235 research outputs found
Life cycle in practice: capacity building aiming European SME’s
The application of life cycle approaches – including life cycle assessment, ecodesign and environmental labelling – is becoming an increasing reality for business, and a growing challenge in many economic sectors. Businesses are facing increasing legal and market requirements to enhance resource efficiency and reduce the environmental impact of their products & services. To significantly address this
challenge, the Life Cycle in Practice (LCiP) project was conceived, aiming to promote the uptake of LC approaches particularly in SMEs. The LCiP project helps SMEs in France, Belgium, Portugal and Spain reduce the environmental impacts of their products and services across the entire Life Cycle in three sectors: Buildings & Construction, Waste Management and Energy Equipment. LCiP’s specific objectives are to foster the widespread uptake of these approaches by SMEs beyond the duration of the project, by (i) Demonstrating the environmental and business benefits of applying LC Approaches through practical application in 32 businesses; (ii) Providing physical and online resource centres to support regional application of LC approaches; (iii) Building capacity for on-going implementation of LC approaches through a network of Life Cycle Champions and (iv) (Re)designing practical tools & methods tailored to the needs of the three industrial sectors. This paper presents the project's activities and expected results, as well as the conclusions of a
maturity assessment on life cycle approaches that has been performed in the three sectors and four partner regions, as a means to identify needs and gaps that LCiP should fulfil
Sequential design of computer experiments for the estimation of a probability of failure
This paper deals with the problem of estimating the volume of the excursion
set of a function above a given threshold,
under a probability measure on that is assumed to be known. In
the industrial world, this corresponds to the problem of estimating a
probability of failure of a system. When only an expensive-to-simulate model of
the system is available, the budget for simulations is usually severely limited
and therefore classical Monte Carlo methods ought to be avoided. One of the
main contributions of this article is to derive SUR (stepwise uncertainty
reduction) strategies from a Bayesian-theoretic formulation of the problem of
estimating a probability of failure. These sequential strategies use a Gaussian
process model of and aim at performing evaluations of as efficiently as
possible to infer the value of the probability of failure. We compare these
strategies to other strategies also based on a Gaussian process model for
estimating a probability of failure.Comment: This is an author-generated postprint version. The published version
is available at http://www.springerlink.co
Pericentrosomal targeting of Rab6 secretory vesicles by Bicaudal-D-related protein 1 (BICDR-1) regulates neuritogenesis
Membrane and secretory trafficking are essential for proper neuronal development. However, the molecular mechanisms that organize secretory trafficking are poorly understood. Here, we identify Bicaudal-D-related protein 1 (BICDR-1) as an effector of the small GTPase Rab6 and key component of the molecular machinery that controls secretory vesicle transport in developing neurons. BICDR-1 interacts with kinesin motor Kif1C, the dynein/dynactin retrograde motor complex, regulates the pericentrosomal localization of Rab6-positive secretory vesicles and is required for neural development in zebrafish. BICDR-1 expression is high during early neuronal development and strongly declines during neurite outgrowth. In young neurons, BICDR-1 accumulates Rab6 secretory vesicles around the centrosome, restricts anterograde secretory transport and inhibits neuritogenesis. Later during development, BICDR-1 expression is strongly reduced, which permits anterograde secretory transport required for neurite outgrowth. These results indicate an important role for BICDR-1 as temporal regulator of secretory trafficking during the early phase of neuronal differentiation
Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression
<p>Abstract</p> <p>Background</p> <p>Previous results showed that over-expression of the <it>WTH3 </it>gene in MDR cells reduced <it>MDR1 </it>gene expression and converted their resistance to sensitivity to various anticancer drugs. In addition, the <it>WTH3 </it>gene promoter was hypermethylated in the MCF7/AdrR cell line and primary drug resistant breast cancer epithelial cells. <it>WTH3 </it>was also found to be directly targeted and up regulated by the <it>p53 </it>gene. Furthermore, over expression of the <it>WTH3 </it>gene promoted the apoptotic phenotype in various host cells.</p> <p>Methods</p> <p>To further confirm <it>WTH3</it>'s drug resistant related characteristics, we recently employed the small hairpin RNA (shRNA) strategy to knockdown its expression in HEK293 cells. In addition, since the <it>WTH3 </it>promoter's p53-binding site was located in a CpG island that was targeted by methylation, we were interested in testing the possible effect this epigenetic modification had on the <it>p53 </it>transcription factor relative to <it>WTH3 </it>expression. To do so, the <it>in vitro </it>methylation method was utilized to examine the <it>p53 </it>transgene's influence on either the methylated or non-methylated <it>WTH3 </it>promoter.</p> <p>Results</p> <p>The results generated from the gene knockdown strategy showed that reduction of <it>WTH3 </it>expression increased <it>MDR1 </it>expression and elevated resistance to Doxorubicin as compared to the original control cells. Data produced from the methylation studies demonstrated that DNA methylation adversely affected the positive impact of <it>p53 </it>on <it>WTH3 </it>promoter activity.</p> <p>Conclusion</p> <p>Taken together, our studies provided further evidence that <it>WTH3 </it>played an important role in MDR development and revealed one of its transcription regulatory mechanisms, DNA methylation, which antagonized <it>p53</it>'s positive impact on <it>WTH3 </it>expression.</p
Influence of cyclin type and dose on mitotic entry and progression in the early Drosophila embryo
Cyclins are key cell cycle regulators, yet few analyses test their role in timing the events that they regulate. We used RNA interference and real-time visualization in embryos to define the events regulated by each of the three mitotic cyclins of Drosophila melanogaster, CycA, CycB, and CycB3. Each individual and pairwise knockdown results in distinct mitotic phenotypes. For example, mitosis without metaphase occurs upon knockdown of CycA and CycB. To separate the role of cyclin levels from the influences of cyclin type, we knocked down two cyclins and reduced the gene dose of the one remaining cyclin. This reduction did not prolong interphase but instead interrupted mitotic progression. Mitotic prophase chromosomes formed, centrosomes divided, and nuclei exited mitosis without executing later events. This prompt but curtailed mitosis shows that accumulation of cyclin function does not directly time mitotic entry in these early embryonic cycles and that cyclin function can be sufficient for some mitotic events although inadequate for others
WTH3 is a direct target of the p53 protein
Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene
Whacked and Rab35 polarize dynein-motor-complex-dependent seamless tube growth
Seamless tubes form intracellularly without cell–cell or autocellular junctions. Such tubes have been described across phyla, but remain mysterious despite their simple architecture. In Drosophila, seamless tubes are found within tracheal terminal cells, which have dozens of branched protrusions extending hundreds of micrometres. We find that mutations in multiple components of the dynein motor complex block seamless tube growth, raising the possibility that the lumenal membrane forms through minus-end-directed transport of apical membrane components along microtubules. Growth of seamless tubes is polarized along the proximodistal axis by Rab35 and its apical membrane-localized GAP, Whacked. Strikingly, loss of whacked (or constitutive activation of Rab35) leads to tube overgrowth at terminal cell branch tips, whereas overexpression of Whacked (or dominant-negative Rab35) causes formation of ectopic tubes surrounding the terminal cell nucleus. Thus, vesicle trafficking has key roles in making and shaping seamless tubes
Hereditary sensory neuropathy type I
Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma. Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease
Glucosamine and chondroitin sulfate supplementation to treat symptomatic disc degeneration: Biochemical rationale and case report
BACKGROUND: Glucosamine and chondroitin sulfate preparations are widely used as food supplements against osteoarthritis, but critics are skeptical about their efficacy, because of the lack of convincing clinical trials and a reasonable scientific rationale for the use of these nutraceuticals. Most trials were on osteoarthritis of the knee, while virtually no documentation exists on spinal disc degeneration. The purpose of this article is to highlight the potential of these food additives against cartilage degeneration in general, and against symptomatic spinal disc degeneration in particular, as is illustrated by a case report. The water content of the intervertebral disc is a reliable measure of its degeneration/ regeneration status, and can be objectively determined by Magnetic Resonance Imaging (MRI) signals. CASE PRESENTATION: Oral intake of glucosamine and chondroitin sulfate for two years associated with disk recovery (brightening of MRI signal) in a case of symptomatic spinal disc degeneration. We provide a biochemical explanation for the possible efficacy of these nutraceuticals. They are bioavailable to cartilage chondrocytes, may stimulate the biosynthesis and inhibit the breakdown of their extracellular matrix proteoglycans. CONCLUSION: The case suggests that long-term glucosamine and chondroitin sulfate intake may counteract symptomatic spinal disc degeneration, particularly at an early stage. However, definite proof requires well-conducted clinical trials with these food supplements, in which disc de-/regeneration can be objectively determined by MRI. A number of biochemical reasons (that mechanistically need to be further resolved) explain why these agents may have cartilage structure- and symptom-modifying effects, suggesting their therapeutic efficacy against osteoarthritis in general
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