Biology subjects

Celik, E.

Publications and source records attributed to Celik, E..

7 recordsLinked to original sources

bioRxiv2025

RetiGene, a comprehensive gene atlas for inherited retinal diseases (IRDs)

Inherited retinal diseases (IRDs) are rare disorders, typically presenting as Mendelian traits, that result in stationary or progressive visual impairment. They are characterized by extensive genetic heterogeneity, possibly the highest among all human genetic diseases, as well as diverse inheritance patterns. Despite advances in gene discovery, limited understanding of gene function and challenges in accurately interpreting variants continue to hinder both molecular diagnosis and genetic research in IRDs. One key problem is the absence of a comprehensive and widely accepted catalogue of disease genes, which would ensure consistent genetic testing and reliable molecular diagnoses. With the rapid pace of IRD gene discovery, gene catalogues require frequent validation and updates to remain clinically and scientifically useful. To address these gaps, we developed RetiGene, an expert-curated gene atlas that integrates variant data, bulk and single-cell RNA sequencing, and functional annotations. Through the integration of diverse data sources, RetiGene supports candidate gene prioritization, functional studies, and therapeutic development in IRDs.

genetics↗

bioRxiv2025

An ATM-PPM1D Circuit Controls the Processing and Restart of DNA Replication Forks

In response to DNA replication stress, DNA damage signaling kinases inhibit origin firing and promote the remodeling and stabilization of replication forks, leading to a systemic reduction in DNA synthesis, which collectively protects genomic integrity. Little is understood about the regulatory mechanisms of replication stress recovery, including the mechanisms involved in the restart of stalled replication forks. Here, we identify the oncogenic phosphatase PPM1D/WIP1 as a regulator of replication fork restart. During recovery from replication stress, PPM1D prevents excessive MRE11- and DNA2-dependent nucleolytic degradation of stalled forks. Loss of PPM1D function leads to defects in RAD51 recruitment to chromatin and impairs RAD51-dependent fork restart. Phosphoproteomic analysis reveals that PPM1D regulates a network of ATM substrates, several of which are phosphorylated at an S/T-Q-(E/D)n motif. Strikingly, inhibition of ATM suppresses the deleterious consequences of impaired PPM1D function at replication forks, enabling timely fork restart. The dominant effect of ATM hyper-signaling in suppressing fork restart occurs, in part, through the excessive engagement of 53BP1 and consequent RAD51 antagonization. These findings uncover a new mode of ATM signaling responding to fork stalling and highlight the need for PPM1D to restrain ATM signaling and facilitate proper fork restart.

biochemistry↗

bioRxiv2021

Task-Dependent Warping of Semantic Representations During Search for Visual Action Categories

Object and action perception in cluttered dynamic natural scenes relies on efficient allocation of limited brain resources to prioritize the attended targets over distractors. It has been suggested that during visual search for objects, distributed semantic representation of hundreds of object categories is warped to expand the representation of targets. Yet, little is known about whether and where in the brain visual search for action categories modulates semantic representations. To address this fundamental question, we studied human brain activity recorded via functional magnetic resonance imaging while subjects viewed natural movies and searched for either communication or locomotion actions. We find that attention directed to action categories elicits tuning shifts that warp semantic representations broadly across neocortex, and that these shifts interact with intrinsic selectivity of cortical voxels for target actions. These results suggest that attention serves to facilitate task performance during social interactions by dynamically shifting semantic selectivity towards target actions, and that tuning shifts are a general feature of conceptual representations in the brain.

neuroscience↗

bioRxiv2020

Lentiviral vector-based SARS-CoV-2 pseudovirus enables analysis of neutralizing activity in COVID-19 convalescent plasma

As the COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to spread around the globe, effective vaccination protocols are under deployment. Alternatively, the use of convalescent plasma (CP) therapy relies on the transfer of the immunoglobulin repertoire of a donor that has recovered from the disease as a means of passive vaccination. While the lack of an effective antiviral treatment inadvertently increases the interest in CP products, initial clinical evaluation on COVID-19 patients revealed that critical factors determining the outcome of CP therapy need to be defined clearly if clinical efficacy is to be expected. Measurement of neutralizing activity against SARS-CoV-2 using wildtype virus presents a reliable functional assay but the availability of suitable BSL3 facilities for virus culture restricts its applicability. Instead, the use of pseudovirus particles containing elements from the SARS-CoV-2 virus is widely applied to determine the activity of CP or other neutralizing agents such as monoclonal antibodies. In this study, we present our approach to optimize GFP-encoding lentiviral particles pseudotyped with the SARS-CoV-2 Spike and Membrane proteins for use in neutralization assays. Our results show the feasibility of pseudovirus production using a C-terminal truncated Spike protein which is greatly enhanced by the incorporation of the D614G mutation. Moreover, we report that the use of Sodium Butyrate during lentiviral vector production dramatically increases pseudovirus titers. Analysis of CP neutralizing activity against particles pseudotyped with wildtype or D614G mutant Spike protein in the presence or absence the M protein revealed differential activity in CP samples that did not necessarily correlate with the amount of anti-SARS-CoV-2 antibodies. Our results indicate that the extent of neutralizing activity in CP samples depends on the quality rather than the quantity of the humoral immune responses and varies greatly between donors. Functional screening of neutralizing activity using pseudovirus-based neutralization assays must be accepted as a critical tool for choosing CP donors if clinical efficacy is to be maximized.

immunology↗

bioRxiv2020

Attentional Modulation of Hierarchical Speech Representations in a Multi-Talker Environment

Humans are remarkably adept in listening to a desired speaker in a crowded environment, while filtering out non-target speakers in the background. Attention is key to solving this difficult cocktail-party task, yet a detailed characterization of attentional effects on speech representations is lacking. It remains unclear across what levels of speech features and how much attentional modulation occurs in each brain area during the cocktail-party task. To address these questions, we recorded whole-brain BOLD responses while subjects either passively listened to single-speaker stories, or selectively attended to a male or a female speaker in temporally-overlaid stories in separate experiments. Spectral, articulatory, and semantic models of the natural stories were constructed. Intrinsic selectivity profiles were identified via voxelwise models fit to passive listening responses. Attentional modulations were then quantified based on model predictions for attended and unattended stories in the cocktail-party task. We find that attention causes broad modulations at multiple levels of speech representations while growing stronger towards later stages of processing, and that unattended speech is represented up to the semantic level in parabelt auditory cortex. These results provide insights on attentional mechanisms that underlie the ability to selectively listen to a desired speaker in noisy multi-speaker environments.

neuroscience↗

bioRxiv2020

Identifying Genomic Alterations in Stage IV Breast Cancer Patients using MammaSeq™: An International Collaborative Study

BackgroundIdentification of genomic alterations present in cancer patients may aid in cancer diagnosis and prognosis and may identify therapeutic targets. In this study, we aimed to identify clinically actionable variants present in stage IV breast cancer (BC) samples. Materials and MethodsDNA was extracted from formalin fixed paraffin embedded (FFPE) samples of BC (n=41). DNA was sequenced using MammaSeq, a BC specific next generation sequencing panel targeting 79 genes and 1369 mutations. Ion Torrent Suite 4.0 was used to make variant calls on the raw data and the resulting single nucleotide variants were annotated using CRAVAT toolkit. SNVs were filtered to remove common polymorphisms and somatic variants. CNVkit was employed to identify copy number variations. The Precision Medicine Knowledgebase (PMKB) and OncoKB Precision Oncology Database were used to associate clinical significance with the identified variants. ResultsA total of 41 Turkish BC patient samples were sequenced (read depth of 94 - 13340, median of 1529). These samples were from patients diagnosed with various BC subtypes including invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), apocrine BC and micropapillary BC. In total, 59 different alterations (49 SNVs and 10 CNVs) were identified. From these, 8 alterations (3 CNVs - ERBB2, FGFR1 and AR copy number gains and 5 SNVs - IDH1.R132H, TP53.E204*, PI3KCA.E545K, PI3KCA.H1047R and PI3KCA.R88Q) were identified to have some clinical significance by PMKB and OncoKB. Moreover, the top five genes with most SNVs included PIK3CA, TP53, MAP3K1, ATM and NCOR1. Additionally, copy number gains and losses were found in ERBB2, GRB7, IGFR1, AR, FGFR1, MYC and IKBKB, and BRCA2, RUNX1 and RB1 respectively. ConclusionWe identified 59 unique alterations in 38 genes in 41 stage IV BC tissue samples using MammaSeq. Ten of these alterations were found to have some clinical significance by OncoKB and PKMB. This study highlights the potential use of cancer specific NGS panels in clinic to get better insight into the patient-specific genomic alterations. Highlights- 41 stage IV stage breast cancer patients of Turkish descent were sequenced using MammaSeq - 49 single nucleotide variations and 10 copy number variations identified - PIK3CA and TP53 mutations were present in 24% and 17% of the samples respectively - 37% of the samples had ERBB2/GRB7 gains and 7% had loss of BRCA2/RB1 locus - Eight clinically significant alterations were identified Micro AbstractWe performed targeted sequencing using DNA from FFPE samples of 41 stage IV breast cancer patients using MammaSeq, a breast cancer gene specific targeted sequencing panel. In total, 49 single nucleotide variations (SNVs) and 10 copy number variations (CNVs) were identified. Eight alterations (3 CNVs - ERBB2, FGFR1 and AR copy number gains and 5 SNVs - IDH1.R132H, TP53.E204*, PI3KCA.E545K, PI3KCA.H1047R and PI3KCA.R88Q) were identified to have clinical significance by PMKB and OncoKB databases.

genomics↗

bioRxiv2019

Biased competition in semantic representation during natural visual search

Humans divide their attention among multiple visual targets in daily life, and visual search gets more difficult as the number of targets increases. The biased competition hypothesis (BC) has been put forth as an explanation for this phenomenon. BC suggests that brain responses during divided attention are a weighted linear combination of the responses during search for each target individually. Furthermore, this combination is biased by the intrinsic selectivity of cortical regions. Yet, it is unknown whether attentional modulations of semantic representations of cluttered and dynamic natural scenes are consistent with this hypothesis. Here, we investigated whether BC accounts for semantic representation during natural category-based visual search. Human subjects viewed natural movies, and their whole-brain BOLD responses were recorded while they attended to \"humans\", \"vehicles\" (i.e. single-target attention tasks), or \"both humans and vehicles\" (i.e. divided attention) in separate runs. We computed a voxelwise linearity index to assess whether semantic representation during divided attention can be modeled as a weighted combination of representations during the two single-target attention tasks. We then examined the bias in weights of this linear combination across cortical ROIs. We find that semantic representations during divided attention are linear to a substantial degree, and that they are biased toward the preferred target in category-selective areas across ventral temporal cortex. Taken together, these results suggest that the biased competition hypothesis is a compelling account for attentional modulations of semantic representation across cortex.\n\nSignificance Statement\n\nNatural vision is a complex task that involves splitting attention between multiple search targets. According to the biased competition hypothesis (BC), limited representational capacity of the cortex inevitably leads to a competition among representation of these targets and the competition is biased by intrinsic selectivity of cortical areas. Here we examined BC for semantic representation of hundreds of object and action categories in natural movies. We observed that: 1) semantic representation during simultaneous attention to two object categories is a weighted linear combination of representations during attention to each of them alone, and 2) the linear combination is biased toward semantic representation of the preferred object category in strongly category-selective areas. These findings suggest BC as a compelling account for attentional modulations of semantic representation across cortex in natural vision.

neuroscience↗