The epidemiology of acne vulgaris in a multiethnic adolescent population from Rotterdam, the Netherlands: A cross-sectional study.

BACKGROUND: Although acne is a prevalent multifactorial inflammatory skin condition, few studies were performed in multiethnic populations. OBJECTIVES: To study the prevalence and determinants of acne in a multiethnic study at the start of puberty. METHODS: This cross-sectional study is embedded in Generation R, a population-based prospective study from Rotterdam, the Netherlands. Three-dimensional facial photos at the center visit in 2016-2019 (of ∼13-year-olds) were used to grade acne severity using the Global Evaluation of the Acne Severity (GEA). Analyses were stratified by biological sex and explored through chi-square tests and multivariable ordinal logistic regression. RESULTS: A total of 4561 children (51% girls) with a median age of 13.5 (IQR 13.3-13.6) were included. The visible acne prevalence (GEA 2-5) for girls vs boys was 62% vs 45% and moderate-to-severe acne (GEA 3-5) 14% vs 9%. Higher puberty stages (adjusted odds ratios: 1.38 [1.20-1.59] and 2.16 [1.86-2.51] for girls and boys, respectively) and darker skin colors V and VI (adjusted odds ratios: 1.90 [1.17-3.08] and 2.43 [1.67-3.56]) were associated with more severe acne in both sexes, and being overweight in boys (adjusted odds ratio: 1.58 [1.15-2.17]). LIMITATIONS: Cross-sectional design. CONCLUSIONS: Acne prevalence was high at the age of 13 years and was associated with advanced puberty, darker skin color, and weight status.

Skin microbiome dysbiosis and the role of Staphylococcus aureus in atopic dermatitis in adults and children: A narrative review.

A dysfunctional epidermal barrier, which may be associated with mutations in the filaggrin gene in genetically predisposed individuals or harmful effects of environmental agents and allergens, contributes to the development of atopic dermatitis (AD) due to an interplay between the epithelial barrier, immune defence and the cutaneous microbiome. The skin of patients with AD is frequently over-colonized by biofilm-growing Staphylococcus aureus, especially during flares, causing dysbiosis of the cutaneous microbiota and a decrease in bacterial diversity that inversely correlates with AD severity. Specific changes in the skin microbiome can be present before clinical AD onset in infancy. Additionally, local skin anatomy, lipid content, pH, water activity and sebum secretion differ between children and adults and generally correlate with the predominant microbiota. Considering the importance of S. aureus in AD, treatments aimed at reducing over-colonization to rebalance microbial diversity may help manage AD and reduce flares. Anti-staphylococcal interventions in AD will contribute to a decrease in S. aureus superantigens and proteases that cause damage and inflammation of the skin barrier while concomitantly increasing the proportion of commensal bacteria that secrete antimicrobial molecules that protect healthy skin from invading pathogens. This review summarizes the latest data on targeting skin microbiome dysbiosis and S. aureus over-colonization to treat AD in adults and children. Indirect AD therapies, including emollients 'plus', anti-inflammatory topicals and monoclonal antibodies, may have an impact on S. aureus and help control bacterial diversity. Direct therapies, including antibacterial treatments (antiseptics/topical or systemic antibiotics), and innovative treatments specifically targeting S. aureus (e.g. anti-S. aureus endolysin, and autologous bacteriotherapy), may be effective alternatives to mitigate against an increase in microbial resistance and allow a proportionate increase in the commensal microbiota.

Flow path monitoring by discontinuous time-lapse ERT: An application to survey relationships between secondary effluent infiltration and roots distribution.

The infiltration of secondary treated effluent (STE) into the soil downstream of wastewater treatment plants is becoming increasingly common in a climate change context. In STE infiltration, STE is discharged onto the soil over a large surface allowing for a gradual infiltration of the water. This paper investigates a novel time-lapse electrical resistivity tomography strategy to evaluate the impact of STE infiltration on the water pathways of two planted loamy-soil trenches located in a Fluvisol region in southwestern France. The system has been monitored for 3 years using discontinuous monitoring of electrical resistivity tomography during four saline tracer tests. Results show that: 1) the new methodology has successfully highlighted the evolution of water pathways in the soil over time; 2) such evolution is in agreement with reeds root distribution in the trenches which seems to be affected by water quality i.e. sludge losses and TSS, for this study case. Indeed, for the infiltration trench receiving STE with lower pollution levels (2.2 mg TSS. L-1, 26 mg COD. L-1), the infiltration capacity is maintained over the years (4-6 mm h-1) and reed roots developed deeper in the soil. A sludge deposit present at the bottom of the second infiltration trench receiving higher pollution levels (7.2 mg TSS. L-1, 45 mg COD. L-1, plus episodic sludge release) could lead roots to develop close to the surface affecting the infiltration capacity which did not evolve over time. This work highlights the importance of long-term flow pathway monitoring in understanding the hydraulic behavior of infiltration surfaces submitted to STE.

Topical S. aureus - Targeting Endolysin Significantly Improves Symptoms and QoL in Individuals With Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic skin condition affecting an increasing number of children and adults whose quality of life is impacted by chronic itch and pain. It is characterized by an altered epidermal barrier, skin inflammation, and skin microbiome dysbiosis particularly over-colonization of Staphylococcus aureus. The efficacy and tolerance of a cream containing a S. aureus-targeting technology (endolysin) was assessed in an open-label, two-week study in children and adults with mild-to-moderate atopic dermatitis. A total of 43 patients ranging from 7 months to 57 years old were included and all patients finished the study without any tolerance problem. Disease severity, measured with SCORAD, quickly reduced by 43% in 7 days and by 68 % in 14 days. The benefit was perceived by the whole panel with a marked improvement in overall QoL. This study shows the efficacy of a highly specific S. aureus-targeted technology in alleviating symptoms and improving QoL in children and adults with atopic dermatitis. It could also be beneficial in reducing and preventing flares in subjects with S. aureus load due to its good tolerance and specific action. J Drugs Dermatol. 2021;20(12):1323-1328. doi:10.36849/JDD.6363.

Activation of Plant Innate Immunity by Extracellular High Mobility Group Box 3 and Its Inhibition by Salicylic Acid.

Damage-associated molecular pattern molecules (DAMPs) signal the presence of tissue damage to induce immune responses in plants and animals. Here, we report that High Mobility Group Box 3 (HMGB3) is a novel plant DAMP. Extracellular HMGB3, through receptor-like kinases BAK1 and BKK1, induced hallmark innate immune responses, including i) MAPK activation, ii) defense-related gene expression, iii) callose deposition, and iv) enhanced resistance to Botrytis cinerea. Infection by necrotrophic B. cinerea released HMGB3 into the extracellular space (apoplast). Silencing HMGBs enhanced susceptibility to B. cinerea, while HMGB3 injection into apoplast restored resistance. Like its human counterpart, HMGB3 binds salicylic acid (SA), which results in inhibition of its DAMP activity. An SA-binding site mutant of HMGB3 retained its DAMP activity, which was no longer inhibited by SA, consistent with its reduced SA-binding activity. These results provide cross-kingdom evidence that HMGB proteins function as DAMPs and that SA is their conserved inhibitor.

A Bioinspired Synthesis of Polyfunctional Indoles.

Polyfunctional indoles bearing substituents at C5 and C6 are prevalent in natural products, pharmaceuticals, agrochemicals, and materials. Owing to the remoteness of the C5 and C6 positions, indoles of this family can be difficult to prepare, and often require multistep syntheses. Herein, we describe a concise process that converts simple derivatives of tyrosine into 5,6-difunctionalized indoles by direct oxidation of C-H, N-H, and O-H bonds. Our work draws inspiration from the biosynthetic polymerization of tyrosine to make melanin pigments, but makes an important departure to provide well-defined indole heterocycles.

Aspirin's Active Metabolite Salicylic Acid Targets High Mobility Group Box 1 to Modulate Inflammatory Responses.

Salicylic acid (SA) and its derivatives have been used for millennia to reduce pain, fever and inflammation. In addition, prophylactic use of acetylsalicylic acid, commonly known as aspirin, reduces the risk of heart attack, stroke and certain cancers. Because aspirin is rapidly de-acetylated by esterases in human plasma, much of aspirin's bioactivity can be attributed to its primary metabolite, SA. Here we demonstrate that human high mobility group box 1 (HMGB1) is a novel SA-binding protein. SA-binding sites on HMGB1 were identified in the HMG-box domains by nuclear magnetic resonance (NMR) spectroscopic studies and confirmed by mutational analysis. Extracellular HMGB1 is a damage-associated molecular pattern molecule (DAMP), with multiple redox states. SA suppresses both the chemoattractant activity of fully reduced HMGB1 and the increased expression of proinflammatory cytokine genes and cyclooxygenase 2 (COX-2) induced by disulfide HMGB1. Natural and synthetic SA derivatives with greater potency for inhibition of HMGB1 were identified, providing proof-of-concept that new molecules with high efficacy against sterile inflammation are attainable. An HMGB1 protein mutated in one of the SA-binding sites identified by NMR chemical shift perturbation studies retained chemoattractant activity, but lost binding of and inhibition by SA and its derivatives, thereby firmly establishing that SA binding to HMGB1 directly suppresses its proinflammatory activities. Identification of HMGB1 as a pharmacological target of SA/aspirin provides new insights into the mechanisms of action of one of the world's longest and most used natural and synthetic drugs. It may also provide an explanation for the protective effects of low-dose aspirin usage.

The Arabidopsis oligopeptidases TOP1 and TOP2 are salicylic acid targets that modulate SA-mediated signaling and the immune response.

Salicylic acid (SA) is a small phenolic molecule with hormonal properties, and is an essential component of the immune response. SA exerts its functions by interacting with protein targets; however, the specific cellular components modulated by SA and critical for immune signal transduction are largely unknown. To uncover cellular activities targeted by SA, we probed Arabidopsis protein microarrays with a functional analog of SA. We demonstrate that thimet oligopeptidases (TOPs) constitute a class of SA-binding enzymes. Biochemical evidence demonstrated that SA interacts with TOPs and inhibits their peptidase activities to various degrees both in vitro and in plant extracts. Functional characterization of mutants with altered TOP expression indicated that TOP1 and TOP2 mediate SA-dependent signaling and are necessary for the immune response to avirulent pathogens. Our results support a model whereby TOP1 and TOP2 act in separate pathways to modulate SA-mediated cellular processes.

Efficacy of a multitargeted, salicylic acid-based dermocosmetic cream compared to benzoyl peroxide 5% in Acne vulgaris: Results from a randomized study.

INTRODUCTION: Acne vulgaris (acne) is characterized by both inflammatory and non-inflammatory lesions. Benzoyl peroxide (BPO) 5% is approved to treat acne but may cause skin irritation and/or contact allergy. OBJECTIVES: To compare the benefit in acne of a multitargeted dermocosmetic cream containing salicylic acid, lipohydroxy acid, niacinamide, 2-oleamido-1,3-octadecanediol, piroctone olamine, zinc, Aqua posae filiformis, and thermal spring water (DC-Eff) to BPO 5% gel. MATERIALS AND METHODS: 150 Caucasian subjects (50% female) aged between 18 and 40 years, with mild to moderate acne according to the GEA (Global Evaluation of Acne) grading system were randomized into two parallel groups (DC-Eff or BPO to be applied twice daily for 56 days). IGA (investigator global assessment), GEA, lesion count, clinical signs and symptoms, and subject assessment were evaluated at baseline, and after 28 and 56 days (D28 and D56) of treatment. RESULTS: The responder analyses of the IGA and GEA scores showed that 62.2% and 47.3%, respectively, in the DC-Eff, compared with 50.0% and 36.5%, respectively, in the BPO, had improved by at least one point at D56. Inflammatory, non-inflammatory, and total lesion counts significantly (p < 0.0001) decreased with both products from baseline, with no between-group difference. Subjects considered that their skin was smoother and that DC-Eff was easy to apply. DC-Eff was better tolerated than BPO. CONCLUSIONS: DC-Eff applied twice daily is as beneficial as BPO in improving mild-to-moderate acne. DC-Eff was better tolerated than BPO and highly appreciated.

A multi-study analysis enables identification of potential microbial features associated with skin aging signs.

Introduction: During adulthood, the skin microbiota can be relatively stable if environmental conditions are also stable, yet physiological changes of the skin with age may affect the skin microbiome and its function. The microbiome is an important factor to consider in aging since it constitutes most of the genes that are expressed on the human body. However, severity of specific aging signs (one of the parameters used to measure "apparent" age) and skin surface quality (e.g., texture, hydration, pH, sebum, etc.) may not be indicative of chronological age. For example, older individuals can have young looking skin (young apparent age) and young individuals can be of older apparent age. Methods: Here we aim to identify microbial taxa of interest associated to skin quality/aging signs using a multi-study analysis of 13 microbiome datasets consisting of 16S rRNA amplicon sequence data and paired skin clinical data from the face. Results: We show that there is a negative relationship between microbiome diversity and transepidermal water loss, and a positive association between microbiome diversity and age. Aligned with a tight link between age and wrinkles, we report a global positive association between microbiome diversity and Crow's feet wrinkles, but with this relationship varying significantly by sub-study. Finally, we identify taxa potentially associated with wrinkles, TEWL and corneometer measures. Discussion: These findings represent a key step towards understanding the implication of the skin microbiota in skin aging signs.

Endogenous nitric oxide regulates the recovery of the radiation-resistant bacterium Deinococcus radiodurans from exposure to UV light.

Deinococcus radiodurans (Dr) withstands desiccation, reactive oxygen species, and doses of radiation that would be lethal to most organisms. Deletion of a gene encoding a homolog of mammalian nitric oxide synthase (NOS) severely compromises the recovery of Dr from ultraviolet (UV) radiation damage. The Deltanos defect can be complemented with recombinant NOS, rescued by exogenous nitric oxide (NO) and mimicked in the wild-type strain with an NO scavenging compound. UV radiation induces both upregulation of the nos gene and cellular NO production on similar time scales. Growth recovery does not depend on NO being present during UV irradiation, but rather can be manifested by NO addition hours after exposure. Surprisingly, nos deletion does not increase sensitivity to oxidative damage, and hydrogen peroxide does not induce nos expression. However, NOS-derived NO upregulates transcription of obgE, a gene involved in bacterial growth proliferation and stress response. Overexpression of the ObgE GTPase in the Deltanos background substantially alleviates the growth defect after radiation damage. Thus, NO acts as a signal for the transcriptional regulation of growth in D. radiodurans.

Role of arginine guanidinium moiety in nitric-oxide synthase mechanism of oxygen activation.

Nitric-oxide synthases (NOS) are highly regulated heme-thiolate enzymes that catalyze two oxidation reactions that sequentially convert the substrate L-Arg first to N(omega)-hydroxyl-L-arginine and then to L-citrulline and nitric oxide. Despite numerous investigations, the detailed molecular mechanism of NOS remains elusive and debatable. Much of the dispute in the various proposed mechanisms resides in the uncertainty concerning the number and sources of proton transfers. Although specific protonation events are key features in determining the specificity and efficiency of the two catalytic steps, little is known about the role and properties of protons from the substrate, cofactors, and H-bond network in the vicinity of the heme active site. In this study, we have investigated the role of the acidic proton from the L-Arg guanidinium moiety on the stability and reactivity of the ferrous heme-oxy complex intermediate by exploiting a series of L-Arg analogues exhibiting a wide range of guanidinium pK(a) values. Using electrochemical and vibrational spectroscopic techniques, we have analyzed the effects of the analogues on the heme, including characteristics of its proximal ligand, heme conformation, redox potential, and electrostatic properties of its distal environment. Our results indicate that the substrate guanidinium pK(a) value significantly affects the H-bond network near the heme distal pocket. Our results lead us to propose a new structural model where the properties of the guanidinium moiety finely control the proton transfer events in NOS and tune its oxidative chemistry. This model may account for the discrepancies found in previously proposed mechanisms of NOS oxidation processes.

Defining natural baselines for rates of change in New Zealand's groundwater quality: Dealing with incomplete or disparate datasets, accounting for impacted sites, and merging into state of the-environment reporting.

To effectively manage sustainably groundwater bodies, it is essential to establish what the naturally occurring ranges of chemical concentrations in groundwaters are and how they change over time. We defined baseline trends for New Zealand groundwaters using: 1) pattern recognition techniques to deal with inconsistent monitoring suites between the national (110 sites) and the denser regional network (>1000 sites), and 2) multivariate statistics to identify and remove impacted sites from the enhanced dataset. Rates of changes were calculated for 13 parameters between January 2005 and December 2014 at more than 1000 groundwater quality monitoring sites. The resulting dataset included 262 complete cases (CC), which was enhanced using Machine-Learning (ML) techniques to a total of 607 sites. Hierarchical cluster analysis was used to identify trend clusters that were consistent between the CC, ML-enhanced datasets and a 2006 study based on solely on the national network. The largest cluster (WR) consisted of low magnitude changes across all parameters and was attributed to water-rock interaction processes. The second largest cluster (I) exhibited fast changes particularly for parameters linked to human-induced impact. The third largest cluster (D) comprised decreases of all parameters and was associated with dilution processes. Trend clusters were further refined using groundwater quality state information, enabling the identification of impacted sites outside of Cluster I in the ML-enhanced and CC datasets. Corresponding trend baselines were subsequently derived at unimpacted sites using univariate quantile distribution (5th and 95th percentile thresholds). Finally, we developed classifications combining baselines (state and trend) and natural variability to enhance state of the environment reporting. This allowed the new identification of deteriorating trends at sites where groundwater quality state is not yet affected in addition to trend reversals. These classifications can be adapted to incorporate new knowledge or align with surface water quality reporting.

NO synthesis and signaling in plants--where do we stand?

Over the past 20 years, nitric oxide (NO) research has generated a lot of interest in various aspects of plant biology. It is now clear that NO plays a role in a wide range of physiological processes in plants. However, in spite of the significant progress that has been made in understanding NO biosynthesis and signaling in planta, several crucial questions remain unanswered. Here we highlight several challenges in NO plant research by summarizing the latest knowledge of NO synthesis and by focusing on the potential NO source(s) and players involved. Our goal is also to provide an overview of how our understanding of NO signaling has been enhanced by the identification of array of genes and proteins regulated by NO.

A baseline assessment of emerging organic contaminants in New Zealand groundwater.

Emerging organic contaminants (EOCs) are manufactured compounds, used for a range of purposes, that are a rising concern for freshwater quality, human and aquatic health. Their occurrence in groundwater has been demonstrated in several international surveys. We conducted the first baseline survey on EOC occurrence in New Zealand groundwater, using a wide-screening approach (723 compounds) and a novel stratified to mean residence time (MRT) randomised design to inform future monitoring. A total of 61 sites were sampled: 51 baseline sites from the State of the Environment (SOE) network in the Waikato region and 10 targeted sites located in the vicinity of known EOC sources for comparison. EOCs were detected at 91% of the baseline sites at concentrations ranging from 0.1 to 11,000 ng·L-1. Multiple groups of EOCs were encountered: pesticides (48 compounds), pharmaceuticals (11), industrial (10), preservatives/food additives (3) and personal care products (1). Similar diversity and concentration range of EOCs were observed at the targeted sites, with the addition of drugs of abuse and life-style compounds. EOC detections occurred across young (1-11 yrs. MRT), intermediate (11-50 yrs. MRT) and old (50-250 yrs. MRT) groundwaters with higher concentrations and more types of EOCs detected at sites in the youngest age category. Concentrations of the 73 compounds detected at baseline sites were comparable to those found in overseas groundwaters with 28 compounds measured at concentrations greater than the EU maximum admissible concentration for pesticides. We used the survey results to: review current pesticide monitoring; propose complementary monitoring; identify potential EOC groundwater tracers and identify compounds for which cost-effective national laboratory capability is needed. The Waikato survey results demonstrated ubiquitous occurrence of unmonitored, unregulated EOCs in groundwater and limitations in using targeted approaches to establish monitoring.

Bacterial bioclusters relate to hydrochemistry in New Zealand groundwater.

Groundwater is a major source of New Zealand's water supply and supports base flows in rivers. Microbial communities in groundwater ecosystems mediate biogeochemical processes, and it is therefore crucial to understand microbial diversity in these ecosystems. We analysed bacterial assemblages from 35 New Zealand groundwater monitoring sites with varying hydrogeochemical conditions across the country. Proteobacteria was the most abundant phylum, and Variovorax represented the most common taxon. Pseudomonas, Burkholderia, Acidovorax, Janthinobacterium, Polaromonas and Caulobacter were the other common taxa. There was no Operational Taxonomic Unit (OTU) that was found in every one of the 35 samples. Here, we introduce a framework that has potential utility for groundwater ecosystem management, where the samples with similar microbial communities are grouped together into 'bioclusters'. Metabolic inferences derived from the taxonomic data were used to predict the oxygen requirements, metabolic potential and bacterial energy sources of each biocluster. Groundwater chemistry explains 59% of the variation in the relative abundance of all OTUs, with NO3-N, pH, DO, NH4-N, Fe, Br and SO4 displaying the strongest relationships to bioclusters. We propose that the biocluster framework, coupled with metabolic inferences derived from the taxonomic data, may have application outside New Zealand for on-going monitoring of the health of groundwater ecosystems.

Importance of valine 567 in substrate recognition and oxidation by neuronal nitric oxide synthase.

Nitric oxide (NO) is synthesised by a two-step oxidation of -arginine (L-Arg) in the active site of nitric oxide synthase (NOS) with formation of an intermediate, N omega-hydroxy-L-Arg (NOHA). Crystal structures of NOSs have shown the importance of an active-site Val567 residue (numbered for rat neuronal NOS, nNOS) interacting with non-amino acid substrates. To investigate the role of this Val residue in substrate recognition and NO-formation activity by nNOS, we generated and purified four Val567 mutants of nNOS, Val567Leu, Val567Phe, Val567Arg and Val567Glu. We characterized these proteins and tested their ability to generate NO from the oxidation of natural substrates L-Arg and NOHA, and from N-hydroxyguanidines previously identified as alternative substrates for nNOS. The Val567Leu mutant displayed lower NO formation activities than the wild type (WT) in the presence of all tested compounds. Surprisingly, the Val567Phe mutant formed low amounts of NO only from NOHA. These two mutants displayed lower affinity for L-Arg and NOHA than the WT protein. Val576Glu and Val567Arg mutants were much less stable and did not lead to any formation of NO. These results suggest that Val567 is an important residue for preserving the integrity of the active site, for substrate binding, and subsequently for NO-formation in nNOS.

Structure of the Arabidopsis thaliana TOP2 oligopeptidase.

Thimet oligopeptidase (TOP) is a zinc-dependent metallopeptidase. Recent studies suggest that Arabidopsis thaliana TOP1 and TOP2 are targets for salicylic acid (SA) binding and participate in SA-mediated plant innate immunity. The crystal structure of A. thaliana TOP2 has been determined at 3.0 Å resolution. Comparisons to the structure of human TOP revealed good overall structural conservation, especially in the active-site region, despite their weak sequence conservation. The protein sample was incubated with the photo-activated SA analog 4-azido-SA and exposed to UV irradiation before crystallization. However, there was no conclusive evidence for the binding of SA based on the X-ray diffraction data. Further studies are needed to elucidate the molecular mechanism of how SA regulates the activity of A. thaliana TOP1 and TOP2.

Identification of multiple salicylic acid-binding proteins using two high throughput screens.

Salicylic acid (SA) is an important hormone involved in many diverse plant processes, including floral induction, stomatal closure, seed germination, adventitious root initiation, and thermogenesis. It also plays critical functions during responses to abiotic and biotic stresses. The role(s) of SA in signaling disease resistance is by far the best studied process, although it is still only partially understood. To obtain insights into how SA carries out its varied functions, particularly in activating disease resistance, two new high throughput screens were developed to identify novel SA-binding proteins (SABPs). The first utilized crosslinking of the photo-reactive SA analog 4-AzidoSA (4AzSA) to proteins in an Arabidopsis leaf extract, followed by immuno-selection with anti-SA antibodies and then mass spectroscopy-based identification. The second utilized photo-affinity crosslinking of 4AzSA to proteins on a protein microarray (PMA) followed by detection with anti-SA antibodies. To determine whether the candidate SABPs (cSABPs) obtained from these screens were true SABPs, recombinantly-produced proteins were generated and tested for SA-inhibitable crosslinking to 4AzSA, which was monitored by immuno-blot analysis, SA-inhibitable binding of the SA derivative 3-aminoethylSA (3AESA), which was detected by a surface plasmon resonance (SPR) assay, or SA-inhibitable binding of [(3)H]SA, which was detected by size exclusion chromatography. Based on our criteria that true SABPs must exhibit SA-binding activity in at least two of these assays, nine new SABPs are identified here; nine others were previously reported. Approximately 80 cSABPs await further assessment. In addition, the conflicting reports on whether NPR1 is an SABP were addressed by showing that it bound SA in all three of the above assays.

Salicylic acid binds NPR3 and NPR4 to regulate NPR1-dependent defense responses.

Salicylic acid (SA) is widely recognized as a key player in plant immunity. While several proteins have been previously identified as the direct targets of SA, SA-mediated plant defense signaling mechanisms remain unclear. The Nature paper from Xinnian Dong's group demonstrates that the NPR1 paralogues NPR3 and NPR4 directly bind SA, and this binding modulates their interaction with NPR1 and thereby degradation of this key positive regulator of SA-mediated defense, shedding important new insight into the mechanism(s) of SA-mediated, NPR1-dependent plant defense signal transduction.