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Item Metadata only Author correction: The effect of ketamine on affective modulation of the startle reflex and its resting-state brain correlates(Nature Research, 2023) 0000-0001-6503-8665; Sen, Zümrüt Duygu; Chand, Tara; Danyeli, Lena Vera; Kumar, Vinod Jangir; Colic, Lejla; Li, Meng; Yemisken, Merve; Javaheripour, Nooshin; Refisch, Alexander; Opel, Nils; Macharadze, Tamar; Kretzschmar, Moritz; Deliano, Matthias; Walter, Martin; N/A; Özkan, Esra; Researcher; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/ACorrection to: Scientific Reports, published online 16 August 2023 The original version of this Article omitted affiliations for Tara Chand. The correct affiliations are listed below. Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743, Jena, Germany Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany Department of Clinical Psychology, Friedrich Schiller University Jena, Am Steiger 3-1, 07743, Jena, Germany Jindal Institute of Behavioural Sciences, O. P. Jindal Global University (Sonipat), Haryana, India The original Article has been corrected.Item Metadata only Aspergillus Carneus metabolite Averufanin induced cell cycle arrest and apoptotic cell death on cancer cell lines via inducing DNA damage(Nature Portfolio, 2023) 0000-0003-1302-1997; N/A, 0000-0001-5037-7883; Ozkaya, Ferhat Can; Ebrahim, Weaam; N/A; Sokullu, Emel; Demirel, Deren; Şahin, İrem Durmaz; Faculty Member; PhD Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Health Sciences; School of Medicine; 163024; N/A; 303825Cancer is one of the leading causes of death worldwide, accounting for nearly 10 million deaths in 2020. Current treatment methods include hormone therapy, & gamma;-radiation, immunotherapy, and chemotherapy. Although chemotherapy is the most effective treatment, there are major obstacles posed by resistance mechanisms of cancer cells and side-effects of the drugs, thus the search for novel anti-cancer compounds, especially from natural sources, is crucial for cancer pharmaceutics research. One natural source worthy of investigation is fungal species. In this study, the cytotoxicity of 5 metabolic compounds isolated from filamentous fungus Aspergillus Carneus. Arugosin C, Averufin, Averufanin, Nidurifin and Versicolorin C were analyzed using NCI-SRB assay on 10 different cell lines of breast cancer, ovarian cancer, glioblastoma and non-tumorigenic cell lines. Averufanin showed highest cytotoxicity with lowest IC50 concentrations especially on breast cancer cells. Therefore, Averufanin was further investigated to enlighten cell death and molecular mechanisms of action involved. Cell cycle analysis showed increase in SubG1 phase suggesting apoptosis induction which was further confirmed by Annexin V and Caspase 3/7 Assays. H2A.X staining revealed accumulation of DNA damage in cells treated with Averufanin and finally western blot analysis validated DNA damage response and downstream effects of Averufanin treatment in various signaling pathways. Consequently, this study shows that Averufanin compound induces cell cycle arrest and cell death via apoptosis through causing DNA damage and can be contemplated and further explored as a new therapeutic strategy in breast cancer.Item Metadata only Artificial intelligence assisted patient blood and urine droplet pattern analysis for non-invasive and accurate diagnosis of bladder cancer(Nature Portfolio, 2024) 0000-0001-6435-7883; N/A; N/A; 0000-0001-6749-8518; 0000-0001-5379-6151; 0000-0003-0724-1942; 0000-0001-7739-2346; Bilir, Sukriye; Williams, Rhodri; Christy, John; Tinay, Ilker; N/A; N/A; N/A; N/A; N/A; Department of Computer Engineering; N/A; Demir, Ramiz; Koç, Soner; Öztürk, Deniz Gülfem; Özata, İbrahim Halil; Akkoç, Yunus; Demir, Çiğdem Gündüz; Gözüaçık, Devrim; PhD Student; PhD Student; Researcher; Teaching Faculty; Researcher; Faculty Member; Faculty Member; Koç Üniversitesi İş Bankası Yapay Zeka Uygulama ve Araştırma Merkezi (KUIS AI)/ Koç University İş Bank Artificial Intelligence Center (KUIS AI); Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; Graduate School of Health Sciences; N/A; School of Medicine; N/A; College of Engineering; School of Medicine; N/A; N/A; N/A; 177151; N/A; 43402; 40248Bladder cancer is one of the most common cancer types in the urinary system. Yet, current bladder cancer diagnosis and follow-up techniques are time-consuming, expensive, and invasive. In the clinical practice, the gold standard for diagnosis remains invasive biopsy followed by histopathological analysis. In recent years, costly diagnostic tests involving the use of bladder cancer biomarkers have been developed, however these tests have high false-positive and false-negative rates limiting their reliability. Hence, there is an urgent need for the development of cost-effective, and non-invasive novel diagnosis methods. To address this gap, here we propose a quick, cheap, and reliable diagnostic method. Our approach relies on an artificial intelligence (AI) model to analyze droplet patterns of blood and urine samples obtained from patients and comparing them to cancer-free control subjects. The AI-assisted model in this study uses a deep neural network, a ResNet network, pre-trained on ImageNet datasets. Recognition and classification of complex patterns formed by dried urine or blood droplets under different conditions resulted in cancer diagnosis with a high specificity and sensitivity. Our approach can be systematically applied across droplets, enabling comparisons to reveal shared spatial behaviors and underlying morphological patterns. Our results support the fact that AI-based models have a great potential for non-invasive and accurate diagnosis of malignancies, including bladder cancer.Item Metadata only EDA2R-NIK signalling promotes muscle atrophy linked to cancer cachexia(Nature Portfolio, 2023) N/A; 0000-0002-7785-2143; N/A; 0000-0002-2661-3505; N/A; N/A; 0000-0002-0990-3543; N/A; N/A; N/A; N/A; Department of Molecular Biology and Genetics; N/A; N/A; Bilgiç, Şevval Nur; Waraich, Aylin Domaniku; Toledo, Batu; Ağca, Samet; Weber, Bahar Çamurdanoğlu.; Arabacı, Hilal Dilşad; Özörnek, Zeynep; PhD Student; PhD Student; Master Student; PhD Student; Researcher; PhD Student; PhD Student; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Sciences and Engineering; N/A; N/A; N/A; N/A; N/A; N/A; N/ASkeletal muscle atrophy is a hallmark of the cachexia syndrome that is associated with poor survival and reduced quality of life in patients with cancer(1). Muscle atrophy involves excessive protein catabolism and loss of muscle mass and strength(2). An effective therapy against muscle wasting is currently lacking because mechanisms driving the atrophy process remain incompletely understood. Our gene expression analysis in muscle tissues indicated upregulation of ectodysplasin A2 receptor (EDA2R) in tumour-bearing mice and patients with cachectic cancer. Here we show that activation of EDA2R signalling promotes skeletal muscle atrophy. Stimulation of primary myotubes with the EDA2R ligand EDA-A2 triggered pronounced cellular atrophy by induction of the expression of muscle atrophy-related genes Atrogin1 and MuRF1. EDA-A2-driven myotube atrophy involved activation of the non-canonical NF?B pathway and was dependent on NF?B-inducing kinase (NIK) activity. Whereas EDA-A2 overexpression promoted muscle wasting in mice, deletion of either EDA2R or muscle NIK protected tumour-bearing mice from loss of muscle mass and function. Tumour-induced oncostatin M (OSM) upregulated muscle EDA2R expression, and muscle-specific oncostatin M receptor (OSMR)-knockout mice were resistant to tumour-induced muscle wasting. Our results demonstrate that EDA2R-NIK signalling mediates cancer-associated muscle atrophy in an OSM-OSMR-dependent manner. Thus, therapeutic targeting of these pathways may be beneficial in prevention of muscle loss.Item Metadata only Reconfigurable intelligent surface-empowered MIMO systems(Oxford Univ Press, 2023) 0000-0001-5566-2392; Department of Electrical and Electronics Engineering; Başar, Ertuğrul; Faculty Member; College of Engineering; 149116A brief overview is presented in this perspective, considering the application of reconfigurable intelligent surfaces for future multiple-input multiple-output (MIMO) systems.Item Metadata only Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: experience from the MJFF Global Genetic Parkinson's Disease Project(Public Library Science, 2023) 0000-0001-6977-2517; 0000-0003-3413-0332; 0000-0003-1339-243X; Vollstedt, Eva-Juliane; Madoev, Harutyun; Aasly, Anna; Ahmad-Annuar, Azlina; Al-Mubarak, Bashayer; Alcalay, Roy N.; Alvarez, Victoria; Amorin, Ignacio; Annesi, Grazia; Arkadir, David; Bardien, Soraya; Barker, Roger A.; Barkhuizen, Melinda; Bonifati, Vincenzo; Boon, Agnita; Brighina, Laura; Brockmann, Kathrin; Belin, Andrea Carmine; Carr, Jonathan; Clarimon, Jordi; Cornejo-Olivas, Mario; Guedes, Leonor Correia; Corvol, Jean-Christophe; Crosiers, David; Damasio, Joana; Das, Parimal; de Carvalho Aguiar, Patricia; De Rosa, Anna; Dorszewska, Jolanta; Ferese, Rosangela; Ferreira, Joaquim; Gatto, Emilia; Genc, Gencer; Giladi, Nir; Gomez-Garre, Pilar; Hanagasi, Hasmet; Hattori, Nobutaka; Hentati, Faycal; Hoffman-Zacharska, Dorota; Illarioshkin, Sergey N.; Jankovic, Joseph; Jesus, Silvia; Kaasinen, Valtteri; Kievit, Anneke; Klivenyi, Peter; Kostic, Vladimir; Koziorowski, Dariusz; Kuehn, Andrea A.; Lang, Anthony E.; Lim, Shen-Yang; Lin, Chin-Hsien; Lohmann, Katja; Markovic, Vladana; Martikainen, Mika Henrik; Mellick, George; Merello, Marcelo; Milanowski, Lukasz; Mir, Pablo; Pimentel, Marcia Mattos Goncalves; Pulkes, Teeratorn; Puschmann, Andreas; Rogaeva, Ekaterina; Sammler, Esther M.; Skaalum Petersen, Maria; Skorvanek, Matej; Spitz, Mariana; Suchowersky, Oksana; Tan, Ai Huey; Termsarasab, Pichet; Thaler, Avner; Tumas, Vitor; Valente, Enza Maria; van de Warrenburg, Bart; Williams-Gray, Caroline H.; Wu, Ruey-Mei; Zhang, Baorong; Zimprich, Alexander; Solle, Justin; Padmanabhan, Shalini; Klein, Christine; N/A; Başak, Ayşe Nazlı; Çakmak, Özgür Öztop; Ertan, Fatoş Sibel; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; 1512; 299358; 112829Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting similar to 7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.Item Metadata only Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential(Nature Portfolio, 2022) 0000-0002-0861-5013; 0000-0001-7399-5844; Kneppers, Jeroen; Severson, Tesa M.; Siefert, Joseph C.; Schol, Pieter; Joosten, Stacey E. P.; Yu, Ivan Pak Lok; Huang, Chia-Chi Flora; Morova, Tunc; Altintas, Umut Berkay; Giambartolomei, Claudia; Seo, Ji-Heui; Baca, Sylvan C.; Carneiro, Isa; Emberly, Eldon; Pasaniuc, Bogdan; Jeronimo, Carmen; Henrique, Rui; Freedman, Matthew L.; Wessels, Lodewyk F. A.; Bergman, Andries M.; Zwart, Wilbert; N/A; Altıntaş, Umut Berkay; Lack, Nathan Alan; Master Student; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Sciences and Engineering; School of Medicine; N/A; 120842Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients' outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.Item Metadata only Investigation of the effect of carnitine on cerebral vasospasm in experimental subarachnoid hemorrhage model(Nature Research, 2023) 0000-0003-1342-7663; 0000-0002-3132-4839; Resitoglu, Gokhan; Oztanir, Mustafa Namik; N/A; Akgün, Mehmet Yiğit; Ateş, Özkan; Doctor; Faculty Member; School of Medicine; N/A; Koç University Hospital; N/A; N/A; 118533The vasospasm, which develops after subarachnoid hemorrhage (SAH), is an unenlightened table in terms of etiology and results. It is usually associated with decreased perfusion, which is associated with decreased blood flow distal to the affected artery and can be demonstrated radiologically. Acetyl-L-carnitine (ALCAR) can be found in brain tissue and easily crosses the blood–brain barrier. Therefore, in this study, we aimed to investigate the therapeutic efficacy of ALCAR, which is an effective antioxidant amine, on vasospasm development after experimental SAH. In our study, 35 adults male Wistar RATs weighing between 235–250 g were used. These RATs were divided into five groups with n = 7. Group 1 Control group, Group 2 SAH + SF (carrier solution), Group 3 SAH + ALCAR 50 mg\kg intraperitoneally, Group 4 SAH + ALCAR 100 mg\kg intraperitoneally and Group 5 SAH. Subarachnoid hemorrhage was induced by giving autologous arterial blood to the cisterna magna of the animals in groups 2, 3, 4, and 5. At 0.-12.- 24.- 36.- 48.- 60. and 72. h, Group 2 was injected with SF, Group 3 with intraperitoneally ALCAR 50 mg\kg, and Group 4 with intraperitoneally ALCAR 100 mg\kg, respectively. Following perfusion and fixation, the animals were subjected to a wide craniectomy, and the brain, cerebellum, and brain stems were removed globally. Then, sections were taken from the basilar arteries of all animals and photographed at 40X magnification. Basilar artery lumen cross-sectional areas, basilar artery areas, and wall thicknesses were measured from these sections. The basilar artery lumen cross-sectional area was found to be significantly larger in the groups in which SAH was formed and ALCAR 50 mg\kg and ALCAR 100 mg\kg were given compared to the group with only SAH and SAH + SF (p = 0.0408). Basilar artery wall thickness increased in all groups except the control group (p < 0.05). In light of all these findings, it was concluded in our study that Carnitine was effective in the resolution of vasospasm in the experimental SAH model.Publication Metadata only An image-guided microfluidic system for single-cell lineage tracking(Public Library Science, 2023) Kamil, Mahmut Aslan; Fourneaux, Camille; Stavros, Stavrakis; Parmentier, Romuald J.; Paldi, Andras; Gonin-Giraud, Sandrine; deMello, Andrew; Gandrillon, Olivier; Yılmaz, Alperen; Graduate School of Sciences and EngineeringCell lineage tracking is a long-standing and unresolved problem in biology. Microfluidic technologies have the potential to address this problem, by virtue of their ability to manipulate and process single-cells in a rapid, controllable and efficient manner. Indeed, when coupled with traditional imaging approaches, microfluidic systems allow the experimentalist to follow single-cell divisions over time. Herein, we present a valve-based microfluidic system able to probe the decision-making processes of single-cells, by tracking their lineage over multiple generations. The system operates by trapping single-cells within growth chambers, allowing the trapped cells to grow and divide, isolating sister cells after a user-defined number of divisions and finally extracting them for downstream transcriptome analysis. The platform incorporates multiple cell manipulation operations, image processing-based automation for cell loading and growth monitoring, reagent addition and device washing. To demonstrate the efficacy of the microfluidic workflow, 6C2 (chicken erythroleukemia) and T2EC (primary chicken erythrocytic progenitors) cells are tracked inside the microfluidic device over two generations, with a cell viability rate in excess of 90%. Sister cells are successfully isolated after division and extracted within a 500 nL volume, which was demonstrated to be compatible with downstream single-cell RNA sequencing analysis.Publication Metadata only Audible pain squeaks can mediate emotional contagion across pre-exposed rats with a potential effect of auto-conditioning(Nature Portfolio, 2023) Packheiser, Julian; Paradiso, Enrica; Michon, Frederic; Ramaaker, Eline; Sahin, Neslihan; Muralidharan, Sharmistha; Woehr, Markus; Gazzola, Valeria; Keysers, Christian; Department of Psychology; Department of Psychology; Soyman, Efe; College of Social Sciences and HumanitiesFootshock self-experience enhances rodents' reactions to the distress of others. Here, we tested one potential mechanism supporting this phenomenon, namely that animals auto-condition to their own pain squeaks during shock pre-exposure. In Experiment 1, shock pre-exposure increased freezing and 22 kHz distress vocalizations while animals listened to the audible pain-squeaks of others. In Experiment 2 and 3, to test the auto-conditioning theory, we weakened the noxious pre-exposure stimulus not to trigger pain squeaks, and compared pre-exposure protocols in which we paired it with squeak playback against unpaired control conditions. Although all animals later showed fear responses to squeak playbacks, these were weaker than following typical pre-exposure (Experiment 1) and not stronger following paired than unpaired pre-exposure. Experiment 1 thus demonstrates the relevance of audible pain squeaks in the transmission of distress but Experiment 2 and 3 highlight the difficulty to test auto-conditioning: stimuli weak enough to decouple pain experience from hearing self-emitted squeaks are too weak to trigger the experience-dependent increase in fear transmission that we aimed to study. Although our results do not contradict the auto-conditioning hypothesis, they fail to disentangle it from sensitization effects. Future studies could temporarily deafen animals during pre-exposure to further test this hypothesis. While audible pain squeaks among rats are relevant in the transmission of distress, it is difficult to disentangle whether animals can be auto-conditioned to the sound of their own pain squeaks.