Whether serum uric acid (UA) is associated with all-cause mortality in patients with acute coronary syndrome (ACS) following percutaneous coronary intervention (PCI) remains unclear.  We performed a retrospective cohort study of 2296 patients with ACS. Curve-fitting and Cox proportional-hazard regression models with a hazard ratio (HR) and 95% confidence interval (CI) were used. n = 566) and the low-UA group (n = 1730)] based on the serum UA threshold value (5.6 mg/dl) identified through curve fitting. Fifty-three (9.36%) patients died in the high-UA group, and 115 (6.65%) patients died in the low-UA group. The difference between groups was statistically significant (P = 0.031). Univariate analysis showed that the risk of all-cause mortality in the high-UA group was significantly greater than that in the low-UA group . This difference persisted after adjustment for baseline characteristics, medical history, and medication history .  During a mean follow-up of 246.31 ± 49.16 days, 168 (7.32%) patients died from all causes. Patients were divided into two groups [the high-UA group ( Our study demonstrated that elevated serum UA (>5.6 mg/dl) is associated with all-cause mortality in ASC patients after PCI. Coronary heart disease (CHD) is caused by atherosclerosis accompanied by stenosis or lumen obstruction, resulting in myocardial ischemia, hypoxia, and necrosis –3. As thP = 0.013)  depending on their level of serum UA  through curve fitting and ROC.Results are presented as a number (percent) for categorical variables and as the mean ± SD for continuous variables. Categorical variables were compared using the chi-square test, and between-group comparisons of continuous variables were done using the unpaired Student's .6 mg/dl . In addi.6 mg/dl . FinallyWe also performed univariate and multivariate logistic regression analyses to estimate all-cause mortality between the two groups. In multivariate logistic regression analysis, demographic and clinical factors, including age, sex, BMI, SBP, DBP, heart rate, serum creatinine, total bilirubin, total cholesterol, triglyceride, HDL, LDL, LVEF, medical history, and medication history, were adjusted to obtain accurate results. Additionally, a Cox proportional-hazard regression model was used to explore the association between baseline serum uric acid levels and all-cause mortality. A hazard ratio (HR) with a 95% confidence interval (CI) was used to estimate the results.Considering the differences in serum UA levels between sex and different diseases, we further conducted a subgroup analysis to explore the relationship between serum UA levels and all-cause mortality based on sex, history of heart failure, history of atrial fibrillation, history of stroke, history of PCI, history of hypertension, history of diabetes, and smoking.P value < 0.05 considered to be statistically significant. Data analysis was performed using IBM SPSS Statistics for Windows, version 21.0 , R statistical software version 3.3.2 (available at: http://www.r-project.org), and EmpowerStats (http://www.empowerstats.com).All reported probability values were 2-sided with a n = 566) and the low-UA group (n = 1730)] according to the level of serum UA  . However, the high-UA group had higher serum creatinine and triglycerides and a lower prevalence of diabetes compared with the low-UA group (P < 0.05). In addition, the proportion of females in the low-UA group was higher than that in the high-UA group (35.84% vs. 20.85%).From February 2013 to January 2016, 2296 ACS patients who had undergone PCI were consecutively enrolled in the study. During a mean follow-up of 246.31 ± 49.16 days, 168 (7.32%) patients died from all causes. Through curve fitting and the result of ROC, all patients were divided into two groups [the high-UA group (P = 0.031).During a mean follow-up of 246.31 ± 49.16 days, 168 (7.32%) patients died from all causes. Fifty-three (9.36%) of these patients were in the high-UA group, and 115 (6.65%) were in the low-UA group. The difference in all-cause mortality rates was statistically significant between the groups , age , history of heart failure , history of atrial fibrillation , history of diabetes , serum creatinine , and baseline serum UA  to be significantly associated with all-cause mortality . When poFor a mean follow-up of 246.31 ± 49.16 days, the results using the Cox regression model are shown in In subgroup analysis, we found that serum UA levels are associated with all-cause mortality in ACS patients after PCI, regardless of male  or female . Besides, subgroup analysis also illuminated that patients with a history of hypertension heart failure , atrial fibrillation , and diabetes  will have a higher risk of all-cause mortality .Patients with ACS often suffer from an increased risk of all-cause mortality and reduced survival time after PCI. Previous studies have found that the risk of all-cause mortality in patients with ACS was 20.34% within one year after PCI . TherefoIn this retrospective cohort study, our data reveal that patients with a higher level of UA at baseline  had a higher risk of all-cause mortality compared to patients with a lower level of UA. Similar results were attained when potentially confounding factors  were adjusted using multivariate logistic regression analysis and Cox proportional-hazard regression model , which means that the UA level might be used to better stratify cardiovascular risk in clinical practice. To the best of our knowledge, this retrospective cohort study of 2296 patients is the first to evaluate the association between baseline serum UA levels and all-cause mortality in a Chinese population of ACS patients after PCI.Our results suggest that as the UA level increases, the incidence of all-cause mortality also increases. This means that there is a positive correlation between the level of UA and all-cause mortality in ACS patients after PCI. This finding is very important for patients, the social health care system, and the National Health and Family Planning Commission and warrants more attention and support. Early intervention and management in order to reduce risk is important to improve the prognosis of these patients in the long term.P < 0.05) [In recent years, it has gradually been found that UA is a risk factor for many diseases, such as dementia , hyperte < 0.05) . ConsistThe exact mechanisms to explain the relationship between uric acid and all-cause mortality are as follows. Some scholars suggest that high UA levels promote the occurrence and development of atherosclerosis –40. It iPrevious studies have showed that elevated uric acid levels appear to significantly increase the risk of all-cause mortality in men, but not in women, which is inconsistent with our results . The posOur study has several strengths. First, to the best of our knowledge, this is the first study to evaluate the association between baseline serum UA and all-cause mortality in ACS patients after PCI. The implication for clinical practice is that taking appropriate measures to reduce UA levels may significantly reduce all-cause mortality in these patients. Serum UA levels are part of the routine examinations of inpatients and can easily be addressed using sodium bicarbonate, which is low cost. Second, the threshold value for serum UA levels (5.6 mg/dl) was determined through curve fitting, which better represents the real-world situation compared to the traditional grouping method. Finally, although this was a retrospective cohort study, we performed a multivariate logistic regression analysis to minimize residual confounding, including adjustment for demographic and clinical factors.Our study also has several limitations. First, as a retrospective cohort study, there is inevitably some confounding bias, such as selection bias and retrospect bias. Second, this research is a single-center study in a Chinese population. Further studies are needed to confirm whether these results are applicable in other areas and, especially, other populations. Finally, some previous baseline data were not available. For example, data regarding the degree of coronary artery disease stenosis, type of stent implantation, and the number of implanted stents were not available.Our study demonstrated that elevated serum UA (>5.6 mg/dl) is associated with all-cause mortality in ASC patients after PCI. However, more studies are needed to confirm this finding.


Brassinosteroids (BRs) are a class of phytohormones, which regulate various processes during plant life cycle. Intensive studies conducted with genetic, physiological and molecular approaches allowed identification of various components participating in the BR signaling—from the ligand perception, through cytoplasmic signal transduction, up to the BR-dependent gene expression, which is regulated by transcription factors and chromatin modifying enzymes. The identification of new components of the BR signaling is an ongoing process, however an emerging view of the BR signalosome indicates that this process is interconnected at various stages with other metabolic pathways. The signaling crosstalk is mediated by the BR signaling proteins, which function as components of the transmembrane BR receptor, by a cytoplasmic kinase playing a role of the major negative regulator of the BR signaling, and by the transcription factors, which regulate the BR-dependent gene expression and form a complicated regulatory system. This molecular network of interdependencies allows a balance in homeostasis of various phytohormones to be maintained. Moreover, the components of the BR signalosome interact with factors regulating plant reactions to environmental cues and stress conditions. This intricate network of interactions enables a rapid adaptation of plant metabolism to constantly changing environmental conditions. Plants as sessile organisms, in order to adapt to the constantly changing environment and react to stress conditions, have evolved very effective molecular mechanisms, which allow rapid and adequate alteration in metabolic and physiological processes . RegulatArabidopsis thaliana , allowed various components of the BR signalosome to be identified and characterized functionally [Studies conducted for the last three decades with the genetic, biochemical, physiological and molecular approaches, carried out mostly in the model plant species tionally . The numtionally . A compltionally ,9. Curretionally ,11,12,13tionally ,15.Arabidopsis Shaggy-like Kinases (ASKs). Several of the genes are redundantly involved in the BR signaling [BRI1 gene, what constitutes a negative feedback mechanism [The BR ligand is perceived by the transmembrane receptor kinase Brassinosteroid-Insensitive1 (BRI1). The ligand perception triggers numerous phosphorylations in various domains of the receptor, which lead to activation of the kinase domain ,16,17. Tignaling ,30,31,32ignaling . The actignaling ,35. The ignaling ,36,37,38ignaling . Interesechanism . BZR1 anechanism ,42,43. Bechanism ,45. NoteHowever, the identification of new components of the BR signaling is an ongoing process. The current model of the BR signaling regulation is depicted in BRI1 gene is under developmental, organ-specific and diurnal regulation [BRI1 gene [Expression of the gulation . It is kRI1 gene , whereasRI1 gene ,49. At lRI1 gene . InteresRI1 gene . InteracRI1 gene ,53, whatRI1 gene . Note thBKI1 gene expression by a feedback regulation [In the absence of BR, the BRI1 receptor is kept in its basal state by several mechanisms, which include auto-inhibitory effect of its C-terminal domain, autophosphorylation on Thr-872 in its kinase domain, and interaction with the BRI1 Kinase Inhibitor (BKI1) ,56,57,58gulation .The BR-activated signaling needs to be attenuated in a feedback mechanism to ensure hormonal homeostasis. The feedback regulation is mediated by the PP2A phosphatase, which dephosphorylates the activated BRI1 receptor . A recenAP-2 gene mutants indicated that an impairment of the BRI1 endocytosis enhances the BR signaling. It indicated that the clathrin-mediated endocytosis is a negative regulator of the BR signaling [It was recently reported that the BRI1 receptor carries polyubiquitin chains on several lysine residues located in the cytoplasmic part of the protein. The polyubiquitin chains are organized through ubiquitin moieties linked by their lysine-63 residues and enhance a proteasome-independent BRI1 degradation. Expression of the non-ubiquitinatable, mutated version of the BRI1 receptor leads to an increase in the plasma membrane pool of the protein, and eventually to the BR hypersensitivity. Hence, it indicates that the cell surface is the primary site of the BR signaling initiation . Activitignaling ,74 , what enables the cGMP-dependent signaling . cGMP is2+ concentration, what initiates the Ca2+ signaling cascade [2+ concentration, which mediate cellular responses. Binding of Ca2+ to CaM induces its conformational changes, which enable interacting with target proteins resulting in alteration of their activities [2+-dependent binding of the CaM protein to the kinase domain of BRI1 represses auto- and transphosphorylation activity of this kinase. It is suggested that the interaction between CaM and BRI1 constitutes a link, which connects the BR and Ca2+ signal transduction pathways [2+-induced and CaM-mediated suppression of the BRI1 phosphorylation activity may ultimately attenuate the BR signaling in a negative feedback manner [2+ signaling pathways appears to be more complex, as it was reported that one of the enzymes involved in the BR biosynthesis (DWARF1) is activated by CaM, what indicated that the cytosolic Ca2+ concentration may influence the BR homeostasis [It was reported that the BR ligand perception by the receptor complex causes an immediate increase in the cytosolic Ca cascade . Calmodutivities ,88. Intepathways . Thus, tk manner . Howevereostasis   protein, which interacts with BRI1 in a BR-independent manner . TWD1 isignaling . Howeverlization . It is slization ,94. Therlization . Intereslization .N-ethyl-maleimide sensitive factor adaptor protein receptor (SNAREs) domain-containing proteins. The SNARE proteins are known to participate in vesicle-associated membrane fusion. Overexpression of the AtBS14b caused insensitivity to exogenously applied BRs. AtBS14b directly interacts with the Membrane Steroid-Binding Protein1 (MSBP1) at vesicular compartments, but not with BRI1 or BAK1 [AtBS14b gene is down-regulated by BR in the BRI1-mediated process. AtBS14b acts via interacting with MSBP1 in the trans-Golgi network to enhance transport of MSBP1 to plasma membrane and its interaction with BAK1 [The BR signaling is also regulated by a mechanism, which involves the AtBS14b protein belonging to the family of  or BAK1 . The MSB or BAK1 . Interes or BAK1 . Transcrith BAK1   [BSK genes displays a specific expression pattern at various stages of development. Moreover, BSKs compete among themselves for the interaction with BRI1, however they differ in their signaling capability [Recently, another mechanism of the BR signaling regulation has been described. The BSK kinases, apart from the kinase domain, contain a C-terminal tetratricopeptide repeat (TPR) domain, which functions as a phosphorylation-dependent autoregulatory domain to control the BSK activity. Function of the BSK proteins is conserved in Arabidopsis and rice ( sativa) . In Arabpability . The BRIpability  , which contain the Kelch-like repeat domains ,104. It The major negative regulator of the BR signaling, the BIN2 kinase, belongs to the family of Arabidopsis Shaggy/GSK3-like kinases (AtSKs), which consists of ten members. These kinases play diverse roles in the regulation of plant growth, stress responses, flowering and stomatal development ,108,109.HDA6 gene. Surprisingly, a physical interaction between HDA6 and one of the major transcription factors, which regulate the BR-dependent gene expression, BES1, has also been reported, what suggests that HDA6 may modulate the BES1 activity, however a detailed mechanism is currently not known [kink suppressed in bzr1-1D), which is an E3 ubiquitin ligase, mediates a BR-induced ubiquitination and degradation of the BIN2 kinase, thus it is a positive regulator of the BR signaling. KIB1 directly interacts with BIN2 in a BR-dependent manner. The negative effect of KIB1 on BIN2 relies on dual mechanism, which involves preventing BIN2 from interaction with its substrate (BZR1) and subsequent ubiquitination of the BIN2 kinase, which results in its proteasomal degradation. As a consequence, it leads to accumulation of unphosphorylated, active form of BZR1. It is currently suggested that the BR-induced BIN2 inactivation proceeds in two steps: the BR signaling leads to an initial, partial inactivation of BIN2 via BSU1-mediated dephosphorylation, which is followed by the KIB1-mediated ubiquitination and ultimate degradation [Another mechanism of the BIN2 kinase activity regulation has been recently reported. Histone deacetylase HDA6 interacts with and deacetylates BIN2, what results in repression of its kinase activity. Therefore, HDA6 is a positive regulator of the BR signaling. Moreover, the amino acid residue, lys-189, was identified as the BIN2 acetylation site, which is deacetylated by HDA6 to impact the BIN2 activity. Acetylation neutralizes positive charge of the lys-189 side chain, which results in a decrease in phospho-binding by BIN2. Despite the direct interaction, BIN2 does not phosphorylate the HDA6 deacetylase. Interestingly, glucose may influence the BIN2 acetylation level, what suggests a regulatory connection to a cellular energy status. In this model, the acetylated form of BIN2 is more efficient in suppressing the BR signal transduction. Under the low energy conditions HDA6 is activated to deacetylate and thus inhibit the BIN2 kinase, what eventually results in the BR signaling stimulation. As a feedback mechanism, the BR signaling represses transcription of the ot known  , which is specifically expressed in phloem , directlSorghum bicolor) a new component of the BR signaling has been identified. Protein product of the dwarfing gene (DW1) interacts with the BIN2 kinase and inhibits its nuclear localization, therefore DW1 functions as a positive regulator of the BR signaling. Comparative genomic analysis indicated that DW1 evolved in the land plant lineage after the divergence from chlorophyte. It is suggested that emergence of DW1 enabled plants to modulate the BR signaling through the BIN2 inactivation [Activity of the BIN2 kinase is also regulated by Heat Shock Protein 90 (HSP90) . Heat Shtivation   gene in a BR-dependent manner, and the MYBL2 protein, a transcription repressor, interacts with BES1 to co-operatively suppress the BR-inhibited gene expression. The inhibition of the BR-repressed gene expression is crucial for optimal BR response, therefore MYBL2 is a positive regulator of the BR signaling. However, BRs induce degradation of MYBL2 in a proteasome-mediated mechanism [Apart from the above-mentioned effect on the two major transcription factors which mediate the BR-dependent gene expression, BZR1 and BES1, BIN2 was reported to regulate stability and activity of many signaling components involved in the BR and other signaling pathways ,122,123.echanism . Both trechanism ,126. Theechanism   [BSS1/BOP1 gene encodes a protein with ankyrin repeats, which regulates leaf development. The BSS1/BOP1 protein interacts with the BZR1 and BES1 transcription factors to form a cytosolic complex. Thus, the BSS1/BOP1 complex inhibits the BZR1 transport from the cytosol to the nucleus, and consequently negatively regulates the BR signaling. The protein complex is dissolved by the BR treatment, which enables the BZR1 transport to the nucleus. Moreover, the BSS1/BOP1 gene expression is decreased by BR [The BZR1 and BES1 transcription factors constitute a core of the complicated network, which coordinately regulates the BR-dependent gene expression . The com D (FLD) . BZR1 in D (FLD) . Recentled by BR  , which oxidizes BZR1. The BR-activated and BRI1-mediated signaling stimulates accumulation of H2O2 to induce the BZR1 oxidation, and the H2O2 accumulation is required for the BR-dependent cell division and elongation. The H2O2-mediated oxidation results in enhanced transcriptional activity of BZR1 and promotes interaction of BZR1 with key regulators of auxin and light signaling pathways. The H2O2-dependent regulation affects expression of genes involved in several BR-related processes. Thus, BR and H2O2 control the BZR1 activity through distinct mechanisms, which involve nuclear localization/DNA binding and interaction with other factors, respectively [Hordeum vulgare) that BR-insensitive mutants contain significantly lower concentrations of glutathione under the control conditions. Therefore, it was postulated that BR sensitivity is required for normal accumulation of this non-enzymatic antioxidant [It was recently reported that function of the BZR1 factor is positively regulated by hydrogen peroxide  kinase. TOR is an evolutionarily conserved regulator, which integrates nutrient and energy signaling to modulate plant growth. TOR plays a pivotal role in sugar-induced plant growth in the dark, and inhibition of TOR activity leads to plant growth repression and decreased expression of the BR-responsive genes. Thus, the TOR-mediated sugar signaling promotes plant growth through activation of the BR signaling and the BZR1 accumulation, whereas starvation induces the BZR1 protein degradation. This mechanism allows a balance between plant growth and carbon availability to be maintained .Arabidopsis thaliana (SINAT) [Apart from the modifications of the BZR1/BES1 activity, phosphorylation status and the cytoplasm-nucleus shuttling, stability of these transcription factors is an important aspect in regulation of the BR signaling output. The recent years have witnessed a significant progress in elucidating the molecular mechanisms of the BZR1/BES1 stability regulation . Protein (SINAT) ,136,137. (SINAT) . The E3  (SINAT) . The E3  (SINAT) . COP1 an (SINAT) ,137. The (SINAT) . It is s (SINAT)   to be synergistically regulated. Moreover, the AGB1-BES1 interaction alters the BES1 phosphorylation status, which results in accumulation of dephosphorylated/active BES1 in the nucleus. Interestingly, AGB1 promotes proteasomal degradation of the phosphorylated form of BES1 [Recently, a mechanism of molecular regulation of the BR signaling by the signal transduction pathway, which is mediated by the heterotrimeric guanine nucleotide-binding protein (G-protein), to cooperatively regulate cell division and elongation has been proposed . G-prote of BES1 . AGB1 in of BES1 , what ma of BES1 . Another of BES1 . The UVR of BES1 . The UVR of BES1 . The UV- of BES1 ,143  antagonize each other at the protein level in regulating cell elongation. PRE1 (and ILI1) function as non-DNA binding HLH transcription factors that specifically suppress activity of IBH1. Therefore, BRs exert a double inhibitory effect on IBH1 at the transcript and protein level. This indicates that a conserved mechanism of BR-dependent regulation of plant development has evolved, which functions through the pairs of antagonizing HLH/bHLH transcription factors, which act downstream of BZR1. Moreover, members of the PRE1/ILI1 group of transcription factors integrate multiple signaling pathways, which regulate plant development [ATBS1-Interacting Factor 2 (AIF2) gene. The AIF2 gene encodes the atypical bHLH transcription factor, which has suppressive effect on plant growth and specifically interacts with and is phosphorylated by the BIN2 kinase [A similar mechanism has been described for another transcription factors participating in the BR signaling. The above-mentioned PRE1 protein and its rice homolog Increased Lamina Inclination1 (ILI1) may inactivate inhibitory bHLH transcription factors through heterodimerization . Memberselopment . The nonelopment ,153. PREelopment . The trielopment . Another2 kinase . Previou2 kinase . BRs ind2 kinase   histone methyltransferase, which mediates the H3K36 di- and trimethylation, what enables modulating the BR-dependent gene expression . A positpression . Howeverpression . BZR1 inet genes . The intet genes . Intereset genes   and hydrogen peroxide, as well as increased expression of the cell death-regulating genes. Interestingly, the transgenic plant showed growth abnormalities despite of the enhanced BR sensitivity, due to occurrence of spontaneous cell death. Phenotype of the BAK1-overexpressing plant indicated that it results from a constitutive activation of the SA-regulated defense response [It is known that the BR signaling antagonizes the pathogen-triggered responses ,173. Comresponse . It was response ,174,175.response ,181,182.response . It shouresponse ,185. Intresponse . Activitresponse ,188. BIKresponse . Note thresponse . It was response ,191. Intresponse ,193. It response . It is kresponse ,195. Actresponse . The BSKresponse . BSK1 seresponse ,195  BIN2 gene promotes plant tolerance to drought and salt stress. It is known that expression of various representatives of the GSK3 family is stimulated by stress conditions. Interestingly, the soybean BIN2 gene was overexpressed in Arabidopsis and led to the enhanced stress tolerance, indicating an evolutionarily conserved mechanism. Importantly, the BIN2 overexpression caused up-regulation of the major drought-response gene, RD29, even in the absence of stress conditions [The BIN2 kinase and the PP2A phosphatase have recently been implicated in phosphorylation/dephosphorylation-mediated regulation of the ABA-responsive Kinase Substrates , which belong to bHLH transcription factors. It is known that ABA induces phosphorylation of the AKS transcription factors . When unnditions   gene, which encodes an enzymes involved in the GA biosynthesis, to regulate its transcription [GA20ox-2 and GA3ox-2 genes, encoding the GA biosynthetic enzymes, and promoter of the GA2ox-3 gene, which encodes an enzyme involved in the GA catabolism, to induce the GA biosynthesis but suppress the GA inactivation, what eventually results in stimulation of cell growth [The BZR1 and BES1 transcription factors play a critical role in a crosstalk between the BR and gibberellic acid (GA) signaling pathways, and the BZR1/BES1-mediated inter-hormonal interplay occurs via direct protein-DNA and protein-protein interactions ,209. It cription . In ricel growth . Apart fl growth ,213,214.l growth ,213. In l growth . DELLAs l growth   gene, which encodes an enzyme involved in the BR degradation. Interestingly, the BZR1 and ARF7 transcription factors compete with each other during binding to a common motif in the BAS1 promoter and their interaction mutually decreases their DNA-binding capacity [SAUR19 genes was enhanced in lines expressing a constitutively active form of BZR1 [SAUR19 genes is regulated by both GA and BR signaling pathways [SAUR19 genes are repressed by Suppressor of Phytochrome B4-#3 (SOB3) and light, but were found to be induced by auxin. SOB3 is also known to repress expression of genes regulating the auxin biosynthesis [SAUR19 gene expression [Although synergistic physiological effects of auxin and BRs has been known for a long time, the underlying mechanisms have become elucidated only recently. BR and auxin have similar effect on expression of numerous genes, which are regulated synergistically or interdependently. An accumulated body of evidence indicated that an intact auxin signaling is crucial for the BR responses ,217,218.rocesses . Note thcapacity . Anothercapacity . Thus, Bcapacity . It was capacity . It was  of BZR1 . Experimpathways ,212. Theynthesis . Thus, Spression   and ABI5. BES1 forms a transcriptional repressor complex with the above-mentioned TPL transcription factor and Histone Deacetylase19 (HDA19), which mediates deacetylation of chromatin encompassing the cription . As ABI3esponses . Moreoveignaling . Thus, Bucidated   gene, which encodes a transcription factor regulating this process [PIF4 transcription in response to elevated ambient temperatures, what results in amplification of the signaling output [PRE genes [PRE expression, and consequently in an enhanced accumulation of DELLAs, what constitutes a core of a mechanism providing a switch between skoto- and photomorphogenesis [BZR1 participates also in thermomorphogenesis through direct binding to promoter of the  process . The PIF process . BZR1 eng output . Apart fg output ,237,238.g output . Active g output . PIFs arg output ,241,242.g output ,45,167. RE genes ,238,243.ogenesis ,148,150.ogenesis ,245. It ogenesis   gene, which delays senescence and stimulates plant tolerance to salinity and heat [DWARF4 and GA3ox1 [The BZR1 and BES1 transcription factors are also involved in a regulation of components, which mediate signaling pathways of various environmental stresses . It was and heat ,259. Thed GA3ox1 . Therefod GA3ox1 . It was d GA3ox1   transcription factor, which positively regulates expression of the BR biosynthetic genes, contributes to a constitutive expression of C-Repeat Binding Factor/Dehydration-Responsive Element Binding Factors (CBFs/DREBs), which are key regulators of the Cold Responsive (COR) gene expression [CBF expression, but do not impact the CBF expression in early responses to BR or cold [CBF1 and CBF2 genes, which encode transcription regulators playing the pivotal role in plant response to the cold stress. Moreover, BZR1 binds to promoters of several COR genes, whose transcription is regulated in the CBF-independent manner, to influence the cold stress response [Cold stress belongs to major environmental factors that adversely impact plant growth and development . It was pression . BRs conpression . Sumoylapression . The CBFpression ,273,274. or cold . Cold stresponse . Thus, tresponse ,257,268.Responsive to Desiccation26 (RD26) gene [RD26 expression. Under the drought conditions, the RD26 gene expression is rapidly stimulated and RD26 interacts with BES1 to repress its function [wrky46/wrky54/wrky70 mutant shows the BR-specific defects in growth but an enhanced drought tolerance, what confirms their dual role in regulation of the BR-dependent growth and drought response [Research conducted during the recent years provided an insight into the mechanism of crosstalk between the BR signalosome and molecular process of drought response. It seems that the BR response is suppressed during plant reaction to drought stress. The recent studies conducted in monocot and dicot species indicated that mutants with defects in the BR perception or biosynthesis show enhanced tolerance to drought ,275,276.26) gene , which e26) gene ,279,280.26) gene . The RD226) gene . Recentlfunction . It shoufunction . The BESfunction . It is aresponse . Moreoveresponse . Howeverresponse , the DSKresponse , and desresponse . These mresponse . It shouresponse   [Zea mays) [Triticum aestivum) [SERK genes and two homologs of BIN2 were characterized [Research conducted for the last two decades in rice enabled identification and functional analysis of genes encoding components of the BR receptor complex (OsBRI1 and OsBAK1), homologs of the BIN2 kinase (OsGSK1 and OsGSK2), the OsBZR1 transcription factor, proteins belonging to the 14-3-3 family, and a group of HLH transcription factors. Interestingly, the studies led to identification of some components of the BR signaling, which are specific for rice, such as the OsDLT, OsLIC and OsRAVL1 transcription factors, as well as the OsPRA2, OsELT1, OsTUD1 and OsGW5 proteins ,303,304.h barley ,306,307,tachyon) , maize (ea mays)  and wheaestivum) . Moreovecterized ,312. NevA novel component of the BR signaling in rice has been recently identified. A small GTPase, OsPRA2, directly binds to the OsBRI1 receptor to inhibit its kinase activity. OsBRI1 and OsPRA2 co-localize at the plasma membrane. Thus, OsPRA2 is a negative regulator of the BR signaling . MoreoveIt was recently reported in rice that the Enhanced Leaf inclination and Tiller number1 (ELT1) transmembrane receptor-like protein specifically interacts with the OsBRI1 receptor (the interaction occurs between the intracellular domains of the proteins), and promotes the BR signaling by repressing internalization and the endocytosis-mediated degradation of the polyubiquitinated OsBRI1. The ELT1-BRI1 interaction prevents the BRI1 ubiquitination. Thus, ELT1 acts as a positive regulator of the BR signal transduction by increasing the OsBRI1 receptor accumulation .Brachytic1 gene, which encodes the alpha subunit of the heterotrimeric G protein has been identified and functionally analyzed [It was reported that in rice, apart from the OsBRI1 receptor, the Rice heterotrimeric G protein Alpha1 (RGA1) is also involved in the BR signaling ,315. In analyzed ,320.tud1 mutant is insensitive to BRs. It is suggested that the TUD1 and RGA1 proteins directly interact to mediate the BR signaling pathway which is parallel or slightly overlapping with the canonical OsBRI1-mediated pathway. TUD1 functions directly downstream of RGA1 and mediates the G-protein signaling response to BR. Note that TUD1 is not involved in the GA signaling or biosynthesis and is not associated with the cytokinin metabolism [It was reported that the RGA1 protein interacts directly with the Taihu Dwarf1 (TUD1) U-box E3 ubiquitin ligase  and these proteins cooperate to mediate the BR signaling ,305,321.tabolism .DLT is negatively regulated by exogenous and endogenous BRs in the OsBZR1-dependent feedback manner. However, DLT stimulates the OsBZR1 expression, and this interaction enables fine-tuning of the BR response [Another component of the rice BR signalosome, DWARF and Low-Tillering (DLT) belongs to the plant-specific GRAS family of transcription factors. Expression of response . DLT is response ,300. Intresponse . InteresOsOFP1 gene is promoted by BRs in the OsBZR1-dependent manner. Note that, OsOFP1 belongs to a vast protein family and plays a redundant function with other OFP family members [OsOFP1 and OsOFP2 genes also repressed the GA biosynthesis and resulted in a decreased plant height [OsOFP8 gene transcription inhibits the OsBZR1 and DLT gene expression, what suggests a diverse regulatory mechanism. OsOFP8 specifically interacts with and is phosphorylated by the OsGSK2 kinase and the phosphorylation stimulates proteasomal degradation of OsOFP8 [Recently, a DLT-interacting protein, the Ovate Family Protein1 (OsOFP1) transcription factor was identified in rice, and found to be ubiquitously expressed. Expression of the  members . Interes members . Similart height ,325. Howt height . Anotherf OsOFP8 .OsMIR396d gene. Overexpression of the gene results in an enhancement of the BR signaling, but in repression of the GA biosynthesis and signaling. OsBZR1 directly promotes accumulation of the OsmiR396d, which controls the BR response and the GA biosynthesis. The OsMIR396d gene expression is induced by applying a high concentration of GA. It indicates that OsmiR396d mediates the GA signaling and regulates the GA biosynthesis. Thus, it was suggested that OsmiR396d is involved in the feedback regulation of the GA biosynthesis [In rice the BR-GA signaling crosstalk is also mediated by the ynthesis .Another factor, which is involved in the BR response in rice, Brassinosteroid Upregulated1 (BU1), belongs to a group of the HLH non-DNA binding transcription regulators . BU1 shoPRE1 gene is positively regulated by BRs, auxin and GA, therefore PRE1 may regulate the interplay between these hormones. ILI1 interacts with the bHLH transcription factor ILI1-binding bHLH protein1 (IBH1). Expression of the IBH1 gene is down-regulated by BRs. As mentioned above, function of the ILI1 protein is similar to the PRE1 activity in Arabidopsis—the BR-induced HLH proteins (ILI1 and PRE1) interact with and inactivate the negative regulators of the BR response, the bHLH transcription factors IBH1. The negative regulation of the IBH1 gene expression is also conserved in these species—BRs suppress its transcription in the BZR1-dependent manner. Thus, BRs inhibits the IBH1 function at the transcriptional and protein level [Another HLH protein in rice, Increased Leaf Inclination1 (ILI1) shares significant similarity with the above-described BU1 from rice and PRE1 from Arabidopsis. Function of the ILI1/PRE1 proteins is conserved in monocots and dicots. Expression of the in level . Therefoin level .OsBZR1 and ILI1 genes. Moreover, OsLIC activates transcription of the IBH1 gene [OsLIC and IBH1 genes, but stimulates transcription of the ILI1 gene, thus antagonizes the OsLIC function [Another rice-specific transcription factor, Leaf and Tiller Angle Increased Controller (OsLIC), functions antagonistically to OsBZR1 in the BR response. OsLIC acts as a negative regulator of the BR signaling and represses the BZR1 activity by attenuating transcription of the BH1 gene . On the function ,301. Intfunction .OsBRI1 and the BR biosynthetic genes. Interestingly, in contrast to OsBZR1, RAVL1 is not involved in feedback repression of these genes, and therefore it is suggested to ensure a basal activity of the BR metabolism [RAVL1 expression level. The other hormones do not seem to alter the RAVL1 expression. It is suggested that auxin response factors (ARFs) might be involved in the auxin induction of RAVL1 transcription, however further studies are required. RAVL1 activates both BR and ethylene signaling in rice. RAVL1 was also found to activate ethylene-related genes and positively regulate the ethylene response. Thus, suppression of the RAVL1 expression by ethylene might be a part of feedback mechanism. Interestingly, RAVL1 may activate the ethylene response in the BR signaling-independent manner. Moreover, RAVL1 is suggested to activate the OsBRI1 and the BR-biosynthetic genes independently of the ethylene signaling [Another component of the BR signalosome in rice, Related to ABI3/VP1 RAV-Like1 (RAVL1), is a B3-domain transcription factor that regulates the BR homeostasis by directly activating expression of the tabolism . Howeverignaling .GW5 gene is expressed in various rice organs and encodes a calmodulin-binding protein. The GW5 protein is localized to the plasma membrane and directly interacts with and represses the OsGSK2 kinase. GW5 inhibits both auto- and transphosphorylation activity of OsGSK2 [Recently, a novel regulator of the BR signaling in rice has been identified. The f OsGSK2 . It is kf OsGSK2 ,305. Thef OsGSK2 .OsWRKY53 gene transcription. Moreover, OsWRKY53 may attenuate its own expression. OsWRKY53 acts downstream of the OsBRI1 receptor and phosphorylation of OsWRKY53 by the OsMAPKK4 and OsMAPK6 kinases is crucial for its function [It was recently reported that the rice transcription factor OsWRKY53, which is involved in a defense response, is also an important regulator of the BR signaling. OsWRKY53 positively regulates the BR signaling in rice, but also mediates a feedback repression of the BR biosynthetic genes. Interestingly, BRs stimulate the OsWRKY53 protein accumulation, but suppress the function .Brassinosteroids regulate the broad range of processes during the plant life cycle. Research conducted for the last decades in Arabidopsis provided an insight into molecular mechanisms of the BR signaling and the BR-dependent gene expression. The BR signalosome is interconnected at various stages with signaling pathways of other phytohormones and environmental cues. This extensive and complex crosstalk allows the coordinated regulation of the physiological processes and rapid adaptation to environmental conditions. Nevertheless, further research is needed to fully clarify complicated regulatory mechanisms, which control the signaling interplay. Transfer of information about the crosstalk between the BR signalosome and other signaling pathways from the model species (Arabidopsis) to cereal crops is feasible, as the molecular mechanisms are evolutionarily conserved. It is an important issue as the BR signaling is considered as an ideal target to enhance crop yield and stress tolerance, especially taking into account the approaching global climate change.


Efficient integration of various external and internal signals is required to maintain adaptive cellular function. Numerous distinct signal transduction systems have evolved to allow cells to receive these inputs, to translate their codes and, subsequently, to expand and integrate their meanings. Two of these, cyclic AMP and cyclic GMP, together referred to as the cyclic nucleotide signaling system, are between them. The cyclic nucleotides regulate a vast number of processes in almost all living organisms. Once synthesized by adenylyl or guanylyl cyclases, cyclic nucleotides transduce signals by acting through a number of cellular effectors. Because the activities of several of these effectors are altered simultaneously in response to temporal changes in cyclic nucleotide levels, agents that increase cAMP/cGMP levels can trigger multiple signaling events that markedly affect numerous cellular functions. In this mini review, we summarize recent evidence supporting the existence of cNMP effectors in plant cells. Specifically, we highlight cAMP-dependent protein kinase A (PKA), cGMP-dependent kinase G (PKG), and cyclic nucleotide phosphodiesterases (PDEs). Essentially this manuscript documents the progress that has been achieved in recent decades in improving our understanding of the regulation and function of cNMPs in plants and emphasizes the current gaps and unanswered questions in this field of plant signaling research. Both the frequency (amplitude and duration) and location of changes in the levels of cNMPs depend on the activity of cNMP PDEs, which catalyze cNMP hydrolysis. Consequently, an increase in intracellular cNMP levels affects the activity of downstream effectors, particularly protein kinases, ion channels, and transcription factors, enabling the divergence of cNMP signals.Figure 1. Nonetheless, we are still far from obtaining a complete understanding of the functions of these systems. The roles and biosynthesis of cNMPs in plants have been discussed for many years  . AlthougTriticum aestivum germ  PDEs responsible for the inactivation of 2′,3′-cyclic nucleotides  or (2) the inactivation of 3′,5′-cyclic nucleotides . The first putative PDEs shown to catalyze the hydrolysis of 2′,3′-cNMP to 2′-NMP were originally purified from vum germ , and thevum germ . Anothero 2′-NMP .Pisum sativum seedlings. This enzyme catalyzes the hydrolysis of 2′,3′-cAMP to 3′-AMP, whereas 3′,5′-cAMP is hydrolyzed to a mixture of 3′-AMP and 5′-AMP  or micromolar concentrations of cAMP and decreased after the application of a PKA inhibitor    . Bioinfo (cAPKα) . An analproteins . TherefoA. thaliana (AtBRI)   . Further1g79680) , a pepti1g79680)  and phyt1g79680) . Both At1g79680) . Currentproteome .The production of cGMP may be due to the presence of endogenous factors that down-regulate kinase activity . GC-kinaThe discovery of “moonlighting proteins” is very promising, however several less optimistic reports have been published. The GC activity of AtBRI1 was not confirmed in studies examining its crystal structure . This acA. thaliana proteins were characterized as CNBPs, and their putative physiological roles in the photorespiration pathway and Calvin cycle were described. Moreover, a number of CNBP candidates were post-translationally modified by NO, transcriptionally co-expressed and functionally annotated to hydrogen peroxide signaling (H2O2) pathway and plant response to stress. The authors suggested that the newly identified CNBPs function together as a point of cross-talk between the cNMP, NO, and H2O2 signaling pathways that are activated during the plant defense response (For several years, research has also been conducted to identify new and unusual downstream CNBPs. Twelve response .A. thaliana proteome (Other proteomic analyses revealed the cAMP-dependent changes in the proteome , particuproteome . Based oproteome .cNMPs are now known to act as regulators of specific elements in the promoters of genes, as shown for gibberellic acid- and ethylene-responsive genes . MoreoveDetailed structural studies of cNMP turnover or binding and of the various protein or nucleic acid effectors may help identify new classes of binding sites. These studies may also facilitate the rational design of molecules that inhibit or modulate cNMP action.E. coli AC-deficient mutant colonies complemented by cloned plant ACs has routinely been performed (PDE genes (Together with the universality of cNMP signaling, the diversity and differential expression of cNMP effectors make them important elements in cell signaling. Decades of work have refined some details of cAMP and cGMP signal transduction pathways in plants and have revealed an increasing number of areas in which these signaling events are important and even central contributors. Collectively, the data reported here reveal the complex mechanisms controlling cNMP, thus raising the question of the physiological relevance of these sophisticated mechanisms in plants. Current studies require the precise characterization of cyclases, cNMP scavengers, and different types of effectors. Clearly, cNMP is produced in multiple, discrete subcellular gradients that may carry information, thus indicating that the subcellular localizations of enzymes involved in cNMP metabolism are of critical importance. Over the next few years, our knowledge of cAMP and cGMP signaling in plant cells will continue to increase. Mathematical modeling of cNMP regulation may identify new mechanisms that are involved in the synthesis, action and degradation of cNMP. Firstly, the creation of new bioinformatics tools, such as the recently reported “GCPred” tool for predicting the GC functional center will significantly improve the search for new candidate cNMP-related proteins . Secondlerformed . SimilarDE genes . To dateTherefore, new bioinformatics algorithms and molecular tools may provide opportunities to broaden our currently limited understanding of cNMP-dependent protein kinases and PDEs in plants. Ultimately, a better understanding of the function and interaction of these signaling pathways will enhance our appreciation of their contribution to the normal function of plants and their adaptations to unfavorable conditions.However, the regulatory role of cNMP in plant cells may be based mainly on CNGC activation, and other cNMP sensors might play extremely marginal roles in this signaling pathway.BŚ and MD wrote the manuscript. KJ and AS-J revised and critically evaluated the manuscript. All authors read and approved the manuscript.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.


TRAF proteins are a family of signaling adaptors that play diverse roles in signaling by a broad range of receptors involved in immunity and inflammation. First identified as signaling adaptors downstream of TNFR2/CD120b .There are 7 mammalian TRAFs. TRAFs 1 through 6 share the conserved TRAF domain, responsible for hetero- and homo-oligomerization of TRAF proteins, as well as recruitment to TRAF motifs in the cytoplasmic domains of cell surface receptors, and certain cytoplasmic and nuclear proteins . CrystalShi and Sun. Shi and Sun discuss the role of TRAFs 2 and 6 as positive regulators of NF-κB and MAPK signaling, downstream of multiple receptors, the anti-inflammatory role of TRAF2 and 3 in restraining non-canonical NF-κB signaling, as well as TRAF3 as a negative regulator of TLR signaling.NF-κB pathways—including both the canonical and non-canonical/NF-κB2 pathways—play important roles in the functions of TRAF proteins. These pathways, and related MAPK pathways, are the focus of a review by Dhillon et al. discuss the role of TRAFs in both positive and negative regulation of these pathways.TRAF proteins have important roles in regulation of inflammation through their role in activation of pattern recognition receptors, including Toll-like receptors, RIG-I like receptors, Nod-like receptors, inflammasomes, and STING signaling. In their mini-review, in vivo functions of these molecules. This has in turn highlighted the cell-type-specific functions that characterize several of the TRAFs. Boyce et al. discuss the roles played by TRAF3 in regulating the balance between osteoblasts and osteoclasts in bone health, as well as disorders detrimentally impacting this balance. Their article summarizes studies showing that TRAF3 can both limit osteoclast formation by limiting signaling through the TNFR superfamily member RANK, as well as inhibiting TNF-induced osteoclast formation. The review by Bishop et al. demonstrates that TRAF3 regulates normal and malignant B cell biology via multiple mechanisms, including the pathways just mentioned as well as by modulating glucose metabolism, and inhibiting targets of the nuclear CREB complex.The physiologic importance of TRAFs 2, 3, and 6 was not easy to determine initially, because germline deletion of their genes in mice led to peri-natal lethality with multiple severe developmental abnormalities .T cell differentiation, leading to the development of a T follicular helper (Tfh) response, is critical for the development of germinal centers and affinity maturation of the B cell response . TRAFs aZapata et al., who propose that different TRAF trimer configurations can allow formation of a complex, higher order signalosome with opportunities for recruitment of diverse signaling molecules. The authors also discuss the use of agonists against 4-1BB in cancer therapy and the implications of understanding 4-1BB signaling for design of new cancer treatments .A more in depth look at the 4-1BB signalosome is provided by Nagashima et al. discuss how IL-6R in naïve CD4 T cells binds TRAF2 and 5, thereby restricting the binding of JAKs to gp130, and limiting subsequent IL-6-mediated Stat3 activation. Thus, knockdown of TRAF2 or 5 enhances Th17 development and exacerbates EAE.Signaling through the IL-6 receptor (IL-6R) plays an essential role in differentiation of CD4 T cells into Th17 cells , cells wOverall, the articles in this Frontiers topic address the pivotal roles that TRAF proteins play as positive and negative regulators of inflammation and immunity mediated by a diverse array of receptors and cell types. The fact that each of the TRAF proteins can play both positive and negative roles in particular pathways or contexts, defies simple generalization. The dysregulation of TRAF proteins in cancer and a number of inflammatory diseases, suggests that this is an area that needs further attention. However, the nuanced role of TRAF proteins in each context will need to be carefully evaluated before they can be manipulated therapeutically.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


To the Editor: Blood donors in Australia who test positive for transfusion-transmissible infections, including human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus, and HIV, undergo posttest counseling, as previously described (HBV shares transmission routes with HTLV-1 and is highly infectious, including through minor blood exposures (At the time of posttest counseling, no previous HTLV results were available for donors reporting self-flagellation or for their family members. Until the known modes of vertical and sexual transmission have been excluded by such results, the likelihood of self-flagellation as an infective risk factor remains unclear. Although India and Pakistan are not known to be geographic risk areas for HTLV-1, few prevalence studies are available (


There is currently no method that can predict whether or under what condition hypopnea, even obstructive sleep apnea (OSA), will occur during sleep for individuals based on credible parameters measured under waking condition. We propose a threshold concept based on the narrowest cross-sectional area of the upper airway (CSA-UA) and aim to prove our hypothesis on the threshold of the area for hypopnea onset (TAHO), which can be used as an indicator of hypopnea onset during sleep and measured while awake.We performed magnetic resonance imaging for 20 OSA patients to observe CSA-UA changes during fluid accumulation in the neck caused by elevating their legs, and identified TAHO by capturing the sudden enlargement in CSA-UA. Correlation analyses between TAHO and the body mass index (BMI), and between the reduction in CSA-UA and the increase in the neck circumference (NC) with fluid accumulation were performed. Logistic regression analysis was performed for identifying OSA patients based on the behaviors of their CSA-UA changes during leg raising. Shape changes of airway cross-section were also investigated.2 was identified for normal breathing. Data showed a positive correlation between TAHO and BMI , and a negative correlation between the reduction in CSA-UA and the increase in NC  with fluid accumulation. A sigmoid function for the probability of being a OSA patient p = 1/[1 + exp. (4.836 + 3.850 t-8.4 h)] was obtained to effectively separate OSA patients from normal subjects. The upper airway narrowing occurred in anteroposterior, lateral, or both directions, suggesting different tendencies of upper airway collapse in patients. Three types of shape changes in the cross-section of the upper airway, which had different effects on airway resistance, were measured.Four CSA-UA change patterns after fluid redistribution were identified. Six patients had similar CSA-UA variation behaviors observed in healthy subjects. From the other three change patterns involving 14 patients, a threshold value of CSA-UA 0.63 ± 0.21 cmOur findings prove TAHO hypothesis. The threshold measured while awake for normal breathing can be used clinically as the indicator of hypopnea onset during sleep, and therefore to identify OSA patients under waking condition and design effective personalized treatments for OSA patients. Both shape and size changes in the cross-section of the upper airway affect airway resistance significantly. Shape change in the cross-section of the upper airway can provide key clinical information on the collapse patterns of the upper airway for individuals. As a common disorder of the respiratory system, the awareness rate of obstructive sleep apnea (OSA) and its complications in the general population is low , 2. ManyUA is the channel to supply oxygen to the human body. To provide enough oxygen for organs and tissues, a certain air flux is needed during breathing. From the physiological and mechanical points of view, the resistance of UA strongly depends on UA geometry , 9. UA rAlthough the exact threshold value of CSA-UA may vary among individuals, one rule is clear: to provide organs with sufficient oxygen, CSA-UA must not be smaller than a critical value in order to maintain normal breathing. CSA-UA is closely related to the activation of pharyngeal dilator muscles. Studies have revealed that while awake, enhanced dilator muscle activations can maintain the airway size for normal breathing. The muscle activations in OSA patients are much stronger than those for healthy people under waking condition because the passive UA is narrower in patients –14. HoweHowever, it is a big challenge to measure TAHO under waking condition. We propose the following hypothesis: While awake, once CSA-UA reaches TAHO, muscles will activate in order to enlarge UA immediately to avoid the occurrence of hypopnea. Therefore, if one can gradually increase the tissue volume surrounding UA in a proper way to narrow the airway, a sudden enlargement of CSA-UA will appear at TAHO due to a rapid increase in muscle activations. The minimum value of CSA-UA observed right before the triggering of the strong muscle activation can be considered TAHO.Our previous MRI study in healthy subjects under waking condition shows that when the legs of subjects lying supine are elevated, the fluid in the lower body will shift into the head and neck region due to gravity. This process increases the volume of the soft tissues, and therefore compresses the airway to reduce CSA-UA . This naIn this study, we aim to prove our hypothesis by capturing the sudden enlargement in CSA-UA of OSA patients using a convenient and non-invasive method based on MRI, and therefore to measure TAHO under waking condition at daytime. Meanwhile, we also want to classify the types of UA obstructions in patients by observing the shape changes in the cross-section of UA during airway collapse.Potential OSA candidates not previously treated for OSA were recruited. Patients with histories of cardiovascular or neurological disease were excluded. An overnight polysomnography study was performed for all potential candidates using Alice 5 Diagnostic Sleep System . Patients with apnea-hypopnea index ≥15 participated in the MRI study because the changes in their airway cross-sectional area could be more obvious, and therefore, it should be easier to observe and measure TAHO. The research protocol was approved by the Ethics Committee of the Capital Medical University, Beijing, China (2013SY67). All subjects provided written informed consent prior to participation.Using a spoiled gradient echo sequence used previously for healthy subjects , three-dEach participant lay supine on the MRI sliding bed with their head fixed in the neutral position. After a 15-min relaxing, the patient was moved into the device. Scans, starting at the end of a tidal expiration, were performed under four conditions: baseline while lying supine, 1 min and 8 min after elevating both legs by more than 40°, and then immediately after lowering the legs. The total time spent in the MRI device was about 16 min.To reduce the measurement error, instead of identifying the image with the narrowest caliber of UA in each of the four scanning stages, we use a mean value to define CSA-UA for each stage. For each participant we selected ten consecutive axial images in the narrowest part of the retropalatal airway, which cover 1.3 cm in length for each scanning stage at the same location. Therefore, 40 images were selected for each participant. We enlarged the images and outlined the boundaries of UA manually. We then extracted their coordinates to calculate CSA-UA for each scanning stages. For each participant, CSA-UA was calculated by averaging the ten corresponding cross-sectional areas for a given stage. The shapes of UA cross-section under different conditions were also collected.A power analysis was performed to estimate the required patient size for this study. Measured values were expressed as means ± standard deviations. A curve of the change in CSA-UA with 4 scanning status was plotted for each patient. The minimum value of CSA-UA curve during leg raising was considered as TAHO. Correlation analyses between TAHO and the body mass index (BMI), and between the reduction in CSA-UA and the increase in the neck circumference (NC) with fluid shift were performed to observe their relationships. A logistic regression analysis was performed for identifying OSA patients based on the behaviors of their CSA-UA changes during leg raising. The logistic regression model was established based on the data of the patients as well as of normal subjects from our previous fluid shift study . For norThe results of a power analysis with α = 0.05 and power = 0.8 show that to perform such a study to identify TAHO of OSA patients from the changes of the CSA-UA with fluid shift in 8 min, the required patient size is 18. Twenty-six candidates were recruited initially. One candidate withdrew after the polysomnography, and 2 patients quit during MRI due to claustrophobia. Data for 3 patients were excluded because of image blurring. The characteristics of the remaining 20 participants are given in Table 2, which was much smaller than 1.31 ± 0.68 cm2 measured in healthy subjects  was obtained to effectively separate OSA patients (labeled 1) from normal subjects (labeled 0). Here, t is a dimensionless time variable defined as the time to reach TAHO divided by 10 min, and h is a dimensionless height variable defined as the height divided by 180 cm. Figure A logistic function logit = − 4.836-3.850 t + 8.4 h or a sigmoid function for the probability of being a OSA patient An important observation was the shape changes in UA cross-section caused by fluid redistribution. We observed the direction of the airway narrowing due to fluid accumulation, which is valuable in evaluating the behaviors of UA collapse. In addition to UA narrowing in both anteroposterior and lateral directions, Figs. Shape change could affect the flow resistance and the airway collapsibility significantly. If we classified the shape changes based on the ratio of the length to the short axis of UA cross-section, as that we did previously : the ratIn this study, we propose the important concept of CSA-UA threshold and develop an effective method to measure the parameter TAHO when awake, which can be used clinically as an indicator of hypopnea onset when asleep. We want to point out that although we call this parameter as a threshold for hypopnea, it is not limited to hypopnea only. Actually, once CSA-UA falls below TAHO during sleep, either hypopnea or apnea can occur if the airway continues to narrow. Using MRI, we successfully observed the increase in CSA-UA with fluid accumulation in the neck and identified their TAHO in 14 of the total 20 OSA patients. One may have noticed that although the 6 patients in group 1 did not show an increase in CSA-UA, as that behaved by 14 patients in groups 2, 3, and 4, during fluid redistributions, their CSA-UA at 8 min leg raising (Table p value is a little bit larger than 0.05, presents a tendency that a larger increase in NC corresponds to a smaller reduction in the airway size, and a smaller increase in NC corresponds to a lager reduction in the airway caliber. This is not surprising, and it is consistent with our previous studies [A positive correlation between TAHO and BMI obtained in this study suggests that weight gain may increase TAHO, and therefore, increase the risk of hypopnea and even OSA because a large TAHO value means that a large airway cross section is required for normal breathing. A negative correlation between the reduction in CSA-UA and the increase in NC with the time of fluid shift, although the  studies . MRI Stu studies . This is studies . Because studies , for thoThe potential clinical significance of TAHO is clear. TAHO can be conveniently obtained while awake by measuring the minimum value of CSA-UA versus fluid accumulation curve for OSA patients. This is because UA of patients is narrow. When the fluid in the legs shifts into the neck region under waking condition, the volume expansion of the soft tissues, caused by the increased fluid amount, will compress the airway so that CSA-UA can easily fall below the threshold, triggering dilator muscle activations. Compared to patients, when a similar amount of fluid accumulates in the head and neck region of normal subjects, their airway size does not fall below the threshold . TherefoFor a potential OSA patient, a further diagnosis may be done in the following way: After measuring the personal TAHO using the method developed in this study, one can reduce the ability of genioglossal muscle activity of the subject to a level similar to that during sleep in a traditional way, for example via local anaesthesia of the tongue muscle. One can then measure CSA-UA under such a condition and compare it with TAHO to determine whether OSA will happen during sleep.For a diagnosed OSA patient, TAHO can be used to optimize the design of personalized non-CPAP treatment by predicting the efficiency of a treatment design in advance, and therefore increase the probability of success. To predict whether a treatment is effective, the key is to determine whether CSA-UA of the individual can fall below its threshold during sleep after such a treatment. Currently, a potential method for predicting therapeutic outcomes is to perform the numerical simulation using computer models. Combining medical imaging with finite element analysis models, one can simulate the process of upper airway collapse and obstruction corresponding to the personalized treatment design –26. A coUsing MRI, we can obtain not only the value of CSA-UA, but also the cross-sectional shape of UA. By observing the shape changes caused by fluid redistribution, we can identify different types of UA collapse among patients. As shown in this study, someone had the major UA collapse in the anteroposterior direction, someone had the major collapse in the lateral, and someone had circular collapse. This individual information, obtained under waking condition, is particularly important when designing a personalized surgery for a patient.A limitation of this study is that we could not measure genioglossal muscle activation simultaneously when performing MRI. Therefore, we could not provide actual electromyogram data corresponding to CSA-UA increase at the current stage, and more tests are needed in future studies. Another limitation is that we have only four scanning stages, and an airway enlargement may happen between two scanning stages. Therefore, the real TAHO may be lower than that obtained in this study. Our value is actually an upper limit of TAHO. For more accurate measurement on TAHO, one needs to shorten the time interval between two scanning stages.The important findings in this study prove our hypothesis on the threshold of the narrowest cross-sectional area of UA. The threshold measured while awake for normal breathing can be used clinically as the indicator of hypopnea onset during sleep. Both shape and size changes in UA cross-section can affect airway resistance significantly. Shape change in UA cross-section can provide key clinical information on UA collapse patterns for individuals. The concept of CSA-UA threshold for hypopnea onset during sleep, the method to measure the parameter TAHO when awake and to identify OSA patients based on TAHO, and UA collapse tendency judged by the cross-sectional shape change of UA will lead to new insights into the development of new methods for OSA diagnosis and treatments.


The proper place and the optimal use of antidepressants in treating bipolar depression continues to be an area of great interest and greater controversy with passionate opinions more common than good studies. Even the handful of meta-analyses in the area disagree with each other. Overall, the evidence that antidepressants are effective in treating bipolar depression is weak. Additionally, many experts and clinicians worry greatly about the capacity of antidepressants to cause affective switching or mood destabilization. Yet, in short term controlled studies, with most patients also taking mood stabilizers, antidepressants are not associated with switches into mania/hypomania. Evidence of cycle acceleration with antidepressants primarily reflects treatment with older antidepressants, e.g., tricyclics. Similar evidence with modern antidepressants such as selective serotonin reuptake inhibitors (SSRIs) is lacking. The key questions should not be: are antidepressants effective in bipolar depression?; And: do antidepressants worsen the course of bipolar disorder? Rather, the question should be focused on subgroups: for which patients are antidepressants helpful and safe, and for which patients will they be harmful? Predictors of affective switching with antidepressants include: bipolar I disorder (vs. bipolar II), mixed features during depression, tricyclics vs. modern antidepressants, rapid cycling and possibly a history of drug abuse, especially stimulant abuse. Additionally, a number of recent studies have demonstrated both the safety and efficacy of antidepressant monotherapy in treating bipolar II depression. Finally, a subgroup of bipolar individuals need antidepressants in addition to mood stabilizers as part of an optimal maintenance treatment regimen. Among the three phases of treatment of bipolar disorder-acute mania, maintenance treatment and acute depression, the latter poses the greatest difficulty in a variety of ways. Assuredly, this is due to a number of factors including: the relative paucity of studies in the area ; the discrepancy in conclusions between meta-analyses; and the heated debates on the specific role of antidepressants in treating bipolar depression. On the latter issue—the proper place of antidepressants for bipolar depression—experts view the same handful of controlled studies and derive markedly diverse clinical recommendations with many if not most papers recommending caution (or sometimes extreme caution) in their use. A thoughtful Consensus statement from the International Society for Bipolar Disorders (ISBD) on the topic published 5 years ago concluded that “the available evidence, both the value and the risks of antidepressant treatment in bipolar disorder is remarkably limited, and much of it is methodologically weak”  definition of definite TEAS would be the emergence of a syndromal mania/hypomania within 8 weeks of either the initiation of the antidepressant or an increase in its dose  and side effects. There are no credible reasons to worry about the proposed treatment exacerbating the disorder. . The two added concerns when treating bipolar depression with antidepressants are switching into mania/hypomania and/or the induction of rapid cycling. Switching into mania/hypomania, now called treatment emergent affective switch (TEAS) . Both narrative reviews , switch rates do not differ between antidepressants and placebo with p values = 0.89 and 0.93  randomized study, continued antidepressant treatment with mood stabilizers was associated with somewhat less severe depressive symptoms and a mildly delayed time to depressive relapse with no difference in depressive episode prevalence , antidepressants were superior to placebo in preventing depressive episodes , with or without mood stabilizers with no increase in manic/hypomanic episodes .No consistent evidence has demonstrated cycle acceleration in bipolar patients on modern antidepressants .Bipolar II patients may be treated safely (at least in the short term) with antidepressants.A subset of bipolar patients, both bipolar I and II, will need a maintenance regimen of mood stabilizers plus antidepressants and will not show mood instability with this regimen.To summarize a relatively small but confusing literature:The key questions should not be simple dichotomous choices: are antidepressants effective for bipolar depression?, and are antidepressants harmful in bipolar patients? Rather, the right questions should be: For which bipolar patients will antidepressants be helpful? and for which bipolar patients will antidepressants be harmful? Additionally, the evidence of differential switch rates across antidepressant classes make the risk/benefit ratio depend on the specific antidepressant prescribed. Table Even with the predictors just noted, we cannot know about the risk/benefit ratio of antidepressants for any individual patient. Thus, an antidepressant may be prescribed with patient  and psychiatrist aware of the potential risks. Both TEAS and cycle acceleration typically occur early in antidepressant treatment and can be monitored.With bipolar II patients, most experts would agree that mood stabilizers should be prescribed first, before antidepressant monotherapy . But some bipolar II patients will refuse a mood stabilizer as a first treatment for depression but will agree to take an antidepressant. In this situation, antidepressant monotherapy with proper education and monitoring is appropriate. With the exception of a few studies  and longer term (6 month to 2 years) studies in both bipolar I and bipolar II patients Gitlin . Longer


We further explored this result with a large, diverse sample of 34 musical excerpts from different genres, including Blues, Salsa, Heavy metal, and many others, a broad sample of 10 emotion-related rating scales, and a large range of 15 rated music–perceptual features. We found systematic music-to-color associations between perceptual features of the music and perceptual dimensions of the colors chosen as going best/worst with the music . However, these associations were also consistent with emotional mediation . Indeed, partialling out the variance due to emotional content eliminated all significant cross-modal correlations between lower level perceptual features. Parallel factor analysis  revealed two latent affective factors—arousal and valence—which mediated lower level correspondences in music-to-color associations. Participants thus appear to match music to colors primarily in terms of common, mediating emotional associations.When people make cross-modal matches from classical music to colors, they choose colors whose emotional associations fit the emotional associations of the music, supporting the  Music–color synesthesia is a rare and interesting neurological phenomenon in which listening to music automatically and involuntarily leads to the conscious experience of color . Althougdirect link hypothesis asserts that musical sounds and visual colors are related via direct correspondences between the perceived properties of the two types of stimuli , so the role of emotion in their color–music associations could be assessed. Results showed strong correlations between the emotion-related ratings of the musical excerpts and the emotion-related ratings of the colors people chose as going best/worst with the music  carry information that helps determine the emotional character of the music  picked to go with the music relate to these music–perceptual features. Third, we expanded the set of emotion-related scales to a wider range including appealing/disgusting, spicy/bland, serious/whimsical, and like/dislike (like/dislike) because preferences play a significant role in cross-modal odor-to-color pairings  genres, including Salsa, Heavy metal, Hip-hop, Jazz, Country-western, and Arabic music, among others . Second,and more . We then/dislike . We inclpairings —people tferences . Finallyferences  to underThree independent groups of participants all gave written informed consent and received either course credit or monetary compensation for their time. The experimental protocol was approved by the Committee for the Protection of Human Subjects at the University of California, Berkeley .Thirty participants  performed Tasks A1 to A4 described later. All had normal color vision, as screened with the Dvorine Pseudo-Isochromatic Plates, and none had any form of synesthesia, as assessed by the initial Synesthesia Battery questionnaire .Fifteen musicians , who were members of either the University of California Marching Band or the University of California Wind Ensemble, provided ratings for the musical excerpts in terms of 15 global musical features, as described in Task B1.The color–perceptual ratings data from 48 participants from The colors were the Berkeley Color Project 37 (BCP-37) colors studied by L), medium gray (AM), and dark gray (AD). In this notation, “A” stands for achromatic, and the subscript stands for light (L), medium (M), and dark (D). AL had approximately the average luminance of all eight L-colors, AM had approximately the average luminance of all eight M-colors (and of the S-colors), and AD had approximately the average luminance of all eight D-colors. The colors were always presented on a gray background .There were also five achromatic colors: white (WH), black (BK), light gray . In tasks that displayed the 37 colored squares, the task was completed in a dark room. The monitor was characterized using a Minolta CS100 Chromometer to ensure that the correct colors were presented. The deviance between the target color's CIE xyY coordinates (Table S1) and its measured CIE xyY coordinates was < .01 for x and y and less than 5 cd/m2 for Y.In the music-to-color association task, the 37 colors were displayed on the screen in the spatial array shown in 4 None of these selections should be interpreted as standing for the entire genre used to label them, but only as single examples that were chosen to achieve a diversity of excerpts that come from different (author-identified) genres. Because musical genres are highly variable, they span wide ranges of variation that cannot be represented by any single example.The 34 musical stimuli were instrumental excerpts from 34 different genres , 2016. TThe same authors chose the names used in referring to the genres and the excerpts, which were never displayed or mentioned to the participants. In most instances, the genre name corresponded to the genre the artist affiliated with their music on their website or album or the genre label of the given musical selection on iTunes. The exceptions were two musical excerpts that were labeled by the dominant timbre (Gamelan and Piano), as well as the three classical pieces, which were labeled with the name of the composer—Mozart, Bach, and Stravinsky—to differentiate easily among them. We make no claim that the genre-excerpts studied were sampled systematically from among all forms of music, only that the present musical excerpts were more diverse than stimuli used in several previous studies examining music-to-color associations.audacity.sourceforge.net) by clipping a 15-s excerpt and adding a 2-s fade-in and fade-out. All musical excerpts were presented through closed-ear headphones (Sennheiser Model HD 270). The level was determined by having a different set of 19 participants listen to the 34 excerpts through the same headphones and adjust the volume “to the appropriate loudness level” for that musical selection. The level of each musical selection for the main experiment was determined by the average data from this task. This method was used to present the excerpts at more natural, ecologically valid listening levels than if the level had been constant across musical stimuli.The musical excerpts were edited using Audacity software (n = 28 participants (see S1 Text). The 15 music–perceptual features were selected by examining the music cognition literature  and choosing any feature that seemed potentially relevant to the 34 musical excerpts in the experimenters' collective judgment  of all 37 colors were always rated first to avoid being contaminated by the other emotion-related ratings.Participants then rated each of the 37 colors on each of 10 bipolar emotion-related scales, including their personal preference . The preNot At All to Very Much. Each color was centered on the screen above the response scale. Participants slid the cursor along the response scale and clicked at the appropriate position to record their response. To anchor the scale prior to making their ratings, participants were shown the entire 37-color array, asked to point to the color they liked the most, and were told that they should rate that color at or near the Very Much end point of the scale. They were then asked to point to the color they liked the least and were told that they should rate that color at or near the Not At All end point of the scale.Color preferences were rated on a continuous line-mark scale from Before performing the other nine emotion-related rating tasks, participants were anchored on each scale by analogous anchoring procedures with appropriate labels at the ends of the bipolar response scale. This anchoring procedure was completed verbally with the experimenter for all nine scales before the subject rated any color on any scale. All nine ratings for one color were made before the next color was presented, and the order of the scales was randomized for each color within participants. The order in which the colors were presented was randomized across participants.happiest (or the saddest), and to click at or near the happy (or sad) end of the response scale for that selection. The musical excerpts were played one at a time in a random order, and each had to be heard all the way through once before being rated on the scales. All nine scales were rated for one musical excerpt before the next excerpt was presented.Participants rated the same 34 musical excerpts on all 10 emotion-related scales  in a manIn the final task, each participant took the Synesthesia Battery questionnaire . If theyelectric, distorted, loud, heavy, low pitch, and punchy, whereas the Piano selection was included as an extreme example of clear, few instruments, soft, light, high pitch, and smooth). No mention was made of these or any other musical features either before or during the initial presentation of these five selections, however. After listening to all five selections, participants completed an anchoring procedure analogous to the anchoring procedure for the emotion-related rating task for music as described earlier. The 34 excerpts were then presented in a random order and looped continuously until participants completed the task for that excerpt.The 15 musicians rated each musical excerpt on their perception of each of the 15 bipolar, music–perceptual features listed in saturated/desaturated, light/dark, red/green, and yellow/blue—using a 400 pixel line-mark rating scale analogous to those described earlier. The anchoring procedure for each dimension was also analogous to that described earlier for color–emotion ratings (Task A2). Trials were blocked by colors, and the order of the dimensions was randomized within color blocks. The order of colors was randomized across participants.The 48 participants described in All participants completed their given tasks, so there were no missing data points. Across-subject agreement for each rating scale was measured using Cronbach's alpha, and all indicated good-to-excellent consistency (Table S4). Examination of the Q-Q plots of all of the average rating scales suggested the normality assumption did not adhere for some of the scales. To be conservative, all correlations correspond to Spearman's Rho. Parafac does not make any assumptions about the distribution of the data. The only assumption is that the data display systematic variation across three or more modes, which fits well with our three-mode ratings data sets, consisting of stimuli, ratings scales, and subjects.loud/soft, fast/slow) for each excerpt using the ratings from Task B1. These averages were combined with the data from the music-to-color associations (Task A1) and the color–perceptual ratings (Task C1) to compute four Perceptual Music–Color Association scores  for each of the 34 musical excerpts . The four Perceptual-MCA scores  by each participant.First, we computed 15 across-subject average music–perceptual feature scores  = .642; punchy: rs(32) = .591, redder colors—loud: rs(32) = .772; punchy: rs(32) = .643, and darker colors—loud: rs(32) = −.557; punchy: rs(32) = −.517. Such correlations show that there are indeed strong perceptual-level music-to-color correspondences. We analyze and discuss the nature of these correlations in more detail in the subsection “Results of dimensional compression of emotion-related scales” later. Next, we computed the correlations between the average music–perceptual ratings of the 34 musical excerpts and the average Perceptual-MCA scores of the colors people associated with the same musical excerpts . Holm's red/green dimension of the associated colors in the present data, which were not previously found for classical orchestral music by Bach, Mozart, and Brahms  and punchy (rs = .665), whereas the corresponding relations were likely absent in the well-controlled, synthesized, single-line piano melodies by Mozart (n > 100) sample size of musical excerpts. This is an open area for future research.A second contrast with previous findings concerns differences in the color associations for different tempi. Similar to previous reports for classical music, we found that more saturated colors were selected for faster music. However, unlike previous reports for classical music in which faster tempi and greater note densities—which have similar effects on color associations despite being musically distinct—were associated with lighter, yellower colors , 2016, hy Mozart . Differey Mozart , hence mmore saturated, darker, and redder when listening to more agitated-sounding music than when listening to calmer-sounding music. The results, plotted in like/dislike shows at least one significant correlation at the .05 level using To examine whether the systematic associations between the music–perceptual and color–appearance dimensions could be mediated by emotion, we conducted corresponding analyses of higher level emotion-related aspects of music-to-color associations. First, we computed the across-subject averages of the 10 music–emotion ratings (from Task A3) for each of the 34 musical excerpts. Next, we correlated each of the average music–emotion ratings with the four Perceptual-MCAs of the colors chosen as going best/worst with the music, analogous to those defined in the previous section. These correlations reflect how the emotional properties of the music correspond to the properties of the colors chosen as going best/worst with them: for example, the extent to which people chose colors that were yellow/blue color–appearance dimension (happy/sad (+.55) and warm/cool (+.72)  . This respicy, loud, agitated, complex sounding music was consistently associated with more saturated, redder, darker colors. In Set 1B, appealing, harmonious, liked music was consistently paired with lighter colors that tended to be a bit greenish and somewhat desaturated. In Set 2, happy, whimsical, warm sounding music was consistently associated with more saturated, yellower colors. This is in contrast to Sets 1A and 1B, where the emotion-related scales were unrelated to the yellow/blueness of color choices.Further scrutiny of disgusting/appealing, dissonant/harmonious, and disliked/liked), the pattern for Set 1B would look qualitatively similar to that for Set 1A. Thus, the patterns of correlations between music emotions and color–appearance dimensions represented in agitated, spicy, loud, complex, disgusting, dissonant, disliked music elicits more saturated, darker, redder color choices, and one for Set 2, in which more whimsical, happy, warm music elicits more saturated, yellower color choices.It is important to note that the correlations for Set1B are nearly opposite to those for Set 1A. If we had plotted the correlations for Set 1B using reversed polarities of the same features . As evident in p < .0001, one-tailed) for spicy/bland5 to a low of .584  for whimsical/serious and are thus consistent with emotional mediation of some sort. Although not quite as high as the corresponding correlations in the study using classical orchestral music . These correlations identify the degree to which people chose colors whose emotional associations matched the emotional associations of the music: for example, choosing like/dislike ratings for the musical excerpts and the like/dislike EMCA scores for the chosen colors for each musical excerpts (the rightmost bar in rs(32) = .406, p = .0086 > .005, one-tailed. The evidence that people chose colors they like/dislike as going better with music that they like/dislike is thus quite weak, at least for this sample of music, colors, and Western participants.The 10th comparison was between preferences for the music and preferences for the colors chosen: that is, correlations between the unsystematically affected after partialling out the contribution of emotional associations . A pure version of the emotional mediation hypothesis  implies that all significant perceptual-feature correlations in eliminated after partialling out the contributions of all covarying emotional associations.We have now reported evidence for both direct perceptual associations and emotionally mediated associations, but it is unclear that the degree to which the higher level correlations from music emotions to colors  can explrs ≤ +.489, p > .05 ).The partial correlation results support the strong form of the emotional mediation hypothesis. All of the music–perceptual correlations in To better understand the shared emotional content of the music–color associations, we used the Parafac model  to discoarousal (or activation) and valence (or pleasure)  its interpretability, (b) its consistency with previous results , 2016, , (d) thee) e.g., . The twox-axis) is most closely aligned with ratings of agitated, spicy, loud, and complex on the positive end versus calm, bland, quiet, and simple on the negative end. We refer to this latent dimension by its affective interpretation, arousal. Likewise, factor 2  is most closely aligned with ratings of happy, appealing, whimsical, and warm on the positive end versus sad, disgusting, serious, and cool on the negative end. We interpreted this latent factor in terms of affect: namely, as valence. For clarity, the term “affect” refers to the two latent factors and the term “emotion” refers specifically to the emotion-related rating scales themselves.The estimated Parafac weights are plotted in arousal and valence. These plots are useful for visualizing the perceptual interrelations among the stimuli with respect to the two factors. For example, saturated red, yellow, and orange are happy, agitated colors, high in arousal and valence, whereas dark grays and blues are sad, calm colors, low in arousal and valence  are constructed from varying degrees of activation along core affective dimensions, typically labeled arousal  and valence   that are biologically innate and universal  , althougniversal . A greatniversal , but conniversal . Indeed,niversal . The prearousal and valence. arousing, agitated music elicited colors that were more saturated—rs(32) = .720, darker—rs(32) = −.549, and redder—rs(32) = .755, than did calmer, less arousing music. This pattern corresponds quite closely to that of the emotion-related scales of Sets 1A and 1B in positively valenced, happier music elicited colors that were lighter, rs(32) = .484, and yellower, rs(32) = .466, than did sadder, negatively valenced music. This pattern appears to correspond well with the emotion-related scales in Set 2 of Next, we computed the same correlations as reported in the subsection “Results of Higher Level Emotional Correlations in Music-to-Color Associations” but replaced the across-subject average of the 10 music–emotion ratings for the 34 musical excerpts (Task A3) with the Parafac factor scores corresponding to the 34 music selections: that is, the estimated saturated/desaturated, light/dark, etc.) were replaced with the color–emotion Parafac weights representing the emotional associations of the colors that were chosen as going best with the musical selection. These Parafac-based Emotional-MCAs for the 34 musical excerpts were then correlated with the music–emotion Parafac weights for the 34 musical excerpts as represented in arousal, rs(32) = .833, p < .0001, and valence, rs(32) = .678, <.0001. These significant correlations for the present diverse sample of music once again support the conclusions that music-to-color choices are consistent with emotional mediation and that the relevant emotional content is well captured by just the two latent affective factors of arousal and valence.We also conducted correlational analyses between the music–emotional scales and the color–emotion scales of the colors chosen as going best/worst with the music  using the Parafac solutions. These correlations, shown in arousal and valence. Interestingly, the results showed that, once again, none of the correlations in r < +.38, p > .05 ). These findings closely resemble those from the Emotional-MCA partial correlation analysis ), implying that the two latent factors capture much of the shared emotional content that is relevant in accounting for the perceptual music–color associations represented in To better understand how the two latent factors identified by the Parafac analysis relate to the results of the Emotional-MCA partial correlation analysis , we condarousal and valence) together account for the greatest proportion of variance in the saturation (72.2%) and lightness (68.3%) dimensions, slightly less in red/green (58.3%) and the least amount in yellow/blue (33.3%).To compare direct, low-level music–perceptual associations and higher level affective mediation, we further analyzed the ability of each hypothesis to predict the chosen colors along the four color–appearance dimensions using multiple linear regression (MLR) analyses. The music–stimuli weights were entered into the regression and fitted using the ordinary least squares method, with factor 1 always entered into the model first. The results, shown in the red bars of electronic/acoustic and fast/slow (see S3 Text for further information). The MLR results based on this two-dimensional solution are shown in the blue bars of saturation (40.3%), lightness (50.5%), and yellow/blue (20.4%) but was about the same in accounting for red/green variations (59.1%). The average amount of variance explained by the two affective Parafac factors was thus 58%, about one third more than the average of 42.6% explained by the two music–perceptual Parafac factors.For direct comparison, we performed an analogous MLR on the stimuli weights from a corresponding two-dimensional Parafac analysis of the 15 music–perceptual features. The two latent music–perceptual factors were interpreted as arousal and valence. These two latent affective dimensions coincided with the two dimensions of affect that (a) permeate much of the literature on the dimensional structure of human emotions  rather than direct (music → color) using more conclusive methods than previously employed , 2016. Ans e.g.,  and (b) ns e.g., , 2016. Ied/green . These rThe interpretation of the present findings converges with previous evidence that emotional/affective mediation also occurs in two additional sets of perceptual mappings: namely, from music to pictures of expressive faces and from pictures of expressive faces to colors . In bothWe hasten to add that the present or previous findings do not rule out the possibility that other kinds of information might also influence music-to-color associations. Semantic effects could arise, for example, if musical excerpts trigger associations with objects or entities that have strong color associations cf. . For exaHowever, another possibility is consistent with direct associations, namely, through statistical covariation cf. . Here, tConsidering the role of prior experience in music-to-color associations raises the interesting possibility of cultural influences. Would people from different cultures choose the same colors as going with the same music or would they be systematically different? The only existing evidence comes from prior research on music-to-color associations for classical orchestral selections in the United States and Mexico . The Mexjoy, anger, sadness, and peace while listening to music), the results tend to support generality across cultures , activity , and dominance—rather than on basic emotions. Nevertheless, what data exist generally indicate a fair amount of agreement across cultures in their assessment of these dimensions  or experienced emotion . The distinction is illustrated by the fact that people can clearly perceive the intended emotionality of a piece of music or a combination of colors without actually experiencing that emotion . For insWell Tempered Clavier, they chose colors that were consistent with nonsynesthetic color choices. However, because synesthetes were not asked to pick the colors that were most similar to their synesthetic experiences—rather, they picked the colors that “best fit the music”—it is unclear whether synesthetic experiences are emotionally mediated, or whether synesthetes are simply capable of making best fitting cross-modal music-to-color choices that are similar to those of nonsythesthetes.The consistent finding that nonsynesthetes show strong emotion-related effects in cross-modal music-to-color associations, both here and in prior studies , 2016, wA competing claim is that synesthetic experiences occur via hyperconnectivity from one area of sensory cortex to another e.g., . By thisThey present robust evidence of emotional mediation of cross-modal music-to-color mappings over a broad range of 34 musical excerpts and 10 emotion-related scales.loudness, harmony, distortion, beat strength, and complexity, among others).The present experiment investigated a larger and more diverse set of 15 underlying musical features, many of which have not been previously studied for their color associations  are more effective and efficient in predicting the color–appearance dimensions of music-to-color associations than the corresponding two music–perceptual factors.MLR analyses showed that the two affective factors (The results of this study contribute importantly to the understanding of music-to-color associations in at least four ways.Overall, the present results have brought us closer to understanding the role of emotion in people's cross-modal associations to music.Click here for additional data file.Supplemental material, Supplemental Data1 for Color, Music, and Emotion: Bach to the Blues by Kelly L. Whiteford, Karen B. Schloss, Nathaniel E. Helwig and Stephen E. Palmer in i-PerceptionClick here for additional data file.Supplemental Material for Color, Music, and Emotion: Bach to the Blues by Kelly L. Whiteford, Karen B. Schloss, Nathaniel E. Helwig and Stephen E. Palmer in i-Perception