REGULATORY MODIFICATIONS OF MICRORNA AND SHORT HAIRPIN RNA PRECURSORS

RNA-interference (RNAi) is ubiquitously used as a research tool, with dozens of candidates using this technology currently in FDA clinical trials. A particular segment of the RNAi world, short hairpin RNAs (shRNAs) seeks to enable stable, long-term reduction of a target protein. Here, we present an optimization of shRNA structure that allows increased reduction of targeted proteins as unwanted processing events are bypassed, increasing the amount of mature RNAi species created. In Chapter 1, we present current literature as it pertains to RNAi biogenesis, regulation, and optimization of shRNA effectiveness. In Chapter 2, we present our findings of extensive shRNA precursor degradation, and complete an unbiased screen for structures that bypass this degradation and optimize RNAi activity. In Chapter 3, we offer our observations of negative processing events associated with RNA Polymerase III (RNAPIII)-driven shRNAs, including but not limited to the same extensive precursor degradation. Together, these data present new details in the dysregulation of endogenous miRNA biogenesis by shRNAs, and offer guidance towards more accurate and potent engineered shRNA regulators less likely to induce off-target effects.Doctor of Philosoph

Supplementary Report On The Feasibility Study Of Submerged Cylinder Wave Energy Device

This report has been compiled as the result o f a four-month supplementary contract to our first broad look at submerged cylinder wave energy devices. In this further period we have discussed widely within the wave energy community the findings of our main Report dated October 1979. We have also considered topics that were either not within our earlier brief or were only peripheral to its principal purpose of identifying how the device could be engineered using proven technology, and the likely range of unit costs that this could involve. The present Report therefore covers a wide spectrum of topics. These are mostly pitched in the form of 'Appe ndix' notes to subjects studied and presented in our main Report. They serve to clarify points of detail, and have been pursued in sufficient depth to show whether they need be studied further in the next phase of this enquiry. We have also continued our studies of the main subjects underlying the behaviour and performance of the device, especially its dyna mic behaviour in response to wave motion and how energy is best transmitted to and through the seabed power takeoff units. This supplementary period has therefore allowed us to narrow our options, Although we believe it is still premature to expect the preferred system of mooring and power takeoff to be selected with certainty, our earlier recommendations are upheld by the further findings now presented. This system will therefore form the basis for the optimisation study of the device that now logically follows, but we will continue to seek improvements both to the overall arrangement of the device and to its component parts in the light of all further information that becomes available to us. We conclude that the submerged cylinder device is a technically sound and efficient way of capturing wave energy. On the basis of present knowledge we have reason to believe that, from the thorough optimisation study that constitutes the next phase of our work, the device may also turn out to be an economic proposition. In this case it should be advanced through a full engineering design phase to the prototype construction of perhaps five units at full scale in say 1984/5

Final Report On Submerged Cylinder Wave Energy Device

A first overall assessment of the submerged cylinder device has been prepared, from which at outline design for the principal components has been produced. A budget estimate for this design has been made, including allowances for annual operation and maintenance charges. The efficiency characteristics of the device have been determined from selected tank tests. With these efficiencies, the energy captured by each cylinder of an array has been estimated. Allowances have been made for the probable energy losses in each component through to the National network at Perth. On the basis of the preliminary specification for the device agreed in June 1979, at the end of Stage 1 of this Contract, the price of electricity delivered to the network is estimated to be 11. 4 p/kWh. This assumes a 5% discount rate and a 20 year operating life. A number of improvements to the reference design are already clear. Principally its tuned frequency should be increased so that the efficiency characteristics match the wave spectrum more closely. This single improvement in gross output appears sufficient to reduce the unit cost to about 8.5 p/kWh because of the significance of annual maintenance charges on the net annual revenue from sales of electricity. There is considerable scope to improve the design. Other power take off and energy transfer techniques deserve attention, and there is scope to rationalise the mooring and foundation arrangements. Because of the nature of its working environment, the same philosophy of using proven components or reasonable derivatives therefrom should be retained. The stable behaviour of the device in all sea conditions studied, and its high efficiency in the more persistent waves, confirm that this further step towards a comprehensive design of the basically simple, efficient and robust system is justified

MODELO DE SIMULACIÓN PARA CALCULAR LA RESERVA DE CONTINGENCIA EN PROYECTOS DE INVERSIÓN PARA MIPYMES

El abandono empresarial está asociado a la baja rentabilidad del negocio y a su vez, se relaciona con problemas del emprendedor para identificar nichos de mercados y gestionar los riesgos que se le presenten. Utilizar herramientas de predicción de riesgos ayudaría en el proceso, pero se requieren competencias teóricas y habilidades técnicas para optimizar los resultados de este tipo de aplicativos. Partiendo de la revisión de los diferentes modelos y herramientas ofertados en el mercado para gestionar y evaluar riesgos, y del análisis de los métodos de evaluación en proyectos, se propone estructurar un modelo de simulación  que permita medir la reserva de contingencia y de gestión de acuerdo al nivel de riesgo aceptado por pequeños inversionistas; esto con el propósito de que los responsables de estos nuevos entes económicos, puedan generar estrategias de gestión de riesgos efectivas al identificar el valor requerido de inversión total en sus emprendimientos, y así, lograr la permanencia y crecimiento en el mercado

Trusted CI Experiences in Cybersecurity and Service to Open Science

This article describes experiences and lessons learned from the Trusted CI project, funded by the US National Science Foundation to serve the community as the NSF Cybersecurity Center of Excellence. Trusted CI is an effort to address cybersecurity for the open science community through a single organization that provides leadership, training, consulting, and knowledge to that community. The article describes the experiences and lessons learned of Trusted CI regarding both cybersecurity for open science and managing the process of providing centralized services to a broad and diverse community.Comment: 8 pages, PEARC '19: Practice and Experience in Advanced Research Computing, July 28-August 1, 2019, Chicago, IL, US

Essential Function of Dicer in Resolving DNA Damage in the Rapidly Dividing Cells of the Developing and Malignant Cerebellum

Maintenance of genomic integrity is critical during neurodevelopment, particularly in rapidly dividing cerebellar granule neuronal precursors that experience constitutive replication-associated DNA damage. As Dicer was recently recognized to have an unexpected function in the DNA damage response, we examined whether Dicer was important for preserving genomic integrity in the developing brain. We report that deletion of Dicer in the developing mouse cerebellum resulted in the accumulation of DNA damage leading to cerebellar progenitor degeneration, which was rescued with p53 deficiency; deletion of DGCR8 also resulted in similar DNA damage and cerebellar degeneration. Dicer deficiency also resulted in DNA damage and death in other rapidly dividing cells including embryonic stem cells and the malignant cerebellar progenitors in a mouse model of medulloblastoma. Together, these results identify an essential function of Dicer in resolving the spontaneous DNA damage that occurs during the rapid proliferation of developmental progenitors and malignant cells

MicroRNA circulating in the early aftermath of motor vehicle collision predict persistent pain development and suggest a role for microRNA in sex-specific pain differences

Abstract Background Molecular mediators influencing the transition from acute to persistent musculoskeletal pain following common stress exposures such as motor vehicle collision (MVC) remain poorly understood. In this exploratory, proof of concept study, we compared circulating microRNA (miRNA) expression profiles in the early aftermath of MVC among individuals who did and did not subsequently develop persistent pain. Blood RNA samples were obtained from African American individuals (n = 53) who presented to the emergency department after MVC and were discharged to home after evaluation. The presence or absence of severe pain in the axial region, the most common and morbid region in which post-MVC pain occurs, was assessed 6 weeks following MVC via standardized questionnaire. miRNA expression was determined using miRNA-sequencing; nonparametric analyses were used to compare miRNA expression levels among individuals with and without persistent pain. Results Thirty-two mature miRNA were differentially expressed (p < 0.05) in those with and without severe axial pain at 6 weeks. miR-135a-5p, a regulator of the serotonin receptor that is known to be stress-responsive, differed most significantly between groups (p = 3 × 10−4). This miRNA, and miR-3613-3p (p = 0.001) survived correction for multiple testing (FDR = 0.15) in this small sample. Interestingly, differentially expressed miRNA were enriched for X chromosome location. In secondary analyses, the eight X chromosome miRNA were (a) more significantly associated with axial pain in women than men, (b) expressed more highly in the peripheral blood of women than men, and (c) predicted in pathway analyses (DIANA miRPath v 2.0) to regulate neuronal and neuroendocrine pathways previously implicated in various pain pathologies. Conclusions These results show that circulating miRNA predict persistent severe axial pain after MVC and suggest that they may be involved in the pathogenesis of post-traumatic musculoskeletal pain. However, further studies are needed to determine if these miRNA play a direct causal role

The orchid : [a novel] /

Mode of access: Internet.Spec. Coll. copy is part of a collection (Collection 1607). To page this item, use the collection record; to find the collection record, search the title: Gullans-Espey Collection of Designer Bookbindings. Item is in box 63. Medium brownish yellow cloth, stamped in light green, red and black, with vignette of a country club. Publisher's advertisements: [4] p. at end. Gift of Charles Gullans and John Espey, 1986

Severn tidal power TWG7 - caisson engineering report on civil engineering

SIGLELD:8253.977(STP--19). / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Severn tidal power pre-feasibility study Further report on caissons and other civil engineering work

SIGLELD:8253.977(STP--55). / BLDSC - British Library Document Supply CentreGBUnited Kingdo