Engineering Cellular Communication Systems for Synthetic Biology

Synthetic biology is an emerging interdisciplinary field of biology that aims to system-atically design artificial biological systems. As synthetic biologists seek increasingly complex control over cellular processes to achieve robust and predictable systems. A new frontier in synthetic biology is engineering synthetic microbial consortia. This ap-proach employs the concept of division of labor, instead of introducing large genetic cir-cuitry to homogenous cell populations. In this approach, different cell types are assigned to execute a portion of the overall circuit. Each cell type communicates with their co-worker subpopulations to complete the circuit. The main advantage of this strategy is the reduced metabolic burden on each cell type. Thus, leading to more reliable and stable overall performance. In this work, to simplify cellular communication between the mem-bers of the consortium, we used the simple architecture of quorum sensing machinery. We constructed a toolbox that contains promoter, receptor and quorum sensing signal synthase genes along with fluorescent reporters. Using this toolbox, we constructed dif-ferent cell types that can be used in synthetic consortia forming various communication topologies. We characterized the constructed cell types individually and in co-cultures

Highly conjugated visible and near-infrared light photoinitiating systems for radical and cationic polymerizations

In this communication, we report highly conjugated thiophenes having [1,2,5]-thiadiazolo and [1,2,5]-selenadiazolo [3,4-f]-benzo [1,2,3] triazole in conjunction with diphenyliodonium hexafluorophosphate salt(DPI) as new visible and near-infrared light (NIR) photoinitiator systems for free radical (FRP) and cationicpolymerizations (CP). The postulated mechanism is based on the electron transfer reactions between the excitedconjugated molecule and DPI ions. The radicals and Bronsted acid formed this way initiate FRP and CP ofappropriate monomers such as methylacrylate (MA), methyl methacrylate (MMA), triethylene glycol dimethacrylate(TEGDMA) and cyclohexene oxide (CHO), isobutyl vinylether (IBVE) respectively. The possibility of insitu hybrid polymerization is also demonstrated using bifunctional monomer glycidyl methacrylate (GMA)

Synthesis and study of novel multifunctional cyclodextrin‐deferasirox hybrids

Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal‐selective chelation therapy. Deferasirox, 4‐[(3Z,5E)‐3,5‐bis(6‐oxo‐1‐cyclohexa‐2,4‐dienylidene)‐1,2,4‐triazolidin‐1‐yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions. Cyclodextrins are cyclic glucose units that are extensively used in the pharmaceutical industry as formulating agents as well as for encapsulating hydrophobic molecules such as in the treatment of Niemann Pick C or for hypervitaminosis. We have conjugated deferasirox, via an amide coupling reaction, to both 6A‐amino‐6A‐deoxy‐β‐cyclodextrin and 3A‐amino‐3A‐deoxy‐2A(S),3A(R)‐β‐cyclodextrin, at the upper and lower rim respectively creating hybrid molecules with dual properties, capable of both metal chelation and cholesterol encapsulation. Our findings emphasize the importance of the conjugation of β‐cyclodextrin with deferasirox to significantly improve the biological properties and reduce the cytotoxicity of this drug

Acetyl-leucine slows disease progression in lysosomal storage disorders

Acetyl-DL-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies acetyl-DL-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-DL-leucine and its enantiomers acetyl-L-leucine and acetyl-D-leucine in symptomatic Npc1-/- mice and observed improvement in ataxia with both individual enantiomers and acetyl-DL-leucine. When acetyl-DL-leucine and acetyl-L-leucine were administered pre-symptomatically to Npc1-/- mice, both treatments delayed disease progression and extended life span, whereas acetyl-D-leucine did not. These data are consistent with acetyl-L-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the L enantiomer in Npc1-/- mice. When the standard of care drug miglustat and acetyl-DL-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-DL-leucine treatment, rates of disease progression were slowed, with stabilisation or improvement in multiple neurological domains. A beneficial effect of acetyl-DL-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-L-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders

CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice

Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C$_{16:0}$ ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity

Faktoring uygulamalarının Türkiye’de kobilerin gelişimi üzerine etkileri

FAKTORİNG UYGULAMALARININ TÜRKİYE’DE KOBİLERİN GELİŞİMİ ÜZERİNE ETKİLERİ KOBİ’ler ülkelerin ekonomik kalkınmasında önemli rol üstlenmektedirler. KOBİ’lerin büyümesini engelleyen en önemli sorunlardan birisi finansal kaynaklara sınırlı erişimdir. Finansal problemler sonucunda KOBİ’lerin düşük olan rekabet gücü daha da zayıflamaktadır. Faktoring, KOBİ’lerin finansal sorunlarını çözmek için son zamanlarda tercih edilen yöntemlerden birisidir. Faktoring, firmaların mal veya hizmet satışı sonucunda elde ettikleri alacakların, temlik altına alınması işlemidir. Bu sayede firmalar ileride gerçekleşecek alacaklarını vadesinden önce elde etme imkanına kavuşmaktadır. Faktoring faizleri günümüzde banka kredilerinin iki katı durumundadır. Faktoringin dezavantajlarından biri firmaların yüksek faize maruz kalmak zorunda olmasıdır. Çalışma kapsamında faktoring uygulamalarının KOBİ’ler üzerindeki etkileri araştırılmıştır. Bu kapsamda, 390 KOBİ’nin katıldığı bir anket online ortamda oluşturulmuş ve faktoring kullanım istatistikleri incelenmiştir. Araştırma sonucunda ortaya çıkan sonuçlar KOBİ’ler ve sektör yöneticileri için sonuçlar sunmaktadır. -------------------- THE EFFECT OF FACTORING APPLICATIONS ON THE DEVELOPMENT OF SMEs IN TURKEY SMEs play an important role in the economic development of countries. One of the most important problems preventing SMEs from developing is limited access to financial resources. As a result of financial problems, the low competitiveness of SMEs is further weakened. Factoring has recently been one of the preferred methods for solving the financial problems of SMEs. Factoring is the process of transferring the receivables of the firms as a result of the sale of goods or services. In this way, companies have the opportunity to obtain their future receivables before maturity. As a more advantageous financing method, factoring enables the companies to convert some of its receivables into cash when compared to high interest bank loans. In this study, the effects of factoring applications on SMEs were investigated. In this context, a survey of 390 SMEs was created online and factoring usage statistics were analysed. The results of the research provide results for SMEs and sector executives

Faktoring uygulamalarının Türkiye’de kobilerin gelişimi üzerine etkileri

FAKTORİNG UYGULAMALARININ TÜRKİYE’DE KOBİLERİN GELİŞİMİ ÜZERİNE ETKİLERİKOBİ’ler ülkelerin ekonomik kalkınmasında önemli rol üstlenmektedirler. KOBİ’lerin büyümesini engelleyen en önemli sorunlardan birisi finansal kaynaklara sınırlı erişimdir. Finansal problemler sonucunda KOBİ’lerin düşük olan rekabet gücü daha da zayıflamaktadır. Faktoring, KOBİ’lerin finansal sorunlarını çözmek için son zamanlarda tercih edilen yöntemlerden birisidir. Faktoring, firmaların mal veya hizmet satışı sonucunda elde ettikleri alacakların, temlik altına alınması işlemidir. Bu sayede firmalar ileride gerçekleşecek alacaklarını vadesinden önce elde etme imkanına kavuşmaktadır. Faktoring faizleri günümüzde banka kredilerinin iki katı durumundadır. Faktoringin dezavantajlarından biri firmaların yüksek faize maruz kalmak zorunda olmasıdır. Çalışma kapsamında faktoring uygulamalarının KOBİ’ler üzerindeki etkileri araştırılmıştır. Bu kapsamda, 390 KOBİ’nin katıldığı bir anket online ortamda oluşturulmuş ve faktoring kullanım istatistikleri incelenmiştir. Araştırma sonucunda ortaya çıkan sonuçlar KOBİ’ler ve sektör yöneticileri için sonuçlar sunmaktadır.--------------------THE EFFECT OF FACTORING APPLICATIONS ON THE DEVELOPMENT OF SMEs IN TURKEYSMEs play an important role in the economic development of countries. One of the most important problems preventing SMEs from developing is limited access to financial resources. As a result of financial problems, the low competitiveness of SMEs is further weakened. Factoring has recently been one of the preferred methods for solving the financial problems of SMEs. Factoring is the process of transferring the receivables of the firms as a result of the sale of goods or services. In this way, companies have the opportunity to obtain their future receivables before maturity. As a more advantageous financing method, factoring enables the companies to convert some of its receivables into cash when compared to high interest bank loans. In this study, the effects of factoring applications on SMEs were investigated. In this context, a survey of 390 SMEs was created online and factoring usage statistics were analysed. The results of the research provide results for SMEs and sector executives

Pharmacological approaches for lysosomal storage diseases

NiemannâPick disease Type C (NPC) is a neurodegenerative lysosomal storage disorder that arises from defects in lysosomal proteins involved in intracellular lipid trafficking. Cellular pathology leads to clinical neurological manifestations, including ataxia. The anti-vertigo drug N-Acetyl-DL-Leucine (ADLL) has been found to be beneficial for treating vestibular anomalies and cerebellar ataxia. ADLL has also been found to ameliorate cerebellar symptoms in 12 NPC patients treated with this drug in observational clinical studies. However, the mode of action of this drug requires further study. This project has investigated the effects of ADLL and other leucine amino acid derivatives in in vitro and in vivo models of NPC. We found that ADLL, and its individual enantiomers acetyl-l-leucine (ALL) and acetyl-d-leucine (ADL) improve symptoms of ataxia in a mouse model of NPC (Npc1-/-). However, when ADLL and ALL were administered pre-symptomatically to Npc1-/- mice they were neuroprotective and ADLL synergised with the standard of care drug, miglustat. Altered energy metabolism was implicated as the mechanism of action in Npc1-/- mice. A neuroprotective effect of ADLL was also demonstrated in a mouse model of GM2 gangliosidosis (Sandhoff disease mouse) with differential effect on metabolism. We also explored the efficacy of natural, non-acetylated forms of leucine including DL-leucine, L-leucine, D-leucine and an ethyl ester form of l-leucine and found that N-acetylation of either L-leucine or D-leucine led to increased efficacy in vivo in Npc1-/- mice. Interestingly, esterification provided neuroprotective effect to L-leucine, which was not seen with N-acetylation. NPC1 null CHO cells responded to all leucine isomers in terms of correction of mitochondrial volume and mitochondrial reactive oxygen species defects characteristic of NPC but also reduced lysosomal volume and lipid storage. Finally, we performed discovery proteomics to identify ALL interacting proteins in NPC1 cells and found 9 potential interactors that could represent new therapeutic targets. </p

Biomarkers of acute kidney injury and their role in clinical patient management

Acute kidney injury (AKI) is a common public health problem and has a significant impact on cardiovascular disease, mortality and increased hospital costs. Also, AKI can progress to chronic kidney disease (CKD). Therefore, early diagnosis is very important for AKI. Serum creatinine (SCr) is a well-known biomarker in the diagnosis of AKI. However, changes in SCr levels are insufficient in early diagnosis so, new biomarkers are needed. Because of that, the search for biomarkers for the early detection of AKI is an ongoing process. In recent years, early diagnosis, prognostic and predictive biomarkers have been discovered to replace or support SCr in the diagnosis of AKI. New biomarkers can help early diagnosis and effective management of AKI. Since there are many biomarkers, when and under which condition these biomarkers should be used cause confusion. In this review, we aimed to construct and ease to use classification of these AKI biomarkers and summarize the current literature. We have divided the biomarkers into two main categories: renal and non-renal origin. Then, we have classified the biomarkers of renal origin as glomerular, tubular and unknown renal site. We have also described the clinical use of these biomarkers for diagnosis and prognosis