The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism

Notch signaling regulates many aspects of metazoan development and tissue renewal. Accordingly, the misregulation or loss of Notch signaling underlies a wide range of human disorders, from developmental syndromes to adult-onset diseases and cancer. Notch signaling is remarkably robust in most tissues even though each Notch molecule is irreversibly activated by proteolysis and signals only once without amplification by secondary messenger cascades. In this Review, we highlight recent studies in Notch signaling that reveal new molecular details about the regulation of ligand-mediated receptor activation, receptor proteolysis, and target selection

Performance Analysis Of Pde Based Parallel Algorithms On Different Computer Architectures

Tez (Yüksek Lisans) -- İstanbul Teknik Üniversitesi, Bilişim Enstitüsü, 2009Thesis (M.Sc.) -- İstanbul Technical University, Institute of Informatics, 2009Son yıllarda dağıtık algoritmaların farklı platformlarda kullanılabilmesi platform ve uygulama bağımsız performans analizi uygulamaları ihtiyacını arttırmıştır. Farklı donanımları ve haberleşme metodlarını destekleyen uygulamalar kullanıcılara donanım ve yazılımdan bağımsız ortak bir zemin hazırladıkları için kolaylık sağlamaktadır. Kısmi fark denklemleri hesaplamalı bilim ve mühendisliğin bir çok alanında kullanılmaktadır (ısı, dalga yayılımı gibi). Bu denklemlerin sayısal çözümü yinelemeli yöntemler kullanılarak yapılmaktadır. Problemin boyutu ve hata değerine göre çözüme ulaşmak için gereken yineleme sayısı ve buna bağlı olarak süresi değişmektedir. Kısmi fark denklemelerinin tek işlemcili bilgisayarlardaki çözümü uzun sürdüğü ve yüksek boyutlarda hafızaları yetersiz kaldığı için paralelleştirilerek birden fazla bilgisayarın işlemcisi ve hafızası kullanılarak çözülmektedir. Tezimde eliptik kısmi fark denklemlerini Gauss-Seidel ve Successive Over-Relaxation (SOR) metodlarını kullanarak çözen paralel algoritmalar kullanılmıştır. Performans analizi ve eniyilemesi kabaca üç adımdan oluşmaktadır; ölçüm, sonuçların analizi, darboğazların tespit edilip yazılımda iyileştirme yapılması. Ölçüm aşamasında programın koşarken ürettiği performans bilgisi toplanır, toplanan bu veriler görselleştirme araçları ile anlaşılır hale getirilerek yorumlanır. Yorumlama aşamasında tespit edilen dar boğazlar belirlenir ve giderilme yöntemleri araştırılır. Gerekli iyileştirmeler yapılarak program yeniden analiz edilir. Bu aşamaların her birinde farklı uygulamalar kullanılabilir fakat tez çalışmamda uygulamaları tek çatı altında toplayan TAU kullanılmıştır. TAU (Tuning and Analysis Utilities) farklı donanımları ve işletim sistemlerini destekleyerek farklı paralelleştirme metodlarını analiz edebilmektedir. Açık kaynak kodlu olan TAU diğer açık kaynak kodlu uygulamalar ile uyumlu olup birçok seviyede bütünleşme sağlanmıştır. Bu tez çalışmasında, iki farklı platformda aynı uygulamanın performans analizi yapılarak platform farkının getirdiği farklılıklar incelenmektedir. Performans analizinde bir algoritmanın eniyilemesini yapmak için genel bir kural olmadığından her algoritma her platformda incelenerek gerekli değişiklikler yapılmalıdır. Bu bağlamda kullandığım PDE algoritmasının her iki sistemdeki analizi sonucu elde edilen bilgiler yorumlanmıştır.In last two decades, use of parallel algorithms on different architectures increased the need of architecture and application independent performance analysis tools. Tools that support different communication methods and hardware prepare a common ground regardless of equipments provided. Partial differential equations (PDE) are used in several applications (such as propagation of heat, wave) in computational science and engineering. These equations can be solved using iterative numerical methods. Problem size and error tolerance effects iteration count and computation time to solve equation. PDE computations take long time using single processor computers with sequential algorithms, and if data size gets bigger single processors memory may be insufficient. Thus, PDE?s are solved using parallel algorithms on multiple processors. In this thesis, elliptic partial differential equation is solved using Gauss-Seidel and Successive Over-Relaxation (SOR) methods parallel algorithms. Performance analysis and optimization basically has three steps; evaluation, analysis of gathered information, defining and optimizing bottlenecks. In evaluation, performance information is gathered while program runs, then observations are made on gathered information by using visualization tools. Bottlenecks are defined and optimization techniques are researched. Necessary improvements are made to analyze the program again. Different applications in each of these stages can be used but in this thesis TAU is used, which collects these applications under one roof. TAU (Tuning and Analysis Utilities) supports many hardware, operating systems and parallelization methods. TAU is an open source application and collaborates with other open source applications at different levels. In this thesis, differences based on performance analysis of an algorithm in different two architectures are investigated. In performance analysis and optimization there is no golden rule to speed up algorithm. Each algorithm must be analyzed on that specific architecture. In this context, the performance analysis of a PDE algorithm on two architectures has been interpreted.Yüksek LisansM.Sc

Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin

γ-secretase is a multiprotein intramembrane-cleaving protease with a growing list of protein substrates including the Notch receptors and the amyloid precursor protein. The four components of γ-secretase complex - presenilin (PS), nicastrin (NCT), Pen2, and Aph1 - are all thought to be essential for activity. The catalytic domain resides within PS proteins; NCT has been suggested to be critical for substrate recognition; the contributions of Pen2 and Aph1 remain unclear. The role of NCT has been challenged recently by the observation that a critical residue (E332) in NCT, thought to be essential for γ-secretase activity, is instead involved in complex maturation. Here we report that NCT is dispensable for γ-secretase activity. NCT-independent γ-secretase activity can be detected in two independent NCT-deficient MEF lines, and blocked by the γ-secretase inhibitors DAPT and L-685,458. This catalytic activity requires prior ectodomain shedding of the substrate, and can cleave ligand-activated endogenous Notch receptors, indicating presence at the plasma membrane. siRNA knockdown experiments demonstrated that NCT-independent γ-secretase activity requires the presence of PS1, Pen2 and Aph1a but can tolerate knockdown of PS2 or Aph1b. We conclude that a PS1/Pen2/Aph1a trimeric complex is an active enzyme, displaying similar biochemical properties to those of γ-secretase and roughly 50% of its activity when normalized to PS1 NTF levels. This PS1/Pen2/Aph1a complex, however, is highly unstable. Thus, NCT acts to stabilize γ-secretase, but is not required for substrate recognition

Rapid identification of homologous recombinants and determination of gene copy number with reference/query pyrosequencing (RQPS)

Manipulating the mouse genome is a widespread technology with important applications in many biological fields ranging from cancer research to developmental biology. Likewise, correlations between copy number variations (CNVs) and human diseases are emerging. We have developed the reference-query pyrosequencing (RQPS) method, which is based on quantitative pyrosequencing and uniquely designed probes containing single nucleotide variations (SNVs), to offer a simple and affordable genotyping solution capable of identifying homologous recombinants independent of the homology arm size, determining the micro-amplification status of endogenous human loci, and quantifying virus/transgene copy number in experimental or commercial species. In addition, we also present a simple pyrosequencing-based protocol that could be used for the enrichment of homologous recombinant embryonic stem (ES) cells

Skin-Derived TSLP Triggers Progression from Epidermal-Barrier Defects to Asthma

A skin-derived cytokine with high systemic availability provides a mechanistic explanation for atopic march and highlights a potential therapeutic target for preventing the development of asthma among people with atopic dermatitis

Forensic prevention of crimes in criminal investigation techniques

The purpose of the article is to determine the place and role of forensic prevention in the structure of methods of investigation of certain types of crimes. The subject of research is the concept and features of forensic prevention. The research methodology includes general scientific and special methods of legal science: historical and legal method; structural and functional method; system and structural method, logical and semantic analysis method, formal and legal analysis method. Research results. The issues related to the characteristics of forensic crime prevention are considered. Different points of view on the role, significance and structure of forensic crime prevention are summarized and the conclusion that this legal institution is an integral part of forensic science is made. Practical implementation. The main methods and means of forensic prevention of criminal offenses are determined. Value / originality. It is concluded that the prevention of crimes should be aimed at neutralizing and eliminating the causes that contribute to their commission, and the pre-trial investigation authorities should play the key role in this process

Tasks and powers of the National police of Ukraine in ensuring information security of the state

The purpose of the article is to examine the role of the National Police of Ukraine in ensuring the information security of Ukraine. The subject of the study: The subject of the study is the competence of the National Police of Ukraine in ensuring the information security of Ukraine. Methodology: Dialectical method, epistemological method, analytical method, formal and legal method, normative and dogmatic method, the methods of legal modeling and forecasting were used in the research. The results of the study: The definition of “information security” and “cyber security” is provided. The main factors that negatively affect the information space in Ukraine, as well as current threats to Ukraine’s national security in the information sphere are identified. Practical implications: It is established that the number of crimes in the information sphere is growing every year. In this regard, the task of the National Police is to combat crimes and other offenses in this area, as well as to protect relevant rights and freedoms of citizens, society and the State. Value/originality: The tasks and powers in the area of information security protection of the National Police in general and the Department of Cyber Security, in particular, are defined

Sistemik sklerozda tam kan sayımı parametreleri ve nötrofil/lenfosit, monosit/lenfosit, eozinofil/lenfosit oranlarının hastalık bulguları, aktivitesi ve şiddeti ile ilişkisi

Sistemik skleroz, nadir görülen ancak mortalitesi yüksek olan bir hastalıktır. Hastalığın prognozunu akciğer, böbrek ve kalp gibi iç organ tutulumları belirlemektedir. Bu nedenle organ tutulumu gelişme potansiyeli olan hastaların erken belirlenmesi, tedaviye erken başlanarak sağkalımın arttırılması açısından önemlidir. Çeşitli otoimmun hastalıklarda NLR, MLR ve ELR değerlerinin hastalık aktivitesi ile ilişkisi ve hastalık prognozunu öngörebilmek açısından yararlı olduğu önceki çalışmalarda gösterilmiş olup çalışmamızda hemogram parametreleri ve NLR, MLR ve ELR değerlerinin sistemik skleroz hastalarının hastalık aktivitesi ve şiddeti ile ilişkisini ve hastalık prognozunu değerlendirmede yararlı belirteçler olup olamayacağını araştırdık. Bu amaçla Trakya Üniversitesi Tıp Fakültesi Romatoloji Bilim Dalı’nda takipli olan 50 hastanın hasta dosyaları incelenerek ve yüz yüze hasta görüşmeleri yapılarak hastaların demografik bilgileri, klinik özellikleri, laboratuvar ve radyolojik bulguları ile ilgili bilgiler edinildi. Hastalar diffüz ve limitli skleroderma olmak üzere iki alt tipe ayrıldı. Çalışmanın sonucunda diffüz sklerodermalı hastaların nötrofil ve lökosit sayısı limitli sklerodermalılara göre daha yüksek, Hb ise daha düşük saptandı. Dijital pitting skarı bulunan hastalarda bulunmayanlara göre nötrofil sayısı ve MLR’nin daha yüksek, monosit sayısının daha düşük olduğu görüldü. Modifiye Rodnan cilt skoru ile Hb arasında negatif ilişki saptandı. Pulmoner hipertansiyonu bulunan hastalarda nötrofil, NLR, MLR ve RDW bulunmayanlara göre daha yüksek, lenfosit ise daha düşük saptandı. Gastrointestinal sistem tutulumu olan hastalarda Hb daha düşük görüldü. EScSG hastalık aktivitesi puanı ile lenfosit sayısı ters ilişkili görüldü. Medsger hastalık şiddeti puanı ile NLR, RDW ve MPV arasında pozitif, Hb ve lenfosit arasında negatif ilişki görüldü. Çoklu regresyon analizlerinde NLR, MLR ve ELR değerlerinin hastalığın organ tutulumları, hastalık aktivite ve şiddeti ile bağımsız ilişkisi saptanmadı. Yalnızca lenfosit sayısı ile Medsger hastalık şiddeti arasında anlamlıya yakın bağımsız ilişki olduğu görüldü.Systemic sclerosis is a rare disease with high mortality. Internal organ involvements such as lung, kidney and heart determine the prognosis of the disease. Therefore, early identification of patients with the potential to develop organ involvement is important in terms of increasing survival by initiating treatment early. In the previous studies it has been shown that there exists a relationship between NLR, MLR, ELR values and disease activity in various autoimmune diseases. In our study we investigated that if hemogram parameters and NLR, MLR, ELR are useful markers to evaluate the disease activity and severity of systemic sclerosis patients and prognosis of disease For this purpose patients files of 50 patients who are followed by Trakya University Medical Faculty Rheumatology Department were investigated and the patients were interviewed face to face. In this way the informations about the patients’ demographic and clinical features, findings of laboratory and radiological were obtained. The patients were separated into limited and diffuse scleroderma subtypes. As a result of the study, neutrophil and leukocyte counts of patients with diffuse scleroderma were higher than those with limited scleroderma and Hb was lower. Neutrophil count and MLR were higher and monocyte count was lower in patients with digital pitting scar than those without. A negative relationship was detected between the modified Rodnan skin score and Hb. Neutrophils, NLR, MLR and RDW were found higher in patients with pulmonary hypertension than those without, and lymphocytes were lower. Hb was lower in patients with gastrointestinal system involvement. EScSG disease activity score and lymphocyte count were negatively correlated. A positive correlation was found between Medsger disease severity score and NLR, RDW and MPV, and negative correlation between Hb and lymphocyte was found. No independent relationships between NLR, MLR, ELR values and organ involvement, activity and severity were identifiable except the lymphocyte count and Medsger score

E-Learning mit Moodle

Статья посвящена актуальной проблематике - оптимизации подготовки студентов вуза с использованием электронной образовательной платформы MOODLE. The article is devoted to a very topical problem of a more efficient training of students by means of e-learning environment MOODLE

Randomized trial of calcipotriol combined with 5-fluorouracil for skin cancer precursor immunotherapy

BACKGROUND. Actinic keratosis is a precursor to cutaneous squamous cell carcinoma. Long treatment durations and severe side effects have limited the efficacy of current actinic keratosis treatments. Thymic stromal lymphopoietin (TSLP) is an epithelium-derived cytokine that induces a robust antitumor immunity in barrier-defective skin. Here, we investigated the efficacy of calcipotriol, a topical TSLP inducer, in combination with 5-fluorouracil (5-FU) as an immunotherapy for actinic keratosis. METHODS. The mechanism of calcipotriol action against skin carcinogenesis was examined in genetically engineered mouse models. The efficacy and safety of 0.005% calcipotriol ointment combined with 5% 5-FU cream were compared with Vaseline plus 5-FU for the field treatment of actinic keratosis in a randomized, double-blind clinical trial involving 131 participants. The assigned treatment was self-applied to the entirety of the qualified anatomical sites (face, scalp, and upper extremities) twice daily for 4 consecutive days. The percentage of reduction in the number of actinic keratoses (primary outcome), local skin reactions, and immune activation parameters were assessed. RESULTS. Calcipotriol suppressed skin cancer development in mice in a TSLP-dependent manner. Four-day application of calcipotriol plus 5-FU versus Vaseline plus 5-FU led to an 87.8% versus 26.3% mean reduction in the number of actinic keratoses in participants (P < 0.0001). Importantly, calcipotriol plus 5-FU treatment induced TSLP, HLA class II, and natural killer cell group 2D (NKG2D) ligand expression in the lesional keratinocytes associated with a marked CD4(+) T cell infiltration, which peaked on days 10–11 after treatment, without pain, crusting, or ulceration. CONCLUSION. Our findings demonstrate the synergistic effects of calcipotriol and 5-FU treatment in optimally activating a CD4(+) T cell–mediated immunity against actinic keratoses and, potentially, cancers of the skin and other organs. TRIAL REGISTRATION. ClinicalTrials.gov NCT02019355. FUNDING. Not applicable (investigator-initiated clinical trial)