Abstract
Endosome maturation depends on membrane contact sites (MCSs) formed between endoplasmic reticulum (ER) and endolysosomes (LyLEs). The mechanism underlying lipid supply for this process and ...its pathophysiological relevance remains unclear, however. Here, we identify PDZD8—the mammalian ortholog of a yeast ERMES subunit—as a protein that interacts with protrudin, which is located at ER-LyLE MCSs. Protrudin and PDZD8 promote the formation of ER-LyLE MCSs, and PDZD8 shows the ability to extract various lipids from the ER. Overexpression of both protrudin and PDZD8 in HeLa cells, as well as their depletion in mouse primary neurons, impairs endosomal homeostasis by inducing the formation of abnormal large vacuoles reminiscent of those apparent in spastin- or REEP1-deficient neurons. The protrudin-PDZD8 system is also essential for the establishment of neuronal polarity. Our results suggest that protrudin and PDZD8 cooperatively promote endosome maturation by mediating ER-LyLE tethering and lipid extraction at MCSs, thereby maintaining neuronal polarity and integrity.
The activity of a self-sufficient cytochrome P450 enzyme, CYP505D6, from the lignin-degrading basidiomycete
was characterized. Recombinant CYP505D6 was produced in
and purified. In the presence of ...NADPH, CYP505D6 used a series of saturated fatty alcohols with C
carbon chain lengths as the substrates. Hydroxylation occurred at the ω-1 to ω-6 positions of such substrates with C
carbon chain lengths, except for 1-dodecanol, which was hydroxylated at the ω-1 to ω-7 positions. Fatty acids were also substrates of CYP505D6. Based on the sequence alignment, the corresponding amino acid of Tyr51, which is located at the entrance to the active-site pocket in CYP102A1, was Val51 in CYP505D6. To understand the diverse hydroxylation mechanism, wild-type CYP505D6 and its V51Y variant and wild-type CYP102A1 and its Y51V variant were generated, and the products of their reaction with dodecanoic acid were analyzed. Compared with wild-type CYP505D6, its V51Y variant generated few products hydroxylated at the ω-4 to ω-6 positions. The products generated by wild-type CYP102A1 were hydroxylated at the ω-1 to ω-4 positions, whereas its Y51V variant generated ω-1 to ω-7 hydroxydodecanoic acids. These observations indicated that Val51 plays an important role in determining the regiospecificity of fatty acid hydroxylation, at least that at the ω-4 to ω-6 positions. Aromatic compounds, such as naphthalene and 1-naphthol, were also hydroxylated by CYP505D6. These findings highlight a unique broad substrate spectrum of CYP505D6, rendering it an attractive candidate enzyme for the biotechnological industry.
is a white-rot fungus whose metabolism of lignin, aromatic pollutants, and lipids has been most extensively studied. This fungus harbors 154 cytochrome P450-encoding genes in the genome. As evidenced in this study,
CYP505D6, a fused protein of P450 and its reductase, hydroxylates fatty alcohols (C
) and fatty acids (C
) at the ω-1 to ω-7 or ω-1 to ω-6 positions, respectively. Naphthalene and 1-naphthol were also hydroxylated, indicating that the substrate specificity of CYP505D6 is broader than those of the known fused proteins CYP102A1 and CYP505A1. The substrate versatility of CYP505D6 makes this enzyme an attractive candidate for biotechnological applications.
Targeted proteomics approaches are of value for deep and accurate quantification of protein abundance. Extending such methods to quantify large numbers of proteins requires the construction of ...predefined targeted assays. We developed a targeted proteomics platform-in vitro proteome-assisted multiple reaction monitoring (MRM) for protein absolute quantification (iMPAQT)-by using >18,000 human recombinant proteins, thus enabling protein absolute quantification on a genome-wide scale. Our platform comprises experimentally confirmed MRM assays of mass tag (mTRAQ)-labeled peptides to allow for rapid and straightforward measurement of the absolute abundance of predefined sets of proteins by mass spectrometry. We applied iMPAQT to delineate the quantitative metabolic landscape of normal and transformed human fibroblasts. Oncogenic transformation gave rise to relatively small but global changes in metabolic pathways resulting in aerobic glycolysis (Warburg effect) and increased rates of macromolecule synthesis. iMPAQT should facilitate quantitative biology studies based on protein abundance measurements.
Personality has been shown to predict postpartum depressive symptoms (PDS) assessed by the Edinburgh Postnatal Depression Scale (EPDS). However, existing studies have not considered the underlying ...symptom dimensions in the EPDS. We analyzed data from 15,012 women who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Personality was assessed in middle pregnancy using the short-form Eysenck Personality Questionnaire-Revised. PDS were defined as EPDS score ≥ 9 at 1 month after delivery. The EPDS items were further divided into three dimensions: depressed mood, anxiety, and anhedonia. Multiple analyses were conducted to examine the associations of each personality scale with PDS and three dimensions in the EPDS, adjusting for age, parity, mode of delivery, education, income, and social isolation. The prevalence of PDS assessed by the EPDS at 1 month after delivery was 13.1%. Higher neuroticism scores were associated with PDS (odds ratio OR, 2.63; 95% confidence interval CI, 2.48 to 2.79) and all three dimensions (all p < 0.001). Lower extraversion scores were associated with PDS (OR, 0.74; 95% CI, 0.70 to 0.78) and all three dimensions (all p < 0.001). Lower psychoticism scores were associated with PDS (OR, 0.89; 95% CI, 0.85 to 0.94) and anxiety (p < 0.001), but not with depressed mood (p = 0.20) or anhedonia (p = 0.92). In conclusion, higher neuroticism and lower extraversion were associated with PDS and the three underlying dimensions in the EPDS, while lower psychoticism was associated with anxiety, but not with depressed mood or anhedonia.
•We examined the association between personality and alcohol use during pregnancy.•Higher extraversion was associated with alcohol use in early and middle pregnancy.•Higher psychoticism was ...associated with continued use into middle pregnancy.•Neuroticism was not associated with alcohol use during pregnancy.•Lower lie was associated with alcohol use in early, but not in middle pregnancy.
Studies on associations between maternal personality and alcohol use have examined only one time point during pregnancy in Western countries. We aimed to examine the association between maternal personality and alcohol use in early and middle pregnancy in Japan.
We analyzed data from 17,144 pregnant women in Japan who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. Personality was assessed using the short-form Eysenck Personality Questionnaire-Revised. Women were dichotomized as current drinkers or non-drinkers in both early and middle pregnancy. Odds ratios (ORs) and 95% confidence intervals (CIs) for alcohol use in early and middle pregnancy and continued alcohol use between early and middle pregnancy were calculated for 1 standard deviation increase in each personality scale, adjusted for age, as well as education, work status, fertility treatment, and parity.
Higher extraversion scores were associated with alcohol use in early (OR, 1.16; 95% CI, 1.12–1.20) and middle pregnancy (OR, 1.17; 95% CI, 1.10–1.25). Higher psychoticism scores were associated with continued alcohol use into middle pregnancy (OR, 1.07; 95% CI, 1.01–1.14) and alcohol use in middle pregnancy (OR, 1.07; 95% CI, 1.02–1.13). Neuroticism was not associated with alcohol use in early or middle pregnancy. Lower lie was associated with alcohol use in early (OR, 0.95; 95% CI, 0.91–0.98), but not in middle pregnancy.
Different personality scales are associated with alcohol use at different points during pregnancy.
The association between high sugar-sweetened beverages (SSB) intake during pregnancy and offspring overweight/obesity has been reported only from Western countries. The objective of this study was to ...examine the association between SSB intake before and during pregnancy and offspring overweight/obesity among Japanese women.
Japanese prospective birth cohort study.
We analysed mother-offspring pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study from 2013 to 2017. SSB intake during pregnancy was evaluated using the FFQ and classified into three groups: none (0 g/d), medium (<195 g/d) and high (>195 g/d). Overweight or obesity at 1 year of age in offspring was defined as having a BMI
-score greater than 2 sd, calculated based on the BMI reference data for Japanese children. Multiple logistic regression analyses were performed to examine the associations between SSB intake before and during pregnancy and offspring overweight/obesity, after adjusting for covariates.
Japanese mother-offspring pairs (
7114).
The overweight/obesity rate of the offspring was 8·8 %. Pregnant women with a high intake of SSB in early to mid-pregnancy had a higher risk of overweight/obesity in their offspring compared with those who did not; the OR was 1·52 (95 % CI (1·09, 2·12)).
High SSB intake in early to mid-pregnancy was associated with an increased risk of offspring overweight/obesity at 1 year of age.
Natural disasters can have serious mental health consequences. We aimed to examine the long-term effects of the 2011 Great East Japan Earthquake (GEJE) on postpartum depressive symptoms (PDS).
The ...Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study recruited pregnant women in Miyagi Prefecture from 2013 to 2016. Data from 11,403 participants were used in this study. Women were asked about their traumatic experiences of the GEJE with questions addressing threat, witness, and loss. PDS were defined as Edinburgh Postnatal Depression Scale score ≥9 at 1 month after delivery. Multiple logistic regression analyses were conducted to examine the associations of different traumatic experiences of the GEJE and number of traumatic experiences with PDS, after adjustment for age, parity, feelings toward pregnancy, education, income, social isolation, house damage caused by the GEJE, and survey year.
About two-fifths of women had at least one traumatic experience of the GEJE. The prevalence of PDS at 1 month after delivery was 13.3 %. Life-threatening experience and witnessing another person's actual or threatened death were associated with PDS: the odds ratios (ORs) were 1.40 (95 % confidence interval CI, 1.24–1.59) and 1.28 (95 % CI, 1.08–1.53), respectively. Loss of close person was not associated with PDS: the OR was 1.13 (95 % CI, 0.99–1.30). Larger number of traumatic experiences of the GEJE was associated with increased risk of PDS (p for trend <0.001).
PDS was self-reported.
Traumatic experiences of the GEJE prior to pregnancy were associated with increased risks of PDS.
•Life-threatening experience was associated with postpartum depressive symptoms.•Loss of close person was not associated with postpartum depressive symptoms.•Larger number of experiences was associated with postpartum depressive symptoms.•The long-term effect of a natural disaster on women's mental health was suggested.
Although there is evidence that maternal perinatal mental disorders are associated with emotional/behavioral problems in children, the long-term impacts of postnatal bonding disorder remain unclear. ...We aimed to examine the associations between maternal postnatal bonding disorder and emotional/behavioral problems in preschool children.
We analyzed data from 7220 mother–child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Maternal bonding disorder was defined as Mother-to-Infant Bonding Scale score ≥5 at 1 month after delivery. The Child Behavior Checklist for Ages 1½–5 was used to assess emotional/behavioral problems, and its subscales were used to assess internalizing and externalizing problems in children at 4 years of age. Multiple logistic regression analyses were conducted to examine the associations of postnatal bonding disorder with emotional/behavioral, internalizing, and externalizing problems after adjustment for age, education, income, parity, prenatal psychological distress, postnatal depressive symptoms, child's sex, preterm birth, and birth defects.
The prevalence of postnatal bonding disorder was 14.8 %. Postnatal bonding disorder was associated with an increased risk of emotional/behavioral problems in children: the odds ratio (OR) was 2.06 (95 % confidence interval CI, 1.72–2.46). Postnatal bonding disorder was also associated with increased risks of internalizing problems and externalizing problems in children: the ORs were 1.69 (95 % CI, 1.42–2.02) and 1.90 (95 % CI, 1.59–2.26), respectively.
Bonding and problems were self-reported.
Bonding disorder at 1 month after delivery was associated with an increased risk of emotional/behavioral problems in children at 4 years of age.
•Bonding disorder was associated with emotional/behavioral problems in children.•Lack of affection was associated with emotional/behavioral problems in children.•Anger and rejection were associated with emotional/behavioral problems in children.•These associations were found for both internalizing and externalizing problems.
This study aimed to construct a prediction model for small-for-gestational-age (SGA) infants in Japan by creating a risk score during pregnancy. A total of 17,073 subjects were included in the Tohoku ...Medical Megabank Project Birth and Three-Generation Cohort Study, a prospective cohort study. A multiple logistic regression model was used to construct risk scores during early and mid-gestational periods (11-17 and 18-21 weeks of gestation, respectively). The risk score during early gestation comprised the maternal age, height, body mass index (BMI) during early gestation, parity, assisted reproductive technology (ART) with frozen-thawed embryo transfer (FET), smoking status, blood pressure (BP) during early gestation, and maternal birth weight. The risk score during mid-gestation also consisted of the maternal age, height, BMI during mid-gestation, weight gain, parity, ART with FET, smoking status, BP level during mid-gestation, maternal birth weight, and estimated fetal weight during mid-gestation. The C-statistics of the risk scores during early- and mid-gestation were 0.658 (95% confidence interval CI: 0.642-0.675) and 0.725 (95% CI: 0.710-0.740), respectively. In conclusion, the predictive ability of the risk scores during mid-gestation for SGA infants was acceptable and better than that of the risk score during early gestation.
It is essential to clarify factors associated with mental health and behavioral problems in early childhood, because children are critical stages of life for mental health. We aimed to prospectively ...examine the associations between maternal social isolation and behavioral problems in preschool children. We analyzed data from 5842 mother–child pairs who participated in the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. The Lubben Social Network Scale-abbreviated version was used to assess social isolation (defined as scores < 12) one year after delivery. The Child Behavior Checklist 1½–5 was used to assess behavioral problems, and its subscales were used to assess internalizing and externalizing problems in children at 4 years of age. Multiple logistic regression analyses were conducted to examine the associations between social isolation and behavioral problems, after adjustment for age, education, income, work status, marital status, extraversion, neuroticism, depressive symptoms, child sex, and number of siblings. Multiple logistic regression analyses were also conducted for internalizing problems and externalizing problems. The prevalence of maternal social isolation was 25.4%. Maternal social isolation was associated with an increased risk of behavioral problems in children: the odds ratio (OR) was 1.37 (95% confidence interval CI 1.14–1.64). Maternal social isolation was also associated with increased risks of internalizing problems and externalizing problems in children: the ORs were 1.33 (95% CI, 1.12–1.59) and 1.40 (95% CI, 1.18–1.66), respectively. In conclusion, maternal social isolation one year after delivery was associated with behavioral problems in children at 4 years of age.
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