53BP1-ACLY-SLBP-coordinated activation of replication-dependent histone biogenesis maintains genomic integrity.

p53-binding protein 1 (53BP1) regulates the DNA double-strand break (DSB) repair pathway and maintains genomic integrity. Here we found that 53BP1 functions as a molecular scaffold for the nucleoside diphosphate kinase-mediated phosphorylation of ATP-citrate lyase (ACLY) which enhances the ACLY activity. This functional association is critical for promoting global histone acetylation and subsequent transcriptome-wide alterations in gene expression. Specifically, expression of a replication-dependent histone biogenesis factor, stem-loop binding protein (SLBP), is dependent upon 53BP1-ACLY-controlled acetylation at the SLBP promoter. This chain of regulation events carried out by 53BP1, ACLY, and SLBP is crucial for both quantitative and qualitative histone biogenesis as well as for the preservation of genomic integrity. Collectively, our findings reveal a previously unknown role for 53BP1 in coordinating replication-dependent histone biogenesis and highlight a DNA repair-independent function in the maintenance of genomic stability through a regulatory network that includes ACLY and SLBP.

Clinical response and pharmacokinetics of bendamustine as a component of salvage R-B(O)AD therapy for the treatment of primary central nervous system lymphoma (PCNSL).

BACKGROUND: A relatively high proportion of patients diagnosed with primary CNS lymphoma will experience recurrent disease, yet therapy options are limited in salvage therapy. This is the first study to evaluate a bendamustine-based combination regimen for the treatment of relapsed/refractory PCNSL and to characterize bendamustine pharmacokinetics in the human CSF. METHODS: Patients received bendamustine 75 mg/m2 for two days as part of R-B(O)AD administered intravenously every 4 weeks for up to 4 cycles. Response and adverse events of the regimen were assessed. A sparse sampling strategy and population based modeling approach was utilized for evaluation of plasma and CSF levels of bendamustine. RESULTS: Ten patients were enrolled into study of whom 70% were of refractory disease and with high IELSG prognostic risk scores. The ORR of R-BOAD was 50% (95% CI, 0.24 to 0.76) with one patient achieving CR and four PR. Primary toxicity of the regimen was reversible myelosuppression, mostly grade 3 or 4 neutropenia. The Cmax mean for plasma and CSF were 2669 ng/mL and 0.397 ng/mL, respectively, and patients with response at deep tumor sites displayed higher trends in peak exposure. Pharmacokinetic data was best described by a four-compartment model with first-order elimination of drug from central plasma and CSF compartments. CONCLUSIONS: R-BOAD is an effective salvage option for PCNSL, but with significant hematologic toxicity. Bendamustine CSF levels are minimal; however correspond to plasma exposure and response. TRIAL REGISTRATION: ClinicalTrials.gov NCT03392714 ; retrospectively registered January 8, 2018.

Obox4-silencing-activated STAT3 and MPF/MAPK signaling accelerate nuclear membrane breakdown in mouse oocytes.

Mouse oocytes begin to mature in vitro once liberated from ovarian follicles. Previously, we showed that oocyte-specific homeobox 4 (Obox4) is critical for maintaining the intact nuclear membrane of the germinal vesicle (GV) in oocytes and for completing meiosis at the metaphase I-II (MI-MII) transition. This study further examines the molecular mechanisms of OBOX4 in regulating GV nuclear membrane breakdown. Maturation-promoting factor (MPF) and MAPK are normally inactive in GV stage oocytes but were activated prematurely in arrested GV stage oocytes by 3-isobutyl-1-metyl-xanthine (IBMX) in vitro after Obox4 RNA interference (RNAi). Furthermore, signal transducer and activator of transcription 3 (STAT3) was significantly activated by Obox4 RNAi. We confirmed that this Obox4 RNAi-induced premature STAT3 and MPF/MAPK activation at the GV stage provoked subsequent GV breakdown (GVBD) despite the opposing force of high cAMP in the IBMX-supplemented medium to maintain intact GV. When cumulus-oocyte complexes were exposed to interferon α (IFNA), a STAT3 activator, oocytes matured and cumulus cells expanded to resume nuclear maturation in IBMX-supplemented medium, suggesting that STAT3 activation is sufficient for stimulating the continuation of meiosis. Using Stattic, a specific STAT3 inhibitor, we confirmed that GVBD involves STAT3 activation in Obox4-silenced oocytes. Based on these findings, we concluded that i) Obox4 is an important upstream regulator of MPF/MAPK and STAT3 signaling, and ii) Obox4 is a key regulator of the GV arrest mechanism in oocytes.

Anti-inflammatory and antipruritic effects of luteolin from Perilla (P. frutescens L.) leaves.

Perilla (Perilla frutescens L.) leaves have shown therapeutic efficacy in the treatment of inflammatory disorders, allergies, bronchial asthma, and systemic damage due to free radicals. In the present study we analyzed the active constituents in perilla leaves using high-performance liquid chromatography (HPLC) and isolated luteolin, a polyphenolic flavonoid. We investigated the anti-inflammatory and antipruritic properties of luteolin. Luteolin inhibited the secretion of inflammatory cytokines such as interleukin-1ß (IL-1 ß) and tumor necrosis factor-α (TNF-α) from human mast cells (HMC-1) stimulated with phorbol myristate acetate plus calcium ionophore A23187 in a dose-dependent manner. Luteolin also significantly reduced the histamine release from rat peritoneal mast cells stimulated by compound 48/80, a potent histamine liberator. Furthermore, the administration of luteolin markedly inhibited the scratching behavior and vascular permeability induced by pruritogens, such as compound 48/80 or serotonin, in ICR mice. These results suggested that luteolin has potential as a therapeutic agent against inflammation and itch-related skin diseases.

Influence of inter-stimulus interval on 40-Hz auditory steady-state response in patients with schizophrenia.

Decreased 40-Hz auditory steady-state response (ASSR) is believed to reflect abnormal gamma oscillation in patients with schizophrenia (SZ). However, previous studies have reported conflicting results due to variations in inter-stimulus interval (ISI) used. In this study, we aimed to investigate the influence of varying ISI on the 40-Hz ASSR, particularly for patients with SZ and healthy controls (HCs). Twenty-four SZ patients (aged 40.8 ± 13.9 years, male: n = 11) and 21 HCs (aged 33.3 ± 11.3 years, male: n = 8) were recruited. For every participant, 40-Hz ASSRs were acquired for three different stimulus types: 500, 2000, and 3500 ms of ISIs. Two conventional ASSR measures (total power and inter-trial coherence, ITC) were calculated. Several additional ASSR measures were also analyzed: (i) ISI-dependent power; (ii) power onset slope; (iii) power centroid latency; (iv) ISI-dependent ITC; (v) ITC onset slope (500, 2000, 3500 ms); (vi) ITC centroid latency (500, 2000, 3500 ms). As ISI increased, total power and ITC increased in patients with SZ but decreased in HCs. In addition, patients with SZ showed higher ISI-dependent ITC, which was positively correlated with the psychotic symptom severity. The abnormal ITC onset slope and centroid latency for the ISI-500 ms condition were associated with cognitive speed decline in patients with SZ. Our study confirmed that the 40-Hz ASSR could be severely influenced by ISI. Furthermore, our results showed that the additional ASSR measures (ISI-dependent ITC, ITC onset slope, ITC centroid latency) could represent psychotic symptom severity or impairment in cognitive function in patients with SZ.

Oxytocin receptor genes moderate BDNF epigenetic methylation by childhood trauma.

OBJECTIVES: Gene-Environment (G × E) interaction is of increasing importance in understanding the pathophysiology of posttraumatic stress disorder (PTSD). This study investigated the interaction effect of childhood traumatic experience and epigenetic methylation of brain-derived neurotrophic factor (BDNF) and a possible moderating effect of oxytocin receptor (OXTR) gene rs53576. METHODS: Ninety-nine patients with PTSD and 81 healthy controls (HCs) were recruited. Clinical assessments, including the childhood trauma questionnaire (CTQ) and posttraumatic stress disorder Checklist (PCL) were performed. BDNF methylation and OXTR genotyping (A vs. G allele) were conducted through blood sampling. A two-way multivariate analysis and a moderated regression analysis were conducted to investigate the moderating effect of the OXTR gene on the relationship between CTQ and BDNF methylation. RESULTS: As for the HC group, the interaction effect of the CTQ and OXTR genotype was significant on BDNF methylation, and the moderation model showed that CTQ and OXTR group are significant predictors of BDNF methylation. In the G-OXTR type, the high CTQ group showed a greater BDNF methylation level. As for the PTSD group, no interaction or moderation effects were found. LIMITATIONS: The present study did not control the dosage, duration of medications, and different trauma types and the assessment of childhood trauma was based on self-report. CONCLUSIONS: These results suggested that childhood traumatic experience showed a significant impact on BDNF methylation, and OXTR genes have a moderating effect on this epigenetic mechanism in people who have experienced the childhood traumatic episodes.

Association between Dissociative Symptoms and Morning Cortisol Levels in Patients with Post-traumatic Stress Disorder.

Objective: Patients with post-traumatic stress disorder (PTSD) showed inconsistencies in their cortisol level, an index of the hypothalamic-pituitary-adrenal axis function. This study examined the relationship between dissociation, childhood trauma, and morning cortisol levels in PTSD patients. Methods: This study included 69 (23 males and 46 females) patients and 82 (22 males and 60 females) healthy controls (HCs). Clinical assessments, including the Childhood Trauma Questionnaire (CTQ) and Peri-traumatic Dissociative Experiences Questionnaire scores, and morning cortisol levels were evaluated. The morning cortisol levels were compared between PTSD with high dissociation and low dissociation (PTSD-LD) groups. The effect of CTQ subtype on morning cortisol levels was analyzed. Results: The PTSD with high dissociation group showed significantly lower cortisol levels than that of the PTSD-LD and HC groups. A significant inverse correlation was found between cortisol levels and dissociation. A significant positive correlation was found between dissociation and physical abuse and sexual abuse scores. Morning cortisol levels showed a significant positive correlation with emotional abuse, emotional neglect, and physical neglect, respectively. There was no moderating or mediating effect of CTQ on the relationship between cortisol level and dissociation. Conclusion: These findings suggest that dissociation is a significant factor related to hypocortisolism in PTSD patients. Additionally, basal morning cortisol levels and dissociation scores were closely associated with childhood trauma.

Risk and Protective Factors for Childhood Physical Abuse and Suicidal Ideation: The Effect of Brain-Derived Neurotrophic Factor Polymorphism and Social Support.

OBJECTIVE: This study aimed to explore the relationship between childhood physical abuse and suicidal ideation considering the effects of genetic and environmental factors in patients with post-traumatic stress disorder (PTSD) by focusing on brain-derived neurotrophic factor (BDNF) polymorphism and social support, respectively. METHODS: One-hundred fourteen patients with PTSD and 94 healthy controls (HCs) were genotyped with respect to BDNF Val66Met polymorphism. All participants underwent psychological assessments. The hierarchical regression analysis and the simple slope analysis were conducted. RESULTS: As for patients with PTSD, the moderation effect of BDNF polymorphism was significant but not for social support. Specifically, the BDNF Val/Val genotype worked as a risk factor and strengthens the relationship between childhood physical abuse and suicidal ideation. As for the HCs, the significant moderation effect was found only in social support, but not for BDNF polymorphism. The relationship between childhood physical abuse and suicidal ideation was weakened for the HCs with high social support. CONCLUSION: This study demonstrated a significant BDNF genetic vulnerability for suicide in patients with PTSD who experienced childhood physical abuse. Our results suggested that social support provided a mitigating effect on the relationship between childhood physical abuse and suicidal ideation only in the HCs.

Identification of an autosomal dominant locus for intracranial aneurysm through a model-based family collection in a geographically limited area.

Intracranial aneurysm (IA) is characterized by an abnormal bulging of one of the arteries in the brain and is heavily affected by genetic factors. Although IA is a very serious disease because of its severity and prevalence in the general public, the gene causing IA has not yet been identified due mainly to the lack of definitive genetic loci for the disease. Following a model-based family collection that recruited families from a geographically limited area that inherited IA as an autosomal dominant trait, we conducted a genome-wide linkage analysis. Significant evidence of linkage to IA was found on chromosome 8p22.2 with a maximum two-point logarithm of the odds ratio score of 3.61 under an autosomal dominant model of inheritance. The methods described in this study could be applied to localize disease-causing genes of other complex diseases through either a genome-wide linkage analysis or a genome-wide association study.

Obox4 critically regulates cAMP-dependent meiotic arrest and MI-MII transition in oocytes.

Extra follicular oocytes spontaneously resume meiosis in vitro, but the intact germinal vesicle (GV) is retained if the oocytes are cultured in medium containing phosphodiesterase (PDE) inhibitors or cAMP analogues. On the basis of our finding that Obox4 is prominently expressed in oocytes, the present study was conducted to determine the functional role of the homeodomain-containing factor Obox4 during in vitro oocyte maturation. After microinjection of Obox4 dsRNA into the cytoplasm of GV oocytes cultured in M16 medium, oocytes were arrested at metaphase I (MI, 77.7%) and metaphase II (MII, 22.3%). Surprisingly, however, 89% of Obox4 RNAi-treated oocytes resumed meiosis and developed to MI and MII when cultured in medium containing 0.2 mM 3-isobutyl-1-methyl-xanthine (IBMX), in which untreated oocytes maintain intact GVs. Spindles were aberrant, and chromosomes were severely aggregated with decreased MPF and MAP kinase activities in arrested MI oocytes after exposure to Obox4 RNAi. Oocytes overexpressing Obox4 retained intact GVs when cultured in M16 medium. Taken together, for the first time to our knowledge, these findings indicate that Obox4 plays a key role in the cAMP-dependent signaling cascades that maintain GV arrest. Oocytes not expressing Obox4 failed to maintain intact GVs in IBMX-supplemented medium, while GVs remained intact when oocytes were kept in plain medium and overexpressing Obox4, suggesting that Obox4 plays a critical role in cAMP-dependent cascade for maintaining intact GVs.

The Mediation Effect of Hyperarousal Symptoms on the Relationship Between Childhood Physical Abuse and Suicidal Ideation of Patients With PTSD.

Objective: This study examined the relationship of childhood physical abuse, posttraumatic stress disorder (PTSD), depression, and suicide in patients with PTSD through path analysis. Materials and Methods: A total of 114 patients with PTSD (36 men and 78 women) were recruited and completed psychological assessments including the Childhood Trauma Questionnaire, the scale for suicidal ideation, the clinician-administered PTSD scale for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the PTSD checklist, and the Hospital Anxiety and Depression Scale. Structural equation modeling was used to evaluate the results. We developed a model including childhood physical abuse experience as the causal variable, suicidal ideation as a result variable, and PTSD and depression as mediation variables. PTSD symptoms were divided into four clusters [intrusion, avoidance, negative cognition and mood, and altered arousal and reactivity (hyperarousal)] to determine predictive power for suicide. Results: PTSD symptoms fully mediated the relationship between childhood physical abuse and suicidal ideation. Furthermore, PTSD symptoms fully mediated the relationship between childhood physical abuse and depression. Among the PTSD symptoms, hyperarousal was the only symptom cluster that mediated the relationship between childhood physical abuse and suicidal ideation. The symptom clusters of negative cognition and mood as well as hyperarousal mediated the relationship between childhood physical abuse and depression. Conclusions: This study presents a link between childhood physical abuse and current symptoms in patients with PTSD, and highlights specific PTSD symptom clusters (i.e., hyperarousal, negative cognition and mood) that may increase the risk for psychopathology later in life.

Memory for diverse faces in a racially attentive context.

Two experiments assessed how racial ambiguity and racial salience moderates the cross-race effect (CRE). In experiment 1, White and Black participants studied and identified the race of Asian, Black, Latino, and White faces that varied in ethnic typicality (high or low ET). For White participants, the CRE was larger when comparing high-ET White faces to high-ET other-race faces than low-ET other-race faces. Black participants showed a similar CRE reduction by ethnic typicality, but also showed a less prevalent CRE than White participants. Experiment 2 replicated experiment 1 procedures, but without the race identification task and only with White participants. Experiment 2 findings were comparable to experiment 1. Furthermore, experiment 2 showed a noticeably smaller CRE on Black faces than experiment 1, eliciting questions about increased racial salience amplifying the CRE. Results' general implications and the conceptual roots that indirectly link the CRE and racism will be discussed.

Influence of FKBP5 Variants and Childhood Trauma on Brain Volume in Non-clinical Individuals.

The present study aimed to investigate the possible influence of childhood trauma and its interaction effect with 10 single-nucleotide polymorphisms (SNPs) of the FK506-binding protein 51 (FKBP5) gene on brain volume in non-clinical individuals. One hundred forty-four non-clinical volunteers (44 men and 100 women) were genotyped with respect to 10 variants (rs9296158, rs3800373, rs1360780, rs9470080, rs4713916, rs4713919, rs6902321, rs56311918, rs3798345, and rs9380528) of FKBP5. Participants underwent magnetic resonance imaging (MRI) scan and psychological assessments such as the childhood Trauma Questionnaire (CTQ), Hospital Anxiety and Depression Scale, rumination response scale, and quality of life assessment instrument. Individuals with the high CTQ score showed enlarged volume of the left orbitofrontal cortex (OFC) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, rs4713919, rs6902321, and rs3798345 and enlarged volume of the left middle temporal gyrus (MTG) if they have childhood trauma-susceptible genotype of FKBP5 rs3800373, rs1360780, rs4713916, and rs3798345. Among those with the childhood trauma-susceptible genotype, the left OFC and left MTG showed significant negative correlations with positive feelings about life, and the left OFC showed significant positive correlations with negative cognition. This is one of the few studies to identify the volume alteration of the left OFC and the left MTG for the FKBP5 gene-childhood trauma interaction in non-clinical individuals.

EEG Source Network for the Diagnosis of Schizophrenia and the Identification of Subtypes Based on Symptom Severity-A Machine Learning Approach.

A precise diagnosis and a comprehensive assessment of symptom severity are important clinical issues in patients with schizophrenia (SZ). We investigated whether electroencephalography (EEG) features obtained from EEG source network analyses could be effectively applied to classify the SZ subtypes based on symptom severity. Sixty-four electrode EEG signals were recorded from 119 patients with SZ (53 males and 66 females) and 119 normal controls (NC, 51 males and 68 females) during resting-state with closed eyes. Brain network features (global and local clustering coefficient and global path length) were calculated from EEG source activities. According to positive, negative, and cognitive/disorganization symptoms, the SZ patients were divided into two groups (high and low) by positive and negative syndrome scale (PANSS). To select features for classification, we used the sequential forward selection (SFS) method. The classification accuracy was evaluated using 10 by 10-fold cross-validation with the linear discriminant analysis (LDA) classifier. The best classification accuracy was 80.66% for estimating SZ patients from the NC group. The best classification accuracy between low and high groups in positive, negative, and cognitive/disorganization symptoms were 88.10%, 75.25%, and 77.78%, respectively. The selected features well-represented the pathological brain regions of SZ. Our study suggested that resting-state EEG network features could successfully classify between SZ patients and the NC, and between low and high SZ groups in positive, negative, and cognitive/disorganization symptoms.

Prediction of Antidepressant Treatment Outcome Using Event-Related Potential in Patients with Major Depressive Disorder.

(1) Background: Prediction of treatment outcome has been one of the core objectives in clinical research of patients with major depressive disorder (MDD). This study explored the possibility of event-related potential (ERP) markers to predict antidepressant treatment outcomes among MDD patients; (2) Methods: Fifty-two patients with MDD were recruited and evaluated through Hamilton depression (HAM-D), Hamilton anxiety rating scale (HAM-A), and CORE. Patients underwent a battery of ERP measures including frontal alpha symmetry (FAA) in the low alpha band (8-10 Hz), mismatch negativity (MMN), and loudness-dependent auditory evoked potentials (LDAEP); (3) Results: During the eight weeks of study, 61% of patients achieved remission, and 77% showed successful treatment responsiveness. Patients with low FAA in F5/F6 demonstrated a significantly higher remission/response ratio and better treatment responsiveness (F (2.560, 117.755) = 3.84, p = 0.016) compared to patients with high FAA. In addition, greater FAA in F7/F8 EEG channels was significantly associated with greater melancholia scores (r = 0.34, p = 0.018). Other ERP markers lacked any significant effect; (4) Conclusions: Our results suggested low FAA (i.e., greater left frontal activity) could reflect a good treatment response in MDD patients. These findings support that FAA could be a promising index in understanding both MDD and melancholic subtype.

Phylogenetic analysis of severe fever with thrombocytopenia syndrome virus in Korean water deer (Hydropotes inermis argyropus) in the Republic of Korea.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic tick-borne disease caused by SFTS virus, which circulates among ticks and their host animals, including wildlife. However, few studies have examined SFTS virus infection in wildlife present in the Republic of Korea (ROK). We evaluated SFTS virus infection in tissue samples from Korean water deer (Hydropotes inermis argyropus), one of the most common wild ungulates in ROK. In this study, we evaluated tissue samples of 129 water deer carcasses collected in 2017 and detected SFTS viral RNA by conventional PCR. SFTS viral RNA was found in 3 of the 129 carcasses, showing a prevalence of 2.3 %; 2 of which were collected in Gyeongsangnam-do and 1 of which was in the Gangwon-do region. Among the 6 internal organs studied, only the spleen samples were positive. Phylogenetic analysis revealed close relationships between deer- and human-derived strains. The medium segments of the three positive cases clustered with genotype B, which is the predominant genotype in ROK. In the small segment, two cases clustered with genotype B, samples 17WD044 and 17WD065. The third sample, 17WD068 from Gangwon-do province, showed genotype A, which circulates mainly in China. The disagreement in the genotypes of the two tested segments suggests a potential reassortment between genotype A and B, resulting in genetic recombination as observed in sample 17WD068, which may be co-circulating in China and Korea. Further studies in wildlife and humans are necessary to understand the genetic characteristics of SFTS viruses circulating in ROK.

Correction: miR146a-mediated targeting of FANCM during inflammation compromises genome integrity.

[This corrects the article DOI: 10.18632/oncotarget.10275.].

Wild boar harbouring African swine fever virus in the demilitarized zone in South Korea, 2019.

The African swine fever virus (ASFV) was first detected in wild boar in the Demilitarized Zone, a bordered area between South and North Korea, on 2 October 2019. Phylogenetic analyses of ASFV genes encoding p72 and CD2v indicated that the causative strain belongs to genotype II and serogroup 8, respectively, and contained additional tandem repeat sequences between the I73R and the I329L protein genes.

Role of Bcl2-like 10 (Bcl2l10) in Regulating Mouse Oocyte Maturation.

Previously, we have shown that Bcl2l10 is highly expressed in metaphase II (MII)-stage oocytes. The objective of this study was to characterize Bcl2l10 expression in ovaries and to examine the function of Bcl2l10 in oocyte maturation using RNA interference. Bcl2l10 transcript expression was ovary and oocyte specific. Bcl2l10 was highly expressed in oocytes and pronuclear-stage embryos; however, its expression decreased at the two-cell stage and dramatically disappeared thereafter. Microinjection of Bcl2l10 double-stranded RNA into the cytoplasm of germinal vesicle oocytes resulted in a marked decrease in Bcl2l10 mRNA and protein and metaphase I (MI) arrest (78.9%). Most MI-arrested oocytes exhibited abnormalities in their spindles and chromosome configurations. Bcl2l10 RNA interference had an obvious effect on the activity of maturation-promoting factor but not on that of mitogen-activated protein kinase. We concluded that the role of Bcl2l10 is strongly associated with oocyte maturation, especially at the MI-MII transition.

Erratum to: Flavobacterium parvum sp. nov., isolated from soil polluted by sewer water.

In the article by Lee et al. published in Journal of Microbiology 2018; 56, 542-548, The KACC 19447T on 26th line of 4th paragraph in the section of 'Description of Flavobacterium parvum sp. nov.' on page 546 should be corrected in KACC 19448T. The sentence should have read: The type strain, HS916T (= KACC 19448T, = JCM 32368T), was isolated from soil polluted by sewer water in Cheonan, South Korea.We apologize for any inconvenience that this may have caused.