacter asiaticus population inside the phloem of citrus trees.

Phytopathology 2020 Oct 22. Epub 2020 Oct 22.

University of Florida, Citrus Research and Education Center, 700 Experiment Station Road, Lake Alfred, Florida, United States, 33850;

Candidatus Liberibacter asiaticus (CLas) is the predominant causal agent of citrus huanglongbing (HLB). The pathogen population size in local tissues and the whole plant are critical for the development of disease symptoms via pathogenicity factors and causing metabolic burden to the host. However, the total population size of CLas in a whole plant and the ratio of CLas vs. citrus cells in local tissues have not been addressed previously. The total CLas population size for 2.5-year-old Valencia sweet orange trees was quantified using quantitative PCR to be approximately 1.74 x 109, whereas that of 7 and 20-year-old sweet orange trees were estimated to be 4.3 x 1010, and 6.0 x 1010, respectively. The majority of CLas cells were distributed in the leaf tissues (55.58%), followed by that in the branch tissues (36.78%), feeder roots (4.75%), trunk (2.39%), and structural root (0.51%) tissues. The ratios of citrus cells vs. CLas cells for branch, leaf, trunk, feeder root, and structural root samples were approximately 39, 44, 153, 191, and 561, respectively, representing the metabolic burden of CLas in different organs. Approximately 0.01% of the total citrus phloem volume was estimated to be occupied by CLas. The CLas titer inside the leaf was estimated to be approximately 1.64 x 106 cells/leaf or 9.2 x 104 cells cm-2 in leaves, approximately 104 times less than that of typical apoplastic bacterial pathogens. This study provides quantitative estimates of phloem colonization by bacterial pathogens and further understands the biology and virulence mechanism of CLas.
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http://dx.doi.org/10.1094/PHYTO-09-20-0388-RDOI Listing
October 2020

Sec-Delivered Effector 1 (SDE1) of ' Liberibacter asiaticus' Promotes Citrus Huanglongbing.

Mol Plant Microbe Interact 2020 Dec 3;33(12):1394-1404. Epub 2020 Nov 3.

Department of Microbiology and Plant Pathology, University of California, Riverside, CA 92521, U.S.A.

Sec-delivered effector 1 (SDE1) from the huanglongbing (HLB)-associated bacterium ' Liberibacter asiaticus' was previously characterized as an inhibitor of defense-related, papain-like cysteine proteases in vitro and in planta. Here, we investigated the contributions of SDE1 to HLB progression. We found that SDE1 expression in the model plant caused severe yellowing in mature leaves, reminiscent of both ' L. asiaticus' infection symptoms and accelerated leaf senescence. Induction of senescence signatures was also observed in the SDE1-expressing lines. These signatures were apparent in older leaves but not in seedlings, suggesting an age-associated effect. Furthermore, independent lines of transgenic (L.) Macfadyen (Duncan grapefruit) that express exhibited hypersusceptibility to ' L. asiaticus'. Similar to , transgenic citrus expressing SDE1 showed altered expression of senescence-associated genes, but only after infection with ' L. asiaticus'. These findings suggest that SDE1 is a virulence factor that contributes to HLB progression, likely by inducing premature or accelerated senescence in citrus. This work provides new insight into HLB pathogenesis.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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http://dx.doi.org/10.1094/MPMI-05-20-0123-RDOI Listing
December 2020

The immunity of Meiwa kumquat against Xanthomonas citri is associated with a known susceptibility gene induced by a transcription activator-like effector.

PLoS Pathog 2020 09 15;16(9):e1008886. Epub 2020 Sep 15.

Citrus Research and Education Center, Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Lake Alfred, United States of America.

Citrus canker caused by Xanthomonas citri subsp. citri (Xcc) is one of the most devastating diseases in citrus. Meiwa kumquat (Fortunella crassifolia) has shown a durable resistance against Xcc. Here, we aimed to characterize the mechanisms responsible for such a durable resistance by characterizing the transcriptional and physiological responses of Meiwa kumquat to Xcc. Inoculation of Meiwa kumquat with Xcc promoted immune responses such as upregulation of PR genes, accumulation of salicylic acid, hypersensitive response (HR)-like cell death and early leaf abscission. Hypertrophy and hyperplasia symptoms, which are known to be caused by Xcc-induction of the canker susceptibility gene LOB1 through the transcription activator-like effector (TALE) PthA4, always appear prior to the development of cell death. Mutation of pthA4 in Xcc abolished the induction of LOB1, canker symptoms, cell death, and leaf abscission and reduced the expression of PR genes in inoculated kumquat leaves without reducing Xcc titers in planta. Transcriptome analysis demonstrated that PthA4 promotes plant biotic and abiotic stress responses and the biosynthesis of abscisic acid. Transcriptional induction of LOB1 homologs in Meiwa kumquat by Xcc pthA4 mutant strains carrying a repertoire of designer TALEs promoted the elicitation of HR-like phenotype and leaf abscission, suggesting that kumquat response to Xcc is associated with upregulation of LOB1. Our study suggests a novel mechanism of plant resistance to Xanthomonas via elicitation of immune responses by upregulation of a host susceptibility gene.
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http://dx.doi.org/10.1371/journal.ppat.1008886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518600PMC
September 2020

Citrus Vascular Proteomics Highlights the Role of Peroxidases and Serine Proteases during Huanglongbing Disease Progression.

Mol Cell Proteomics 2020 12 3;19(12):1936-1952. Epub 2020 Sep 3.

Department of Plant Pathology, University of California, Davis, California, USA. Electronic address:

Huanglongbing (HLB) is the most devastating and widespread citrus disease. All commercial citrus varieties are susceptible to the HLB-associated bacterium, Liberibacter asiaticus (Las), which resides in the phloem. The phloem is part of the plant vascular system and is involved in sugar transport. To investigate the plant response to Las, we enriched for proteins surrounding the phloem in an HLB susceptible sweet orange variety, Washington navel ( (L) Osbeck). Quantitative proteomics revealed global changes in the citrus proteome after Las inoculation. Plant metabolism and translation were suppressed, whereas defense-related proteins such as peroxidases, proteases and protease inhibitors were induced in the vasculature. Transcript accumulation and enzymatic activity of plant peroxidases in CLas infected sweet orange varieties under greenhouse and field conditions were assessed. Although peroxidase transcript accumulation was induced in Las infected sweet orange varieties, peroxidase enzymatic activity varied. Specific serine proteases were up-regulated in Washington navel in the presence of Las based on quantitative proteomics. Subsequent activity-based protein profiling revealed increased activity of two serine proteases, and reduced activity of one protease in two sweet orange varieties under greenhouse and field conditions. The observations in the current study highlight global reprogramming of the citrus vascular proteome and differential regulation of enzyme classes in response to Las infection. These results open an avenue for further investigation of diverse responses to HLB across different environmental conditions and citrus genotypes.
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http://dx.doi.org/10.1074/mcp.RA120.002075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710146PMC
December 2020

Variability and heritability of mouse brain structure: Microscopic MRI atlases and connectomes for diverse strains.

Neuroimage 2020 11 18;222:117274. Epub 2020 Aug 18.

Duke Center for In Vivo Microscopy, Department of Radiology, Duke University, Duke University Medical Center Box 3302, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA. Electronic address:

Genome-wide association studies have demonstrated significant links between human brain structure and common DNA variants. Similar studies with rodents have been challenging because of smaller brain volumes. Using high field MRI (9.4 T) and compressed sensing, we have achieved microscopic resolution and sufficiently high throughput for rodent population studies. We generated whole brain structural MRI and diffusion connectomes for four diverse isogenic lines of mice (C57BL/6J, DBA/2J, CAST/EiJ, and BTBR) at spatial resolution 20,000 times higher than human connectomes. We measured narrow sense heritability (h) I.e. the fraction of variance explained by strains in a simple ANOVA model for volumes and scalar diffusion metrics, and estimates of residual technical error for 166 regions in each hemisphere and connectivity between the regions. Volumes of discrete brain regions had the highest mean heritability (0.71 ± 0.23 SD, n = 332), followed by fractional anisotropy (0.54 ± 0.26), radial diffusivity (0.34 ± 0.022), and axial diffusivity (0.28 ± 0.19). Connection profiles were statistically different in 280 of 322 nodes across all four strains. Nearly 150 of the connection profiles were statistically different between the C57BL/6J, DBA/2J, and CAST/EiJ lines. Microscopic whole brain MRI/DTI has allowed us to identify significant heritable phenotypes in brain volume, scalar DTI metrics, and quantitative connectomes.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117274DOI Listing
November 2020

Application of FIB-SEM Techniques for the Advanced Characterization of Earth and Planetary Materials.

Scanning 2020 25;2020:8406917. Epub 2020 Jul 25.

Key Laboratory of Earth and Planetary Physics, Institute of Geology and Geophysics, Chinese Academy of Sciences, Beijing, China.

Advanced microanalytical techniques such as high-resolution transmission electron microscopy (HRTEM), atom probe tomography (APT), and synchrotron-based scanning transmission X-ray microscopy (STXM) enable one to characterize the structure and chemical and isotopic compositions of natural materials down towards the atomic scale. Dual focused ion beam-scanning electron microscopy (FIB-SEM) is a powerful tool for site-specific sample preparation and subsequent analysis by TEM, APT, and STXM to the highest energy and spatial resolutions. FIB-SEM also works as a stand-alone technique for three-dimensional (3D) tomography. In this review, we will outline the principles and challenges when using FIB-SEM for the advanced characterization of natural materials in the Earth and Planetary Sciences. More specifically, we aim to highlight the state-of-the-art applications of FIB-SEM using examples including (a) traditional FIB ultrathin sample preparation of small particles in the study of space weathering of lunar soil grains, (b) migration of Pb isotopes in zircons by FIB-based APT, (c) coordinated synchrotron-based STXM characterization of extraterrestrial organic material in carbonaceous chondrite, and finally (d) FIB-based 3D tomography of oil shale pores by slice and view methods. Dual beam FIB-SEM is a powerful analytical platform, the scope of which, for technological development and adaptation, is vast and exciting in the field of Earth and Planetary Sciences. For example, dual beam FIB-SEM will be a vital technique for the characterization of fine-grained asteroid and lunar samples returned to the Earth in the near future.
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http://dx.doi.org/10.1155/2020/8406917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397446PMC
July 2020

Citrus CsACD2 Is a Target of Liberibacter Asiaticus in Huanglongbing Disease.

Plant Physiol 2020 10 5;184(2):792-805. Epub 2020 Aug 5.

Citrus Research and Education Center, Department of Microbiology and Cell Science, University of Florida/Institute of Food and Agricultural Sciences, Lake Alfred, Florida 33850

Citrus Huanglongbing (HLB), caused by Liberibacter asiaticus (Las), is one of the most destructive citrus diseases worldwide, yet how Las causes HLB is poorly understood. Here we show that a Las-secreted protein, SDE15 (CLIBASIA_04025), suppresses plant immunity and promotes Las multiplication. Transgenic expression of SDE15 in Duncan grapefruit () suppresses the hypersensitive response induced by ssp. () and reduces the expression of immunity-related genes. SDE15 also suppresses the hypersensitive response triggered by the effector protein AvrBsT in , suggesting that it may be a broad-spectrum suppressor of plant immunity. SDE15 interacts with the citrus protein CsACD2, a homolog of Arabidopsis () ACCELERATED CELL DEATH 2 (ACD2). SDE15 suppression of plant immunity is dependent on , and overexpression of in citrus suppresses plant immunity and promotes Las multiplication, phenocopying overexpression of SDE15. Identification of CsACD2 as a susceptibility target has implications in genome editing for novel plant resistance against devastating HLB.
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http://dx.doi.org/10.1104/pp.20.00348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536665PMC
October 2020

Development of multiplex genome editing toolkits for citrus with high efficacy in biallelic and homozygous mutations.

Plant Mol Biol 2020 Oct 3;104(3):297-307. Epub 2020 Aug 3.

Citrus Research and Education Center, Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences (IFAS), University of Florida, Lake Alfred, FL, USA.

Key Message: We have developed multiplex genome editing toolkits for citrus that significantly improve citrus genome editing efficacy. CRISPR/Cas systems have been engineered for genome editing in many organisms, including plants. However, the gene editing efficiency in citrus via CRISPR technology remains too low to be implemented for genetic improvement in practice. Moreover, it is very difficult to obtain homozygous or biallelic knockout mutants in citrus. Here, we have developed multiplex genome editing toolkits for citrus including PEG-mediated protoplast transformation, a GFP reporter system that allows the rapid assessment of CRISPR constructs, citrus U6 promoters with improved efficacy, and tRNA-mediated or Csy4-mediated multiplex genome editing. Using the toolkits, we successfully conducted genome modification of embryogenic protoplast cells and epicotyl tissues. We have achieved a biallelic mutation rate of 44.4% and a homozygous mutation rate of 11.1%, representing a significant improvement in citrus genome editing efficacy. In addition, our study lays the foundation for nontransgenic genome editing of citrus.
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http://dx.doi.org/10.1007/s11103-020-01043-6DOI Listing
October 2020

mCherry fusions enable the subcellular localization of periplasmic and cytoplasmic proteins in Xanthomonas sp.

PLoS One 2020 30;15(7):e0236185. Epub 2020 Jul 30.

Department of Technology, School of Agricultural and Veterinarian Sciences, São Paulo State University (UNESP), Jaboticabal, SP, Brazil.

Fluorescent markers are a powerful tool and have been widely applied in biology for different purposes. The genome sequence of Xanthomonas citri subsp. citri (X. citri) revealed that approximately 30% of the genes encoded hypothetical proteins, some of which could play an important role in the success of plant-pathogen interaction and disease triggering. Therefore, revealing their functions is an important strategy to understand the bacterium pathways and mechanisms involved in plant-host interaction. The elucidation of protein function is not a trivial task, but the identification of the subcellular localization of a protein is key to understanding its function. We have constructed an integrative vector, pMAJIIc, under the control of the arabinose promoter, which allows the inducible expression of red fluorescent protein (mCherry) fusions in X. citri, suitable for subcellular localization of target proteins. Fluorescence microscopy was used to track the localization of VrpA protein, which was visualized surrounding the bacterial outer membrane, and the GyrB protein, which showed a diffused cytoplasmic localization, sometimes with dots accumulated near the cellular poles. The integration of the vector into the amy locus of X. citri did not affect bacterial virulence. The vector could be stably maintained in X. citri, and the disruption of the α-amylase gene provided an ease screening method for the selection of the transformant colonies. The results demonstrate that the mCherry-containing vector here described is a powerful tool for bacterial protein localization in cytoplasmic and periplasmic environments.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236185PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392301PMC
September 2020

Identifying key genes and drug screening for preeclampsia based on gene expression profiles.

Oncol Lett 2020 Aug 9;20(2):1585-1596. Epub 2020 Jun 9.

Reproductive Sciences Institute, Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China.

Preeclampsia (PE) is characterized by gestational hypertension and proteinuria, and is a leading cause of maternal death and perinatal morbidity globally. Although the exact cause of PE remains unclear, several studies have suggested a role for abnormal expression of multiple genes. The aim of the present study was to identify key genes and related pathways, and to screen for drugs that regulate these genes for potential PE therapy. The GSE60438 dataset was acquired from the Gene Expression Omnibus database to analyze differentially expressed genes (DEGs). By constructing a protein-protein interaction network and performing reverse transcription-quantitative PCR verification, proteasome 26S subunit, non-ATPase 14, prostaglandin E synthase 3 and ubiquinol-cytochrome reductase core protein 2 were identified as key genes in PE. In addition, PE was found to be associated with 'circadian rhythm', 'fatty acid metabolism', 'DNA damage response detection of DNA damage', 'regulation of DNA repair' and 'endothelial cell development'. Through connectivity map analysis of DEGs, furosemide and droperidol were suggested to be therapeutic drugs that may target the hub genes for PE treatment. Results analysis of GSEA were included in the discussion section of this article. In conclusion, the current study identified novel key genes associated with the onset of PE and potential drugs for PE treatment.
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http://dx.doi.org/10.3892/ol.2020.11721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377100PMC
August 2020

A basic/helix-loop-helix transcription factor controls leaf shape by regulating auxin signaling in apple.

New Phytol 2020 12 18;228(6):1897-1913. Epub 2020 Aug 18.

State Key Laboratory of Crop Biology, College of Horticulture Science and Engineering, Shandong Agricultural University, Tai'an, Shandong, 271018, China.

Climate-driven phenological change across local spatial gradients leads to leaf shape variation. At higher elevations, leaves of broadleaf species tend to become narrower, but the underlying molecular mechanism is largely unknown. In this study, a series of morphometric analyses and biochemical assays, combined with functional identification in apple, were performed. We show that the decrease in apple leaf width with increasing altitude is controlled by a basic/helix-loop-helix transcription factor (bHLH TF), MdbHLH3. The MdbHLH3-overexpressing lines have a lower transcript abundance of MdPIN1 encoding an auxin efflux carrier but a higher transcript abundance of MdGH3-2 encoding a putative auxin amido conjugate synthase, resulting in a lower free auxin concentration; feeding the transgenic leaves with exogenous auxin partially restores leaf width. MdbHLH3 transcriptionally suppresses and activates MdPIN1 and MdGH3-2, respectively, by specifically binding to their promoters. This alters auxin homeostasis and transport, consequently leading to changes in leaf shape. These findings suggest that the bHLH TF MdbHLH3 directly modulates auxin signaling in controlling leaf shape in response to local spatial gradients in apple.
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http://dx.doi.org/10.1111/nph.16828DOI Listing
December 2020

The bacterial community and metabolome dynamics and their interactions modulate fermentation process of whole crop corn silage prepared with or without inoculants.

Microb Biotechnol 2021 03 6;14(2):561-576. Epub 2020 Jul 6.

State Key Laboratory of Grassland and Agro-ecosystems, School of Life Sciences, Lanzhou University, Lanzhou, 730000, China.

Multi-omics approach was adopted to investigate the modulation of bacterial microbiota and metabolome as well as their interactions in whole crop corn ensiling systems by inoculating homofermentative Lactobacillus plantarum or heterofermentative Lactobacillus buchneri. Inoculations of the two different inoculants resulted in substantial differences in microbial community and metabolic composition as well as their dynamics in ensiled corn. Inoculants also altered the correlations of microbiota in different manners, and various keystone species were identified in corn silages with different treatments. Many metabolites with biofunctional activities like bacteriostatic, antioxidant, central nervous system inhibitory and anti-inflammatory were found in the present silage. A constitutive difference in microbiota dynamics was found for several pathways, which were upregulated by specific taxa in middle stage of fermentation, and widespread associations between metabolites with biofunctions and the species of lactic acid bacteria dominated in silage were observed. Multiple microbial and metabolic structures and dynamics were correlated and affected the fermentation process of the corn ensiling systems. Results of the current study improve our understanding of the complicated biological process underlying silage fermentation and provide a framework to re-evaluate silages with biofunctions, which may contribute to target-based regulation methods to produce functional silage for animal production.
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http://dx.doi.org/10.1111/1751-7915.13623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936295PMC
March 2021

ACOD1 in immunometabolism and disease.

Cell Mol Immunol 2020 08 29;17(8):822-833. Epub 2020 Jun 29.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.

Immunometabolism plays a fundamental role in health and diseases and involves multiple genes and signals. Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is emerging as a regulator of immunometabolism in inflammation and infection. Upregulation of ACOD1 expression occurs in activated immune cells (e.g., macrophages and monocytes) in response to pathogen infection (e.g., bacteria and viruses), pathogen-associated molecular pattern molecules (e.g., LPS), cytokines (e.g., TNF and IFNs), and damage-associated molecular patterns (e.g., monosodium urate). Mechanistically, several immune receptors (e.g., TLRs and IFNAR), adapter proteins (e.g., MYD88), ubiquitin ligases (e.g., A20), and transcription factors (e.g., NF-κB, IRFs, and STATs) form complex signal transduction networks to control ACOD1 expression in a context-dependent manner. Functionally, ACOD1 mediates itaconate production, oxidative stress, and antigen processing and plays dual roles in immunity and diseases. On the one hand, activation of the ACOD1 pathway may limit pathogen infection and promote embryo implantation. On the other hand, abnormal ACOD1 expression can lead to tumor progression, neurodegenerative disease, and immune paralysis. Further understanding of the function and regulation of ACOD1 is important for the application of ACOD1-based therapeutic strategies in disease.
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http://dx.doi.org/10.1038/s41423-020-0489-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395145PMC
August 2020

Coexpression analysis of a large-scale transcriptome identified a calmodulin-like protein regulating the development of adventitious roots in poplar.

Tree Physiol 2020 10;40(10):1405-1419

Forestry Department, College of Horticulture and Forestry Sciences, Huazhong Agricultural University, Wuhan 430070, China.

Poplars are important woody plants, and the ability to form adventitious roots (ARs) is the key factor for their cultivation because most poplars are propagated by cloning. In previous studies, Ca2+ was confirmed to regulate AR formation in poplar. In this study, wild-type poplar cuttings grown in 1.0 mM Ca2+ solution showed the best visible performance of AR development. Coexpression analysis of a large-scale RNA-Seq transcriptome was conducted to identify Ca2+-related genes that regulate AR development in poplar. A total of 15 coexpression modules (CMs) were identified, and two CMs showed high association with AR development. Functional analysis identified a number of biological pathways, including 'oxidation-reduction process', 'response to biotic stimulus' and 'metabolic process', in tissues of AR development. The Ca2+-related pathway was specifically selected, and its regulation in poplar AR development was predicted. A Ca2+ sensor, PdeCML23-1, which is a member of the calmodulin-like protein (CML) family, was found to promote AR development by phenotypic assay of overexpressed PdeCML23-1 transgenic lines at various growing conditions. By measuring cytosolic Ca2+ in AR tips, PdeCML23-1 seemed to play a role in decreasing cytosolic Ca2+ concentration. Additionally, the expression profiles of some genes and phytohormone indole acetic acid (IAA) were also changed in the overexpressed PdeCML23-1 transgenic lines. According to this study, we were able to provide a global view of gene regulation for poplar AR development. Moreover, we also observed the regulation of cytosolic Ca2+ concentration by PdeCML23-1, and this regulation was involved in AR development in poplar. We also predicted that PdeCML23-1 possibly regulates AR development by modulating IAA content in poplar.
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http://dx.doi.org/10.1093/treephys/tpaa078DOI Listing
October 2020

Metformin protects against ischaemic myocardial injury by alleviating autophagy-ROS-NLRP3-mediated inflammatory response in macrophages.

J Mol Cell Cardiol 2020 08 26;145:1-13. Epub 2020 May 26.

Department of Pathophysiology, School of Basic Medical Science, Central South University, Changsha, Hunan 410008, China; Hunan Key Laboratory of Sepsis Translational Medicine, Central South University, Changsha, Hunan 410008, China. Electronic address:

Myocardial ischaemia is usually accompanied by inflammatory response which plays a critical role in the myocardial healing and scar formation, while persistent inflammatory response contributes greatly to the myocardial remodeling and consequent heart failure. Metformin (Met), a widely used hypoglycemic drug, has increasingly been shown to exert remarkable cardioprotective effect on ischaemic myocardial injury such as acute myocardial infarction (AMI). However, the underlying mechanisms are still far from being fully understood. In this study, a mouse model of AMI was established through ligating the left anterior descending coronary artery (LAD), 100 mg/kg Met was given immediately after operation once daily for 3 days. It was demonstrated that Met effectively improved the cardiac haemodynamics (LVSP, LVEDP, +dp/dt, -dp/dt), diminished the infarct size, alleviated the disarrangement of myocardial cells and reduced the infiltration of inflammatory cells (macrophages, neutrophils and lymphocytes) in the heart of AMI mice. Mechanistically, Met decreased the expression of NLRP3 and enhanced the accumulation of LC3 puncta in F4/80-positive macrophages in the heart of AMI mice. Single cell suspension of cardiac macrophages was prepared from AMI mice and exhibited increased NLRP3 mRNA and protein expression. In contrast, Met decreased the expression of NLRP3 and p62, whereas increased the ratio of LC3II/LC3I. Additionally, both conditioned medium from H9c2 cardiomyocytes exposed to hydrogen peroxide (H9c2-HO-CM) and combination of mtDNA and ATP (mtDNA-ATP) increased the expression of NLRP3 and cleaved caspase-1 (p10) as well as intracellular ROS production in RAW264.7 macrophages, which were abrogated by Met treatment. Strikingly, chloroquine (CQ), 3-methyladenine (3-MA) and knockdown of autophagy-related gene (Atg5) abrogated the inhibitory effects of Met on H9c2-HO-CM and mtDNA-ATP-induced NLRP3 expression, release of IL-1β and IL-18 as well as ROS production in RAW264.7 macrophages. Collectively, these findings suggest that Met protects against ischaemic myocardial injury through alleviating autophagy-ROS-NLRP3 axis-mediated inflammatory response in macrophages.
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http://dx.doi.org/10.1016/j.yjmcc.2020.05.016DOI Listing
August 2020