REGULATION OF PLATELET EXOCTOSIS AND ITS ROLE IN DISEASES

In addition to their role in hemostasis, platelets appear to contribute to vascular inflammatory diseases. Platelets achieve this through the secretion of various prothrombotic and pro-inflammatory molecules. Platelet secretion is mediated by integral membrane proteins called Soluble NSF Attachment protein REceptors (SNAREs). SNAREs come from both granule/vesicle membranes (v-SNAREs) and target membranes (t-SNAREs) to form a trans-bilayer complex that promotes membrane fusion and subsequent granule cargo release. The work described in this dissertation dissects various, yet related aspects of platelet secretion in both physiological relevant and pathological circumstances. Atherosclerosis is a leading cause of death in the westernized countries and a major contributor to heart attacks and strokes. Given the potential involvement of platelets in atherosclerosis and previous work from our laboratory showing that VAMP-8 is the primary v-SNARE for platelet secretion, one part of this dissertation focuses on the role of VAMP-8- mediated secretion in atherosclerosis. The data showed that the deletion of VAMP-8 in the ApoE-/- null model of chronic atherosclerosis attenuated plaque development compared to the wild type littermates. Aged (50 week) VAMP-8-/-/ApoE-/- mice showed a reduction in lesion size compared to ApoE-/- controls, as measured by Oil Red-O staining of the plaques in the aortic sinus and by en face analysis of plaques in the aortic arch. These data show that the loss of VAMP-8 attenuates the development of atherosclerotic plaques and suggest that platelet secretion contributes to atherosclerosis. Considering the vital role of platelet secretion in both physiological and pathological conditions, it is essential to understand how it is regulated. SNARE proteins are controlled by a range of regulatory molecules that affect where, when, and with whom they form trans-bilayer complexes for membrane fusion. One family of such regulators is the Munc18 family: platelets contain three (Munc18a-c). The second part of this dissertation focuses on the role of Munc18b/STXBP2. Mutations in the Munc18b/STXBP2 gene underlie Familial Hemophagocytic Lymphohistocytosis type 5 (FHL5), which is a life- threatening disease caused by dysregulation of the immune system. Platelets from two biallelic FHL5 patients had almost undetectable levels of Munc18b/STXBP2 levels; the levels of Munc18a increased slightly and Munc18c levels were unaffected. Syntaxin 11 levels were affected but the levels of other secretory machinery proteins were normal. Platelet secretion from dense and alpha granule in two biallelic patients and the one heterozygous patient was decreased. The release of serotonin from dense granules, and platelet factor 4 (PF4) from alpha granules was profoundly affected in the biallelic patients and partially affected in the heterozygote heterozygous patient. Lysosome release was affected only from the platelets of the biallelic patients. These data indicate that Munc18b plays a key role in platelet secretion. Ras is the prototypical member of a family of low molecular weight, GTP-binding proteins. It affects various cellular functions by cycling between an active, guanine triphosphate (GTP) and an inactive guanine diphosphate (GDP) -bound state. Little is known about the role of Ras activation in platelets. The third part of this dissertation focuses on what could be learned about Ras’ role by analyzing platelets from patients with Noonan Syndrome. Specific mutations in the genes encoding elements of Ras signaling pathways are associated with Noonan Syndrome. Platelets from Noonan Syndrome patients with a mutation in kRas (F156V) were analyzed and shown to have a defect in aggregation in response to low levels of agonist. These data suggest that Ras may play a functionally relevant role in platelet activation. In summary, the experiments presented in investigations of this dissertation support a role for platelet secretion in several pathological conditions and suggest that platelet secretion assays may serve as useful as diagnostic tools for some genetic diseases. In addition, these studies elucidate the importance of understanding the regulation of platelet exocytosis, to drive the development of new antithrombotic therapeutics

Innovative design of an educational physical simulation tool for investigating energy consumption in buildings for enhancing public engagement

Reducing carbon emission and energy consumption in buildings is becoming an important priority on global level. Buildings consume significant amount of energy for heating or air-conditioning in most countries. The drive to enhance the understanding of building insulation and its effect on energy use, is critical for improving public engagement to achieve reduce carbon emission towards more sustainable future. This paper presents the design and the development an educational and research simulation tool to study and understand the thermal performance and energy efficiency of buildings. The novel design includes small-scale multi-layered model of buildings where insulation layers can be added to or removed from the building model in a modular and interchangeable manner to allow changes to the thermal performance. The results show that this novel model will provide a new educational tool to enhance the understanding of energy consumption and insulation in buildings. The design can be used to engage the young generation regarding building insulation and energy efficiency. It also could provide an advanced research and teaching tool for energy in buildings, instrumentation and infrared thermography

An innovative approach towards enhancing energy conservation in buildings via public engagement using DIY infrared thermography surveys

Energy consumption in urban environment in the EU accounts for about 40% of the total energy consumption, and the majority of this energy is utilised for heating and air conditioning of buildings. Hence the process of insulating and retrofitting of relatively old buildings is essential to enhance the thermal performance and hence contribute to energy and carbon emission reduction. There is a need to enhance people's engagement and education in relation to such issues to inspire and encourage positive actions and investment from the public. This paper presents an approach of combining a novel training process using a low-cost infrared thermal camera with small scale building model to promote DIY (Do-It-Yourself) infrared survey for the public to evaluate the performance of their own homes in order to identify any issues related to insulation or air leaks from the building envelop to encourage them to take corrective actions. The work included the engagement of 50 people to survey their own homes to capture the technical findings as well as their personal reaction and feedback. The results show that 88% of participants have found the educational session helpful to understand the infrared thermography; and 92% have considered the infrared camera to be an effective tool to indicate location of heat losses. Additionally, 90% of participants trust that the thermal camera has helped them to identify insulation defects that cause heat losses in their homes. Moreover, 84% believe that the thermal imaging has convinced them to think more seriously about the heat losses of their homes and what they could do to improve that. The experimental thermography surveys have shown that many houses have limitations in terms of thermal insulation which have been identified by the participants. This DIY interaction has provided enhanced public engagement and energy awareness via the use of the technology. The financial issues are also found to be critical, as none of the participants would have done the survey if they had to pay for it. Hence, this paper provides a solution for households with limited budgets

Enhancing the sustainability and energy conservation in heritage buildings: the case of Nottingham Playhouse

Today, there is a growing interest in developing energy efficient buildings since it is estimated that buildings account for about 40% of the total primary energy consumption in the world. In relation to existing buildings, energy efficiency retrofits have become an important opportunity to upgrade the energy performance of commercial, public and residential buildings that may reduce the energy consumption, demand and cost. In this paper we cover the energy efficiency deep retrofit process that has been carried out for Nottingham Playhouse theatre building for the aim of enhancing its environmental performance and analysing the energy efficiency gained after implementing certain proposed modifications. It is a nationally protected historic building, listed as Grade II* on The National Heritage List for England (NHLE). The building has had insulation enhancement, doors modifications, solar energy installations, energy-saving lights, in addition to improved heating and air conditioning system. The paper presents a novel methodology; and its results indicate significant improvements in the building's energy performance which is demonstrated using infrared thermographic images and data logger sensors where significant energy savings to the building's thermal performance are obtained. The energy saving measures have been completed while maintaining the heritage building's general appearance and architectural features, which have received a Commendation Certificate from The Nottingham Civic Society for this achievement

An educational and research apparatus for simulating thermal performance and energy efficiency of buildings

Apparatus intended as a teaching aid for studying the thermal efficiency of buildings comprising a scale model of a building or buildings with sensors that monitor the internal and external environments of the model building. The models temperature may be monitored by way or infrared thermography. Insulating layers can be added and removed to walls, roof, windows and doors in a modular, interchangeable manner. The thermal environment can be controlled by way of heating or air-conditioning systems and wind circulation and solar radiation can be simulated. The heating and cooling can be computer controlled. The model may be housed in a chamber that may have a removable cover or a handle for transportation

Survey on camel husbandry in Qassim region, Saudi Arabia : herding strategies, productivity and mortality

A small survey was carried out on 38 camel herds in Qassim region of Saudi Arabia to study production and reproduction parameters, herding strategies, offtake and constraints to camel production. The study also recorded the rate and causes of mortality in the surveyed herds over one year. Four distinct herding strategies were discovered. Type one herders were companies or merchants who kept large herds (mean = 1260 camels) in semi-intensive operations and who marketed milk, meat and young camels on a regular basis. Type two herders were unspecialized merchants who kept medium-sized herds (mean = 86 camels) for family use without apparent commercial benefit. The third type of herders consisted of pastoralists or agropastoralists who kept smaller herds (mean = 14 camels) always with other animals (mainly sheep and goats, and occasionally cattle). Type four herders were classical camel merchants who also kept a relatively small group of camels (mean = 17 camels) in a feedlot for sale at a profit at the first opportunity. The calving rate was 68%, the mean age at first calving was four years and four months and the mean intercalving interval was 20 months. The highest mortality was recorded in the period from birth to one year of age and averaged 17% in all the data. In large commercial herds, an additional age group with high mortality was the two- to three-year-old females in which up to 9% mortality was recorded. Most of the male camels were sold for meat at around one year of age and only 4.3% males remained in the herds

Development of a Composite Sustainability Index for Roadway Intersection Design Alternatives in the UAE

Many studies have been carried out to evaluate the sustainability of transportation systems, but little attention has been given for the design of roadway intersections. This study aimed to establish a framework and develop a tool to assess the sustainability of roadway intersections from a road-user perspective. Sustainability indicators at the strategic level were extracted from the literature and were utilized with relative weights to develop economic, environmental, and social indices that would be combined into a composite sustainability index (CSI) tool. The tool was applied to four case studies of intersections in Al Ain, United Arab Emirates. For each case study, the sustainability of fifteen design alternatives was evaluated for different scenarios of traffic volume and operational speed. Dimensional indices and the overall CSI were determined using the Multi-Criteria Decision Making method. Results indicated that traffic volume had a significant impact on intersection sustainability ranking, while the effect of operational speed was insignificant. Moreover, weight assignment had an effect on determining the most sustainable design alternative, where the best alternatives of the dimension with the major weight would most likely be the most sustainable. The developed tool would assist decision-makers in other cities to assess intersection projects that correspond to their regional goals

Recent Microextraction Techniques for Determination and Chemical Speciation of Selenium

Research designed to improve extraction has led to the development of microextraction techniques (ME), which involve simple, low cost, and effective preconcentrationof analytes in various matrices. This review is concerned with the principles and theoretical background of ME, as well as the development of applications for selenium analysis during the period from 2008 to 2016. Among all ME, dispersive liquid-liquid microextraction was found to be most favorable for selenium. On the other hand, atomic absorption spectrometry was the most frequently used instrumentation. Selenium ME have rarely been coupled to spectrophotometry and X-ray spectrophotometry methods, and there is no published application of ME with electrochemical techniques. We strongly support the idea of using a double preconcentration process, which consists of microextraction prior to preconcentration, followed by selenium determination using cathodic stripping voltammetry (ME-CSV). More attention should focus on the development of accurate, precise, and green methods for selenium analysis