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Published: 4 February 2020
Theoretical Medicine and Bioethics, Volume 41, pp 39-52; https://doi.org/10.1007/s11017-020-09516-x

Abstract:
Jerome Wakefield’s harmful dysfunction analysis (HDA) of medical disorder is an influential hybrid of naturalist and normative theories. In order to conclude that a condition is a disorder, according to the HDA, one must determine both that it results from a failure of a physical or psychological mechanism to perform its natural function and that it is harmful. In a recent issue of this journal, I argued that the HDA entails implausible judgments about which disorders there are and how they are individuated. The same arguments apply to other views that incorporate a harm criterion. More recently, David G. Limbaugh has modified the HDA by providing a novel account of the way in which a disorder must be harmful. Here, I briefly review the relevant issues and then critically assess Limbaugh’s account. I argue in the end that Limbaugh’s revisions do not succeed in making accounts like the HDA more attractive.
, Daniela Segantini, Marco Feligioni, Maurizio Raiteri
Published: 29 January 2005
British Journal of Pharmacology, Volume 144, pp 293-299; https://doi.org/10.1038/sj.bjp.0705960

The publisher has not yet granted permission to display this abstract.
Hugo A. J. Gielkens, Corine Penning, Anita Van Dan Biggelaar, Willem Onkenhout, Cornelis B. H. W. Lamers, Ad A. M. Masclee
Journal of Parenteral and Enteral Nutrition, Volume 23, pp 56-60; https://doi.org/10.1177/014860719902300256

Abstract:
Background: Parenteral nutrients suppress oral food intake. Separate IV infusion of amino acids (IVAA) at high doses affects gastrointestinal motility and secretion. However, little is known on the effects of separate IV infusion of amino acids at these high doses on satiety. Therefore, we have studied the effect of two different doses of a commercially available mixed amino acids solution on satiety and food intake. Methods: Six healthy volunteers (ages 20 to 34 years) were studied on three separate occasions in random order during (a) IV saline (control), (b) low-dose IVAA ([LDA] 125 mg protein/kg/h, Vamin 18EF; Kabi Pharmacia BV, Woerden, The Netherlands), or (c) high-dose IVAA ([HDA] 250 mg protein/kg/h) for 360 minutes. Subjective criteria such as wish to eat, prospective feeding intentions, and feelings of hunger and fullness were scored on 100-mm visual analog scales at 30-minute intervals. Food preference also was measured every 60 minutes with food selection lists. At the end of the experiment a meal was presented. Results: Feelings of fullness were significantly (p < .05) increased during both LDA and HDA. The wish to eat was significantly (p < .05) decreased during HDA compared with control and LDA. Prospective feeding intentions also tended to be reduced during HDA (not significant). Feelings of hunger were not significantly different between the three experiments. Total food selection was significantly (p < .05) decreased during LDA and HDA, mainly because of a significantly (p < .05) decreased preference for fat-rich items. However, the total amount of food consumed at the end of the experiment was not significantly different between the three experiments. Conclusions: The present study shows that in healthy volunteers, IVAA (1) increase satiety ratings, (2) increase feelings of fullness, (3) decrease preprandial food selection, and (4) have no effect on subsequent oral food intake. (Journal of Parenteral and Enteral Nutrition 23:56-60, 1999)
Elisaveta Milusheva, Mária Baranyi, Agnes Kittel, Adam Fekete, Tibor Zelles, E Sylvester Vizi, Beáta Sperlágh
Published: unknown date
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E. S. Vizi, I. E. Tóth, E. Orsó, K. Sz. Szalay, D. Szabo, M. Baranyi, G. P. Vinson
Published: 1 November 1993
Journal of Endocrinology, Volume 139, pp 213-26; https://doi.org/10.1677/joe.0.1390213

Abstract:
The effect of supramaximal electric field stimulation on [3H]dopamine (DA) release by rat adrenal capsuleglomerulosa preparations was studied using a microvolume perfusion system. When the tissues were preloaded with [3H]DA, a considerable amount of [3H]DA and [3H]noradrenaline (NA) were released in response to field stimuli. Reserpinization, calcium removal or tetrodotoxin blocking of Na+ influx all completely inhibited the stimulation-evoked release of DA/NA, indicating that the radioactivity released is of neuronal and vesicular origin. In the adrenal cortex, a substantial proportion of tyrosine hydroxylase and dopamine-β-hydroxylase immunoreactive nerve fibres and varicosities were observed around the zona glomerulosa. DA-containing nerves were not seen in the adrenal cortex; however, the same immunocytochemical procedures clearly demonstrated dopaminergic nerve cells and fibres in the substantia nigra and the striatum respectively, and cells of the adrenal medulla. Like the NA release from noradrenergic varicosities in the zona glomerulosa, the DA release from noradrenergic endings is not subject to negative feedback modulation through DA2 receptors since apomorphine, a DA2-receptor agonist, and sulpiride, a selective DA2-receptor antagonist, failed to affect the release. After in-vivo i.v. administration of [3H]DA, the glomerulosa content of DA and NA and the in-vitro release of [3H]DA and [3H]NA of zona glomerulosa both increased, indicating that the local varicose axon terminals were able to accumulate DA from the circulation, convert it into NA and release it in response to neural activity. This local arrangement of noradrenergic axon terminals, able to take up DA from the circulation and release it or convert it into NA, provides the possibility of a fine tuning of local circulation and aldosterone synthesis in the zona glomerulosa. Journal of Endocrinology (1993) 139, 213–226
Li Qian, Zongli Xu, Wei Zhang, Belinda Wilson, Jau-Shyong Hong, Patrick M Flood
Published: unknown date
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H. E. Murray, G. E. Gillies
Published: 1 December 1993
Journal of Endocrinology, Volume 139, pp 403-14; https://doi.org/10.1677/joe.0.1390403

Abstract:
Using fetal rat hypothalamic cells in primary culture maintained in a serum-free defined medium we have investigated the morphological and functional development of the dopamine (DA)-containing neurones intrinsic to the hypothalamus. Immunocytochemical studies demonstrated the presence of three morphologically distinct subtypes of tyrosine hydroxylase-immunopositive neurones. On day 3 in vitro unipolar, bipolar and multipolar cell types were apparent. The latter two subtypes persisted to later days in culture and increased both in perikarya size and neurite length. All subtypes have been shown to have correlates in vivo. Biochemical studies employing [3H]DA demonstrated a time- and temperature-dependent uptake mechanism within the cultures which was significantly attenuated by the uptake inhibitors benztropine and nomifensine in a dose-dependent manner. [3H]DA was also released under both basal and 56 mmol K+/l-stimulated conditions and the magnitude of the response was reduced by exclusion of calcium from the release medium. The amount of [3H]DA accumulated and released by the cultured cells increased with the age of the culture, suggesting functional maturation of the DA-containing neurones within this preparation. The role of oestradiol-17β in regulating hypothalamic dopaminergic function was also investigated both indirectly with the use of [3H]DA and by direct measurement of endogenously synthesized DA using high-performance liquid chromatography coupled with electrochemical detection. Both uptake and release of [3H] and release of endogenous DA were significantly modulated by the concentration of steroid in the defined medium. These results demonstrate that hypothalamic dopaminergic neurones, when maintained in primary culture, undergo morphological and functional maturation which have several correlates in vivo. In addition, we have demonstrated that at least one sub-population of dopaminergic neurones within this preparation is responsive to oestradiol-17β. As DA is considered to be a vital component in the regulation of neuroendocrine activity we suggest that this model is valuable for the investigation of the functional development of the DA systems of the hypothalamus and the relationship existing between neurotransmitters, neuropeptides and neuroactive steroids. Journal of Endocrinology (1993) 139, 403–414
Elisaveta Milusheva, Mária Baranyi, Agnes Kittel, Adam Fekete, Tibor Zelles, E Sylvester Vizi, Beáta Sperlágh
Published: unknown date
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Elisaveta Milusheva, Mária Baranyi, Agnes Kittel, Adam Fekete, Tibor Zelles, E Sylvester Vizi, Beáta Sperlágh
Published: unknown date
by 10.6084
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L. Keith Henry, Michael Dean Allen, Madhur Shetty, Allison Cwikla, Isaac Nies
Published: 1 April 2018
The FASEB Journal, Volume 32, pp 680.6-680.6; https://doi.org/10.1096/fasebj.2018.32.1_supplement.680.6

The publisher has not yet granted permission to display this abstract.
David Oyewola, Emmanuel Dada
International Journal of Applied Mathematics Electronics and Computers, Volume 10, pp 1-10; https://doi.org/10.18100/ijamec.984201

Abstract:
The global health crisis that started in December 2019 resulted in an outbreak of coronavirus named COVID-19. Scientists worldwide are working to demystify the transmission and pathogenic mechanisms of the deadly coronavirus. The World Health Organization has declared COVID-19 a pandemic in March 2020, which makes it essential to track and analyse the research state of COVID-19 for guidance on further research. This research was conducted using scientometric analysis, knowledge-mapping analysis, COVID-19 studies and journal classifications. The publications used in this study include over 3000 COVID-19 papers made available to the public from 1 January 2018 to 15 April 2021 in the PubMed databases. In this study, it was discovered that the rapid reaction of researchers worldwide resulted in a fast growth trend between 2019 and 2021 in the number of publications related to COVID-19. It was discovered that the largest number of studies is in the United States of America, which is one of the countries most affected by a pandemic. The method adopted for this study involved the use of documents such as Case Reports (CAT), Journal Article (JAT), letter (LTR), EAT, and Editorial (EDT). This is followed by the classification of COVID-19 related publications that were retrieved from PubMed between 2019 and 2021 using machine learning (ML) models such as Naïve Bayes (NB), Bayesian Generalized Linear Model (BGL), Heteroscedastic Discriminant Analysis (HDA) and Multivariate Adaptive Regression Spline (MAR). Simulation results show that the classification accuracy of MAR is better than that of other ML models used in this study. The sensitivity of the MAR is within the range of 100%. This shows that MAR performs better than NB, BGL and HDA. MAR performs better with an overall accuracy of 89.62%. Our results show a high degree of strong collaboration in coronavirus research and the exchange of knowledge in the global scientific community.
Duong Hong Anh, Vu Minh Tuan, Van Thi Thanh Huyen, Nguyen Manh Huy, Nguyen Thanh Dam
VNU Journal of Science: Natural Sciences and Technology, Volume 35; https://doi.org/10.25073/2588-1140/vnunst.4964

Abstract:
The optimized capillary electrophoresis (CE) was applied to separate and detect the 10-hydroxy-2-decenoic acid (10-HAD) in royal jelly products. The method only requires that the sample solution need to be centrifuged and filtered before analyzed by the home-made capillary electrophoresis system. Firstly, 10-HDA was separated in a fused silica column with a diameter of 50 um using 20 mM Tris/Acetic buffer (pH 8.5) as a background electrolyte and a separation voltage of -17kV. Then, 10-HDA was detected by capacitively coupled contactless conductivity detection (C4D) with the migration time less than 8 minutes. Nine commercial products of royal jelly with Vietnamese and imported origin including pure royal jelly cream, lyophilized royal jelly (powder and gel) and honey with royal jelly were collected for analysis. The results of this study showed that content of 10-HDA were detected in the range of 0.5 mg/g to 23.1 mg/g. Using paired t test showed that the difference between results obtained from CE-C4D method and from HPLC method as a reference method was not statistically significant. Keywords: 10-HDA, royal jelly products, CE-C4D. References [1] M. Viuda Martos, Y. Ruiz Navajas, J. Fernández López, J.A. Pérez Álvarez, Functional properties of honey, propolis, and royal jelly”, Journal of food science 73 (2007) 117-124. https://doi:10.1111/j. 1750-3841.2008.00966.x.[2] M.F. Ramadan, A. Al-Ghamdi, Bioactive compounds and health-promoting properties of royal jelly: A review, Journal of Functional Foods 4 (2012) 39- 52. https://doi.org/10.1016/j.jff. 2011. 12.007.[3] Dimitrios Kanelis, Chrysoula Tananaki, Vasilis Liolios, Maria Dimou, Georgios Goras, Maria Anna Rodopoulou, Emmanuel Karazafris, and Andreas Thrasyvoulou, A suggestion for royal jelly specifcations, Archives of Industrial Hygiene and Toxicology 66 (2015) 275-284. Https://doi: 10.1515/aiht-2015-66-2651.[4] Brazil Ministério Da Agricultura e Do Abaste Imento. Secretaria De Defesa Agropecuária. Instrução normativa nº3, de 19 de janeiro de 2001. Regulamento técnico para fxação de identidade e qualidade de geléia real, Regulamento técnico para fxação de identidade e qualidade de geléia real liofilizada. Http:// www.engetecno.com.br/port/ legislacao/mel_geleia_real.htm.[5] Mahmut Genc¸ Abdurrahman Aslan, Determination of trans-10-hydroxy-2-decenoic acid content in pure royal jelly and royal jelly products by column liquid chromatography, Journal of Chromatography A. 839 (1999) 265 – 268. Http://doi: 10.1016/s0021-9673(99)00151-x.[6] F. Ferioli, E. Armaforte, M.F. Caboni, Comparison of the Lipid Content, Fatty Acid Profile and Sterol Composition in Local Italian and Commercial Royal Jelly Samples” Journal of the American Oil Chemists' Society, 91(2014) 875-884. Http://doi. org/10.1007/s11746-014-2446-x.[7] J. Kim, J. Lee, Quantitative analysis of trans-10-hydroxy-2-decenoic acid in royal jelly products purchased in USA by high performance liquid chromatography”, Journal of Apicultural Science, 54 (2010) 77-85. Https://pdfs.semanticscholar. org/e85f/dfc1823d778a40c ca2eefa4be8ba4b4d98 6c.pdf.[8] C.I. Pavel, L.A. Mărghitaş, D.S. Dezmirean, L.I. Tomoş, V. Bonta, A. Şapcaliu, A. Buttstedt, Comparison between local and commercial royal jelly-use of antioxidant activity and 10-hydroxy-2-decenoic acid as quality parameter”, Journal of Apicultural Research 53 (2014) 116-123. https:// doi.org/10.3896/IBRA.1.53.1.12.[9] Mahmut Genc¸ Abdurrahman Aslan, Determination of trans-10-hydroxy-2-decenoic acid content in pure royal jelly and royal jelly products by column liquid chromatography, Journal of Chromatography A, 839 (1999) 265 – 268. Https://doi:10.1016/s0021-9673(99)00151-x.[10] Jinhui Zhou, Xiaofeng Xue, Yi Li, Jinzhen Zhang and Jing Zhao, Optimized determination method for trans-10-hydroxy-2-decenoic acid content in royal jelly by high-performance liquid chromatography with an internal standard, Journal of AOAC International, 90(2007) 244-249. https://www.ncbi.nlm.nih.gov/pubmed/17373456.[11] Federico Ferioli, Gian Luigi Marcazzan, Maria Fiorenza Caboni, Determination of (E)-10-hydroxy-2-decenoic acid content in pure royal jelly: A comparison between a new CZE method and HPLC”, J. Sep. Sci .30 (2007) 1061-1069. Http://doi:10.1002/jssc.200600416.[12] Orlando Muñoz, Susana Decap, Francisco Ruiz, José Arbildua, Octavio Monasterio, Determination of 10- hydroxy-2-decenoic acid in royal jelly by capillary electrophoresis, J. Chil. Chem. Soc., 56 (2010) 738-740. http://dx.doi.org/10.4067/S0717 97072011000300004.
Li Qian, Zongli Xu, Wei Zhang, Belinda Wilson, Jau-Shyong Hong, Patrick M Flood
Published: unknown date
by 10.6084
The publisher has not yet granted permission to display this abstract.
Y. Gui, Z. Zhang, J. Zhao
Published: 23 May 2022
by BMJ
Clinical and Experimental Rheumatology, Volume 81, pp 1220.2-1221; https://doi.org/10.1136/annrheumdis-2022-eular.2574

Abstract:
Background Despite the constant updating of rheumatoid arthritis (RA) treatment strategies, whether poor prognostic factors (PPFs) can guide RA treatment is still controversial. There are limited data about the presence of PPFs in Chinese RA patients. Objectives To describe the profile of PPFs based on European League Against Rheumatism (EULAR) recommendations in Chinese RA patients, and explore the significance of these factors in adjusting treatment therapy. Methods In this real-world study, RA patients were enrolled from 2012 to 2020. The baseline characteristics and prognostic factors based on EULAR recommendations include acute-phase reactant levels, rheumatoid factor (RF), anti-cyclic citrullinate peptide (anti-CCP antibody), swollen joint counts (SJC), early bone erosions, and responses to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) at month 3 or month 6 were collected. Disease activity was assessed by disease activity score of 28 joints-erythrocyte sedimentation rate (DAS28-ESR), DAS28-C-reactive protein (DAS28-CRP), simple disease activity index (SDAI), and clinical disease activity index (CDAI). The association of different factors was represented by a Venn diagram. The number of patients presenting with different combinations of prognostic factors was graphically displayed by UpSetR. Correlation between binary variables was analyzed by the Chi-square test. Results 1252 registered RA patients were enrolled. 901/1252 (72.0%) patients had elevated ESR or CRP and 1027/1164 (88.2%) patients had positive RF or anti-CCP antibody. 397/1252 (31.7%) patients had ors was graphicas. 166/444 (37.0%) patients had early bone erosions, which usually coexisted with other PPFs. 394 (34.4%) of the 1105 patients who received csDMARD therapy as prescribed had persistent moderate or high disease activity (MDA/HDA). Failure of two or more csDMARDs was found in 245 (22.2%) patients. 99% of RA patients had at least one PPF. Patients with MDA/HDA usually coexisted with other PPF. MDA/HDA was significantly correlated with elevated ESR/CRP or high SJC and is not correlated with positive RF/anti-CCP antibody or early bone erosion. Conclusion PPFs are prevalent in RA patients in real-world data. It is inappropriate to guide treatment strategies just based on the presence or absence of PPFs. The categories of PPFs should be simplified and the role of different combinations of PPFs in guiding treatment therapies remains to be explored. References [1]Hu, H., et al., Burden of rheumatoid arthritis from a societal perspective: A prevalence-based study on the cost of this illness for patients in China. International journal of rheumatic diseases, 2018. 21(8): p. 1572-1580. [2]Muñoz-Fernández, S., et al., Use of prognostic factors of rheumatoid arthritis in clinical practice and perception of their predictive capacity before and after exposure to evidence. Rheumatology international, 2018. 38(12): p. 2289-2296. [3]Koga, T., et al., Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy. Medicine, 2016. 95(17): p. e3476. [4]Smolen, J.S., et al., EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Annals of the rheumatic diseases, 2020. 79(6): p. 685-699. [5]Fraenkel, L., et al., 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis care & research, 2021. 73(7): p. 924-939. Coexistence of 6 PPFs including positive RF/anti-CCP antibody, elevated ESR/CRP, high SJC, persistent MDA/HDA, failure of two or more csDMARDs, and early bone erosion. Acknowledgements This study was based on the contributions of all colleagues in our department during the outpatient visits over the past decade. Disclosure of Interests None declared
P. Tzanis, K. Klavdianou, S. Katechis, C. Katsimpari, L. Athanassiou, O. Gioti, I. I. Giannakopoulou, S. Koutsoviti, I. Sofianos, A. Lazarini, et al.
Published: 23 May 2022
by BMJ
Clinical and Experimental Rheumatology, Volume 81, pp 1246.3-1247; https://doi.org/10.1136/annrheumdis-2022-eular.343

Abstract:
Background: Patients with active rheumatoid arthritis (RA) are at risk for poor functional outcomes, affecting quality of life (QoL). SF-36 is a validated instrument to measure health-related quality of life (HRQoL) in various domains of physical and mental health1, and has been validated in RA. Nevertheless, data on the impact of RA disease activity on SF-36 scores in Greek patients are lacking.Objectives: To compare SF-36 scores in Greek RA patients versus the general population and to assess the impact of disease activity on HRQoL.Methods: Cross-sectional study in RA patients followed in the Department of Rheumatology, Asklepieio Voulas General Hospital (05-10/2021). Demographic characteristics, state of disease activity and current treatment for RA were recorded at most recent visit. All patients completed SF-36 questionnaires and were classified in three subgroups of DAS28-disease activity: i) Remission or Low disease activity (LDA), ii) Moderate disease activity (MDA), and iii) High disease activity (HDA). Data from the SF-36 validation study in the Greek general population with 1007 participants, were used as historical controls2. Descriptive statistics, one-way ANOVA and linear regression were used for statistical analyses.Results: 107 patients participated in the study (80,4% females, mean (SD) age 63.3 (12.1) years, 64.5% seropositive, 72% overweight or obese). One third (n=36) were active smokers and 63% (n=67) were receiving a biologic disease modifying antirheumatic drug (bDMARD).Patients with RA exhibited low scores in all SF-36 domains and reported significantly worse results compared to the general population (Figure 1). Figure 1. Physical component score (PCS) and Mental component score (MCS) of the SF-36 showed a negative correlation with DAS28 (β= -8.28, p= <0.001 and β= -6.2, p= <0.001, respectively). Patients with remission or LDA exhibited better SF-36 scores compared to the other subgroups; moreover, patients with MDA had better SF-36 scores than those with HDA (Table 1). When patients with MDA were further divided into low- and high-moderate disease activity (DAS28: 3,21-4,19 and 4,2-5,1, respectively), no significant difference in any SF-36 domain was found between the two groups. Table 1. SF-36 domain mean±SD RDA or LDA 51% MDA 37,2% HAD 11,7% p-value PF 48,43 ±34,23 32,14 ±19,83 20 ± 19,75 0.003 RP 34,9 ±43,68 20,71 ± 32,92 0 ± 0 0.015 BP 51,2 ±30,47 28,24 ± 24,49 18,86 ± 23,54 <0.001 GH 48,83 ±45 41,57 ± 24,25 32,27 ± 19,54 0.043 VT 49,48 ±22,22 34,14 ± 18,57 30,91 ± 15,94 0.001 SF 52,16 ±35,33 40,36 ± 27,13 28,41 ± 14,89 0.041 RE 39,01 ±44,68 27,62 ± 40,81 18,18 ± 34,52 0.246 MH 54,08 ±23,24 47,57 ± 21,75 40 ± 18,59 0.124 Conclusion: HRQoL assessed by SF-36 is dampened in RA patients, in both physical and mental component. Disease activity had a negative impact on both physical and mental components of HRQoL. Patients with remission or LDA showed better HRQoL outcomes, suggesting that the treat-to-target approach may also positively affect QoL.References: [1]Ware, J. E., Jr, & Gandek, B. (1998) Journal of clinical epidemiology, 51(11), 903–912.[2]Pappa E et al. Qual Life Res. 2005 Jun;14(5):1433-8Disclosure of Interests: None declared
B. Dreo, D. R. Pietsch, R. Husic, A. Lackner, J. Fessler, J. Rupp, A. S. Muralikrishnan, J. Thiel, M. Stradner, P. Bosch
Published: 23 May 2022
by BMJ
Clinical and Experimental Rheumatology, Volume 81, pp 854.1-854; https://doi.org/10.1136/annrheumdis-2022-eular.767

Abstract:
Background: Numerous cytokines that influence disease activity in psoriatic arthritis (PsA) are modulators of the Janus Kinases/Signal Transducers and Activators of Transcription (JAK/STAT) pathway. The JAK1/STAT1/STAT3/STAT5 network can drive the expansion of Th17 and regulatory T cells via proinflammatory cytokines in PsA joints,[1], [2] while hyperphosphorylation of STAT3 in immune cells has previously been shown to promote PsA pathogenesis through the Interleukin (IL)-23/IL-17/IL-22 axis.[3] Therefore, the phosphorylation status of STAT molecules in leucocytes of PsA patients may indicate active disease and could potentially guide treatment with JAK inhibitors.Objectives: To analyse phosphorylated STAT (pSTAT) levels of circulating leucocyte subsets in PsA patients with active and inactive diseaseMethods: Whole blood was drawn on consecutive PsA patients fulfilling the CASPAR criteria[4] to perform flow cytometry analysis using the BD FACSLyric platform. Disease activity was assessed using the Disease activity for psoriasis arthritis (DAPSA) score.[5] All steps from storage of drawn blood to cell fixation were performed at 4°C to prevent auto-activation of leucocytes. The geometric mean fluorescence intensities (gMFI) of pSTATs in granulocytes, monocytes, B cells and CD4+/- naïve/memory T cells were compared between patients with moderate to high (MoDA/HDA) and remission to low disease activity (REM/LDA). Correlation analysis between gMFIs and DAPSA scores were performed.Results: Forty-two patients (female ratio: 0.48) with established PsA (median ± standard deviation, age: 56 ± 12.54 years, disease duration: 8.50 ± 7.10 years) were included in this study. Twenty-one percent of patients were in MoDA/HDA, while the remaining 79% were in REM/LDA. Patients in MoDA/HDA showed significantly higher pSTAT3 levels in CD4+ naïve (gMFI median ± standard deviation: 284.5 ± 79.9 vs 238 ± 92.9, p = 0.011), CD4- naïve (297 ± 107.5 vs 238 ± 98.4, p = 0.04), CD4+ memory (227 ± 62.9 vs 190.5 ± 72.2, p = 0.009) and CD4- memory T cells (209 ± 66.8 vs 167.0 ± 64.9, p = 0.036). On the other hand, PsA patients in remission or low disease activity displayed higher pSTAT1 levels in granulocytes (2509 ± 1887 vs 1330.5 ± 784.1, p = 0.040) and monocytes (255 ± 230 vs 144 ± 62.5, p = 0.049). Positive correlations were found between DAPSA scores and pSTAT3 in CD4+ naïve and memory T cells (Spearman’s correlation coefficient rho (ρ) = 0.5, p = 0.0012 and ρ = 0.47, p = 0.0025 resp.) whereas pSTAT1 in granulocytes and monocytes were negatively correlated with the DAPSA scores (ρ = -0.45, p = 0.0074 and ρ = -0.34, p = 0.05).Conclusion: Differential phosphorylation of STAT3 and STAT1 molecules in circulating leucocyte subsets indicates PsA disease activity. Further studies to examine the value of STAT phosphorylation patterns guiding JAK inhibitor therapy are underway.References: [1]U. Fiocco et al., “Ex vivo signaling protein mapping in T lymphocytes in the psoriatic arthritis joints,” J. Rheumatol., vol. 93, pp. 48–52, 2015, doi: 10.3899/jrheum.150636.[2]S. K. Raychaudhuri, C. Abria, and S. P. Raychaudhuri, “Regulatory role of the JAK STAT kinase signalling system on the IL-23/IL-17 cytokine axis in psoriatic arthritis,” Ann. Rheum. Dis., vol. 76, no. 10, pp. e36–e36, 2017.[3]E. Calautti, L. Avalle, and V. Poli, “Psoriasis: A STAT3-centric view,” International Journal of Molecular Sciences, vol. 19, no. 1. MDPI AG, Jan. 06, 2018, doi: 10.3390/ijms19010171.[4]W. Taylor, D. Gladman, P. Helliwell, A. Marchesoni, P. Mease, and H. Mielants, “Classification criteria for psoriatic arthritis: Development of new criteria from a large international study,” Arthritis Rheum., vol. 54, no. 8, pp. 2665–2673, 2006, doi: 10.1002/art.21972.[5]M. M. Schoels, D. Aletaha, F. Alasti, and J. S. Smolen, “Disease activity in psoriatic arthritis (PsA): Defining remission and treatment success using the DAPSA score,” Ann. Rheum. Dis., vol. 75, no. 5, pp. 811–818, 2016, doi: 10.1136/annrheumdis-2015-207507.Disclosure of Interests: Barbara Dreo: None declared, Daniel Ruben Pietsch: None declared, Rusmir Husic Speakers bureau: MSD, Lilly und Abbvie, Angelika Lackner: None declared, Johannes Fessler: None declared, Janine Rupp: None declared, Anirudh Subramanian Muralikrishnan: None declared, Jens Thiel Speakers bureau: GSK, BMS, AbbVie, Novartis, Consultant of: GSK, Novartis, Grant/research support from: BMS, Martin Stradner Speakers bureau: Eli Lilly, Pfizer, MSD, BMS, AbbVie, Janssen, Consultant of: Eli Lilly, AbbVie, Janssen, Philipp Bosch Grant/research support from: Pfizer
, L Raiteri, L Patti, M Parodi, F Robino, M Raiteri,
Published: 1 November 2006
British Journal of Pharmacology, Volume 149, pp 724-732; https://doi.org/10.1038/sj.bjp.0706914

Abstract:
Background and purpose: Two metabolites of tryptophan, 5‐hydroxyindole and kynurenic acid (kynurenate) affect the function of α7 nicotinic acetylcholine receptors (nAChRs), as measured by electrophysiological and Ca2+ fluorescence techniques. To better understand the modulations by 5‐hydroxyindole and kynurenate of the function of nAChR subtypes, we compared the effects of 5‐hydroxyindole and kynurenate on the release of various transmitters evoked by nAChR activation. Experimental approach: The function of α7nAChRs located on glutamatergic terminals was investigated by monitoring the release of [3H]D‐aspartate or of endogenous glutamate from neocortical synaptosomes. We also comparatively considered non‐α7 release‐enhancing nAChRs localized on hippocampal noradrenergic or cholinergic terminals, as well as on striatal dopaminergic terminals. Key results: Epibatidine or nicotine, inactive on their own on basal release, enhanced [3H]D‐ aspartate and glutamate efflux in presence of 5‐hydroxyindole. The release evoked by nicotine plus 5‐hydroxyindole was abolished by methyllycaconitine or α‐bungarotoxin. Presynaptic nAChRs mediating the release of [3H]noradrenaline ([3H]NA), [3H]dopamine ([3H]DA), or [3H]ACh were inhibited by 5‐OHi. The α7nAChR‐mediated release of [3H]D‐aspartate was reduced by kynurenate at concentrations unable to affect the non‐α7 receptor‐mediated release of tritiated NA, DA or ACh. Conclusions and Implications: (i) 5‐hydroxyindole permits selective activation of α7nAChRs mediating glutamate release; (ii) kynurenate down‐regulates the permissive role of 5‐hydroxyindole on α7nAChR activation; (iii) the non‐α7nAChRs mediating release of NA, DA or ACh can be inhibited by 5‐hydroxyindole, but not by kynurenate. These findings suggest up the possibility of developing novel drugs able to modulate selectively the cholinergic‐glutamatergic transmission. British Journal of Pharmacology (2006) 149, 724–732. doi:10.1038/sj.bjp.0706914
Raúl Walder, Octavio M. Suárez
International Journal of Epidemiology, Volume 5, pp 375-384; https://doi.org/10.1093/ije/5.4.375

Abstract:
Walder, R (Instituto Venezolano de investigaciones Científicas Centro de Microbiología y Biología Celular Laboratorio de Virus Animales, Apartado 1827. caracas. Venezuels). and Suárez, O.M.Studies of Arboviruses in Southwestern Venezuela: I. Isolations of Venezuelan and Eastern equine encephalitis viruses from sentinel hamsters in the Catastumbo region. International Journal of Epidemiology 1976, 5: 375–384. The purpose of this report is to describe isolations of Venezuelan (VEE) and Eastern (EEE) Equine Encephalitis virus made in the lowland moist tropical forest of the Catatumbo region on the southwestern part of the State of Zulia, Venezuela. We have isolated four strains of VEEV from sentinel hamsters exposed at Caño Mocho and Madre Vieja sites in 1973 and 1974, and three strains of EEEV in Hacienda (Hda.) Las Nubes in 1975. Both viruses were recovered during silent interepidemic periods and we believe these viruses are maintained in this region in sylvatic conditions. The recovered virus strains were detected within 24 to 48 hours, both in SMB and Vero Cell monolayer cultures and the sentinel hamsters yielded virus infectivities up to 104 PFU ml. Our VEEV isolate (IVIC PAn 23645–47), recovered during the silent interepizodemic period had an elution profile on the hydroxylapatite column corresponding to that of a I-D (VEEV-3880) or a I-E (VEEV-63A216) ‘enzootic’ subtype. However, considering other in vitro criteria (KHI; HA pH 5.8–6.0; small plaque size in Vero monolayers with suitable overlay media), this later and other previous isolates had some very distinct properties of the ‘epizootic’ strains. Thus, the evidence suggests that in Venezuela the VEEV cycle in nature is maintained either by the soc alled ‘enzootic’ and/or ‘epizootic’ virus types, or the virus population of the isolates have particular in vitro properties which do not correlate to the virulence markers in vivo. We consider this important question must be further clarified, and in addition, the isolation of three strains of EEEV are reported; this is the first report of the presence of this virus in Venezuela. Although the EEEV isolates may be of the South American type, they must be considered as potentially dangerous in the case of outbreaks
T Jehle, J Bauer, E Blauth, A Hummel, M Darstein, T M Freiman, T J Feuerstein
Published: 1 July 2000
British Journal of Pharmacology, Volume 130, pp 1227-1234; https://doi.org/10.1038/sj.bjp.0703424

The publisher has not yet granted permission to display this abstract.
Katherine Connor Martin
Dictionaries: Journal of the Dictionary Society of North America, Volume 26, pp 160-173; https://doi.org/10.1353/dic.2005.0005

Abstract:
Gendered Aspects of Lexicographic Labeling1 Ii Katherine Connor Martin "n his preface to the Dictionary of American Slang, Stuart .Flexner remarked that "most American slang is created and used by males" (1960, xii). While efforts have been made to evaluate the accuracy of this often repeated assertion (see, for example, Grossman and Tucker [1997]), the possibility of doing so is complicated by the subjective nature of the slang category, which has historically excluded speech associated with women. Since a sense of masculinity permeates the slang concept, the conclusion that women use slang less than men is circular. As Dale Spender has noted, this sort of circular reasoning, in which assumptions about gendered language use are built into the foundations of the very methodologies intended to test them, has frequently plagued studies seeking to compare men's and women's speech (Spender 1980/1998, 32). This paper explores the ways in which lexicographic practice engages with assumptions about gendered language difference, specifically concerning the application of slang as a register label or organizational criterion. In contrast to formal attributes of lexical items, like the transitivity of a verb, register and otiier usage labeling is necessarily subjective . For that reason, die accuracy of statements like "men use more 1An earlier version of this paper was presented in January 2005 at the annual meeting of the American Dialect Society. I am very grateful for the comments and suggestions of the conference attendees. Dictionaries:Journal oftheDictionary Society ofNorth America 26 (2005) _____________Gendered Aspects of Lexicographic Labeling__________161 slang than women" or "slang is misogynist" cannot be evaluated convincingly ; they depend upon definitions of the slang concept that themselves are inextricable from assumptions about gender and language. Because the slang concept is associated with vitality, creativity, and novelty—qualities generally regarded as positive and exciting— recognition of its association with masculinity initially seems troubling; one would not want to suggest mat women are less likely than men to engage with and contribute to English in this inspired, creative way. But such a conclusion is not inevitable: in fact, acknowledgement of the integrally masculine aspects of the slang category should serve as a catalyst for recognizing historical contributions to the lexicon from the domain of femininity. Cultural developments over the course of the twentieth century have caused the relationship between slang and masculinity to soften somewhat; one need only think of the speech of teenaged girls as it has been presented in, say, the television show Buffy the Vampire Slayer or the film Clueless to see a high correlation between femininity and slang. Nonetheless, recognition of slang's legacy of masculinity is important, in particular for historical dictionaries, which are in many ways constrained by the priorities and assumptions of the (primarily male) lexicographers of generations past. It is a commonplace that slang is impossible to define, though most people have a common sense understanding of the concept. Bethany Dumas andJonathan Lighter, noting the wide variability with which lexicographers had applied slang as a label, and the vagueness with which it was invoked in scholarlyjournals, sought a more rigorous definition of the term. They stressed the importance of the speaker's intent, concluding that slang usages were characterized by "their undeniable lack of dignity and their deliberate, widespread use within a social group (or many social groups) to defy social or linguistic convention ," and stating that an awareness of mis special lexical category was a basic concept informing tiieir own linguistic behavior (Dumas and Lighter 1978, 16) . The years since have seen me publication of the first two volumes of Lighter's pioneering Historical Dictionary ofAmerican Slang (HDAS) , the most comprehensive resource on the American slang lexicon. In the introduction to HDAS, Lighter expands and refines his earlier definition, stressing the social context of slang, its function in expressing speakers' relationships with both their interlocutors and the concepts under discussion. The importance of social context to the concept of slang, however, contributes to what Sidney Landau has called the "circularity" of the slang label, application of 162Katherine Connor Martin which often depends more upon the context in which a term is used than the attributes of the lexical item itself (Landau 2001, 239). Social context is also...
Alexandra Fisher, Anna Lavis, Sheila Greenfield, Hugh Rickards
Published: 1 September 2018
by BMJ
Abstract:
Background A project to study social cognition (Fisher, Lavis et al., 2018) in the messiness (Gabb, 2010) of real life is proposed; but doing this without stifling the natural activity and social functioning which is vital to the observations and demonstrating that the research will do no harm is a difficult balance to ascertain. Critics of international ethical review processes suggest that doing so is restrictive to many forms of qualitative methods (Allbutt, 2010). Aims To find methods which are true to the ethnographic methodology of the project but satisfy the principles of the World Medical Association Helsinki Treaty (World Medical Association, 2013) and American Anthropological Association (American Anthropological Association, 1998) ethical frameworks. Methods After a literature review of many of the ethical dilemmas posed by working with couples/families/people with HD and populations classed as hard to reach, there were still several outstanding questions which a review board could raise concerns about. However, the review also strongly indicated an answer to this conundrum – talk with your population, ask their opinion, after all you’re studying and working alongside them. Results/Conclusion A precis of questions evolved from the review and has been put together for the UK HDA patient involvement group ‘HD Voice’ to comment on. Their critique and ideas will be integrated into the ethics application prior to submission. This work is ongoing at the time of writing this References . Allbutt H. Ethnography and the ethics of undertaking research in different mental healthcare settings. Journal of Psychiatric & Mental Health Nursing2010;17(3):210–216. . American Anthropological Association. 1998-last update, Code of Ethics2018. Available: https://s3.amazonaws.com/rdcms-aaa/files/production/public/FileDownloads/pdfs/issues/policy-advocacy/upload/ethicscode.pdf . Fisher A, Lavis A, Greenfield S, Rickards H. Is social cognition in huntington’s disease more than just a marker for disease progression? An exploration of social functioning in the day-to-day experiences of people with HD, their companions and friends 2018. . Gabb J. Home truths: Ethical issues in family research. Qualitative Research2010;10(4):461–478. . World Medical Association. 2013-last update, The Helsinki DeclarationFebruary, 2016. Available: http://www.wma.net/en/30publications/10policies/b3/index.html
, JinJie Li, Soyon Park, Nam-Chon Paek
Published: 19 August 2020
Frontiers in plant science, Volume 11; https://doi.org/10.3389/fpls.2020.01293

Abstract:
Editorial on the Research TopicRegulatory Mechanisms of Leaf Senescence Under Environmental Stress Leaf senescence defines the final stage of the leaf developmental program and is characterized by extensive destabilization of intracellular organelles and decomposition of macromolecules in order to relocate nutrients to the actively developing organs. Over the last two decades, a number of genes associated with leaf senescence have been identified, thus significantly enhancing our understanding of the regulatory mechanisms underlying this phenomenon (Woo et al., 2019; Sakuraba et al., 2020). However, given the complexity of leaf senescence, many molecular mechanisms and associated factors involved in this process might still be unknown. The purpose of this Research Topic is to identify the genes or regulatory mechanisms associated with environmental stress-induced leaf senescence or the regulatory mechanisms underlying environmental stress responses that are potentially important for the regulation of leaf senescence. In this Research Topic, a total of 10 research articles have been accepted for publication; these articles focus on a wide range of plant species, including the model plant Arabidopsis thaliana and various crops such as rice (Oryza sativa), tobacco (Nicotiana tabacum), and cotton (Gossypium hirsutum). Light deprivation is one of the many environmental stresses that induce leaf senescence. In Arabidopsis, dark-induced leaf senescence requires phytochrome-interacting transcription factors (TFs), PIF4 and PIF5 (Sakuraba et al., 2014), as well as phytohormones such as abscisic acid (ABA) and ethylene. In this Research Topic, Ueda et al. investigated the relationship between ethylene, ABA, and PIFs in dark-induced leaf senescence in Arabidopsis. The pif4 pif5 double mutant exhibited delayed yellowing during dark-induced leaf senescence. However, they showed that during ABA-induced leaf senescence under light, the pif4 pif5 double mutant did not show decreased sensitivity to ABA, suggesting that PIF4 and PIF5 act upstream of ABA signaling. On the other hand, the triple mutant of pif4 pif5 and ethylene-insensitive ein2 exhibited a stronger delayed senescence phenotype than the ein2 single mutant and pif4 pif5 double mutant, suggesting that EIN2-mediated ethylene signaling and PIF4/PIF5 independently regulate dark-induced leaf senescence. NAC and WRKY TFs are considered to play important roles in the regulation of leaf senescence. In this Research Topic, Doll et al. reported that Arabidopsis WRKY25 acts as a negative regulator of hydrogen peroxide (H2O2)-mediated promotion of leaf senescence. WRKY25 binds to and enhances the activity of the promoter of the WRKY53 gene, which encodes a key TF that promotes leaf senescence; however, WRKY25 directly represses the activity of its own gene promoter. Additionally, Doll et al. showed that MEKK1, a component of the mitogen-activated protein kinase (MAPK) signaling pathway, enhances the ability of WRKY25 to activate the WRKY53 promoter. Thus, WRKY25 and WRKY53 form a highly complex and robust regulatory network to regulate H2O2-mediated promotion of leaf senescence. On the other hand, Gu et al. reported that in cotton (Gossypium hirsutum), GhWRKY91 acts as a negative regulator of leaf senescence. Constitutive expression of GhWRKY91 in Arabidopsis delayed leaf yellowing during natural leaf senescence and under dehydration stress. Furthermore, they demonstrated that GhWRKY91 activates the promoter of GhWRKY17, which is involved in ABA signaling and reactive oxygen species (ROS) production. Compared with NAC and WRKY TFs, roles of other TFs in the regulation of leaf senescence remain unclear. Zhang et al. reported that DEAR4, a DREB/CBF family TF, acts as a positive regulator of leaf senescence in Arabidopsis. Transgenic Arabidopsis plants overexpressing DEAR4 exhibited accelerated leaf yellowing during natural and dark-induced senescence. In addition, they also showed that DEAR4 overexpressing plants were more sensitive to high salinity and drought stresses than wild-type plants, and DEAR4 increased the sensitivity to these environmental stresses probably by enhancing ROS production. On the other hand, Lim et al. identified a novel senescence-associated AP2/ERF family TF in rice, ETHYLENE RESPONSE FACTOR 101 (OsERF101). OsERF101 directly activates the transcription of genes encoding OsNAP and OsMYC2 TFs, both of which activate genes associated with chlorophyll degradation and jasmonate (JA) signaling. A balance between carbon (C) and nitrogen (N) availability is one of the key determinants affecting the progression of leaf senescence. Arabidopsis plants grown under N-deficient conditions with elevated CO2 levels exhibited precocious leaf senescence (Aoyama et al., 2014). Li et al. identified several key components of the C/N-nutrient response including a leucine-rich repeat receptor-like kinase with extracellular malectin-like domain (LMK1) using phosphoproteomics approaches. Further analyses revealed that LMK1 exhibits cell death induction activity in plant leaves. Thus, LMK1 potentially acts as a key regulator of the progression of C/N imbalance-induced leaf senescence. Cytokinin (CK) negatively regulates leaf senescence and enhances tolerance to environmental stresses, such as drought and high salinity. In tobacco, constitutive expression of ISOPENTENYL TRANSFERASE (IPT), which encodes a key CK biosynthetic enzyme, delayed leaf senescence but also caused negative growth phenotypes, such as dwarfism and root growth inhibition (Smart et al., 1991). In this Research Topic, Avni et al. reported that transgenic tobacco plants overexpressing the IPT gene under the control of the stress-inducible promoter of the ArabidopsisMETALLOTHIONEIN gene were tolerant to dehydration and high salinity stresses and showed normal growth and metabolic maintenance. Thus, environmental stress-specific induction of CK biosynthesis is a useful approach for developing plants with improved biomass and yield under environmental stress conditions, and this approach can be applied to various crop species. The phytohormone ABA is closely associated with the drought stress response. In this Research Topic, three studies identified proteins involved in the ABA-dependent drought stress response in Arabidopsis. Baek et al. reported the role of Arabidopsis PR5 receptor-like kinase 2 (AtPR5K2) in the drought stress response. They showed that AtPR5K2 physically interacts with and phosphorylates Type 2C protein phosphatases, ABA-INSENSITIVE 1 (ABI1) and ABI2, which regulate the initiation of ABA signaling. Baek et al. investigated the role of Arabidopsis RPD3-type HISTONE DEACETYLASE 9 (HDA9) in the ABA-dependent drought stress response. HDA9 physically interacts with ABA-INSENSITIVE 4 (ABI4), a key ABA signaling TF, and the results of chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) indicated that the HDA9–ABI4 complex directly represses the expression of CYP707A1 and CYP707A2 genes, which encode ABA catabolic enzymes. On the other hand, a previous study showed that the HDA9–POWERDRESS (PWR) complex participates in the regulation of leaf senescence, flowering time, and floral dormancy. Khan et al. showed that both HDA9 and PWR interact with ABI4, probably forming the PWR–HDA9–ABI4 complex, and repress the expression of genes associated with ABA metabolism and signaling. In conclusion, we believe that studies included within the Research Topic “Regulatory Mechanisms of Leaf Senescence Under Environmental Stress” improve our understanding of the molecular mechanisms of environmental stress-induced leaf senescence. We sincerely appreciate all scientists who kindly allowed us to publish their work in this Research Topic. All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication. YS is supported by a grant from JSPS KAKENHI (grant no. 17H05024). The authors declare that the research was conducted in the absence of any commercial or financial relationship that could be constructed as a potential conflict of interest. We thank Dr. Stefan Hörtensteiner for his support as a guest editor of this Research Topic “Regulatory Mechanisms of Leaf Senescence under Environmental Stresses.” Aoyama, S., Reyes, T. H., Guglielminetti, L., Lu, Y., Morita, Y., Sato, T., et al. (2014). Ubiquitin ligase ATL31 functions in leaf senescence in response to the balance between atmospheric CO2 and nitrogen availability in Arabidopsis. Plant Cell Physiol. 55, 293–305. doi: 10.1093/pcp/pcu002 PubMed Abstract | CrossRef Full Text | Google Scholar Sakuraba, Y., Jeong, J., Kang, M. Y., Kim, J., Paek, N. C., Choi, G. (2014). Phytochrome-interacting transcription factors PIF4 and PIF5 induce leaf senescence in Arabidopsis. Nat. Commun. 5, 4636. doi: 10.1038/ncomms5636 PubMed Abstract | CrossRef Full Text | Google Scholar Sakuraba, Y., Kim, D., Han, S. H., Kim, S. H., Piao, W., Yanagisawa, S., et al. (2020). Multilayered regulation of membrane-bound ONAC054 is essential for abscisic acid-induced leaf senescence in rice. Plant Cell 32, 630–649. doi: 10.1105/tpc.19.00569 PubMed Abstract | CrossRef Full Text | Google Scholar Smart, C. M., Scofield, S. R., Bevan, M. W., Dyer, T. A. (1991). Delayed leaf senescence in tabacco plants transformed with Tmr, a gene for cytokinin production in Agrobacterium. Plant Cell 3, 647–656. doi: 10.1104/tpc.3.7.647 PubMed Abstract | CrossRef Full Text | Google Scholar Woo, H. R., Kim, H. J., Lim, P. O., Nam, H. G. (2019). Leaf Senescence: System and Dynamics Aspects. Annu. Rev. Plant Biol. 70, 347–376. doi: 10.1146/annurev-arplant-050718-095859 PubMed Abstract | CrossRef Full Text | Google Scholar Keywords: leaf senescence, stay green, environmental stress, phytohormones, transcription factors Citation: Sakuraba Y, Li J, Park S and Paek N-C (2020) Editorial: Regulatory Mechanisms of Leaf Senescence Under Environmental Stresses. Front. Plant Sci. 11:1293. doi: 10.3389/fpls.2020.01293 Received: 08 July 2020; Accepted: 07 August 2020; Published: 19 August 2020. Edited by: Reviewed by: Copyright © 2020 Sakuraba, Li, Park and Paek. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Yasuhito Sakuraba, [email protected]
Phillip Mackie, Adithya Gopinath, Leila Saadatpour, Jose Pino, Habibeh Khoshbouei
Published: 1 April 2018
The FASEB Journal, Volume 32, pp 693.4-693.4; https://doi.org/10.1096/fasebj.2018.32.1_supplement.693.4

The publisher has not yet granted permission to display this abstract.
, Gabino Ríos, Tomasz Jacek Sarnowski, , , Jean-Benoit Charron,
Published: 10 January 2020
Frontiers in plant science, Volume 10; https://doi.org/10.3389/fpls.2019.01661

Abstract:
Editorial on the Research Topic New Insights Into Mechanisms of Epigenetic Modifiers in Plant Growth and Development In eukaryotic cells, chromatin, a highly dynamic nucleoprotein complex, plays a critical role in controlling gene expression notably by regulating the interaction between transcription factors and regulatory elements. The structure of the chromatin is determined by epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling. A growing body of evidence indicates that epigenetic regulations are involved in plant adaptation to environmental stresses, and in plant development, including flowering control, fruit and root development, as well as seed maturation and germination. Furthermore, epigenetic mechanisms have the potential to stabilize cell identity and maintain tissue organization. Hence, epigenetic diversity is now emerging as a new source of phenotypic variation to improve adaptation to changing environment and ensure yield and quality of crops. The 14 articles published in this Research Topic highlight recent progresses, opinions, and reviews to advance our knowledge in the role of the epigenome on controlling plant development, plant response to environmental stresses, and plant evolution. For instance, gene duplication and chromatin remodeling contribute to increase the morphological and cellular complexity of plants during their evolution according to Hajheidari et al. Chromatin modifications, including DNA methylation and histone modifications, are critical in regulating gene transcription, and thus may reprogram cell differentiation and development (Inácio et al.; Zhang et al.; Hajheidari et al.). For instance, Inácio et al. immunolocalized various epigenetic marks and correlated epigenomic changes with transcriptional regulation when studying cork formation and quality in cork oak, a genuinely forest-specific process. Furthermore, changes in the acetylation levels of the lysine 9 of the histone H3 (H3K9) and lysine 5 of the histone H4 (H4K5) were found associated with the heat stress-dependent inhibition of lateral root formation in maize (Zhang et al.). Interestingly, whereas a global increase in histone acetylation was observed in response to heat stress, H3K9 and H4K5 acetylation decreased significantly in the promoter region of the haem oxygenase-1 (ZmHO-1) and giberellic acid–stimulated like-1 (ZmGSL-1) genes, two inhibitors of lateral root formation (Zhang et al.). Plant cells have the capability to dedifferentiate in totipotent cells, a prerequisite to asexual embryogenesis. Recent papers support a role of histone deacetylation and DNA methylation in cellular reprogramming leading to callus formation and asexual embryogenesis through the regulation of key developmental genes such as Wuschel (Pasternak and Dudits). In addition to somatic embryogenesis, the epigenome also controls the juvenile-to-adult developmental transition notably by modulating the expression of regulatory genes. Indeed, in Arabidopsis plants, this transition is regulated by miR156/157 and its target-squamosa promoter binding protein-like gene (Xu et al.). Other epigenetic changes controlling the juvenile-to-adult developmental transition include DNA methylation, and histone modification (Xu et al.). Ultimately, these chemical changes lead to a remodeling of the chromatin. The SWI/SNF chromatin remodeling complexes play a central role in this biological process by controlling phytohormone biosynthesis, the establishment and maintenance of meristems, organ development, and floral transition (Ojolo et al.; Maury et al.). Supporting the central role of chromatin remodeling and histone modifications in controlling development of plant, Kang et al. studied the role of the chromatin-remodeling factor inositol auxotrophy 80 and the histone chaperones nap1-related protein 1 and 2 in modulating auxin fluxes and the activity of the inflorescence and root apical meristems. Another interesting study highlights the impact of the epigenome in controlling transcriptional initiation. The single-stranded DNA-binding protein whirly1 promoted the acetylation of H3K9 and repressed the trimethylation of H3K4 to enhance the recruitment of the RNA polymerase II on the wrky53 promoter (Huang et al.). Epigenetic alterations also control the response of plants to environmental stresses including light perception and various abiotic stresses (e.g. salinity, drought, UV-B radiation, temperature, and heavy metal toxicity). As described by Lee et al. the circadian regulation of two proteins of the Sin3-histone deacetylase complex, encoded by SAP30 function-related 1 (AFR1) and AFR2 genes, is critical for the proper regulation of Arabidopsis circadian rhythm. These two proteins directly bind to the circadaian clock associated 1 (CCA1) and pseudo-response regulator 9 (PRR9) promoters in order to locally deacetylate the histone H3 and negatively affect their expression. This is just a first level of the epigenetic regulation of the Arabidopsis circadian clock. Indeed, Hung et al. described a more complex transcriptional regulation of the circadian clock: the recruitment of the lysine-specific demethylase 1 (LSD1)-like 1/2 (LDL1/2) and histone deacetylase 6 (HDA6) proteins by circadian clock associated 1 (CCA1)/late elongated hypocotyl (LHY) is needed to repress the expression of timing of cab expression 1 (TOC1). Acting as a negative feedback regulatory loop, TOC1 also interacts with LDL1/2 and HDA6 proteins to repress the expression of CCA1/LHY. A broader picture of the role of the epigenome on the plant circadian clock is provided in the Du et al. review paper. Environmental stresses also induce the formation of stress-responding agents such as nitric oxide. In soybean, Sun et al. revealed that the de novo deposition of trimethylated histone H3 lysine 27 residue in the promoter and coding sequence of plant genes is needed to repress their transcription in response to salt stress. Mechanistically, Ageeva-Kieferle et al. described in their review the role of nitric oxide as inhibitors of histone deacetylase through the S-nitrosation of selected cysteine residues. Nitric oxide also regulates the epigenome by controlling the expression of genes encoding DNA and histone methyltransferases and demethylases. Taken together, nitric oxide is a chemical agent controlling plant gene activity in response to environmental stresses notably by regulating the activity of various histone acetyltransferases, deacetylases, methyltransferases and demethylases, and DNA methyl transferases and demethylases. This special topic clearly highlights the central role of the epigenome in the regulation of gene expression that influences many plant biological processes such as plant development and plant response to environmental stresses. A deeper analysis of the chromatin remodeling and transcription related mechanisms will be needed to better understand the epigenetic regulation of gene expression. Single cell -omic technologies such as single cell RNA-seq and ATAC-seq will enable further discoveries by capturing the transcriptome and epigenome for each cell composing a complex organ. While single cell RNA-seq was recently applied on Arabidopsis root protoplasts, there is a need to develop plant single cell ATAC-seq technology to gain a more complete picture of the plant cell epigenome. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The work was supported by Youth Innovation Promotion Association, Chinese Academy of Sciences (2017399), Guangdong Natural Science Foundation (2018A030313350), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA13020603), the National Science Centre, Poland UMO-2014/13/B/NZ2/01187, Natural Sciences and Engineering Research Council of Canada (06679), the Chinese University of Hong Kong direct grant for research (#4053383), the National Science Foundation (awards #1854326 and #1339194), the Spanish Ministry of Economy, Industry and Competitiveness-INIA-FEDER (RTA2017-00011-C03-01) and by the Nebraska Research Initiative core facility research grant. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Keywords: epigenetic regulation, plant development, histone modification, chromatin modification, DNA methylation, small RNAs Citation: Luo M, Ríos G, Sarnowski TJ, Zhang S, Mantri N, Charron J-B and Libault M (2020) Editorial: New Insights Into Mechanisms of Epigenetic Modifiers in Plant Growth and Development. Front. Plant Sci. 10:1661. doi: 10.3389/fpls.2019.01661 Received: 30 October 2019; Accepted: 25 November 2019; Published: 10 January 2020. Edited and reviewed by: Jin-Gui Chen, Oak Ridge National Laboratory (DOE), United States Copyright © 2020 Luo, Ríos, Sarnowski, Zhang, Mantri, Charron and Libault. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Ming Luo, [email protected]; Marc Libault, [email protected]
, , Anne-Laure Le Gac, Julien Genitoni, ,
Published: 5 April 2019
Frontiers in plant science, Volume 10; https://doi.org/10.3389/fpls.2019.00395

Abstract:
Plants grow continuously, forming new meristem-derived organs and tissues throughout their post-embryonic life. As sessile organisms, plants need to constantly integrate and reflect environmental fluctuations in their growth and development, which can translate into high level of developmental plasticity in response to environmental changes (Gaillochet and Lohmann, 2015). Alternatively, variable environments can select for robustness, where organisms function across a wide range of conditions with little change in phenotype. Plant growth is then governed by complex interplay of phytohormone signaling, chromatin structure remodeling and gene expression reprogramming. How these regulatory levels are interconnected remains largely enigmatic, but mechanistic evidence of crosstalk between phytohormone signaling and chromatin organization is emerging. Here we review (1) evidences of molecular mechanisms that mediate the crosstalk between phytohormone signaling, chromatin structure and gene expression (2) how this crosstalk may link to plant developmental plasticity and robustness and finally (3) why meristems may represent central places for this crosstalk allowing plasticity and environmental memory. Phytohormone and epigenetic regulation can interact on multiple levels (Figure 1): (1) phytohormone signaling directly affects expression or activity of key chromatin modifiers, (2) chromatin machinery target genes of the phytohormone metabolic/signaling pathways, (3) both players interact on genes involved in developmental or stress responses. Figure 1. Schematic model of phytohormones and chromatin crosstalk during plant developmental plasticity and robustness. Stem cell niches in SAM, RAM, or cambium are center of morphogenesis giving rise to the aerial and root systems or wood formation in perennials and plasticity in response to various environmental cues. Environmental signals are perceived directly or indirectly by meristems and could affect hormonal balance and/or chromatin structure in a complex crosstalk: (1) hormones can alter chromatin structure and modifiers or (2) chromatin can regulate hormones signaling/biosynthesis. These two mechanisms could then interact separately (3 and 4), jointly or successively (5) affecting genes expression and /or TEs mobilization. Thus, the hormone/chromatin crosstalk can participate in developmental choice (Robustness vs. Plasticity) by controlling cell gene identity in meristems, hormone balance integration, or chromatin stabilization of gene expression. While most of these changes are transient (resetting of hormonal and chromatin modifications) allowing the plant to be respond to new environmental conditions, chromatin states could be maintained through cell division allowing an epigenetic memory and a potential priming of new meristem-derived-organs. Several examples show that components of phytohormone signaling pathways directly control the activity of key chromatin modifiers such as POLYCOMB REPRESSIVE COMPLEX (PRC) 1 and 2 with histone-methyltransferase activity playing a major role in transcriptional regulation during development (Bratzel et al., 2010; Chen et al., 2010, 2016; Ikeuchi et al., 2015; Mozgová et al., 2017). For example, the brassinosteroid (BR) signaling TFs BRASSINAZOLE-RESISTANT 1 (BZR1) recruits the H3K27me3-demethylase EARLY FLOWERING (ELF) 6 to antagonize the H3K27me3-activity of PRC2, a chromatin modifier, at the flowering repressor FLOWERING LOCUS C (FLC), preventing precocious floral transition (Yu et al., 2008; Li et al., 2018). Additionally, chromatin complexes can be post-translationally modified by components of phytohormone signaling pathways that influence their activity. For example, abscisic acid (ABA) signaling induces SnRK-mediated phosphorylation of the chromatin remodeling ATPase BRAHMA (BRM), inhibiting its repressive activity at ABA-responsive genes (Peirats-Llobet et al., 2016). These examples demonstrate that activity of chromatin modifiers can be directed to specific loci or directly modulated by phytohormone signaling cascades. Another possibility is that changes in chromatin structure control phytohormone biosynthesis, signaling and response. Variation in DNA methylation in response to water availability in poplar or among Arabidopsis epigenetic recombinant inbred lines (epiRILs) is associated with changes in jasmonic (JA), salicylic acid (SA) and ethylene responses (Latzel et al., 2012; Lafon-Placette et al., 2018). Similarly, rice plants with reduced H3K27me3 exhibit significant differences in the auxin indole-3-acetic acid (IAA), gibberellin (GA), ABA, JA, and SA content (Liu et al., 2016). Nevertheless, these effects may be pleiotropic and may reflect altered general physiological states. As more direct evidence, PRC2 activity in Arabidopsis seed coat is downregulated by fertilization-dependent auxin, and is required for repressing GA production prior to fertilization, mediating the crosstalk between two phytohormonal pathways (Figueiredo et al., 2015, 2016; Figueiredo and Köhler, 2018). PRC2 also represses auxin biosynthesis and signaling genes in the SAM and leaves of Arabidopsis (Lafos et al., 2011). Conversely, in the RAM, the expression of the auxin efflux carrier-encoding PIN-FORMED (PIN) genes is positively regulated by BRM establishing local auxin maxima and stimulating the expression of the RAM-specifying PLETHORA genes PLT1 and PLT2 (Yang et al., 2015). BRM also binds to GA-related genes to stimulate GA biosynthesis and signaling (Archacki et al., 2013). Apart from biosynthesis and signaling, phytohormone-response genes are under direct control of chromatin modifiers. Initially described as involved in auxin homeostasis (Sorin et al., 2005), the ARGONAUTE protein AGO1, guided by small RNAs and associating with SWI/SNF complexes, was recently described to bind genes activated upon JA, auxin, and SA stimuli in Arabidopsis (Liu C. et al., 2018). ABA-responsive genes in Arabidopsis are repressed by histone deacetylation (Perrella et al., 2013) through the action of MULTICOPY SUPRESSOR OF IRA (MSI) 1 recruiting the HISTONE DEACETYLASE (HDA)19 (Alexandre et al., 2009; Mehdi et al., 2016) and also by BRM-mediated chromatin remodeling (Han et al., 2012). Significantly, expression of 80% GA–responsive genes relies on the chromatin remodeler PICKLE (PKL) (Park et al., 2017). Consequently, plants with reduced MSI1, HDA19, or BRM levels are more sensitive to ABA, display ABA-dependent growth defects and higher tolerance to drought, and absence of PKL results in GA-reversible root swelling and embryonic lipid accumulation (Ogas et al., 1997) demonstrating the developmental importance of chromatin modifiers in phytohormone-mediated responses. Hormone signaling and chromatin crosstalk can participate in developmental paths by distinct ways: (1) control of cell identity genes in meristems, (2) chromatin-mediated stabilization of gene expression beyond the hormonal initial signal, (3) chromatin-governed integration of separate hormone signaling pathways. Chromatin-modifying complexes target key phytohormone-regulated genes that specify meristem cell identity and whose ectopic expression can result in cell reprogramming and homeosis (Zuo et al., 2002; Galinha et al., 2007). For example, the SAM-organizing homeobox gene WUSCHEL (WUS) is regulated by cytokinin signaling, DNA methylation, H3K27me, or chromatin remodeling (Kwon, 2005; Dodsworth, 2009; Cao et al., 2015; Liu H. et al., 2018), and loss of DNA methylation in WUS promoter is connected to in-vitro shoot initiation induced by cytokinin (Li et al., 2011). Other stem cell niche-defining TFs such as WOX4, WOX5, PLT1, or PLT2 are potential PRC2 targets (Oh et al., 2008; Lafos et al., 2011). Co-expression of these TFs can be triggered by environmental and hormone cues or ectopically induced in PRC2-depleted plants, resulting in cell reprogramming (Chanvivattana et al., 2004; Barrero et al., 2007; Ikeuchi et al., 2015; Mozgová et al., 2017). Increased or dispersed expression of cell identity-defining TFs and change and/or loss of cell identity also occurs in mutants of chromatin modifiers such as the repressive H2A-ubiquitinase complex PRC1 (Xu and Shen, 2008; Bratzel et al., 2010; Chen et al., 2010, 2016), histone deacetylases HDA6 and HAD19 (Tanaka et al., 2008; Pi et al., 2015), PKL (Ogas et al., 1999) or replication-dependent H3/H4 chaperone CHROMATIN ASSEMBLY COMPLEX (CAF)-1 (Kaya et al., 2001). Thus, chromatin structure appears to restrict expression of developmental genes to retain cell identities. Similarly, repression of ABA response by several chromatin modifiers (MSI1, HDA19, BRM) could act to prevent an ectopic stress response in favorable environmental conditions. Chromatin structure may stabilize gene expression state beyond the duration of the environmental or phytohormone stimulus. An example is the cold-induced establishment of H3K27me3 at FLC during vernalization that is stable through mitosis, providing an in-cis memory system of FLC repression even after transfer to warmth (Berry et al., 2015; Hepworth and Dean, 2015). Persistent H3K4me2/3, H3/H4ac or local nucleosome depletion are found at genes primed for biotic or abiotic stress responses including priming by phytohormones or their analogs (Jaskiewicz et al., 2011; Lämke and Bäurle, 2017; Laura et al., 2018; Liu H. C. et al., 2018) demonstrating that also “accessible” chromatin structure contributes to mitotic memory (Figure 1). Chromatin-modifying proteins may also serve as integrators defining the final outcome of interplay of various hormone signaling pathways. Phytohormone-induced change of chromatin structure may rely on multiple different chromatin modifiers as is exemplified by modulators of ABA signaling. A single chromatin modifier can also be implicated in responses to different hormones, as is exemplified by BRM (Sarnowska et al., 2016). Chromatin can thus provide a robust hub integrating different incoming cues while potentiating the persistence of the gene expression patterns through its stability during mitotic cell divisions. The biological significance of the crosstalk in meristems is supported by (1) their central role in postembryonic morphogenesis, plasticity and memory, (2) their particularities for phytohomone signaling and chromatin remodeling, (3) first evidences reported for this crosstalk in SAM. The meristems represent major sites of stem cell niches in plants (Scheres, 2007; Tucker and Laux, 2007; Aichinger et al., 2012). Apical meristems, together with the secondary meristem, the cambium, have the capacity to maintain and self-renew populations of undifferentiated cells, underlying continuous post-embryonic organ development modulated by environmental conditions (Figure 1; Gaillochet and Lohmann, 2015; Pavlovic and Radotic, 2017; Xiao et al., 2017). The SAM is also the place of epigenetic memory as reported for vernalization and some priming effects (Hepworth and Dean, 2015; Lämke and Bäurle, 2017). Phytohormone and epigenetic pathways play overlapping/complementary roles in meristem functions and developmental plasticity or robustness, laying the basis for a biologically significant crosstalk. Importantly, meristems have been shown to be the place of epigenetic control for stem cell pluripotency, differentiation, and reprogramming (Cao et al., 2015; Gaillochet and Lohmann, 2015; Pi et al., 2015; Morao et al., 2016; Ojolo et al., 2018) whose epigenetic setup may differ from the surrounding tissues (Yadav et al., 2009; Baubec et al., 2014). Major evidence for phytohormone-chromatin crosstalk was obtained using Arabidopsis mutants, or applying phytohormones or chemical inhibitors of chromatin modifiers in various developmental processes (Yamamuro et al., 2016; Campos-Rivero et al., 2017; Wong et al., 2017; Guo et al., 2018; Ojolo et al., 2018; Wakeel et al., 2018; Zheng et al., 2018). Only a few reports highlight potential crosstalk directly in the meristems as exemplified by PRC2 repressing particular PIN genes (auxin transporters) in the SAM of Arabidopsis clv3 mutants (Lafos et al., 2011). Recent studies in vernalized sugar beet (Hébrard et al., 2016) and in poplar under drought or cold exposure (Conde et al., 2017; Lafon-Placette et al., 2018; Le Gac et al., 2018) have recently shown that differentially expressed genes under DNA methylation control in SAM correspond to a limited developmental gene network mainly involved in growth and phytohormone pathways such as jasmonate activators and ethylene repressors. Indeed, Le Gac et al. (2018) show that hormone-related epigenome reprogramming in the SAM of poplar hybrids is stable for at least several months after the stress period in winter-dormant SAM providing evidence of an environmental epigenetic memory. Recently, this phenomenon was also described in the SAM of natural populations of black poplar under drought conditions (Sow et al., 2018a). Similarly, support for epigenetic memory of climatic conditions is found in Norway spruce trees grown from somatic embryos produced at different temperatures (Yakovlev et al., 2011, 2016). Considering the absence of post-embryonic organs, the SAM could play a major role in the transmission of the environmentally-established chromatin states during early development. In conclusion, phytohormone action and chromatin modifiers seem to be tightly interacting but the extent to which they act jointly or independently remains unclear (Ojolo et al., 2018). However, the multi-layered control of local chromatin structure in response to hormonal cues may provide an important hub that integrates the incoming cues, conferring developmental robustness while retaining a sufficient potential for gene transcription change, stabilization and phenotypic plasticity (Lachowiec et al., 2016). Current knowledge leads to the opinion that this crosstalk in meristems can integrate environmental cues for developmental outcome. Erasure of this signaling may allow continuous adjustment to new environmental conditions. Its maintenance through persistent chromatin states can however stimulate mitotic memory that could prime later organ formation. How the balance between erasure and memory is achieved remains enigmatic (Figure 1). While the mechanistic events could be more easily deciphered in well-established model annuals such as Arabidopsis, it is important to establish perennial models where the impact of mitotic epigenetic memory is of importance in the context of climate change. In addition to SAM and RAM, cambium, whose activity is crucial for environmentally controlled wood formation, may be an appropriate and highly relevant model (Wang et al., 2016; Oles et al., 2017; Figure 1). Deciphering this crosstalk in the meristems requires improving single-cell methodologies to study the dynamics of chromatin structure in response to complex phytohormone-associated environmental and developmental responses and its memory. Exploiting epigenetic variation and the potential to derive primed plants from meristem regeneration or somatic embryos (Achour et al., 2017; Gallusci et al., 2017; Springer and Schmitz, 2017; Sow et al., 2018b) seems also promising. SM suggested and designed the opinion article. MDS and SM designed the Figure 1. IM and SM finalized and revised the article. All the authors checked and confirmed the final version of the manuscript. All the authors drafted the entire manuscript. MDS and JG received Ph.D. grants from the Ministère de la Recherche et Enseignement Supérieur and INRA—Région Bretagne, respectively. This work was funded by the ANR France, within the project EPITREE (ANR-17-CE32-0009-01) to SM and by the Czech Science Foundation (GACR 16-08423Y) to IM. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors thank Dr. Nicolas Bouché (INRA Versailles, France) for carefully reading the manuscript before submission. We apologize to all colleagues whose work was not cited due to length limitations. Achour, Z., Archipiano, M., Barneche, F., Baurens, C., Beckert, M., Ben, C., et al. (2017). “Epigenetics in plant breeding,” in Article de positionnement du Groupement d'intérêt scientifique Biotechnologies vertes et de l'Alliance nationale de recherche pour l'environnement. 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Plant Sci. 10:395. doi: 10.3389/fpls.2019.00395 Received: 24 October 2018; Accepted: 14 March 2019; Published: 05 April 2019. Edited by: Reviewed by: Copyright © 2019 Maury, Sow, Le Gac, Genitoni, Lafon-Placette and Mozgova. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Stéphane Maury, [email protected] †Present Address: Iva Mozgova, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czechia
, Céline Masclaux-Daubresse, Yuji Moriyasu, Wim Van Den Ende, Diane C. Bassham
Published: 30 September 2019
Frontiers in plant science, Volume 10; https://doi.org/10.3389/fpls.2019.01190

Abstract:
Editorial on the Research TopicSugars and Autophagy in Plants Sugars perform an important regulatory role in plants. Part of this regulatory role is exerted by the SNF1-related kinase 1 (SnRK1), which acts as an energy sensor. The target of rapamycin (TOR) kinase is a master regulator of cell growth and metabolism and is negatively regulated by SnRK1. Through these kinases, sugars can modulate metabolism according to the energetic status of the cells. Autophagy is an important process by which cells can recycle cellular compounds to generate energy under unfavorable growth conditions. These conditions include carbon or nitrogen deficiency or a wide range of abiotic and biotic stresses. Autophagy also plays a role during leaf senescence, contributing to nitrogen mobilization to seeds. Autophagic degradation of cellular components requires their transport to lytic vacuoles, either through double-membrane vesicles called autophagosomes (macroautophagy) or through direct invagination of the vacuolar membrane (microautophagy). The best-studied type of autophagy is macroautophagy, which requires a conserved set of autophagy-related (ATG) proteins for the formation of autophagosomes and the delivery of cargo. This Research Topic contains articles discussing the role of sugars in plant autophagy and includes one original research paper focused on the comparison of autophagic activity in shoot and roots of the resurrection plant Tripogon loliiformis under desiccation conditions (Asami et al.), one mini-review about the role of sugars in controlling autophagy in plants (Janse van Rensburg et al.), one mini-review on the regulatory pathways underlying plant autophagy (Yang et al.), and two mini-reviews about the degradation of chloroplasts by autophagy (Izumi et al.; Zhuang and Jiang). Asami et al. show that autophagy can be differentially regulated in different organs of the same plant subjected to the same conditions. In particular, they showed that unlike in shoot, autophagy is not activated in roots of T. loliiformis during dehydration (Asami et al.). Part of this difference was attributed to the fact that roots accumulate much more sucrose and T6P, which at high levels inhibit autophagy, via SWEET sugar transporters. Thus, this work demonstrates the importance of analyzing autophagy in different organs before drawing general conclusions. The mini-review from Janse van Rensburg et al. highlights the relevance of the cell wall invertases, which convert sucrose into glucose and fructose extracellularly, where the produced glucose can interact with Regulator of G-protein (RGS1) to induce autophagy by a still-uncharacterized mechanism. The authors propose that autophagy is induced by SnRK1 under sugar starvation and by RGS1 under sugar excess. Besides the control of autophagy by sugars, the authors also mention the role of autophagy in regulating sugar homeostasis (Janse van Rensburg et al.), in which the selective degradation of chloroplasts or chloroplast components by autophagy plays a major role (Izumi et al.; Zhuang and Jiang). Multiple pathways contribute to the degradation of chloroplast components by autophagy (Izumi et al.; Zhuang and Jiang), including the formation of rubisco-containing bodies (RCBs), which allow degradation of stromal proteins; ATG8-interacting (ATI) bodies, which transport chloroplast components interacting with ATG8; the transport of small starch granule-like structures (SSGLs); and the transport of entire chloroplasts, all of them being autophagy machinery-dependent (Izumi et al.; Zhuang and Jiang). Additionally, Izumi et al. discuss the contribution of chloroplast degradation to increasing levels of free amino acids, which are used by mitochondria as respiratory substrates. Zhuang and Jiang present a table of putative ATG8-interacting motif (AIM)–containing proteins and their potential role in recognition by the autophagy machinery to target the degradation of chloroplasts. The mini-review presented by Yang et al. assesses recent findings on the regulatory pathways underlying plant autophagy at transcriptional, post-transcriptional, and post-translational levels. They mention that some transcription factors are subjected to feedback regulation, in which autophagy is activated by these transcription factors, which are in turn degraded by autophagy (Yang et al.). They also discuss the role of the histone deacetylase 9 (HDA9) in suppressing ATG9 gene expression and the importance of phosphorylation, ubiquitination, and lipidation of ATG proteins in the control of their activity (Yang et al.). Over the past few years, significant progress has been made in our understanding of autophagy in plants, its regulation, and the involvement of sugars as signaling molecules in this process. It is clear that there are still many outstanding questions that need to be resolved in the future. Some of the challenges arising from this research topic are: the identification of novel regulators of plant autophagy (Yang et al.); understanding how G-protein signaling promotes autophagy (Janse van Rensburg et al.); the identification of chlorophagy receptors (Zhuang and Jiang); deciphering how chloroplasts interact with the autophagy machinery (Izumi et al.); and the identification of intermediate structures during chlorophagy (Zhuang and Jiang). SS prepared the first draft of this editorial. DB and SS revised the editorial. SS, CMD, YM, WVdE and DCB approved it for publication. DB is supported by grants from the National Institutes of Health (1R01GM120316-01A1) and the National Science Foundation (MCB-1714996). WE is supported by funding from FWO Vlaanderen. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. SS is thankful to the Uruguayan National System of Researchers (SNI, Uruguay). Keywords: ATG, SnRK1, chlorophagy, TOR, RGS1 Citation: Signorelli S, Masclaux-Daubresse C, Moriyasu Y, Van den Ende W and Bassham DC (2019) Editorial: Sugars and Autophagy in Plants. Front. Plant Sci. 10:1190. doi: 10.3389/fpls.2019.01190 Received: 23 August 2019; Accepted: 29 August 2019; Published: 30 September 2019. Edited and reviewed by: Liwen Jiang, The Chinese University of Hong Kong, China Copyright © 2019 Signorelli, Masclaux-Daubresse, Moriyasu, Van den Ende and Bassham. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Santiago Signorelli, [email protected]
, Amy H. Kao, Aida Aydemir, Joan T. Merrill
Published: 11 November 2020
Frontiers in Immunology, Volume 11; https://doi.org/10.3389/fimmu.2020.592639

Abstract:
A Commentary onSystematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated DisordersBy Kaegi C, Steiner UC, Wuest B, et al. (2020). Front Immunol. 11:433. doi: 10.3389/fimmu.2020.00433 We read with interest the systematic review article published in Frontiers in Immunology by Kaegi and colleagues, which analyzed information from studies of atacicept across several immune-mediated disorders. Whilst we welcome the effort the authors have made in collating studies of atacicept in different therapy areas, especially the benefit for clinicians and researchers in the field, we have identified several inconsistencies, errors, omissions, and critical flaws in the reporting and interpretation of efficacy and safety. Here, we have highlighted some of the methodological and factual errors in the review (summarized in detail in Table 1) to provide essential balance and context. This response was supported by Merck KGaA, Darmstadt, Germany, who are developing atacicept. Table 1 Details of missing, misleading and incorrect information in the Kaegi et al. systematic review article. The authors identified 10 studies of atacicept in multiple sclerosis (MS), optic neuritis (ON), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) suitable for inclusion in their systematic review. The search period was short, from October 2016 to July 2018, and key publications from 2019 were not included. It was claimed that only studies with a minimum number of patients to show a relevant treatment effect were eligible, however, 3 of the 10 studies included were not powered to show clinical treatment effect (1–3) and a further 2 studies did not reach the sample size required for a full evaluation (4, 5). The review was said to be guided by the PRISMA checklist, but there is incomplete or incorrect information provided to meet PRISMA requirements (Table 1). For example, the risk of bias across studies is not assessed and treatment effect measures are not reported in the text. These details are essential for readers to interpret the results correctly. Four SLE studies were included without discussion of the challenging nature of using clinical outcome composite endpoints in this setting, which can result in apparently conflicting results. For example, the primary endpoint in the TULIP-1 trial of anifrolumab using SLE Responder Index-4 was not met (14), whereas the TULIP-2 trial which used the British Isles Lupus Assessment Group-based Combined Lupus Assessment did meet its primary endpoint (15). The atacicept flare prevention trial (APRIL-SLE) provided a novel approach including patients who had recently had a lupus flare that was controlled by a relatively short course of glucocorticoids, but this was not mentioned in the review (12). The analysis of the ADDRESS II primary endpoint focuses on statistical significance, which is misleading as a trend was observed in the 150 mg group (13). SLE is a clinically heterogenous disease and so it is important to identify specific cohorts of patients who may respond to a treatment; the beneficial effect of atacicept in a predefined subpopulation of ADDRESS II patients with high disease activity (HDA, SLEDAI-2K ≥10) (7, 13) was not discussed in the review article. Inaccuracies are also evident in the reporting of efficacy data relating to MS and RA trials for atacicept, as summarized in Table 1. Safety data are reported out of context or with insufficient detail (Table 1). A large safety analysis of atacicept, comprising 17 clinical studies of 1568 subjects and including 761 SLE patients, was not included or discussed (6). The safety profile and number of reported deaths in atacicept studies were found to be comparable with that of other biologic therapies, including belimumab and blisibimod for SLE, but this context was not given in the review article (6, 16–18). Data for atacicept across all studies show that infections and infestations are the most commonly reported treatment-emergent adverse event (45.6%) (6). This is not unexpected since atacicept reduces immunoglobulin levels and B and plasma cell numbers, and is consistent with other biologic agents used to treat autoimmune diseases (6, 19). Overall, atacicept is associated with increased infection rates compared with placebo, however, serious and severe infections are not higher with atacicept in patients with SLE, RA or ON (6). The authors correctly report that two infection-related deaths occurred in the 150 mg arm of the APRIL-SLE trial, but this led to discontinuation of the 150 mg arm only, not the whole trial as stated (12). Unfortunately, many trials in SLE record a small number of deaths. The APRIL-LN study in SLE was stopped with six patients enrolled due to a decline in serum IgG and the occurrence of serious infections (4). On further analysis the decline in IgG levels was linked to the mycophenolate prescribed prior to the addition of atacicept. A risk mitigation strategy was implemented for subsequent studies; in the Phase II ADDRESS II study of over 300 SLE patients, infection rates were lower and no deaths associated with atacicept were reported (13). Therefore, with the implementation of effective mitigation measures to reduce the risk of infection, the benefit of atacicept for SLE patients with HDA may outweigh the risks (6). It is imperative that this is highlighted in the review article. Kaegi et al. conclude that atacicept failed to show superior effect on disease activity in comparison to placebo in MS, ON, RA and SLE without inclusion of all relevant data, especially in the case of SLE, or full acknowledgement of the limitations of the review. In fact, in all studies, atacicept did show an effect on disease activity (as indicated by a reduction in biomarkers) but this was not always translated to measurable clinical efficacy over placebo (standard of care). In the Phase II trials in RA, while the efficacy endpoint was not met, the safety profile was acceptable. MS and ON studies were discontinued due to increased disease activity. However, SLE published data indicate that atacicept is beneficial for SLE patients with HDA, which is the target population for future SLE trials with atacicept. This offers some hope of positive clinical outcome in a field notorious for the number of failed trials. Future studies will further assess and confirm clinical efficacy of atacicept in SLE. It is therefore misleading to state that on this basis atacicept was not approved in these therapeutic areas when the drug has never been submitted for approval. Clinical investigation of atacicept continues in SLE and IgA nephropathy. All authors contributed to the article and approved the submitted version. All authors agree to be accountable for this article. The development of this article included medical writing support, provided by Bioscript Science, Macclesfield, UK and funded by Merck KGaA, Darmstadt, Germany. DAI has received consultant fees from EMD Serono Research and Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany), Celgene, AstraZeneca and Servier; consulting fees have been passed to a local arthritis charity. JTM has received grants/research support from GSK and BMS (investigator-initiated studies); consultant or data quality management fees from EMD Serono Research and Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany), Eli Lilly, Remegen, GSK, UCB, Celgene, Abbvie, Amgen, Daitchi Sankyo, Astellas, Pfizer, Genentech, AstraZeneca, Jannsen, Servier, ILTOO and Xencor. AK and AA are employees of EMD Serono Research and Development Institute, Inc. (an affiliate of Merck KGaA, Darmstadt, Germany). Merck KGaA sponsored the clinical development of atacicept and were involved in study design, collection, analysis, interpretation of data, the writing of this article and the decision to submit it for publication. Bioscript Science, Macclesfield, UK provided medical writing support, funded by Merck KGaA, Darmstadt, Germany. We thank the patients and study teams involved in the clinical trials of atacicept. 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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: David A. Isenberg, [email protected]
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