Characterization of Fms-interacting protein (FMIP), a novel substrate for tyrosine kinase : connection between receptor tyrosine kinase signaling and mRNA-processing

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Pathways linking aging and atheroprotection in Mif‐deficient atherosclerotic mice

Atherosclerosis is a chronic inflammatory condition of our arteries and the main underlying pathology of myocardial infarction and stroke. The pathogenesis is age-dependent, but the links between disease progression, age, and atherogenic cytokines and chemokines are incompletely understood. Here, we studied the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) in atherogenic Apoe−/− mice across different stages of aging and cholesterol-rich high-fat diet (HFD). MIF promotes atherosclerosis by mediating leukocyte recruitment, lesional inflammation, and suppressing atheroprotective B cells. However, links between MIF and advanced atherosclerosis across aging have not been systematically explored. We compared effects of global Mif-gene deficiency in 30-, 42-, and 48-week-old Apoe−/− mice on HFD for 24, 36, or 42 weeks, respectively, and in 52-week-old mice on a 6-week HFD. Mif-deficient mice exhibited reduced atherosclerotic lesions in the 30/24- and 42/36-week-old groups, but atheroprotection, which in the applied Apoe−/− model was limited to lesions in the brachiocephalic artery and abdominal aorta, was not detected in the 48/42- and 52/6-week-old groups. This suggested that atheroprotection afforded by global Mif-gene deletion differs across aging stages and atherogenic diet duration. To characterize this phenotype and study the underlying mechanisms, we determined immune cells in the periphery and vascular lesions, obtained a multiplex cytokine/chemokine profile, and compared the transcriptome between the age-related phenotypes. We found that Mif deficiency promotes lesional macrophage and T-cell counts in younger but not aged mice, with subgroup analysis pointing toward a role for Trem2+ macrophages. The transcriptomic analysis identified pronounced MIF- and aging-dependent changes in pathways predominantly related to lipid synthesis and metabolism, lipid storage, and brown fat cell differentiation, as well as immunity, and atherosclerosis-relevant enriched genes such as Plin1, Ldlr, Cpne7, or Il34, hinting toward effects on lesional lipids, foamy macrophages, and immune cells. Moreover, Mif-deficient aged mice exhibited a distinct plasma cytokine/chemokine signature consistent with the notion that mediators known to drive inflamm'aging are either not downregulated or even upregulated in Mif-deficient aged mice compared with the corresponding younger ones. Lastly, Mif deficiency favored formation of lymphocyte-rich peri-adventitial leukocyte clusters. While the causative contributions of these mechanistic pillars and their interplay will be subject to future scrutiny, our study suggests that atheroprotection due to global Mif-gene deficiency in atherogenic Apoe−/− mice is reduced upon advanced aging and identifies previously unrecognized cellular and molecular targets that could explain this phenotype shift. These observations enhance our understanding of inflamm'aging and MIF pathways in atherosclerosis and may have implications for translational MIF-directed strategies

The role of expert wi̇tness testi̇mony i̇n medi̇cal malprracti̇ce cases

Thesis (M.A.)--Özyeğin University, Graduate School of Social Sciences, Department of Institute of Social Sciences Department of Private Law, 2014.Bilirkişi görüşlerinin davaların sonuçlandırılmasında çok etkili bir rolü vardır. Mahkemeler, ceza ve hukuk davalarında, Hakimlerin çözmekte zorlandığı bilimsel konulara açıklık getirmek için bilirkişilerin görüşlerine başvururlar. Ülkemizde son yıllarda hatalı tıbbi müdahale iddiasıyla açılan davalarda büyük bir artış gözlenmektedir. Mahkemeler ve Hakimler, bilirkişilerin temel tıp kurallarına, kabul edilebilir tedavi seçeneklerine ilişkin açıklamaları ve yorumları olmadan tıbbi müdahale hatalarını komplikasyonlardan ayıramazlar. Ülkemizdeki kanunlara göre, mesleği yapmaya yetkili olan tüm hekimlerin tıbbi bilirkişilik yükümlülüğü de vardır. Adli Tıp Kurumu, Yüksek Sağlık Şurası, Adli Tıp Enstitüleri ve Üniversiteler halen ülkemizde bilirkişilik hizmeti veren kurumlardır. Biz burada, tıp camiasında, mahkemelerde ve sosyal mediada sıklıkla tartışma konusu olan tıbbi müdahale hatasıyla komplikasyonun ayırımını inceledik. Adli Tıp Kurumu ve Yüksek Sağlık Şurası tarafından verilen bir takım hatalı, eksik ve bilimsel olmayan tıbbi bilirkişi raporlarını mercek altına aldık. Bu çalışma güvenilir, tarafsız, objektif ve bilimsel tıbbi bilirkişi raporlarının hatalı tıbbi müdahale davalarındaki önemini tartışmakta, tıbbi bilirkişilerin bilginin tarafsız taşıyıcısı olmaları gerektiğini vurgulamaktadır. Tıbbi bilirkişilerin verdikleri hizmetin kalitesini arttırmak ve nihayetinde daha doğru, dürüst ve adil sonuçlara ulaşabilmesi için tavsiyelerde bulunduk. İnsanların daha sağlıklı ve adil bir yaşam sürmelerini sağlayarak, global düzeyde iyi olma halini hedefleyen tıp ve hukuk bilim dallarının birlikte harmoni içinde çalışmaları halinde çok daha etkili olabilecekleri sonucuna vardık.The expert witness testimony plays an essential role in the litigation process. Courts rely on expert witness testimony in most civil and criminal cases to explain scientific matters that may not be understood by judges. Malpractice litigation proceedings begin to rise significiantly in our country recenntly. Courts and Judges can not distinguish malpractice cases from the compliciations without the medical expert's explanation of the acceptable treatment modalities and interpretation of medical facts. We here examined the issue of deciding between a medical complication and a medical error, the subject which has been frequently debated among doctors, at court trials and in media. According to the legislation laws in our country, medical expert testimony charge has been given to all physicians that are authorized in their profession. Forensic Medicine Institution, Superior Healt Council, Forensic Medicine Institudes and Universities currently serve as medical experts in our country. We focused on the some inaccurate, incomplete or unscientific expert testimony reports given by the Forensic Medicine Institution and Superior Healt Cuncil in medical malpractice law cases. The paper discusses the importance of reliable, objective, unbiased and scientific expert witness testimony in medical malpractices cases and stresses that expert witnesses should be unbiased conveyers of information. We made some recommendations in order to improve the quality of medical expert witnesss testimony in legal malpractice proceedings and thereby, achieve the much more fair, honest and equitable outcomes. We concluded that Both law and medicine are critical tools for improving health and well-being on a global level, and each profession is more effective when the two work together

D-dopachrome tautomerase in cardiovascular and inflammatory diseases-A new kid on the block or just another MIF?

Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF

Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts

The TREX (transcription/export) complex has been conserved throughout evolution from yeast to man and is required for coupled transcription elongation and nuclear export of mRNAs. The TREX complex in mammals and Drosophila is composed of the THO subcomplex (THOC1, THOC2, THOC5, THOC6, and THOC7), THOC3, UAP56, and Aly/THOC4. In human and Drosophila, various studies have shown that THO is required for the export of heat shock mRNAs, but nothing is known about other mRNAs. Our previous study using conditional THOC5 (or FMIP) knockout mice revealed that the presence of THOC5 is critical in hematopoietic cells but not for terminally differentiated cells. In this study, we describe the establishment of a mouse embryo fibroblast cell line (MEF), THOC5 flox/flox. Four days after infection of MEF THOC5 flox/flox with adenovirus carrying Cre-recombinase gene (Ad-GFP-Cre), THOC5 is down-regulated >95% at the protein level, and cell growth is strongly suppressed. Transcriptome analysis using cytoplasmic RNA isolated from cells lacking functional THOC5 reveals that only 2.9% of all genes were down-regulated more than twofold. Although we examined these genes in fibroblasts, one-fifth of all down-regulated genes (including HoxB3 and polycomb CBX2) are known to play a key role in hematopoietic development. We further identified 10 genes that are spliced but not exported to the cytoplasm in the absence of THOC5. These mRNAs were copurified with THOC5. Furthermore, Hsp70 mRNA was exported in the absence of THOC5 at 37°C, but not under heat shock condition (42°C), suggesting that THOC5 may be required for mRNA export under stress and/or upon signaling-induced conditions

MIF Promotes B Cell Chemotaxis through the Receptors CXCR4 and CD74 and ZAP-70 Signaling

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine-like functions that plays a pivotal role in the pathogenesis of inflammatory diseases by promoting leukocyte recruitment. We showed that MIF promotes the atherogenic recruitment of monocytes and T cells through its receptors CXCR2 and CXCR4. Effects of MIF on B cell recruitment have not been addressed. In this study, we tested the involvement of MIF in B cell chemotaxis and studied the underlying mechanism. We show that MIF promotes primary murine B cell chemotaxis in a dose-dependent manner, comparable to the B cell chemokines CXCL13 and CXCL12. Splenic B cells express CXCR4 and the receptor CD74 but not CXCR2. Inhibition of CXCR4 or CD74 or a genetic deficiency of Cd74 in primary B cells fully abrogated MIF-mediated B cell migration, implying cooperative involvement of both receptors. MIF stimulation of B cells resulted in a rapid increase in intracellular Ca²⁺ mobilization and F-actin polymerization. Intriguingly, the tyrosine kinase ZAP-70 was activated upon MIF and CXCL12 treatment in a CXCR4- and CD74-dependent manner. Pharmacological inhibition of ZAP-70 resulted in abrogation of primary B cell migration. Functional involvement of ZAP-70 was confirmed by small interfering RNA-mediated knockdown in Ramos B cell migration. Finally, primary B cells from ZAP-70 gene-deficient mice exhibited ablated transmigration in response to MIF or CXCL12. We conclude that MIF promotes the migration of B cells through a ZAP-70-dependent pathway mediated by cooperative engagement of CXCR4 and CD74. The data also suggest that MIF may contribute to B cell recruitment in vivo (e.g., in B cell-related immune disorders)