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 concept of an educational physical simulation tool for teaching energy consumption in buildings for enhancing public engagement

Buildings consume significant amount of energy for heating or air-conditioning in most countries. Therefore, educating the public and young generations to enhance their engagement and encourage them to reduce carbon emission and energy consumption in their daily life is becoming essential worldwide to drive continuous improvement towards more sustainable future. This paper presents an innovative educational tool to simulate energy performance and its use in educating university students and teaching school children about the subject. The paper outlines the developed educational tool and presents its benefits via two detailed case studies, with wide and diverse level of knowledge and learning outcomes. The educational technology includes a small-scale multi-layered model of buildings where insulation layers can be added to or removed from the building's envelop to influence energy performance. Qualitative and quantitative research has been conducted . The results show that the technology is capable of engaging the young generation and to help them to understand the thermal performance and energy efficiency of buildings

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

THE EFFICACY OF BIFOCAL RIGHT VENTRICULAR PACING IN CARDIAC RESYNCHRONIZATION THERAPY FOR THE TREATMENT OF HEART FAILURE

Background: It has been reported that bifocal pacing (BiFP) in the right ventricle (RV) may be an alternative to unsuccessful left ventricular (LV) lead implantation.Aim: This study seeks to assess the improvement in the clinical and hemodynamic parameters after long term BiFP in patients eligible for cardiac resynchronization therapy (CRT), in whom conventional biventricular (BiV) implantation was not feasible or failed.Methods: The three leads (right atrial appendage, RV apex and RV outflow tract) of a BiFP were implanted in 46 patients, among whom16 lost follow up within one month of BiFP implantation, so 30 patients (19 male/11 female) were enrolled in the study with the mean follow up period of 8.7 (± 6.7) months. All patients had heart failure refractory to medical therapy, New York Heart Association (NYHA) functional class of II, III and IV, ejection fraction (EF) ≤ 35 %, left bundle branch block (LBBB) with QRS duration ≥ 130 milliseconds and functional mitral regurgitation. The parameters (QRS duration, NYHA class, EF, and cardiomegaly) were evaluated before and 1, 3, 6, 12 and 24 months after BiFP implantation. A six minute walk test (6MWT) was performed on 7 patients, before and after implantation.Results: The results showed significant improvement in whole parameters, after both acute and long term BiFP. The improvement increased during subsequent follow up.Conclusions: The study concluded that BiFP is a feasible type of CRT in patients with refractory HF and can be used as an alternative to biventricular pacing when LV lead implantation is infeasible

Up-modulation of membrane lipid composition and functionality by seed priming under salinity in the Hasawi rice variety

In this study, we investigated the role of seed priming in mitigating depressive effects of high salinity on membrane lipid composition and membrane functionality in seedlings of Hasawi rice cultivar (Oryza sativa L). Results indicated that seed pre-treatment with hydropriming (HP) and priming with 50 mM NaCl solution enhanced germination performance and early seedling growth under salinity condition. Priming treatments were found effective in maintaining membrane stability and integrity by increasing total membrane lipid content and reducing membrane damage. Concentrations of monogalactosyldiacylglycerol, digalactosyldiacylglycerol and phosphatidylglycerol were greatly increased when seeds were primed. Priming also increased phosphatidylcholine PC (lipid forming lamellar structure) and maintained phosphatidylethanolamine PE (non-bilayer-forming lipid) levels resulting in enhanced PC/PE ratio under salinity condition. Membrane unsaturation level was also increased, suggesting an improvement in membrane fluidity under salinity conditions. HP and NaCl-priming with 50 mM also induced increased contents of total phenolics, total soluble sugar and proline as compared to unprimed seedlings subjected to salinity. It is concluded that HP and priming with 50 mM NaCl solution can offer perspectives to improve germination and early growth of Hasawi rice under high salinity. This could be achieved through down-regulation of oxidative stress, accumulation of osmoprotectant compounds and improving cell membrane fluidity and integrity

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

Antimicrobial Natural Products

Although the first antibiotic, penicillin, was discovered in 1928 from a microbial natural source (a mould, Penicillium notatum), there is earlier evidence of using natural materials including moulds and herbs for the treatment of infections. Following the serendipitous discovery of penicillin by Alexander Fleming, there have been hundreds of antibiotics (natural, semisynthetic and synthetic) discovered for clinical uses. However, the pathogenic organisms have developed resistances to existing antibiotics though various mechanisms. Such antibiotic resistance or antimicrobial resistance (AMR) is a critical problem of today’s healthcare system urging the development of new antibiotics. This chapter has primarily focused into antimicrobial compounds developed through natural routes that are currently available as antibiotics for clinical uses and/or are at various developmental stages within the drug development pipeline for potential treatment of minor and life threatening infections. The chapter also provides an overview on the catastrophic problem of antimicrobial resistance, its causes, how it spreads as well as modes of developing antimicrobial resistance (AMR)

Implementasi strategi marketing mix (7p) pada produk Mudharabah (MDA) berjangka di BMT UGT Sidogiri Indonesia Cabang Malang Kota

مستخلص البحث: تنمية الإقتصادية في المجال المالية كلما تتقدم وكثيرة المطلوبة للمجتمع. منها بيت المال والتمويل، هي المؤسسة التعاونية، الصيانة الأدخار والقرض لمنتسبها الذين يراق عقد المضاربة والإستثمارات الخالي من الربا. وكان بيت المال والتمويل كحلاً للمجتمع ليكون خاليًا من الفائدة المصرفية ويمكنه الاستثمارات في الحفاظ على قيمة المواد أو النقود حتى لا يتعرض الإنخفاض. تبحث هذه الدراسة عن تطبيق خليط التسويق على المضاربة المنتجات الآجلة في بيت المال والتمويل سيداكيري ايندونيسيا. أهداف من البحث لمعرفة إستراتيجية خليط التسويق على المضاربة المنتجات الآجلة في بيت المال والتمويل سيداكيري ايندونيسيا. المنهجية من هذا البحث يعني وصفية نوعية. أما مصادر من هذه البيانات المستخدمة يعني البيانات الأساسية من نتيجة المقابلة التي تم الحصول عليها مباشرة من بيت المال والتمويل سيداكيري ايندونيسية. وتؤيد بالبيانات الثانوية يعني مراجعة النظرية كمادة داعمة في تحليل تطبيق خليط التسويق على المضاربة المنتجات الآجلة في بيت المال والتمويل سيداكيري اندونيسيا. تحليل البيانات مع الحد من البيانات. تحليل هذه البيانات بالحد من البيانات. الأساس النظرية المستخدمة هي نظرية خليط التسويق والتسويق الإسلامي والمضاربة. بناء على البيانات التي تم الحصول عليها، فإن الاستنتاج هو أن نظرية تطبيق إستراتيجية خليط التسويق، التي يتم استخدامها في فقط وهي (المكان ، والترقية ، والأشخاص) الأماكن الاستراتيجية ، والترقيات مع نظام التقاط الكرة ، والمعاملات مع العقد و المبادئ الإسلامية. هذه تجعل السهلة على العملاء للتعامل ABSTRACT: Economic development in the financial services has increasingly advanced and interested the society. Including BMT (Baitul Mal Wattamwil). BMT is the saving and loan institution for every member who prioritize mudharabah and usury-free contracts. This BMT institution becomes a solution for the society that want to be freed from the bank interest and to invest in maintaining the money that can be avoided from the cutbacks. This research elaborates about the implementation of Marketing Mix (7p) at the Mudharabah feature products (MDA) in BMT UGT Sidogiri Indonesia. The aim of this research is to know the strategy of Marketing Mix at Mudharabah future product (MDA) in BMT UGT Sidogiri Indonesia. Qualitative descriptive is a method that used in this research. The data source that used in this research is the primer data from the interview of members’ BMT UGT Sidogiri Indonesia supported by the secondary data that is literature review to analyze the implementation of Marketing Mix (7p) at Mudharabah future product (MDA) in BMT UGT Sidogiri Indonesia. The data is analyzed by data reduction. The theoretical basic that used in this research is Marketing Mix theory, Islamic Marketing theory, and Mudharabah. Based on the result of this research, it can be concluded that the strategy that used by BMT UGT is 3p (place, promotions, and people). Through the strategies place, the promotions by visiting the customers, and transactions with the syari’ah contracts and principles can make the transaction becomes easier. ABSTRAK: Perkembangan ekonomi di bidang jasa keuangan semakin maju dan banyak diminati masyarakat, salah satunya adalah BMT (Baitul Maal Wattamwil). BMT merupakan lembaga koperasi penyedia jasa simpan pinjam bagi anggotanya yang lebih mengedepankan akad Mudharabah dan investasi bebas riba. Keberadaan lembaga BMT ini menjadi solusi bagi masyarakat untuk dapat terbebas dari bunga bank dan dapat berinvestasi mempertahankan nilai suatu barang atau uang sehingga tidak mengalami penyusutan. Penelitian ini mengkaji tentang Implementasi Marketing mix (7P) Pada Produk Mudharabah (MDA) berjangka di BMT UGT Sidogiri Indonesia. Tujuan Penelitian ini adalah untuk mengetahui Strategi Marketing Mix (7P) Pada produk Mudharabah (MDA) berjangka di BMT UGT Sidogiri Indonesia. Metode yang digunakan dalam penelitian ini adalah metode kualitatif-deskriptif, Adapun sumber data yang digunakan yaitu data primer dari hasil wawancara yang diperoleh langsung dari Pihak BMT UGT Sidogiri Indonesia. Didukung dengan data sekunder berupa kajian pustaka sebagai bahan penunjang dalam menganalisis Implementasi Marketing mix (7P) Pada Produk Mudharabah (MDA) berjangka di BMT UGT Sidogiri Indonesia. Data dianalisa dengan reduksi data. Landasan teori yang digunakan yaitu teori Marketing mix, marketing Islami, dan mudharabah. Berdasarkan data yang didapat, maka dihasilkan kesimpulan bahwa dari teori Strategi Marketing Mix (7P), yang dipakai di BMT hanya (3P) yakni (place,promotion, dan people) tempat yang strategis, promosi dengan sistem jemput bola, dan bertransaksi dengan akad dan pirinsip syariah. Dengan 3p ini lebih memudahkan nasabah untuk bertransaksi