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Publication Metadata only 3D ultrasound assessment of effect of controlled ovarian stimulation on endometrioma volume(Oxford University Press (OUP), 2016) Seyhan, A.; Balaban, B.; Urman, Cumhur Bülent; Ata, Mustafa Barış; Faculty Member; Faculty Member; School of Medicine; School of Medicine; 12147; 232576N/APublication Metadata only A comprehensive comparative transcriptional and translational analyses of the impact of ovarian response type, stimulation protocol and mode of trigger on the luteal function(Elsevier Science Inc, 2018) Seyhan, A; Yakın, Kayhan; Ata, Mustafa Barış; Öktem, Özgür; Bildik, Gamze; Urman, Cumhur Bülent; Faculty Member; Faculty Member; Faculty Member; Teaching Faculty; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; 106822; 182910; 102627; N/A; 12147Objective: We aimed to compare molecular characteristics of the luteal granulosa cells between natural vs. stimulated IVF cycles in good and poor-responders. Design: Translational research study. Materials and Methods: Luteinized granulosa cells were obtained from good (n=154) and poor responder (n=64) IVF patients comparable for age, type and dose of gonadotropin and IVF etiology. Good-responders (4-15 oocytes) underwent natural (n=22), GnRH agonist (long protocol n=44) and antagonist IVF cycles triggered with rec-hCG (n=46) or GnRH agonist leuprolide acetate (n=42). Poor-responders fulfilling the Bologna criteria consisted of 64 patients undergoing GnRH antagonist protocol triggered with hCG (n=36) or hCG+GnRH agonist (n=28). Results: In the good-responders, natural cycle (NC) granulosa cells were significantly more viable (88%) compared to the stimulated IVF cycles (66%, 64% and 37% for agonist and antagonist cycles triggered with hCG and agonist respectively, p<0.05). The mRNA expression of steroidogenic enzymes (SCC, stAR, 3B-HSD, 17B-HSD and aromatase), LH receptor and VEGF and in vitro E2 and P productions were comparable between hCG-triggered agonist and antagonist cycles, but significantly higher than NC in the first days of culture. However, on the following days their hormone productions and viability began to decline very rapidly with the most drastic decrease being observed in the agonist triggered cycles. By contrast, NC granulosa cells maintained their viability and produced E 2 and P in increasing amounts in culture up to six days. The expression of anti-apoptotic genes (AKT-1, BCL2-L2) were significantly lower, and pro-apoptotic genes (BAD, BID, BAX, Cas3) were significantly higher in the stimulated cycles particularly in the agonist triggered ones compared to NC granulosa cells. Pulse exposure to cisplatin induced apoptosis only in a small fraction of the cells from the NCs whereas the same exposure caused massive apoptosis in the cells of the stimulated cycles (27% vs. 78% respectively, p<0.01). In the poor-responders both viability and steroidogenic activity of the cells were more severely reduced compared to the antagonist cycles of the good-responders. There were no significant differences between hCG and hCG+agonist triggered cycles in terms of viability, hormone production, VEGF and LH receptor expressions in the luteal granulosa cells. Conclusions Reduced survival and increased apoptosis of luteal granulosa cells leading to defective steroid production in stimulated cycles in comparison to natural ones may at least in part explain why luteal phase is defective and requires exogenous P supplementation for support in these cycles. Also dual trigger does not appear to improve luteal function in the poor-responders.Publication Open Access A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability(eLife Sciences Publications, 2018) Chia, Poh Hui; Zhong, Franklin Lei; Niwa, Shinsuke; Bonnard, Carine; Utami, Kagistia Hana; Zhang, Ruizhu; Lee, Hane; Eskin, Ascia; Nelson, Stanley F.; Xie, William H.; Al-Tawalbeh, Samah; El-Khateeb, Mohammad; Shboul, Mohammad; Pouladi, Mahmoud A.; Al-Raqad, Mohammad; N/A; Reversade, Bruno; Faculty Member; School of MedicineCalcium/calmodulin-dependent protein kinase II (CAMK2) plays fundamental roles in synaptic plasticity that underlies learning and memory. Here, we describe a new recessive neurodevelopmental syndrome with global developmental delay, seizures and intellectual disability. Using linkage analysis and exome sequencing, we found that this disease maps to chromosome 5q31.1-q34 and is caused by a biallelic germline mutation in CAMK2A. The missense mutation, p. His477Tyr is located in the CAMK2A association domain that is critical for its function and localization. Biochemically, the p.His477Tyr mutant is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme.ln vivo, CAMK2A(H477Y) failed to rescue neuronal defects in C. elegans lacking unc-43, the ortholog of human CAMK2A. In vitro, neurons derived from patient iPSCs displayed profound synaptic defects. Together, our data demonstrate that a recessive germline mutation in CAMK2A leads to neurodevelopmental defects in humans and suggest that dysfunctional CAMK2 paralogs may contribute to other neurological disorders.Publication Metadata only A novel and simple method to schedule GNRH antagonist cycles with a short course of oral estradiol in the early follicular phase(Oxford Univ Press, 2019) Angun, B.; Türkgeldi, Engin; Yıldız, Şule; Ata, Mustafa Barış; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; 329649; 134205; 182910N/APublication Metadata only Adaptive tracking algorithm for trajectory analysis of cells and layer-by-layer assessment of motility dynamics(Pergamon-Elsevier Science Ltd, 2022) Bayraktar, Halil; N/A; Department of Molecular Biology and Genetics; Qureshi, Mohammad Haroon; PhD Student; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); N/A; Graduate School of Sciences and Engineering; College of Sciences; N/A; 105301Tracking biological objects such as cells or subcellular components imaged with time-lapse microscopy enables us to understand the molecular principles about the dynamics of cell behaviors. However, automatic object detection, segmentation and extracting trajectories remain as a rate-limiting step due to intrinsic challenges of video processing. This paper presents an adaptive tracking algorithm (Adtari) that automatically finds the op-timum search radius and cell linkages to determine trajectories in consecutive frames. A critical assumption in most tracking studies is that displacement remains unchanged throughout the movie and cells in a few frames are usually analyzed to determine its magnitude. Tracking errors and inaccurate association of cells may occur if the user does not correctly evaluate the value or prior knowledge is not present on cell movement. The key novelty of our method is that minimum intercellular distance and maximum displacement of cells between frames are dynamically computed and used to determine the threshold distance. Since the space between cells is highly variable in a given frame, our software recursively alters the magnitude to determine all plausible matches in the trajectory analysis. Our method therefore eliminates a major preprocessing step where a constant distance was used to determine the neighbor cells in tracking methods. Cells having multiple overlaps and splitting events were further evaluated by using the shape attributes including perimeter, area, ellipticity and distance. The features were applied to determine the closest matches by minimizing the difference in their magnitudes. Finally, reporting section of our software were used to generate instant maps by overlaying cell features and trajectories. Adtari was validated by using videos with variable signal-to-noise, contrast ratio and cell density. We compared the adaptive tracking with constant distance and other methods to evaluate performance and its efficiency. Our algorithm yields reduced mismatch ratio, increased ratio of whole cell track, higher frame tracking efficiency and allows layer-by-layer assessment of motility to characterize single-cells. Adaptive tracking provides a reliable, accurate, time efficient and user-friendly open source software that is well suited for analysis of 2D fluorescence microscopy video datasets.Publication Open Access Archaeogenetic analysis of Neolithic sheep from Anatolia suggests a complex demographic history since domestication(Nature Portfolio, 2021) Yurtman, Erinç; Özer, Onur; Yüncü, Eren; Dağtaş, Nihan Dilşad; Koptekin, Dilek; Çakan, Yasin Gökhan; Özkan, Mustafa; Akbaba, Ali; Kaptan, Damla; Atağ, Gözde; Vural, Kıvılcım Başak; Gündem, Can Yümni; Martin, Louise; Kılınç, Gülşah Merve; Ghalichi, Ayshin; Açan, Sinan Can; Yaka, Reyhan; Sağlıcan, Ekin; Lagerholm, Vendela Kempe; Krzewinska, Maja; Gunther, Torsten; Miranda, Pedro Morell; Pişkin, Evangelia; Sevketoğlu, Müge; Bilgin, C. Can; Atakuman, Ciğdem; Erdal, Yılmaz Selim; Sürer, Elif; Altınışık, N. Ezgi; Lenstra, Johannes A.; Yorulmaz, Sevgi; Abazari, Mohammad Foad; Hoseinzadeh, Javad; Baird, Douglas; Bıcakcı, Erhan; Çevik, Özlem; Gerritsen, Fokke; Gotherstrom, Anders; Somel, Mehmet; Togan, İnci; Özer, Füsun; Department of Archeology and History of Art; Özbal, Rana; Faculty Member; Department of Archeology and History of Art; College of Social Sciences and Humanities; 55583Sheep were among the first domesticated animals, but their demographic history is little understood. Here we analyzed nuclear polymorphism and mitochondrial data (mtDNA) from ancient central and west Anatolian sheep dating from Epipaleolithic to late Neolithic, comparatively with modern-day breeds and central Asian Neolithic/Bronze Age sheep (OBI). Analyzing ancient nuclear data, we found that Anatolian Neolithic sheep (ANS) are genetically closest to present-day European breeds relative to Asian breeds, a conclusion supported by mtDNA haplogroup frequencies. In contrast, OBI showed higher genetic affinity to present-day Asian breeds. These results suggest that the east-west genetic structure observed in present-day breeds had already emerged by 6000 BCE, hinting at multiple sheep domestication episodes or early wild introgression in southwest Asia. Furthermore, we found that ANS are genetically distinct from all modern breeds. Our results suggest that European and Anatolian domestic sheep gene pools have been strongly remolded since the Neolithic.Publication Metadata only Are live birth rate and obstetric outcomes different between immediate and delayed embryo transfers following a freeze-all cycle? a retrospective study combined with a meta-analysis(Oxford Univ Press, 2021) N/A; N/A; N/A; N/A; N/A; N/A; Yıldız, Şule; Türkgeldi, Engin; Kalafat, Erkan; Gökyer, Dilan; Keleş, İpek; Ata, Mustafa Barış; Faculty Member; Faculty Member; Faculty Member; Undergraduate Student; Doctor; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; School of Medicine; Koç University Hospital; 134205; 329649; 197389; N/A; N/A; 182910Study Question: Do livebirth rate (LBR), obstetric and perinatal outcomes vary between frozen embryo transfers (FET) in the first or subsequent menstrual cycles following a freeze-all approach? Summary Answer: Immediate FET has a higher LBR and similar perinatal outcomes than delayed FET. Quantitative synthesis of available literature shows an increased LBR with immediate transfer. What is Known Already: Whether FET should be done in the first menstrual cycle following oocyte collection (OC) is controversial and the duration of a possible detrimental effect of supraphysiological sex steroid levels on pregnancy outcome is unknown. A multinational survey centers showed that, 61% of clinicians prefer to wait for a washout period before proceeding to FET, even after a failed fresh embryo transfer. Limited number of studies compared FET in the first menstrual cycle with delayed FET in a subsequent cycle with varying results. There is limited data on obstetric outcomes of pregnancies resulting from FET in the first menstrual cycle. Study Design, Size, Duration: 198 women who underwent a freeze-all cycle followed by FET between July 2017 and June 2020 were included. 119 FET in the first menstrual cycle (<30 days from oocyte collection) and 79 FET in subsequent cycles (>30 days from oocyte collection) were retrospectively compared. MEDLINE was searched on 01 January 2021 using relevant keywords. Cohort studies comparing immediate versus delayed transfer following freeze all cycles were included and quantitative summary for LBR was obtained. Participants/Materials, Setting, Methods: Freeze-all was undertaken when (i) the woman is deemed to be at high risk for OHSS, (ii)serum progesterone level is > 1.5 ng/ml on the day of trigger, (iii)preimplantation genetic testing is planned, (iv)the woman will undergo surgery prior to ET, (v)couple preference. Main Results and the Role of Chance: Baseline characteristics were similar between the groups except for antral follicle count (22 vs 18, MD = 5, 95% CI = 0 to 8), and number of metaphase-two oocytes (13 vs 10, MD = 3, 95% CI = 1 to 6) all of which were significantly higher in the immediate transfer group. Clinical pregnancy rate (CPR) per ET was similar in two groups (50.4% vs 44.3%, RR = 1.14, 95% CI = 0.84 to 1.54). Miscarriage rate per pregnancy was significantly lower (12.3 vs 31.1, RR = 0.40, 95% CI = 0.19 to 0.84) and LBR per ET was significantly higher (42.9 vs 26.6, RR = 1.61, 95% CI = 1.06 to 2.46) in the immediate transfer group. Median gestational age at delivery was similar (267.5 (262.5–273) vs 268 (260–271.5) days, MD = 1.00, 95% CI= –4.00 to 5.00). Median birthweight was significantly higher in the delayed transfer group (3520 vs 3195 grams, MD= –300, 95% CI= –660 to –20 grams). Birthweight percentile, height at birth and head circumference were similar between groups. Literature search revealed 1712 studies from which nine were eligible for quantitative summary. Cumulative risk ratio showed a 10% increase in LBR with immediate transfer ompared to delayed transfer (RR = 1.10, 95% CI = 1.01 – 1.20, I2=67%, 17369 embryo transfers). Limitations, Reasons for Caution: Our study is limited by its retrospective design and relatively limited sample size for multivariate analyses. Yet, it is reassuring that the majority of our findings are consistent with previous publications. Wider Implications of the Findings: The hypotheses generated by our retrospective findings, i.e., FET in the immediate menstrual cycle resembling fresh ETs with strong trends towards lower birthweight and lower incidence of preeclampsia is noteworthy for the design of future studies, and these outcomes should be followed and reported.Publication Metadata only Assessment of the reliability of the Bologna criteria in predicting ovarian response and live birth rates in subsequent IVF attempts: An external validity study(Oxford University Press (OUP), 2017) Işıklar, A.; Balaban, B.; N/A; N/A; N/A; N/A; Yakın, Kayhan; Öktem, Özgür; Yıldız, Şule; Urman, Cumhur Bülent; Faculty Member; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; 106822; 102627; 134205; 12147N/APublication 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; Soyman, Efe; Department of Psychology; 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.Publication Metadata only Avian responses to selective logging shaped by species traits and logging practices(The Royal Society, 2015) Burivalova, Zuzana; Lee, Tien Ming; Giam, Xingli; Wilcove, David S.; Koh, Lian Pin; Department of Molecular Biology and Genetics; Şekercioğlu, Çağan Hakkı; Faculty Member; Department of Molecular Biology and Genetics; College of Sciences; 327589Selective logging is one of the most common forms of forest use in the tropics. Although the effects of selective logging on biodiversity have been widely studied, there is little agreement on the relationship between life-history traits and tolerance to logging. In this study, we assessed how species traits and logging practices combine to determine species responses to selective logging, based on over 4000 observations of the responses of nearly 1000 bird species to selective logging across the tropics. Our analysis shows that species traits, such as feeding group and body mass, and logging practices, such as time since logging and logging intensity, interact to influence a species' response to logging. Frugivores and insectivores were most adversely affected by logging and declined further with increasing logging intensity. Nectarivores and granivores responded positively to selective logging for the first two decades, after which their abundances decrease below pre-logging levels. Larger species of omnivores and granivores responded more positively to selective logging than smaller species from either feeding group, whereas this effect of body size was reversed for carnivores, herbivores, frugivores and insectivores. Most importantly, species most negatively impacted by selective logging had not recovered approximately 40 years after logging cessation. We conclude that selective timber harvest has the potential to cause large and long-lasting changes in avian biodiversity. However, our results suggest that the impacts can be mitigated to a certain extent through specific forest management strategies such as Llengthening the rotation cycle and implementing reduced impact logging.