Premature ageing in mice expressing defective mitochondrial DNA polymerase

Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate in a variety of tissues during ageing in humans, monkeys and rodents. These mutations are unevenly distributed and can accumulate clonally in certain cells, causing a mosaic pattern of respiratory chain deficiency in tissues such as heart, skeletal muscle and brain. In terms of the ageing process, their possible causative effects have been intensely debated because of their low abundance and purely correlative connection with ageing. We have now addressed this question experimentally by creating homozygous knock-in mice that express a proof-reading-deficient version of PolgA, the nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show that the knock-in mice develop an mtDNA mutator phenotype with a threefold to fivefold increase in the levels of point mutations, as well as increased amounts of deleted mtDNA. This increase in somatic mtDNA mutations is associated with reduced lifespan and premature onset of ageing-related phenotypes such as weight loss, reduced subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the spine), osteoporosis, anaemia, reduced fertility and heart enlargement. Our results thus provide a causative link between mtDNA mutations and ageing phenotypes in mammals.     

Sleep inspires insight

Insight denotes a mental restructuring that leads to a sudden gain of explicit knowledge allowing qualitatively changed behaviour. Anecdotal reports on scientific discovery suggest that pivotal insights can be gained through sleep. Sleep consolidates recent memories and, concomitantly, could allow insight by changing their representational structure. Here we show a facilitating role of sleep in a process of insight. Subjects performed a cognitive task requiring the learning of stimulus-response sequences, in which they improved gradually by increasing response speed across task blocks. However, they could also improve abruptly after gaining insight into a hidden abstract rule underlying all sequences. Initial training establishing a task representation was followed by 8 h of nocturnal sleep, nocturnal wakefulness, or daytime wakefulness. At subsequent retesting, more than twice as many subjects gained insight into the hidden rule after sleep as after wakefulness, regardless of time of day. Sleep did not enhance insight in the absence of initial training. A characteristic antecedent of sleep-related insight was revealed in a slowing of reaction times across sleep. We conclude that sleep, by restructuring new memory representations, facilitates extraction of explicit knowledge and insightful behaviour.     

Hox cluster disintegration with persistent anteroposterior order of expression in Oikopleura dioica

Tunicate embryos and larvae have small cell numbers and simple anatomical features in comparison with other chordates, including vertebrates. Although they branch near the base of chordate phylogenetic trees, their degree of divergence from the common chordate ancestor remains difficult to evaluate. Here we show that the tunicate Oikopleura dioica has a complement of nine Hox genes in which all central genes are lacking but a full vertebrate-like set of posterior genes is present. In contrast to all bilaterians studied so far, Hox genes are not clustered in the Oikopleura genome. Their expression occurs mostly in the tail, with some tissue preference, and a strong partition of expression domains in the nerve cord, in the notochord and in the muscle. In each tissue of the tail, the anteroposterior order of Hox gene expression evokes spatial collinearity, with several alterations. We propose a relationship between the Hox cluster breakdown, the separation of Hox expression domains, and a transition to a determinative mode of development.     

Neues Verfahren zur experimentellen Erzeugung permanenten und reversiblen Hochdruckes durch standardisierte Kompression der Niere

Summary A new simple method for the production of experimental hypertension has been developed. Anoxæmia of the kidney has been produced by encapsulating the organ in tubes of acetyl cellulose. Development and degree of hypertension is directly depending on the ratio between size of kidney and tube, so that standard size tubes for definite animal weight may be used with high percentage of success.     

Serotoninstoffwechsel bei chronischem Alkoholismus

Summary Serotonin was determined in platelets of 47 patients with alcoholism during the state of withdrawal as well as in a group of healthy persons. The results show that serotonin values were significantly lower in the group of patients with alcoholism as compared with the control group of healthy persons.     

Ectodomain shedding of the receptor for advanced glycation end products: a novel therapeutic target for Alzheimer’s disease

Receptor for advanced glycation end products (RAGE) mediates diverse physiological and pathological effects and is involved in the pathogenesis of Alzheimer’s disease (AD). RAGE is a receptor for amyloid β peptides (Aβ), mediates Aβ neurotoxicity and also promotes Aβ influx into the brain and contributes to Aβ aggregation. Soluble RAGE (sRAGE), a secreted RAGE isoform, acts as a decoy receptor to antagonize RAGE-mediated damages. Accumulating evidence has suggested that sRAGE represents a promising pharmaceutic against RAGE-mediated disorders. Recent studies revealed proteolysis of RAGE as a previously unappreciated means of sRAGE production. In this review we summarize these findings on the proteolytic cleavage of RAGE and discuss the underlying regulatory mechanisms of RAGE shedding. Furthermore, we propose a model in which proteolysis of RAGE could restrain AD development by reducing Aβ transport into the brain and Aβ production via BACE. Thus, the modulation of RAGE proteolysis provides a novel intervention strategy for AD.     

产生埃博霉素的纤维堆囊菌的分子筛选

为寻找潜在的产生埃博霉素(epothilone)的纤维堆囊菌(Sorangium cellulosum),以埃博霉素生物合成基因簇中的epoA,epoC和epoK基因为探针,分别对60株不同土壤样品来源的纤维堆囊菌的DNA样品进行PCR筛选.筛选结果得到了7株阳性菌株,进一步对其进行发酵和粗提物的HPLC-MS分析,检测结果显示3株菌XMU-Nc-03,XMU-So-64和XMU-So-112能产生埃博霉素B,其中XMU-So-112的产量最高.本实验在筛选产埃博霉素活性菌株的同时,还建立了一个快速可靠的发现埃博霉素产生菌的方法.     

SMC1beta-deficient female mice provide evidence that cohesins are a missing link in age-related nondisjunction

Mitotic chromosome segregation is facilitated by the cohesin complex, which maintains physical connections between sister chromatids until anaphase. Meiotic cell division is considerably more complex, as cohesion must be released sequentially to facilitate orderly segregation of chromosomes at both meiosis I and meiosis II. This necessitates meiosis-specific cohesin components; recent studies in rodents suggest that these influence chromosome behavior during both cell division and meiotic prophase. To elucidate the role of the meiosis-specific cohesin SMC1beta (encoded by Smc1l2) in oogenesis, we carried out meiotic studies of female SMC1beta-deficient mice. Our results provide the first direct evidence that SMC1beta acts as a chiasma binder in mammals, stabilizing sites of exchange until anaphase. Additionally, our observations support the hypothesis that deficient cohesion is an underlying cause of human age-related aneuploidy.