NDUFA12 as a Functional Target of the Anticancer Compound Ertredin in Human Hepatoma Cells As Revealed by Label-Free Chemical Proteomics.

Many attempts have been made to develop new agents that target EGFR mutants or regulate downstream factors in various cancers. Cell-based screening showed that a natural small molecule, Ertredin, inhibited the growth of EGFRvIII mutant cancer cells. Previous studies have shown that Ertredin effectively inhibits anchorage-independent 3D growth of sphere-forming cells transfected with EGFRvIII mutant cDNA. However, the underlying mechanism remains unclear. In this study, we investigated the target protein of Ertredin by combining drug affinity-responsive target stability (DARTS) assays with liquid chromatography-mass spectrometry using label-free Ertredin as a bait and HepG2 cell lysates as a proteome pool. NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 12 (NDUFA12) was identified as an Ertredin-binding protein that was responsible for its biological activity. The interaction between NDUFA12 and Ertredin was validated by DARTS and cellular thermal shift assays. In addition, the genetic knockdown of the identified target, NDUFA12, was shown to suppress cell proliferation. NDUFA12 was identified as a biologically relevant target protein of Ertredin that is responsible for its antitumor activity, and these results provide insights into the role of NDUFA12 as a downstream factor in EGFRvIII mutants.

Understanding the Fluctuations in Korea's Suicide Rates: A Change-Point Analysis and Interrupted Time Series Analysis.

BACKGROUND: Korea has witnessed significant fluctuations in its suicide rates in recent decades, which may be related to modifications in its death registration system. This study aimed to explore the structural shifts in suicide trends, as well as accidental and ill-defined deaths in Korea, and to analyze the patterns of these changes. METHODS: We analyzed age-adjusted death rates for suicides, deaths due to transport accidents, falls, drowning, fire-related incidents, poisonings, other external causes, and ill-defined deaths in Korea from 1997 to 2021. We identified change-points using the 'breakpoints' function from the 'strucchange' package and conducted interrupted time series analyses to assess trends before and after these change-points. RESULTS: Korea's suicide rates had three change-points in February 2003, September 2008, and June 2012, characterized by stair-step changes, with level jumps at the 2003 and 2008 change-points and a sharp decline at the 2012 change-point. Notably, the 2003 and 2008 spikes roughly coincided with modifications to the death ascertainment process. The trend in suicide rates showed a downward slope within the 2003-2008 and 2008-2012 periods. Furthermore, ill-defined deaths and most accidental deaths decreased rapidly through several change-points in the early and mid-2000s. CONCLUSION: The marked fluctuations in Korea's suicide rate during the 2000s may be largely attributed to improvements in suicide classification, with potential implications beyond socio-economic factors. These findings suggest that the actual prevalence of suicides in Korea in the 2000s might have been considerably higher than officially reported.

Serum cortisol and neuroticism for post-traumatic stress disorder over 2 years in patients with physical injuries.

AIM: This study aimed to explore the relationships between serum cortisol levels, personality traits, and the development of Post-Traumatic Stress Disorder (PTSD) over 2 years among individuals with physical injuries. METHODS: Participants were consecutively recruited from a trauma center and followed prospectively for 2 years. At baseline, serum cortisol levels were measured, and personality traits were categorized into five dimensions (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness), using the Big Five Inventory-10. The diagnosis of PTSD during follow-up (at 3, 6, 12, and 24 months post-injury) was determined using the Clinician-Administered PTSD Scale for DSM-5. Binary and multinomial logistic regression analyses were conducted to examine the interactions between cortisol levels, personality traits, and PTSD development. RESULTS: Among 923 patients analyzed, 112 (12.1%) were diagnosed with PTSD at some point during the study period, with prevalence rates decreasing from 8.8% at 3 months to 3.7% at 24 months post-injury. Direct associations between cortisol levels or personality traits and PTSD were not observed. However, a significant interaction between lower cortisol levels and higher Neuroticism in relation to PTSD risk was identified, especially during the early follow-up periods (3 to 6 months), but this association waned from the 12-month follow-up onward. CONCLUSION: Our findings reveal Neuroticism-dependent associations between serum cortisol levels and PTSD development, exhibiting temporal variations. These results suggest that PTSD development may be influenced by a complex, time-sensitive interplay of biological and psychosocial factors, underscoring the importance of considering individual differences in stress reactivity and personality in PTSD research and treatment.

Prevalence and Associated Factors of Depression and Anxiety Among Healthcare Workers During the Coronavirus Disease 2019 Pandemic: A Nationwide Study in Korea.

BACKGROUND: A healthcare system's collapse due to a pandemic, such as the coronavirus disease 2019 (COVID-19), can expose healthcare workers (HCWs) to various mental health problems. This study aimed to investigate the impact of the COVID-19 pandemic on the depression and anxiety of HCWs. METHODS: A nationwide questionnaire-based survey was conducted on HCWs who worked in healthcare facilities and public health centers in Korea in December 2020. Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) were used to measure depression and anxiety. To investigate factors associated with depression and anxiety, stepwise multiple logistic regression analysis was performed. RESULTS: A total of 1,425 participating HCWs were included. The mean depression score (PHQ-9) of HCWs before and after COVID-19 increased from 2.37 to 5.39, and the mean anxiety score (GAD-7) increased from 1.41 to 3.41. The proportion of HCWs with moderate to severe depression (PHQ-9 ≥ 10) increased from 3.8% before COVID-19 to 19.5% after COVID-19, whereas that of HCWs with moderate to severe anxiety (GAD-7 ≥ 10) increased from 2.0% to 10.1%. In our study, insomnia, chronic fatigue symptoms and physical symptoms after COVID-19, anxiety score (GAD-7) after COVID-19, living alone, and exhaustion were positively correlated with depression. Furthermore, post-traumatic stress symptoms, stress score (Global Assessment of Recent Stress), depression score (PHQ-9) after COVID-19, and exhaustion were positively correlated with anxiety. CONCLUSION: In Korea, during the COVID-19 pandemic, HCWs commonly suffered from mental health problems, including depression and anxiety. Regularly checking the physical and mental health problems of HCWs during the COVID-19 pandemic is crucial, and social support and strategy are needed to reduce the heavy workload and psychological distress of HCWs.

Triptycene Branched Poly(aryl-co-aryl piperidinium) Electrolytes for Alkaline Anion Exchange Membrane Fuel Cells and Water Electrolyzers.

Alkaline polymer electrolytes (APEs) are essential materials for alkaline energy conversion devices such as anion exchange membrane fuel cells (AEMFCs) and water electrolyzers (AEMWEs). Here, we report a series of branched poly(aryl-co-aryl piperidinium) with different branching agents (triptycene: highly-rigid, three-dimensional structure; triphenylbenzene: planar, two-dimensional structure) for high-performance APEs. Among them, triptycene branched APEs showed excellent hydroxide conductivity (193.5 mS cm-1 @80 °C), alkaline stability, mechanical properties, and dimensional stability due to the formation of branched network structures, and increased free volume. AEMFCs based on triptycene-branched APEs reached promising peak power densities of 2.503 and 1.705 W cm-2 at 75/100 % and 30/30 % (anode/cathode) relative humidity, respectively. In addition, the fuel cells can run stably at a current density of 0.6 A cm-2 for 500 h with a low voltage decay rate of 46 µV h-1 . Importantly, the related AEMWE achieved unprecedented current densities of 16 A cm-2 and 14.17 A cm-2 (@2 V, 80 °C, 1 M NaOH) using precious and non-precious metal catalysts, respectively. Moreover, the AEMWE can be stably operated under 1.5 A cm-2 at 60 °C for 2000 h. The excellent results suggest that the triptycene-branched APEs are promising candidates for future AEMFC and AEMWE applications.

Multiple serum biomarkers for predicting suicidal behaviours in depressive patients receiving pharmacotherapy.

BACKGROUND: Predictive values of multiple serum biomarkers for suicidal behaviours (SBs) have rarely been tested. This study sought to evaluate and develop a panel of multiple serum biomarkers for predicting SBs in outpatients receiving a 12-month pharmacotherapy programme for depressive disorders. METHODS: At baseline, 14 serum biomarkers and socio-demographic/clinical characteristics including previous suicidal attempt and present suicidal severity were evaluated in 1094 patients with depressive disorders without a bipolar diagnosis. Of these, 884 were followed for increased suicidal severity and fatal/non-fatal suicide attempt outcomes over a 12-month treatment period. Individual and combined effects of serum biomarkers on these two prospective SBs were estimated using logistic regression analysis after adjustment for relevant covariates. RESULTS: Increased suicidal severity and fatal/non-fatal suicide attempt during the 12-month pharmacotherapy were present in 155 (17.5%) and 38 (4.3%) participants, respectively. Combined cortisol, total cholesterol, and folate serum biomarkers predicted fatal/non-fatal suicide attempt, and these with interleukin-1 beta and homocysteine additionally predicted increased suicidal severity, with clear gradients robust to adjustment (p values < 0.001). CONCLUSIONS: Application of multiple serum biomarkers could considerably improve the predictability of SBs during the outpatient treatment of depressive disorders, potentially highlighting the need for more frequent monitoring and risk appraisal.

Data-mining analysis of media frame effects on social perception of schizophrenia renaming in Korea.

BACKGROUND: In 2011, Korean Neuropsychiatric Association renamed schizophrenia from 'mind split disorder' ('Jungshinbunyeolbyung' in Korean) to 'attunement disorder' ('Johyeonbyung' in Korean), in a strategic way to reduce social stigma toward people with schizophrenia. However, there remains an elusive consensus that how the renaming effort has contributed to changes in the social perception of schizophrenia in Korea. METHODS: With this regard, we explored whether media frames alter the social perception, in ways of respecting or disrespecting schizophrenia patients before and after the renaming. This study extensively investigated media keywords related to schizophrenia across the time by applying both language and epidemiologic analyses. RESULTS: In results, the media keywords have been negatively described for schizophrenia patients both before and after the renaming. Further, from an analysis using the regression model, a significant correlation was observed between the frequency of negative keywords and the hospitalization frequency of schizophrenia patients. CONCLUSIONS: These findings suggest that the social perception of schizophrenia has been scarcely changed, but rather remained negatively biased against schizophrenia patients, in spite of the renaming effort. Notably, the biased media frames have been demonstrated to negatively impact on the social perception, and even on the medical use patterns of general schizophrenia patients. In conclusion, we suggest that the unbiased media frames along with the renaming effort may collectively help reduce the negative social perception of schizophrenia. TRIAL REGISTRATION: This study was approved from the Institute of Review Board (IRB) of the Yoing-In Mental Hospital (IRB No. YIMH-IRB-2019-02).

Exposure to volatile organic compounds and polycyclic aromatic hydrocarbons is associated with the risk of non-alcoholic fatty liver disease in Korean adolescents: Korea National Environmental Health Survey (KoNEHS) 2015-2017.

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent liver diseases among adolescents. Several animal studies have suggested that volatile organic compounds (VOCs) and polycyclic aromatic hydrocarbons (PAHs) increase NAFLD risk. However, few epidemiological studies have confirmed the association between VOCs, PAHs and NAFLD in the general adolescent population. Therefore, we analyzed 798 adolescents from the Korean National Environmental Health Survey (KoNEHS), 2015-2017, to examine the associations of urinary metabolites of VOCs and PAHs with serum alanine aminotransferase (ALT) activity and NAFLD prevalence. We performed linear regression, logistic regression, and Bayesian kernel machine regression (BKMR) to evaluate the association of urinary VOCs and PAHs metabolites with ALT levels and NAFLD prevalence. After adjusting for all covariates, urinary benzylmercapturic acid and 2-hydroxyfluorene levels were found to increase ALT activity and NAFLD prevalence. Additionally, the BKMR analyses showed a significantly positive overall effect on ALT activity and NAFLD prevalence with urinary concentrations of VOCs and PAHs metabolites, with 2-hydroxyfluorene as the biggest contributor. Our study suggests that exposure to low-level VOCs and PAHs may have a detrimental effect on NAFLD risk in adolescents. Given the increasing prevalence of NAFLD in adolescents, future cohort studies are confirmed to comprehend the effect of these chemicals on NAFLD risk.

Psychological and Personality Characteristics Associated With COVID-19 Vaccination Behavior in Korean General Population.

BACKGROUND: This study characterized coronavirus disease 2019 (COVID-19) vaccination behavior in the Korean general population using cluster analysis and explored related psychological factors. METHODS: We categorized 1,500 individuals based on their attitudes toward COVID-19 vaccination using hierarchical clustering and identified their level of vaccine acceptance. We examined the associations between vaccine acceptance and behavioral and psychological characteristics. RESULTS: Clustering revealed three groups according to vaccine acceptance: 'totally accepting' (n = 354, 23.6%), 'somewhat accepting' (n = 523, 34.9%), and 'reluctant' (n = 623, 41.5%). Approximately 60% of all participants who belonged to the 'totally accepting' and 'somewhat accepting' groups were willing to receive a COVID-19 vaccine despite concerns about its side effects. High vaccine acceptance was associated with older age, regular influenza vaccination, and trust in formal sources of information. Participants with high vaccine acceptance had higher levels of gratitude, extraversion, agreeableness, and conscientiousness, and lower levels of depression, anxiety, and neuroticism. CONCLUSIONS: People weighed the benefits of COVID-19 vaccination against the risk of side effects when deciding to receive the COVID-19 vaccine. Our findings also indicate that this vaccination behavior may be affected by coping mechanisms and psychological factors.

Durable Multiblock Poly(biphenyl alkylene) Anion Exchange Membranes with Microphase Separation for Hydrogen Energy Conversion.

Anion exchange membrane fuel cells (AEMFCs) and water electrolysis (AEMWE) show great application potential in the field of hydrogen energy conversion technology. However, scalable anion exchange membranes (AEMs) with desirable properties are still lacking, which greatly hampers the commercialization of this technology. Herein, we propose a series of novel multiblock AEMs based on ether-free poly(biphenyl ammonium-b-biphenyl phenyl)s (PBPA-b-BPPs) that are suitable for use in high performance AEMFC and AEMWE systems because of their well-formed microphase separation structures. The developed AEMs achieved outstanding OH- conductivity (162.2 mS cm-1 at 80 °C) with a low swelling ratio, good alkaline stability, and excellent mechanical durability (tensile strength >31 MPa and elongation at break >147 % after treatment in 2 M NaOH at 80 °C for 3750 h). A PBPA-b-BPP-based AEMFC demonstrated a remarkable peak power density of 2.41 W cm-2 and in situ durability for 330 h under 0.6 A cm-2 at 70 °C. An AEMWE device showed a promising performance (6.25 A cm-2 at 2 V, 80 °C) and outstanding in situ durability for 3250 h with a low voltage decay rate (<28 µV h-1 ). The newly developed PBPA-b-BPP AEMs thus show great application prospects for energy conversion devices.

Proteomics-based diagnostic peptide discovery for severe fever with thrombocytopenia syndrome virus in patients.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) virus is an emerging infectious virus which causes severe hemorrhage, thrombocytopenia, and leukopenia, with a high fatality rate. Since there is no approved therapeutics or vaccines for SFTS, early diagnosis is essential to manage this infectious disease. METHODS: Here, we tried to detect SFTS virus in serum samples from SFTS patients by proteomic analysis. Firstly, in order to obtain the reference MS/MS spectral data of SFTS virus, medium from infected Vero cell culture was used for shotgun proteomic analysis. Then, tryptic peptides in sera from SFTS patients were confirmed by comparative analysis with the reference MS/MS spectral data of SFTS virus. RESULTS: Proteomic analysis of culture medium successfully discovered tryptic peptides from all the five antigen proteins of SFTS virus. The comparative spectral analysis of sera of SFTS patients revealed that the N-terminal tryptic peptide of the nucleocapsid (N) protein is the major epitope of SFTS virus detected in the patient samples. The prevalence of the peptides was strongly correlated with the viral load in the clinical samples. CONCLUSIONS: Proteomic analysis of SFTS patient samples revealed that nucleocapsid (N) protein is the major antigen proteins in sera of SFTS patients and N-terminal tryptic peptide of the N protein might be a useful proteomic target for direct detection of SFTS virus. These findings suggest that proteomic analysis could be an alternative tool for detection of pathogens in clinical samples and diagnosis of infectious diseases.

Prospective associations of multimodal serum biomarkers with 12-week and 12-month remission in patients with depressive disorders receiving stepwise psychopharmacotherapy.

Prognostic biomarkers for depression treatment outcomes have yet to be elucidated. This study sought to evaluate whether a multi-modal serum biomarker panel was prospectively associated with 12-week and 12-month remission in outpatients with depressive disorders receiving stepwise psychopharmacotherapy. At baseline, 14 serum biomarkers and socio-demographic/clinical characteristics were evaluated in 1094 patients. They received initial antidepressant monotherapy followed, as required by a protocol of successive alternative pharmacological strategies administered in 3-week steps during the acute (3-12 week) phase (N = 1086), and in 3-month steps during the continuation (6-12 month) phase (N = 884). Remission was defined as a Hamilton Depression Rating Scale score of ≤ 7. Remission was achieved in 490 (45.1%) over the 12-week, and in 625 (70.7%) over the 12-month, treatment periods. Combination scores of four serum biomarkers (high-sensitivity C-reactive protein, interleukin-1 beta, interleukin-6, and leptin) were prospectively associated with 12-week remission; and four (high-sensitivity C-reactive protein, tumor necrosis factor-alpha, interleukin-1 beta, and brain-derived neurotrophic factor) were prospectively associated with 12-month remission in a clear gradient manner (P-values < 0.001) and after adjustment for relevant covariates. These associations were evident after the Step 1 treatment monotherapy but weakened with increasing treatment steps, falling below statistical significance after 4 + treatment steps. Application of combined multiple serum biomarkers, particularly on inflammatory markers, could improve predictability of remission at acute and continuation treatment phases for depressive disorders. Patients with unfavourable biomarkers might require alternative treatment regimes for better outcomes.

Interaction effect between childhood abuse and interleukin-1ß levels on suicidality in depressed patients.

INTRODUCTION: The roles of childhood abuse and interleukin (IL)-1ß levels, a representative pro-inflammatory cytokine, in suicidal behavior are unclear. This study investigated the main and interactive effects of childhood abuse and IL-1ß levels on suicidal behavior in patients with a depressive disorder before and after pharmacological treatment. METHODS: At baseline, exposure to self-reported childhood abuse, including emotional, physical, and sexual abuse, before the age of 16 years, and IL-1ß levels, were measured in 1,094 outpatients with a depressive disorder, 884 of whom were followed for 1 year. Suicidal behavior was evaluated, including previous suicide attempts (at baseline), suicidal ideation (at baseline and follow-up), and fatal/non-fatal suicide attempts (at follow-up). The main and interaction effects of self-reported childhood abuse and IL-1ß level on the four types of suicidal behavior were analyzed using logistic regression after adjusting for covariates. RESULTS: Individual associations of self-reported childhood abuse were significant only with previous suicidal attempt but not with other suicidal behaviors. There was no significant association of plasma IL-1ß level with any suicidal behavior. There were significant interactive associations of self-reported childhood abuse and a high IL-1ß level on previous suicide attempts, baseline suicidal ideation, and fatal/non-fatal suicidal attempts during follow-up. CONCLUSION: Suicidal behavior in patients with a depressive disorder could be influenced by considering the interactive effect of childhood abuse and IL-1ß levels. Our study suggests that childhood trauma and biochemical factors play roles in the pathology of suicide in depressed patients.

Digital Twin-Based Integrated Monitoring System: Korean Application Cases.

A digital twin is a virtual model of a process, product, or service, which is one of the key technologies in the fourth industry. The pairing of the virtual and physical world allows analysis of data and monitoring of systems to head off problems before they occur. This paper presents a digital twin architecture and a system based on an interoperable data model. It explains how to build a digital twin for the integrated control monitoring using edge devices, data analytics, and realistic 3D visualization. The system allows continuous collaboration between field engineers for data gathering, designers for modeling 3D models, and layout engineers for layout changing by generating 3D digital twin models automatically. The system helps stakeholders focus on their respective roles to build digital twins. Examples applied to the Korean automotive parts makers are also introduced in this paper. The system can be easily used by small and medium-sized enterprises (SMEs) as well as large companies. Beyond simply watching the production site with CCTV, the production site can be intuitively managed based on the digital twin.

Depressed mood, associated factors, and understanding of delirium among caregivers of patients with delirium.

OBJECTIVE: Delirium is stressful for both the patient and caregiver. However, caregivers have attracted minimal attention. We here identify depressed moods and associated factors among caregivers and caregiver knowledge of the delirium and non-pharmacological management. METHODS: This was a cross-sectional study. Caregiver and patient demographic characteristics, and patient clinical data, were collected. Caregiver depressed mood was analysed using the Hospital Anxiety and Depression Scale-depression subscale (HADS-D). We explored caregiver understanding of delirium and knowledge of non-pharmacological management. We used a multivariate linear regression model to identify factors associated with caregiver depressed mood. RESULTS: For 224 caregivers, the median (interquartile range) HADS-D score was 8.0 (4.0-11.8). More than half (54.9%) had scores ≥8. Answers to multiple choice questions revealed that delirium was frequently misinterpreted as "anxiety" (25.9%) or "dementia" (25.4%). Of all caregivers, 74% had received no information on non-pharmacological delirium management. Younger age of patient, a longer time from delirium detection to consultation, a patient past history of depression, a spousal relation with the patient, and misinterpretation of delirium as dementia were associated with the depressed mood of caregivers. CONCLUSIONS: The mental health of caregivers of patients with delirium requires more attention; they should be recommended to be informed and educated about delirium. Also, the clinicians need to find an easier term for the delirium to help caregivers understand.

Site-Specific Glycan Microheterogeneity Evaluation of Aflibercept Fusion Protein by Glycopeptide-Based LC-MSMS Mapping.

The evaluation of the protein glycosylation states of samples of aflibercept obtained from three different regions was conducted by site-specific N-linked glycan microheterogeneity profiling. Glycopeptide-based nano-LC MSMS mapping of tryptic-digested samples of each aflibercept lot provided site-specific information about glycan microheterogeneity on each of the five N-glycosylation sites (two sites in the VEGFR-1 region, two sites in the VEGFR-2 region, and one site in the human IgG Fc region). Next, the glycopeptide-mapping results obtained from the three different aflibercept lots were compared to evaluate the similarity between the samples. Three aflibercept lots showed a high degree of similarity in glycan composition, fucosylation level, sialylation level, and branching, when all five N-glycosylation sites were assessed together as a group. On the other hand, noticeable variations between lots in the glycan types and sialylation levels on the two sites of the VEGFR-2 domain were observed when each of the five N-glycosylation sites were assessed using the glycopeptide-based method. The presence of N-glycolylneuraminic acid (NeuGc) glycans, which may mediate adverse immune reactions in antibody therapeutics, were also detected on the sites of VEGFR1 and VEGFR2 domains, but not on the IgG Fc domain site. These results imply that analyses of the glycosylation profiles of fusion proteins containing multiple N-glycosylation sites, such as aflibercept, being done as a part of quality control for the therapeutics manufacturing process or for biosimilar development, can be done with a more applicable outcome by assessing each site separately.

Regulation of hypoxia responses by flavin adenine dinucleotide-dependent modulation of HIF-1α protein stability.

Oxygen deprivation induces a range of cellular adaptive responses that enable to drive cancer progression. Here, we report that lysine-specific demethylase 1 (LSD1) upregulates hypoxia responses by demethylating RACK1 protein, a component of hypoxia-inducible factor (HIF) ubiquitination machinery, and consequently suppressing the oxygen-independent degradation of HIF-1α. This ability of LSD1 is attenuated during prolonged hypoxia, with a decrease in the cellular level of flavin adenine dinucleotide (FAD), a metabolic cofactor of LSD1, causing HIF-1α downregulation in later stages of hypoxia. Exogenously provided FAD restores HIF-1α stability, indicating a rate-limiting role for FAD in LSD1-mediated HIF-1α regulation. Transcriptomic analyses of patient tissues show that the HIF-1 signature is highly correlated with the expression of LSD1 target genes as well as the enzymes of FAD biosynthetic pathway in triple-negative breast cancers, reflecting the significance of FAD-dependent LSD1 activity in cancer progression. Together, our findings provide a new insight into HIF-mediated hypoxia response regulation by coupling the FAD dependence of LSD1 activity to the regulation of HIF-1α stability.

Open stomata 1 exhibits dual serine/threonine and tyrosine kinase activity in regulating abscisic acid signaling.

Open Stomata 1 (OST1)/SnRK2.6 is a critical component connecting abscisic acid (ABA) receptor complexes and downstream components, including anion channels and transcription factors. Because OST1 is a serine/threonine kinase, several autophosphorylation sites have been identified, and S175 is known to be critical for its kinase activity. We previously reported that BAK1 interacts with and phosphorylates OST1 to regulate ABA signaling. Here, we mapped additional phosphosites of OST1 generated by autophosphorylation and BAK1-mediated transphosphorylation in Arabidopsis. Many phosphosites serve as both auto- and transphosphorylation sites, especially those clustered in the activation loop region. Phospho-mimetic transgenic plants containing quadruple changes in Y163, S164, S166, and S167 rescued ost1 mutant phenotypes, activating ABA signaling outputs. Moreover, we found that OST1 is an active tyrosine kinase, autophosphorylating the Y182 site. ABA induced tyrosine phosphorylation of Y182 in OST1; this event is catalytically important for OST1 activity in plants. ABA-Insensitive 1 (ABI1) and its homologs ABI2 and HAB1, PP2C serine/threonine phosphatases that are known to dephosphorylate OST1 at S175, function as tyrosine phosphatases acting on the phosphorylated Y182 site. Our results indicate that phosphorylation cycles between OST1 and ABI1, which have dual specificity for tyrosine and serine/threonine, coordinately control ABA signaling in Arabidopsis.

Investigating associations of childhood abuse and serum brain-derived neurotrophic factor levels with suicidal behaviours in patients with depressive disorders.

BACKGROUND: The role of childhood abuse and serum brain-derived neurotrophic factor (BDNF) levels in suicidal behaviour is controversial. AIMS: We aimed to investigate the individual and interactive effects of the childhood abuse and serum BDNF on suicidal behaviour before and after pharmacologic treatment in patients with depressive disorders. METHOD: At baseline, reported childhood emotional, physical and sexual abuse were ascertained and serum BDNF levels were measured in 1094 patients with depressive disorder, 884 of whom were followed during a 1-year period of stepwise pharmacotherapy. Suicidal behaviours evaluated at baseline were previous suicide attempt and baseline suicide severity, and suicidal behaviours evaluated at follow-up were increased suicide severity and fatal/non-fatal suicide attempt. Individual and interactive associations of any childhood abuse and serum BDNF levels with four types of suicidal behaviours were analysed using logistic regression models, after adjusting relevant covariates. RESULTS: Individual associations of childhood abuse were significant only with previous suicide attempt, and no significant individual associations were found for serum BDNF with any suicide outcome. However, the presence of both childhood abuse and lower serum BDNF levels was associated with the highest prevalence/incidence of all four suicidal behaviours, with significant interactions for baseline suicide severity and fatal/non-fatal suicide attempt during follow-up. CONCLUSIONS: Synergistic interactive effects of child abuse and serum BDNF levels on suicidal behaviours were found before and after pharmacologic treatment in patients with depressive disorders. Information combining childhood abuse and serum BDNF levels could improve predictions of suicidal behaviour in patients with depressive disorders.

Long-term cardiac outcomes of depression screening, diagnosis and treatment in patients with acute coronary syndrome: the DEPACS study.

BACKGROUND: To investigate the impacts of depression screening, diagnosis and treatment on major adverse cardiac events (MACEs) in acute coronary syndrome (ACS). METHODS: Prospective cohort study including a nested 24-week randomised clinical trial for treating depression was performed with 5-12 years after the index ACS. A total of 1152 patients recently hospitalised with ACS were recruited from 2006 to 2012, and were divided by depression screening and diagnosis at baseline and 24-week treatment allocation into five groups: 651 screening negative (N), 55 screening positive but no depressive disorder (S), 149 depressive disorder randomised to escitalopram (E), 151 depressive disorder randomised to placebo (P) and 146 depressive disorder receiving medical treatment only (M). RESULTS: Cumulative MACE incidences over a median 8.4-year follow-up period were 29.6% in N, 43.6% in S, 40.9% in E, 53.6% in P and 59.6% in M. Compared to N, screening positive was associated with higher incidence of MACE [adjusted hazards ratio 2.15 (95% confidence interval 1.63-2.83)]. No differences were found between screening positive with and without a formal depressive disorder diagnosis. Of those screening positive, E was associated with a lower incidence of MACE than P and M. M had the worst outcomes even compared to P, despite significantly milder depressive symptoms at baseline. CONCLUSIONS: Routine depression screening in patients with recent ACS and subsequent appropriate treatment of depression could improve long-term cardiac outcomes.