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Structure and Function of the Urokinase-Type Plasminogen Activator Gene
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Yoshikuni Negamine, Janet S. Lee, Pierre-Alain Menoud, Rika Nanbu
Several lines of evidence suggest that a negative regulator is involved in u-PA gene regulation. We have shown that protein synthesis inhibition enhances cAMP-induced but not TPA-induced u-PA gene transcription in LLC-PK1 cells,86 implying that a labile protein is negatively involved in cAMP-dependent u-PA gene activation. The presence of a negative regulator was also envisioned from a study using a genetic approach.87 We have isolated mutant LLC-PK1 cells in which the u-PA gene is constitutively active. The genetic phenotype of the mutation is recessive, and it is likely, therefore, that the lesion is in a negative regulatory factor. We do not know yet whether putative negative regulators presumed from two independent analyses are identical. Functional analysis of u-PA gene promoters revealed the presence of a silencer approximately 2 kb upstream of the transcription initiation site in the human88 and pig36 genes. It would be interesting to know whether these observations are related to each other. Further data identifying these factors and the silencer sequence are awaited.
Introduction to Genomics
Published in Altuna Akalin, Computational Genomics with R, 2020
Silencers are similar to enhancers; however their effect is opposite of enhancers on the transcription of the target gene, and results in decreasing their level of transcription. They contain binding sites for repressive transcription factors. Repressor transcription factors can either block the binding of an activator , directly compete for the same binding site, or induce a repressive chromatin state in which no activator binding is possible. Silencer effects, similar to those of enhancers, are independent of orientation and distance to target genes. In contradiction to this general view, in Drosophila there are two types of silencers, long-range and short-range. Short-range silencers are close to promoters and long-range silencers can silence multiple promoters or enhancers over kilobases away. Like enhancers, silencers bound by repressors may also induce changes in DNA structure by looping and creating higher-order structures. One class of such repressor proteins, which is thought to initiate higher-order structures by looping, is Polycomb group proteins (PcGs).
How successful has targeted RNA interference for hepatic fibrosis been?
Published in Expert Opinion on Biological Therapy, 2018
Mohube Betty Maepa, Abdullah Ely, Patrick Arbuthnot
Although results from studies using exogenous synthetic or expressed silencers are encouraging, several key issues require attention before the technology is translated to the clinic. Many of the challenges are common to other topics of gene therapy and developments in the broader field will benefit advancing RNAi-based therapy for hepatic fibrosis. High costs of production, poor delivery efficiency, difficulties with scalability, safety, durability and potency of targeted effects are important examples of such issues that need to be addressed. Although likely to be important, it is not yet clear what influence fibrosis has on delivery efficiency of viral vectors and NVVs. Effects of fibrosis on susceptibility of the different classes of cells to nucleic acid uptake are also yet to be established.
Military and industrial performance: the critical role of noise controls
Published in International Journal of Audiology, 2019
Kurt. D. Yankaskas, Jeffrey M. Komrower
Often, it is not possible to isolate the source and stop the vibrational energy transmission. In this situation, the methodology for preventing acoustic radiation would be to reduce the vibration of the radiating structure. In the example shown in Figure 3, where a structural bulkhead was radiating acoustic energy into a compartment during launch, a unique spray-on damping treatment, which was developed through another ONR SBIR (N04-221) (Meyer 2012), was applied to the bulkhead. This treatment reduced noise levels in the space by 4–6 dB. This damping treatment has also been successfully applied to radiating ductwork in several power plants – another example of technology developed through Navy programmes, successfully deployed on other applications. Silencers are typically used, for example where there is a loud fan, as was the case in several of the power plants previously mentioned. These fans were high volume units used to provide cooling air flow to the generators. Acoustic silencers, placed at the fan exhaust, which function by absorbing the acoustical energy, successfully reduced noise levels by 4–8 dB. Acoustic silencers can also be employed in hydraulic lines, which often emit high energy acoustic tones, to reduce noise. An excellent example of this can be found in Yankaskas and Fast (1999). In this example, the raising and lowering of the jet blast deflector (JBD) used during aircraft carrier launches, was creating a loud hydraulic orifice noise. The solution was to create a bi-directional multi-orifice muffler to replace the existing orifices in the JBD hydraulic lines. This fix was successful, resulting in noise attenuations of over 20 dB.
Noise exposures of sugar cane mill workers in Guatemala
Published in International Journal of Audiology, 2020
Ashley M. Stumpf, Grant Erlandson, Jennifer Ruths, Deanna K. Meinke, Lee S. Newman, Lyndsay Krisher, Daniel Pilloni, Alex Cruz, Claudia Asensio
The hierarchy of noise control recommends elimination of the hazardous noise source or reduction of the noise levels as a first order approach to the prevention of noise-induced hearing loss. Subsequent to the noise dosimetry sampling in 2017, a noise control survey (Leq sound levels, octave-band analysis and machine specific measurements) was conducted during seasonal production in 2019 (G. Erlandson, personal communication, 26 May 2019). Five major noise sources were identified across the mill: steam venting, steam leaks, shredders, evaporator washing, and power generation. Of those five, steam vents and leaks were by and large the dominant noise source in the mill and corresponded with the highest noise exposures. Steam vents were highly prevalent in the evaporator work space and leaks were regularly found above and inside the juice extraction work space. However, steam related noise was present in a large majority of job locations. Recommendations for prioritisation of noise controls and options within those recommendations were then provided to the company by an external contractor. The company has implemented a series of noise control measures inside the mill since the noise dosimetry was completed. These include the purchasing of a silencer for one of the boilers. The “rock watch” job position was substituted for video-camera controls. However, further engineering noise controls are warranted, and the company is in the process of evaluation and implementation of those recommendations [C. Asensio, personal communication, 23 May 2019). Double hearing protection policy was implemented for the evaporator cleaner job position and administrative noise control is planned to reduce individual exposure time. The company has also established an alliance with 3 M to standardise the use and fit of hearing protection devices.