The Regulation of Glucose Metabolism during Osteoblast Differentiation

Differentiation and cell-specific functions are coupled with metabolic alterations to meet the needs of the cell. In this thesis, I have investigated the alterations of cellular metabolism in osteoblast-lineage cells in response to two different bone anabolic signals, WNT and PTH. I have further elucidated the mechanism underlying the metabolic changes, and have explored the functional importance of such changes for bone anabolism. Osteoblasts, the principal bone-forming cells, are differentiated from mesenchymal progenitor cells through sequential stages. These stages are identifiable by molecular markers, cell morphology and location. Transcription factors and developmental signals important for osteoblast differentiation have been studied in detail. One such developmental signal is the WNT family of proteins. WNTs are a large family of glycoproteins that activate beta-catenin-dependent or -independent intracellular pathways, both of which are involved in bone formation. However, the mechanism through which WNT signaling stimulates osteoblast differentiation is not well understood. Early studies demonstrated that bone cells consume a large amount of glucose, producing lactate as the major end product even in aerobic conditions, a phenomenon known as aerobic glycolysis. However, the significance of increased aerobic glycolysis for bone formation was not known. Based on the link between metabolic abnormalities and the genetic mutations in WNT pathway components, I hypothesized that WNT regulates cellular metabolism and that such regulation contributes to osteoblast differentiation. I tested this hypothesis in vitro by using ST2 cells, and showed that WNT signaling increased glucose utilization, stimulated aerobic glycolysis via induction of glycolytic enzymes, and suppressed glucose entry to TCA cycle. This process was mostly regulated by a signaling cascade dependent on Lrp5-Rac1-mTORC2 and independent of beta-catenin. Increased glycolysis was important for in vitro osteoblast differentiation and correlated with increased bone formation in WNT hyperactivation mouse models. I tested the functional importance of enhanced aerobic glycolysis in vivo by two different models. First, I showed that pharmacological enhancement of pyruvate entering the TCA cycle attenuated the high-bone mass phenotype caused by hyperactive WNT signaling in the mouse. Second, I showed that genetic deletion of LDHA, the enzyme catalyzing the last step of glycolysis, from osteoblast-lineage cells suppressed normal postnatal bone accrual due to reduced osteoblast number and function. Thus, WNT signaling reprograms glucose metabolism, and WNT-induced metabolic reprogramming contributes to osteoblast differentiation both in vitro and in vivo. Moreover, LDHA is required for optimal bone formation in postnatal mice. Parathyroid hormone (PTH) has been an effective bone anabolic drug in the clinic by targeting osteoblasts and stimulating bone formation. However, it is not well understood how PTH signaling stimulates bone formation. In early studies, PTH was shown to alter cellular metabolism towards lactate production. In light of the role of metabolic regulation in WNT-induced bone formation, I examined the potential role of metabolic alterations in mediating the anabolic effect of PTH. In MC3T3-E1 cells and neonatal calvarial cells, I showed that PTH enhanced glucose uptake and aerobic glycolysis, activated pentose phosphate pathway but reduced contribution of glucose to TCA cycle. PTH-induced glucose utilization required IGF-PI3K-SGK1 signaling. Importantly, pharmacological enhancement of pyruvate entering the TCA cycle attenuated the bone anabolic effect by PTH. Thus, changes in cellular glucose metabolism may be an important mechanism mediating the anabolic effect of PTH. This thesis confirms the earlier findings that lactate-producing glycolysis is an important feature of osteoblasts, and further characterizes the alterations of cellular metabolism during osteoblast differentiation in response to both WNT and PTH pathways. More importantly, this thesis shows for the first time that metabolic alterations are functionally important for the differentiation process

INVESTIGATING THE RELATIONSHIP BETWEEN TRUST TO MANAGER AND TRUST TO ORGANIZATION IN SERVICE SECTOR

Güven uzun süreli ilişkilerin, geçmiş deneyimlerin neticesinde doğan ve bu ilişkilerin kalitesine göre sürdürülebilir olan bir kavramdır. Güvenin özünde, dürüstlük, tutarlılık, açıklık, eşitlik, kararlara katılım, karşılıklı iletişim, güdülenme, destek görme gibi bağlılık yaratan değerler yatmaktadır. Örgüt içerisinde güven kavramının ortaya çıkış alanları ise, özellikle kuruma güven ve yöneticiye güven şekillerinde olmaktadır. Yöneticiye güven dendiğinde, çalışanın bağlı olduğu yöneticisine karşı duyduğu itimat, bağlılık, sadakat akla gelmektedir. Çalışan yöneticisine güven duyduğu zaman, bu güveni çalıştığı kuruma da mal edebilmekte ve genelleyebilmektedir. Hatta kurumunu, bağlı olduğu yöneticisi ile ifade etmekte veya özdeşleştirmektedir. Kuruma güven dendiğinde de, tüm çalışanların beklentilerinin ve inançlarının karşılanması akla gelmektedir. Bu araştırmada, hizmet sektöründe çalışanların yöneticilerine duydukları güven ile kurumlarına duydukları güven arasındaki ilişki belirlenmeye çalışılmıştır. Bu amaçla, sektör kapsamında 280 çalışana kuruma güven ve yöneticiye güveni ayrı ayrı ölçen bir anket uygulanmıştır. Çıkan sonuçlara göre, kurumun güven sağlayan özellikleri ile yöneticinin güven sağlayan özellikleri arasında anlamlı ve kuvvetli ilişkiler bulunmuştur.Trust is a concept which is sustainable emerged from long-term relationships and the result of past experiences and based on the quality of these relationships. Such values which creates honesty, integrity, openess, equality, participation to decision, communication, motivation inherence in trust. Related trust areas in the organization are trust to organization and trust to manager. Trust to managers is based on belief, commitment and loyalty of employees. When employees trust to their managers, this trust can generalize to the organization. Trust to managers is about meeting employees’ expectations and beliefs. In this study, the relationship between trust to manager and trust to organization are examined in service sector. By this purpose, a questionnaire which measures trust to manager and trust to organization was applied to 280 employees in service sector. According to results of the study, it was found that there is a strong and significant relations between trust to managers and trust to organizatio

WHISTLEBLOWING IN ORGANIZATIONS

Günümüzde çalışma hayatında ahlaki olarak nitelendirilebilecek davranışlarkadar, ahlaki olmayan ve hem kuruma, hem de çalışanlara zarar veren davranışlara dasıklıkla rastlanmaktadır. İşletmenin kaynaklarını kötüye kullanmak, hırsızlık yapmak,rüşvet vermek veya almak, ayrımcılık yapmak, yasaları ihlal etmek gibi birçok davranış bukategoride değerlendirilirken, bu davranışların ortaya çıkışı ile birlikte hem örgüt içindehem de örgüt dışında duyurulması da önemli hale gelmiştir. Whistleblowing (duyurma)kavramı, işte kurumlarda ahlaki olmayan bu davranışların kurum içinde ve kurum dışındaduyurulmasını ifade etmektedir.Bu çalışmanın amacı, whistleblowing kavramına ilişkin olarak yapılacakoperasyonel bir tanım çerçevesinde, kavramın çalışma hayatında hukuki açıdandeğerlendirmesini yapmak ve bu eylemi yapan çalışanların korunmasına yönelik olarakbaşvurulabilecek olanaklara ilişkin değerlendirmelerde bulunmaktır. In organizations, employees meet ethical behavior and also unethical behaviorwhich damage organizations and employees. Whistleblowing occurs as usingorganizations' resources badly, stealing, bribing, discrimination, do not obeying the rulesin organizations. That is so important to blowing these kinds of behaviors. Whistleblowingis about reflecting unethical behavior inside and outside the organizations.The purpose of the study is giving an operational definition of whistleblowing,investigating whistleblowing in organizations in terms of legal regulations and evaluatingof protecting whistleblowers

Fusariosis manifesting as targetoid purpuric cutaneous lesions in immunocompromised patients

[No abstract available

Increased glutamine catabolism mediates bone anabolism in response to WNT signaling

WNT signaling stimulates bone formation by increasing both the number of osteoblasts and their protein-synthesis activity. It is not clear how WNT augments the capacity of osteoblast progenitors to meet the increased energetic and synthetic needs associated with mature osteoblasts. Here, in cultured osteoblast progenitors, we determined that WNT stimulates glutamine catabolism through the tricarboxylic acid (TCA) cycle and consequently lowers intracellular glutamine levels. The WNT-induced reduction of glutamine concentration triggered a general control nonderepressible 2–mediated (GCN2-mediated) integrated stress response (ISR) that stimulated expression of genes responsible for amino acid supply, transfer RNA (tRNA) aminoacylation, and protein folding. WNT-induced glutamine catabolism and ISR were β-catenin independent, but required mammalian target of rapamycin complex 1 (mTORC1) activation. In a hyperactive WNT signaling mouse model of human osteosclerosis, inhibition of glutamine catabolism or Gcn2 deletion suppressed excessive bone formation. Together, our data indicate that glutamine is both an energy source and a protein-translation rheostat that is responsive to WNT and suggest that manipulation of the glutamine/GCN2 signaling axis may provide a valuable approach for normalizing deranged protein anabolism associated with human diseases

Outcomes of high-risk breast lesions diagnosed using image-guided core needle biopsy: results from a multicenter retrospective study

PURPOSEThe clinical management of high-risk lesions using image-guided biopsy is challenging. This study aimed to evaluate the rates at which such lesions were upgraded to malignancy and identify possible predictive factors for upgrading high-risk lesions.METHODSThis retrospective multicenter analysis included 1.343 patients diagnosed with high-risk lesions using an image-guided core needle or vacuum-assisted biopsy (VAB). Only patients managed using an excisional biopsy or with at least one year of documented radiological follow-up were included. For each, the Breast Imaging Reporting and Data System (BI-RADS) category, number of samples, needle thickness, and lesion size were correlated with malignancy upgrade rates in different histologic subtypes. Pearson’s chi-squared test, the Fisher–Freeman–Halton test, and Fisher’s exact test were used for the statistical analyses.RESULTSThe overall upgrade rate was 20.6%, with the highest rates in the subtypes of intraductal papilloma (IP) with atypia (44.7%; 55/123), followed by atypical ductal hyperplasia (ADH) (38.4%; 144/375), lobular neoplasia (LN) (12.7%; 7/55), papilloma without atypia (9.4%; 58/611), flat epithelial atypia (FEA) (8.7%; 10/114), and radial scars (RSs) (4.6%; 3/65). There was a significant relationship between the upgrade rate and BI-RADS category, number of samples, and lesion size Lesion size was the most predictive factor for an upgrade in all subtypes.CONCLUSIONADH and atypical IP showed considerable upgrade rates to malignancy, requiring surgical excision. The LN, IP without atypia, pure FEA, and RS subtypes showed lower malignancy rates when the BI-RADS category was lower and in smaller lesions that had been adequately sampled using VAB. After being discussed in a multidisciplinary meeting, these cases could be managed with follow-up instead of excision

The Role of Trust on the Relationship Between Organizational Engagement and Corporate Reputation(Çalışanların Örgüte Cezbolması ve Kurumların İtibarı İlişkisinde Güvenin Rolü)

The purpose of this study is to examine the role of organizational trust between corporate reputation practices and organizational engagement in airline sector. In the first section, results of the relationship between corporate reputation practices, organizational trust and organizational engagement are examined. In the following section, data was gathered from 343 participants. According to the results of the study, corporate reputation practices and organizational trust have effect on organizational engagement but organizational trust hasn’t had any intervening role between these variables

The role of trust on the relationship between organizational engagement and corporate reputation = (Çalışanların örgüte cezbolması ile kurumların itibar uygulamaları ilişkisinde güvenin rolü)

ÖZETÇALIŞANLARIN ÖRGÜTE CEZBOLMASI İLE KURUMLARIN İTİBAR UYGULAMALARI İLE İLİŞKİSİNDE GÜVENİN ROLÜBu araştırmanın amacı, kurumların itibarlarını yansıtacak şekilde kurum içindeki ve kurum dışındaki paydaşlara yönelik olarak yapmış oldukları faaliyetlerin, çalışanların kurumlarına güven duymaları üzerindeki etkisini ortaya koymak ve kuruma duyulan güvenin, çalışanların örgütlerine cezbolmalarını ne derecede etkilediğini havacılık sektöründe saptayabilmektir.Bu doğrultuda birinci bölümde, araştırma modelinde yer verilen değişkenlerden kurumların itibar uygulamaları, kuruma güven, yöneticiye güven ve örgüte cezbolma kavramları açıklanmış ve bu kavramların birbirleriyle olan ilişkisine değinilmiştir. Araştırmanın ikinci bölümünde ise, havacılık sektöründe yapılan ve 343 denekten toplanan anket verileri değerlendirmeye alınmıştır. Çıkan sonuçlara göre, kurumların itibar uygulamaları ve kuruma güven, yöneticiye güven çalışanların örgüte cezbolmasını ortaya çıkarırken, örgüte cezbolmayı açıklayan en önemli değişkenin yöneticiye güven olduğu ortaya konmuştur. Bununla birlikte kurumların itibar uygulamaları ile örgüte cezbolma arasındaki ilişkide kuruma güvenin aracı olmadığı ifade edilmiştir. Kurumların itibar uygulamaları, kuruma güven ve yöneticiye güven açısından en yüksek değerlendirmelere sahip katılımcılar, eğitim seviyesi yüksek olanlar ile yönetici pozisyonunda olanlardır. Yüzde yüz yabancı şirketlerde çalışanlar, kuruma güveni en yüksek olanlardır. Ayrıca çalışma süresi daha uzun olanlar, kurumların itibarını yükselten uygulamaların daha yaygın olduğunu düşünmektedir.ABSTRACTTHE ROLE OF TRUST ON THE RELATIONSHIP BETWEEN ORGANIZATIONAL ENGAGEMENT AND CORPORATE REPUTATION The purpose of this study is to examine the role of organizational trust between corporate reputation practices, which reflects the shareholders’ perceptions and organizational engagement in airline sector. Corporate reputation practices which reflect the importance of practices for employees are assumed as a moderating variable to change the relationship between corporate reputation practices and organizational trust and also, managerial trust is assumed to change the relationship between organizational trust and organizational engagement. In the first section, results of the relationship between corporate reputation practices, importance of corporate reputation practices, organizational trust, managerial trust and organizational trust are examined. In the following section, data was gathered from 343 participants. According to the results of the study, managerial trust, corporate reputation practices, organizational trust have effect on organizational engagement. Especially managerial trust has the highest effect on organizational engagement. Also, Employees who are highly educated and have managerial positions, have high scores about corporate reputation practices, organizational trust and managerial trust. Employees who work in 100% foreign companies, have high trust in their organization and employees who have long working experience believe that corporate reputation practices are more common in the organization