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Supplementary Figures S1-2,4, describe cell viability curves of tested cell lines. Figure S3 and S5 show bioinformatic data for resistance upregulated gene sets (S3) and cisplatin-taxane comparison analysis(S5). Figure S6 shows ECAR and OCR experiments. Figure S7 is a heatmap of combination indices of cisplatin with JQ1. Figure S8 shows apoptosis rates of cell lines. S9-12 describe cell viability dynamics of SOX9 KOs.

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers.Significance:Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.

Epithelial tissues such as lung and skin are exposed to the environment and therefore particularly vulnerable to damage during injury or infection. Rapid repair is therefore essential to restore function and organ homeostasis. Dysregulated epithelial tissue repair occurs in several human disease states, yet how individual cell types communicate and interact to coordinate tissue regeneration is incompletely understood. Here, we show that pannexin 1 (Panx1), a cell membrane channel activated by caspases in dying cells, drives efficient epithelial regeneration after tissue injury by regulating injury-induced epithelial proliferation. Lung airway epithelial injury promotes the Panx1-dependent release of factors including ATP, from dying epithelial cells, which regulates macrophage phenotype after injury. This process, in turn, induces a reparative response in tissue macrophages that includes the induction of the soluble mitogen amphiregulin, which promotes injury-induced epithelial proliferation. Analysis of regenerating lung epithelium identified Panx1-dependent induction of Nras and Bcas2 , both of which positively promoted epithelial proliferation and tissue regeneration in vivo. We also established that this role of Panx1 in boosting epithelial repair after injury is conserved between mouse lung and zebrafish tailfin. These data identify a Panx1-mediated communication circuit between epithelial cells and macrophages as a key step in promoting epithelial regeneration after injury.

Our bodies turn over billions of cells daily via apoptosis and are in turn cleared by phagocytes via the process of "efferocytosis." Defects in efferocytosis are now linked to various inflammatory diseases. Here, we designed a strategy to boost efferocytosis, denoted "chimeric receptor for efferocytosis" (CHEF). We fused a specific signaling domain within the cytoplasmic adapter protein ELMO1 to the extracellular phosphatidylserine recognition domains of the efferocytic receptors BAI1 or TIM4, generating BELMO and TELMO, respectively. CHEF-expressing phagocytes display a striking increase in efferocytosis. In mouse models of inflammation, BELMO expression attenuates colitis, hepatotoxicity, and nephrotoxicity. In mechanistic studies, BELMO increases ER-resident enzymes and chaperones to overcome protein-folding-associated toxicity, which was further validated in a model of ER-stress-induced renal ischemia-reperfusion injury. Finally, TELMO introduction after onset of kidney injury significantly reduced fibrosis. Collectively, these data advance a concept of chimeric efferocytic receptors to boost efferocytosis and dampen inflammation.

Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Uncovering mechanisms responsible for the heterogeneous clinical features of this disease is an essential step toward developing improved and more specific therapeutic approaches. Here, we sought to identify transcriptional regulators of aggressive PDAC growth through in vivo CRISPR screening of epigenetic and transcription factors in an orthotopic model. We identified the ISL LIM homeobox 2 (ISL2) gene as a tumor suppressor whose depletion enhances the proliferation of human PDAC cells in vitro and in vivo and cooperates with activated KRAS to initiate PDAC in a murine model. Conversely, the upregulation of ISL2 expression through CRISPR-mediated locus-specific epigenetic editing results in reduced cell proliferation. Importantly, ISL2 is epigenetically silenced through DNA methylation in ~60% of PDAC tumors, which correlates with poor patient outcome. Functional studies showed that ISL2 loss rewires metabolic gene expression, and consequently potentiates oxidative phosphorylation while reducing glycolysis. This metabolic shift creates selective vulnerability to small molecule inhibitors of mitochondrial respiration and fatty acid oxidation. Collectively, these findings reveal ISL2 as a novel tumor suppressor whose inactivation drives metabolic reprogramming in an aggressive PDAC subset and point to potential therapeutic vulnerabilities in these tumors.

Renin cells are crucial for survival - they control fluid-electrolyte and blood pressure homeostasis, vascular development, regeneration, and oxygen delivery to tissues. During embryonic development, renin cells are progenitors for multiple cell types that retain the memory of the renin phenotype. When there is a threat to survival, those descendants are transformed and reenact the renin phenotype to restore homeostasis. We tested the hypothesis that the molecular memory of the renin phenotype resides in unique regions and states of these cells' chromatin. Using renin cells at various stages of stimulation, we identified regions in the genome where the chromatin is open for transcription, mapped histone modifications characteristic of active enhancers such as H3K27ac, and tracked deposition of transcriptional activators such as Med1, whose deletion results in ablation of renin expression and low blood pressure. Using the rank ordering of super-enhancers, epigenetic rewriting, and enhancer deletion analysis, we found that renin cells harbor a unique set of super-enhancers that determine their identity. The most prominent renin super-enhancer may act as a chromatin sensor of signals that convey the physiologic status of the organism, and is responsible for the transformation of renin cell descendants to the renin phenotype, a fundamental process to ensure homeostasis.

Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types., Predicting the response to chemotherapy is a major goal of cancer research. Here the authors use CRISPR knockout screens in pancreatic ductal adenocarcinoma cells to identify deletions synergistic with MEK inhibitors.

Diabetes mellitus is a metabolic disease that causes increased morbidity and mortality in developed and developing countries. With recent advancements in technology, alternative treatment methods have begun to be investigated in the world. This study aims to evaluate the effect of pulsed magnetic field (PMF) on vascular complications and contractile activities of aortic rings along with Kir6.1 and Kir6.2 subunit expressions of ATP-sensitive potassium channels (KATP) in aortas of controlled-diabetic and non-controlled diabetic rats. Controlled-diabetic and non-controlled diabetic adult male Wistar rats were exposed to PMF for a period of 6 weeks according to the PMF application protocol (1 h/day; intensity: 1.5 mT; consecutive frequency: 1, 10, 20, and 40 Hz). After PMF exposure, body weight and blood glucose levels were measured. Then, thoracic aorta tissue was extracted for relaxation–contraction and Kir6.1 and Kir6.2 expression experiments. Blood plasma glucose levels, body weight, and aortic ring contraction percentage decreased in controlled-diabetic rats but increased in non-controlled diabetic rats. PMF therapy repressed Kir6.1 mRNA expression in non-controlled diabetic rats but not in controlled diabetic rats. Conversely, Kir6.2 mRNA expressions were repressed both in controlled diabetic and non-controlled diabetic rats by PMF. Our findings suggest that the positive therapeutic effects of PMF may act through (KATP) subunits and may frequently occur in insulin-free conditions. Bioelectromagnetics. 2018;9999:XX–XX. © 2018 Wiley Periodicals, Inc.

Russians, aiming to establish diplomaticties with the Ottoman Empire and to build up their trade in the Black Searegion and Ottoman territories towards the end of the 15th century,has gained for the first time the right to trade in the Black Sea and theMediterranean with their own vessels with the Treaty of Küçük Kaynarca of 1774.In later years, Russians has gained commercial benefits continuously byOttoman-Russian Trade Agreement of 1783, Treaty of Adrianople of 1829, Treatyof Hünkar İskelesi of 1833, Ottoman-Russian Trade Agreement of 1846 and 1862.Signing similar trade agreements withother European states, Ottoman Empire had integrated to an internationalcommercial system in the second half of the 19th century. Especiallywith the promotion of foreign companies Ottoman statesmen had started thebranding process in 1871 with the regulation named “Eşya-yıTicariyyeye ve Alamet-i Farikalara Dair Nizamname” in order to prevent imitation,counterfeiting and fraud. In accordance with this new regulation, companiesstarted to register their brands to Alamet-I Farika Registers and theseregisters were kept records till 1931. In this era, Russian companies had alsoregistered their brands in the sectors of raw materials, rolling paper (forcigarettes), confection, cosmetics and shoe.Inthis work, firstly the background of Turco-Russian commercial relations will beinvestigated and afterwards Russian brands which were registered in the Ottomanand Republican eras will be emphasized. Also a sectoral analysis will becarried on and with the statistical data, a new perspective of Turco-Russiancommercial relations will be shown., XV. yüzyılın sonlarına doğru Osmanlı Devleti ile diplomatik ilişkiler kurarak Karadeniz ve Osmanlı ülkesindeki ticareti geliştirmeyi hedefleyen Ruslar, 1774 Küçük Kaynarca Antlaşması ile ilk defa kendi gemileri ile Karadeniz ve Akdeniz’de ticaret yapabilme hakkına sahip olmuşlardır. Ruslar ilerleyen yıllarda Osmanlı-Rus Ticaret Antlaşması (1783), Edirne Antlaşması (1829), Hünkâr İskelesi Antlaşması (1833), Osmanlı-Rus Ticaret Antlaşması (1846) ve Osmanlı-Rus Ticaret Antlaşması (1862) ile devamlı olarak kendi lehlerine ticarî imtiyazlar elde etmişlerdir. Rusya ile imzaladığı antlaşmaları İngiltere ve Fransa gibi diğer Avrupa ülkeleri ile de imzalayan Osmanlı Devleti, XIX. yüzyılın ikinci yarısından itibaren uluslararası ticarî sisteme entegre olmuştur. Özellikle yabancı şirketlerin zorlamasıyla Osmanlı devlet adamları, ticarî ürünler ile ilgili başta taklitçilik olmak üzere sahtecilik, dolandırıcılık gibi hususların önüne geçmek için 1871 tarihli “Eşya-yı Ticariyyeye ve Alamet-i Farikalara Dair Nizamname”si ile markalaşma sürecini başlatmışlardır. Bu nizamname çerçevesinde şirketler markalarını Alamet-i Farika Defterleri’ne kaydettirmişler ve bu defterler 1931 yılına kadar tutulmuştur. Bu dönem içerisinde Rus şirketleri de petrol, gaz, benzin, sigara kâğıdı, iplik, yumak, dikiş makinaları, kozmetik ve ayakkabı gibi farklı sektörlerde ürünlerini tescil ettirmişlerdir. Bu çalışmada öncelikle Türk-Rus ticarî ilişkilerinin arka planı incelenecek, daha sonra Osmanlı ve Cumhuriyet dönemlerinde marka tescili yaptırılan Rus markaları üzerinde durulacaktır. Ayrıca bu markaların dağılım gösterdikleri sektörler üzerinde analizleri yapılarak, elde edilen istatistiki verilerle, Türk-Rus ticarî ilişkilerine farklı bir perspektiften bakılacaktır.

Chemoresistance is driven by unique regulatory networks in the genome that are distinct from those necessary for cancer development. Here, we investigate the contribution of enhancer elements to cisplatin resistance in ovarian cancers. Epigenome profiling of multiple cellular models of chemoresistance identified unique sets of distal enhancers, super-enhancers (SE), and their gene targets that coordinate and maintain the transcriptional program of the platinum-resistant state in ovarian cancer. Pharmacologic inhibition of distal enhancers through small-molecule epigenetic inhibitors suppressed the expression of their target genes and restored cisplatin sensitivity in vitro and in vivo. In addition to known drivers of chemoresistance, our findings identified SOX9 as a critical SE-regulated transcription factor that plays a critical role in acquiring and maintaining the chemoresistant state in ovarian cancer. The approach and findings presented here suggest that integrative analysis of epigenome and transcriptional programs could identify targetable key drivers of chemoresistance in cancers. Significance: Integrative genome-wide epigenomic and transcriptomic analyses of platinum-sensitive and -resistant ovarian lines identify key distal regulatory regions and associated master regulator transcription factors that can be targeted by small-molecule epigenetic inhibitors.

The revolution which took part in Nevesin, Herzegovina in 1875 spread out to almost all parts of Bosnia and Herzegovina within a short period because of the inanition of the Ottoman Government. While the revolution was spreading out, hesitating from the entrance of Serbia and Montenegro to the revolution and refraining from the anxiety of the major European powers, the Ottoman Government, had not used power in order to suppress the revolution and this policy end up with the internalization of the trouble. Spanish ambassadors in Istanbul, Wien, Berlin and St. Petersburg, by means of their reports from the beginning of the revolution, informed their respective government about the progress of the rebellion of Herzegovina. In this study, it is aimed to present how these ambassadors describe and comment on the incidents about the rebellion in their reports. In this framework, 32 ambassador reports which have been determined in the Archive of Spanish Ministry of Foreign Affairs will be investigated.

MicroRNAs are short non-coding RNAs that provide global regulation of gene expression at the post-transcriptional level. Such regulation has been found to play a role in stress-induced epigenetic responses in the brain. The norepinephrine transporter (NET) and glucocorticoid receptors are closely related to the homeostatic integration and regulation after stress. Our previous studies demonstrated that NET mRNA and protein levels in rats are regulated by chronic stress and by administration of corticosterone, which is mediated through glucocorticoid receptors. Whether miRNAs are intermediaries in the regulation of these proteins remains to be elucidated. This study was undertaken to determine possible regulatory effects of miRNAs on the expression of NET and glucocorticoid receptors in the noradrenergic neuronal cell line. Using computational target prediction, we identified several candidate miRNAs potentially targeting NET and glucocorticoid receptors. Western blot results showed that over-expression of miR-181a and miR-29b significantly repressed protein levels of NET, which is accompanied by a reduced [3H] norepinephrine uptake, and glucocorticoid receptors in PC12 cells. Luciferase reporter assays verified that both miR-181a and miR-29b bind the 3′UTR of mRNA of NET and glucocorticoid receptors. Furthermore, exposure of PC12 cells to corticosterone markedly reduced the endogenous levels of miR-29b, which was not reversed by the application of glucocorticoid receptor antagonist mifepristone. These observations indicate that miR-181a and miR-29b can function as the negative regulators of NET and glucocorticoid receptor translation in vitro. This regulatory effect may be related to stress-induced up-regulation of the noradrenergic phenotype, a phenomenon observed in stress models and depressive patients. This study demonstrated that miR-29b and miR-181a, two short non-coding RNAs that provide global regulation of gene expression, markedly repressed protein levels of norepinephrine (NE) transporter and glucocorticoid receptor (GR), as well as NE uptake by binding the 3′UTR of their mRNAs in PC12 cells. Also, exposure of cells to corticosterone significantly reduced miR-29b levels through a GR-independent way.

Human cells are exposed to exogenous insults and continuous production of different metabolites. These insults and unwanted metabolic products might interfere with the stability of genomic DNA. Recently, many studies have demonstrated that different psychiatric disorders show substantially high levels of oxidative DNA damage in the brain accompanied with morphological and functional alterations. It reveals that damaged genomic DNA may contribute to the pathophysiology of these mental illnesses. In this article, we review the roles of oxidative damage and reduced antioxidant ability in some vastly studied psychiatric disorders and emphasize the inclusion of treatment options involving DNA repair. In addition, while most currently used antidepressants are based on the manipulation of the neurotransmitter regulation in managing different mental abnormalities, they are able to prevent or reverse neurotoxin-induced DNA damage. Therefore, it may be plausible to target on genomic DNA alterations for psychiatric therapies, which is of pivotal importance for future antipsychiatric drug development.

Osmanlı Devletiile İspanya’da 19. yüzyılın ikinci yarısından itibaren eşzamanlı olarak liberalgelişmeler yaşanmaya başlamıştır. Osmanlı Devleti’nde Sultan Abdülaziz’in hal’iile meşrutî monarşi düzenine geçiş başlamışken, İspanya’da da Kraliçe II.Isabel tahttan indirilmiş ve cumhuriyet rejimi denemesi yapılmıştır. İki ülkedede bu süreçler kısa sürmüş ve monarşiler liberal hareketlere karşı üstünlüksağlamışlardır. Bu süreçler içerisinde, İspanya, kendisiyle aynı türdengelişmelerin yaşandığı dostu Osmanlı Devleti’ndeki gelişmeleri yakından takipetmiştir. İspanyol basını da, Sultan Abdülaziz’in hal’inden itibaren süreciyakından takip etmiş ve İspanya halkını bu gelişmelerden haberdar etmiştir. Çalışmanıntemel kaynağı olarak kullanılan İspanyol gazetelerinde yayımlanan haberler,İspanya Milli Kütüphanesi ve İspanya Kültür ve Spor Bakanlığı bünyelerindekigazete arşivlerinden temin edilmiştir. Haberlerde sadece bilgiler verilmeklekalınmamış ve yapılan yorumlarla İspanyolların Osmanlı Devleti’ndeki gelişmelerleilgili düşünce ve yargıları da ortaya konulmuştur. Haberlerde ele alınan temelkonular, Sultan Abdülaziz’in hal’i, Sultan V. Murad’ın tahta çıkışı,faaliyetleri ve hastalığı ile Sultan II. Abdülhamid’in tahta çıkışıdır.Bunların yanı sıra, İspanyol basınında, özellikle Sultan Abdülaziz’in hal’indeönemli rol oynayan softalarla ilgili de ayrıntılı bilgilere rastlanmaktadır., From the second half of the 19th century, there hasbeen liberal movements in the Ottoman Empire and Spain simultaneously. In theOttoman part, after the demolition of Sultan Abdulaziz transition process tothe constitutional monarchy had started. In Spain, similar movements haddethroned the Queen Isabel II and republican regimen had tried for the firsttime. In both countries, these processes had ceased in a short time andmonarchs had outbalanced against liberal movements. Within these processes,Spain had closely tracked the similar developments in the allied Ottoman Empire.Even Spanish press, have closely followed up the liberal process in the OttomanEmpire after the demolition of Sultan Abdulaziz and kept Spaniards informedabout the improvements. News in the Spanish newspapers as the main source ofthis work, was collected from the newspaper archives of Spanish NationalLibrary and Spanish Ministry of Culturee and Sports. Newspapers not only gaveinformation about the movement in the Ottoman Empire but also transmittedthoughts and judgments of Spaniards by making comments in the news. Mainsubjects handled in the news were, demolition of Sultan Abdulaziz, accession ofSultan Murad V. to the throne, his activities and illness and accession of SultanAbdulhamid to the throne. Besides these, Spanish newspapers gave detailedinformation especially on “Softa”s which played an important role in thedemolition of Sultan Abdülaziz.

Cell-type specific gene expression programs are tightly linked to epigenetic modifications on DNA and histone proteins. Here, we used a novel CRISPR-based epigenome editing approach to control gene expression spatially and temporally. We show that targeting dCas9–p300 complex to distal non-regulatory genomic regions reprograms the chromatin state of these regions into enhancer-like elements. Notably, through controlling the spatial distance of these induced enhancers (i-Enhancer) to the promoter, the gene expression amplitude can be tightly regulated. To better control the temporal persistence of induced gene expression, we integrated the auxin-inducible degron technology with CRISPR tools. This approach allows rapid depletion of the dCas9-fused epigenome modifier complex from the target site and enables temporal control over gene expression regulation. Using this tool, we investigated the temporal persistence of a locally edited epigenetic mark and its functional consequences. The tools and approaches presented here will allow novel insights into the mechanism of epigenetic memory and gene regulation from distal regulatory sites. © 2018

Background The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. Results We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. Conclusions Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer. Electronic supplementary material The online version of this article (10.1186/s13059-018-1572-4) contains supplementary material, which is available to authorized users.

Purpose: The aim of this study was to show the effects of nicotine on expression levels of SOX2 and SOX4 genes, which are known for their master gene features, in human amniotic cell cultures. The study also aimed to show the effects of resveratrol, an antioxidant, on expression levels of these genes in human amniotic cell cultures, which are treated by nicotine.Material and Methods: Twenty patients were included in this study and for each patient; control, nicotine treated and nicotine + resveratrol treated cell culture groups are formed. The expression levels of SOX2 and SOX4 genes are examined in each group by using real time RT-PCR.Results: Change in expression levels of SOX2 and SOX4 genes in nicotine treated group were found to be statistically significant. Also, when groups treated with nicotine and nicotine + resveratrol were compared the difference was found to be statistically significant.Conclusions: Nicotine increased the expression levels of SOX2 and SOX4 genes by 60% in human amniotic cell cultures and resveratrol was found to be an important antioxidant that reduces the increased expression levels of SOX2 and SOX4 genes caused by nicotine treatment., Amaç: Sigarada bulunan en önemli toksik bileşenlerden bir tanesi nikotindir. Prenatal dönemde sigara dumanına maruz kalmak yeni doğanda bilişsel, duygusal, davranışsal problemler ve çocukluk kanserleriyle birlikte birçok farklı problem ortaya çıkarabilmektedir. Bu çalışmada, nikotinin master gen özelliklerine sahip genlerden olan SOX2 ve SOX4 genlerinin ekspresyon düzeylerine etkilerinin insan amniyotik hücre kültüründe araştırılması amaçlanmıştır. Ek olarak, bir antioksidan olan resveratrolün nikotin ile muamele edilmiş hücrelerde bu genlerin ekspresyon düzeylerine etkileri insan amniyotik hücre kültüründe incelenmiştir.Yöntem: Çalışmaya 20 hasta dahil edilmiştir ve her hasta için kontrol, nikotin ve nikotin+resveratrol hücre kültürü grupları oluşturulmuştur. SOX2 ve SOX4 genlerinin ekspresyon düzeyleri her grup için real time RT-PCR yöntemi kullanılarak tespit edilmiştir.Bulgular: SOX2 ve SOX4 genleri için nikotin ile muamele edilen grupta tespit edilen ekspresyon düzeylerindeki değişim istatistiksel olarak anlamlı bulunmuştur (p= 0.005 SOX2, p=0.000 SOX4). Ayrıca, nikotin ve nikotin+resveratrol ile muamele edilmiş gruplar karşılaştırıldığında sonuç istatistiksel olarak anlamlı bulunmuştur.Sonuç: Nikotin, insan amniyotik hücrelerinde SOX2 ve SOX4 genlerinin ekspresyon düzeylerini %60 oranında artırmıştır ve resveratrolün bu artmış ekspresyon düzeylerini düşüren önemli bir antioksidan olduğu tespit edilmiştir.

Objective In the present study, we aimed to compare the amount of epicardial adipose tissue in subjects with and without xanthelasma. Subjects and Methods Fifty-two subjects with xanthelasma and 52 age- and gender-matched control subjects were enrolled in this study. Epicardial adipose tissue was assessed by measuring epicardial fat thickness (EFT) with echocardiography. Participants were dichotomized according to median EFT, which was 4 mm. The group with EFT >4 mm was defined as the supramedian group. Body mass index (BMI) was calculated by weight (kilograms) divided by height (meters) squared. Conditional logistic regression analysis was performed to find independent factors associated with supramedian EFT (>4 mm). Results Subjects with xanthelasma had higher BMI (31.2 ± 5.6 vs. 28.6 ± 5.7, p = 0.01) and higher levels of total cholesterol (216 ± 54 vs. 181 ± 42 mg/dl, p < 0.001), LDL cholesterol (142 ± 45 vs. 115 ± 36 mg/dl, p = 0.003) and triglycerides (median, 154 vs. 101 mg/dl, p = 0.01) than control subjects. EFT was significantly higher in subjects with xanthelasma than in controls (5.04 ± 2.02 vs. 3.81 ± 2.03 mm, p = 0.002). In the conditional logistic regression analysis, the presence of xanthelasma (OR, 3.55; 95% CI, 1.43-8.78, p = 0.006) and lower HDL cholesterol level (OR, 0.96; 95% CI, 0.92-0.99, p = 0.023) were independently associated with supramedian EFT. Conclusion The amount of epicardial adipose tissue found in subjects with xanthelasma was higher than in subjects without xanthelasma. In addition, the presence of xanthelasma was independently associated with supramedian EFT.

CRISPR-Cas9-induced DNA damage may have deleterious effects at high-copy-number genomic regions. Here, we use CRISPR base editors to knock out genes by changing single nucleotides to create stop codons. We show that the CRISPR-STOP method is an efficient and less deleterious alternative to wild-type Cas9 for gene-knockout studies. Early stop codons can be introduced in ∼17,000 human genes. CRISPR-STOP-mediated targeted screening demonstrates comparable efficiency to WT Cas9, which indicates the suitability of our approach for genome-wide functional screenings.

Diabetes mellitus is a metabolic disease that causes increased morbidity and mortality in developed and developing countries. With recent advancements in technology, alternative treatment methods have begun to be investigated in the world. This study aims to evaluate the effect of pulsed magnetic field (PMF) on vascular complications and contractile activities of aortic rings along with Kir6.1 and Kir6.2 subunit expressions of ATP-sensitive potassium channels (K

Methylation is a chemical reaction in biological systems for normal genome regulation and development. It is a well known type of epigenetic mechanism. Methylation which regulates gene expression via epigenetic events like gene activation, repression, and chromatin remodelling, consists of two methylation systems. One of these systems is DNA methylation whereas the other is protein (histone) methylation. These systems are associated with some fundamental abnormalities and diseases. This review highlights the role of methylation in normal genome function, how it can be arranged and which diseases it cause. Furthermore, the role of methylation in some diseases and its functions in epigenetic mechanism has been reviewed. [Archives Medical Review Journal 2012; 21(4.000): 274-282]

Corticotropin releasing factor (CRF) has been implicated to act as a neurotransmitter or modulator in central nervous activation during stress. In this study, we examined the regulatory effect of CRF on the expression and function of the norepinephrine transporter (NET) in vitro. SK-N-BE (2) M17 cells were exposed to different concentrations of CRF for different periods. Results showed that exposure of cells to CRF significantly increased mRNA and protein levels of NET in a concentration- and time-dependent manner. The CRF-induced increase in NET expression was mimicked by agonists of either CRF receptor 1 or 2. Furthermore, similar CRF treatments induced a parallel increase in the uptake of [(3) H] norepinephrine. Both increased expression and function of NET caused by CRF were abolished by simultaneous administration of CRF receptor antagonists, indicating a mediation by CRF receptors. However, there was no additive effect for the combination of both receptor antagonists. Chromatin immunoprecipitation assays confirm an increased acetylation of histone H3 on the NET promoter following treatment with CRF. Taken together, this study demonstrates that CRF up-regulates the expression and function of NET in vitro. This regulation is mediated through CRF receptors and an epigenetic mechanism related to histone acetylation may be involved. This CRF-induced regulation on NET expression and function may play a role in development of stress-related depression and anxiety. This study demonstrated that corticotropin release factor (CRF) up-regulated the expression and function of norepinephrine transporter (NET) in a concentration- and time-dependent manner, through activation of CRF receptors and possible histone acetylation in NET promoter. The results indicate that their interaction may play an important role in stress-related physiological and pathological status.

Hearing loss (HL) is the most common sensory disorder, affecting all age groups, ethnicities, and genders. Several genes responsible for hearing loss are related to ion recycling and homeostasis in the inner ear. Mutations in GJB2 gene, the gene encoding gap junction protein connexin26 (Cx26), are most common detected in patients with congenital, recessively inherited, nonsyndromic HL in humans. In order to investigate the molecular etiology of patients with congenital, recessively inherited, and nonsyndromic HL and healthy individuals as control in a family, they were included in this study. Thus, exons of GJB2 gene were amplified by polymerase chain reaction (PCR) and sequenced. In this family, V27I missense mutation and V27I + E114G compound heterozygosity were detected in the results of sequence analysis. The V27I mutation was found in patient with severe HL and healthy individuals. The V27I + E114G compound heterozygosity was detected only in deaf patients. Based on our data, V27I mutations could be considered as a polymorphism not leading to HL. Since V27I + E114G compound heterozygosity was found only in deaf patients, it could be considered as a contributor of HL severity.

İslamiyet’i kabul etmiş olan Türk devletleri, İslam hukukunun gerektirdiği şekilde, Müslüman ve Gayr-i Müslim unsurlara eşit bir şekilde davranarak, onlara, din ve vicdan hürriyeti içerisinde yaşama fırsatı tanımıştır. Selçuklu Devleti ile birlikte Anadolu’da başlayan Türk yönetimi de aynı şekilde İslam hukukunun gereklerini yerine getirerek âdil ve hoşgörülü bir yönetim sergilemiştir. Anadolu’da Türk yönetiminin tesisinden önce Bizans Devleti’nin baskısı ve zulmü ile karşı karşıya olan Gayr-i Müslim topluluklar, bu hoşgörü ortamında Türk yönetimini kabullenmiş ve yaşamlarını refah ve huzur içerisinde sürdürmüşlerdir. Osmanlıların yönetiminde Gayr-i Müslimlere karşı bu adalet anlayışı gelişerek devam etmiştir. Türk yönetiminde din değiştirmeye zorlanmayan, kendi ibadetlerini özgürce yapmalarına izin verilen Hıristiyanlardan bir kısmı, Türklerle aynı sosyal çevrede İslamiyet’i benimseyerek dinlerini değiştirdiler. Bu çalışma ile Türkiye Selçuklu ve Osmanlı devletlerinin adil ve hoşgörülü yönetimi, örnekleriyle incelenecektir.

Memelilerin bilimsel deneylerde kullanilmasinin mumkun oldugunca kisitlanmasi gerekliligi, biyomedikal calismalarin farkli pek cok alaninda hucre kulturlerinin gelistirilmesi ve kullanilmasina yol acmistir. Hucre kulturleri mikrobiyolojide ozellikle viruslerin uretilmesi ve tanimlanmasi, virus asilarinin uretimi amaciyla kullanilmaktadirlar. Yeni yuzyilda ise kanser arastirmalarinin hiz kazanmasi ile ozellikle kanser ilaclarinin gelistirilmesinde, etkilerinin saptanmasinda hucre kulturleri ozellikle

06.03.2018 tarihli ve 30352 sayılı Resmi Gazetede yayımlanan “Yükseköğretim Kanunu İle Bazı Kanun Ve Kanun Hükmünde Kararnamelerde Değişiklik Yapılması Hakkında Kanun” ile 18.06.2018 tarihli “Lisansüstü Tezlerin Elektronik Ortamda Toplanması, Düzenlenmesi ve Erişime Açılmasına İlişkin Yönerge” gereğince tam metin erişime açılmıştır. Osmanlı-Hollanda iliskileri Osmanlı Devleti dıs politikası üzerine yapılançalısmalarda üzerinde pek fazla durulmayan bir konudur. ki ülkenin sınırı olmadıgı vearalarında herhangi bir savas geçmedigi için bu konunun üzerine pek fazlagidilmemistir. Bu çalısma ile Osmanlı Devleti dıs politikasındaki bu açıgı bir nebzeolsun kapatmak ve 19. yüzyılın ikinci yarısında iki ülke arasındaki iliskilerin OsmanlıDevleti'ne etkilerini saptamak amaçlanmıstır.Çalısmanın ilk bölümünde Osmanlı Devleti ile Hollanda arasında diplomatik iliskilerinkurulma safhası ve 18. yüzyıla kadar iki ülke arasındaki iliskiler ana hatları ileverilmistir.kinci Bölümde Tanzimat dönemine kadar Osmanlı- Hollanda iliskilerinin gelisimiverilerek 19. yüzyılın ikinci yarısındaki iliskilerin seyrinin anlasılmasına katkıdabulunulmustur.Çalısmanın üçüncü ve son bölümünde ise Sultan Abdulmecid döneminden Sultan II.Abdulhamid döneminin sonuna kadarki Osmanlı-Hollanda iliskileri üzerindedurulmus, bu dönemdeki iliskilerin önemi vurgulanarak kronolojik bir yapı içerisindeolaylar anlatılmıstır. Bu olaylar içerisinde en önemli olaylar olarak gözüken LaheyKonferansı ve Hıfz-ı Sıhha Kongreleri ayrı bir baslık altında sunulmustur. Ayrıca yinebu dönemde ön plana çıkan Osmanlı Devleti'nin Hollanda büyükelçisi Yusuf MisakEfendi hakkında verilen bilgiler de ayrı bir baslık altında toplanmıstır. Çalısmanınüçüncü bölümünde Basbakanlık Osmanlı Arsivinde yapılan taramalar sonucu eldeedilen arsiv belgelerinden büyük ölçüde faydalanılmıstır. Bu çalısma ile Osmanlı dıspolitikasında Hollanda'nın yerinin anlasılması hedeflenmektedir.Anahtar kel imeler: Hollanda, Osmanlı Devleti Dıs Politikası, Osmanlı-Hollanda liskileri, Lahey Konferansı, Yusuf Misak Efendi Almost there are no studies at the subject of Ottoman foreign policy as Ottoman-Dutch Relations. Because of there are no borders between these to states and also thereare no wars, this subject didn?t examined deeply. With this study we wanted to exposethe relations of the relations of these to states and the effects of the relationship to theOttoman State at the time of Abdulhamid II.In the first chapter we studied on the establishment of the diplomatic relations betweenOttoman State and The Netherlands and the basic of the relations between the twocountries up to the 18th century.In the second chapter we studied on the progress of the relations between OttomanState and The Netherlands up to the Tanzimat Era to understand the relations in thesecond period of the 19th century.In the third and the last chapter we studied on the relations between Ottoman State andThe Netherlands from the period of Sultan Abdulmecid to the period of SultanAbdulhamid II, and while we were stressing the importance of the relations weexplained the events in a chronological structure. The most important events likeLahey Peace Conference and the Congresses of Health Care were given underseparated titles. And also we gave another important subject as a separated title aboutthe Dutch ambassador Hovsep Missakian in the Ottoman State at the same period. Atthe last chapter we mostly used the archival sources from Prime Ministry OttomanArchives. With this study we are expecting to make the importance of the relationsbetween Ottoman State and The Netherlands clear.Keywords: The Netherlands, Congress of Health Care, Ottoman-Dutch Relations,Lahey Peace Conference, Hovsep Missakian

06.03.2018 tarihli ve 30352 sayılı Resmi Gazetede yayımlanan “Yükseköğretim Kanunu İle Bazı Kanun Ve Kanun Hükmünde Kararnamelerde Değişiklik Yapılması Hakkında Kanun” ile 18.06.2018 tarihli “Lisansüstü Tezlerin Elektronik Ortamda Toplanması, Düzenlenmesi ve Erişime Açılmasına İlişkin Yönerge” gereğince tam metin erişime açılmıştır. Çerkesler Kafkasya'nın otokton halklarından biridirler. Tarih öncesi devirlerden beri Kafkasya'nın sakini olarak sürdürdükleri yaşamları Rus işgali ile sekteye uğramıştır. Çarlık Rusya'sı XIX. yüzyılın başından itibaren Kafkasya'yı işgal etmek için askeri faaliyetler yürütmüştür. Bu işgal yöntemlerine askeri mücadele ile karşılık veren Çerkeslerin direnişi 1859'da Şeyh Şamil'in Ruslarca esir alınması ile kırılmıştır. 1853 yılında yapılan Kırım Savaşı'nın sonuca bağlandığı Paris Antlaşmasını takip eden yıllarda Rusya'nın işgal yöntemleri sertleştiği gibi Kafkasya'dan yapılan göçler de hızlanmıştır. 1863 ve 1865 yılları arasında işgal edilen topraklarından sürgün edilen Çerkeslerin en yaygın yerleştikleri yer Osmanlı Devleti topraklarıdır. Osmanlı Devleti, Çerkesleri topraklarında kabul ederek yerleştirmiştir. Bu çalışma, Çerkes ülkesinin işgali, sürgün edilmeleri ve Osmanlı topraklarına yerleştirilmeleri süreçlerini Osmanlı gazetelerinden alınan veriler ışığında inceleyerek açıklığa kavuşturmayı amaçlamaktadır. Circassians are one of the autochthonous peoples of the caucasus. The calm life of the Circassians since prehstoric times has been interrupted with the Russians occupy. Tsarist Russia has carried out military activities for occupy the Caucasus since the beggining of the 19th century. The resistance of the Circassians who responded to these methods of occupation with military struggl, was broken in 1859 by the capture of Shayk Shamil by the Russians. In the years followings Treaty of Paris where the Crimean War was concluded in 1853, the occupation methods of Russia were hardened and the migration from the Caucasus was accelerated. The most common settlement of the Circassians, who were exiled from the occupied territories between 1863 and 1865, was the Ottoman Empire. The Ottoman Empire adopted Circassians in its territory. This study will clarify the process of exile from the occupation of the Circassians country and its placement in the Ottoman lands in the light of the data obtained from the Ottoman newspapers.

Milli mücadelenin kazanılmasından sonra Mustafa Kemal'in önderliğinde tüm yurtta inkılapların ağırlık kazandığı bir dönem başladı. Cumhuriyeti kuran kadrolar yeni bir ülke inşa etme idealiyle her alanda fikir üretmeye devrimlere destek olacak halk kitlelerini oluşturmaya çalıştı. Devrimler devam ederken bir taraftan da yeni kurulan devlete ve o devletin dayanacağı yeni topluma dünyanın gidişatına da uygun bir ideoloji arayışı başladı. Kemalizm olarak adlandırılan bu ideolojinin çerçevesini belirlemeye çalışan aydınlar ve kurucu bürokratlar temel dayanakları ayrı olan çeşitli fikirler ortaya koydular. Ülkü dergisi ve dergide yazı yazan isimler rejimin ideolojisini belirlemede önemli etkileri olan kişilerdir. Günümüzde oluşan Kemalizm anlayışının temellerini anlamak ve oluşum sürecini ortaya koymak açısından derginin incelenesi oldukça önemlidir. 1933-1950 yılları arasındaki sayılarda yapılan çalışma ile hem dönemin fikir dünyasına ışık tutulmaya çalışılmış hem de oldukça etkili isimlerin yazı yazdığı ve ortak bir dil oluşturmayı hedefledikleri dergi üzerinden Kemalizm kaynakları ortaya konulmaya çalışılmıştır. Yapılan çalışma sonunda ortaya çıkan genel kanı günümüzde etkili olan resmi Kemalizm anlayışının büyük oranda Ülkü dergisi çıkaran ve orada yazı yazan aydın ve bürokratların çizdiği çerçevedir After the national struggle being won, a period in which the reforms in the whole country gained importance under the leadership of Mustafa Kemal began. The staff that founded the Republic tried to create public masses that would support the revolutions in every field with the ideal of building a new country. While the revolutions were continuing, the seek for a new ideology began in accordance with the new state and the new society on which the state would be based. The intellectuals and the founder bureaucrats trying to determine the framework of this ideology called Kemalism put forward various ideas that their basic foundations were different. The journal of Ülkü and names writing for the journal are the people who have important influences on determining the ideology of the regime. It is quite important to examine the journal so as to understand the fundamentals of the Kemalism concept that is being formed in terms of presenting the process of formation. With the study conducted in the issues published from 1933 to 1950, it was tried to shed light on the world of ideas of the period, and the sources of Kemalism were tried to be revealed through the journal where highly influential names wrote and aimed to create a common language. The general consensus that emerged at the end of the study is that the framework was drawn by the intellectuals and bureaucrats who published the journal of Ülkü and wrote a large part of the official concept of Kemalism holding its presence today. 204