The Genetics of Birth Timing: Insights into a Fundamental Component of Human Development

The timing of birth necessitates the coupling of fetal maturation with the onset of parturition, and occurs at characteristic, but divergent gestations between mammals. Preterm birth in humans is an important but poorly understood outcome of pregnancy that uncouples fetal maturation and birth timing. The etiology of preterm birth is complex, involving environmental and genetic factors whose underlying molecular and cellular pathogenic mechanisms remain poorly understood. Animal models, although limited by differences with human physiology, have been crucial in exploring the role of various genetic pathways in mammalian birth timing. Studies in humans of both familial aggregation and racial disparities in preterm birth have contributed to the understanding that preterm birth is heritable. A significant portion of this heritability is due to polygenic causes with few true Mendelian disorders contributing to preterm birth. Thus far, studies of the human genetics of preterm birth using a candidate gene approach have met with limited success. Emerging research efforts using unbiased methods may yield promising results if concerns about study design can be adequately addressed. The findings from this frontier of research may have direct implications for the allocation of public health and clinical resources as well as spur the development of more effective therapeutics.     

Characterization of contraction-mediating prostanoid receptors in human hand veins: effects of the thromboxane receptor antagonists BM13, 505 and AH23848

The effects of prostaglandin F_2α, prostaglandin E₁, prostaglandin E₂ and the thromboxane A₂ analogue U46619 were determined in ring segments of human hand veins. All prostanoids except prostaglandin E₁ elicited contraction. The order of potency was U46619 > prostaglandin F_2α > prostaglandin E₂. The thromboxane receptor antagonists BM13, 505 and AH23848 both caused a parallel rightward displacement of the concentration-response curve for U46619 without depression of the maximum contraction, suggesting competitive antagonism. Schild plots for both antagonists yielded regression lines with slope indices not significantly different from unity. The pA₂ values for BM13, 505 and AH23848 were 7.9 and 8.4 respectively. Both antagonists also effectively inhibited prostaglandin F_2α-induced contractions. However, AH23848 significantly reduced the maximum response, and the results with BM13, 505 gave no clear indication of the type of inhibition. In vein segments submaximally contracted by 5-hydroxytryptamine, prostaglandins E₁ and E₂ produced a biphasic response with a relaxation at low and a contraction at high concentrations. Prostaglandin F_2α and U46619 failed to elicit relaxation under these conditions. However, in the presence of either thromboxane receptor antagonist, prostaglandin F_2α but not U46619 produced a relaxation. The results are compatible with the presence of at least two prostanoid receptors in human hand veins, a contraction-mediating thromboxane receptor and an as yet unclassified receptor eliciting relaxation. U46619 was a potent agonist at the thromboxane receptor and prostaglandin E₁ and E₂ preferentially stimulated the relaxation-mediating receptor, whereas prostaglandin F_2α appeared to be active at both receptor sites.     

N6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation

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在端脑发育过程中胆碱能前体细胞发生和分化与不同浓度骨形态发生蛋白4的影响

目的:在神经元的发育过程中,骨形态发生蛋白具有多向诱导功能,实验观察不同浓度骨形态发生蛋白4对端脑胆碱能前体细胞发生和分化的影响,探寻其诱导条件及作用规律。方法:实验于2004-11/2005-03在吉林大学白求恩医学院组织胚胎学教研室细胞培养室和免疫组化实验室完成。采用无血清原代培养E16大鼠端脑细胞,分别在实验组培养液中加入终浓度为10,20和40μg/L骨形态发生蛋白4,细胞培养4 d时,实施乙酰胆碱转移酶免疫细胞化学染色,同时计算乙酰胆碱转移酶免疫反应阳性细胞的百分率。结果:乙酰胆碱转移酶免疫阳性反应细胞分布于对照组和实验组细胞团的边缘和细胞团之间。20μg/L骨形态发生蛋白4组细胞团之间分散的细胞多伸出突起为乙酰胆碱转移酶免疫阳性反应,可见少量具有典型放射状胶质细胞形态的细胞也呈乙酰胆碱转移酶免疫阳性反应。10μg/L骨形态发生蛋白4组与对照组相比乙酰胆碱转移酶免疫反应阳性细胞数量差异无显著性(P>0.05),20μg/L骨形态发生蛋白4组乙酰胆碱转移酶免疫阳性反应细胞数量明显多于对照组(P<0.05),40μg/L骨形态发生蛋白4组乙酰胆碱转移酶免疫阳性反应细胞数量明显少于对照组(P<0.05)。结论:低浓度(20μg/L)骨形态发生蛋白4可诱导端脑胆碱能前体细胞发生和分化;较高浓度(40μg/L)骨形态发生蛋白4抑制端脑胆碱能前体细胞发生和分化。     

猪源性异种骨支架材料的生物相容性

目的:异种骨来源广泛,价格低廉,经过适当处理既能保留骨诱导作用,并作为骨支架使其具有骨传导作用。检测猪源性骨支架材料与人源性骨支架材料的生物相容性有无明显差异,为猪源性骨支架材料取代人源性骨支架材料提供实验依据。方法:实验于2006-08/2007-03在南方医科大学人体解剖学系实验室(广东省组织构建与检测重点实验室)完成。①实验材料:人源性、猪源性骨支架材料(为课题组前期制备);脂肪源间充质细胞(前期培养)。②实验方法及评估:体外细胞毒性实验:提取人源性、猪源性骨支架材料浸提液,用此浸提液培养脂肪源间充质细胞,并用无浸提液的DMEM培养基做对照,镜下观察细胞生长状况,流式细胞术检测细胞生长周期;人源性、猪源性骨支架材料皮下植入试验:于8只新西兰大白兔皮下,脊柱左侧植入异种骨支架材料,右侧植入同种异体骨支架材料。分别于4,8,12,16周将植入材料连同周围组织取出,进行组织切片观察及电镜观察。对动物处置符合动物伦理学标准。结果:①体外细胞毒性实验结果:在同一时间点,浸提液组、正常培养组细胞生长状况均良好,未见明显细胞抑制;流式细胞术检测细胞周期,3组细胞G1、G2、S期细胞百分率差异无统计学意义(P>0.05)。②皮下植入实验结果:组织切片光镜及电镜观察,4周两种植入材料周围均见结缔组织包绕,有大量巨噬细胞、浆细胞、中性粒细胞、单核细胞浸润,材料表面光滑,与结缔组织界限清楚;8周时炎症反应减轻,可见部分材料开始降解,材料表面稍显粗糙,有少量结缔组织长入材料内部;12周炎症反应基本消失、材料降解明显、异位成骨趋势明显,材料表面更加粗糙,周围有大量结缔组织长入材料;16周均无炎症反应,两种材料大部分降解,并且猪源性骨支架材料降解更为迅速,均有新骨形成,材料表面粗糙程度较12周时为甚,骨支架材料基本消失。结论:猪源性异种骨支架材料有良好的生物相容性,与人源性异种骨支架材料无明显差别。     

磷酸三钙骨水泥骨长入的实验

目的:找出磷酸三钙骨水泥中磷酸三钙合适的比例(既能成骨又不影响骨水泥的机械性能),并观察磷酸三钙骨水泥中在动物实验中骨长入的特点。方法:①磷酸三钙比例的筛选:根据骨粒骨水泥的研究基础,将普通骨水泥(上海第二医科大学第九人民医院科技开发公司出品)中加入30%,35%,40%的直径200～300μm能成骨的磷酸三钙颗粒(法国Bio-LuCo.提供),测试其抗压强度和弹性模量,找出合适的比例。②动物实验:将25只成年新西兰大白兔随机分成术后2,4,8,12,16周组5组,每组5只。无菌下在两侧股骨远端垂直于股骨做直径6mm,长12mm的圆柱样缺损,两侧随机填入35%磷酸三钙骨水泥(实验侧)和普通骨水泥(对照侧)进行骨长入的观察。分别于术后2,4,8,12和16周取材,观察骨水泥表面的骨生长和机械强度变化。结果:①随着磷酸三钙的比例增加,磷酸三钙骨水泥的抗压强度逐渐下降,而其弹性模量则逐渐上升(P<0.05),加入35%磷酸三钙时抗压强度为(86.30±0.57)MPa,弹性模量为(2.80±0.16)GPa,比例合适。②磷酸三钙骨水泥植入兔股骨2周时表面无明显变化,4周即开始有表面粗糙,但表面骨组织附着不明显,植入8周时骨水泥表面少量骨组织附着;12周骨水泥表面骨组织附着明显;16周骨水泥表面骨组织附着明显增多。对照侧仅见一薄层纤维结缔组织。③磷酸三钙骨水泥植入兔股骨第4周时抗压强度低于植入第2周[(83.50±1.21),(85.20±0.85)MPa,P<0.05],随后上升,至植入第16周时为(87.10±1.00)MPa(P<0.05)。弹性模量在植入12周时低于植入第2周[(2.30±0.16),(2.70±0.15)GPa,P<0.05],但在16周时上升为(2.80±0.16)GPa]。结论:①磷酸三钙骨水泥中磷酸三钙的比例35%最为合适。②随着骨水泥表面的磷酸三钙颗粒被吸收和新骨长入,具备部分生物活性,机械强度符合骨缺损充填的基本要求。