Child Maltreatment and Oxytocin as the Physiological Bases for Social Functioning and Stress Coping

The number of child maltreatment reports in Japan quadrupled over the last decade (Ministry of Health Labour and Welfare, 2021). Among various effects of such maltreatment, social dysfunction has been found to be one of the major sequelae of exposure to child maltreatment (Jenny & Isaac, 2006; Kessler et al., 1997; Nelson et al., 2007). However, findings on specific behavioral expressions of social problems in people with child maltreatment history are not consistent and include both over-engagement, such as aggressive/disruptive behaviors, violent crimes, and sexualized behaviors, and disengagement, i.e. social withdrawal, indicating opposite effects of early life experiences on their behaviors. This study investigates the oxytocin (OT) system, suggesting that the OT plays an important role that link child maltreatment and social functioning since both are known to effect the processes of social cognition and stress coping. Thus, this study aims to examine the effects of child maltreatment on the OT by incorporating a more detailed and comprehensive assessment of the child maltreatment experience to gain a deeper understanding of the mechanism. First, a literature review on child maltreatment and OT was conducted to identify the gap in research methodology and findings. Then, Empirical Study 1 examined the validity of the Japanese version of Childhood Trauma Questionnaire (CTQ-J), in which adolescents in the institutionalized group (N=31) and those in the community group (N=46) completed a questionnaire packet and their scores on CTQ-J were compared to their childhood welfare records. Results showed that the total score as well as the scores of the five subscales of CTQ-J was able to discriminate people with documented experience of any maltreatment and five types of maltreatment, i.e., emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect, respectively. Empirical Study 2 measured salivary oxytocin concentrations of both institutionalized and community groups by enzyme linked immunosorbent assay. Results revealed that physical abuse was associated with higher OT, while emotional neglect showed an inverse relationship to OT. A U-shaped association between the number of maltreatment types and OT was identified. As the number of maltreatment types increased from zero to one, OT declined, but as the number increased from one maltreatment type to 2 or 3 types and to 4 or 5 types, OT also increased. The results indicated that the effect of child maltreatment on salivary OT concentrations varied according to the types of maltreatment experienced by each individual. While lower OT levels may lead individuals to disengage from interpersonal relationships, i.e., fight-or-flight responses, higher OT levels may reduce the stress reactivity of physiological systems and trigger a tend-and-befriend response in the face of anxiety provoking situations. Therefore, the differential OT levels derived from early life experiences could account for the heterogenous nature of social problems associated with child maltreatment.甲南大学令和4年度(2022年度

Disruption of Child Environments and Its Psychological Consequences After the Fukushima Disaster: a Narrative Review Based on the Ecological Systems Model

Purpose of review: A high prevalence of clinically significant mental health problems was found in children affected by the Fukushima disaster in Japan. We reviewed the literature on child mental health to examine how disasters impacted children in Fukushima. Recent findings: Children's environments, such as family and peer systems, were disrupted by radiation concerns and evacuation. As children struggled with less resources at home and school, they also had to deal with discrimination. Various interventions were implemented, ranging from government financial assistance to several mental health services provided by local care resources to families and children. In addition to organizing such interventions discretely in each microsystem, a collaborative approach involving various intervening entities across multiple levels was deemed necessary for providing comprehensive support to the affected children and their families. To promote the healthy psychological development of children, it is necessary to provide multidimensional support for their families, particularly parents, through multidisciplinary collaboration between professionals involved in child and family care

Pilot study of the optimal protocol of low dose step‐up follicle stimulating hormone therapy for infertile women

Purpose: To evaluate the optimized protocol of low dose follicle‐stimulating hormone (FSH) therapy that has a starting dose of 50 IU/62.5 IU with a small increment dose (12.5 IU) for women with World Health Organization (WHO) II ovulatory disorder and unexplained infertility. Methods: Anovulatory women with WHO group II ovulatory disorder (ovulation induction [OI] patients, n = 29), and with an unexplained infertility (ovarian stimulation [OS] patients, n = 21) were enrolled. The protocol of low dose step‐up FSH therapy was optimized for the starting dose as 50 IU (body mass index [BMI] < 20 group) and 62.5 IU (BMI ≥ 20 group) with the increment dose of 12.5 IU. Study outcomes were ovulation, monofollicular development and other variables. Results: In the OIpatients, the ovulation rate was 100% (BMI < 20 group) and 90.9% (BMI ≥ 20 group). Monofollicular development was 80.0% (BMI < 20) and 77.3% (BMI ≥ 20). The pregnancy rate was 60% (3/5 BMI < 20) and 18.2% (4/22 BMI ≥ 20). There was no multiple pregnancy. In the OSpatients, the ovulation rate was 100%. Monofollicular development was 85.7% (BMI < 20) and 76.6% (BMI ≥ 20). No pregnancy was achieved in the OSpatients. Conclusion: Optimized protocol of low dose FSH therapy setting a starting dose 50 IU/62.5 IU by BMI with an increment dose of 12.5 IU was safe and highly effective in WHO group II anovulatory patients. However, this protocol seemed uneffective for patients with unexplained infertility

Structural insights into tetraspanin CD9 function

Umeda, R., Satouh, Y., Takemoto, M. et al. Structural insights into tetraspanin CD9 function. Nat Commun 11, 1606 (2020). https://doi.org/10.1038/s41467-020-15459-

Effects of a high-fat diet on the electrical properties of porcine atria

AbstractBackgroundBecause obesity is an important risk factor for atrial fibrillation (AF), we conducted an animal study to examine the effect of a high-fat diet (HFD) on atrial properties and AF inducibility.MethodsTen 8-week-old pigs (weight, 18–23kg) were divided into two groups. For 18 weeks, five pigs were fed a HFD (HFD group) and five were fed a normal diet (control group). Maps of atrial activation and voltages during sinus rhythm were created for all pigs using the EnSite NavX system. Effective refractory period (ERP) and AF inducibility were also determined. When AF was induced, complex fractionated atrial electrogram (CFAE) mapping was performed. At 18 weeks, hearts were removed for comparing the results of histological analysis between the two groups. Body weight, lipid levels, hemodynamics, cardiac structures, and electrophysiological properties were also compared.ResultsTotal cholesterol levels were significantly higher (347 [191–434] vs. 81 [67–88]mg/dL, P=0.0088), and left atrium pressure was higher (34.5 [25.6–39.5] vs. 24.5 [21.3–27.8]mmHg, P=0.0833) in the HFD group than in the control group, although body weight only increased marginally (89 [78–101] vs. 70 [66–91]kg, P=0.3472). ERPs of the pulmonary vein (PV) were shorter (P<0.05) and AF lasted longer in the HFD group than in the control group (80 [45–1350] vs. 22 [3–30]s, P=0.0212). Neither CFAE site distribution nor histopathological characteristics differed between the two groups.ConclusionsThe shorter ERPs for the PV observed in response to the HFD increased vulnerability to AF, and these electrophysiological characteristics may underlie obesity-related AF

Mechanistic insights into intramembrane proteolysis by E. coli site-2 protease homolog RseP

細胞膜の中ではたらく特殊なタンパク質分解酵素の構造を解明 --細菌感染症の新たな治療法の開発へ期待--. 京都大学プレスリリース. 2022-08-25.Site-2 proteases are a conserved family of intramembrane proteases that cleave transmembrane substrates to regulate signal transduction and maintain proteostasis. Here, we elucidated crystal structures of inhibitor-bound forms of bacterial site-2 proteases including Escherichia coli RseP. Structure-based chemical modification and cross-linking experiments indicated that the RseP domains surrounding the active center undergo conformational changes to expose the substrate-binding site, suggesting that RseP has a gating mechanism to regulate substrate entry. Furthermore, mutational analysis suggests that a conserved electrostatic linkage between the transmembrane and peripheral membrane-associated domains mediates the conformational changes. In vivo cleavage assays also support that the substrate transmembrane helix is unwound by strand addition to the intramembrane β sheet of RseP and is clamped by a conserved asparagine residue at the active center for efficient cleavage. This mechanism underlying the substrate binding, i.e., unwinding and clamping, appears common across distinct families of intramembrane proteases that cleave transmembrane segments

Time-resolved serial femtosecond crystallography reveals early structural changes in channelrhodopsin

X線自由電子レーザーを用いて、光照射によるチャネルロドプシンの構造変化の過程を捉えることに成功. 京都大学プレスリリース. 2021-03-26.Channelrhodopsins (ChRs) are microbial light-gated ion channels utilized in optogenetics to control neural activity with light . Light absorption causes retinal chromophore isomerization and subsequent protein conformational changes visualized as optically distinguished intermediates, coupled with channel opening and closing. However, the detailed molecular events underlying channel gating remain unknown. We performed time-resolved serial femtosecond crystallographic analyses of ChR by using an X-ray free electron laser, which revealed conformational changes following photoactivation. The isomerized retinal adopts a twisted conformation and shifts toward the putative internal proton donor residues, consequently inducing an outward shift of TM3, as well as a local deformation in TM7. These early conformational changes in the pore-forming helices should be the triggers that lead to opening of the ion conducting pore

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target