Deubiquitination and Activation of AMPK by USP10.

The AMP-activated protein kinase (AMPK) is the master regulator of metabolic homeostasis by sensing cellular energy status. When intracellular ATP levels decrease during energy stress, AMPK is initially activated through AMP or ADP binding and phosphorylation of a threonine residue (Thr-172) within the activation loop of its kinase domain. Here we report a key molecular mechanism by which AMPK activation is amplified under energy stress. We found that ubiquitination on AMPKα blocks AMPKα phosphorylation by LKB1. The deubiquitinase USP10 specifically removes ubiquitination on AMPKα to facilitate AMPKα phosphorylation by LKB1. Under energy stress, USP10 activity in turn is enhanced through AMPK-mediated phosphorylation of Ser76 of USP10. Thus, USP10 and AMPK form a key feedforward loop ensuring amplification of AMPK activation in response to fluctuation of cellular energy status. Disruption of this feedforward loop leads to improper AMPK activation and multiple metabolic defects.

Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1.

Mutations in the E3 ubiquitin ligase Parkin have been linked to familial Parkinson's disease. Parkin has also been implicated in mitosis through mechanisms that are unclear. Here we show that Parkin interacts with anaphase promoting complex/cyclosome (APC/C) coactivators Cdc20 and Cdh1 to mediate the degradation of several key mitotic regulators independent of APC/C. We demonstrate that ordered progression through mitosis is orchestrated by two distinct E3 ligases through the shared use of Cdc20 and Cdh1. Furthermore, Parkin is phosphorylated and activated by polo-like kinase 1 (Plk1) during mitosis. Parkin deficiency results in overexpression of its substrates, mitotic defects, genomic instability, and tumorigenesis. These results suggest that the Parkin-Cdc20/Cdh1 complex is an important regulator of mitosis.

WSB1 promotes tumor metastasis by inducing pVHL degradation.

The von Hippel-Lindau tumor suppressor pVHL is an E3 ligase that targets hypoxia-inducible factors (HIFs). Mutation of VHL results in HIF up-regulation and contributes to processes related to tumor progression such as invasion, metastasis, and angiogenesis. However, very little is known with regard to post-transcriptional regulation of pVHL. Here we show that WD repeat and SOCS box-containing protein 1 (WSB1) is a negative regulator of pVHL through WSB1's E3 ligase activity. Mechanistically, WSB1 promotes pVHL ubiquitination and proteasomal degradation, thereby stabilizing HIF under both normoxic and hypoxic conditions. As a consequence, WSB1 up-regulates the expression of HIF-1α's target genes and promotes cancer invasion and metastasis through its effect on pVHL. Consistent with this, WSB1 protein level negatively correlates with pVHL level and metastasis-free survival in clinical samples. This work reveals a new mechanism of pVHL's regulation by which cancer acquires invasiveness and metastatic tendency.

Longitudinal symptom network structure in first-episode psychosis: a possible marker for remission.

BACKGROUND: Network approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up. METHODS: Participants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time. RESULTS: Global network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range. CONCLUSION: Our findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

Estimation of Local Bone Loads for the Volume of Interest.

Computational bone remodeling simulations have recently received significant attention with the aid of state-of-the-art high-resolution imaging modalities. They have been performed using localized finite element (FE) models rather than full FE models due to the excessive computational costs of full FE models. However, these localized bone remodeling simulations remain to be investigated in more depth. In particular, applying simplified loading conditions (e.g., uniform and unidirectional loads) to localized FE models have a severe limitation in a reliable subject-specific assessment. In order to effectively determine the physiological local bone loads for the volume of interest (VOI), this paper proposes a novel method of estimating the local loads when the global musculoskeletal loads are given. The proposed method is verified for the three VOI in a proximal femur in terms of force equilibrium, displacement field, and strain energy density (SED) distribution. The effect of the global load deviation on the local load estimation is also investigated by perturbing a hip joint contact force (HCF) in the femoral head. Deviation in force magnitude exhibits the greatest absolute changes in a SED distribution due to its own greatest deviation, whereas angular deviation perpendicular to a HCF provides the greatest relative change. With further in vivo force measurements and high-resolution clinical imaging modalities, the proposed method will contribute to the development of reliable patient-specific localized FE models, which can provide enhanced computational efficiency for iterative computing processes such as bone remodeling simulations.

Computational comparison study of virtual compression and shear test for estimation of apparent elastic moduli under various boundary conditions.

Virtual compression tests based on finite element analysis are representative noninvasive methods to evaluate bone strength. However, owing to the characteristic porous structure of bones, the material obtained from micro-computed tomography images in the finite-element model is not uniformly distributed. These characteristics cause differences in the apparent elastic moduli depending on the boundary conditions and affect the accuracy of bone-strength evaluation. Therefore, this study aimed to evaluate and compare the apparent elastic moduli under various, virtual-compression and shear-test boundary conditions. Four, nonuniform models were constructed with increasing model complexity. For representative boundary conditions, two, different, testing directions, and constrained surfaces were applied. As a result, the apparent elastic moduli of the nonuniform model varied up to 55.2% based on where the constrained surface was located in the single-end-cemented condition. Additionally, when connectivity in the test direction was lost, the accuracy of the apparent elastic moduli was low. A graphical comparison showed that the equivalent-stress distribution was more advantageous for analyzing load transferability and physical behavior than the strain-energy distribution. These results clearly show that the prediction accuracy of the apparent elastic moduli can be guaranteed if the boundary condition on the constraint and loading surfaces of the nonuniform model are applied symmetrically and the connectivity of the elements in the testing direction is well maintained. This study will aid in precision improvement of bone-strength-indicator determination for osteoporosis prevention.

Romo1 is a negative-feedback regulator of Myc.

Degradation of Myc protein is mediated by E3 ubiquitin ligases, including SCF(Fbw7) and SCF(Skp2), but much remains unknown about the mechanism of S-phase kinase-associated protein (Skp2)-mediated Myc degradation. In the present study, we show that upregulated Myc protein, which triggers the G1-S phase progression in response to growth-stimulatory signals, induces reactive oxygen species modulator 1 (Romo1) expression. Romo1 subsequently triggers Skp2-mediated ubiquitylation and degradation of Myc by a mechanism not previously reported in normal lung fibroblasts. We also show that reactive oxygen species (ROS) derived from steady-state Romo1 expression are necessary for cell cycle entry of quiescent cells. From this study, we suggest that the generation of ROS mediated by pre-existing Romo1 protein is required for Myc induction. Meanwhile, Romo1 expression induced by Myc during G1 phase stimulates Skp2-mediated Myc degradation in a negative-feedback mechanism.

Characteristics associated with low resilience in patients with depression and/or anxiety disorders.

PURPOSE: Despite a growing body of research on resilience and its clinical significance in depression and anxiety disorders, relatively little is known about contributing factors for resilience in patients with these illnesses. We aimed to find characteristics of patients having low resilience for elucidating its clinical implications in depression and/or anxiety disorders, primarily focused on potentially modifiable variables. METHODS: A total of 121 outpatients diagnosed with depression and/or anxiety disorders completed questionnaires measuring socio-demographic, clinical, and positive psychological factors. We divided patients into the three groups based on their Connor-Davidson resilience scale scores and investigated predictors of the low- and medium- versus high-resilience groups using multinomial logistic regression analysis. RESULTS: In the final regression model, low spirituality was revealed as a leading predictor of lower-resilience groups. Additionally, low purpose in life and less frequent exercise were associated with the low- and medium-resilience groups, respectively. Severe trait anxiety characterized the low- and medium-resilience groups, although it was not included in the final model. CONCLUSIONS: Spirituality, purpose in life, and trait anxiety contribute to different levels of resilience in patients with depression and/or anxiety disorders. Our results would deepen the understanding of resilience and provide potential targets of resilience-focused intervention in these patients.

Quantitative Load Dependency Analysis of Local Trabecular Bone Microstructure to Understand the Spatial Characteristics in the Synthetic Proximal Femur.

Analysis of the dependency of the trabecular structure on loading conditions is essential for understanding and predicting bone structure formation. Although previous studies have investigated the relationship between loads and structural adaptations, there is a need for an in-depth analysis of this relationship based on the bone region and load specifics. In this study, the load dependency of the trabecular bone microstructure for twelve regions of interest (ROIs) in the synthetic proximal femur was quantitatively analyzed to understand the spatial characteristics under seven different loading conditions. To investigate the load dependency, a quantitative measure, called the load dependency score (LDS), was established based on the statistics of the strain energy density (SED) distribution. The results showed that for the global model and epiphysis ROIs, bone microstructures relied on the multiple-loading condition, whereas the structures in the metaphysis depended on single or double loads. These results demonstrate that a given ROI is predominantly dependent on a particular loading condition. The results confirm that the dependency analysis of the load effects for ROIs should be performed both qualitatively and quantitatively.

Effects of Long-acting Injectable 3-Monthly Paliperidone Palmitate on the Clinical and Social Performance of Patients with Schizophrenia.

Objective: To investigate the effects of long-acting injectable 3-monthly paliperidone palmitate on the clinical and social functioning of patients with schizophrenia. Methods: This study enrolled patients with schizophrenia receiving long-acting injectable 1-monthly paliperidone palmitate for at least 4 months and who subsequently received 3-monthly paliperidone palmitate. Accordingly, 418 patients were followed up for 24 weeks. Their clinical symptoms and social functioning were measured using the Clinical Global Impression-Severity of Illness and Personal and Social Performance scales. Results: The Personal and Social Performance total score was significantly higher after 3-monthly paliperidone palmitate treatment than at baseline (baseline vs. week 24: 54.3 ± 18.0 vs. 61.0 ± 14.5 [mean ± standard deviation]; p < 0.001; Wilcoxon signed-rank test); the proportion of patients in the mildly ill group (scores 71-100) also increased significantly (baseline vs. week 24: 16.5% vs. 20.6%; p < 0.001; McNemar-Bowker test). The mean Clinical Global Impression-Severity of Illness score decreased significantly (baseline vs. week 24: 3.7 ± 1.0 vs. 3.4 ± 0.9; p < 0.001; Wilcoxon signed-rank test), as did the proportion of patients in the severely ill group (baseline vs. week 24: 4.1% vs. 2.1%; p < 0.001; McNemar-Bowker test). Conclusion: Continuous 3-monthly paliperidone palmitate treatment significantly enhances the personal and social performance of patients with schizophrenia and reduces the proportion of those with severe illness. These findings suggest that long-acting injectable antipsychotic administration at intervals longer than 1 month might improve the social functioning of and promote return to activities of daily living in patients with schizophrenia.

Predictors of full recovery in patients with early stage schizophrenia spectrum disorders.

To promote recovery in psychosis, targeting modifiable factors related to recovery is critical. Using more strict definition of full recovery, we examined predictors for recovery in patients with early stage schizophrenia spectrum disorders (SSD) followed up to 6.5 years. The target subjects were 375 patients with early stage SSD who had been over at least 1-year after registration and evaluated. The criteria for full recovery were having the score of the Positive and Negative Syndrome Scale (PANSS) 8-item ≤ 2 and adequate functional recovery for at least 1-year. We performed univariate Cox and stepwise Cox regression in both total and acute patients. In stepwise Cox regression, several independent predictors for recovery, i.e., negative symptoms of the PANSS, duration of untreated psychosis (DUP) and non-professional job were identified in patients with early stage SSD. In acute patients, other factors such as professional job and subjective well-being under neuroleptics were more important. The present study identified independent predictors for recovery modifiable by various psychosocial intervention and early intervention services. Moreover, it highlights the need of providing different treatment strategies depending on clinical status.

The simplified Edinburgh Postnatal Depression Scale (EPDS) for antenatal depression: is it a valid measure for pre-screening?

The identification of antenatal depression is critical but poorly conducted. The aim of this study was to construct a simplified depression survey scale and to verify its efficacy as a pre-screening for antenatal depression. A total of 494 pregnant women in the third trimester of gestation who had received antenatal care at Seoul St. Mary's Hospital from July 2009 to June 2010 were included. The Edinburgh Postnatal Depression Scale (EPDS) questionnaire was completed by them. The subjects were randomly divided into two groups: 250 of training set and 244 of validation set. We designed a simplified questionnaire comprising two items of EPDS using the training set. We then validated its efficacy with the training set and reaffirmed the results with the validation set. The sum of item 5 (scare or panic) and item 8 (sadness or misery) explained 75.5% of the total score of the EPDS (AUC = 0.947). Using a score of 3 as a cut-off value of the simplified scale, sensitivity was 92.4% and specificity was 86.3%. The positive and negative predictive values were 56.2% and 98.4%, retrospectively. This study suggests that the simplified EPDS can be an efficient instrument to rule out depression during pregnancy.

Feeling of cold hands and feet is a highly heritable phenotype.

The prevalence of the feeling of cold hands and feet (FCHF) is high in the general population but the etiology of FCHF is largely unknown. The aim of the present study was to explore whether the FCHF is heritable. Eight hundred and ninety-four pairs of twins completed a question about FCHF. Tetrachoric correlations for FCHF were .58, .29, .67, .52, and .04 for monozygotic male, dizygotic male, monozygotic female, and dizygotic female twins, respectively. Model-fitting analyses suggested that in the best fitting model, additive genetic and nonshared environmental variance including measurement error were 64% (95% CI: 55%-72%) and 36% (28%-45%), respectively. Sex differences in genetic and environmental influences were not significant.

Topology Optimization-Based Localized Bone Microstructure Reconstruction for Image Resolution Enhancement: Accuracy and Efficiency.

Topology optimization is currently the only way to provide bone microstructure information by enhancing a 600 µm low-resolution image into a 50 µm high-resolution image. Particularly, the recently proposed localized reconstruction method for the region of interest has received much attention because it has a high possibility to overcome inefficiency such as iterative large-scale problems of the conventional reconstruction. Despite the great potential, the localized method should be thoroughly validated for clinical application. This study aims to quantitatively validate the topology optimization-based localized bone microstructure reconstruction method in terms of accuracy and efficiency by comparing the conventional method. For this purpose, this study re-constructed bone microstructure for three regions of interest in the proximal femur by localized and conventional methods, respectively. In the comparison, the dramatically reduced total progress time by at least 88.2% (20.1 h) as well as computational resources by more than 95.9% (54.0 gigabytes) were found. Moreover, very high reconstruction accuracy in the trabecular alignment (up to 99.6%) and morphometric indices (up to 2.71%) was also found. These results indicated that the localized method could reconstruct bone microstructure, much more effectively preserving the originality of the conventional method.

Methylome-wide Association Study of Patients with Recent-onset Psychosis.

Objective: Dysregulation of gene expression through epigenetic mechanisms may have a vital role in the pathogenesis of schizophrenia (SZ). In this study, we investigated the association of altered methylation patterns with SZ symptoms and early trauma in patients and healthy controls. Methods: The present study was conducted to identify methylation changes in CpG sites in peripheral blood associated with recent-onset (RO) psychosis using methylome-wide analysis. Lifestyle factors, such as smoking, alcohol, exercise, and diet, were controlled. Results: We identified 2,912 differentially methylated CpG sites in patients with RO psychosis compared to controls. Most of the genes associated with the top 20 differentially methylated sites had not been reported in previous methylation studies and were involved in apoptosis, autophagy, axonal growth, neuroinflammation, protein folding, etc. The top 15 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways included the oxytocin signaling pathway, long-term depression pathway, axon guidance, endometrial cancer, long-term potentiation, mitogen-activated protein kinase signaling pathway, and glutamatergic pathway, among others. In the patient group, significant associations of novel methylated genes with early trauma and psychopathology were observed. Conclusion: Our results suggest an association of differential DNA methylation with the pathophysiology of psychosis and early trauma. Blood DNA methylation signatures show promise as biomarkers of future psychosis.

The factor structure and clinical utility of clinician-rated dimensions of psychosis symptom severity in patients with recent-onset psychosis: Results of a 1-year longitudinal follow-up prospective cohort study.

The classic subtype classification of schizophrenia has been removed, and DSM-5 now includes the Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS). In the present study, a factor analysis of the CRDPSS was performed, and we assessed whether patient classification using the derived factor structure helps predict the clinical course. The participants were 390 patients with recent-onset psychosis enrolled in the Korean Early Psychosis Cohort Study (KEPS). Two factors were identified: psychotic (including delusions, hallucinations, disorganization, and abnormal psychomotor behavior) and negative-cognitive (including negative symptoms and impaired cognition). Patients were grouped based on the factor structure and changes in clinical course were monitored over 1 year. The negative-cognitive group demonstrated longer duration of untreated psychosis, earlier onset, and a higher rate of psychiatric comorbidities. Baseline Positive and Negative Syndrome Scale (PANSS) total and Clinical Global Impression-Severity (CGI-S) scores were higher in psychotic group, but group differences were not observed after 2 months. Conversely, the PANSS negative scale score was significantly higher in negative-cognitive group throughout follow-up, and CGI-S score was reversed at 12 months. The findings indicate that the factor structure derived herein for the CRDPSS could be helpful for predicting the clinical course of recent-onset psychosis patients.

Effects of COVID-19-related stress and fear on depression in schizophrenia patients and the general population.

This study compared the coronavirus disease 2019 (COVID-19)-related stress, fear of infection, loneliness, and depression between patients with schizophrenia and the general population. A face-to-face survey was administered to 1340 patients with a schizophrenia spectrum disorder and online survey of the general population (n = 2000) was conducted. The information gathered included the level of COVID-19-related stress, fear of infection, the Patient Health Questionnaire-9 score, and the three-item UCLA Loneliness Scale score. Structural equation modeling revealed a significant effect of fear of COVID-19 infection on depression among the general population and on loneliness among patients with schizophrenia. Loneliness experienced during COVID-19 exacerbated depression in both groups. In the COVID-19-related stress-loneliness-depression pathway, the partial mediating effect of loneliness was significant in both groups. Conversely, in the COVID-19-related fear-loneliness-depression pathway, the full mediating effect of loneliness was only significant in patients with schizophrenia. In conclusion, the loneliness associated with COVID-19-related stress and fear of infection was an important factor influencing depression, and the impact was greater in patients with schizophrenia compared with the general population. Thus, different mental health intervention plans are needed for patients with schizophrenia during the COVID-19 pandemic. During the long-lasting COVID-19 pandemic, social support and provision of mental health services to prevent loneliness and consequent depression are required in patients with schizophrenia.

Symptomatic and full remission rates in first-episode psychosis: A 12-month follow-up study in Korea.

AIM: In the present study, the prevalence and predictors of symptomatic and full remission were investigated in patients with first-episode psychosis (FEP) at the 12-month follow-up. METHODS: A total of 308 participants aged 18-45 years fulfilled the study inclusion criteria and 214 completed the 12-month follow-up. RESULTS: At the 12-month follow-up, 67.3% (142) and 25.9% (55) of the FEP patients met the criteria for symptomatic and full remission, respectively. Stepwise logistic regression analysis showed a shorter duration of untreated psychosis (DUP), no family history, lower Positive and Negative Syndrome Scale (PANSS) negative symptom scores at baseline and higher familial support predicted symptomatic remission at the 12-month follow-up. A higher educational level, shorter DUP, lower PANSS general symptoms scores at baseline and higher subjective well-being under neuroleptics emotional regulation scores predicted full remission. CONCLUSIONS: Our findings regarding the rates of symptomatic and full remission are consistent with previous studies. The results indicate a large discrepancy between symptomatic versus full remission rates at a 12-month follow-up in patients with FEP. Effective psychosocial interventions are necessary to improve the outcomes of FEP patients.

DNA Methylation Profiles of the DRD2 and NR3C1 Genes in Patients with Recent-Onset Psychosis.

Objectives: Dopamine receptor D2 gene (DRD2) and glucocorticoid receptor gene (NR3C1) are implicated in the development of psychosis. We investigated methylation levels of DRD2 and NR3C1 in peripheral blood of patients with recent-onset (RO) psychosis using bisulfite pyrosequencing as well as its association with childhood trauma and rumination. Methods: In all, 51 individuals with RO psychosis and 47 healthy controls were recruited. DNA methylation levels in the targeted regions of two genes were analyzed and compared. Childhood trauma and rumination were evaluated using the Early Trauma Inventory Self-Report Short Form (ETI-SF) and Brooding Scale (BS), respectively. Correlations between the scores of the ETI-SF and BS and methylation levels were explored. Results: For DRD2, we found no significant differences between groups in terms of methylation level or association with childhood trauma or rumination. For NR3C1, we found a trend level significance for average value of all CpG sites and significant hypermethylation or hypomethylation at specific sites. There was also a significant positive correlation between the methylation level at the CpG8 site of NR3C1 exon 1F and negative symptom subscale score of the PANSS (PANSS-N). Conclusion: Epigenetic alterations of NR3C1 are associated with the pathophysiology of psychosis. Further epigenetic studies will elucidate the molecular mechanisms underpinning the pathophysiology of psychosis.

Development of the Korea-Polyenvironmental Risk Score for Psychosis.

OBJECTIVE: Comprehensive understanding of polyenvironmental risk factors for the development of psychosis is important. Based on a review of related evidence, we developed the Korea Polyenvironmental Risk Score (K-PERS) for psychosis. We investigated whether the K-PERS can differentiate patients with schizophrenia spectrum disorders (SSDs) from healthy controls (HCs). METHODS: We reviewed existing tools for measuring polyenvironmental risk factors for psychosis, including the Maudsley Environmental Risk Score (ERS), polyenviromic risk score (PERS), and Psychosis Polyrisk Score (PPS). Using odds ratios and relative risks for Western studies and the "population proportion" (PP) of risk factors for Korean data, we developed the K-PERS, and compared the scores thereon between patients with SSDs and HCs. In addition, correlation was performed between the K-PERS and Positive and Negative Syndrome Scale (PANSS). RESULTS: We first constructed the "K-PERS-I," comprising five factors based on the PPS, and then the "K-PERS-II" comprising six factors based on the ERS. The instruments accurately predicted participants' status (case vs. control). In addition, the K-PERS-I and -II scores exhibited significant negative correlations with the negative symptom factor score of the PANSS. CONCLUSION: The K-PERS is the first comprehensive tool developed based on PP data obtained from Korean studies that measures polyenvironmental risk factors for psychosis. Using pilot data, the K-PERS predicted patient status (SSD vs. HC). Further research is warranted to examine the relationship of K-PERS scores with clinical outcomes of psychosis and schizophrenia.