A Proposed Curricula Time Schedule Appliance to Eighth Grade Modern Mathematics

The purpose of this study was to examine several possible curricula time schedules in light of the objectives of eighth grade modern mathematics, and to develop a schedule best suited to meet these objectives. It was further postulated that a flexible schedule would: 1. allow time for completion of materials by students with average and above capabilities. 2. allow for student individual differences. 3. allow most effective use of staff

Regulation of ribosome biogenesis in health and disease

PhD ThesisRibosome biogenesis is one of the most energy consuming and regulated cellular processes. Due to the fundamental importance of ribosomes in cellular biology, it is unsurprising that defects in their biogenesis are linked to a range of human disorders, termed ribosomopathies. This project aimed to investigate different mechanisms through which ribosome production is regulated in relation to health and disease. When ribosome biogenesis is defective, the 5S RNP, a large subunit (LSU) assembly intermediate, accumulates, activating the tumour suppressor p53 through inhibition of its regulator. Unexpectedly, small subunit (SSU) production defects also activate p53 through the 5S RNP. In this study, SSU production defects were found to activate p53 early and in the absence of changes in mature SSU levels, contrary to previous research. SSU production defects result in impaired export of the pre-LSU and reduced levels of the late, cytoplasmic pre-5.8S ribosomal RNA. This implies that defective SSU production activates p53 through stalling the late stages of LSU maturation. Ribosomal proteins are produced in excess and are protected from aggregation by chaperones. RPL3 and its dedicated chaperone GRWD1 were both shown to be required to produce the LSU and SSU and were both shown to bind a novel inhibitor of ribosome biogenesis, C8ORF33. The GRWD1 binding site of RPL3 is required for this interaction and is required for ribosome production. These proteins had different but diverging roles during ribosome production and may be involved in regulatory mechanisms. The chaperone binding site of RPL3 is highly conserved between humans and yeast except for serine residues in humans that have been reported as phosphorylation sites. Phosphorylation offers a mechanism through which protein functions can be modified to diversify cellular responses. However, such modifications do not impact GRWD1 binding but are linked to minor changes in pre-ribosomal RNA processing.MR

Near-zero environmental impact aircraft

The fundamental challenge facing today's aviation industry is to achieve net zero climate impacts while simultaneously sustaining growth and global connectivity. Aviation's impact on surface air quality, which is comparable to aviation's climate impact when monetized, further heightens this challenge. Prior studies have proposed solutions that aim to mitigate either aviation's climate or air quality impacts. No previous work has proposed an aircraft-energy system that simultaneously addresses both aviation's climate and air quality impacts. In this paper we (1) use a multi-disciplinary design approach to optimize aircraft and propulsion systems, (2) estimate lifecycle costs and emissions of producing sustainable fuels including the embodied emissions associated with electricity generation and fuel production, (3) use trajectory optimization to quantify the fuel penalty to avoid persistent contrail formation based on a full year of global flight operations (including, for the first time, contrail avoidance for a hydrogen burning aircraft), and (4) quantify climate and air quality benefits of the proposed solutions using a simplified climate model and sensitivities derived from a global chemistry transport model. We propagate uncertainties in environmental impacts using a Monte-Carlo approach. We use these models to propose and analyze near-zero environmental impact aircraft, which we define as having net zero climate warming and a greater than 95% reduction in air quality impacts relative to present day. We contrast the environmental impacts of today's aircraft-energy system against one built around either "drop-in" fuels or hydrogen. We find that a "zero-impact" aircraft is possible using either hydrogen or power-to-liquid "drop-in" fuels. The proposed aircraft-energy systems reduce combined climate and air quality impacts by 99%, with fuel costs increasing by 40% for hydrogen and 70% for power-to-liquid fueled aircraft relative to today's fleet (i.e., within the range of historical jet fuel price variation). Beyond the specific case presented here, this work presents a framework for holistic analysis of future aviation systems that considers both climate and air quality impacts.The fundamental challenge facing the aviation industry is to achieve near-zero environmental impacts while sustaining growth. We propose a near-zero impact aircraft, taking a lifecycle perspective across fuels, aircraft design, and operation

Coherence protection in coupled quantum systems

HMC acknowledges studentship funding from EPSRC under grant no. EP/G03673X/1. PGK acknowledges support from EPSRC (EP/M010910/1). BWL acknowledges support from EPSRC (EP/K025562/1). PRE acknowledges funding from SFI (15/IACA/3402). JK acknowledges financial support from EPSRC programs “TOPNES” (EP/I031014/1) and “Hybrid-Polaritonics” (EP/M025330/1).The interaction of a quantum system with its environment causes decoherence, setting a fundamental limit on its suitability for quantum information processing. However, we show that if the system consists of coupled parts with different internal energy scales then the interaction of one part with a thermal bath need not lead to loss of coherence from the other. Remarkably, we find that the protected part can remain coherent for longer when the coupling to the bath becomes stronger or the temperature is raised. Our theory will enable the design of decoherence-resistant hybrid quantum computers.Publisher PDFPeer reviewe

Validation study of a web-based assessment of functional recovery after radical prostatectomy

<p>Abstract</p> <p>Background</p> <p>Good clinical care of prostate cancer patients after radical prostatectomy depends on careful assessment of post-operative morbidities, yet physicians do not always judge patient symptoms accurately. Logistical problems associated with using paper questionnaire limit their use in the clinic. We have implemented a web-interface ("STAR") for patient-reported outcomes after radical prostatectomy.</p> <p>Methods</p> <p>We analyzed data on the first 9 months of clinical implementation to evaluate the validity of the STAR questionnaire to assess functional outcomes following radical prostatectomy. We assessed response rate, internal consistency within domains, and the association between survey responses and known predictors of sexual and urinary function, including age, time from surgery, nerve sparing status and co-morbidities.</p> <p>Results</p> <p>Of 1581 men sent an invitation to complete the instrument online, 1235 responded for a response rate of 78%. Cronbach's alpha was 0.84, 0.86 and 0.97 for bowel, urinary and sexual function respectively. All known predictors of sexual and urinary function were significantly associated with survey responses in the hypothesized direction.</p> <p>Conclusions</p> <p>We have found that web-based assessment of functional recovery after radical prostatectomy is practical and feasible. The instrument demonstrated excellent psychometric properties, suggested that validity is maintained when questions are transferred from paper to electronic format and when patients give responses that they know will be seen by their doctor and added to their clinic record. As such, our system allows ready implementation of patient-reported outcomes into routine clinical practice.</p

Feasibility study of a clinically-integrated randomized trial of modifications to radical prostatectomy

<p>Abstract</p> <p>Background</p> <p>Numerous technical modifications to radical prostatectomy have been proposed. Such modifications are likely to lead to only slight improvements in outcomes. Although small differences would be worthwhile, an appropriately powered randomized trial would need to be very large, and thus of doubtful feasibility given the expense, complexity and regulatory burden of contemporary clinical trials. We have proposed a novel methodology, the clinically-integrated randomized trial, which dramatically streamlines trial procedures in order to reduce the marginal cost of an additional patient towards zero. We aimed to determine the feasibility of implementing such a trial for radical prostatectomy.</p> <p>Methods</p> <p>Patients undergoing radical prostatectomy as initial treatment for prostate cancer were randomized in a factorial design to involvement of the fascia during placement of the anastomotic sutures, urethral irrigation, both or neither. Endpoint data were obtained from routine clinical documentation. Accrual and compliance rates were monitored to determine the feasibility of the trial.</p> <p>Results</p> <p>From a total of 260 eligible patients, 154 (59%) consented; 56 patients declined to participate, 20 were not approached on recommendation of the treating surgeon, and 30 were not approached for logistical reasons. Although recording by surgeons of the procedure used was incomplete (~80%), compliance with randomization was excellent when it was recorded, with only 6% of procedures inconsistent with allocation. Outcomes data was received from 71% of patients at one year. This improved to 83% as the trial progressed.</p> <p>Conclusions</p> <p>A clinically-integrated randomized trial was conducted at low cost, with excellent accrual, and acceptable compliance with treatment allocation and outcomes reporting. This demonstrates the feasibility of the methodology. Improved methods to ensure documentation of surgical procedures would be required before wider implementation.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00928850">NCT00928850</a></p

Canagliflozin impairs T cell effector function via metabolic suppression in autoimmunity

Augmented T cell function leading to host damage in autoimmunity is supported by metabolic dysregulation, making targeting immunometabolism an attractive therapeutic avenue. Canagliflozin, a type 2 diabetes drug, is a sodium glucose co-transporter 2 (SGLT2) inhibitor with known off-target effects on glutamate dehydrogenase and complex I. However, the effects of SGLT2 inhibitors on human T cell function have not been extensively explored. Here, we show that canagliflozin-treated T cells are compromised in their ability to activate, proliferate, and initiate effector functions. Canagliflozin inhibits T cell receptor signaling, impacting on ERK and mTORC1 activity, concomitantly associated with reduced c-Myc. Compromised c-Myc levels were encapsulated by a failure to engage translational machinery resulting in impaired metabolic protein and solute carrier production among others. Importantly, canagliflozin-treated T cells derived from patients with autoimmune disorders impaired their effector function. Taken together, our work highlights a potential therapeutic avenue for repurposing canagliflozin as an intervention for T cell-mediated autoimmunity