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Item Metadata only In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype(Oxford Univ Press, 2023) 0000-0002-4070-7997; Laberthonniere, Camille; Delourme, Megane; Chevalier, Raphael; Dion, Camille; Ganne, Benjamin; Hirst, David; Caron, Leslie; Perrin, Pierre; Adelaide, Jose; Chaffanet, Max; Xue, Shifeng; Nguyen, Karine; Reversade, Bruno; Dejardin, Jerome; Baudot, Anais; Robin, Jerome D.; Magdinier, Frederique; N/A; Reversade, Bruno; Faculty Member; School of Medicine; 274182Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.Item Metadata only Dynamic regulation of the serine loop by distant mutations reveals allostery in cryptochrome1(Taylor and Francis Inc, 2023) 0000-0001-6624-3505; N/A; Gul, Seref; Department of Chemical and Biological Engineering; N/A; Kavaklı, İbrahim Halil; Özcan, Onur; Faculty Member; PhD Student; College of Engineering; Graduate School of Sciences and Engineering; 40319; N/ACryptochromes (CRYs) are essential components of the molecular clock that generates circadian rhythm. They inhibit BMAL1/CLOCK-driven transcription at the molecular level. There are two CRYs that have differential functions in the circadian clock in mammals. It is not precisely known how they achieve such differential functions. In this study, we performed molecular dynamic simulations on eight CRY mutants that have been experimentally shown to exhibit reduced repressor activities. Our results revealed that mutations in CRY1 affect the dynamic behavior of the serine loop and the availability of the secondary pocket, but not in CRY2. Further analysis of these CRY1 mutants indicated that the differential flexibility of the serine loop leads to changes in the volume of the secondary pocket. We also investigated the weak interactions between the amino acids in the serine loop and those in close proximity. Our findings highlighted the crucial roles of S44 and S45 in the dynamic behavior of the serine loop, specifically through their interactions with E382 in CRY1. Considering the clinical implications of altered CRY1 function, our study opens up new possibilities for the development of drugs that target the allosteric regulation of CRY1.Communicated by Ramaswamy H. SarmaItem Metadata only Boric Acid Improved Cryopreserved Mouse Embryo Development(Springernature, 2023) 0000-0002-2365-7246; askin, A. C.; N/A; Kocabay, Ahmet; Other; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/ABoric acid (BA) is an essential trace element that is required to support the metabolic pathways in plants, humans, and animals. The present study investigates the in vitro development and quality of single-cell mouse embryos in a BA-added culture medium after cryopreservation using the solid-surface vitrification method. For this purpose, the pronuclear-stage embryos derived from superovulated C57Bl/6j mouse strains and the one-cell embryos were then cryopreserved using the solid-surface vitrification (SSV) method. After thawing, the embryos were cultured in a BA-added medium at 37 degrees C in a 5% CO2 environment until the blastocyst stage. The resulting in vitro development rates of the embryos in the control group, SSV group, and SSV + 1.62 x 10-4 mu M BA group were 68.11% (36/59), 40.16% (16/48), and 64.92% (28/48) respectively, indicating that the BA supported the in vitro development of the embryos cryopreserved using the SSV method. Our results suggest that the addition of boric acid to the culture media increased the development rate of the embryos that were vitrified using the SSV method.Item Metadata only Behçet's disease: a comprehensive review on the role of HLA-B*51, antigen presentation, and inflammatory cascade(MDPI, 2023) 0000-0002-0866-865X; 0000-0001-6561-196X; 0000-0003-3222-874X; 0000-0002-9923-205X; N/A; N/A; N/A; N/A; Khoshbakht, Saba; Vural, Seçil; Vural, Atay; Başkurt, Defne; PhD Student; Faculty Member; Faculty Member; Undergraduate Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; School of Medicine; School of Medicine; School of Medicine; N/A; 189340; 182369; N/ABehcet's disease (BD) is a complex, recurring inflammatory disorder with autoinflammatory and autoimmune components. This comprehensive review aims to explore BD's pathogenesis, focusing on established genetic factors. Studies reveal that HLA-B*51 is the primary genetic risk factor, but non-HLA genes (ERAP1, IL-10, IL23R/IL-12RB2), as well as innate immunity genes (FUT2, MICA, TLRs), also contribute. Genome-wide studies emphasize the significance of ERAP1 and HLA-I epistasis. These variants influence antigen presentation, enzymatic activity, and HLA-I peptidomes, potentially leading to distinct autoimmune responses. We conducted a systematic review of the literature to identify studies exploring the association between HLA-B*51 and BD and further highlighted the roles of innate and adaptive immunity in BD. Dysregulations in Th1/Th2 and Th17/Th1 ratios, heightened clonal cytotoxic (CD8+) T cells, and reduced T regulatory cells characterize BD's complex immune responses. Various immune cell types (neutrophils, gamma delta T cells, natural killer cells) further contribute by releasing cytokines (IL-17, IL-8, GM-CSF) that enhance neutrophil activation and mediate interactions between innate and adaptive immunity. In summary, this review advances our understanding of BD pathogenesis while acknowledging the research limitations. Further exploration of genetic interactions, immune dysregulation, and immune cell roles is crucial. Future studies may unveil novel diagnostic and therapeutic strategies, offering improved management for this complex disease.Item Metadata only SGLT-2 Inhibitors and Nephroprotection in Patients with Diabetic and Non-diabetic Chronic Kidney Disease(Bentham Science Publ Ltd, 2023) 0000-0002-1297-0675; Sarafidis, Pantelis; Pella, Eva; Papagianni, Aikaterini; N/A; Kanbay, Mehmet; Faculty Member; School of Medicine; 110580For several years, blood pressure control and blocking of the renin-angiotensin system (RAS) represented the cornerstones of chronic kidney disease (CKD) treatment. Cardiovascular outcome trials with sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with type 2 diabetes mellitus (DM) suggested that these agents can effectively delay the progression of CKD in these individuals. A major nephroprotective effect of canagliflozin was also shown in a renal outcome trial in patients with proteinuric diabetic CKD. The Study-to- Evaluate-the-Effect- of-Dapagliflozin-on-Renal-Outcomes-and-Cardiovascular- Mortality-in-Patients-With-Chronic-Kidney-Disease (DAPA-CKD) is a recent milestone in the field, as it included patients with both diabetic and non-diabetic proteinuric CKD and showed impressive reduction in the primary renal outcome of CKD progression, as well as the risk of hospitalization for heart failure and all-cause mortality on top of standard- of-care treatment. These benefits were consistent for patients with diabetic and non-diabetic CKD, including patients with ischemic or hypertensive nephropathy and glomerulonephritides (IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy). Based on the above, relevant guidelines should accommodate their recommendations to implement treatment with SGLT-2 inhibitors for CKD patients.Item Metadata only The signalling lipid PI3,5P 2 is essential for timely mitotic exit(Royal Society Publishing, 2023) 0000-0003-2570-1367; N/A; N/A; 0000-0002-3470-7421; Department of Molecular Biology and Genetics; N/A; N/A; N/A; Çaydaşı, Ayşe Koca; Bektaş, Şeyma Nur; Bekdaş, Barış; Huda, Mariam; Faculty Member; PhD Student; Master Student; PhD Student; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; 252978; N/A; N/A; N/ACoordination of mitotic exit with chromosome segregation is key for successful mitosis. Mitotic exit in budding yeast is executed by the mitotic exit network (MEN), which is negatively regulated by the spindle position checkpoint (SPOC). SPOC kinase Kin4 is crucial for SPOC activation in response to spindle positioning defects. Here, we report that the lysosomal signalling lipid phosphatidylinositol-3,5-bisphosphate (PI3,5P 2) has an unanticipated role in the timely execution of mitotic exit. We show that the lack of PI3,5P 2 causes a delay in mitotic exit, whereas elevated levels of PI3,5P 2 accelerates mitotic exit in mitotic exit defective cells. Our data indicate that PI3,5P 2 promotes mitotic exit in part through impairment of Kin4. This process is largely dependent on the known PI3,5P 2 effector protein Atg18. Our work thus uncovers a novel link between PI3,5P 2 and mitotic exit. © 2023 Royal Society Publishing. All rights reserved.Item Metadata only Exosome-loaded microneedle patches: Promising factor delivery route(Elsevier, 2023) 0000-0003-2945-018X; Fathi-Karkan, Sonia; Narmi, Maryam Taghavi; Mardi, Narges; Amini, Hassan; Saghati, Sepideh; Abrbekoh, Fateme Nazary; Saghebasl, Solmaz; Rahbarghazi, Reza; Khoshfetrat, Ali Baradari; N/A; Heidarzadeh, Morteza; PhD Student; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health SciencesDuring the past decades, the advent of different microneedle patch (MNPs) systems paves the way for the targeted and efficient delivery of several growth factors into the injured sites. MNPs consist of several micro-sized (25-1500 & mu;m) needle rows for painless delivery of incorporated therapeutics and increase of regenerative outcomes. Recent data have indicated the multifunctional potential of varied MNP types for clinical applications. Advances in the application of materials and fabrication processes enable researchers and clinicians to apply several MNP types for different purposes such as inflammatory conditions, ischemic disease, metabolic disorders, vaccination, etc. Exosomes (Exos) are one of the most interesting biological bioshuttles that participate in cell-tocell paracrine interaction with the transfer of signaling biomolecules. These nano-sized particles, ranging from 50 to 150 nm, can exploit several mechanisms to enter the target cells and deliver their cargo into the cytosol. In recent years, both intact and engineered Exos have been increasingly used to accelerate the healing process and restore the function of injured organs. Considering the numerous benefits provided by MNPs, it is logical to hypothesize that the development of MNPs loaded with Exos provides an efficient therapeutic platform for the alleviation of several pathologies. In this review article, the authors collected recent advances in the application of MNP-loaded Exos for therapeutic purposes.Publication Metadata only 3D printed styrax liquidus (liquidambar orientalis miller)-loaded poly (l-lactic acid)/chitosan based wound dressing material: fabrication, characterization, and biocompatibility results(Elsevier, 2023) Cakmak, Hanife Yuksel; Ege, Hasan; Yilmaz, Senanur; Agturk, Gokhan; Enguven, Gozde; Sarmis, Abdurrahman; Cakmak, Zeren; Gunduz, Oguzhan; Ege, Zeynep Ruya; Yöntem, Fulya Dal; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of MedicineThe medicinal plant of Styrax liquidus (ST) (sweet gum balsam) which extracted from Liquidambar orientalis Mill tree, was loaded into the 3D printed polylactic acid (PLA)/chitosan (CS) based 3D printed scaffolds to investigate its wound healing and closure effect, in this study. The morphological and chemical properties of the ST loaded 3D printed scaffolds with different concentrations (1 %, 2 %, and 3 % wt) were investigated by Scanning Electron Microscopy (SEM) and Fourier Transform Infrared Spectroscopy (FT-IR), respectively. In addition, the me-chanical and thermal properties of the materials were investigated by Tensile test and Differential Scanning Calorimetry (DSC), respectively. The antimicrobial activities of the ST loaded 3D printed scaffolds and their incubation media in the PBS (pH 7.4, at 37 degrees C for 24 h) were investigated on two Gram-positive and two Gram -negative standard pathogenic bacteria with the agar disc diffusion method. The colorimetric MTT assay was used to determine the cell viability of human fibroblast cells (CCD-1072Sk) incubated with free ST, ST loaded, and unloaded 3D printed scaffolds. The 1 % and 2 % (wt) ST loaded PLA/CS/ST 3D printed scaffolds showed an increase in the cell number. Annexin V/PI double stain assay was performed to test whether early or late apoptosis was induced in the PLA/CS/1 % ST and PLA/CS/2 % ST loaded groups and the results were consistent with the MTT assay. Furthermore, a wound healing assay was carried out to investigate the effect of ST loaded 3D printed scaffolds on wound healing in CCD-1072Sk cells. The highest wound closure compared to the control group was observed on cells treated with PLA/CS/1 % ST for 72 h. According to the results, novel biocompatible ST loaded 3D printed scaffolds with antimicrobial effect can be used as wound healing material for potential tissue engineering applications.Publication Metadata only Author correction: combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma(Nature Research, 2024) Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT.; Koç University HospitalIn the originally published version of this article, there were errors in the histological sections depicted in Supplementary Figs. 4 and 10. Specifically: In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped In Supplementary Fig. 4, the image of the Ki67 immunohistochemistry (IHC) for the Gemcitabine+JQ1 group was incorrect In Supplementary Fig. 10, the pSTAT3 image for the IHC for the JQ1 group was incorrect In Supplementary Fig. 10, Ki67 and MYC IHC images for JQ1 and JQ1+SAHA were swapped The original data were available and these errors have been corrected in the Supplementary Information accompanying this notice. Additionally, the authors wish to clarify that the Sirius Red staining for the control and JQ1 groups were identical in both Supplementary Figs. 4 and 10 because the control mice (JQ1 only or control treatment) were shared between experiments. To avoid confusion, the sections depicting Sirius Red staining for the control and JQ1 groups in Supplementary Fig. 4 were replaced with alternative sections from the same respective samplesPublication Metadata only Characterization and comparison of insulinoma tumor model and pancreatic damage caused by the tumor, and identification of possible markers(Springer Science and Business Media B.V., 2024) Karatug Kacar, Ayse; Aylar, Dilara; Celikten, Mert; Bolkent, Sehnaz; Bulutay, Pınar; School of MedicineInsulinoma is a neuroendocrine tumor. It arises from the uncontrolled proliferation of pancreatic β cells. In this study, we created an insulinoma tumor model in nude mice. INS-1 cells were injected in two different ways, subcutaneously (S.C.) or intraperitoneally (I.P.). Body weight, tumor weight, and size were measured. ELISA kits were used analyze to Glucose, insulin, and CA19-9 levels in serum, pancreas, and tumor tissues. KCNN4, KCNK1, GLUT2, IR, HSP70, HSF1, and HSP90 levels were analyzed by western blotting of membrane and/or cytosolic fractions of tumor and pancreas tissue. Tumor formation occurred in nude mice, but it did not occur in Wistar albino rats. The tumor has neuroendocrine cell morphology. Insulin and CA19-9 levels increased in pancreas tissue. In tumor tissue, KCNN4 levels were higher in both membrane and cytosolic fractions, while KCNK1 levels were lower in the membrane fraction of the S.C. group. HSP70 levels were also lower in the S.C. group. In pancreas tissue, KCNK1 levels were lower in the membrane fraction of the S.C. and I.P. groups. GLUT2 levels increased in both groups according to the control group, while IR levels decreased in the S.C. group compared to the control group. However, HSF1 levels increased in the I.P. group, while HSP90 decreased in the S.C. group in pancreatic tissues. The S.C. group is a more suitable insulinoma tumor model. KCNN4, KCNK1, and HSP70 proteins may be important biomarkers in the diagnosis and treatment of insulinoma.