A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memor

P2X7 Receptor Promotes Mouse Mammary Cancer Cell Invasiveness and Tumour Progression, and Is a Target for Anticancer Treatment

The P2X7 receptor is an ATP-gated cation channel with a still ambiguous role in cancer progression, proposed to be either pro- or anti-cancerous, depending on the cancer or cell type in the tumour. Its role in mammary cancer progression is not yet defined. Here, we show that P2X7 receptor is functional in highly aggressive mammary cancer cells, and induces a change in cell morphology with fast F-actin reorganization and formation of filopodia, and promotes cancer cell invasiveness through both 2- and 3-dimensional extracellular matrices in vitro. Furthermore, P2X7 receptor sustains Cdc42 activity and the acquisition of a mesenchymal phenotype. In an immunocompetent mouse mammary cancer model, we reveal that the expression of P2X7 receptor in cancer cells, but not in the host mice, promotes tumour growth and metastasis development, which were reduced by treatment with specific P2X7 antagonists. Our results demonstrate that P2X7 receptor drives mammary tumour progression and represents a pertinent target for mammary cancer treatment

NLRP6 controls pulmonary inflammation from cigarette smoke in a gut microbiota-dependent manner

Chronic obstructive pulmonary disease (COPD) is a major health issue primarily caused by cigarette smoke (CS) and characterized by breathlessness and repeated airway inflammation. NLRP6 is a cytosolic innate receptor controlling intestinal inflammation and orchestrating the colonic host–microbial interface. However, its roles in the lungs remain largely unexplored. Using CS exposure models, our data show that airway inflammation is strongly impaired in Nlrp6-deficient mice with drastically fewer recruited neutrophils, a key cell subset in inflammation and COPD. We found that NLRP6 expression in lung epithelial cells is important to control airway and lung tissue inflammation in an inflammasome-dependent manner. Since gut-derived metabolites regulate NLRP6 inflammasome activation in intestinal epithelial cells, we investigated the link between NLRP6, CS-driven lung inflammation, and gut microbiota composition. We report that acute CS exposure alters gut microbiota in both wild-type (WT) and Nlrp6-deficient mice and that antibiotic treatment decreases CS-induced lung inflammation. In addition, gut microbiota transfer from dysbiotic Nlrp6-deficient mice to WT mice decreased airway lung inflammation in WT mice, highlighting an NLRP6-dependent gut-to-lung axis controlling pulmonary inflammation

A new mouse model for the trisomy of the Abcg1–U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome

Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1–U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1–U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1–U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1–U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory

Analyse fonctionnelle et biochimique de l'hetero-regulation de recepteurs: etude des recepteurs D1 dopaminergiques du cortex prefrontal et mu-opiaces du striatum

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : T 80314 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

data- inhibitions of NA/5-HT transmissions against alcoholism

Raw data obtained in behavioral sensitization to amphetamine and alcohol experimental procedure: effect of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) in C57Bl6 mice and to alcohol in DBA2 mice. Raw data obtained in alcohol intake procedure in mice habituated to alcohol (10 % v/v).  <br

Complementarity of gluCEST and 1^1H‐MRS for the study of mouse models of Huntington's disease

International audienceIdentification of relevant biomarkers is fundamental to understand biological processes of neurodegenerative diseases and to evaluate therapeutic efficacy. Atrophy of brain structures has been proposed as a biomarker, but it provides little information about biochemical events related to the disease. Here, we propose to identify early and relevant biomarkers by combining biological specificity provided by 1H‐MRS and high spatial resolution offered by gluCEST imaging. For this, two different genetic mouse models of Huntington's disease (HD)—the Ki140CAG model, characterized by a slow progression of the disease, and the R6/1 model, which mimics the juvenile form of HD—were used. Animals were scanned at 11.7 T using a protocol combining 1H‐MRS and gluCEST imaging. We measured a significant decrease in levels of N‐acetyl‐aspartate, a metabolite mainly located in the neuronal compartment, in HD animals, and the decrease seemed to be correlated with disease severity. In addition, variations of tNAA levels were correlated with striatal volumes in both models. Significant variations of glutamate levels were also observed in Ki140CAG but not in R6/1 mice. Thanks to its high resolution, gluCEST provided complementary insights, and we highlighted alterations in small brain regions such as the corpus callosum in Ki140CAG mice, whereas the glutamate level was unchanged in the whole brain of R6/1 mice. In this study, we showed that 1H‐MRS can provide key information about biological processes occurring in vivo but was limited by the spatial resolution. On the other hand, gluCEST may finely point to alterations in unexpected brain regions, but it can also be blind to disease processes when glutamate levels are preserved. This highlights in a practical context the complementarity of the two methods to study animal models of neurodegenerative diseases and to identify relevant biomarker

Optical capture system for Real-time convection PCR instrument

本實驗在即時熱對流核酸擴增儀 (Real-time convection PCR instrument) 中，設計大收光量光信號截取系統，以同時讀取系統當中八個毛細管中兩種螢光特性。先以光學模擬軟體ZEMAX來模擬成像系統，本系統N.A值為0.19，收光量可提升至10倍 。成像品質上，系統之徑向能量累積 (Radial energy distribution, RED) 分佈均在74%以上，調變轉換函數(Modulation transfer function, MTF)在100 lp/mm均為0.8以上，且中心鏡組與邊緣鏡組之光通量差異為10%，實際測量差為7%。另一方面測量濃度0.45μM的Fluorescein的螢光訊號，且總螢光強度約為背景值之10倍，系統的收光量也比直接收光大約10倍。In this study Real-time convection PCR instrument, the design of a large amount of light received the optical signal of the intercepted system to read eight of the capillary system of two fluorescent properties. First of all, using ZEMAX optical software to simulate the imaging system, the system received 0.19 of N.A, the flux can be increased to 10 times. Image quality, the system of Radial energy distribution is 74%. Modulation transfer function at 100 lp / mm is 0.8, the center with the edge of the flux difference are 10%, the actual measured difference is 7%. Actually, measuring the concentration of 0.45μM of Fluorescein signal, and the total fluorescence intensity is about 10 times of the background value, The system of the flux is higher 10 times than directly received light.第一章 緒論............................1 1.1 序言...............................1 1.2 聚合酶連鎖反應.....................2 1.3熱對流式聚合酶連鎖反應..............5 1.4 即時聚合酶連鎖反應.................7 第二章 光學系統設計...................10 2.1 光通量............................10 2.2 光學系統設計......................11 2.3 成像品質評估函數..................12 第三章 成像鏡組設計...................17 3.1 物鏡設計..........................17 3.2 轉向透鏡設計......................18 3.3 兩片式鏡..........................19 3.4 兩片式物鏡與轉向透鏡整體結構 .....20 3.5 三片式鏡..........................25 3.6 三片式物鏡與轉向透鏡整體結構.......26 3.7三片式物鏡與轉向透鏡結構之模擬討論..33 第四章 實體架設........................34 4.1實體公差分析........................34 4.2實體結構............................36 4.3轉向透鏡測試........................37 4.4螢光檢測............................38 第五章 總結............................40 參考附錄...............................41 圖目錄 頁次 圖1 聚合酶連鎖反應之三階段..................4 圖2 聚合酶連鎖反之DNA複製的數量級...........5 圖3 Rayleigh-Be′nard convection cell......5 圖4 Convective PCR in a Rayleigh–B′enard cell ..6 圖5 層形熱對流PCR..................................7 圖6 環形熱對流.....................................7 圖7螢光強度........................................8 圖8 Taqman probe method .........................9 圖9 光通量比較圖..................................10 圖10光學讀取系統設計..............................12 圖11三種單色像差..................................13 圖12 RED示意圖....................................14 圖13點擴散函數....................................15 圖14經光學系統後之測試條紋........................16 圖15條紋測試標準..................................16 圖16 MTF定義比較圖...............................16 圖17 MTF曲線 ....................................16 圖18 MTF曲線 ....................................16 圖19平行光顯微物鏡................................17 圖20 轉向透鏡之功用...............................18 圖21物鏡一片鏡組 .................................19 圖22物鏡一片光斑圖................................19 圖23物鏡兩片......................................19 圖24 物鏡兩片光斑圖...............................19 圖25 兩片式物鏡與轉向透鏡整體結構 ................20 圖26 兩片式物鏡轉向透鏡 F200. ....................21 圖27 兩片式物鏡轉向透鏡F200反轉...................21 圖28兩片式物鏡轉向透鏡F200雙凸....................22 圖29 兩片式整體成像品質..........................23 圖30兩片式整體模擬討論............................24 圖31三片式物鏡 ...................................25 圖32 三片式物鏡MTF圖 ....................................25 圖33三片式物鏡RED ...........................25 圖34 三片式物鏡與轉向透鏡整體結構 .................26 圖35三片式物鏡與轉向透鏡F200球面......................27 圖36三片式物鏡之像散............................27 圖37球面與非球面透鏡 ..........................28 圖38三片式物鏡 轉向透鏡F200非球面 ............29 圖39三片式物鏡轉向透鏡非球面之整體成像品質...........30 圖40式物鏡 轉向透鏡F400X2模擬討論.......................31 圖41三片式物鏡與轉向透鏡F400x2之整體成像品質.............32 圖42三片式物鏡轉向透鏡整體模擬討論 ....................33 圖43鏡片距離對焦距、成像品質影響 ....................34 圖44模擬實際系統放大率驗算...............................35 圖45系統放大率...................................35 圖46CCD成像面.................................35 圖47實際測試 .......................36 圖48未加轉向透鏡F400X2前...............................37 圖49加轉向透鏡F400x2後.............................37 圖50 螢光檢測 Ι.................................38 圖51螢光檢測 ΙΙ 軟體轉換..........................3

Effect of ifenprodil (ifen) and cyproheptadine (cypro) in combination on alcohol preference during 2 hour sessions with alcohol (10%) and water bottles.

<p>The preference index Alcohol/Water (Pref.) is calculated as follows: Pref. = (Alcohol consumption–water consumption) / (Alcohol consumption + water consumption). All groups (Saline, N = 12, cypro 1 + ifen 1, N = 8, cypro 3 + ifen 3, N = 9 received saline treatment at the first two sessions, cyproheptadine and ifenprodil treatments started at the arrow. Results are expressed as mean values ± S.E.M. Statistical analyses: repeated measures ANOVA, group effect F_2;26 = 223.2, p< 0.001, session effect F_6;156 = 45.7, p< 0.001, group × session interaction F_12;156 = 9.5, p< 0.001; one-way ANOVAs, differences between groups in session 1 F_2;21 = 0.7, p = ns; in session 6 F_2;26 = 0.1, p = ns; in sessions 7–12, F_2;26≥ 6.1, p< 0.01; post-hoc comparisons, Dunnett test, (a) significantly different (<i>p</i><0.05) from saline group.</p