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Similar to mammalian neural progenitors, Drosophila neuroblasts progressively lose competence to make early-born neurons. In neuroblast 7-1 (NB7-1), Kruppel (Kr) specifies the third-born U3 motoneuron and Kr misexpression induces ectopic U3 cells. However, competence to generate U3 cells is limited to early divisions, when the Eve(+) U motoneurons are produced, and competence is lost when NB7-1 transitions to making interneurons. We have found that Polycomb repressor complexes (PRCs) are necessary and sufficient to restrict competence in NB7-1. PRC loss of function extends the ability of Kr to induce U3 fates and PRC gain of function causes precocious loss of competence to make motoneurons. PRCs also restrict competence to make HB9(+) Islet(+) motoneurons in another neuroblast that undergoes a motoneuron-to-interneuron transition, NB3-1. In contrast to the regulation of motoneuron competence, PRC activity does not affect the production of Eve(+) interneurons by NB3-3, HB9(+) Islet(+) interneurons by NB7-3, or Dbx(+) interneurons by multiple neuroblasts. These findings support a model in which PRCs establish motoneuron-specific competence windows in neuroblasts that transition from motoneuron to interneuron production. 相似文献
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de Jong JW Ekkerink JL Touma I Koopmans RT 《Tijdschrift voor gerontologie en geriatrie》2005,36(2):72-76
There is scant literature about patients in the final phase of dementia. Uniform terminology and operational definition of the final phase of dementia is lacking. Furthermore, it is difficult to monitor these patients because existing assessment scales face bottom- or ceiling effects in this population. The aim of this study was to assess the prevalence and the characteristics of patients in the final phase of dementia in a group of 210 Dutch nursing home patients with dementia. Stage 7 of the Global Deterioration Scale of Reisberg et al. was used to operationally define the final phase of dementia. All patients were scored on a self-constructed assessment scale. Furthermore, treatment aspects and advance directives were registered. 相似文献
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Impaired daily glucocorticoid rhythm in Per1
Brd
mice 总被引:1,自引:0,他引:1
Robert Dallmann Chadi Touma Rupert Palme Urs Albrecht Stephan Steinlechner 《Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology》2006,192(7):769-775
Biological clocks have evolved in all kinds of organisms in order to anticipate and adjust to the daily light–dark cycle. Within the last decade, the molecular machinery underlying the circadian system was unraveled. In the present study, the impact of the loss of the Per1 or Per2 genes, key components of the core clock oscillator, on body mass, food and water intake, glucose metabolism, and hypothalamic-pituitary-adrenal axis, was investigated in the Per1
Brd
and Per2
Brd
mouse models. The results reveal that the lack of Per1 but not Per2 has severe consequences for the regulation of these parameters. Specifically, in Per1
Brd
animals, we found an impaired daily glucocorticoid rhythm, with markedly elevated levels during the day compared to control animals. In addition, Per1
Brd
mice showed significant differences in body mass as well as food and water intake. Although the Per1
Brd
are lighter than wildtype mice, food and water intake per gram body mass is elevated. In addition, the Per1
Brd
mice exhibit an increased glucose metabolism after i.p. injection with glucose. In conclusion, our study presents first evidence for a link between an altered metabolism in Per1 and Per2 deficient mice, which in the case of the Per1
Brd
animals might be due to an impaired corticosterone rhythm. 相似文献
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Dieter Blottner Najet Serradj Michele Salanova Chadi Touma Rupert Palme Mitchell Silva Jean Marie Aerts Daniel Berckmans Laurence Vico Yi Liu Alessandra Giuliani Franco Rustichelli Ranieri Cancedda Marc Jamon 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2009,179(4):519-533
Environmental conditions likely affect physiology and behaviour of mice used for life sciences research on Earth or in Space.
Here, we analysed the effects of cage confinement on the weightbearing musculoskeletal system, behaviour and stress of wild-type
mice (C57BL/6JRj, 30 g b.wt., total n = 24) housed for 25 days in a prototypical ground-based and fully automated life support habitat device called “Mice in Space”
(MIS). Compared with control housing (individually ventilated cages) the MIS mice revealed no significant changes in soleus
muscle size and myofiber distribution (type I vs. II) and quality of bone (3-D microarchitecture and mineralisation of calvaria,
spine and femur) determined by confocal and micro-computed tomography. Corticosterone metabolism measured non-invasively (faeces)
monitored elevated adrenocortical activity at only start of the MIS cage confinement (day 1). Behavioural tests (i.e., grip
strength, rotarod, L/D box, elevated plus-maze, open field, aggressiveness) performed subsequently revealed only minor changes
in motor performance (MIS vs. controls). The MIS habitat will not, on its own, produce major effects that could confound interpretation
of data induced by microgravity exposure during spaceflight. Our results may be even more helpful in developing multidisciplinary
protocols with adequate scenarios addressing molecular to systems levels using mice of various genetic phenotypes in many
laboratories.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
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Chadi Touma Thomas Fenzl J?rg Ruschel Rupert Palme Florian Holsboer Mayumi Kimura Rainer Landgraf 《PloS one》2009,4(1)
Background
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, including hyper- or hypo-activity of the stress hormone system, plays a critical role in the pathophysiology of mood disorders such as major depression (MD). Further biological hallmarks of MD are disturbances in circadian rhythms and sleep architecture. Applying a translational approach, an animal model has recently been developed, focusing on the deviation in sensitivity to stressful encounters. This so-called ‘stress reactivity’ (SR) mouse model consists of three separate breeding lines selected for either high (HR), intermediate (IR), or low (LR) corticosterone increase in response to stressors.Methodology/Principle Findings
In order to contribute to the validation of the SR mouse model, our study combined the analysis of behavioural and HPA axis rhythmicity with sleep-EEG recordings in the HR/IR/LR mouse lines. We found that hyper-responsiveness to stressors was associated with psychomotor alterations (increased locomotor activity and exploration towards the end of the resting period), resembling symptoms like restlessness, sleep continuity disturbances and early awakenings that are commonly observed in melancholic depression. Additionally, HR mice also showed neuroendocrine abnormalities similar to symptoms of MD patients such as reduced amplitude of the circadian glucocorticoid rhythm and elevated trough levels. The sleep-EEG analyses, furthermore, revealed changes in rapid eye movement (REM) and non-REM sleep as well as slow wave activity, indicative of reduced sleep efficacy and REM sleep disinhibition in HR mice.Conclusion/Significance
Thus, we could show that by selectively breeding mice for extremes in stress reactivity, clinically relevant endophenotypes of MD can be modelled. Given the importance of rhythmicity and sleep disturbances as biomarkers of MD, both animal and clinical studies on the interaction of behavioural, neuroendocrine and sleep parameters may reveal molecular pathways that ultimately lead to the discovery of new targets for antidepressant drugs tailored to match specific pathologies within MD. 相似文献8.
Ruvini Kariawasam Christine Touma Liza Cubeddu Roland Gamsjaeger 《Biomolecular NMR assignments》2016,10(2):297-300
Single-stranded DNA-binding proteins (SSBs) are highly important in DNA metabolism and play an essential role in all major DNA repair pathways. SSBs are generally characterised by the presence of an oligonucleotide binding (OB) fold which is able to recognise single-stranded DNA (ssDNA) with high affinity. We discovered two news SSBs in humans (hSSB1 and hSSB2) that both contain a single OB domain followed by a divergent spacer region and a charged C-terminus. We have extensively characterised one of these, hSSB1 (NABP2/OBFC2B), in numerous important DNA processing events such as, in DNA double-stranded break repair and in the response to oxidative DNA damage. Although the structure of hSSB1 bound to ssDNA has recently been determined using X-ray crystallography, the detailed atomic level mechanism of the interaction of hSSB1 with ssDNA in solution has not been established. In this study we report the solution-state backbone chemical shift assignments of the OB domain of hSSB1. In addition, we have utilized NMR to map the DNA-binding interface of hSSB1, revealing major differences between recognition of ssDNA under physiological conditions and in the recently determined crystal structure. Our NMR data in combination with further biophysical and biochemical experiments will allow us to address these discrepancies and shed light onto the structural basis of DNA-binding by hSSB1 in solution. 相似文献
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Maria Razzoli Kewir Nyuyki‐Dufe Allison Gurney Connor Erickson Jacob McCallum Nicholas Spielman Marta Marzullo Jessica Patricelli Morito Kurata Emily A. Pope Chadi Touma Rupert Palme David A. Largaespada Alessandro Bartolomucci 《Aging cell》2018,17(4)
Stress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon. 相似文献
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Li X Wang H Touma E Rousseau E Quigg RJ Ryaby JT 《Journal of cellular biochemistry》2007,100(2):527-543
Bone repair consists of inflammation, intramembranous ossification, chondrogenesis, endochondral ossification, and remodeling. To better understand the translational regulation of these distinct but interrelated cellular events, we used the second generation of BD Clontechtrade mark Antibody Microarray to dissect and functionally characterize proteins differentially expressed between intact and fractured rat femur at each of these cellular events. Genetic network analysis showed that proteins differentially expressed within a given cellular event tend to be physically or functionally correlated. Seventeen such interacting networks were established over five cellular events that were most frequently associated with cell cycle, cell death, cell-to-cell signaling and interaction, and cell growth and proliferation. Eighteen molecular pathways were significantly enriched during the bone repair process, of which ERK/MAPK, NF-kB, PDGF, and T-cell receptor signaling pathways were significant during three or more cellular events. The analyses revealed dynamic temporal expression patterns and cellular-event-specific functions. The inflammation event on Day 1 was characteristic of the cell cycle-related molecular changes. The relative quiet stage of intramembranous ossification on Day 4 and the molecularly most active stage of chondrogenesis on Day 7 were featured by coordinated cell death and cell-proliferation signals. Endochondral ossification on Day 14 experienced a clear transition from the molecular/cellular function to the physiological system development/function. The osteoclast-mediated remodeling on Day 28 was highlighted by the integrin signaling pathway. The distinct changes in protein expression during these cellular events provide a molecular basis for developing cellular event-targeted therapeutic strategy to accelerate bone healing. 相似文献