Bone marrow transplantation alters the tremor phenotype in the murine model of globoid-cell leukodystrophy

Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe’s disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse’s movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe’s disease

Alcohol-induced apoptosis of oligodendrocytes in the fetal macaque brain

BACKGROUND: In utero exposure of the fetal non-human primate (NHP) brain to alcohol on a single occasion during early or late third-trimester gestation triggers widespread acute apoptotic death of cells in both gray and white matter (WM) regions of the fetal brain. In a prior publication, we documented that the dying gray matter cells are neurons, and described the regional distribution and magnitude of this cell death response. Here, we present new findings regarding the magnitude, identity and maturational status of the dying WM cells in these alcohol-exposed fetal NHP brains. RESULTS: Our findings document that the dying WM cells belong to the oligodendrocyte (OL) lineage. OLs become vulnerable when they are just beginning to generate myelin basic protein in preparation for myelinating axons, and they remain vulnerable throughout later stages of myelination. We found no evidence linking astrocytes, microglia or OL progenitors to this WM cell death response. The mean density (profiles per mm(3)) of dying WM cells in alcohol-exposed brains was 12.7 times higher than the mean density of WM cells dying by natural apoptosis in drug-naive control brains. CONCLUSIONS: In utero exposure of the fetal NHP brain to alcohol on a single occasion triggers widespread acute apoptotic death of neurons (previous study) and of OLs (present study) throughout WM regions of the developing brain. The rate of OL apoptosis in alcohol-exposed brains was 12.7 times higher than the natural OL apoptosis rate. OLs become sensitive to the apoptogenic action of alcohol when they are just beginning to generate constituents of myelin in their cytoplasm, and they remain vulnerable throughout later stages of myelination. There is growing evidence for a similar apoptotic response of both neurons and OLs following exposure of the developing brain to anesthetic and anticonvulsant drugs. Collectively, this body of evidence raises important questions regarding the role that neuro and oligo apoptosis may play in the human condition known as fetal alcohol spectrum disorder (FASD), and also poses a question whether other apoptogenic drugs, although long considered safe for pediatric/obstetric use, may have the potential to cause iatrogenic FASD-like developmental disability syndromes

Influence of rural-urban migration on the fertility of migrants in developing

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Bone Marrow Transplantation Alters the Tremor Phenotype in the Murine Model of Globoid-Cell Leukodystrophy

This is the publisher's version, also available electronically from "http://www.mdpi.com".Tremor is a prominent phenotype of the twitcher mouse, an authentic genetic model of Globoid-Cell Leukodystrophy (GLD, Krabbe’s disease). In the current study, the tremor was quantified using a force-plate actometer designed to accommodate low-weight mice. The actometer records the force oscillations caused by a mouse’s movements, and the rhythmic structure of the force variations can be revealed. Results showed that twitcher mice had significantly increased power across a broad band of higher frequencies compared to wildtype mice. Bone marrow transplantation (BMT), the only available therapy for GLD, worsened the tremor in the twitcher mice and induced a measureable alteration of movement phenotype in the wildtype mice. These data highlight the damaging effects of conditioning radiation and BMT in the neonatal period. The behavioral methodology used herein provides a quantitative approach for assessing the efficacy of potential therapeutic interventions for Krabbe’s disease

p53 Activation by Knockdown Technologies

Morpholino phosphorodiamidate antisense oligonucleotides (MOs) and short interfering RNAs (siRNAs) are commonly used platforms to study gene function by sequence-specific knockdown. Both technologies, however, can elicit undesirable off-target effects. We have used several model genes to study these effects in detail in the zebrafish, Danio rerio. Using the zebrafish embryo as a template, correct and mistargeting effects are readily discernible through direct comparison of MO-injected animals with well-studied mutants. We show here indistinguishable off-targeting effects for both maternal and zygotic mRNAs and for both translational and splice-site targeting MOs. The major off-targeting effect is mediated through p53 activation, as detected through the transferase-mediated dUTP nick end labeling assay, acridine orange, and p21 transcriptional activation assays. Concurrent knockdown of p53 specifically ameliorates the cell death induced by MO off-targeting. Importantly, reversal of p53-dependent cell death by p53 knockdown does not affect specific loss of gene function, such as the cell death caused by loss of function of chordin. Interestingly, quantitative reverse-transcriptase PCR, microarrays and whole-mount in situ hybridization assays show that MO off-targeting effects are accompanied by diagnostic transcription of an N-terminal truncated p53 isoform that uses a recently recognized internal p53 promoter. We show here that MO off-targeting results in induction of a p53-dependent cell death pathway. p53 activation has also recently been shown to be an unspecified off-target effect of siRNAs. Both commonly used knockdown technologies can thus induce secondary but sequence-specific p53 activation. p53 inhibition could potentially be applicable to other systems to suppress off-target effects caused by other knockdown technologies

Changes in the global value of ecosystem services

In 1997, the global value of ecosystem services was estimated to average $33. trillion/yr in 1995$US ($46. trillion/yr in 2007$US). In this paper, we provide an updated estimate based on updated unit ecosystem service values and land use change estimates between 1997 and 2011. We also address some of the critiques of the 1997 paper. Using the same methods as in the 1997 paper but with updated data, the estimate for the total global ecosystem services in 2011 is $125. trillion/yr (assuming updated unit values and changes to biome areas) and$145. trillion/yr (assuming only unit values changed), both in 2007 $US. From this we estimated the loss of eco-services from 1997 to 2011 due to land use change at$4.3-20.2. trillion/yr, depending on which unit values are used. Global estimates expressed in monetary accounting units, such as this, are useful to highlight the magnitude of eco-services, but have no specific decision-making context. However, the underlying data and models can be applied at multiple scales to assess changes resulting from various scenarios and policies. We emphasize that valuation of eco-services (in whatever units) is not the same as commodification or privatization. Many eco-services are best considered public goods or common pool resources, so conventional markets are often not the best institutional frameworks to manage them. However, these services must be (and are being) valued, and we need new, common asset institutions to better take these values into account. © 2014 Elsevier Ltd

Linking Ecology and Economics for Ecosystem Management

This article outlines an approach, based on ecosystem services, for assessing the trade-offs inherent in managing humans embedded in ecological systems. Evaluating these trade-offs requires an understanding of the biophysical magnitudes of the changes in ecosystem services that result from human actions, and of the impact of these changes on human welfare.We summarize the state of the art of ecosystem services?based management and the information needs for applying it. Three case studies of Long Term Ecological Research (LTER) sites?coastal, urban, and agricultural? illustrate the usefulness, information needs, quantification possibilities, and methods for this approach. One example of the application of this approach, with rigorously established service changes and valuations taken from the literature, is used to illustrate the potential for full economic valuation of several agricultural landscape management options, including managing for water quality, biodiversity, and crop productivity

Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization

OBJECTIVES: The natural history of limbs affected by ischemic ulceration is poorly understood. In this report, we describe the outcome of limbs with stable chronic leg ulcers and arterial insufficiency that were treated with wound-healing techniques in patients who were not candidates for revascularization. METHODS: A prospectively maintained database of limb ulcers treated at a comprehensive wound center was used to identify patients with arterial insufficiency, defined as an ankle-brachial index (ABI) 2.5 mg/dL), severity of ischemia measured by ABI or toe pressure, wound grade, wound size, and wound location. RESULTS: Between January 1999 and March 2005, 142 patients with 169 limbs having arterial insufficiency and full-thickness ulceration were treated without revascularization. Mean patient age was 70.8 +/- 4.5. Diabetes mellitus was present in 70.4% of limbs and chronic renal insufficiency in 27.8%. Toe amputations or other foot-sparing procedures were performed in 28% of limbs. Overall, limb loss occurred in 37 patients. By life-table analysis, 19% of limbs required amputation 0.5 (P = .01). The only risk factor associated with wound closure was initial wound size (P < .005). CONCLUSIONS: Limb salvage can be achieved in most patients with arterial insufficiency and uncomplicated chronic nonhealing limb ulcers using a program of wound management without revascularization. Healing proceeds slowly, however, requiring more than a year in many cases. Patients with an ABI <0.5 are more likely to require amputation. Interventions designed to improve outcomes in critical limb ischemia should stratify outcomes based on hemodynamic data and should include a comparative control group given the natural history of ischemic ulcers treated in a dedicated wound program