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Summary: Atrial fibrillation (AF) is the most common arrhythmia in the world. Human genetics can provide strong AF therapeutic candidates, but the identification of the causal genes and their functions remains challenging. Here, we applied an AF fine-mapping strategy that leverages results from a previously published cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAAs) obtained from two cohorts with distinct ancestry, and a paired RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) LAA single-nucleus assay (sn-multiome). At nine AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Data integration identified several candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system.

Abstract Background Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with poor prognosis. Further mechanistic insights into the molecular mechanisms of CCA are needed to develop more effective target therapy. Methods The expression of the histone lysine acetyltransferase KAT2B in human CCA was analyzed in human CCA tissues. CCA xenograft was developed by inoculation of human CCA cells with or without KAT2B overexpression into SCID mice. Western blotting, ChIP-qPCR, qRT-PCR, protein immunoprecipitation, GST pull-down and RNA-seq were performed to delineate KAT2B mechanisms of action in CCA. Results We identified KAT2B as a frequently downregulated histone acetyltransferase in human CCA. Downregulation of KAT2B was significantly associated with CCA disease progression and poor prognosis of CCA patients. The reduction of KAT2B expression in human CCA was attributed to gene copy number loss. In experimental systems, we demonstrated that overexpression of KAT2B suppressed CCA cell proliferation and colony formation in vitro and inhibits CCA growth in mice. Mechanistically, forced overexpression of KAT2B enhanced the expression of the tumor suppressor gene NF2, which is independent of its histone acetyltransferase activity. We showed that KAT2B was recruited to the promoter region of the NF2 gene via interaction with the transcription factor SP1, which led to enhanced transcription of the NF2 gene. KAT2B-induced NF2 resulted in subsequent inhibition of YAP activity, as reflected by reduced nuclear accumulation of oncogenic YAP and inhibition of YAP downstream genes. Depletion of NF2 was able to reverse KAT2B-induced reduction of nuclear YAP and subvert KAT2B-induced inhibition of CCA cell growth. Conclusions This study provides the first evidence for an important tumor inhibitory effect of KAT2B in CCA through regulation of NF2-YAP signaling and suggests that this signaling cascade may be therapeutically targeted for CCA treatment.

Background & Aims: The RNA-binding motif protein 39 (RBM39) functions as both an RNA-binding protein and a splicing factor in a variety of cancer types. However, the function of RBM39 in cholangiocarcinoma (CCA) remains undefined. In this study, we aimed to investigate the role of RBM39 in CCA and explore its potential as a therapeutic target. Methods: The expression of RBM39 in CCA was investigated by analyzing human CCA tumor specimens. CRISPR/Cas9 or shRNA-mediated depletion of RBM39 was performed in vitro and in vivo to document the oncogenic role of RBM39 in CCA. The anti-tumor effect of the RBM39 inhibitor, Indisulam, in combination with the EZH2 degrader MS177 was assessed in vitro and in vivo. Results: RBM39 is significantly increased in human CCA tissues and associated with a poor prognosis in patients with CCA. Depletion of RBM39 by CRISPR/Cas9 or shRNA inhibited CCA cell proliferation in vitro and prevented CCA development and tumor growth in mice. Mechanistically, our results showed that depletion of RBM39 suppressed EZH2 expression via disrupting its mRNA splicing. RBM39-regulated EZH2 controls WNT7B/β-catenin activity. Pharmacological co-targeting of RBM39 (with Indisulam) and EZH2 (with MS177) resulted in a synergistic antitumor effect, both in vitro and in vivo. Conclusion: This study discloses a novel RBM39-EZH2-β-catenin signaling axis that is crucial for CCA growth. Our findings suggest that simultaneous inhibition of RBM39 and EZH2 presents a promising therapeutic strategy for CCA treatment.

Background & Aims: Notch and TAZ are implicated in cholangiocarcinogenesis, but whether and how these oncogenic molecules interact remain unknown. Methods: The development of cholangiocarcinoma (CCA) was induced by hydrodynamic tail vein injection of oncogenes (Notch1 intracellular domain [NICD]/AKT) to the FVB/NJ mice. CCA xenograft was developed by inoculation of human CCA cells into the livers of SCID mice. Tissues and cells were analyzed using quantitative reverse transcription polymerase chain reaction, Western blotting analyses, immunohistochemistry, chromatin immunoprecipitation-quantitative polymerase chain reaction and WST-1 cell proliferation assay. Results: Our experimental findings show that TAZ is indispensable in NICD-driven cholangiocarcinogenesis. Notch activation induces the expression of methyltransferase like-3 (METTL3), which catalyzes N6-methyladenosine modification of TAZ mRNA and that this mechanism plays a central role in the crosstalk between Notch and TAZ in CCA cells. Mechanistically, Notch regulates the expression of METTL3 through the binding of NICD to its downstream transcription factor CSL in the promoter region of METTL3. METTL3 in turn mediates N6-methyladenosine modification of TAZ mRNA, which is recognized by the m6A reader YTHDF1 to enhance TAZ protein translation. We observed that inhibition of Notch signaling decreased the protein levels of both MELLT3 and TAZ. Depletion of METTL3 by short hairpin RNAs or by the next generation GapmeR antisense oligonucleotides decreased the level of TAZ protein and inhibited the growth of human CCA cells in vitro and in mice. Conclusion: This study describes a novel Notch-METTL3-TAZ signaling cascade, which is important in CCA development and progression. Our experimental results provide new insight into how the Notch pathway cooperates with TAZ signaling in CCA, and the findings may have important therapeutic implications.

Ketones, prevalent in many biologically significant molecules, require the development of novel methods to synthesize these structures, which is a critical endeavor in organic synthesis. Transition metal catalysis has proven to be an effective method for synthesizing ketones. However, the scope of these substrates remains relatively limited, particularly due to their incompatibility with sensitive functional groups. Herein, we report a Ni-catalyzed three-component 1,2-carboacylation of alkenes, which activates secondary/tertiary alkyl bromides. This method offers significant advantages: simplicity of operation, ready availability of substrates, and broad substrate applicability. A series of experimental studies have helped clarify the key mechanistic pathways involved in this cascade reaction.

Although plant genotypes are known to be a determinant of microbiome composition, the genetic mechanisms underlying how genotypes affect the microbiome are poorly understood. Citrus is an important, perennial fruit crop that normally contains scion grafted on the rootstock. Here, we investigated the genetic traits underlying the citrus microbiome. We sequenced the metagenome of leaf, root, and rhizosphere soil samples and the genome of corresponding citrus genotypes, which included 66 unique rootstock–scion combinations (56 scion genotypes and 9 rootstock genotypes) from one location using deep shotgun sequencing. Using a genome-wide association study (GWAS) analysis, we identified significant associations between citrus genes and a subset of genera and functional traits of the microbiome. Intriguingly, we found that bacterial secretion systems and mobility-related genes were present in single-nucleotide polymorphism-associated microbial functional traits of leaf and root microbiomes but not in the rhizosphere microbiome, indicating that they are important factors for bacteria to colonize inside or on leaf and root tissues but less so in the rhizosphere. We also discovered that chemotaxis and flagella genes play critical roles for bacteria colonizing leaf tissues but not in root tissues and the rhizosphere. Microbiome-associated host genes were mainly involved in plant immunity, transporters, hormones, cell walls, and the metabolism of carbohydrates, amino acids, and nitrogen. We identified genetic determinants that are associated with the abundance of Bacillus, Bradyrhizobium, Burkholderia, and Cellvibrio, genera that are known to comprise many beneficial bacteria for citrus. This study unraveled the genetic traits underneath the mutual selection of citrus and microbes via GWAS analyses. This study provides useful information that aids the utilization of genotypes and key members of a healthy microbiota for microbiome engineering as well as the editing of specific genes to improve host microbiota. [Graphic: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background RNA N6-Methyladenosine (m6A) modification is implicated in the progression of human cancers including cholangiocarcinoma (CCA). METTL16 is recently identified as a new RNA methyltransferase responsible for m6A modification, although the role of METTL16 in CCA has not yet been examined. The current study aims to investigate the effect and mechanism of the RNA methyltransferase METTL16 in CCA. Methods The expression of METTL16 in CCA was examined by analyzing publicly available datasets or by IHC staining on tumor samples. siRNA or CRISPR/Cas9-mediated loss of function studies were performed in vitro and in vivo to investigate the oncogenic role of METTL16 in CCA. MeRIP-Seq was carried out to identify the downstream target of METTL16. ChIP-qPCR, immunoprecipitation, and immunoblots were used to explore the regulation mechanisms for METTL16 expression in CCA. Results We observed that the expression of METTL16 was noticeably increased in human CCA tissues. Depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. PRDM15 was identified as a key target of METTL16 in CCA cells. Mechanistically, our data showed that METTL16 regulated PRDM15 protein expression via YTHDF1-dependent translation. Accordingly, we observed that restoration of PRDM15 expression could rescue the deficiency of CCA cell proliferation/colony formation induced by METTL16 depletion. Our subsequent analyses revealed that METTL16-PRDM15 signaling regulated the expression of FGFR4 in CCA cells. Specifically, we observed that PRDM15 protein was associated with the FGFR4 promoter to regulate its expression. Furthermore, we showed that the histone acetyltransferase p300 cooperated with the transcription factor YY1 to regulate METTL16 gene expression via histone H3 lysine 27 (H3K27) acetylation in CCA cells. Conclusions This study describes a novel METTL16-PRDM15-FGFR4 signaling axis which is crucial for CCA growth and may have important therapeutic implications. We showed that depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression.

Abstract Background Populus euphratica Olivier is a kind of tree capable of growing in extremely arid desert and semi-desert environments. In this study, a culture-dependent method was used to analyze the bacterial diversity of stem liquid of P. euphratica and resina of P. euphratica, and to further evaluate plant growth promoting (PGP) activity. Results A total of 434 bacteria were isolated from stem fluid and resina of P. euphratica in Ebinur Lake Wetland Nature Reserve and Mulei Primitive forest. The results of taxonomic composition analysis shows that Gammaproteobacteria, Firmicutes, and Actinobacteria_c are the three dominant groups in all the communities, and the representative genera are Bacillus, Nesterenkonia and Halomonas. The diversity analysis shows that the culturable bacterial community diversity of P. euphratica in Ebinur Lake Wetland Nature Reserve is higher than that in Mulei Primitive forest, and the bacterial community diversity of P. euphratica stem fluid is higher than that of resina. According to PGP activity evaluation, 158 functional bacteria with plant growth promoting potential were screened. Among them, 61 strains havephosphorus solubilizing abilities, 80 strains have potassium solubilizing abilities, 32 strains have nitrogen fixation abilities, and 151 strains have iron ammonia salt utilization abilities. The germination rate, plant height, and dry weight of the maize seedlings treated with strains BB33-1, TC10 and RC6 are significantly higher than those of the control group. Conclusion In this study, a large number of culturable bacteria were isolated from P. euphratica, which provides new functional bacteria sources for promoting plant growth.

Abstract PandaX-4T is a ton-scale dark matter direct detection experiment using a dual-phase TPC technique at the China Jinping Underground Laboratory. Various ultra-low background technologies have been developed and applied to material screening for PandaX-4T, including HPGe gamma spectroscopy, ICP-MS, NAA, radon emanation measurement system, krypton assay station, and alpha detection system. Low background materials were selected to assemble the detector. Surface treatment procedures were investigated to further suppress radioactive background. Combining measured results and Monte Carlo simulation, the total material background rates of PandaX-4T in the energy region of 1–25 keVee are estimated to be (9.9 ± 1.9) × 10 −3 mDRU for electron recoil and (2.8 ± 0.6) × 10 −4 mDRU for nuclear recoil. In addition, natKr in the detector is estimated to be < 8 ppt.

Abstract As one of the most widely used nanomaterials in asphalt modification, the nano-silica (nano-SiO2) can significantly improve the self-healing behavior of asphalt eco-friendly. However, understanding of the self-healing mechanism of nano-SiO2 in asphalt is still limited. The objective of the study is to reveal the self-healing mechanism of nano-SiO2 in asphalt by using molecular dynamics (MD) simulations from the nanoscale. A 10 Å (Å) vacuum pad was added between the two same stable asphalt models to represent the micro-cracks inside the asphalt. The self-healing process of virgin asphalt, oxidation aging asphalt, and nano-SiO2 modified asphalt was studied using density evolution, relative concentration, diffusion coefficient, activation energy, and pre-exponential factor. The simulation results conclude that nano-SiO2 improves the self-healing ability of asphalt by increasing the diffusion rate of molecules with aromatic structures without alkyl side chains and molecules with structures with longer alkyl chains. The self-healing capability of asphalt may be principally determined by the diffusion of light components such as saturate, while nano-SiO2 only plays an inducing role. The research findings could provide insights to understand the self-healing mechanism of nano-SiO2 in asphalt for promoting the sustainability of bitumen pavements while increasing their durability. Graphical abstract

ObjectivesMultiple step saccades (MSSs) are an atypical form of saccade that consists of a series of small-amplitude saccades. It has been argued that the mechanism for generating MSS is due to the automatic saccadic plan. This argument was based on the observation that trials with MSS had shorter saccadic latency than trials without MSS in the reactive saccades. However, the validity of this argument has never been verified by other saccadic tasks. Alternatively, we and other researchers have speculated that the function of MSS is the same as that of the corrective saccade (CS), i.e., to correct saccadic errors. Thus, we propose that the function of the MSS is also to rectify saccadic errors and generated by forward internal models. The objective of the present study is to examine whether the automatic theory is universally applicable for the generation of MSSs in various saccadic tasks and to seek other possible mechanisms, such as error correction by forward internal models.MethodsFifty young healthy subjects (YHSs) and fifty elderly healthy subjects (EHSs) were recruited in the present study. The task paradigms were prosaccade (PS), anti-saccade (AS) and memory-guided saccade (MGS) tasks.ResultsSaccadic latency in trials with MSS was shorter than without MSS in the PS task but similar in the AS and MGS tasks. The intersaccadic intervals (ISI) were similar among the three tasks in both YHSs and EHSs.ConclusionOur results indicate that the automatic theory is not a universal mechanism. Instead, the forward internal model for saccadic error correction might be an important mechanism.

The rainfall often causes changes in the physical performance of the embankment, which leads to disasters such as embankment collapse and road surface settlement and cracking. Past research has tended to be limited to traditional embankment seepage models and is mostly based on the assumption that surface precipitation is uniform and rainfall intensity is constant. To adapt to the changes and development of the times, based on the water leakage mode of the flexibly assembled highway embankment, a new rainfall calculation model of the reinforced soil embankment is constructed and combined with the solid-fluid coupling physics theory, the sedimentation amount and slope stability of the embankment are analyzed at multiple levels, the mechanical properties of the new embankment under rainfall conditions are summarized, the factors affecting the settlement of the embankment and the stability of the slope are explored, and the reference model is provided for the construction of the new embankment, and the existing construction process is improved through multilevel cause analysis. We improve and develop the existing theoretical system to reduce the probability of road diseases, improve the efficiency of road construction, and reduce the cost of road maintenance.

Following the outbreak of COVID-19, farmer-assisted live streaming has become a hot topic in China. In this manuscript, we explore the ways in which broadcaster and platform characteristics jointly influence consumers’ purchase intention. To examine our hypotheses, we distributed questionnaires to 261 Chinese consumers who viewed farmer-assisted live streaming. Correlational analyses, regression analyses, and confirmatory factor analyses were conducted to examine our hypotheses. The results show that broadcasters’ expertise is positively related to consumer trust and that platform reputation moderates this relationship. In addition, consumer trust mediates the positive relationship between broadcasters’ expertise and consumer purchase intention. Furthermore, the theoretical and practical implications of these findings are discussed.

We present the constraints on the axial-vector and pseudo-scalar mediated WIMP-nucleus interactions from the PandaX-4T experiment, using the data set corresponding to a total exposure of 0.63 tonne⋅year. No significant signal excess is observed, and the most stringent constraints to date on the mediator mass are set for the axial-vector and pseudo-scalar simplified models. The maximum excluded mass of an axial-vector mediator is 825 GeV/c2 and that of a pseudo-scalar mediator is 106 GeV/c2. In addition, the upper limits on the spin-dependent WIMP-nucleon scattering cross-section for conventional neutron-only and proton-only interactions are derived.

In the two-component Majorana dark matter model, one dark matter particle can scatter off the target nuclei, and turn into a slightly heavier component. In the framework of a simplified model with a vector boson mediator, both the tree-level and loop-level processes contribute to the signal in direct detection experiment. In this paper, we report the search results for such dark matter from PandaX-II experiment, using total data of the full 100.7 tonne⋅day exposure. No significant excess is observed, so strong constraints on the combined parameter space of mediator mass and dark matter mass are derived. With the complementary search results from collider experiments, a large range of parameter space can be excluded.

ObjectiveAlthough multiple step saccades (MSS) is occasionally observed in healthy subjects, it is more pronounced in patients with aging-related neurodegenerative diseases, particularly Parkinson’s disease (PD). Thus, MSS has been treated as a complementary biomarker for diagnosing PD. Despite the aforementioned knowledge, several questions remain unexplored: (1) How does aging affect MSS? (2) Is there a sex difference in MSS? (3) Are there differences in MSS between vertical and horizontal saccades? (4) Are MSS and corrective saccade (CS) the same behavior? (5) How do age and sex affect CS? The objectives of the present study are to address these questions.MethodFour hundred eighty healthy participants were recruited to perform a visually guided reactive saccade task. Participants were divided into six groups according to their ages. Each group consisted of 40 male and 40 female participants. Eye movements were recorded with infrared eye trackers.ResultsThe incidence of MSS increased as a function of age, whereas the incidence of CS first increased with age 20–49 and then decreased with age 50–79. The incidences of both MSS and CS did not show sex differences. The incidence of MSS in vertical saccades was significantly higher than that in horizontal saccades, and their difference increased with increasing age, whereas the incidence of CS showed a reversed pattern.ConclusionAge and saccadic direction affect the occurrences of MSS and CS differently, indicating that MSS and CS are different saccadic behaviors. In addition, measuring saccades could reliably reflect the function of human’s brain which is affected by aging.

The efficient copper-mediated oxidative C–H alkynylation of benzhydrazides was accomplished with terminal alkynes. Thus, a heteroaromatic removable N-2-pyridylhydrazide allowed for domino C–H/N–H functionalization. The approach featured remarkable functional group compatibility and ample substrate scope. Thereby, highly functionalized aromatic and heteroaromatic isoindolin-1-ones were accessed with high efficacy with rate-limiting C–H cleavage.

ObjectiveIt has been argued that the incidence of multiple step saccades (MSS) in voluntary saccades could serve as a complementary biomarker for diagnosing Parkinson’s disease (PD). However, voluntary saccadic tasks are usually difficult for elderly subjects to complete. Therefore, task difficulties restrict the application of MSS measurements for the diagnosis of PD. The primary objective of the present study is to assess whether the incidence of MSS in simply reactive saccades could serve as a complementary biomarker for the early diagnosis of PD.Materials and methodsThere were four groups of human subjects: PD patients, mild cognitive impairment (MCI) patients, elderly healthy controls (EHCs), and young healthy controls (YHCs). There were four monkeys with subclinical hemi-PD induced by injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) through the unilateral internal carotid artery and three healthy control monkeys. The behavioral task was a visually guided reactive saccade.ResultsIn a human study, the incidence of MSS was significantly higher in PD than in YHC, EHC, and MCI groups. In addition, receiver operating characteristic (ROC) analysis could discriminate PD from the EHC and MCI groups, with areas under the ROC curve (AUCs) of 0.76 and 0.69, respectively. In a monkey study, while typical PD symptoms were absent, subclinical hemi-PD monkeys showed a significantly higher incidence of MSS than control monkeys when the dose of MPTP was greater than 0.4 mg/kg.ConclusionThe incidence of MSS in simply reactive saccades could be a complementary biomarker for the early diagnosis of PD.

Cardiac ischemia–reperfusion (I/R) injury represents a key threat to human health. This study reveals that the long noncoding RNA lncRNA-CIRBIL is protective against I/R injury by inhibiting the nuclear translocation of Bclaf1.

Sec-delivered effector 1 (SDE1) from the huanglongbing (HLB)-associated bacterium ‘Candidatus 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 Arabidopsis thaliana caused severe yellowing in mature leaves, reminiscent of both ‘Ca. L. asiaticus’ infection symptoms and accelerated leaf senescence. Induction of senescence signatures was also observed in the SDE1-expressing A. thaliana lines. These signatures were apparent in older leaves but not in seedlings, suggesting an age-associated effect. Furthermore, independent lines of transgenic Citrus paradisi (L.) Macfadyen (Duncan grapefruit) that express SDE1 exhibited hypersusceptibility to ‘Ca. L. asiaticus’. Similar to A. thaliana, transgenic citrus expressing SDE1 showed altered expression of senescence-associated genes, but only after infection with ‘Ca. 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.[Graphic: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Background. In recent years, carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged rapidly in China with the abuse and overuse of antibiotics, and infections caused by CRKP pose a serious threat to global public health safety. The present study aimed to explore the epidemiological characteristics of CRKP isolates in Northern China and to elucidate their drug resistance mechanisms. Methods. 45 CRKP strains were consecutively collected at a teaching hospital from March 1st, 2018 to June 30th, 2018. Antimicrobial susceptibility was determined by the VITEK2 compact system and microbroth dilution method. Polymerase chain reaction (PCR) and sequencing were used to analyze multilocus sequence typing (MLST), drug resistance determinants, and plasmid types. The transfer of resistance genes was determined by conjugation. All statistical analysis was performed using SPSS 22.0 software. Results. All 45 isolates showed multidrug resistance (MDR). MLST analysis showed ST11 (48.9%, 22/45) was the most frequent type. All of the 45 CRKP isolates contained carbapenemase genes, extended-spectrum β-lactamase (ESBL) genes, and plasmid-mediated quinolone resistance (PMQR) genes. For carbapenemase genes, KPC-2 (93.3%, 42/45) was the main genotype, and followed by GES (37.8%, 17/45) and NDM-1 (11.1%, 5/45). Plasmid typing analysis showed that IncFII and IncFIB were the most prevalent plasmids. The carbapenem resistance rate of K.pneumoniae was 11.4% and ICU was the main CRKP infection source. Conclusions. ST11 is the most frequent sequence type and KPC-2 is the predominant carbapenemase of CRKP strains in Northern China. KPC-2-ST11 are representative clonal lineages.

Precise measurement of two-neutrino double beta decay (DBD) half-life is an important step for the searches of Majorana neutrinos with neutrinoless double beta decay. We report the measurement of DBD half-life of 136Xe using the PandaX-4T dual-phase Time Projection Chamber (TPC) with 3.7-tonne natural xenon and the first 94.9-day physics data release. The background model in the fiducial volume is well constrained in situ by events in the outer active region. With a 136Xe exposure of 15.5 kg-year, we establish the half-life as 2.27±0.03stat.±0.10syst.×1021 years. This is the first DBD half-life measurement with natural xenon and demonstrates the physics capability of a large-scale liquid xenon TPC in the field of rare event searches.

Recent innovations are increasingly recognizing applications in precision agricultural systems that use data science techniques as well as so-called machine learning techniques. Big data analytics have created various data-intensive decision-making opportunities. This study reviews the big data analysis practices in the agriculture industry to resolve various problems to provide prospects and exciting fields of application in China. In the successful implementation of precise farming, the high-volume and complicated data generated present challenges for the economic growth of China. Emerging deep learning techniques seem promising and must be reinvented to meet current challenges. Thus, this paper suggests a big data analytics agriculture monitoring system (BDA-AMS) to ensure the highly accurate prediction of crop yield in precision agriculture and economic management using a deep learning algorithm. The convolution neural network gathers the raw images from UAVs and performs early predictions of crop yield. The simulation analysis using an open-source agricultural dataset resulted in a high parameter–precision ratio (98.8%), high accuracy (98.9%), a better performance ratio (95.5%), an improved data transmission rate (97.8%), a reduced power consumption ratio (18.8%), and an enhanced weather forecasting ratio (94.8%), production density ratio (98.8%), and reliability ratio (98.6%) compared to the baseline models.

Abstract All‐inorganic perovskite quantum dots (QDs) CsPbX3 (X = Cl, Br, and I) have recently emerged as a new promising class of X‐ray scintillators. However, the instability of perovskite QDs and the strong optical scattering of the thick opaque QD scintillator film imped it to realize high‐quality and robust X‐ray image. Herein, the europium (Eu) doped CsPbBr3 QDs are in situ grown inside transparent amorphous matrix to form glass‐ceramic (GC) scintillator with glass phase serving as both matrix and encapsulation for the perovskite QD scintillators. The small amount of Eu dopant optimizes the crystallization of CsPbBr3 QDs and makes their distribution more uniform in the glass matrix, which can significantly reduce the light scattering and also enhance the photoluminescence emission of CsPbBr3 QDs. As a result, a remarkably high spatial resolution of 15.0 lp mm−1 is realized thanks to the reduced light scattering, which is so far a record resolution for perovskite scintillator based X‐ray imaging, and the scintillation stability is also significantly improved compared to the bare perovskite QD scintillators. Those results provide an effective platform particularly for the emerging perovskite nanocrystal scintillators to reduce light scattering and improve radiation hardness.

In plants, nucleotide-binding domain and leucine-rich repeat (NLR)-containing proteins can form receptor networks to confer hypersensitive cell death and innate immunity. One class of NLRs, known as NLR required for cell death (NRCs), are central nodes in a complex network that protects against multiple pathogens and comprises up to half of the NLRome of solanaceous plants. Given the prevalence of this NLR network, we hypothesised that pathogens convergently evolved to secrete effectors that target NRC activities. To test this, we screened a library of 165 bacterial, oomycete, nematode, and aphid effectors for their capacity to suppress the cell death response triggered by the NRC-dependent disease resistance proteins Prf and Rpi-blb2. Among 5 of the identified suppressors, 1 cyst nematode protein and 1 oomycete protein suppress the activity of autoimmune mutants of NRC2 and NRC3, but not NRC4, indicating that they specifically counteract a subset of NRC proteins independently of their sensor NLR partners. Whereas the cyst nematode effector SPRYSEC15 binds the nucleotide-binding domain of NRC2 and NRC3, the oomycete effector AVRcap1b suppresses the response of these NRCs via the membrane trafficking-associated protein NbTOL9a (Target of Myb 1-like protein 9a). We conclude that plant pathogens have evolved to counteract central nodes of the NRC immune receptor network through different mechanisms. Coevolution with pathogen effectors may have driven NRC diversification into functionally redundant nodes in a massively expanded NLR network.

Summary: Saccadic eye movements may not stop steadily but fluctuate briefly, known as saccadic dynamic overshoot (SDO). The reported relationships between SDO and saccadic parameters of main saccade and the effect of aging on SDO are controversial. In addition, it is not clear whether aging-related disease, such as mild cognitive impairment (MCI) and Parkinson disease (PD), causes the specific change of SDO. To address these questions, we analyzed the spatiotemporal features of SDO in young healthy subjects, elderly healthy subjects, and subjects with PD and MCI in three oculomotor tasks. We found two types of SDOs—simple and complex SDO. We confirmed that the frequency and amplitude of SDO were positively correlated with the peak velocity and deceleration of main saccades and increased in elderly subjects; however, they were not significantly different among the three elderly groups. Our results support the previous argument that the oculomotor structure in brainstem and cerebellum directly develop SDO.

For a typical pipeline-lifting deep-sea mining system, marine mining pipelines have higher requirements for steel welding. After the pipeline steel is welded, a large amount of residual stress will be generated inside the component because the heat treatment is not carried out, causing the pipeline to form stress corrosion cracks in the seawater environment. For high residual stress, the blind hole method has inaccurate measurement accuracy. Based on the theory of solid mechanics, this paper comprehensively considers the distance between the strain grid and the center of the hole. It introduces the ratio γ of the applied stress to the yield strength of the specimen. The strain relief coefficients under the values were investigated. The variation trend of the strain release coefficient distribution with the γ value of the three kinds of strain gauge flowers commonly used in China was discussed. Finally, the variation law of strain release coefficient with γ value was obtained by fitting. The strain release coefficient was corrected to improve the accuracy of the blind hole method for measuring high residual stress, which provides a reference value for the engineering application of the blind hole method. This has important theoretical significance and engineering value for guiding the welding construction of high-strength pipeline steel in a deep-sea environment.

The reinforced soil-retaining wall has been widely used in coastal projects, and the dry-wet cycles influence the mechanical properties of the reinforced soil interface. This study conducts macro-micro tests and selects four different water content samples of reinforced soil with five types of overburden pressure conditions and three sets of dry-wet cycles, with a total of 60 working conditions. The pull-out test was used to study the mechanical properties of the reinforced soil interface. The scanning electron microscope was used to observe the microscopic characterization of the particles under different working conditions. Through the analysis of the experimental results, we can draw the conclusion as follows. (1) The friction coefficient of the reinforced soil interface decreases with the increase of the number of dry and wet cycles. (2) The apparent cohesion of soil-reinforcement interface decreases with the increase of the number of dry-wet cycles. After 30 dry-wet cycles, the apparent cohesion of the soil-reinforcement interface with water content of 14% is the maximum 5.91 kPa. The variation law of cohesion derived from microstructure analysis conforms to the laws and conclusions obtained by the experiment. (3) The shear stress of the reinforced soil is linearly related to the normal stress, which is in accordance with Coulomb’s law.

Revealing the key influencing factors in urbanization is of great significance to the operability of national urbanization planning and decision-making. Taking 110 cities in the Yangtze River Economic Belt (YREB) as the sample, this paper explores the driving mechanism of urbanization development during 2007–2016 by using Geographically and Temporally Weighted Regression Model (GTWR). The results show that the effects of the four dominant factors of social economy, education, secondary industry, and living environment are in line with expectations, with strong time fluctuation, obvious spatial nonstationarity, and a certain spatial gradient distribution. The formulation and implementation of the urbanization strategy should be based on the driving mechanism shown by the four models, coordinate the use of relevant policies, and give priority to ensuring the effective play of the primary driving factors.

Changes in temperature and stress will lead to the rail creeping of high-speed railway, which becomes a hidden danger in the operation of trains. This paper studies a real-time visual measurement system for creeping displacement monitoring. The bilateral line extraction to determine the target location overcomes the influence of ambient light on image grayscale. The dynamic region of interest setting method is produced to lock and track the target. The self-calibration technology makes the system suitable for field application. The remote transmission of monitoring data is realized through narrow band internet of things (NB-IOT). These methods solve the problems in practical application. The monitoring system provides a reliable guarantee for the safe and stable operation of high-speed railway.

Recent studies have demonstrated the implication of long noncoding RNAs (lncRNAs) in a variety of physiological and pathological processes. However, the majority of lncRNAs are functionally unknown. The current study describes that the lncRNA MALAT1 regulates TGF-β/Smad signaling pathway through formation of a lncRNA-protein complex containing Smads, SETD2 and PPM1A. Our data show that this lncRNA-proteins complex facilitates the dephosphorylation of pSmad2/3 by providing the interaction niche for pSmad2/3 and their specific phosphatase PPM1A, thus terminating TGF-β/Smad signaling in hepatic cells. Based on these mechanistic studies, we performed further experiments to determine whether depletion of MALAT1 would augment cellular TGF-β/Smad signaling. We observed that MALAT1 depletion enhanced TGF-β/Smad signaling response, as reflect by amplification of Smad-mediated differentiation of induced pluripotent stem (iPS) cells to hepatocytes. Our experimental results demonstrate an important role of MALAT1 for regulation of TGF-β/Smad signaling in hepatic cells. Given the diverse functions of TGF-β/Smad pathway in various physiological and pathogenic processes, our results described in the current study will have broad implications for further understanding the role of MALAT1 in TGF-β/Smad pathway in human biology and disease.

A small RNA-based signaling cascade prevents the induction of plant resistance genes (R-genes) in the absence of pathogen challenge. Here Cai et al. show that nuclear accumulation of the R protein SNC1 can activate immunity by suppressing small RNA production and releasing R-gene repression.

Unmanned aerial vehicle (UAV) is a power-driven aircraft that is unmanned and reusable. The purpose of this study is to accurately estimate the state of charge (SOC) of lithium-ion batteries for UAVs. A support vector machine (SVM) method, SVM is a type of learning machine based on statistical learning, is used as the input variable of the battery charging discharge data (current, voltage and temperature). The kernel of the radial basis function is the best kernel of authors’ experiment, where the C, [inline-formula] and g values are 1, 0.012 and 0.0125, respectively. The experimental results from the lithium-ion battery data at NASA Ames Prognostics Center of Excellence demonstrate the potential application of the proposed method as an effective tool for battery SOC prediction. The accuracy of the whole experiment is 98.42%. Mean-squared error is 1.783%. The experimental results show that the model has higher accuracy in predicting the discharge capacity of lithium battery SOC-training samples.

Greening disease threatens the productivity of citrus crops worldwide yet the pathosystem is poorly understood. Here, Clark et al. show that an effector cloned from the associated bacteria can suppress host plant papain-like cysteine proteases' activity, suggesting its probable role in pathogenesis.

With the depletion of land mineral resources, people have turned their attention to the sea. As an important part of deep-sea mining systems, the technical research and development of ore collectors has always been a difficult problem in many countries. According to the characteristic that buffalo hoof is suitable for walking on soft soil, a kind of bionic grouser for a deep-sea mining vehicle is designed in this paper. Through the optimization of Rankine’s passive earth pressure theory, the formula for calculating the tractive force of the grouser is obtained. The accuracy of the analytical solution is verified by finite element simulation, and the force enhancement mechanism of the bionic grouser is revealed. The results show that the design of the bionic grouser has a significant effect on the improvement of tractive force, and the tractive force of the No. 1 bionic grouser is 17.52% higher than that of the straight grouser. On this basis, the geometric parameters of the bionic grouser profile are optimized. The results show that when L is 0 mm and R is 183 mm, the force enhancement effect reaches the maximum of 27%, which provides a design basis for optimizing the grouser and improving the mining efficiency of the collector.

In this paper, in order to improve the durability of optical fiber grating hydrogen sensors, an optical fiber grating hydrogen sensor with high precision, stability, and durability is prepared. Based on the simplified two-dimensional model and finite element analysis, the effects of film thickness, coating speed, and coating times on the residual Mises equivalent stress between the sensor film and substrate were studied, and the optimum coating parameters were determined. The finite element analysis results show that the residual equivalent stress between the film and the substrate increases with the increase in the film thickness between 50 and 150 nm. The range of 200–250 nm is relatively stable, and the value is small. The coating speed has almost no effect on the residual equivalent stress. When the thickness of the film is 200 nm, the residual equivalent stress decreases with the increase in coating times, and the equivalent force is the lowest when the film is coated three times. The best coating parameters are the thickness of 200 nm, the speed of 62.5 μm/s, and the times of coating three times. The results of finite element analysis are verified by the hydrogen sensitivity test and durability test.

Phytophthora pathogens manipulate host plant immune responses by secreting effector proteins into plant cells. Here, Jing et al. show that the Phytophthora sojaeAvh262 effector negatively regulates plant resistance by binding to host BiP proteins and suppressing ER-stress induced cell death

The alkyl-alkoxysilane (AAS) pre-impregnation method and thermal modification were combined to improve the water-related properties of southern yellow pine (Pinus spp.) sapwood. Four types of AAS with varied alkyl chain lengths, including butyltrimethoxysilane (BTMOS), octyltrimethoxysilane (OTMOS), dodecyltrimethoxysilane (DTMOS), and cetyltrimethoxysilane (CTMOS), were used to pre-impregnate wood samples at a concentration of 5% or 15% mass fraction, and the subsequent thermal modification was processed at either 180 °C or 200 °C. The water absorption, dimensional stability, equilibrium moisture content (EMC), mechanical properties (modulus of rupture (MOR), and modulus of elasticity (MOE)), and mold resistance of the treated wood were evaluated. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) were used to reveal the mechanism of the combined treatments in improving the properties of wood. Compared with thermal modification alone, the AAS combined treatment improved the water repellency, mechanical properties, and mold resistance of the modified wood. The study also identified the penetration of AAS into the wood cell wall and its reaction with the chemical components of the cell wall.

Residual stress is inevitable during welding, which will greatly affect the reliability of the structure. The purpose of this paper was to study the residual stress of the hoop structure caused by the cooling shrinkage of the weld when the outer cylinder was wrapped and welded under the condition of the existing inner cylinder. In this paper, the “method of killing activating elements” of ANSYS was used to simulate the three-dimensional finite element of the hoop structure. In the case of applying interlayer friction, the welding-forming process and welding circumferential residual stress of the hoop structure were analyzed. The blind hole method was used to test the residual stress distribution of the hoop structure, and the test results were compared with the finite element simulation results to verify the reliability of the simulation calculation method and the reliability of the calculation results. Then, the influence factors of the maximum welding residual stress of the hoop structure were studied. The results show that the maximum residual stress of the outer plate surface of the hoop structure decreases with the increase of the welding energy, the thickness of the laminate, the width of the weld seam, the welding speed, and the radius of the container. Based on the results of numerical simulation, the ternary first-order equations of the maximum residual stress of the hoop structure with respect to the welding speed, the thickness of the laminate, and the width of the weld seam were established. Then, the optimal welding parameters were obtained by optimizing the equations, which provided an important basis for the safe use and optimal design of the welding hoop structure.

Resistance to antitumor immunity can be promoted by the oncogenic pathways operational in human cancers, including the epidermal growth factor receptor (EGFR) pathway. Here we studied if and how EGFR downstream signaling in head and neck squamous cell carcinoma (HNSCC) can affect the attraction of immune cells. HPV-negative and HPV-positive HNSCC cell lines were analyzed in vitro for CCL2, CCL5, CXCL9, CXCL10, IL-6 and IL-1β expression and the attraction of T cells under different conditions, including cetuximab treatment and stimulation with IFNγ and TNFα using qPCR, ELISA and migration experiments. Biochemical analyses with chemical inhibitors and siRNA transfection were used to pinpoint the underlying mechanisms. Stimulation of HNSCC cells with IFNγ and TNFα triggered the production of T-cell attracting chemokines and required c-RAF activation. Blocking of the EGFR with cetuximab during this stimulation increased chemokine production in vitro, and augmented the attraction of T cells. Mechanistically, cetuximab decreased the phosphorylation of MEK1, ERK1/2, AKT, mTOR, JNK, p38 and ERK5. Chemical inhibition of EGFR signaling showed a consistent and pronounced chemokine production with MEK1/2 inhibitor PD98059 and JNK inhibitor SP600125, but not with inhibitors of p38, PI3K or mTOR. Combination treatment with cetuximab and a MEK1/2 or JNK inhibitor induced the highest chemokine expression. In conclusion, overexpression of EGFR results in the activation of multiple downstream signaling pathways that act simultaneously to suppress type 1 cytokine stimulated production of chemokines required to amplify the attraction of T cells.

The genus Phytophthora consists of notorious and emerging pathogens of economically important crops. Each Phytophthora genome encodes several hundreds of cytoplasmic effectors, which are believed to manipulate plant immune response inside the host cells. However, the majority of Phytophthora effectors remain functionally uncharacterized. We recently discovered two effectors from the soybean stem and root rot pathogen Phytophthora sojae with the activity to suppress RNA silencing in plants. These effectors are designated Phytophthora suppressor of RNA silencing (PSRs). Here, we report that the P. sojae PSR2 (PsPSR2) belongs to a conserved and widespread effector family in Phytophthora. A PsPSR2-like effector produced by P. infestans (PiPSR2) can also suppress RNA silencing in plants and promote Phytophthora infection, suggesting that the PSR2 family effectors have conserved functions in plant hosts. Using Agrobacterium rhizogenes-mediated hairy roots induction, we demonstrated that the expression of PsPSR2 rendered hypersusceptibility of soybean to P. sojae. Enhanced susceptibility was also observed in PsPSR2-expressing Arabidopsis thaliana plants during Phytophthora but not bacterial infection. These experiments provide strong evidence that PSR2 is a conserved Phytophthora effector family that performs important virulence functions specifically during Phytophthora infection of various plant hosts.

The citrus industry is facing an unprecedented crisis due to Huanglongbing (HLB, aka citrus greening disease), a bacterial disease associated with the pathogen Candidatus Liberibacter asiaticus (CLas) that affects all commercial varieties. Transmitted by the Asian citrus psyllid (ACP), CLas colonizes citrus phloem, leading to reduced yield and fruit quality, and eventually tree decline and death. Since adequate curative measures are not available, a key step in HLB management is to restrict the spread of the disease by identifying infected trees and removing them in a timely manner. However, uneven distribution of CLas cells in infected trees and the long latency for disease symptom development makes sampling of trees for CLas detection challenging. Here, we report that a CLas secreted protein can be used as a biomarker for detecting HLB infected citrus. Proteins secreted from CLas cells can presumably move along the phloem, beyond the site of ACP inoculation and CLas colonized plant cells, thereby increasing the chance of detecting infected trees. We generated a polyclonal antibody that effectively binds to the secreted protein and developed serological assays that can successfully detect CLas infection. This work demonstrates that antibody-based diagnosis using a CLas secreted protein as the detection marker for infected trees offers a high-throughput and economic approach that complements the approved quantitative polymerase chain reaction-based methods to enhance HLB management programs.

The original version of this Article contained an error in the spelling of the author Beixin Mo, which was incorrectly given as Beixing Mo. This has now been corrected in both the PDF and HTML versions of the Article.

The clearance of a high-risk human papillomavirus (hrHPV) infection takes time and requires the local presence of a strong type 1 cytokine T cell response, suggesting that hrHPV has evolved mechanisms to resist this immune attack. Using an unique system for non, newly and persistent hrHPV infection, we show that hrHPV infection renders keratinocytes (KCs) resistant to the anti-proliferative and necroptosis inducing effects of IFN and TNFα. HrHPV-impaired necroptosis was associated with the upregulation of several methyltransferases, including EZH2 and the downregulation of RIPK3 expression. Restoration of RIPK3 expression using the global histone methyltransferase inhibitor 3-deazaneplanocin increased necroptosis in hrHPV-positive KCs. Simultaneously, hrHPV effectively inhibited IFN/TNF-mediated arrest of cell growth at the S-phase by downregulating IFITM1 already at 48 hours after hrHPV infection, followed by an impaired increase in the expression of the anti-proliferative gene RARRES1 and a decrease of the proliferative gene PCNA. Knockdown of IFITM1 in uninfected KCs confirmed its role on RARRES1 and its anti-proliferativeory effects. Thus, our study reveals how hrHPV deregulates two pathways involved in cell death and growth regulation to withstand immune mediated control of hrHPV-infected cells.

The white paper reports the deliberations of a workshop focused on biotic challenges to plant health held in Washington, D.C. in September 2016. Ensuring health of food plants is critical to maintaining the quality and productivity of crops and for sustenance of the rapidly growing human population. There is a close linkage between food security and societal stability; however, global food security is threatened by the vulnerability of our agricultural systems to numerous pests, pathogens, weeds, and environmental stresses. These threats are aggravated by climate change, the globalization of agriculture, and an over-reliance on nonsustainable inputs. New analytical and computational technologies are providing unprecedented resolution at a variety of molecular, cellular, organismal, and population scales for crop plants as well as pathogens, pests, beneficial microbes, and weeds. It is now possible to both characterize useful or deleterious variation as well as precisely manipulate it. Data-driven, informed decisions based on knowledge of the variation of biotic challenges and of natural and synthetic variation in crop plants will enable deployment of durable interventions throughout the world. These should be integral, dynamic components of agricultural strategies for sustainable agriculture.

Effector biology exhibits diversity at every level. Effector proteins play key roles in the molecular interplay between plants and plant-associated organisms, and effector biology remains one of the most active areas in the research field of molecular plant-microbe interactions. Using effectors as probes, much has been learned about pathogen virulence and host immunity, which has broad implications in developing disease-resistant crops that are essential for global food security. Thus, the MPMI Editorial Board is publishing this Focus Issue to showcase recent progress in this area.Additional content is available on the Focus on Effector-Triggered Susceptibility.A Phytophthora palmivora Extracellular Cystatin-Like Protease Inhibitor Targets Papain to Contribute to Virulence on PapayaConserved RxLR Effectors From Oomycetes Hyaloperonospora arabidopsidis and Phytophthora sojae Suppress PAMP- and Effector-Triggered Immunity in Diverse PlantsMolecular Basis of Citrus sunki Susceptibility and Poncirus trifoliata Resistance Upon Phytophthora parasitica AttackdaTALbase: A Database for Genomic and Transcriptomic Data Related to TAL EffectorsPhytophthora parasitica Effector PpRxLR2 Suppresses Nicotiana benthamiana ImmunityThe Agrobacterium F-Box Protein Effector VirF Destabilizes the Arabidopsis GLABROUS1 Enhancer/Binding Protein-Like Transcription Factor VFP4, a Transcriptional Activator of Defense Response GenesAccessories Make the Outfit: Accessory Chromosomes and Other Dispensable DNA Regions in Plant-Pathogenic Fungi

The bacterial plant pathogen Pseudomonas syringae depends on the type III secretion system and type III-secreted effectors to cause disease in plants. HopZ is a diverse family of type III effectors widely distributed in P. syringae isolates. Among the HopZ homologs, HopZ1 is ancient to P. syringae and has been shown to be under strong positive selection driven by plant resistance-imposed selective pressure. Here, we characterized the virulence and avirulence functions of the three HopZ1 alleles in soybean and Nicotiana benthamiana. In soybean, HopZ1 alleles have distinct functions: HopZ1a triggers defense response, HopZ1b promotes bacterial growth, and HopZ1c has no observable effect. In N. benthamiana, HopZ1a and HopZ1b both induce plant defense responses. However, they appear to trigger different resistance pathways, evidenced by two major differences between HopZ1a- and HopZ1b-triggered hypersensitive response (HR): i) the putative N-acylation sites had no effect on HopZ1a-triggered cell death, whereas it greatly enhanced HopZ1b-triggered cell death; and ii) the HopZ1b-triggered HR, but not the HopZ1a-triggered HR, was suppressed by another HopZ homolog, HopZ3. We previously demonstrated that HopZ1a most resembled the ancestral allelic form of HopZ1; therefore, this new evidence suggested that differentiated resistance systems have evolved in plant hosts to adapt to HopZ1 diversification in P. syringae.

Plant pathogens secrete an arsenal of effector proteins to impair host immunity. Some effectors possess enzymatic activities that can modify their host targets. Previously, we demonstrated that a Phytophthora sojae RXLR effector Avr3b acts as a Nudix hydrolase when expressed in planta; and this enzymatic activity is required for full virulence of P. sojae strain P6497 in soybean (Glycine max). Interestingly, recombinant Avr3b produced by E. coli does not have the hydrolase activity unless it was incubated with plant protein extracts. Here, we report the activation of Avr3b by a prolyl-peptidyl isomerase (PPIase), cyclophilin, in plant cells. Avr3b directly interacts with soybean cyclophilin GmCYP1, which activates the hydrolase activity of Avr3b in a PPIase activity-dependent manner. Avr3b contains a putative Glycine-Proline (GP) motif; which is known to confer cyclophilin-binding in other protein substrates. Substitution of the Proline (P132) in the putative GP motif impaired the interaction of Avr3b with GmCYP1; as a result, the mutant Avr3bP132A can no longer be activated by GmCYP1, and is also unable to promote Phytophthora infection. Avr3b elicits hypersensitive response (HR) in soybean cultivars producing the resistance protein Rps3b, but Avr3bP132A lost its ability to trigger HR. Furthermore, silencing of GmCYP1 rendered reduced cell death triggered by Avr3b, suggesting that GmCYP1-mediated Avr3b maturation is also required for Rps3b recognition. Finally, cyclophilins of Nicotiana benthamiana can also interact with Avr3b and activate its enzymatic activity. Overall, our results demonstrate that cyclophilin is a "helper" that activates the enzymatic activity of Avr3b after it is delivered into plant cells; as such, cyclophilin is required for the avirulence and virulence functions of Avr3b.

Gram-negative bacterial pathogens deliver a variety of virulence proteins through the type III secretion system (T3SS) directly into the host cytoplasm. These type III secreted effectors (T3SEs) play an essential role in bacterial infection, mainly by targeting host immunity. However, the molecular basis of their functionalities remains largely enigmatic. Here, we show that the Pseudomonas syringae T3SE HopZ1a, a member of the widely distributed YopJ effector family, directly interacts with jasmonate ZIM-domain (JAZ) proteins through the conserved Jas domain in plant hosts. JAZs are transcription repressors of jasmonate (JA)-responsive genes and major components of the jasmonate receptor complex. Upon interaction, JAZs can be acetylated by HopZ1a through a putative acetyltransferase activity. Importantly, P. syringae producing the wild-type, but not a catalytic mutant of HopZ1a, promotes the degradation of HopZ1-interacting JAZs and activates JA signaling during bacterial infection. Furthermore, HopZ1a could partially rescue the virulence defect of a P. syringae mutant that lacks the production of coronatine, a JA-mimicking phytotoxin produced by a few P. syringae strains. These results highlight a novel example by which a bacterial effector directly manipulates the core regulators of phytohormone signaling to facilitate infection. The targeting of JAZ repressors by both coronatine toxin and HopZ1 effector suggests that the JA receptor complex is potentially a major hub of host targets for bacterial pathogens.

The concept of the coevolutionary arms race holds a central position in our understanding of pathogen-host interactions. Here we identify the molecular mechanisms and follow the stepwise progression of an arms race in a natural system. We show how the evolution and function of the HopZ family of type III secreted effector proteins carried by the plant pathogen Pseudomonas syringae are influenced by a coevolutionary arms race between pathogen and host. We surveyed 96 isolates of P. syringae and identified three homologs (HopZ1, HopZ2, and HopZ3) distributed among approximately 45% of the strains. All alleles were sequenced and their expression was confirmed. Evolutionary analyses determined that the diverse HopZ1 homologs are ancestral to P. syringae, and have diverged via pathoadaptive mutational changes into three functional and two degenerate forms, while HopZ2 and HopZ3 have been brought into P. syringae via horizontal transfer from other ecologically similar bacteria. A PAML selection analysis revealed that the C terminus of HopZ1 is under strong positive selection. Despite the extensive genetic variation observed in this family, all three homologs have cysteine-protease activity, although their substrate specificity may vary. The introduction of the ancestral hopZ1 allele into strains harboring alternate alleles results in a resistance protein-mediated defense response in their respective hosts, which is not observed with the endogenous allele. These data indicate that the P. syringae HopZ family has undergone allelic diversification via both pathoadaptive mutational changes and horizontal transfer in response to selection imposed by the host defense system. This genetic diversity permits the pathogen to avoid host defenses while still maintaining a virulence-associated protease, thereby allowing it to thrive on its current host, while simultaneously impacting its host range.