精子介导转基因技术的进展与争论

随着生物医学的不断发展,精子介导转基因技术正成为有希望的转基因方法.与其他基因转移方法相比,精子介导具有简单、高效、低廉、安全的特点.我们探讨精子结合外源DNA和DNA内化的分子模型,介绍精子介导转基因技术的改进方法,并指出存在的问题和伦理学争论,旨在推动该技术在生物技术领域的进一步发展.     

人类精子冷冻保存的回顾与思考

回顾人类精子冷冻保存方法的历史,分别比较分析精液保存的常规冷冻法、玻璃化冷冻法和冷冻干燥保存法的特点和前景。认为人类精子冷冻保存方法是低温生物学与辅助生殖技术相互发展和基础理论研究与临床应用相互作用的结果,简便可靠的冷冻保存方法仍需进一步研究。     

人类精子冷冻保存的回顾与思考

回顾人类精子冷冻保存方法的历史,分别比较分析精液保存的常规冷冻法、玻璃化冷冻法和冷冻干燥保存法的特点和前景.认为人类精子冷冻保存方法是低温生物学与辅助生殖技术相互发展和基础理论研究与临床应用相互作用的结果,简便可靠的冷冻保存方法仍需进一步研究.     

转基因技术安全性的生态伦理浅析

以转基因技术为基础的生物技术是本世纪最具影响力的高新技术产业带。转基因技术在农业、食品、医药、环保等方面有广泛应用,它给人类社会的发展带来巨大的经济效益和社会效益的同时,也存在着潜在危险,即有可能影响生态环境,危害人类健康。本文试图从生态伦理的角度来思考转基因技术的安全性问题。     

针对T细胞介导的胰岛自身免疫的治疗策略

1A型糖尿病是由T细胞所介导的器官特异性自身免疫性疾病。人们利用转基因技术、自身抗原疫苗接种、单克隆抗体治疗等新兴技术通过诱导自身免疫耐受,改变免疫调节因子,调节细胞凋亡等途径阻止了自身免疫反应对胰岛的攻击。这些针对其发病机制所提出的新型治疗策略让人们看到了治疗自身免疫型糖尿病的希望。     

DNA表观遗传修饰在药物成瘾记忆中的作用及机制

DNA表观遗传修饰主要包括DNA甲基转移酶介导的DNA甲基化和10-11易位酶介导的DNA去甲基化。这两种表观遗传修饰都可以响应环境刺激,调控基因表达,引起神经功能和行为的改变。已有大量研究表明DNA甲基化是调控成瘾记忆的重要机制之一,近年来也发现DNA去甲基化参与调控恐惧记忆及成瘾行为,提示DNA表观遗传修饰在成瘾记忆中的作用需要重新评估。本文将重点讨论DNA甲基化和去甲基化可能共同调控成瘾记忆,探讨其调控机制,并试图提出可深入的研究展望。     

理性思考转基因植物生产药物

转基因植物生产药物是植物栽培、基因工程与分子医学三者相结合而发展起来的.目前还没有足够科学证据表明转基因植物具有长远的安全性.利用转基因植物生产药物技术是"双刃剑",应辩证分析安全性,要全面了解其试验和应用范围的可控性、安全评价方法的科学性、应急处理措施的可操作性、安全管理的严格性.     

针对T细胞介导的胰岛自身免疫的治疗策略

1A型糖尿病是由T细胞所介导的器官特异性自身免疫性疾病.人们利用转基因技术、自身抗原疫苗接种、单克隆抗体治疗等新兴技术通过诱导自身免疫耐受,改变免疫调节因子,调节细胞凋亡等途径阻止了自身免疫反应对胰岛的攻击.这些针对其发病机制所提出的新型治疗策略让人们看到了治疗自身免疫型糖尿病的希望.     

对“三亲育子”技术的伦理审视

"三亲育子"技术作为一项新兴基因治疗技术,理论上能阻断线粒体疾病的遗传,为人类征服疾病带来福祉。但外源线粒体基因在"三亲婴儿"的成长过程中会产生何种影响,外源线粒体DNA与双亲DNA是否会出现不匹配,这种不匹配会引发怎样的后果,目前尚不清楚。除了难以预知的技术风险外,"三亲育子"技术还存在"设计婴儿"或"转基因婴儿"等技术滥用的风险。因此,需进行辩证分析,用道德和法律对"三亲育子"技术的研究和运用加以规范,以便引导科研人员理性、合理运用该技术。     

农业转基因研究和应用过程中预防原则及其伦理学解读

转基因食物作为转基因技术的产物,其安全性存在许多不确定的因素,引起了世人的广泛关注和担忧。通过对转基因技术在研究和应用过程中实施安全预防并进行伦理评价、规范和指导,可以防止转基因食物可能造成的危害,使转基因食物更好地造福于人类。     

Chronically increased Gsalpha signaling disrupts associative and spatial learning

The cAMP/PKA pathway plays a critical role in learning and memory systems in animals ranging from mice to Drosophila to Aplysia. Studies of olfactory learning in Drosophila suggest that altered expression of either positive or negative regulators of the cAMP/PKA signaling pathway beyond a certain optimum range may be deleterious. Here we provide genetic evidence of the behavioral and physiological effects of increased signaling through the cAMP/PKA pathway in mice. We have generated transgenic mice in which the expression of a constitutively active form of Gsalpha (Gsalpha* Q227L), the G protein that stimulates adenylyl cyclase activity, is driven in neurons within the forebrain by the promoter from the CaMKIIalpha gene. Despite significantly increased adenylyl cyclase activity, Gsalpha* transgenic mice exhibit PKA-dependent decreases in levels of cAMP due to a compensatory up-regulation in phosphodiesterase activity. Interestingly, Gsalpha* transgenic mice also exhibit enhanced basal synaptic transmission. Consistent with a role for the cAMP/PKA pathway in learning and memory, Gsalpha* transgenic mice show impairments in spatial learning in the Morris water maze and in contextual and cued fear conditioning tasks. The learning deficits observed in these transgenic mice suggest that associative and spatial learning requires regulated Gsalpha protein signaling, much as does olfactory learning in Drosophila.     

Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage

Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII alpha promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.     

Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β (TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.     

APP23 mice as a model of Alzheimer's disease: an example of a transgenic approach to modeling a CNS disorder

Animal models are considered essential in research ensuing elucidation of human disease processes and subsequently, testing of potential therapeutic strategies. This is especially true for neurodegenerative disorders, in which the first steps in pathogenesis are often not accessible in human patients. Alzheimer's disease is vastly becoming a major medical and socioeconomic problem in our aging society. Valid animal models for this uniquely human condition should exhibit histopathological, biochemical, cognitive, and behavioral alterations observed in Alzheimer's disease patients. Major progress has been made since the understanding of the genetic basis of Alzheimer's disease and the development and improvement of transgenic mouse models. All present Alzheimer's disease models developed are partial but nevertheless essential in further unraveling the nature and spatial and temporal development of the complex molecular pathology underlying this condition. One of the more recent transgenic attempts to model Alzheimer's disease is the APP23 transgenic mouse. This article describes the development and assessment of this human amyloid precursor protein overexpression model. We summarize histopathological and biochemical, cognitive and behavioral observations made in heterozygous APP23 mice, thereby emphasizing the model's contribution to clarification of neurodegenerative disease mechanisms. In addition, the first therapeutic interventions in the APP23 model are included.     

辩证看待干细胞移植的热化问题

现代科学技术的发展已经并正在给人类展现一个相互矛盾的事实：一方面是科学技术推动人类社会的巨大进步,促进社会生活的极大提高。如核能的利用、转基因作物、转基因治疗、动物克隆、干细胞的开发与应用等等,无不让人类充分地享受到现代科技带来的种种利益和好处。另外一方面人类的生存危机前所未有的加深,环境的恶化、水资源的污染、新的疾病和变异的菌种诞生等等。怎样运用哲学的理性的思维和方法来评判现代科技对人类的影响,摆脱其发展对社会所造成的两难困境,是一个必须解决的难题。以干细胞移植研究为例,如何辩证看待干细胞移植热化问题,如何运用哲学思维来看待干细胞移植的有利性和危害性,探究科学技术的可持续发展道路。     

农业、生态与人类健康

农业生产与人类生存密切相关。随着机械化大生产、农药和转基因作物的大量应用,农业生产已经对生态环境产生了许多严重的不可逆转的破坏,进而对人类健康构成了极大影响。     

Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function

S100-beta, a calcium-binding astrocytic protein from chromosome 21, has been implicated in CNS function generally and the hippocampus in particular. Elevated levels of S100-beta have been observed reliably in the brains of patients with Alzheimer's Disease and Down Syndrome. Groups of transgenic mice, carrying multiple S100-beta gene copies, and nontransgenic controls were administered a series of behavioral tests (delayed spatial and nonspatial non-matching-to-sample, radial arm maze, socially acquired food preference) that assessed a wide range of cognitive functions. Consistent with the widespread presence of S100-beta throughout the brain, transgenic mice exhibited learning or memory impairment on all tasks. The dementia-like cognitive profile of S100-beta mice represents a promising model for studying comparable cognitive deficits associated with neurodegenerative diseases.     

Transgenic Brain-Derived Neurotrophic Factor Modulates a Developing Cerebellar Inhibitory Synapse

Brain-derived neurotrophic factor (BDNF) has been shown to promote synapse formation and maturation in neurons of many brain regions, including inhibitory synapses. In the cerebellum, the Golgi cell-granule cell GABAergic synaptic responses undergo developmental transition from slow-decaying to fast-decaying kinetics, which parallels a developmental increase of GABA_A receptor α6 subunit expression in the cerebellar granule cells. In culture, BDNF accelerates the expression of GABA_A receptor α6 subunit expression in granule cells. Here we examined synaptic GABA_A response kinetics in BDNF transgenic mice. The mutant mouse, which carries a BDNF transgene driven by a β-actin promoter, overexpresses BDNF (two- to fivefold increase compared with wild types) in all brain regions. Recordings of the spontaneous GABA_A responses indicate that the decay time constant of the GABAergic responses decreases during early postnatal development; this transition is accelerated in the BDNF transgenic mouse. The amplitude of the spontaneous GABA_A responses was also larger in the transgenic mouse than in the wild-type mouse. However, the frequency of the spontaneous GABA_A responses were not different between the two groups. Our results suggest that BDNF may modulate GABAergic synapse maturation in the cerebellum.