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The role of rheumatoid arthritis (RA) flare and cumulative burden of RA severity in the risk of cardiovascular disease
ObjectiveTo examine the role of rheumatoid arthritis (RA) flare, remission and RA severity burden in cardiovascular disease (CVD).MethodsIn a population-based cohort of patients with RA without CVD (age ≥30 years; 1987 American College of Rheumatology criteria met in 1988–2007), we performed medical record review at each clinical visit to estimate flare/remission status. The previously validated RA medical Records-Based Index of Severity (RARBIS) and Claims-Based Index of RA Severity (CIRAS) were applied. Age- and sex-matched non-RA subjects without CVD comprised the comparison cohort. Cox models were used to assess the association of RA activity/severity with CVD, adjusting for age, sex, calendar year of RA, CVD risk factors and antirheumatic medications.ResultsStudy included 525 patients with RA and 524 non-RA subjects. There was a significant increase in CVD risk in RA per time spent in each acute flare versus remission (HR 1.07 per 6-week flare, 95% CI 1.01 to 1.15). The CVD risk for patients with RA in remission was similar to the non-RA subjects (HR 0.90, 95% CI 0.51 to 1.59). Increased cumulative moving average of daily RARBIS (HR 1.16, 95% CI 1.03 to 1.30) and CIRAS (HR 1.38, 95% CI 1.12 to 1.70) was associated with CVD. CVD risk was higher in patients with RA who spent more time in medium (HR 1.08, 95% CI 0.98 to 1.20) and high CIRAS tertiles (HR 1.18, 95% CI 1.06 to 1.31) versus lower tertile.ConclusionsOur findings show substantial detrimental role of exposure to RA flare and cumulative burden of RA disease severity in CVD risk in RA, suggesting important cardiovascular benefits associated with tight inflammation control and improved flare management in patients with RA.
Journal Article
Regulation of growth–defense balance by the JASMONATE ZIM-DOMAIN (JAZ)-MYC transcriptional module
The plant hormone jasmonate (JA) promotes the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins to relieve repression on diverse transcription factors (TFs) that execute JA responses. However, little is known about how combinatorial complexity among JAZ–TF interactions maintains control over myriad aspects of growth, development, reproduction, and immunity.
We used loss-of-function mutations to define epistatic interactions within the core JA signaling pathway and to investigate the contribution of MYC TFs to JA responses in Arabidopsis thaliana.
Constitutive JA signaling in a jaz quintuple mutant (jazQ) was largely eliminated by mutations that block JA synthesis or perception. Comparison of jazQ and a jazQ myc2 myc3 myc4 octuple mutant validated known functions of MYC2/3/4 in root growth, chlorophyll degradation, and susceptibility to the pathogen Pseudomonas syringae. We found that MYC TFs also control both the enhanced resistance of jazQ leaves to insect herbivory and restricted leaf growth of jazQ. Epistatic transcriptional profiles mirrored these phenotypes and further showed that triterpenoid biosynthetic and glucosinolate catabolic genes are up-regulated in jazQ independently of MYC TFs.
Our study highlights the utility of genetic epistasis to unravel the complexities of JAZ–TF interactions and demonstrates that MYC TFs exert master control over a JAZ-repressible transcriptional hierarchy that governs growth–defense balance.
Journal Article
Rewiring of jasmonate and phytochrome B signalling uncouples plant growth-defense tradeoffs
Plants resist infection and herbivory with innate immune responses that are often associated with reduced growth. Despite the importance of growth-defense tradeoffs in shaping plant productivity in natural and agricultural ecosystems, the molecular mechanisms that link growth and immunity are poorly understood. Here, we demonstrate that growth-defense tradeoffs mediated by the hormone jasmonate are uncoupled in an
Arabidopsis
mutant (
jazQ phyB
) lacking a quintet of Jasmonate ZIM-domain transcriptional repressors and the photoreceptor phyB. Analysis of epistatic interactions between
jazQ
and
phyB
reveal that growth inhibition associated with enhanced anti-insect resistance is likely not caused by diversion of photoassimilates from growth to defense but rather by a conserved transcriptional network that is hardwired to attenuate growth upon activation of jasmonate signalling. The ability to unlock growth-defense tradeoffs through relief of transcription repression provides an approach to assemble functional plant traits in new and potentially useful ways.
Plant immune responses are often associated with reduced growth. Here, the authors show that combining mutations in transcriptional repressors of the defense and light perception pathways can confer both robust growth and strong herbivore defense, demonstrating that growth-defense tradeoffs can be uncoupled.
Journal Article
Predicting accurate cathode properties of layered oxide materials using the SCAN meta-GGA density functional
Layered lithium intercalating transition metal oxides are promising cathode materials for Li-ion batteries. Here, we scrutinize the recently developed strongly constrained and appropriately normed (SCAN) density functional method to study structural, magnetic, and electrochemical properties of prototype cathode materials LiNiO2, LiCoO2, and LiMnO2 at different Li-intercalation limits. We show that SCAN outperforms earlier popular functional combinations, providing results in considerably better agreement with experiment without the use of Hubbard parameters, and dispersion corrections are found to have a small effect. In particular, SCAN fares better than Perdew–Burke–Ernzerhof (PBE) functional for the prediction of band-gaps and absolute voltages, better than PBE+U for the electronic density of states and voltage profiles, and better than both PBE and PBE+U for electron densities and in operando lattice parameters. This overall better performance of SCAN may be ascribed to improved treatment of localized states and a better description of short-range dispersion interactions.
Journal Article
A Phytochrome B-Independent Pathway Restricts Growth at High Levels of Jasmonate Defense
The plant hormone jasmonate (JA) promotes resistance to biotic stress by stimulating the degradation of JASMONATE ZIM-DOMAIN (JAZ) proteins, which relieves repression on MYC transcription factors that execute defense programs. JA-triggered depletion of JAZ proteins in Arabidopsis (Arabidopsis thaliana) is also associated with reduced growth and seed production, but the mechanisms underlying these pleiotropic growth effects remain unclear. Here, we investigated this question using an Arabidopsis JAZ-deficient mutant (jazD; jaz1–jaz7, jaz9, jaz10, and jaz13) that exhibits high levels of defense and strong growth inhibition. Genetic suppressor screens for mutations that uncouple growth-defense tradeoffs in the jazD mutant identified nine independent causal mutations in the red-light receptor phytochrome B (phyB). Unlike the ability of the phyB mutations to completely uncouple the mild growth-defense phenotypes in a jaz mutant (jazQ) defective in JAZ1, JAZ3, JAZ4, JAZ9, and JAZ10, phyB null alleles only weakly alleviated the growth and reproductive defects in the jazD mutant. phyB-independent growth restriction of the jazD mutant was tightly correlated with upregulation of the Trp biosynthetic pathway but not with changes in central carbon metabolism. Interestingly, jazD and jazD phyB plants were insensitive to a chemical inhibitor of Trp biosynthesis, which is a phenotype previously observed in plants expressing hyperactive MYC transcription factors that cannot bind JAZ repressors. These data provide evidence that the mechanisms underlying JA-mediated growth-defense balance depend on the level of defense, and they further establish an association between growth inhibition at high levels of defense and dysregulation of Trp biosynthesis.
Journal Article
Temporal Dynamics of Growth and Photosynthesis Suppression in Response to Jasmonate Signaling
Biotic stress constrains plant productivity in natural and agricultural ecosystems. Repression of photosynthetic genes is a conserved plant response to biotic attack, but how this transcriptional reprogramming is linked to changes in photosynthesis and the transition from growth- to defense-oriented metabolism is poorly understood. Here, we used a combination of noninvasive chlorophyll fluorescence imaging technology and RNA sequencing to determine the effect of the defense hormone jasmonate (JA) on the growth, photosynthetic efficiency, and gene expression of Arabidopsis (Arabidopsis thaliana) rosette leaves. High temporal resolution was achieved through treatment with coronatine (COR), a high-affinity agonist of the JA receptor. We show that leaf growth is rapidly arrested after COR treatment and that this effect is tightly correlated with changes in the expression of genes involved in growth, photosynthesis, and defense. Rapid COR-induced expression of defense genes occurred concomitantly with the repression of photosynthetic genes but was not associated with a reduced quantum efficiency of photosystem II. These findings support the view that photosynthetic capacity is maintained during the period in which stress-induced JA signaling redirects metabolism from growth to defense. Chlorophyll fluorescence images captured in a multiscale time series, however, revealed a transient COR-induced decrease in quantum efficiency of photosystem II at dawn of the day after treatment. Physiological studies suggest that this response results from delayed stomatal opening at the nightday transition. These collective results establish a high-resolution temporal view of how a major stress response pathway modulates plant growth and photosynthesis and highlight the utility of chlorophyll fluorescence imaging for revealing transient stress-induced perturbations in photosynthetic performance.
Journal Article
An evo-devo perspective of the female reproductive tract
The vertebrate female reproductive tract has undergone considerable diversification over evolution, having become physiologically adapted to different reproductive strategies. This review considers the female reproductive tract from the perspective of evolutionary developmental biology (evo-devo). Very little is known about how the evolution of this organ system has been driven at the molecular level. In most vertebrates, the female reproductive tract develops from paired embryonic tubes, the Müllerian ducts. We propose that formation of the Müllerian duct is a conserved process that has involved co-option of genes and molecular pathways involved in tubulogenesis in the adjacent mesonephric kidney and Wolffian duct. Downstream of this conservation, genetic regulatory divergence has occurred, generating diversity in duct structure. Plasticity of the Hox gene code and wnt signaling, in particular, may underlie morphological variation of the uterus in mammals, and evolution of the vagina. This developmental plasticity in Hox and Wnt activity may also apply to other vertebrates, generating the morphological diversity of female reproductive tracts evident today.
Journal Article
Transcriptional landscape of the embryonic chicken Müllerian duct
Background
Müllerian ducts are paired embryonic tubes that give rise to the female reproductive tract in vertebrates. Many disorders of female reproduction can be attributed to anomalies of Müllerian duct development. However, the molecular genetics of Müllerian duct formation is poorly understood and most disorders of duct development have unknown etiology. In this study, we describe for the first time the transcriptional landscape of the embryonic Müllerian duct, using the chicken embryo as a model system. RNA sequencing was conducted at 1 day intervals during duct formation to identify developmentally-regulated genes, validated by in situ hybridization.
Results
This analysis detected hundreds of genes specifically up-regulated during duct morphogenesis. Gene ontology and pathway analysis revealed enrichment for developmental pathways associated with cell adhesion, cell migration and proliferation, ERK and WNT signaling, and, interestingly, axonal guidance. The latter included factors linked to neuronal cell migration or axonal outgrowth, such as Ephrin B2, netrin receptor, SLIT1 and class A semaphorins. A number of transcriptional modules were identified that centred around key hub genes specifying matrix-associated signaling factors;
SPOCK1, HTRA3
and
ADGRD1
. Several novel regulators of the WNT and TFG-β signaling pathway were identified in Müllerian ducts, including
APCDD1
and
DKK1
,
BMP3
and
TGFBI
. A number of novel transcription factors were also identified, including
OSR1, FOXE1, PRICKLE1, TSHZ3
and
SMARCA2
. In addition, over 100 long non-coding RNAs (lncRNAs) were expressed during duct formation.
Conclusions
This study provides a rich resource of new candidate genes for Müllerian duct development and its disorders. It also sheds light on the molecular pathways engaged during tubulogenesis, a fundamental process in embryonic development.
Journal Article
