Activation-Induced Cytidine Deaminase Deficiency Causes Organ-Specific Autoimmune Disease

Activation-induced cytidine deaminase (AID) expressed by germinal center B cells is a central regulator of somatic hypermutation (SHM) and class switch recombination (CSR). Humans with AID mutations develop not only the autosomal recessive form of hyper-IgM syndrome (HIGM2) associated with B cell hyperplasia, but also autoimmune disorders by unknown mechanisms. We report here that AID−/− mice spontaneously develop tertiary lymphoid organs (TLOs) in non-lymphoid tissues including the stomach at around 6 months of age. At a later stage, AID−/− mice develop a severe gastritis characterized by loss of gastric glands and epithelial hyperplasia. The disease development was not attenuated even under germ-free (GF) conditions. Gastric autoantigen -specific serum IgM was elevated in AID−/− mice, and the serum levels correlated with the gastritis pathological score. Adoptive transfer experiments suggest that autoimmune CD4+ T cells mediate gastritis development as terminal effector cells. These results suggest that abnormal B-cell expansion due to AID deficiency can drive B-cell autoimmunity, and in turn promote TLO formation, which ultimately leads to the propagation of organ-specific autoimmune effector CD4+ T cells. Thus, AID plays an important role in the containment of autoimmune diseases by negative regulation of autoreactive B cells

〔資 料〕 閉経後女性の体脂肪蓄積，筋肉量および骨密度低下の抑制を 目的とした食事条件を提案するための基礎研究 ―自発運動可能な卵巣摘除メスラットの下肢骨格筋重量，大腿骨骨密度および 走行運動レベルに対する食餌アミノ酸添加の影響―

The present study aims to review whether dietary modifications will prevent body fat accumulation, muscle mass wasting and bone mineral density loss in postmenopausal women who incorporate physical exercise into daily life.9-week-old ovariectomized Wistar strain female rats were divided into four groups: CA-Ex, Gln-Ex, Leu-Ex and CitD-Ex. Depending on which group they were in, the rats were given a 20％ casein protein based experimental diet supplemented with nothing （control diet, CA-Ex）; 5％ of L-glutamine （Gln-Ex）; 5％ of L-leucine （Leu-Ex）; or 2.5％ of L-citrulline＋2.5％ of D-serine （CitD-Ex）, each 11 g per day for 10 weeks. All of these rats were housed in individual cage with a running wheel for 10 weeks. A sham operation was carried out on another group of rats （Sham） and were given the same diet as CA-Ex, the control diet.Results were as follows:1） Uterus weights of the ovariectomized rats, that is group CA-Ex, Gln-Ex, Leu-Ex and CitD-Ex, appeared to show lower values than that of the group Sham. 2） No significant differences were observed in a）changes in body weight, b）blood analyses, c）liver, kidney, uterus and muscle weights, and d）femoral-bone mineral density in groups Gln-Ex, Leu-Ex, and CitD-Ex as compared to the group CA-Ex.3） Relatively higher running activity was observed in group CitD-Ex than that of group CA-Ex. This observation suggests that increasing dietary L-citrulline plus D-serine in postmenopausal rats may lead to an increase in physical activity. Further research is needed to understand the physiological and nutritional significance of the unexpected results that dietary amino acid may accelerate the physical activity

Solvation Structure of a Copper(II) Ion in Protic Ionic Liquids Comprising <i>N</i>‑Hexylethylenediamine

The fine and dynamic structure of the copper­(II) ion solvated in a protic ionic liquid (PIL) comprising monoprotonated <i>N</i>-hexylethylenediaminium (HHexen⁺) and bis­(trifluoromethanesulfonyl)­amide (Tf₂N^–) [or trifluoroacetate (TFA^–)] was determined using NMR, visible electronic, and extended X-ray absorption fine structure (EXAFS) spectroscopy. The chelate-diamine group in the cationic unit facilitates advantageous dissolution of transition-metal salts in the present PIL. The interaction of the copper­(II) ion with the chelate-diamine PIL was explored by the addition of copper­(II) salts to the PIL, demonstrating competitive complexation between the ligand of the added copper­(II) salt and the components of the ionic liquid to the copper­(II) ion. The favorable mode of interaction of the present chelating PIL with the copper­(II) ion was clarified based on a comparison of the interactions with analogous liquids, including the monoprotonated hexylaminium HHexam­(Tf₂N)-PIL, neat <i>N</i>-hexylethylenediamine (Hexen), and neat ethylenediamine (En). The coordination modes of the bis-Hexen and tris-Hexen copper­(II) complexes in molecular liquids and in solids were also studied for comparison of the coordination structures around the copper­(II) ion with those in the present PILs. The paramagnetic-induced relaxations derived from ¹³C (Δ<i>T</i>_1p^–1) and ¹⁵N (Δ<i>T</i>_2p^–1) NMR, the visible electronic spectra, and EXAFS analysis showed that the copper­(II) ion tends to form a bis-Hexen complex in the HHexen-PIL despite the electrostatic repulsion and the fact that the counteranions are located at the axial sites, whereas in the HHexam­(Tf₂N)-PIL, the copper­(II) ion exhibits affinity for the Tf₂N anion over the protonated amines. The lifetime of the copper­(II) complex formed in the PIL was determined to be ≈10^–4 s based on ¹³C (Δ<i>T</i>_1p^–1) and ¹⁴N (Δ<i>T</i>_2p^–1) NMR, which is appreciably longer than that in conventional molecular solvents

Factors associated with the utilization of community assessment models among Japanese nurses

[Objectives] This study aimed to identify factors related to the practical utilization of community health needs assessment (CHNA) models that public health nurses (PHNs) learned in their fundamental education. [Design] A nationwide questionnaire survey was conducted via postal mail. [Sample] We randomly selected 630 public health institutes in Japan. The participants were 3397 full-time novice and mid-level PHNs. [Measurements] The questionnaire included the participants’ basic personal information, six items regarding the perception of CHNA with a 4-point Likert scale, learned models in their undergraduate education, their utilization in practical settings, and the reasons for their answer in narrative form. [Results] There were 951 valid responses. The results of logistic regression showed that the significant positively factors with model utilization were perception of CHNA as “not troublesome” or “not impossible as they learned, ” continuing education with 5 years of experience, and identification of the learned model in continuing education. Furthermore, the results of text mining showed the reasons for non-utilization of the model included being “busy” and having a lack of “opportunity.” [Conclusions] This study showed the associated factors with rare utilization of a learned model for PHNs. These findings may suggest improvement of continuing education and development of an appropriate assessment model

TRPV4 channel activity is modulated by direct interaction of the ankyrin domain to PI(4,5)P2

[プレスリリース]バイオサイエンス研究科分子医学細胞生物学研究室の末次志郎教授らの研究グループが生理的に重要なイオンを運ぶ通り道TRPV4の新たな制御機構を解明（2014/09/29）Mutations in the ankyrin repeat domain (ARD) of ​TRPV4 are responsible for several channelopathies, including Charcot–Marie–Tooth disease type 2C and congenital distal and scapuloperoneal spinal muscular atrophy. However, the molecular pathogenesis mediated by these mutations remains elusive, mainly due to limited understanding of the ​TRPV4 ARD function. Here we show that phosphoinositide binding to the ​TRPV4 ARD leads to suppression of the channel activity. Among the phosphoinositides, phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) most potently binds to the ​TRPV4 ARD. The crystal structure of the ​TRPV4 ARD in complex with ​inositol-1,4,5-trisphosphate, the head-group of PI(4,5)P2, and the molecular-dynamics simulations revealed the PI(4,5)P2-binding amino-acid residues. The ​TRPV4 channel activities were increased by titration or hydrolysis of membrane PI(4,5)P2. Notably, disease-associated ​TRPV4 mutations that cause a gain-of-function phenotype abolished PI(4,5)P2 binding and PI(4,5)P2 sensitivity. These findings identify ​TRPV4 ARD as a lipid-binding domain in which interactions with PI(4,5)P2 normalize the channel activity in ​TRPV4