Biology subjects

Yildirim, S.

Publications and source records attributed to Yildirim, S..

7 recordsLinked to original sources

bioRxiv2025

Integrative Analysis of Neuroimaging and Microbiome Data Predicts Cognitive Decline in Parkinson's Disease

Parkinsons disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment (CI) ranging from mild cognitive impairment (MCI) to Parkinsons disease dementia (PDD). Growing evidence supports the gut-brain axis as playing an essential role in the pathophysiology of PD, suggesting promising applications for combining advanced neuroimaging techniques with microbiome profiling to accelerate biomarker discovery and therapeutic innovation. This study combines resting-state functional magnetic resonance imaging (rs-fMRI) and 16S rRNA sequencing of stool and saliva to identify biomarkers predictive of CI in PD. A stepwise feature selection pipeline, incorporating ANOVA, random forest ranking, and partial correlation analysis, was applied to extract biologically meaningful features from rs-fMRI connectivity matrices and microbial taxa. Independent and joint machine learning models, including Random Forest, support vector machine, XGBoost, and logistic regression, were evaluated for their predictive performance. The joint model, integrating neuroimaging and microbiome features, outperformed modality-specific models in classifying HC, MCI, and PDD stages, achieving an accuracy of 88.9% and AUC of 97.2% with Random Forest. Key fMRI features involved the salience and default mode networks, while microbial biomarkers included taxa such as Faecalibacterium, Veillonella, and Streptococcus. Correlations between microbial taxa and fMRI features suggest potential gut-brain interactions influencing CI. For example, Faecalibacterium abundance was positively associated with connectivity in the salience network, while Veillonella showed links to executive function networks. These findings support the synergistic value of integrating multi-omics data for uncovering mechanisms underlying CI in PD. This study demonstrates the utility of combining neuroimaging and microbiome data to enhance predictive performance and biological insight. The identified biomarkers may serve as a foundation for developing microbiome-targeted interventions and neuroimaging-guided strategies for managing cognitive decline in PD. Future work should focus on larger, longitudinal datasets and explainable AI approaches to further refine this integrative methodology.

bioinformatics↗

bioRxiv2024

Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats

Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunctionLassociated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modelling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.

bioinformatics↗

bioRxiv2024

Temporal Microbiome Changes in Axolotl Limb Regeneration: Stage-Specific Restructuring of Bacterial and Fungal Communities with a Flavobacterium Bloom During Blastema Proliferation

The intricate relationship between regeneration and microbiota has recently gained attention, spanning diverse model organisms. Axolotl (Ambystoma mexicanum) is a critically endangered salamander species and a model organism for regenerative and developmental biology. Despite its significance, a noticeable gap exists in understanding the interplay between axolotl regeneration and its microbiome. Here, we analyze in depth bacterial 16S rRNA amplicon dataset that we reported before as data resource and profile fungal community by sequencing ITS amplicons at the critical stages of limb regeneration (0-1-4-7-30-60 days post amputation, "dpa"). Results reveal a decline in richness and evenness in the course of limb regeneration, with bacterial community richness recovering beyond 30 dpa unlike fungi community. Beta diversity analysis reveals precise restructuring of the bacterial community along the three phases of limb regeneration, contrasting with less congruent changes in the fungal community. Temporal dynamics of the bacterial community highlight prevalent anaerobic bacteria in initiation phase and Flavobacterium bloom in the early phase correlating with limb blastema proliferation. Predicted functional analysis mirrors these shifts, emphasizing a transition from amino acid metabolism to lipid metabolism control. Fungal communities shift from Blastomycota to Ascomycota dominance in the late regeneration stage. Our findings provide ecologically relevant insights into stage specific role of microbiome contributions to axolotl limb regeneration.

microbiology↗

bioRxiv2022

Discovery of therapeutic agents targeting PKLR for NAFLD using drug repositioning

Background & AimsNon-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver pathologies. However, not medical treatment has been approved for the treatment of the disease. In our previous study, we found PKLR could be a potential target for treatment of NALFD. Here, the aim is to investigate the effect of PKLR in in vivo model and perform drug repositioning to identify a drug candidate for treatment of NAFLD. MethodsBiopsies from liver, muscle, white adipose tissue and heart were obtained from control and PKLR knockout mice fed with chow and high sucrose diets. Lipidomics as well as transcriptmics analyses were conducted using these tissue samples. In addition, a computational drug repositioning analysis was performed and drug candidates were identified. The drug candidates were finally tested in both in vitro and in vivo models to evaluated their toxicity and efficacy. ResultsThe Pklr KO reversed the increased hepatic triglyceride level in mice fed with high sucrose diet and partly recovered the transcriptomic changes in liver as well as other three tissues. Both liver and white adipose tissues exhibited dysregulated circadian transcriptomic profiles, and these dysregulations were reversed by hepatic knockout of Pklr. In addition, 10 small molecule drugs were identified as potential inhibitor of PKLR by the drug repositioning pipeline, and two of them significantly inhibited both the PKLR expression and triglyceride level in in vitro model. Finally, the two selected small molecule drugs were evaluated in in vivo rat models and it was demonstrated that these drugs attenuated hepatic steatosis without side effect on other tissues. ConclusionIn conclusion, our study provided biological insights about the critical role of PKLR in NAFLD progression and proposed a treatment strategy for NAFLD patients, which has been validated in preclinical experiment.

systems biology↗

bioRxiv2021

Stratification of the Gut Microbiota Composition Landscape Across the Alzheimer's Disease Continuum in a Turkish Cohort

Alzheimers disease (AD) is a heterogeneous neurodegenerative disorder that spans over a continuum with multiple phases including preclinical, mild cognitive impairment, and dementia. Unlike most other chronic diseases there are limited number of human studies reporting on AD gut microbiota in the literature. These published studies suggest that the gut microbiota of AD continuum patients varies considerably throughout the disease stages, raising expectations for existence of multiple microbiota community types. However, the community types of AD gut microbiota were not systematically investigated before, leaving important research gap for diet-based intervention studies and recently initiated precision nutrition approaches aiming at stratifying patients into distinct dietary subgroups. Here, we comprehensively assessed the community types of gut microbiota across the AD continuum. We analyze 16S rRNA amplicon sequencing of stool samples from 27 mild cognitive patients, 47 AD, and 51 non-demented control subjects using tools compatible with compositional nature of microbiota. To characterize gut microbiota community types, we applied multiple machine learning techniques including partitioning around the medoid clustering, fitting probabilistic Dirichlet mixture model, Latent Dirichlet Allocation model, and performed topological data analysis for population scale microbiome stratification based on Mapper algorithm. These four distinct techniques all converge on Prevotella and Bacteroides partitioning of the gut microbiota across AD continuum while some methods provided fine scale resolution in partitioning the community landscape. The Signature taxa and neuropsychometric parameters together robustly classify the heterogenous groups within the cohort. Our results provide a framework for precision nutrition approaches and diet-based intervention studies targeting AD cohorts. IMPORTANCEThe prevalence of AD worldwide is estimated to reach 131 million by 2050. Most disease modifying treatments and drug trials have failed due partly to the heterogeneous and complex nature of the disease. Unlike other neurodegenerative diseases gut microbiota of AD patients is poorly studied. Recently initiated ambitious precision nutrition initiative or other diet-based interventions can potentially be more effective if the heterogeneous disease such as AD is deconstructed into multiple strata allowing for better identification of biomarkers across narrower patient population for improved results. Because gut microbiota is inherently integral part of the nutritional interventions there is unmet need for microbiota-informed stratification of AD clinical cohorts in nutritional studies. Our study fills in this gap and draws attention to the need for microbiota stratification as one of the essential steps for precision nutrition interventions. We demonstrate that while Prevotella and Bacteroides clusters are the consensus partitions the newly developed probabilistic methods can provide fine scale resolution in partitioning the AD gut microbiome landscape.

microbiology↗

bioRxiv2020

Heritability in friendship networks

Friendship networks account for a large part of an individuals economic success or failure in life. Using data from the German TwinLife study, we explore, within a classical twin design, to which extent friendship networks are related to genes. We find a substantial heritability component in twins network sizes and network homophily, but not in twins network closeness. Addressing indirect ways in which genes could influence network characteristics, we do not find evidence that shared hobbies affects networks.

genetics↗

bioRxiv2018

Experimentally Induced Metamorphosis in Axolotl (Ambystoma mexicanum) Under Constant Diet Restructures Microbiota Accompanied by Reduced Limb Regenerative Capacity

Axolotl (Ambystoma mexicanum) is a critically endangered salamander species and a model organism for regenerative and developmental biology. Despite life-long neoteny in nature and in captive-bred colonies, metamorphosis of these animals can be experimentally induced by administering Thyroid hormones (THs). However, biological consequences of this experimental procedure, such as host microbiota response and implications for regenerative capacity, remain largely unknown. Here, we systematically compared host bacterial microbiota associated with skin, stomach, gut tissues and fecal samples based on 16S rRNA gene sequences, along with limb regenerative capacity, between neotenic and metamorphic Axolotls. Our results show that distinct bacterial communities inhabit individual organs of Axolotl and undergo substantial restructuring through metamorphosis. Drastic restructuring was observed for skin microbiota, highlighted by a major transition from Firmicutes-enriched to Proteobacteria-enriched relative abundance and precipitously decreased diversity. Remarkably, shifts in microbiota was accompanied by a steep reduction in limb regenerative capacity. Fecal microbiota of neotenic and metamorphic Axolotl shared relatively higher similarity, suggesting that diet continues to shape microbiota despite fundamental transformations in the host digestive organs. The results provide novel insights into microbiological and regenerative aspects of Axolotl metamorphosis and will establish a baseline for future in-depth studies.

microbiology↗