The novel benzimidazole derivative BRP-7 inhibits leukotriene biosynthesis in vitro and in vivo by targeting 5-lipoxygenase-activating protein (FLAP).

BACKGROUND AND PURPOSE: Leukotrienes (LTs) are inflammatory mediators produced via the 5-lipoxygenase (5-LOX) pathway and are linked to diverse disorders, including asthma, allergic rhinitis and cardiovascular diseases. We recently identified the benzimidazole derivative BRP-7 as chemotype for anti-LT agents by virtual screening targeting 5-LOX-activating protein (FLAP). Here, we aimed to reveal the in vitro and in vivo pharmacology of BRP-7 as an inhibitor of LT biosynthesis. EXPERIMENTAL APPROACH: We analysed LT formation and performed mechanistic studies in human neutrophils and monocytes, in human whole blood (HWB) and in cell-free assays. The effectiveness of BRP-7 in vivo was evaluated in rat carrageenan-induced pleurisy and mouse zymosan-induced peritonitis. KEY RESULTS: BRP-7 potently suppressed LT formation in neutrophils and monocytes and this was accompanied by impaired 5-LOX co-localization with FLAP. Neither the cellular viability nor the activity of 5-LOX in cell-free assays was affected by BRP-7, indicating that a functional FLAP is needed for BRP-7 to inhibit LTs, and FLAP bound to BRP-7 linked to a solid matrix. Compared with the FLAP inhibitor MK-886, BRP-7 did not significantly inhibit COX-1 or microsomal prostaglandin E2 synthase-1, implying the selectivity of BRP-7 for FLAP. Finally, BRP-7 was effective in HWB and impaired inflammation in vivo, in rat pleurisy and mouse peritonitis, along with reducing LT levels. CONCLUSIONS AND IMPLICATIONS: BRP-7 potently suppresses LT biosynthesis by interacting with FLAP and exhibits anti-inflammatory effectiveness in vivo, with promising potential for further development

Linking epileptic phenotypes and neural extracellular matrix remodeling signatures in mouse models of epilepsy

Epilepsies are multifaceted neurological disorders characterized by abnormal brain activity, e.g. caused by imbalanced synaptic excitation and inhibition. The neural extracellular matrix (ECM) is dynamically modulated by physiological and pathophysiological activity and critically involved in controlling the brain's excitability. We used different epilepsy models, i.e. mice lacking the presynaptic scaffolding protein Bassoon at excitatory, inhibitory or all synapse types as genetic models for rapidly generalizing early-onset epilepsy, and intra-hippocampal kainate injection, a model for acquired temporal lobe epilepsy, to study the relationship between epileptic seizures and ECM composition. Electroencephalogram recordings revealed Bassoon deletion at excitatory or inhibitory synapses having diverse effects on epilepsy-related phenotypes. While constitutive Bsn mutants and to a lesser extent GABAergic neuron-specific knockouts (BsnDlx5/6cKO) displayed severe epilepsy with more and stronger seizures than kainate-injected animals, mutants lacking Bassoon solely in excitatory forebrain neurons (BsnEmx1cKO) showed only mild impairments. By semiquantitative immunoblotting and immunohistochemistry we show model-specific patterns of neural ECM remodeling, and we also demonstrate significant upregulation of the ECM receptor CD44 in null and BsnDlx5/6cKO mutants. ECM-associated WFA-binding chondroitin sulfates were strongly augmented in seizure models. Strikingly, Brevican, Neurocan, Aggrecan and link proteins Hapln1 and Hapln4 levels reliably predicted seizure properties across models, suggesting a link between ECM state and epileptic phenotype

Comparison of various phenotypic methods in detection of extended-spectrum beta-lactamases

Genişlemiş spektrumlu beta-laktamaz (GSBL) enzimi bazı Gram negatif bakterilerde sefalosporinlere, geniş spektrumlu penisilinlere ve monobaktamlara karşı direnç sorununa neden olmaktadır. Tedavi başarısını arttırmak için bu enzimlerin varlığı çeşitli yöntemlerle araştırılmaktadır. Çalışmamızda Düzce Üniversitesi Araştırma ve Uygulama Hastanesi Klinik Mikrobiyoloji Laboratuvarında üretilen Escherichia coli ve Klebsiella suşlarında GSBL saptanmasında kullanılan fenotipik testlerin [disk difüzyon tarama testi (DDTT), çift disk sinerji testi (ÇDST), E-test] etkinliği karşılaştırılmıştır. Klebsiella spp. ve K.pneumoniae suşlarında, tarama testi ve E-test benzer sonuçlar vermiş iken ÇDST diğer testlerin saptayabildiği GSBL’lerin hepsini saptayamamıştır. Bu testin etkinliği, E-test ile karşılaştırıldığında Klebsiella spp. için p=0.002 ve K.pneumoniae için p=0.041 düzeyinde ve tarama testi ile karşılaştırıldığında Klebsiella spp. için p=0.001 ve K.pneumoniae için p=0.041 düzeyinde, anlamlı olarak düşük bulunmuştur. E.coli suşlarında ise farklı olarak; ÇDST ile E-test sonuçları benzer iken (p=0.187), tarama testi ÇDST’ne göre anlamlı derecede daha etkin bulunmuştur (p<0.05). Sonuç olarak, Gram negatif bakteri kaynaklı infeksiyonların tedavisinde antibiyotiklerin hastaya uygulanıp uygulanmaması konusunda karar verirken ÇDST’nin tek başına kullanılmaması gerektiği, DDTT yapılmasının çok önemli olduğu ve E-test ile doğrulanması gerektiği düşünülmüştür.Extended-spectrum beta-lactamase (ESBL) enzymes of some gram-negative bacteria cause resistance to cephalosporins, broad-spectrum penicillins and monobactams. The presence of these enzymes must be investigated by various methods for the success of the treatment. In this study, the effectiveness of various phenotypic methods for detection of extended-spectrum beta-lactamases [disk diffusion screening test (DDTT), double-disk synergy test (DDST), and E-test] in Escherichia coli and Klebsiella strains isolated in Clinical Microbiology Laboratory of Duzce University, Medical Faculty were compared. Similar results were obtained with screening test and E-test, whereas DDST was found insufficient in detecting ESBL&amp;#8217;s that were determined by other methods. The effectivity of this test was found significantly low, when compared with E-test, with results for Klebsiella spp. (p=0.002) and K.pneumoniae (p=0.041) and screening test, with results for the Klebsiella spp. (p=0.001) and K.pneumoniae (p=0.041). For E.coli strains, results obtained with DDST and E-test (p=0.187) were found similar but, screening test was significantly effective than DDST (p&lt;0.05). As a result, for the decision of the choice of antibiotics in the treatment of Gram-negative bacterial infections, DDST should not be used alone. Use of DDTT is very important and E-test should be used for verification

Performative Work: Bridging Performativity and Institutional Theory in the Responsible Investment Field

Callon’s performativity thesis has illuminated how economic theories and calculative devices shape markets, but has been challenged for its neglect of the organizational, institutional and political context. Our seven-year qualitative study of a large financial data company found that the company’s initial attempt to change the responsible investment field through a performative approach failed because of the constraints posed by field practices and organizational norms on the design of the calculative device. However, the company was subsequently able to put in place another form of performativity by attending to the normative and regulative associations of the device. We theorize this route to performativity by proposing the concept of performative work, which designates the necessary institutional work to enable translation and the subsequent adoption of the device. We conclude by considering the implications of performative work for the performativity and the institutional work literatures

Proteases as Insecticidal Agents

Proteases from a variety of sources (viruses, bacteria, fungi, plants, and insects) have toxicity towards insects. Some of these insecticidal proteases evolved as venom components, herbivore resistance factors, or microbial pathogenicity factors, while other proteases play roles in insect development or digestion, but exert an insecticidal effect when over-expressed from genetically engineered plants or microbial pathogens. Many of these proteases are cysteine proteases, although insect-toxic metalloproteases and serine proteases have also been examined. The sites of protease toxic activity range from the insect midgut to the hemocoel (body cavity) to the cuticle. This review discusses these insecticidal proteases along with their evaluation and use as potential pesticides

Cosmology with the Laser Interferometer Space Antenna

The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational wave observations by LISA to probe the universe

Globalleşme sürecindeki dünyada, Türkiye mobilya tasarım anlayışındaki değişmeler

ÖZET Batıdan esen değişim rüzgarları çerçevesinde şekil değiştiren “ Türk Mobilyası” eskiye olan bağını koparır; kültürel, bölgesel üretim teknikleri, kullanılan teknoloji ve çağın gereklilikleri ile seri üretim sistemleriyle üretilen global tasarımlara dönüşür. Global tasarımların yaratılması ve bu ürünlerin seri üretim sistemleriyle makinelere uyumlu olarak üretilebilirliği, ürüne tasarımı yanında üretim teknikleri ile ilgili global bir yön çizer. Ürün tasarımının, dünyanın globalleşme süreci içerisinde değişimi, küresel mobilyaya dönüşüm süreci, Türkiye’de mobilya üretimi paralelinde ele alınmıştır. Üretimin atölye tarzı üretimden fabrikasyon üretime dönüşüm süreci, ürünün tasarım ve üretim sistemlerinde ciddi değişikler meydana getirir. Üretim sistemlerindeki değişmeler, ürünün tasarım süreci ile doğrudan ilgili olması nedeniyle ele alınmıştır. Eski tarzda ustanın el işçiliği ile, müşterinin talepleriyle şekillenen, standart bir kalite ve fiyat kriteri, tasarım kaygısı olmadan üretilen ürün; endüstrileşme döneminde birçok konuda standartlaşmış; kalite, ürün için zorunluluk olmuştur. Seri üretim sisteminde üretilen ürün, ölçü ve model standardizasyonu yanında ; ambalaj , montaj kılavuzu gibi standartlara da kavuşmuştur. Globalleşme sürecinde Türk Mobilya’sı , üretici sayısının artması nedeniyle yoğun bir rekabet ortamında pazardan pay alabilme mücadelesi vermektedir. Yurt içi ve yurt dışı pazarlarda alıcı bulma zorunluluğu içerisinde olan üretici, ürünü küresel çizgilere uygun, özgün tasarımlı, kalite açısından problemsiz üretmek zorundadır. Bu zorunluluk ile yaratılan tasarımlar; gerek pazar şartları, gerekse kullanılan üretim teknik ve teknolojileri gereği kültürel izlerden soyutlanmış, küresel, yalın çizgilere bürünmüş; toplum eğilimlerinin büyük üretici modellerine yönelmesi, atölyeleri de bu tarz modelleri üretmeye yöneltmiştir. Sonuç itibari ile el emeği göz nuru ile üretilen, oyma, kakma sanatlarının uygulandığı, geleneksel yöntemlerle usta – çırak tarzında üretilen “Türk Mobilyası”, global renk ve tarzı ile, ileri teknoloji kullanılan, bir tasarım ürünü olan yeni “Türk Mobilya” sına dönüşmüştür.SUMMARY Because of the wind of changes stammed from the West, Turkish furniture breaks off its bonds with the old style. Cultural, regional production techniques have been left, contemporary techniques and style are chosen by using mass production systems. Globally determined designs and to produce these designs in accordence with mass production systems and high-tech machine standards, evolve Turkish furniture to a universal standard and characteristics. The process of transformation of workshop style production into factory production give rise to serious changes in production systems and product itself. The concepts of “quality control”, “ergonomy”, “standardization”, division of labor”, “high tech machines in the production process”, “optimization”, and etc. began to be important in this process. In the new style production, product is modular and ready to assemble in a safe and flat package. While it requires master’s ability and has no standart quality, price and size in the old style production, in the new style the product has a standardized quality sizes and prices. In the new system of mass production, product reaches the standards of safe packages, assembly prospects in addition to standard sizes and models. In the process of industrialization, Turkish furniture sector has a harsh competition because the amount of producers arises and of course products also. The producers have to produce qualified, originally designed products. On the other hand; in todays globalized world, producers aiming to reach world markets, present their products with the designs fit to global lines, and understandings. So; these conditions stemmed from the market needs and universal production techniques and technological standarts, result with new designs and models, isolated from cultural effects and similar, familiar and universally common modern designs. The tendency of customers turns towards modern designs and this change forces small workshops to copy these kind of models in order to survive. Consequently; Turkish furniture, produced with the hand work and traditional understanding by using the “repousso work” (kakma) techniques evolve into modern design products with its global style and colour

Globalleşme sürecindeki dünyada,Türkiye mobilya tasarım anlayışındaki değişmeler

Batıdan esen değişim rüzgarları çerçevesinde şekil değiştiren “ Türk Mobilyası” eskiye olan bağını koparır; kültürel, bölgesel üretim teknikleri, kullanılan teknoloji ve çağın gereklilikleri ile seri üretim sistemleriyle üretilen global tasarımlara dönüşür. Global tasarımların yaratılması ve bu ürünlerin seri üretim sistemleriyle makinelere uyumlu olarak üretilebilirliği, ürüne tasarımı yanında üretim teknikleri ile ilgili global bir yön çizer. Ürün tasarımının, dünyanın globalleşme süreci içerisinde değişimi, küresel mobilyaya dönüşüm süreci, Türkiye’de mobilya üretimi paralelinde ele alınmıştır. Üretimin atölye tarzı üretimden fabrikasyon üretime dönüşüm süreci, ürünün tasarım ve üretim sistemlerinde ciddi değişikler meydana getirir. Üretim sistemlerindeki değişmeler, ürünün tasarım süreci ile doğrudan ilgili olması nedeniyle ele alınmıştır. Eski tarzda ustanın el işçiliği ile, müşterinin talepleriyle şekillenen, standart bir kalite ve fiyat kriteri, tasarım kaygısı olmadan üretilen ürün; endüstrileşme döneminde birçok konuda standartlaşmış; kalite, ürün için zorunluluk olmuştur. Seri üretim sisteminde üretilen ürün, ölçü ve model standardizasyonu yanında ; ambalaj , montaj kılavuzu gibi standartlara da kavuşmuştur. Globalleşme sürecinde Türk Mobilya’sı , üretici sayısının artması nedeniyle yoğun bir rekabet ortamında pazardan pay alabilme mücadelesi vermektedir. Yurt içi ve yurt dışı pazarlarda alıcı bulma zorunluluğu içerisinde olan üretici, ürünü küresel çizgilere uygun, özgün tasarımlı, kalite açısından problemsiz üretmek zorundadır. Bu zorunluluk ile yaratılan tasarımlar; gerek pazar şartları, gerekse kullanılan üretim teknik ve teknolojileri gereği kültürel izlerden soyutlanmış, küresel, yalın çizgilere bürünmüş; toplum eğilimlerinin büyük üretici modellerine yönelmesi, atölyeleri de bu tarz modelleri üretmeye yöneltmiştir. Sonuç itibari ile el emeği göz nuru ile üretilen, oyma, kakma sanatlarının uygulandığı, geleneksel yöntemlerle usta – çırak tarzında üretilen “Türk Mobilyası”, global renk ve tarzı ile, ileri teknoloji kullanılan, bir tasarım ürünü olan yeni “Türk Mobilya” sına dönüşmüştür. SUMMARY Because of the wind of changes stammed from the West, Turkish furniture breaks off its bonds with the old style. Cultural, regional production techniques have been left, contemporary techniques and style are chosen by using mass production systems. Globally determined designs and to produce these designs in accordence with mass production systems and high-tech machine standards, evolve Turkish furniture to a universal standard and characteristics. The process of transformation of workshop style production into factory production give rise to serious changes in production systems and product itself. The concepts of “quality control”, “ergonomy”, “standardization”, division of labor”, “high tech machines in the production process”, “optimization”, and etc. began to be important in this process. In the new style production, product is modular and ready to assemble in a safe and flat package. While it requires master’s ability and has no standart quality, price and size in the old style production, in the new style the product has a standardized quality sizes and prices. In the new system of mass production, product reaches the standards of safe packages, assembly prospects in addition to standard sizes and models. In the process of industrialization, Turkish furniture sector has a harsh competition because the amount of producers arises and of course products also. The producers have to produce qualified, originally designed products. On the other hand; in todays globalized world, producers aiming to reach world markets, present their products with the designs fit to global lines, and understandings. So; these conditions stemmed from the market needs and universal production techniques and technological standarts, result with new designs and models, isolated from cultural effects and similar, familiar and universally common modern designs. The tendency of customers turns towards modern designs and this change forces small workshops to copy these kind of models in order to survive. Consequently; Turkish furniture, produced with the hand work and traditional understanding by using the “repousso work” (kakma) techniques evolve into modern design products with its global style and colour