Oncogene-induced senescence as an initial barrier in lymphoma development

Acute induction of oncogenic Ras provokes cellular senescence involving the retinoblastoma (Rb) pathway, but the tumour suppressive potential of senescence in vivo remains elusive. Recently, Rb-mediated silencing of growth-promoting genes by heterochromatin formation associated with methylation of histone H3 lysine 9 (H3K9me) was identified as a critical feature of cellular senescence, which may depend on the histone methyltransferase Suv39h1. Here we show that Emicro-N-Ras transgenic mice harbouring targeted heterozygous lesions at the Suv39h1, or the p53 locus for comparison, succumb to invasive T-cell lymphomas that lack expression of Suv39h1 or p53, respectively. By contrast, most N-Ras-transgenic wild-type ('control') animals develop a non-lymphoid neoplasia significantly later. Proliferation of primary lymphocytes is directly stalled by a Suv39h1-dependent, H3K9me-related senescent growth arrest in response to oncogenic Ras, thereby cancelling lymphomagenesis at an initial step. Suv39h1-deficient lymphoma cells grow rapidly but, unlike p53-deficient cells, remain highly susceptible to adriamycin-induced apoptosis. In contrast, only control, but not Suv39h1-deficient or p53-deficient, lymphomas senesce after drug therapy when apoptosis is blocked. These results identify H3K9me-mediated senescence as a novel Suv39h1-dependent tumour suppressor mechanism whose inactivation permits the formation of aggressive but apoptosis-competent lymphomas in response to oncogenic Ras.     

Novel role of PKR in inflammasome activation and HMGB1 release

The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1β, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1β, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.     

A New Mechanism for Transfer Between Conceptual Domains in Scientific Discovery and Education

Confronted with problems or situations that do not yield toknown theories and world views, scientists and students are alike. Theyare rarely able to directly build a model or a theory thereof. Rather,they must find ways to make sense of the circumstances using theircurrent knowledge and adjusting what is recognized in the process. Thisway of thinking, using past ways of perceiving the physical world tobuild new ones does not follow a logical path and cannot be described astheory revision. Likewise, in many situations it is awkward, indeedoften impossible, to resort to analogical reasoning to account for it.This paper presents a new mechanism, called `tunnel effect', that mayexplain, in part, how scientists and students reason while constructinga new conceptual domain. `Tunnel effect' is also contrasted withanalogical reasoning.     

γ-射线血管内照射治疗计划系统的研制

介绍了研究开发的三维血管内照射治疗计划系统，该治疗计划系统建立在三维医学图像和临床上常用的γ－射线源基础之上，集成了放射源剂量学数据管理，三维图像处理，治疗计划设计、剂量分布计算与显示、治疗计划评估和打印输出等功能模块，为了验证治疗计划的有效性，文中给出了2组实验数据，一组是与GammaMed治疗计划系统的对比结果，另一组是对实际弯曲血管的计划结果。     

Geology and palaeontology of the Upper Miocene Toros-Menalla hominid locality,Chad

All six known specimens of the early hominid Sahelanthropus tchadensis come from Toros-Menalla site 266 (TM 266), a single locality in the Djurab Desert, northern Chad, central Africa. Here we present a preliminary analysis of the palaeontological and palaeoecological context of these finds. The rich fauna from TM 266 includes a significant aquatic component such as fish, crocodiles and amphibious mammals, alongside animals associated with gallery forest and savannah, such as primates, rodents, elephants, equids and bovids. The fauna suggests a biochronological age between 6 and 7 million years. Taken together with the sedimentological evidence, the fauna suggests that S. tchadensis lived close to a lake, but not far from a sandy desert, perhaps the oldest record of desert conditions in the Neogene of northern central Africa.     

Cationic and secretory effects of BPDZ 44 and diazoxide in rat pancreatic islets

The present study aimed at comparing the effects of low concentrations of BPDZ 44, a new pyridothiadiazine derivative, and diazoxide on⁸⁶Rb outflow,⁴⁵Ca outflow,⁴⁵Ca uptake and insulin release from rat pancreatic islets. Both drugs caused similar modifications, but the effects of BPDZ 44 on the cationic and secretory events were much more marked than those of diazoxide. It is suggested that BPDZ 44 could be valuable tool for further studies of the K_ATP channels.     

Genome evolution in yeasts

Identifying the mechanisms of eukaryotic genome evolution by comparative genomics is often complicated by the multiplicity of events that have taken place throughout the history of individual lineages, leaving only distorted and superimposed traces in the genome of each living organism. The hemiascomycete yeasts, with their compact genomes, similar lifestyle and distinct sexual and physiological properties, provide a unique opportunity to explore such mechanisms. We present here the complete, assembled genome sequences of four yeast species, selected to represent a broad evolutionary range within a single eukaryotic phylum, that after analysis proved to be molecularly as diverse as the entire phylum of chordates. A total of approximately 24,200 novel genes were identified, the translation products of which were classified together with Saccharomyces cerevisiae proteins into about 4,700 families, forming the basis for interspecific comparisons. Analysis of chromosome maps and genome redundancies reveal that the different yeast lineages have evolved through a marked interplay between several distinct molecular mechanisms, including tandem gene repeat formation, segmental duplication, a massive genome duplication and extensive gene loss.     

Neural substrates of awakening probed with optogenetic control of hypocretin neurons

The neural underpinnings of sleep involve interactions between sleep-promoting areas such as the anterior hypothalamus, and arousal systems located in the posterior hypothalamus, the basal forebrain and the brainstem. Hypocretin (Hcrt, also known as orexin)-producing neurons in the lateral hypothalamus are important for arousal stability, and loss of Hcrt function has been linked to narcolepsy. However, it is unknown whether electrical activity arising from Hcrt neurons is sufficient to drive awakening from sleep states or is simply correlated with it. Here we directly probed the impact of Hcrt neuron activity on sleep state transitions with in vivo neural photostimulation, genetically targeting channelrhodopsin-2 to Hcrt cells and using an optical fibre to deliver light deep in the brain, directly into the lateral hypothalamus, of freely moving mice. We found that direct, selective, optogenetic photostimulation of Hcrt neurons increased the probability of transition to wakefulness from either slow wave sleep or rapid eye movement sleep. Notably, photostimulation using 5-30 Hz light pulse trains reduced latency to wakefulness, whereas 1 Hz trains did not. This study establishes a causal relationship between frequency-dependent activity of a genetically defined neural cell type and a specific mammalian behaviour central to clinical conditions and neurobehavioural physiology.     

Mesenchymal stem cells within tumour stroma promote breast cancer metastasis

Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.