BACKGROUND & AIMS: :MYC is one of the most commonly overexpressed oncogenes in human cancer. The targeted inactivation of MYC is a possible therapy for neoplasia. Conditional transgenic mouse model systems are tractable methods to precisely dissect how and when the inactivation of MYC might be effective in the treatment for human cancer. From these model systems, several general principles emerge. MYC inactivation stereotypically results in the proliferative arrest, differentiation and/or apoptosis of tumor cells. The specific consequences of MYC inactivation appear to depend both on the type of cancer as well as the constellation of genetic events unique to a given tumor. Tumors can escape from dependence upon MYC by acquiring compensatory genetic events. MYC inactivation can uncover the stem cell properties of tumor cells that differentiate into normal appearing cells. In some cases, these differentiated cells are actually dormant tumor cells that recover their neoplastic properties upon MYC reactivation. In other cases, even brief MYC inactivation is sufficient to induce sustained tumor regression. Insights from conditional transgenic mouse models will be useful in the development of therapies that target MYC for the treatment of cancer.

背景与目标： : MYC是人类癌症中最常见的过度表达的癌基因之一。靶向灭活MYC可能是肿瘤形成的一种治疗方法。条件转基因小鼠模型系统是精确剖析MYC失活如何以及何时有效治疗人类癌症的方法。从这些模型系统中，出现了几个一般原则。MYC失活通常导致肿瘤细胞的增殖停滞，分化和/或凋亡。MYC失活的具体后果似乎既取决于癌症的类型，也取决于给定肿瘤特有的遗传事件的星座。肿瘤可以通过获得代偿性遗传事件来摆脱对MYC的依赖。MYC失活可以揭示肿瘤细胞分化为正常出现细胞的干细胞特性。在某些情况下，这些分化的细胞实际上是休眠的肿瘤细胞，在MYC重新激活后恢复其肿瘤特性。在其他情况下，即使短暂的MYC失活也足以诱导肿瘤持续消退。来自条件转基因小鼠模型的见解将有助于开发靶向MYC治疗癌症的疗法。

BACKGROUND & AIMS: :The Slc5a6 gene expresses a plasma membrane protein involved in the transport of the water-soluble vitamin biotin; the transporter is commonly referred to as the sodium-dependent multivitamin transporter (SMVT) because it also transports pantothenic acid and lipoic acid. The relative contribution of the SMVT system toward carrier-mediated biotin uptake in the native intestine in vivo has not been established. We used a Cre/lox technology to generate an intestine-specific (conditional) SMVT knockout (KO) mouse model to address this issue. The KO mice exhibited absence of expression of SMVT in the intestine compared with sex-matched littermates as well as the expected normal SMVT expression in other tissues. About two-thirds of the KO mice died prematurely between the age of 6 and 10 wk. Growth retardation, decreased bone density, decreased bone length, and decreased biotin status were observed in the KO mice. Microscopic analysis showed histological abnormalities in the small bowel (shortened villi, dysplasia) and cecum (chronic active inflammation, dysplasia) of the KO mice. In vivo (and in vitro) transport studies showed complete inhibition in carrier-mediated biotin uptake in the intestine of the KO mice compared with their control littermates. These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake. These studies also provide evidence for a casual association between SMVT function and normal intestinal health.

背景与目标： : Slc5a6基因表达参与水溶性维生素生物素转运的质膜蛋白; 转运蛋白通常被称为钠依赖性多种维生素转运蛋白 (SMVT)，因为它还转运泛酸和硫辛酸。尚未确定SMVT系统对体内天然肠道中载体介导的生物素摄取的相对贡献。我们使用Cre/lox技术生成肠特异性 (条件) SMVT敲除 (KO) 小鼠模型来解决此问题。与性别匹配的同窝仔相比，KO小鼠在肠道中没有SMVT表达，在其他组织中也没有预期的正常SMVT表达。大约3分之2的KO小鼠在6至10周之间过早死亡。在KO小鼠中观察到生长迟缓，骨密度降低，骨长度降低和生物素状态降低。显微镜分析显示KO小鼠的小肠 (绒毛缩短，发育不良) 和盲肠 (慢性活动性炎症，发育不良) 的组织学异常。体内 (和体外) 转运研究表明，与对照同窝小鼠相比，KO小鼠肠道中载体介导的生物素摄取完全抑制。这些研究在天然肠道中首次证实SMVT完全负责肠道生物素的吸收。这些研究还为SMVT功能与正常肠道健康之间的偶然关联提供了证据。

BACKGROUND & AIMS: :Mutations in the gene encoding hepatocyte nuclear factor (HNF)1beta result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing beta-cell mass. The functional role of HNF1beta in normal beta-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1beta, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic beta-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1beta was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1beta also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent beta-cells are sensitive to increased expression of WT HNF1beta and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

背景与目标： : 编码肝细胞核因子 (HNF) 1β 的基因突变通过损害胰岛素分泌反应并可能通过减少 β 细胞质量而导致年轻-(MODY)5的成熟发作糖尿病。HNF1beta在正常 β 细胞中的功能作用知之甚少; 因此，在本研究中，野生型 (WT) HNF1beta或两个自然发生的MODY5突变之一 (激活突变，P328L329del或显性阴性形式，a263insGG) 在胰腺 β 细胞系，胰岛素-1 (INS-1) 中有条件表达，并检查了功能后果。令人惊讶的是，显性阴性突变体的过表达并未改变所研究细胞的任何功能特性 (包括胰岛素分泌，细胞生长和活力)。相比之下，WT hnf1β 的表达与INS-1细胞增殖的时间和剂量依赖性抑制以及凋亡的显着增加有关。WT hnf1β 的诱导还抑制了胰岛素对营养刺激的分泌反应，膜去极化或蛋白激酶A和C的激活，这与胰十二指肠homeobox-1蛋白水平的显着降低有关。然而，由于P328L329del突变体的表达导致细胞增殖速率降低，但未能诱导凋亡或改变胰岛素分泌，因此胰岛素分泌的减弱与增殖的抑制和活力的丧失相分离。综合而言，目前的结果表明，成熟的啮齿动物 β 细胞对WT HNF1beta的表达增加敏感，并且暗示该蛋白的水平受到严格调节以维持分泌能力和细胞活力。

BACKGROUND & AIMS: :Loss of function mouse models comprise knock-out mice, where a gene is deleted in the germline, and conditional knock-out mice with somatic deletion of a floxed allele in defined tissues. Both types of mice are used for comprehensive studies of gene functions in vivo. Here, we describe a simple method for simultaneous generation of mice with conditional or knock-out alleles for the transcription factor fra-2 (Fos-related antigen 2) using a single embryonic stem (ES) cell clone. ES cells with a floxed fra-2 allele were transiently transfected with a Cre-recombinase expression plasmid and plated at low density. Most of the resulting ES cell colonies consisted of a mixture of cells that have either retained or lost the conditional allele. We demonstrate that these mixed ES cell clones can be directly used for generation of chimeras that give rise to offspring with conditional or knock-out alleles simultaneously. This strategy shortens the time and reduces the number of germline transmission events to generate genetically modified mice.

背景与目标： : 功能丧失小鼠模型包括敲除小鼠和条件敲除小鼠，其中基因在种系中缺失，条件敲除小鼠在定义的组织中体细胞缺失了floxed等位基因。两种类型的小鼠均用于体内基因功能的综合研究。在这里，我们描述了一种使用单个胚胎干 (ES) 细胞克隆同时产生具有转录因子fra-2 (Fos相关抗原2) 的条件或敲除等位基因的小鼠的简单方法。用Cre重组酶表达质粒瞬时转染具有絮状fra-2等位基因的ES细胞，并以低密度进行铺板。大多数产生的ES细胞集落由保留或失去条件等位基因的细胞混合物组成。我们证明，这些混合的ES细胞克隆可直接用于产生嵌合体，这些嵌合体会同时产生条件或敲除等位基因的后代。该策略缩短了时间并减少了种系传播事件的数量，以生成转基因小鼠。

BACKGROUND & AIMS: :Proteins are often classified in a binary fashion as either structured or disordered. However this approach has several deficits. Firstly, protein folding is always conditional on the physiochemical environment. A protein which is structured in some circumstances will be disordered in others. Secondly, it hides a fundamental asymmetry in behavior. While all structured proteins can be unfolded through a change in environment, not all disordered proteins have the capacity for folding. Failure to accommodate these complexities confuses the definition of both protein structural domains and intrinsically disordered regions. We illustrate these points with an experimental study of a family of small binding domains, drawn from the RNA polymerase of mumps virus and its closest relatives. Assessed at face value the domains fall on a structural continuum, with folded, partially folded, and near unstructured members. Yet the disorder present in the family is conditional, and these closely related polypeptides can access the same folded state under appropriate conditions. Any heuristic definition of the protein domain emphasizing conformational stability divides this domain family in two, in a way that makes no biological sense. Structural domains would be better defined by their ability to adopt a specific tertiary structure: a structure that may or may not be realized, dependent on the circumstances. This explicitly allows for the conditional nature of protein folding, and more clearly demarcates structural domains from intrinsically disordered regions that may function without folding.

背景与目标： : 蛋白质通常以二元形式分为结构化或无序。然而，这种方法有几个缺陷。首先，蛋白质折叠始终取决于理化环境。在某些情况下结构化的蛋白质在其他情况下会紊乱。其次，它隐藏了行为上的根本不对称。虽然所有结构化的蛋白质都可以通过环境的变化来展开，但并非所有无序的蛋白质都具有折叠的能力。未能适应这些复杂性，混淆了蛋白质结构域和固有无序区域的定义。我们通过对来自腮腺炎病毒及其近亲的RNA聚合酶的小结合结构域家族的实验研究来说明这些观点。按面值评估，域落在结构连续体上，具有折叠，部分折叠和靠近非结构化构件的区域。然而，家庭中存在的疾病是有条件的，这些密切相关的多肽可以在适当的条件下进入相同的折叠状态。任何强调构象稳定性的蛋白质结构域的启发式定义都将该结构域家族一分为二，没有生物学意义。结构域可以通过采用特定三级结构的能力来更好地定义: 根据情况可能实现或不实现的结构。这明确地允许蛋白质折叠的条件性质，并且更清楚地将结构域与可能在没有折叠的情况下起作用的固有无序区域划分开来。

BACKGROUND & AIMS: :Cooperation declines in repeated public good games because individuals behave as conditional cooperators. This is because individuals imitate the social behaviour of successful individuals when their payoff information is available. However, in human societies, individuals cooperate in many situations involving social dilemmas. We hypothesize that humans are sensitive to both success (payoffs) and how that success was obtained, by cheating (not socially sanctioned) or good behaviour (socially sanctioned and adds to prestige or reputation), when information is available about payoffs and prestige. We propose and model a repeated public good game with heterogeneous conditional cooperators where an agent's donation in a public goods game depends on comparing the number of donations in the population in the previous round and with the agent's arbitrary chosen conditional cooperative criterion. Such individuals imitate the social behaviour of role models based on their payoffs and prestige. The dependence is modelled by two population-level parameters: affinity towards payoff and affinity towards prestige. These affinities influence the degree to which agents value the payoff and prestige of role models. Agents update their conditional strategies by considering both parameters. The simulations in this study show that high levels of cooperation are established in a population consisting of heterogeneous conditional cooperators for a certain range of affinity parameters in repeated public good games. The results show that social value (prestige) is important in establishing cooperation.

背景与目标： : 合作在重复的公益游戏中下降，因为个人表现为有条件的合作者。这是因为当个人的收益信息可用时，个人会模仿成功个人的社会行为。然而，在人类社会中，个人在许多涉及社会困境的情况下进行合作。我们假设人类对成功 (收益) 和成功是如何获得的敏感，通过欺骗 (不是社会认可的) 或良好的行为 (社会认可的，并增加了声望或声誉)，当有关收益和声望的信息可用时。我们提出并建立了具有异质条件合作者的重复公共物品博弈模型，其中公共物品博弈中代理人的捐赠取决于比较上一轮人口中的捐赠数量以及代理人任意选择的条件合作标准。这些人根据他们的回报和声望来模仿榜样的社会行为。依赖关系由两个人口水平的参数建模: 对回报的亲和力和对声望的亲和力。这些亲和力会影响代理人对榜样的回报和声望的重视程度。代理通过考虑两个参数来更新其条件策略。这项研究中的模拟表明，在重复的公益游戏中，对于一定范围的亲和力参数，在由异质条件合作者组成的人群中建立了高水平的合作。结果表明，社会价值 (声望) 在建立合作中很重要。

BACKGROUND & AIMS: OBJECTIVES:The aim of this study was to derive longitudinal reference values of fetal growth (estimated fetal weight [EFW] and abdominal circumference [AC]) during the third trimester and to develop coefficients for conditional growth assessment. PATIENTS AND METHODS:A prospective cohort study was conducted involving consecutive singleton pregnancies in a low-risk population for a routine third-trimester scan at 30+0-34+6 weeks and follow-up at 37+0-38+6 weeks for an additional ultrasound. Statistical analysis was based on multilevel modeling using MLwiN software. Unconditional centiles were calculated from z-values at each gestational age, and conditional centiles were calculated from z-values at a given measurement (30-34 weeks) and the expected measurement (37-38 weeks). RESULTS:At 30-34 weeks, 8 and 9.3% of the fetuses had an unconditional EFW below the 10th and above the 90th centile, respectively. At 37-38 weeks, these figures were 10.3 and 9.3%, respectively. Regarding the unconditional AC, at the first scan, 8.9 and 9.6% had values below the 10th and above the 90th centile, while at the second scan 10.5 and 10.5% had values below the 10th and above the 90th centile, respectively. The proportion with a conditional EFW below the 10th and above the 90th centile was 10.2 and 9.4% at the second scan, respectively. For conditional AC, these figures were 10.7 and 10.3%, respectively. CONCLUSION:We have produced reference centiles for EFW and AC growth during the third trimester as a useful tool for quantifying growth.

背景与目标：

BACKGROUND & AIMS: :Lignin based materials and chemicals with outstanding sustainability have drawn increasingly attentions. However, the dark color of lignin limits the utilization in color-depended fields. In this work, the factors that influence the color of lignin were investigated and mechanisms were illustrated by GPC, NBO, 2D HSQC, XPS, SEM, and visible light spectrum. It is found that the condensed structures were mainly separated at higher pH due to its high molecular weight and low solubility. The condensation contributes to the conjugation and unsaturation, which resulted in the dark-color of the lignin precipitated at high pH value. The oxidation is not crucial for the color darkening of lignin in drying, it is the micro aggregation that dominantly determined the color degree. The concentration of chromophore was decreased owing to the decrease of bulk density (caused by the alleviation of aggregation), which endowed lignin with the bright seeing macroscopically. Notably, the selection of light-colored lignin needs to be individually considered regarding different use, since the dominating factors that influence the color at solid or solution are totally different. In summary, this work offers guidance for acquiring light-colored lignin and helps people select the light-colored lignin properly regarding utilizations.

背景与目标： : 具有突出可持续性的木质素基材料和化学品越来越受到关注。但是，木质素的深色限制了在与颜色有关的领域中的利用率。在这项工作中，研究了影响木质素颜色的因素，并通过GPC，NBO，2D HSQC，XPS，SEM和可见光光谱说明了其机理。发现由于其高分子量和低溶解度，缩合结构主要在较高的pH下分离。冷凝会导致共轭和不饱和，从而导致木质素在高ph值下沉淀出深色。氧化对于干燥过程中木质素的颜色变暗不是至关重要的，微聚集主要决定了色度。发色团的浓度由于堆积密度的降低 (由于聚集的减轻而引起) 而降低，这使木质素在宏观上具有明亮的视觉效果。值得注意的是，由于影响固体或溶液颜色的主要因素完全不同，因此需要针对不同的用途单独考虑选择浅色木质素。总之，这项工作为获取浅色木质素提供了指导，并帮助人们在利用方面正确选择浅色木质素。

BACKGROUND & AIMS: :The age-specific sensitivity of a screening program was investigated using a population-based cancer registry as a source of false-negative cancer cases. A population-based screening program for breast cancer was run using either clinical breast examinations (CBE) alone or mammography combined with CBE in the Miyagi Prefecture from 1997 to 2002. Interval cancers were newly identified by linking the screening records to the population-based cancer registry to estimate the number of false-negative cases of screening program. Among 112 071 women screened by mammography combined with CBE, the number of detected cancers, false-negative cases and the sensitivity were 289, 22 and 92.9%, respectively, based on the reports from participating municipalities. The number of newly found false-negative cases and corrected sensitivity when using the registry were 34 and 83.8%, respectively. In detected cancers, the sensitivity of screening by mammography combined with CBE in women ranging from 40 to 49 years of age based on a population-based cancer registry was much lower than that in women 50-59 and 60-69 years of age (40-49: 18, 71.4%, 50-59: 19, 85.8%, 60-69: 19, 87.2%). These data suggest that the accurate outcome of an evaluation of breast cancer screening must include the use of a population-based cancer registry for detecting false-negative cases. Screening by mammography combined with CBE may therefore not be sufficiently sensitive for women ranging from 40 to 49 years of age.

背景与目标： : 使用基于人群的癌症注册表作为假阴性癌症病例的来源，研究了筛查计划的年龄特异性敏感性。在宫城县1997年2002年，仅使用临床乳房检查 (CBE) 或乳房x线摄影结合CBE进行了基于人群的乳腺癌筛查计划。通过将筛查记录与基于人群的癌症登记处联系起来，以估计筛查计划的假阴性病例数，新发现了间隔性癌症。根据参与城市的报告，在112 071名乳房x线摄影联合CBE筛查的妇女中，检测到的癌症、假阴性病例和敏感性分别为289、22和92.9%。使用注册表时，新发现的假阴性病例数和纠正的敏感性分别为34和83.8%。在检测到的癌症中，根据基于人群的癌症登记，在40至49岁的女性中通过乳房x线摄影联合CBE进行筛查的敏感性远低于50-59岁和60-69岁的女性 (40-49: 18，71.4%，50-59: 19，85.8%，60-69: 19，87.2%)。这些数据表明，乳腺癌筛查评估的准确结果必须包括使用基于人群的癌症注册表来检测假阴性病例。因此，对于40至49岁的女性，乳房x线摄影联合CBE筛查可能不够敏感。

BACKGROUND & AIMS: OBJECTIVE:To investigate the functions of Fibroblast Growth Factor Receptor-2 (FGFR2) at different stages of cell differentiation. The engineered murine embryonic stem (ES) cells with conditional knockout of FGFR2 were developed depending on Cre-loxP. METHODS:Cre-loxP system was used in a conditional targeting vector. The competent AM-1 bacteria, which expressed Cre-recombinase, was used to confirm the Cre-mediated deletion of the floxed exons 7 and 8 of FGFR2. The targeting vector was electroporated into the ES cells, and the transfected ES cells were screened with G418 and Ganciclovir. Finally, the ES clones with correct targeting events were identified by Southern Blot and PCR. RESULTS:The targeting vector with conditional knockout of murine FGFR2 was successfully constructed and confirmed by PCR and digestion analysis in bacteria. 86 ES clones were collected by selective culture with G418 and Ganciclovir. Four of the 86 ES clones were found containing the targeting gene sequence in genomic DNA proved by Southern Blot with a 5'-end flank probe. Two of the four ES clones had the correct targeting events that included the insertion of the targeting gene sequence in genomic DNA and were checked by Southern Blot with a 3'-end flanking probe. Finally, the insertion of loxP (loxP3) between exons 8 and 9 in genomic DNA was identified in one of the two ES clones by Southern Blot and PCR. CONCLUSION:FGFR2 conditional knockout depending on Cre-loxP can be successfully used in ES cells.

背景与目标：

BACKGROUND & AIMS: :The negatively charged side chain of an Asp residue in transmembrane domain 2 is likely to play an important role in receptor signalling since it is highly conserved in the whole family of G protein-coupled receptors, except in mammalian gonadotropin-releasing hormone (GnRH) receptors. In this paper we show that the conserved Asp(90) of the catfish GnRH receptor can be substituted by a neutral Asn(90) without abolishing receptor signalling if another negatively charged Glu(93) is introduced in a proximal region of the receptor interior, thereby mimicking the Glu(90)-Lys(121) salt bridge of mammalian GnRH receptors.

背景与目标： : 跨膜结构域2中Asp残基的带负电荷的侧链可能在受体信号传导中起重要作用，因为它在整个g蛋白偶联受体家族中高度保守的，除了哺乳动物促性腺激素释放激素 (GnRH) 受体。在本文中，我们表明，如果在受体的近端区域引入另一个带负电的Glu(93)，则cat鱼GnRH受体的保守Asp(90) 可以被中性Asn(90) 取代，而不会消除受体信号传导内部，从而模仿哺乳动物GnRH受体的Glu(90)-Lys(121) 盐桥。

BACKGROUND & AIMS: :G protein-coupled receptors (GPCRs) coupled to activation of Gs, such as the PTH1 receptor (PTH1R), have long been known to regulate skeletal function and homeostasis. However, the role of GPCRs coupled to other G proteins such as Gi is not well established. We used the tet-off system to regulate the expression of an activated Gi-coupled GPCR (Ro1) in osteoblasts in vivo. Skeletal phenotypes were assessed in mice expressing Ro1 from conception, from late stages of embryogenesis, and after weaning. Long bones were assessed histologically and by microcomputed tomography. Expression of Ro1 from conception resulted in neonatal lethality that was associated with reduced bone mineralization. Expression of Ro1 starting at late embryogenesis resulted in a severe trabecular bone deficit at 12 wk of age (>51% reduction in trabecular bone volume fraction in the proximal tibia compared with sex-matched control littermates; n = 11; P < 0.01). Ro1 expression for 8 wk beginning at 4 wk of age resulted in a more than 20% reduction in trabecular bone volume fraction compared with sex-matched control littermates (n = 16; P < 0.01). Bone histomorphometry revealed that Ro1 expression is associated with reduced rates of bone formation and mineral apposition without a significant change in osteoblast or osteoclast surface. Our results indicate that signaling by a Gi-coupled GPCR in osteoblasts leads to osteopenia resulting from a reduction in trabecular bone formation. The severity of the phenotype is related to the timing and duration of Ro1 expression during growth and development. The skeletal phenotype in Ro1 mice bears some similarity to that produced by knockout of Gs-alpha expression in osteoblasts and thus may be due at least in part to Gi-mediated inhibition of adenylyl cyclase.

背景与目标： : g蛋白偶联受体 (GPCRs) 与Gs的激活 (例如PTH1受体 (PTH1R)) 偶联，长期以来一直已知可以调节骨骼功能和体内平衡。但是，与其他g蛋白 (例如Gi) 偶联的GPCRs的作用尚不明确。我们使用tet-off系统调节体内成骨细胞中活化的Gi偶联GPCR (Ro1) 的表达。在受孕，胚胎发生后期和断奶后表达Ro1的小鼠中评估了骨骼表型。通过组织学和显微计算机断层扫描对长骨进行评估。受孕后Ro1的表达导致新生儿致死，这与骨矿化减少有关。在胚胎发生晚期开始的Ro1的表达导致在12周龄时严重的小梁骨缺损 (与性别匹配的同窝对照相比，胫骨近端的小梁骨体积分数> 51% 减少; n = 11; P <0.01)。与性别匹配的同窝对照组相比，从4周龄开始的8周Ro1表达导致小梁骨体积分数减少20% 以上 (n = 16; P <0.01)。骨组织形态计量学显示，Ro1表达与骨形成和矿物质并置率降低有关，而成骨细胞或破骨细胞表面没有明显变化。我们的结果表明，成骨细胞中Gi偶联GPCR的信号传导导致骨小梁骨形成减少导致骨质减少。表型的严重程度与生长发育过程中Ro1表达的时间和持续时间有关。Ro1小鼠的骨骼表型与成骨细胞中Gs-α 表达的敲除产生的表型相似，因此可能至少部分归因于Gi介导的腺苷酸环化酶的抑制。

BACKGROUND & AIMS: :Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state current-voltage curve was dominated by inward TTX-sensitive persistent sodium current (I(NaP)) that activated near -75 mV and increased steeply with depolarization. In control, total membrane current was net outward (hyperpolarizing) near -70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation current so that total membrane current near -70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of I(NaP), which then depolarizes the cell from -70 mV to spike threshold. We quantified the relative contributions of I(NaP), hyperpolarization-activated cation current (I(h)), and calcium current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive sodium current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium current were minimal. Thus, spontaneous activity is driven primarily by activation of I(NaP) in a positive feedback loop starting near -70 mV and providing increasing inward current to threshold. These results show that the pacemaking "engine" from I(NaP) is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane current near -70 mV, as by muscarinic stimulation.

背景与目标： : 海马CA1锥体神经元通常处于静止状态，但在毒蕈碱激动剂刺激下会自发发射。在来自小鼠CA1锥体神经元的脑切片记录中，我们使用交错的电流钳和电压钳实验检查了这种活动的离子基础。在对照和毒蕈碱刺激后，稳态电流-电压曲线均由内向TTX敏感的持续钠电流 (I(NaP)) 主导，该电流在75 mV附近激活并随着去极化而急剧增加。在对照中，总膜电流净向外 (超极化) 接近70 mV，使得细胞具有稳定的静息电位。毒蕈碱刺激激活小的非选择性阳离子电流，使得接近70 mV的总膜电流移动，几乎变为净向内 (去极化)。小的去极化触发I(NaP) 的再生激活，然后将细胞从-70 mV去极化到尖峰阈值。我们通过使用细胞自身的放电作为电压命令以及特定的阻滞剂，量化了I(NaP)，超极化激活的阳离子电流 (I(h)) 和钙电流对起搏的相对贡献。TTX敏感的钠电流在整个峰间间隔内都很大，随着膜电位接近阈值而增加，而Ih和钙电流都很小。因此，自发活动主要由正反馈回路中的I(NaP) 的激活驱动，该正反馈回路开始接近70 mV并提供增加的内向电流至阈值。这些结果表明，来自I(NaP) 的起搏 “引擎” 是CA1锥体神经元的固有特性，可以通过接近70 mV的净膜电流的小偏移 (如通过毒蕈碱刺激) 来接合或脱离。

BACKGROUND & AIMS: :Genetic epidemiologists routinely assess disease susceptibility in relation to haplotypes, that is, combinations of alleles on a single chromosome. We study statistical methods for inferring haplotype-related disease risk using single nucleotide polymorphism (SNP) genotype data from matched case-control studies, where controls are individually matched to cases on some selected factors. Assuming a logistic regression model for haplotype-disease association, we propose two conditional likelihood approaches that address the issue that haplotypes cannot be inferred with certainty from SNP genotype data (phase ambiguity). One approach is based on the likelihood of disease status conditioned on the total number of cases, genotypes, and other covariates within each matching stratum, and the other is based on the joint likelihood of disease status and genotypes conditioned only on the total number of cases and other covariates. The joint-likelihood approach is generally more efficient, particularly for assessing haplotype-environment interactions. Simulation studies demonstrated that the first approach was more robust to model assumptions on the diplotype distribution conditioned on environmental risk variables and matching factors in the control population. We applied the two methods to analyze a matched case-control study of prostate cancer.

背景与目标： 遗传流行病学家通常评估与单倍型 (即单个染色体上等位基因的组合) 相关的疾病易感性。我们研究了使用来自匹配病例对照研究的单核苷酸多态性 (SNP) 基因型数据来推断单倍型相关疾病风险的统计方法，其中对照在某些选定因素上与病例单独匹配。假设单倍型-疾病关联的逻辑回归模型，我们提出了两种条件似然方法，以解决无法从SNP基因型数据 (阶段模糊性) 确定性推断单倍型的问题。一种方法是基于疾病状态的可能性，以每个匹配层中的病例总数，基因型和其他协变量为条件，另一种方法是基于疾病状态和基因型的联合可能性，仅以病例总数和其他协变量为条件。联合似然方法通常更有效，特别是对于评估单倍型-环境相互作用。模拟研究表明，第一种方法对以环境风险变量和对照人群中的匹配因子为条件的二倍体型分布的模型假设更稳健。我们应用这两种方法分析了一项匹配的前列腺癌病例对照研究。

BACKGROUND & AIMS: :If acquired associations are to accurately represent real relevance relations, there is motivation for the hypothesis that learning will, in some circumstances, be more appropriately modelled, not as direct dependence, but as conditional independence. In a serial compound conditioning experiment, two groups of rats were presented with a conditioned stimulus (CS1) that imperfectly (50%) predicted food, and was itself imperfectly predicted by a CS2. Groups differed in the proportion of CS2 presentations that were ultimately followed by food (25% versus 75%). Thus, the information presented regarding the relevance of CS2 to food was ambiguous between direct dependence and conditional independence (given CS1). If rats learnt that food was conditionally independent of CS2, given CS1, subjects of both groups should thereafter respond similarly to CS2 alone. Contrary to the conditionality hypothesis, subjects attended to the direct food predictability of CS2, suggesting that rats treat even distal stimuli in a CS sequence as immediately relevant to food, not conditional on an intermediate stimulus. These results urge caution in representing indirect associations as conditional associations, accentuate the theoretical weight of the Markov condition in graphical models, and challenge theories to articulate the conditions under which animals are expected to learn conditional associations, if ever.

背景与目标： : 如果获得的关联要准确地表示真实的关联关系，则存在这样的假设的动机，即在某些情况下，学习将被更适当地建模，而不是作为直接依赖，而是作为条件独立性。在连续复合条件调节实验中，向两组大鼠提供了条件刺激 (CS1)，该条件刺激不完全 (50%) 预测食物，而cs2本身则不完全预测食物。组在CS2呈现的比例上有所不同，最终跟随食物 (25% 与75%)。因此，关于CS2与食物相关性的信息在直接依赖和条件独立性之间是模棱两可的 (给定CS1)。如果大鼠得知食物有条件地独立于CS1，则两组的受试者此后应与单独的CS2类似。与条件性假设相反，受试者关注了CS2的直接食物可预测性，这表明大鼠甚至将CS序列中的远端刺激视为与食物立即相关，而不是以中间刺激为条件。这些结果敦促在将间接关联表示为条件关联时要谨慎，在图形模型中强调马尔可夫条件的理论权重，并挑战理论以阐明期望动物学习条件关联的条件 (如果有的话)。