Effects of Assisted Reproduction Technology on Placental Imprinted Gene Expression

We used placental tissue to compare the imprinted gene expression of IGF2, H19, KCNQ1OT1, and CDKN1C of singletons conceived via assisted reproduction technology (ART) with that of spontaneously conceived (SC) singletons. Of 989 singletons examined (ART n = 65; SC n = 924), neonatal weight was significantly lower (P < .001) in the ART group than in the SC group, but placental weight showed no significant difference. Gene expression analyzed by real-time PCR was similar for both groups with appropriate-for-date (AFD) birth weight. H19 expression was suppressed in fetal growth retardation (FGR) cases in the ART and SC groups compared with AFD cases (P < .02 and P < .05, resp.). In contrast, CDKN1C expression was suppressed in FGR cases in the ART group (P < .01), while KCNQ1OT1 expression was hyperexpressed in FGR cases in the SC group (P < .05). As imprinted gene expression patterns differed between the ART and SC groups, we speculate that ART modifies epigenetic status even though the possibilities always exist

グループ間におけるブランド意味解釈の構造的考察

A brand possesses multiple meanings. The nature of interpretation that is given to a brand depends on the perspective from which such a brand is viewed. Consequently, instead of providing a clear content meaning of individual brands, it is important to assess the relationship a brand possesses with respect to a number of related brands through a structural interpretation of brand meaning. In this respect, the following form the objectives of this thesis. 1) By using a framework that considers the structural interpretation of brand meaning (Akaoka, 1995), conduct an examination into whether there exist differences in the structural meaning of brands or not as given by groups. 2) From strategic perspective, identify the important factors that affect the structural meaning of a brand

An Arabidopsis SBP-domain fragment with a disrupted C-terminal zinc-binding site retains its tertiary structure

AbstractSQUAMOSA promoter-binding proteins (SBPs) form a major family of plant-specific transcription factors, mainly related to flower development. SBPs share a highly conserved DNA-binding domain of ∼80 amino acids (SBP domain), which contains two non-interleaved zinc-binding sites formed by eight conserved Cys or His residues. In the present study, an Arabidopsis SPL12 SBP-domain fragment that lacks a Cys residue involved in the C-terminal zinc-binding pocket was found to retain a folded structure, even though only a single Zn2+ ion binds to the fragment. Solution structure of this fragment determined by NMR is very similar to the previously determined structures of the full SBP domains of Arabidopsis SPL4 and SPL7. Considering the previous observations that chelating all the Zn2+ ions of SBPs resulted in the complete unfolding of the structure and that a mutation of the Cys residue equivalent to that described above impaired the DNA-binding activity, we propose that the Zn2+ ion at the N-terminal site is necessary to maintain the overall tertiary structure, while the Zn2+ ion at the C-terminal site is necessary for the DNA binding, mainly by guiding the basic C-terminal loop to correctly fit into the DNA groove

Photopharmacological Manipulation of Mammalian CRY1 for Regulation of the Circadian Clock

CRY1 and CRY2 proteins are highly conserved components of the circadian clock that controls daily physiological rhythms. Disruption of CRY functions are related to many diseases, including circadian sleep phase disorder. Development of isoform-selective and spatiotemporally controllable tools will facilitate the understanding of shared and distinct functions of CRY1 and CRY2. Here, we developed CRY1-selective compounds that enable light-dependent manipulation of the circadian clock. From phenotypic chemical screening in human cells, we identified benzophenone derivatives that lengthened the circadian period. These compounds selectively interacted with the CRY1 photolyase homology region, resulting in activation of CRY1 but not CRY2. The benzophenone moiety rearranged a CRY1 region called the "lid loop"located outside of the compound-binding pocket and formed a unique interaction with Phe409 in the lid loop. Manipulation of this key interaction was achieved by rationally designed replacement of the benzophenone with a switchable azobenzene moiety whose cis-trans isomerization can be controlled by light. The metastable cis form exhibited sufficiently high half-life in aqueous solutions and structurally mimicked the benzophenone unit, enabling reversible period regulation over days by cellular irradiation with visible light. This study revealed an unprecedented role of the lid loop in CRY-compound interaction and paves the way for spatiotemporal regulation of CRY1 activity by photopharmacology for molecular understanding of CRY1-dependent functions in health and disease

日本とその近隣諸国で分離されたShigella sonneiのコリシン型,生化学型および薬剤耐性パターン

A modification of Abbott and Shannon\u27s colicin typing method for Shigella sonnei which was established recently as a standard method in Japan was described. This method increases by three or four indicators of E. coli K-12 mutant origin, and it is not only to make a clear distinction between either types 6 and 11 or types 4 and 14, but also to establish three new colicin types 4A, 9A and 13A. Typing results of 1,148 strains representing "foci" which were isolated in Japan especially in the western part, were presented. In Japan at present, type 14 is at the top of epidemic strains, type 6 ranks next, and types O, 8, 13A, 4, 2, etc. follow in order, among them only types 8 and 13A show some difference in interregional distribution. Besides, 39 strains isolated in the neighboring countries of Japan were used for typing. There was a most distinct difference in colicin type between here and there. The strains examined biochemically were determined by 78 percent as type RM of Gillies (xylose negative, raffinose and melibiose positive), and by 96 percent as type "a" of Szturm-Rubinsten (ONPG positive, rhamnose and xylose negative). Both the biochemical types were equally distributed among colicin types other than type 12; in colicin type 12, strains showing various fermentation patterns were found. The resistance of the strains to sulfa-drug and three antibiotics raised gradually since 1963 and thereabout, and it was at its maximum in 1967 irrespective of colicin type. Only strains of colicin type 14, which appeared for the first time in 1963 showed the maximum from the beginning. In the transition stage of resistance acquisition, it was possible to use resistance pattern as a subsidiary epidemiological marker in combination with colicin type provided that epidemics had been caused by colicin types 6, O, 8, etc. Two examples of application of this combination use were presented; the first case deals with epidemiological analysis of a mass outbreak, and the second with epidemiological connection among many epidemics in a district within a definite period of time.日本で改良され,標準法として一般に実施されているAbbott-ShannonのShigella sonneiコリシン型別法(いわゆる型別部会法)を紹介した.本法は大腸菌K-12変異菌から誘導した抵抗変異株3ないし4株を原法指示菌に追加したもので,原法では区別が困難であった6型と11型,および4型と14型を明瞭に分け,また新コリシン型3種,4A,9A,13Aを追加したものである.主として西日本で分離された,ホーカスを代表する1,148株のS. sonneiが本法による型別に供された.現在の日本では14型が首位,6型これに次ぎ,O型,8型,13A,4≦,2型などがこの順に検出され,うち8型と13Aは国内的に地理的分布上のかなりの差異を示した.ほかに近隣諸国分離の39株を型別したが,その成績は日本のそれと大いに差異があった.生化学的型別の結果は,78%までがGilliesのRM型(キシローゼ陰性,ラフィノーゼ,メリビオーゼ陽性),96%までがSzturm-Rubinstenのa型(ONPG陽性,ラムノーゼ,キシローゼ陰性)であった.この両型はともに12型以外の各コリシン型に平均的に分布し,12型においてのみ各種の糖分解型式を示すものが見出された.これらの菌株のサルファ剤と3種の抗生物質に対する抵抗性は1963年頃から次第に高まり,1967年に至ってコリシン型に関係なくすべてが最高の抵抗を示した.ただし14型だけはそれが最初に現われた1963年には,4剤に対して既に最高の抵抗を示していた.この耐性獲得の途上にある時期では,6型,O型,8型などによる流行の場合に限って,薬剤耐性パターンをコリシン型と組合せて一つの補助的な疫学的マーカーとして利用することが可能であった.この組合せ使用の二つの応用例を記述したが,一つはある集団発生の疫学的分析に関するものであり,もう一つは,ある地方ある期間内における各流行例間の関連に関するものであった

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基礎看護学は,看護学の導入部であり,各看護学に発展・応用されるための基礎として身につけられるよう教授してきた。しかし,基礎看護学実習IIが2年次後期の実施であったため,カリキュラムの進度上学生に混乱を招いていた。そこで,今年度の新カリキュラムの開始に伴い,各看護学との調整を図り,1年次に基礎看護学を位置付け実施した。中でも基礎看護学実習IIは,基礎看護学の最終段階で各看護学への移行時期にあり,実習での学習の成果がその後の学習に反映されていく。そのため,旧カリキュラムと新カリキュラムで実施した学生の学びについて把握する必要性を感じ,基礎看護学実習[終了後の学生のレポートを比較検討した。その結果,知識や経験の差が学びの違いとなって現れていたが,1年生では学内で行っている学習と臨床実習との関連が認識され,これまでの学習姿勢を振り返り,今後の学習意欲につながっていた。そして,経験の乏しい中からも看護の役割を考え,看護する事の喜びを感じ,看護する者として様々な人々の生き方や生きる姿勢を学ぶことが必要だと感じることができていた

Sphingosine 1-Phosphate (S1P) in the Peritoneal Fluid Skews M2 Macrophage and Contributes to the Development of Endometriosis

Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis

Targeting critical kinases and anti-apoptotic molecules overcomes steroid resistance in MLL-rearranged leukaemia.

BACKGROUND: Acute lymphoblastic leukaemia with mixed lineage leukaemia gene rearrangement (MLL-ALL) frequently affects infants and is associated with a poor prognosis. Primary refractory and relapsed disease due to resistance to glucocorticoids (GCs) remains a substantial hurdle to improving clinical outcomes. In this study, we aimed to overcome GC resistance of MLL-ALL. METHODS: Using leukaemia patient specimens, we performed bioinformatic analyses to identify target genes/pathways. To test inhibition of target pathways in vivo, we created pre-clinical therapeutic mouse patient-derived xenograft (PDX)-models by transplanting human MLL-ALL leukaemia initiating cells (LIC) into immune-deficient NSG mice. Finally, we conducted B-cell lymphoma-2 (BCL-2) homology domain 3 (BH3) profiling to identify BH3 peptides responsible for treatment resistance in MLL-leukaemia. FINDINGS: Src family kinases (SFKs) and Fms-like tyrosine kinase 3 (FLT3) signaling pathway were over-represented in MLL-ALL cells. PDX-models of infant MLL- ALL recapitulated GC-resistance in vivo but RK-20449, an inhibitor of SFKs and FLT3 eliminated human MLL-ALL cells in vivo, overcoming GC-resistance. Further, we identified BCL-2 dependence as a mechanism of treatment resistance in MLL-ALL through BH3 profiling. Furthermore, MLL-ALL cells resistant to RK-20449 treatment were dependent on the anti-apoptotic BCL-2 protein for their survival. Combined inhibition of SFKs/FLT3 by RK-20449 and of BCL-2 by ABT-199 led to substantial elimination of MLL-ALL cells in vitro and in vivo. Triple treatment combining GCs, RK-20449 and ABT-199 resulted in complete elimination of MLL-ALL cells in vivo. INTERPRETATION: SFKs/FLT3 signaling pathways are promising targets for treatment of treatment-resistant MLL-ALL. Combined inhibition of these kinase pathways and anti-apoptotic BCL-2 successfully eliminated highly resistant MLL-ALL and demonstrated a new treatment strategy for treatment-resistant poor-outcome MLL-ALL. FUNDING: This study was supported by RIKEN (RIKEN President\u27s Discretionary Grant) for FI, Japan Agency for Medical Research and Development (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report