Search

4- and 6-azasteroids have been shown to be potent inhibitors of human 5α-reductase and certain azasteroids have shown significant clinical benefit in the treatment of androgen-related disorders. In an effort to expand the diversity of steroidal heterocycles synthetically accessible for structure-activity relationship exploration, a novel reaction sequence was applied to the preparation of the 6-azasteroid framework. To this end, photolysis of the oxaziridine derived from 17β-carbomethoxy-3β-triisopropylsilyloxy-6-azaandrost-5-ene (1) yielded a novel 7, 5-steroidal ring system that was evaluated for inhibition of human type 1 and 2 5α-reductase.

An animal model of type 1 diabetes (T1D), in which human beta cell autoantigen(s) are presented to effector cells in the context of human Major Histocompatibility Complex (MHC) diabetes-susceptibility genes, would be highly desirable for studies of molecular mechanisms of disease and development of antigen-specific immune-therapies applicable to man. It would be especially advantageous to develop an animal model of human T1D that also exhibits the chronic complications of diabetes. Our new spontaneous mouse model of T1D wherein mouse MHC-II was replaced by human DQ8 in all antigen-presenting cells (APCs), and pancreatic Beta-cells were made to express human GAD65 autoantigen resembles most human characteristics of the disease. Our humanized transgenics have a genetic background providing for compromised Beta-cell neogenesis and/or regeneration. Immune cells attack Beta-cells, which in turn leads to a chronically progressive disease characterized by the development of anti-GAD65 antibodies. Flow cytometric analysis of pancreas (PN) and peri-pancreatic lymph nodes (PLN) revealed that CD4 and CD8 T cells build up in the PLN while mostly CD8 infiltrate intra-islet locations, which first causes glucose intolerance, and later on diabetes. Animals spontaneously show hyperglycemia of >250 mg/dl at approximately eight weeks of age. Without intervention, animals develop the classic complications observed in human diabetes (i.e., retinopathy, nephropathy, and neuropathy). To date, all complications of diabetes have been observed in our model (1). Our humanized transgenics develop diabetic retinopathy. Diabetic mice develop a significant increase of acellular capillaries in the retina as compared to non-diabetic controls as early as 6 months. Ocular tomography revealed that total retinal thickening was reduced in diabetic mice. Fundoscopic retinal images also revealed vascular leakage only in diabetic mice. Six-month-old diabetic mice also show advanced features of diabetic nephropathy like focal segmental/global glomerular sclerosis and focal tubular atrophy. Basal glomerular membrane doubles in size at three months as shown by electron microscopy as compared to non-diabetic controls. Moreover, our humanized mice also show diabetic neuropathy. Optic nerves of 6-month-old diabetic mice show an increase in the refractory period of the second compound action potential (CAP) as compared to non-diabetic mice (p < 0.05). This increase in the refractory period of CAP in the diabetic optic nerves is consistent with the reduced conduction velocity over non-diabetic controls. Conclusively, our humanized mice model is the closest one to human diabetes and is not just suitable for therapies to halt diabetes and its development but also to address the physiopathology and treatment of diabetes complications. 1) U.S. Provisional Patent #62/713,827 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Topoisomerase II is a critical enzyme involved in unknotting and detangling DNA during replication, transcription, and cell division. Humans have two isoforms of topoisomerase II, α (Top2A) and β (...

Bu çalışmada TRT Türkü Repertuarı'nın tamamı Türk Halk Müziği Sözler Antolojisi 1. ve 2. Cild'i taranarak ortaya çıkarılmış ve sevgiliye ait özelliklerin yer aldığı türküler tespit edilerek çalışmaya aktarılmıştır. Çalışma giriş ve beş bölümden oluşmaktadır. Girişte, halk edebiyatı, âşık edebiyatı, dinî-tasavvufî Türk edebiyatı, divan edebiyatı, Tanzimat edebiyatı ve Cumhuriyet dönemi Türk edebiyatıyla ilgili kısaca bilgi verilmiş, adı geçen edebiyatlarda sevgiliyle ilgili yapılmış olan akademik çalışmalardan örnekler sunulmuştur. Çalışmanın devamında halk edebiyatı anonim halk şiiri olan türkünün tanımına ve türkülerde sevgilinin hangi özellikleriyle ele alındığına değinilmiştir. Çalışmanın birinci bölümünde sevgili ile ilgili dinî içerikli motiflerin yer aldığı türkülere, ikinci bölümünde sevgili hakkında genel bilgi ve sevgilinin fiziksel özelliklerine ait güzellik unsurlarının yer aldığı türkülere, üçüncü bölümde sevgiliye ait eşyaların yer aldığı türkülere, dördüncü bölümde sevgilinin tavır ve davranışlarıyla ilgili türkülere ve son bölümde de sevgili ile ilgili diğer unsurlar dediğimiz, ilk dört bölümde bulunmayan sevgili özelliklerinin yer aldığı türkülere yer verilmiştir. In this study, TRT Türkü Repertuarı was found by scanning the first and second volume of Turkish Folk Music Anthology and folk songs with features belonging to the beloved were identified and transferred to the study. The study consists of five parts.In the introduction part, brief information about folk literature, literature, religious-mystic Turkish literature, divan literature, tanzimat literature and Turkish literature in the Republican period were given. Also the examples of academic studies that are related to beloved were given.in the following work, definition of folk songs which is folk poetry of folk literature and how beloved was mentioned were adressed. In the first part of the study, folk songs which include religious motives about beloved were mentioned. In the second part, general information about the beloved and beauty elements of her/him were stated. In the third part, folk songs which include belongings of beloved were mentioned. In the fourth part, folk songs which include behaviors of the beloved were mentioned and in the last part, folk songs with features which were not mentioned in the first four part were addressed. 342

İnsanlık tarihi boyunca süregelen en temel sorunlardan biri kimlik kurulumları, Ben ve Öteki konumlandırmaları olmuştur. Modern ve Postmodern çağlar içerisinde yeniden kurgulanan kimlik yapıları sonucunda onların karşısına tahsis edilen Öteki türleri, çağın gereklilikleri ve sistemin ihtiyaçları doğrultusunda yeniden üretilmektedir. Bu bağlamda bu temsiliyetlerin en görünür şekilde gözlemlenebileceği alanlardan biri olan sinema, oluşturulan kodları okumak anlamında verimli bir alan sunmaktadır. Bu çalışmadaki ana sorunsal cyberpunk filmlerinde `insan` olma niteliğinin hangi koşullar altında sağlanabildiği, Ötekileştirme mekanizmalarının hangi yollarla kurulduğu ve hangi grupların nasıl temsil edildiği etrafında şekillenmektedir. One of the most fundamental problems that have persisted throughout the history of mankind has been identity setups, I and Other positioning. Types of Other that are allocated to them as a result of identity structures reconstructed in the Modern and Postmodern Era are reproduced in line with the requirements of the age and the needs of the system. In this context, cinema, which is one of the areas where these representations are most visible, offers a productive area to read the generated codes. The main problematic of this study is shaped around under which conditions the quality of being `human` is actualised in cyberpunk films, in which ways the Othering mechanisms are established and which groups are represented in what ways. 93

Summary Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation. For complete details on the use and execution of this protocol, please refer to (Taylor et al., 2018) and (Al-Mrabeh et al., 2020b)., Graphical Abstract, Highlights • Step-by-step description of intraorgan fat quantification in liver and pancreas • Description of in vivo measurement of hepatic lipoprotein triglyceride export • Application of novel magnetic resonance and lipoprotein turnover methods • Easy to reproduce methods without use of isotopes or ionization radiation, Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation.

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[18F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([11C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m−2·min−1) to 3-h saline infusion. Lean controls ( n = 10) were compared with glycemically controlled volunteers with T2DM ( n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption ( P = 0.04) and perfusion ( P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids ( P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions ( P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups ( P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM ( P = 0.003). Myocardial work efficiency was lower in T2DM ( P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization ( P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

International audience; Type II DNA Topoisomerases (Top2) are essential enzymes involved in DNA replication, DNA condensation and chromosome segregation. They remove topological stress that appear in the DNA duplex by releasing catenates, relaxing supercoils and removing knots through transient double strand breaks. This mechanism is currently targeted by compounds used in cancer chemotherapy, that prevent religation of DNA breaks and lead to cell death. The implication of these enzymes in the cell cycle raises the question of their regulation notably by post-translational modifications (PTM). Anti-cancer drugs such as doxorubicin and etoposide were shown to induce hyperphosphorylation or hypophosphorylation in cancer cells. However the role of PTM in the catalytic regulation of Top2 is not clearly understood.In this work, we have focused on the post-translational modifications of the human Top2. We have systematically identified the phosphorylation and acetylation sites in the Top2 isoforms, and observed a distinct distribution of both modifications. This identification allowed us to understand the role of a catalytic residue subject to an acetylation and the potential impact of this modification.

English In view of the current understandings of violence, which tend to present it always negatively, Nietzsche's genealogy allows us to understand that violence also has a positive character in the historical course of the West. It enabled the establishment of civilization, to the extent that it shaped a particular human type. The morality of morals and primitive law were mechanisms of violence and cruelty that made man responsible, predictable, and obedient to standards. By renouncing the immediate satisfaction of instincts, one has internalized the guilt and one has instituted the civilized man. But in this same course grew and dominated the nihilism. portuguesFace as atuais compreensoes da violencia, que tendem a apresenta-la sempre negativamente, a genealogia de Nietzsche permite entender que a violencia tambem possui um carater positivo no percurso historico do ocidente. Ela possibilitou a instauracao da civilizacao, na medida em que modelou um determinado tipo humano. A eticidade do costume e o direito primitivo foram mecanismos de violencia e crueldade que tornaram o homem responsavel, previsivel e obediente as normas. Por meio da renuncia a satisfacao imediata dos instintos, internalizou-se a culpa e se instituiu o homem civilizado. Mas nesse mesmo percurso cresceu e dominou o niilismo.

INTRODUCTION: We recently identified variances in serum metabolomic profiles between fasted diabetic and healthy dogs, some having similarities to those identified in human type 1 diabetes. OBJECTIVES: Compare untargeted metabolomic profiles in the non-fasted state. METHODS: Serum from non-fasted diabetic (n=6) and healthy control (n=6) dogs were analyzed by liquid chromatography-high resolution mass spectrometry. RESULTS: Clear clustering of metabolites between groups were observed, with multiple perturbations identified that were similar to those previously observed in fasted diabetic dogs. CONCLUSION: These findings further support the development of targeted assays capable of detecting metabolites that may be useful as biomarkers of canine diabetes.

In this paper, we develop a system that can express exaggerated objects other than human type and human type, and make it easy to create exaggerated expression animation for users who are not accustomed to animation production. We created a program to determine the extent of the exaggeration of the object by setting the degree of exaggeration to the default value and changing the value as necessary. This system is evaluated by comparative experiment experiments in which subjects generate and evaluate simple exaggerated expression animation. The system developed in this research realizes implementation in Maya using Python, and by moving the joint included in the character by manipulating the slider, it is easy for users not familiar with animation production to easily exaggerate squash and stretch It was possible to express. We evaluated that the developed system is useful as a tool for beginners.

The STZ-Induced Diabetic Rat STZ-Induced Diabetes: Induction, Mechanism(s), and Dose-Dependency, B. Rodrigues, P. Poucheret, M. Battell, and J.H. McNeill Alternations in Myocardial Energy Metabolism in Streptozotocin Diabetes, W. C. Stanley, G.D. Lopaschuk, and K.M. Kivilo Structural and Functional Consequences of Streptozotocin-Induced Diabetes on the Kidney, K. Sharma, D.C. Han, A. Mogyorosi, and F.N. Ziyadeh Physiological and Pathological Consequences of STZ-Diabetes on the Heart, B. Rodrigues and J.H. McNeill The Effects of STZ-Induced Diabetes on the Cytochrome P450 System and Other Metabolic Pathways, C. Ionnides, P.R. Flatt, and C.R. Barnett Nerve and Retinal Changes in Experimental Diabetes, S. Chakrabarti Vascular Reactivity in Streptozotocin-Induced Diabetes, R. Subramanian and K.M. MacLeod Cardiovascular Function in the Intact, STZ-Treated Rat, R. A. Hebden Treatment and Pharmacological Interventions in STZ -Diabetes, M.L. Battell, B. Rodrigues, V.G. Yuen, and J.H. McNeill Other Experimental Models of Diabetes Other Models of Type I Diabetes, M.L. Battell, V.G. Yuen, S. Verman, and J.H. McNeill Spontaneous Insulin Dependent Diabetes Mellitus (IDDM) in Nonobese Diabetic (NOD) Mice: Comparisons with Experimentally Induced IDDM, E.H. Leiter, I.C. Gerling, and J.C. Flynn The Neonatal-STZ Model of Diabetes, S.W. Schaffer and M. Mozaffari The BB Rat: A Unique Model of Human Type 1 Diabetes, C.J. Field and S. Butler Non-Insulin Dependent Animal Models of Diabetes Mellitus, C.H.S. McIntosh and R.A. Pederson

Ali Haydar Haksal Türk Edebiyatının özellikle öykü alanında tanınmış isimlerindendir. Kaleme aldığı anlıklar, olaydan ziyade durum öykücülüğünü çağrıştıran hikâyeleriyle kendine has bir alan oluşturmuştur.Bu çalışmanın amacı; birinci bölümde, Ali Haydar Haksal'ın öykülerindeki insan tiplerini sosyal hayattaki konumları bağlamında ele almak; ikinci bölümde ise bilhassa kent üzerinden çağımızın problemlerine değinmektir. Ali Haydar Haksal is one of famous writers especially in the story field. Instants stories that he has written up created an idiosyncratic field recalling situation stories rather than event stories.He aim of this study to discuss personality types in Ali Haydar Haksal's stories within context of theri social status in the first chapter and mention problems of our age especially regarding city in the second chapter. 111

Yurt, Gülay/Ardahan Üniversitesi Sosyal Bilimler Enstitüsü Yüksek Lisans Tezi, Modernizmin edebiyatımızdaki güçlü kalemlerinden biri olan Yusuf Atılgan, öyküleriyle varoluş sarmalındaki insanın bireyleşme yolundaki sancılarını konu edinir. Özellikle köy, kasaba, kent gibi farklı mekanlarda kendine ve topluma yabancılaşan bireyin siyasi, kültürel ve ekonomik çıkmazlardaki yalnızlıklarını öykü kişilerinin iç sesleriyle okuyucuya sunar. Yusuf Atılgan, “Kasabadan”, Köyden” ve “Kentten” alt başlıklarıyla tasnif ettiği öykülerinde aralarında ruhsal bir yakınlık bulunan köylü, kasabalı ve kentli kişileriyle yeni insan tipini anlatır. Modernleşmenin şekillendirdiği bu yeni tipler varoluş bunaltısının itkisiyle yalnız, iletişime kapalı, yabancılaşmış bireylerin ilk örneklerini oluşturur. Kendini gerçekleştiremeyen bu insan yığını köyde umutsuz, kasabada yalnız, kentte aylak olarak kimliksiz, cinsel yaşamda yetersiz, hayatta amaçsız, sınırları aşmaktan aciz edilgen bireyler olarak karşımıza çıkar. Yusuf Atılgan’ın öykülerinde kullandığı izlekler, güncelin içinde gizlenen imgelerin güftesidir. Öykülerine serpiştirdiği bireyin yalnızlığı, yabancılığı ya da kapalılığı aslında toplumun yalnızlığı, yabancılığı ya da kapalılığıdır., One of the most powerful authors of modernism in Turkish literature, Yusuf Atılgan focuses upon the crises/agonies of existential issues of the human’s struggle towards individuation in his stories. In his triologic works, namely village, town and city, he particularly presents the loneliness of characters, who are alienated to themselves and to society from political, cultural and economic perpectives through their own voices. In his stories subtitled as “From the Village”, “From the Town”, and “From the City”, Yusuf Atılgan narrates the new human types, who are spiritually related as they come from villages, towns and cities. These new types shaped by modernist values form the prototypes of lonely, discennected and alienated individuals due to existential problems. Those human masses, who cannot realize their wishes are presented as hopeless in villages, lonely in towns, wanderers in cities with no identity, inadequate in sexual life, aimless in their lives and unable to surpass the limits sets before them. The themes Yusuf Atılgan makes use of are the composition of images hidden in the daily routine. The loneliness, alienation or disconnectedness of the characters incorporated in the stories are, in fact, the loneliness, disconnectedness and alineation of the society., İÇİNDEKİLER ÖZET -- i ABSTRACT -- ii KISALTMALAR -- v ÖNSÖZ -- vi GİRİŞ -- 1 BİRİNCİ BÖLÜM: YUSUF ATILGAN ÖYKÜLERİNDE YAPISAL UNSURLAR 1.1. Öykülerin Dili/Kimliği -- 3 1.2. Olay Örgüsü -- 4 1. 3. Bakış Açısı ve Anlatıcı -- 10 1.4. Şahıs Kadrosu -- 18 1.4.1. Başkişi -- 21 1.4.2.Norm Karakterler -- 26 1.4.3. Kart Karkterler -- 31 1.4.4. Fon Karakterler -- 35 1.5. Mekân -- 36 1.5.1. Çevresel Mekân -- 38 1.5.2. Algısal Mekân -- 40 1.6. Zaman -- 49 İKİNCİ BÖLÜM: HİKAYELERDE İZLEKSEL KURGU 2.1. Evdeki Öyküsünde Kora Şeması -- 59 2.2. Saatlerin Tıkırtısı Öyküsünde Kora Şeması -- 62 2.3. Tutku Öyküsünde Kora Şeması -- 65 2.4. Kümesin Ötesi Öyküsünde Kora Şeması -- 68 2.5. Dedikodu Öyküsünde Kora Şeması -- 70 2.6. Yük Öyküsünde Kora Şeması -- 74 2.7. Yaşanmaz Öyküsünde Kora Şeması -- 76 2.8. Atılmış Öyküsünde Kora Şeması -- 79 2.9. Çıkılmayan Öyküsünde Kora Şeması -- 82 2.10. Bodur Minareden Öte Öyküsünde Kora Şeması -- 84 2.11. Ağaç Öyküsünde Kora Şeması -- 88 2.12. Eylemci Öyküsünde Kora Şeması -- 90 SONUÇ -- 92 KAYNAKÇA -- 98 ÖZGEÇMİŞ -- 100

Loss of first-phase insulin release is an early pathogenic feature of type 2 diabetes (T2D). Various mouse models exist to study T2D; however, few recapitulate the early β-cell defects seen in humans. We sought to develop a nongenetic mouse model of T2D that exhibits reduced first-phase insulin secretion without a significant deficit in pancreatic insulin content. C57BL/6J mice were fed 10% or 60% fat diet for three weeks, followed by three consecutive, once-daily intraperitoneal injections of the β-cell toxin streptozotocin (STZ; 30, 50, or 75 mg/kg) or vehicle. Four weeks after injections, the first-phase insulin response to glucose was reduced in mice when high-fat diet was combined with 30, 50, or 75 mg/kg STZ. This was accompanied by diminished second-phase insulin release and elevated fed glucose levels. Further, body weight gain, pancreatic insulin content, and β-cell area were decreased in high fat-fed mice treated with 50 and 75 mg/kg STZ, but not 30 mg/kg STZ. Low fat-fed mice were relatively resistant to STZ, with the exception of reduced pancreatic insulin content and β-cell area. Together, these data demonstrate that in high fat-fed mice, three once-daily injections of 30 mg/kg STZ produces a model of β-cell failure without insulin deficiency that may be useful in studies investigating the etiology and progression of human T2D.

Bu çalışma, Nietzsche'nin `Böyle Buyurdu Zerdüşt` adlı eserinde geçen temel kavramları inceliyor ve Nietzsche kavramlarını yorumlamayı amaçlıyor Birinci bölümde `Böyle Buyurdu Zerdüşt` adlı eserde geçen Nietzsche'nin temel kavramları ve bazı sembolik ifadeler yorumlanmaya çalışılıyor. İkinci bölümde ise Nietzsche'nin Nasyonal Sosyalizm ideolojisiyle ilişkisi olup olmadığı bir başlık altında inceleniyor. Nietzsche'nin çağımız için önemine ve bugün niçin okunması gerektiğine dair bir başlıkta tezimizde yer almaktadır. Anahtar Kelimeler; Bengi Dönüş, Tanrı öldü, Üst İnsan, Nihilizm, Güç İstenci This study examines the basic concepts of Nietzsche's work called `Thus Spoke Zarathustra` and aims to interpret Nietzsche's concepts. In the first section, basic concepts mentioned in Nietzsche's work called `Thus Spoke Zarathustra` and some symbolic expressions are being tried to interpret. The second section examines under a topic whether Nietzsche has any relation with the National Socialist ideology or not. Also, there is another title in our thesis stating the importance of Nietzsche for our time and why he should be read today. Key Words; Eternal recurrence, God dead, Overman, Nihilism, The will to power, 116

Protein arginine methyltransferases (PRMTs) play a crucial role in a variety of biological processes. Overexpression of PRMTs has been implicated in various human diseases including cancer. Consequently, selective small-molecule inhibitors of PRMTs have been pursued by both academia and the pharmaceutical industry as chemical tools for testing biological and therapeutic hypotheses. PRMTs are divided into three categories: type I PRMTs which catalyze mono- and asymmetric dimethylation of arginine residues, type II PRMTs which catalyze mono- and symmetric dimethylation of arginine residues, and type III PRMT which catalyzes only monomethylation of arginine residues. Here, we report the discovery of a potent, selective, and cell-active inhibitor of human type I PRMTs, MS023, and characterization of this inhibitor in a battery of biochemical, biophysical, and cellular assays. MS023 displayed high potency for type I PRMTs including PRMT1, -3, -4, -6, and -8 but was completely inactive against type II and type III PRMTs, protein lysine methyltransferases and DNA methyltransferases. A crystal structure of PRMT6 in complex with MS023 revealed that MS023 binds the substrate binding site. MS023 potently decreased cellular levels of histone arginine asymmetric dimethylation. It also reduced global levels of arginine asymmetric dimethylation and concurrently increased levels of arginine monomethylation and symmetric dimethylation in cells. We also developed MS094, a close analog of MS023, which was inactive in biochemical and cellular assays, as a negative control for chemical biology studies. MS023 and MS094 are useful chemical tools for investigating the role of type I PRMTs in health and disease.

Impaired activation of mitochondrial energy metabolism by glucose has been demonstrated in type 2 diabetic β-cells. The cause of this dysfunction is unknown. The aim of this study was to identify segments of energy metabolism with normal or with altered function in human type 2 diabetes mellitus. The mitochondrial membrane potential (ΔψM), and its response to glucose, is the main driver of mitochondrial ATP synthesis and is hence a central mediator of glucose-induced insulin secretion, but its quantitative determination in β-cells from human donors has not been attempted, due to limitations in assay technology. Here, novel fluorescence microscopic assays are exploited to quantify ΔψM and its response to glucose and other secretagogues in β-cells of dispersed pancreatic islet cells from 4 normal and 3 type 2 diabetic organ donors. Mitochondrial volume densities and the magnitude of ΔψM in low glucose were not consistently altered in diabetic β-cells. However, ΔψM was consistently less responsive to elevation of glucose concentration, whereas the decreased response was not observed with metabolizable secretagogue mixtures that feed directly into the tricarboxylic acid cycle. Single-cell analysis of the heterogeneous responses to metabolizable secretagogues indicated no dysfunction in relaying ΔψM hyperpolarization to plasma membrane potential depolarization in diabetic β-cells. ΔψM of diabetic β-cells was distinctly responsive to acute inhibition of ATP synthesis during glucose stimulation. It is concluded that the mechanistic deficit in glucose-induced insulin secretion and mitochondrial hyperpolarization of diabetic human β-cells is located upstream of the tricarboxylic acid cycle and manifests in dampening the control of ΔψM by glucose metabolism.

The concept of grouping Mendelian disorders associated with an up-regulation of type I interferon has only recently been suggested. Here we discuss the progress being made in the delineation and understanding of this novel set of inborn errors of immunity, the human type I interferonopathies.

Human type I interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and immunomodulatory activities. They signal through the same cell surface receptors IFNAR1 and IFNAR2 yet evoking markedly different physiological effects. One differentiating factor of interferon-beta (IFN-β) from other type I interferons is the presence of theAsn-Gly-Arg (NGR) sequence motif, which, upon deamidation, converts to Asp-Gly-Arg (DGR) and iso-Asp-Gly-Arg (iso-DGR) motifs. In other proteins, the NGR and iso-DGR motifs are reported as CD13- and αvβ3, αvβ5, αvβ6, αvβ8 and α5β1 integrin-binding motifs, respectively. The scope of this study was to perform exploratory surface plasmon resonance (SPR) experiments to assess the binding properties of a deamidated IFN-β variant to integrins. For this purpose, integrin αvβ3 was selected as a reference model within the iso-DGR- integrin binding members. The obtained results show that deamidated IFN-β binds integrin αvβ3 with nanomolar affinity and that the response was dependent on the deamidation extent. Based on these results, it can be expected that deamidated IFN-β also binds to other integrin family members that are able to bind to the iso-DGR binding motif. The novel binding properties could help elucidate specific IFN-β attributes that under physiological conditions may be modulated by the deamidation.

This chapter argues that Nietzsche’s critical essay on David Strauss’s last book, The Old and New Faith, is his first sustained attempt at a critique of contemporary culture and modern science. It also argues that the essay presents an early version of the human type called “the last man” in Thus Spoke Zarathustra, but who is called the “cultivated philistine” in the essay on Strauss. Looking back on the essay in Ecce Homo, Nietzsche said that it should not be read as a direct attack on Strauss because Strauss was used merely as a “magnifying glass […] to make visible a general but creeping and elusive [cultural] crisis.” The chapter concludes that Nietzsche took aim at Strauss because Strauss was a pseudo-genius who the Germans mistakenly hailed as a true cultural genius, and because Strauss’s scientific manner of thinking enervated the German spirit.

This chapter highlights medicalized discourses of the disabled body which provided the scientific foundation for Het Dorp as design aimed at rehabilitating the individual and society. Under the rhetoric of inclusion, Het Dorp expelled this cloistered disabled figure into the Village enclave, achieving a double purification: constituting the virtuous Dutch citizen through participation in the collective nationalist project, and cleansing the body politic of its invaliden – invalid bodies. The cultural conception of the body as a machine that can be 'repaired' by technological means owes much to the twentieth-century mechanization of processes and animate beings. Central to the concept of Open Het Dorp's new disabled citizen was the use of science and technology to restore autonomy to the incapacitated body. Het Dorp thus made the disabled body knowable to science, through the sole determinant of disability as a human type. Technology helped to inscribe the idealized body onto the material body of the disabled residents.

A Paulistânia fora denominada como a origem do campo de ação de um ser humano que mais tarde seria designado na literatura sociológica e antropológica como caipira, um tipo de homem que contemplava um modo de vida ligado às lides do trabalho campal. Entretanto, no período colonial, este território teria contornos imaginários, onde primordialmente seria reconhecido pela presença de pontos de permanência com habitações caracterizadas pelas técnicas utilizadas por este ser humano tanto no intuito de sua sobrevivência, quanto no auxílio de uma confecção paisagística que lhe forneceria relações simbólicas importantes em meio à uma vastidão de matas e caminhos a serem explorados. Desta forma, estas habitações revelar-se-iam como ponto nodal do surgimento deste território, oferecendo uma integração pautada pelo fator “tempo” e denunciando a passagem ou permanência do mameluco nesta região. Na ocasião, este território compunha-se de uma vastidão que englobava as áreas dos atuais estados de São Paulo, Paraná, Minas Gerais, Mato Grosso e Goiás, campo de influências e de exploração do antigo paulista nas incursões bandeirista e entradista. Ao longo do tempo, este território foi sendo repartido em áreas administrativas e reduzido às terras paulistas. Entretanto, onde houvesse o tipo humano em questão e as marcas de sua cultura material e imaterial, ali se encontrava a Paulistânia, tal como ficou registrado na literatura. Porém, este artigo também intenta apresentar a Paulistânia como origem do desenvolvimento do drama relacionado à existência caipira, se transformando não somente num arcabouço de relações causais entre meio, homem e luta, mas também num símbolo dos problemas humanos, ou seja, de um homem que tem a necessidade de se construir e de construir um mundo para si próprio.

Aims/hypothesis Pancreatic lymph nodes (PLNs) are critical sites for the initial interaction between islet autoantigens and autoreactive lymphocytes, but the histology of PLNs in tissue from individuals with type 1 diabetes has not been analysed in detail. The aim of this study was to examine PLN tissue sections from healthy donors compared with those at risk of, or with recent-onset and longer-duration type 1 diabetes. Methods Immunofluorescence staining was used to examine PLN sections from the following donor groups: non-diabetic (n=15), non-diabetic islet autoantibody-positive (n=5), recent-onset (≤1.5 years duration) type 1 diabetes (n=13), and longer-duration type 1 diabetes (n=15). Staining for CD3, CD20 and Ki67 was used to detect primary and secondary (germinal centre-containing) follicles and CD21 and CD35 to detect follicular dendritic cell networks. Results The frequency of secondary follicles was lower in the recent-onset type 1 diabetes group compared with the non-diabetic control group. The presence of insulitis (as evidence of ongoing beta cell destruction) and diagnosis of type 1 diabetes at a younger age, however, did not appear to be associated with a lower frequency of secondary follicles. A higher proportion of primary B cell follicles were observed to lack follicular dendritic cell networks in the recent-onset type 1 diabetes group. Conclusions/interpretation Histological analysis of rare PLNs from individuals with type 1 diabetes suggests a previously unrecognised phenotype comprising decreased primary B cell follicle frequency and fewer follicular dendritic cell networks in recent-onset type 1 diabetes.

Despite uncertainty of its exact role, muscle tension has shown an ability to alter human biomechanical response and may have the ability to reduce impact injury severity. The aim of this study was to examine the effects of muscle tension on human impact response in terms of force and energy absorbed and the subjects' perceptions of pain. Seven male martial artists had a 3.9 kg medicine ball dropped vertically from seven different heights, 1.0-1.6 m in equal increments, onto their right thigh. Subjects were instructed to either relax or tense the quadriceps via knee extension (≥60% MVC) prior to each impact. F-scan pressure insoles sampling at 500 Hz recorded impact force and video was recorded at 1000 Hz to determine energy loss from the medicine ball during impact. Across all impacts force was 11% higher, energy absorption was 15% lower and time to peak force was 11% lower whilst perceived impact intensity was significantly lower when tensed. Whether muscle is tensed or not had a significant and meaningful effect on perceived discomfort. However, it did not relate to impact force between conditions and so tensing may alter localised injury risk during human on human type impacts.

International audience; The present study investigated how young drivers assess speed-enforcement warning messages and how these messages affect their motivation to reduce speed. Stemming from deterrence theory (Gibbs, 1985; Homel, 1988) the factors of 'celerity', 'certainty', and 'severity' of the sanction were explored as a function of type of speed enforcement (auto-matic radars vs. police officers) and knowledge of enforcement location (known vs.unknown). Coping factors (e.g., self-efficacy, response cost) from protection motivation theory (PMT; Rogers, 1983) were also considered as critical variables of compliance. Participants (245 students, 51% men) had to choose their speed behavior in a mental simulation of a driving episode on a freeway. As expected, the intention to speed was lower when speed-enforcement warning messages were announced than in the control situation. Threat-certainty ratings were higher when automatic radars were announced, but speeding intentions did not vary according to the automatic versus human type of speed enforcement. Furthermore, automatic radars were perceived as easier to cope with in a maladaptive way (i.e., self-efficacy for avoiding a sanction and adapting speed as a function of speed-enforcement location). An unknown speed-enforcement location was one way of decreasing both women's and men's speed. Men calculated a cost-benefit balance to avoid slowing down when they knew the enforcement location. Concerning the predictors of speeding intentions and motivations to reduce speed, self-efficacy ratings for reducing one's speed proved to be the best PMT predictor

Qualitative modeling tends to be closer to human type of reasoning than traditional numerical modeling and proved to be very useful in certain branches of cognitive robotics. However, due to the lack of precise numerical relations, planning with qualitative models has been achieved to a limited extent. Typically, it is bound to predicting possible future behaviors of the system, and demands additional exploration of numerical relations, before constructed plans can be executed. In this paper we show how qualitative models can be interpreted in terms of reactive planning, to produce executable actions without the need for additional numerical learning. We demonstrate our method on two classical motion planning problems – pursuing and obstacle avoidance, and a complex problem of pushing objects.

Kur'an'ın üçte biri kıssalarından oluşmaktadır. Kur'an'ın amacı tarihi bilgi vermek değil, mesaj iletmektir. Kıssalar mesaj vermenin en kolay yolu olduğu için Kur'an'da oldukça fazla yer tutmuştur. Kur'an'da kıssaların bu kadar çok yer tutması onların doğru anlaşılmasını zorunlu kılmaktadır. Çalışmamızda Peygamber kıssaları ele alınarak bunlardaki olumlu ve olumsuz insan tiplemeleri ortaya konulmaya çalışılmıştır. Çalışmamız sonucunda modern psikoloji biliminin ortaya koyduğu insan tiplemeleri ile Kur'an'da tasvir edilen insan tiplemelerinin farklı olduğu, Kur'an'ın kendine ait bir yaklaşımının olduğu tespit edilmiştir. Peygamber kıssalarındaki olumlu tiplemelerin Peygamber'i ve ashabını motive etmeye dönük olduğu, olumsuz tiplemelerin ise İslam'a karşı çıkan müşrikleri uyarma gayesi güttüğü tespitine yer verilmiştir. One third of the Qur'an consists of parables. The aim of the Qur'an is to convey the message, not to give historical information. Because the parables are the easiest way to post messages, there is a lot of space in the Qur'an. As the parables have so much space in Qur'an, it is imperative that they are understood correctly. In our work, we tried to put forward the positive and negative human typologies in the Prophet parables. As a result of our study, it has been determined that the human typologies revealed by modern science of psychology and the human typologies depicted in the Qur'an are different, and that the Qur'an has its own approach. Positive typologies in the Prophet parables are directed towards motivating the Prophet and his friends, and negative typologies include the determination to warn the polytheists against Islam. 184

Taurine occurs in high concentrations in muscle and is implicated in numerous physiological processes, yet its effects on many aspects of contractility remain unclear. Using mechanically skinned segments of human vastus lateralis muscle fibers, we characterized the effects of taurine on sarcoplasmic reticulum (SR) Ca2+ accumulation and contractile apparatus properties in type I and type II fibers. Prolonged myoplasmic exposure (>10 min) to taurine substantially increased the rate of accumulation of Ca2+ by the SR in both fiber types, with no change in the maximum amount accumulated; no such effect was found with carnosine. SR Ca2+ accumulation was similar with 10 or 20 mM taurine, but was significantly slower at 5 mM taurine. Cytoplasmic taurine (20 mM) had no detectable effects on the responsiveness of the Ca2+ release channels in either fiber type. Taurine caused a small increase in Ca2+ sensitivity of the contractile apparatus in type I fibers, but type II fibers were unaffected; maximum Ca2+-activated force was unchanged in both cases. The effects of taurine on SR Ca2+ accumulation 1) only became apparent after prolonged cytoplasmic exposure, and 2) persisted for some minutes after complete removal of taurine from the cytoplasm, consistent with the hypothesis that the effects were due to an action of taurine from inside the SR. In summary, taurine potentiates the rate of SR Ca2+ uptake in both type I and type II human fibers, possibly via an action from within the SR lumen, with the degree of potentiation being significantly reduced at low physiological taurine levels.

Some dogs develop a form of diabetes mellitus (DM) similar to that seen in children (juvenile, or Type 1 DM). It is characterized by concurrent high blood glucose (BG) and urine glucose concentrations. Elevated breath acetone concentrations have been observed in Type 1 DM in humans, though a quantitative correlation between breath acetone and BG has yet to be determined. The study of breath acetone in diabetic dogs might allow the use of breath acetone as a biomarker for diabetes in both humans and animals. We report on breath acetone analysis of 51 dogs (37 nondiabetic dogs and 14 diabetic dogs). Breath samples were collected and simultaneous BG levels (if applicable) were measured. Breath acetone tests were conducted using a real-time breath acetone analyzer that is based on the cavity ringdown spectroscopy technique. Absolute breath acetone concentrations (upper limits) were determined without the need for breath sample preconcentration and measurement calibration. For the 37 nondiabetic dogs, their exhaled breath acetone concentrations ranged from 0.16 to 2.42 parts per million (ppm). For the 14 diabetic dogs, breath acetone concentrations ranged from 0.17 to 5.80 ppm with a BG range of 30-750 mg/dL. The mean breath acetone concentration in the 14 diabetic dogs is 1.25 ppm, which is higher than that in the 37 nondiabetic dogs, i.e., 0.60 ppm. The mean breath acetone concentration in nondiabetic dogs, 0.60 ppm, is close to the mean breath acetone concentration in healthy humans. Although diabetic dogs exhibit elevated mean breath acetone concentration, as in human Type 1 DM, no correlation was found between breath acetone concentration and BG level in the diabetic dogs in this paper.

Natural products isolated from seaweeds have shown great antiviral potential against numerous viruses such as human type 1 herpes, human immunodeficiency virus, and dengue. Diterpenes produced by the brown seaweeds Dictyota and Canistrocarpus, in particular, have shown antiviral or virucidal activity. Recently, the Zika virus (ZIKV) has become a major public health concern due to its widespread dissemination throughout the Americas. Since no vaccines are available, and no drugs have effectively treated recent cases of infection, our group evaluated products from Dictyota menstrualis for their antiviral potential, alone and in combination with Ribavirin. We first evaluated the compounds’ cytotoxicity at high concentrations, and then evaluated the inhibition of ZIKV replication by crude extracts and acetylated crude extracts and their fractions at 20 μg/mL. The F-6 and FAc-2 fractions, rich in cyclic diterpenes with aldehyde groupings, inhibited ZIKV replication by >74%, with inhibition behaving in a dose-dependent manner and the 50% effective concentration (EC50) values of 2.80 (F-6) and 0.81 (FAc-2) μg/mL. Regarding the mechanism of action, FAc-2 had strong virucidal potential, and F-6 inhibited viral adsorption. Associating FAc-2 with Ribavirin at suboptimal dosages produced a strong synergistic effect that completely inhibited viral replication. Our results indicate that these natural products have excellent inhibitory potential against ZIKV replication and may be promising for developing affective therapies.

Alveolar epithelial cells outnumber alveolar macrophages by ~500 fold and increasing evidence suggests that Mycobacterium tuberculosis may replicate dramatically in these cells during the initial weeks of infecting the lung (Wolf et al., 2008 [1]; Ryndak et al., 2015 [2]). Here, we report in experimental detail the transcriptional profiling of M. tuberculosis replicating at 72 h post-infection in the human type II alveolar epithelial cell line, A549, as compared to M. tuberculosis growing logarithmically in laboratory broth culture (Ryndak et al., 2015 [2]). All resulting transcriptional profiling data was deposited to the Gene Expression Omnibus (GEO) database under the accession number GSE58466.

The high prevalence of diabetes and diabetic complications has caused a huge burden on the modern society. Although scientific advances have led to effective strategies for preventing and treating diabetes over the past several decades, little progress has been made toward curing the disease or even getting it under control, from a public health and overall societal standpoint. There is still a lack of reliable biomarkers indicative of metabolic alterations associated with diabetes and different drug responses, highlighting the need for the development of early diagnostic and prognostic markers for diabetes and diabetic complications. The emergence of metabolomics has allowed researchers to systemically measure the small molecule metabolites, which are sensitive to the changes of both environmental and genetic factors and therefore, could be regarded as the link between genotypes and phenotypes. During the last decade, the progression made in metabolomics has provided insightful information on disease development and disease onset prediction. Recent studies using metabolomics approach coupled with statistical tools to predict incident diabetes revealed a number of metabolites that are significantly altered, including branched-chain and aromatic amino acids, such as isoleucine, leucine, valine, tyrosine and phenylalanine, as diagnostic or highly-significant predictors of future diabetes. This review summarizes the current findings of metabolomic studies in human investigations with the most common form of diabetes, type 2 diabetes.

A total of 23,007 clinical samples, 2,001 were identified as Escherichia coli (E.coli). Among these, 205 strains were haemolytic. One hundred eighty one E.coli were found haemolytic among urinary isolates. Two tests i.e. salt aggregation test (SAT) and haemagglutination test (HAT) with human type A erythrocytes were performed to know the incidence of fimbriated strains amongst haemolytic E.coli isolates. Mannose resistant haemagglutination and Mannose sensitive haemagglutination was observed in 95 (46.34%) and 15 (7.31%) strains respectively. Whereas cell surface hydrophobicity was shown by 139 (67.80%) strains. Seventy nine (38.53%) strains were both SAT and HAT positive. Twenty nine (14.14%) strains were both SAT and HAT negative i.e. non-fimbriated strains. Among urinary isolates, 21.8% were found to possess both haemolytic and haemagglutinating activity. Haemolytic activity of E.coli was found associated with fimbriated strains. Thus, both act as virulence factors for the pathogenesis of Urinary Tract Infection.

Kur'ân-ı Kerîm'de 90. sûre olarak yer alan Beled Sûresi, 20 âyetten oluşan kısa bir sûre olmasına rağmen içerdiği konular kapsamlıdır. Bu tezde, sûrenin tefsiri ve onun ışığında olumlu ve olumsuz insan tipleri araştırılmaya çalışıldı. Araştırma, giriş, üç bölüm ve sonuçtan oluşmaktadır.Birinci bölümde Beled Sûresi hakkında genel bilgilere yer verilmiştir. Bu açıklamaları yaparken Kur'ân-ı Kerîm başta olmak üzere, sûre ile ilgili açıklama yapılan diğer eserlere başvurulmuştur.İkinci bölümde sûrede mevcut olan bazı kelime ve ıstılahlar izah edilmeye çalışılmıştır. Daha sonra mevcut olan Rivâyet ve Dirayet tefsirlerinden faydalanarak sûrenin tefsiri üzerinde durulmuştur.Üçüncü bölümde ise, sûre ışığında olumlu ve olumsuz insan tipleri araştırılmaya çalışılmıştır. As the 90th surah of the Quran, Surah Al-Balad contains 20 ayats and despite the fact of its being a short surah, its topics are very comprehensive. In this study it was aimed to investigate the exegesis of the Surah Al-Balad and the positive and negative kinds of people in its light. This thesis consists of an entry, three chapters and a conclusion.In the first chapter there are given some general details about Surah Al-Balad. While doing these descriptions it was applied to other researches that have to do with this surah and particularly the Quran.In the second chapter it was aimed to explain some words and terminologies of the surah. Afterwards it was worked on the surah's exegesis by using diraya (rational) tafsirs and rivaya (narrative) tafsirs.As for the third chapter it was aimed to research the positive and negative types of people according to Surah Al-Balad. 173