Novel SLC30A2 mutations in the pathogenesis of transient neonatal zinc deficiency

[Importance] Transient neonatal zinc deficiency (TNZD) occurs in breastfed infants due to abnormally low breast milk zinc levels. Mutations in the solute carrier family 30 member 2 (SLC30A2) gene, which encodes the zinc transporter ZNT2, cause low zinc concentration in breast milk. [Objective] This study aimed to provide further insights into TNZD pathophysiology. [Methods] SLC30A2 sequencing was performed in three unrelated Japanese mothers, whose infants developed TNZD due to low-zinc milk consumption. The effects of the identified mutations were examined using cell-based assays and luciferase reporter analysis. [Results] Novel SLC30A2 mutations were identified in each mother. One harbored a heterozygous missense mutation in the ZNT2 zinc-binding site, which resulted in defective zinc transport. The other two mothers exhibited multiple heterozygous mutations in the SLC30A2 promoter, the first mutations in the SLC30A2 regulatory region reported to date. [Interpretation] This report provides new genetic insights into TNZD pathogenesis in breastfed infants

Sp6 downregulation of follistatin gene expression in ameloblasts

Sp6 is a member of the Sp family of transcription factors that regulate a wide range of cellular functions, such as cell growth and differentiation. Sp6, also called epiprofin, is specifically expressed in tooth germ, limb bud, and hair follicle, but there is little information on its function. To investigate the possible role of Sp6 in tooth development, first we established an Sp6- overproducing clone, CHA9, and analyzed the features of the cell, including cell proliferation and gene expression. The parental cells of CHA9 are the ameloblast-lineage G5 cells that we previously established from rat dental epithelia of lower incisor. Sp6 overproduction accelerated cell proliferation and induced the expression of ameloblastin mRNA, a marker of ameloblast differentiation. Second, we performed genome-wide screening of Sp6 target genes by microarray analysis. Out of a total 20,450 genes, 448 genes were up-regulated and 500 genes were down-regulated by Sp6. We found the expression of follistatin, a BMP antagonist, to be 22.4-fold lower in CHA9 than in control cells. Transfection of the Sp6-antisense construct into CHA9 cells restored follistatin expression back to equivalent levels seen in control cells, indicating that Sp6 regulates follistatin gene expression in ameloblasts. Our findings demonstrate that the follistatin gene is one of the Sp6 target genes in ameloblasts and suggest that Sp6 promotes amelogenesis through inhibition of follistatin gene expression

CRISPR/Cas9 mediated genome editing in ES cells and its application for chimeric analysis in mice

Oji, A., Noda, T., Fujihara, Y. et al. CRISPR/Cas9 mediated genome editing in ES cells and its application for chimeric analysis in mice. Sci Rep 6, 31666 (2016). https://doi.org/10.1038/srep3166

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Bacteroides fragilis ATCC25285から得られたアルカリ安定脂質は赤外吸収スペクトルでアミド結合に由来する特徴的な吸収がみられることや,スフィンゴシンを有することなどからスフィンゴリン脂質であることが示された。このスフィンゴリン脂質の薄層クロマトグラフィーによる分析からセラミドホスホリルエタノールアミン(CPE)とセラミドホスホリルグリセロール(CPG)の2種類のスフィンゴリン脂質が検出された。また,Bacteroides属の全10菌種についてスフインゴリン脂質の組成を分析して菌種間の分布を調べたところ,CPEとCPGは7菌種から見いだされた。さらに,薄層クロマトグラフ上にはスフィンゴリン脂質と考えられる未知スポットが見いだされた。各菌種で見いだされたスフィンゴリン脂質組成は,菌種について特徴的であり,菌株間での変異は認められなかった

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

Impacts of anxiety and socioeconomic factors on mental health in the early phases of the COVID-19 pandemic in the general population in Japan: A web-based survey.

Owing to the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic worldwide, individuals experience considerable psychological distress daily. The present study aimed to clarify the prevalence of psychological distress and determine the population most affected by risk factors such as the pandemic, socioeconomic status (SES), and lifestyle-related factors causing psychological distress in the early phases of the pandemic in Japan. This study was conducted via a web-based survey using quota sampling to ensure representativeness of the Japanese population aged 20-64 years. A cross-sectional study of 11,342 participants (5,734 males and 5,608 females) was conducted using a self-administered questionnaire that included the Japanese version of the Kessler 6 Psychological Distress Scale (K6) and questions related to the pandemic, SES, and lifestyle. The prevalence of psychological distress, represented by a K6 score of 5 or more, was 50.3% among males and 52.6% among females. Both males and females with annual household incomes less than 2 million yen and males aged in their twenties had significantly higher K6 scores than those with annual household incomes above 2 million yen and males aged over 30 years. Binary logistic regression analyses found pandemic-related factors such as medical history, inability to undergo clinical tests immediately, having trouble in daily life, unavailability of groceries, new work style, and vague anxiety; SES-related factors such as lesser income; and lifestyle-related factors such as insufficient rest, sleep, and nutritious meals to be significantly related to psychological distress. Psychological distress was more prevalent among people with low income and in younger generations than among other groups. There is an urgent need to provide financial, medical, and social support to those affected by the coronavirus disease 2019 (COVID-19) pandemic

"Tell me what you suggest, and let's do that, doctor": Patient deliberation time during informal decision-making in clinical trials.

Informed consent is an essential part of an ethical clinical trial; to this end, researchers have developed several interventions to promote participants' full understanding of trials and thereby improve the consent process. However, few empirical studies have examined how patients make the decision of whether to give consent. The objective of this study, therefore, is to analyze patients' decision-making process when participating in clinical trials. We conduct an internet survey (n = 2,045) and interview data analysis (n = 40) with patients and categorize respondents into three types of participants: active, passive, and non-participation. Our results show that patients often make informal and quick decisions before medical staff provide them with relevant information during the informed consent process. For example, 55.9% of patients received initial information on clinical trials from an online article or web advertising, and 54.5% consulted no one about whether to participate in the clinical trial before making a decision. Only 20.7% of respondents subjectively spent time making the decision whether to participate; 43.0% of patients who said that they "spent time" coming to a decision took four or more days to reach a decision, while 8.3% of people who "did not spend time" making a decision took this among of time. Based on these results, we were able to break patients' decision-making process into four steps: first contact, informal decision making, relevant information, and formal decision making. Our results show that patients are most likely to make a decision based on the first information they receive on the clinical trial, whatever the source. To this end, having a list of questions for potential participants to ask researchers would be useful in helping better collecting information of clinical trials. In addition, research teams should give patients more than four days to decide between providing them with relevant information and obtaining written consent, even if the patient seems to make a quick decision