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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/6
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Publication Open Access The structural basis of Akt PH domain interaction with calmodulin(Elsevier, 2021) Jang, Hyunbum; Nussinov, Ruth; N/A; Department of Chemical and Biological Engineering; Department of Computer Engineering; Weako, Jackson; Keskin, Özlem; Gürsoy, Attila; Faculty Member; Department of Chemical and Biological Engineering; Department of Computer Engineering; Graduate School of Sciences and Engineering; College of Engineering; N/A; 26605; 8745Akt plays a key role in the Ras/PI3K/Akt/mTOR signaling pathway. In breast cancer, Akt translocation to the plasma membrane is enabled by the interaction of its pleckstrin homology domain (PHD) with calmodulin (CaM). At the membrane, the conformational change promoted by PIP3 releases CaM and facilitates Thr308 and Ser473 phosphorylation and activation. Here, using modeling and molecular dynamics simulations, we aim to figure out how CaM interacts with Akt's PHD at the atomic level. Our simulations show that CaM-PHD interaction is thermodynamically stable and involves a beta-strand rather than an alpha-helix, in agreement with NMR data, and that electrostatic and hydrophobic interactions are critical. The PHD interacts with CaM lobes; however, multiple modes are possible. IP4, the polar head of PIP3, weakens the CaM-PHD interaction, implicating the release mechanism at the plasma membrane. Recently, we unraveled the mechanism of PI3K alpha activation at the atomistic level and the structural basis for Ras role in the activation. Here, our atomistic structural data clarify the mechanism of how CaM interacts, delivers, and releases Akt-the next node in the Ras/PI3K pathway-at the plasma membrane.Publication Open Access Increased hemoglobin oxygen affinity with 5-hydroxymethylfurfural supports cardiac function during severe hypoxia(Frontiers, 2019) Lucas, Alfredo; Ao-ieong, Eilleen S. Y.; Williams, Alexander T.; Jani, Vivek P.; Muller, Cynthia R; Cabrales, Pedro; N/A; Yalçın, Özlem; Researcher; School of Medicine; 218440Acclimatization to hypoxia or high altitude involves physiological adaptation processes, to influence oxygen (O2) transport and utilization. Several natural products, including aromatic aldehydes and isothiocyanates stabilize the R-state of hemoglobin (Hb), increasing Hb-O2 affinity and Hb-O2 saturation. These products are a counter intuitive therapeutic strategy to increase O2 delivery during hypoxia. 5-Hydroxymethylfurfural (5-HMF) is well known Amadori compound formed during the Maillard reaction (the non-enzymatic browning and caramelization of carbohydrate-containing foods after thermal treatment), with well documented effects in Hb-O2 affinity. This study explores the therapeutic potential of 5-HMF on left ventricular (LV) cardiac function (LVCF) during hypoxia. Anesthetized Golden Syrian hamsters received 5-HMF i.v., at 100 mg/kg and were subjected to stepwise increased hypoxia (15, 10, and 5%) every 30 min. LVCF was assessed using a closed chest method with a miniaturized conductance catheter via continuous LV pressure-volume (PV) measurements. Heart hypoxic areas were studied using pimonidazole staining. 5-HMF improved cardiac indices, including stroke volume (SV), cardiac output (CO), ejection fraction (EF), and stroke work (SW) compared to the vehicle group. At 5% O2, SV, CO, EF, and SW were increased by 53, 42, 33, and 51% with 5-HMF relative to vehicle. Heart chronotropic activity was not statistically changed, suggesting that differences in LV-CF during hypoxia by 5-HMF were driven by volume dependent effects. Analysis of coronary blood flow and cardiac muscle metabolism suggest no direct pharmacological effects from 5-HMF, therefore these results can be attributed to 5-HMF-dependent increase in Hb-O2 affinity. These studies establish that naturally occurring aromatic aldehydes, such as 5-HMF, produce modification of hemoglobin oxygen affinity with promising therapeutic potential to increase O2 delivery during hypoxic hypoxia.Publication Open Access Fear of happiness among college students: the role of gender, childhood psychological trauma, and dissociation(Medknow Publications, 2019) Türk, Tuğba; Öztürk, Erdinç; N/A; Şar, Vedat; Faculty Member; School of Medicine; 8542Aims: this study aimed to evaluate the fear of happiness among college students and its relationship to gender, childhood psychological trauma, and dissociation. Setting and Design: College students were addressed as study population, and a relational screening method was implemented. Materials and Methods: among 184 participants, 93 (50.5%) were women. The Fear of Happiness Scale (FHS), the Childhood Trauma Questionnaire (CTQ), and the Dissociative Experiences Scale (DES) were administered to all participants. Statistical Analysis Used: MannuWhitney-U and Student's t-tests were implemented for comparison of groups. Pearson correlation and stepwise multiple regression analyses were conducted to identify associations between variables. Results: there were no differences on DES, FHS, and CTQ total scores between genders. DES was associated with CTQ total scores in both genders. Women had higher scores than men on childhood emotional abuse and fear of "cheerfulness ends up with bad faith." Compared to nonmembers, female dissociative taxon members had higher scores on all childhood trauma types except sexual abuse, and on all types of fear of happiness except "good fortune ends up with disaster" which was the only type of fear significantly elevated among male dissociative taxon members. A stepwise regression analysis revealed that depersonalization, childhood emotional neglect, and physical abuse predicted fear of happiness among women which was predicted by absorption among men. Conclusions: there is a relationship between childhood psychological trauma, dissociation, and fear of happiness. Women seem to be more vulnerable in this path of obsessional thinking which affects different realms in male and female genders.Publication Open Access Al2O3 micro- and nanostructures affect vascular cell response(Royal Society of Chemistry (RSC), 2016) Kiefer, Karin; Akpınar, Gürler; Haidar, Ayman; Ikier, Tuba; Akkan, Çağrı Kaan; Akman, Erhan; Lee, Juseok; Miro, Marina Martinez; Kaçar, Elif; Demir, Arif; Veith, Michael; Kasap, Murat; Kesmez, Mehmet; Abdul-Khaliq, Hashim; Aktaş, Cenk; N/A; Ural, Dilek; Faculty Member; School of Medicine; 1057In-stent restenosis (ISR) is one of the most common and serious complications observed after stent implantation. ISR is characterized by the inordinate proliferation of smooth muscle cells (SMC) that leads to narrowing of the blood vessels. To achieve a healthy endothelium, it is critical to selectively enhance the growth of endothelial cells (EC) while suppressing the growth of smooth muscle cells, which is still a major challenge and yet to be achieved. In this study, novel surfaces have been developed to support the selective growth of endothelial cells. Micro-and nanostructured Al2O3 surfaces with unique topographical features were fabricated and tested. Surface characterization and cellular response of endothelial cells (HUVEC) as well as smooth muscle cells (HUVSMC) has been investigated at cellular and molecular levels. A topography driven selective cell response of ECs over SMCs was demonstrated successfully. This selective response of ECs was also analyzed at protein levels in order to understand the basic mechanism.Publication Open Access PathoNet introduced as a deep neural network backend for evaluation of Ki-67 and tumor-infiltrating lymphocytes in breast cancer(Nature Publishing Group (NPG), 2021) Sabzi, R.; Pakniyat Jahromi, B.; Firouzabadi, D.; Movahedi, F.; Kohandel Shirazi, M.; Majidi, S.; Dehghanian, A.; N/A; Faculty Member; Graduate School of Sciences and EngineeringThe nuclear protein Ki-67 and Tumor infiltrating lymphocytes (TILs) have been introduced as prognostic factors in predicting both tumor progression and probable response to chemotherapy. The value of Ki-67 index and TILs in approach to heterogeneous tumors such as Breast cancer (BC) that is the most common cancer in women worldwide, has been highlighted in literature. Considering that estimation of both factors are dependent on professional pathologists’ observation and inter-individual variations may also exist, automated methods using machine learning, specifically approaches based on deep learning, have attracted attention. Yet, deep learning methods need considerable annotated data. In the absence of publicly available benchmarks for BC Ki-67 cell detection and further annotated classification of cells, In this study we propose SHIDC-BC-Ki-67 as a dataset for the aforementioned purpose. We also introduce a novel pipeline and backend, for estimation of Ki-67 expression and simultaneous determination of intratumoral TILs score in breast cancer cells. Further, we show that despite the challenges that our proposed model has encountered, our proposed backend, PathoNet, outperforms the state of the art methods proposed to date with regard to harmonic mean measure acquired. Dataset is publicly available in https://shiraz-hidc.com and all experiment codes are published in https://github.com/SHIDCenter/PathoNet.Publication Open Access Effects of preeclampsia on the amplitude integrated electroencephalography activity in preterm infants(De Gruyter, 2016) Topçuoğlu, Sevilay; Kolsuz, Leyla Daban; Ovalı, Fahri; Karatekin, Güner; N/A; Gürsoy, Tuğba; Faculty Member; School of Medicine; 214691Objective: Preeclampsia leads to chronic intrauterine hypoxia by interfering with placental blood supply. The aim of this study was to investigate whether preeclampsia exposure has an influence on the central nervous system of infants, as monitored by amplitude integrated electro-encephalography (aEEG).Publication Open Access Nanoengineering InP quantum dot-based photoactive biointerfaces for optical control of neurons(Frontiers, 2021) Ulgut, Burak; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; N/A; Nizamoğlu, Sedat; Kavaklı, İbrahim Halil; Şahin, Afsun; Karatüm, Onuralp; Aria, Mohammad Mohammadi; Eren, Güncem Özgün; Yıldız, Erdost; Melikov, Rustamzhon; Srivastava, Shashi Bhushan; Sürme, Saliha; Doğru-Yüksel, Itır Bakış; Jalali, Houman Bahmani; Faculty Member; Faculty Member; Faculty Member; PhD Student; Researcher; Teaching Faculty; PhD Student; Department of Electrical and Electronics Engineering; Department of Chemical and Biological Engineering; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); College of Engineering; School of Medicine; Graduate School of Sciences and Engineering; Graduate School of Health Sciences; 130295; 40319; 171267; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/A; N/ALight-activated biointerfaces provide a non-genetic route for effective control of neural activity. InP quantum dots (QDs) have a high potential for such biomedical applications due to their uniquely tunable electronic properties, photostability, toxic-heavy-metal-free content, heterostructuring, and solution-processing ability. However, the effect of QD nanostructure and biointerface architecture on the photoelectrical cellular interfacing remained unexplored. Here, we unravel the control of the photoelectrical response of InP QD-based biointerfaces via nanoengineering from QD to device-level. At QD level, thin ZnS shell growth (similar to 0.65 nm) enhances the current level of biointerfaces over an order of magnitude with respect to only InP core QDs. At device-level, band alignment engineering allows for the bidirectional photoelectrochemical current generation, which enables light-induced temporally precise and rapidly reversible action potential generation and hyperpolarization on primary hippocampal neurons. Our findings show that nanoengineering QD-based biointerfaces hold great promise for next-generation neurostimulation devices.Publication Open Access Al-doped MgB2 materials studied using electron paramagnetic resonance and Raman spectroscopy(American Institute of Physics (AIP) Publishing, 2016) Erdem, Emre; Repp, Sergej; Weber, Stefan; N/A; Department of Chemistry; Bateni, Ali; Somer, Mehmet Suat; PhD Student; Faculty Member; Department of Chemistry; Graduate School of Sciences and Engineering; College of Sciences; N/A; 178882Undoped and aluminum (Al) doped magnesium diboride (MgB2) samples were synthesized using a high-temperature solid-state synthesis method. The microscopic defect structures of Al-doped MgB2 samples were systematically investigated using X-ray powder diffraction, Raman spectroscopy, and electron paramagnetic resonance. It was found that Mg-vacancies are responsible for defect-induced peculiarities in MgB2. Above a certain level of Al doping, enhanced conductive properties of MgB2 disappear due to filling of vacancies or trapping of Al in Mg-related vacancy sites. Published by AIP Publishing.Publication Open Access Defect structure of ultrafine MgB2 nanoparticles(American Institute of Physics (AIP) Publishing, 2014) Repp, Sergej; Thomann, Ralf; Acar, Selçuk; Erdem, Emre; N/A; Department of Chemistry; Bateni, Ali; Somer, Mehmet Suat; PhD Student; Faculty Member; Department of Chemistry; Graduate School of Sciences and Engineering; College of Sciences; N/A; 178882Defect structure of MgB2 bulk and ultrafine particles, synthesized by solid state reaction route, have been investigated mainly by the aid of X-band electron paramagnetic resonance spectrometer. Two different amorphous Boron (B) precursors were used for the synthesis of MgB2, namely, boron 95 (purity 95%-97%, <1.5 mu m) and nanoboron (purity >98.5%, <250 nm), which revealed bulk and nanosized MgB2, respectively. Scanning and transmission electron microscopy analysis demonstrate uniform and ultrafine morphology for nanosized MgB2 in comparison with bulk MgB2. Powder X-ray diffraction data show that the concentration of the by-product MgO is significantly reduced when nanoboron is employed as precursor. It is observed that a significant average particle size reduction for MgB2 can be achieved only by using B particles of micron or nano size. The origin and the role of defect centers were also investigated and the results proved that at nanoscale MgB2 material contains Mg vacancies. Such vacancies influence the connectivity and the conductivity properties which are crucial for the superconductivity applications. (C) 2014 AIP Publishing LLC.Publication Open Access Increased srum uric acid over five years is a risk factor for developing fatty liver(Nature Publishing Group (NPG), 2017) Jensen, Thomas; Niwa, Koichiro; Hisatome, Ichiro; Andres-Hernando, Ana; Roncal-Jimenez, Carlos A.; Sato, Yuka; Garcia, Gabriela; Ohno, Minoru; Lanaspa, Miguel A.; Johnson, Richard J.; Kuwabara, Masanari; N/A; Kanbay, Mehmet; Faculty Member; School of Medicine; 110580The prevalence of fatty liver disease (FLD) is increasing. To clarify risk factors for developing FLD, we analyzed a database from healthy Japanese adults who had annual medical check-ups in 2004 and reexamined in 2009. We used the fatty liver index (FLI) to classify participants as FLD (FLI >= 60), borderline FLD (30 <= FLI < 60), and normal liver (FLI < 30). Subjects with hepatitis B or C virus infection and subjects with FLD at the baseline were excluded. The cumulative incidence of FLD from normal liver and from borderline FLD over five years were 0.65% (52/8,025) and 12.9% (244/1,888), respectively. After multiple adjustments, higher serum uric acid (SUA) (OR:1.92; 95% CI:1.40-2.63) and increased SUA change (OR:3.734; 95% CI:2.57-5.42) became risk factors for developing FLD from normal liver, as well as younger age and higher body mass index. The risk factors for developing FLD from borderline FLD were similar. Not only higher baseline SUA but also increased SUA change became independent risks for developing FLD.