Biology subjects

Yilmaz, D.

Publications and source records attributed to Yilmaz, D..

9 recordsLinked to original sources

bioRxiv2026

The Mechanosensitivity of the Regenerative Response in Bone is Retained with Aging in a Mouse Model of Premature Aging.

Aging impairs the regenerative capacity of bone and is associated with poor healing outcomes. The mechanical environment is of fundamental importance to the regenerative response in bone - yet the effect of aging on the mechano-responsive capacity of bone regeneration remains largely unresolved. To investigate age-dependent mechanobiological responses in bone regeneration, we established an experimental framework consisting of: (i) an established femur defect mouse model, (ii) the use of PolgAD257A/D257A (PolgA) mice - a mouse model of premature aging, and (iii) our recently established spatial transcriptomics-based "mechanomics" platform which permits gene expression to be analyzed as a function of the local in vivo mechanical environment. Aging impaired the regenerative response in PolgA mice, resulting in an increased occurrence of delayed and non-unions, delayed bone formation / resorption responses, impaired osteogenesis and delayed mineralization of new bone. Cyclic mechanical loading significantly enhanced the regenerative response in young PolgA mice inducing sustained bone formation, suppressing bone resorption, and enhancing mineralization, with the strongest effects observed in peripheral regions of the fracture site. In aged PolgA mice, the mechanosensitivity of the regenerative response was retained with an anabolic response localized to the defect center. Cyclic mechanical loading applied during the reparative and remodelling phases of fracture healing thus represents a potential translational strategy to harness the mechanosensitivity of aged bone.

physiology↗

bioRxiv2025

Spatial μProBe: a correlative multimodal imaging approach for spatial profiling of biological micro-environments

Despite fundamental advances in spatial omics, investigating cellular and molecular functions within their native environment remains a challenge in multiscale systems biology, especially in response to organ-level events. Here, we introduce Spatial {micro}ProBe (micro-ProBe), a multimodal imaging approach for spatial profiling of biological micro-environments. Spatial {micro}ProBe enables preprocessing, registration and correlative analysis of 2D and 3D imaging modalities, supported by an intuitive user interface. As an application, we investigated bone mechanobiology and characterised the cellular and molecular responses to mechanical loading during adaptation and regeneration, which continuously regulate the local microarchitecture. By integrating time-lapsed micro-computed tomography and end-point spatial transcriptomics, we profiled the local mechanical in vivo environment of thousands of musculoskeletal cells, revealing the spatiotemporal interplay between local mechanics and gene expression driving tissue development. Spatial {micro}ProBe marks a crucial advance in the characterisation of multiscale tissues and signalling, facilitating the exploration of targeted molecular therapies for pathological conditions.

systems biology↗

bioRxiv2024

N-Methyl-D-aspartate receptor hypofunction causes recurrent and transient failures of perceptual inference

1Perception alternates between an external mode, driven by sensory inputs, and an internal mode, shaped by prior knowledge. We found that the external mode is more prevalent during pharmacologically induced N-Methyl-D-aspartate receptor (NMDAR) hypofunction and in schizophrenia. This NMDAR-dependent increase in external mode suggests that psychotic experiences are caused by recurring dissociations of perception from prior knowledge about the world.

neuroscience↗

bioRxiv2024

Exploring sex-specific neuroendocrine influences on the sensorimotor-association axis in single individuals

Human neuroimaging studies consistently show multimodal patterns of variability along a key principle of macroscale cortical organization - the sensorimotor-association (S-A) axis. However, little is known about day-to-day fluctuations in functional activity along this axis within an individual, including sex-specific neuroendocrine factors contributing to such transient changes. We leveraged data from two densely sampled healthy young adults, one female and one male, to investigate intra-individual daily variability along the S-A axis, which we computed as our measure of functional cortical organization by reducing the dimensionality of functional connectivity matrices. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, and was more strongly pronounced in the male subject. Next, we probed local and system-level effects of steroid hormones and self-reported perceived stress on functional organization. Our findings revealed modest effects that differed between participants, hinting at subtle -potentially sex-specific- associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. In sum, our study points to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization, highlighting the need for further research in larger samples.

neuroscience↗

bioRxiv2024

Daily Rhythms in Metabolic and Locomotor Behaviour of Prematurely Ageing PolgA Mice

Ageing is an inherent and intricate biological process that takes place in living organisms as time progresses. It involves the decline of multiple physiological functions, leading to body structure and overall performance modifications. The ageing process differs among individuals and is influenced by various factors, including lifestyle, environment, and genetic makeup. Metabolic changes and reduced locomotor activity are common hallmarks of ageing. Our study focuses on exploring these phenomena in prematurely ageing PolgA(D257A/D257A) mice (also known as PolgA) aged 41-42 weeks, as they closely mimic human ageing. We assess parameters such as oxygen consumption (VO2), carbon dioxide production (VCO2), respiratory exchange ratio (RER), and locomotor activity using a metabolic cage for four days and comparing them with age-matched wild-type littermates (WT). Our findings revealed that VO2, VCO2, RER, locomotor activities, water intake, and feeding behaviour show a daily rhythm, aligning with roughly a 24-hour cycle. We observed that the RER was significantly increased in PolgA mice compared to WT mice during the night-time of the light-dark cycle, suggesting a shift towards a higher reliance on carbohydrate metabolism due to more food intake during the active phase. Additionally, female PolgA mice displayed a distinct phenotype with reduced walking speed, walking distance, body weight, and grip strength in comparison to male PolgA and WT mice, indicating an early sign of ageing. Taken together, our research highlights the impact of sex-specific patterns on ageing traits in PolgA mice aged 41-42 weeks, which may be attributable to human ageing phenotypes. The unique genetic composition and accelerated ageing characteristics of PolgA mice make them invaluable in ageing studies, facilitating the investigation of underlying biological mechanisms and the identification of potential therapeutic targets for age-related diseases.

physiology↗

bioRxiv2024

Unveiling Frailty: Comprehensive and Sex-Specific Characterization in Prematurely Aging PolgA Mice

Frailty, a geriatric syndrome, is assessed using the frailty phenotype (FP) and frailty index (FI). While these approaches have been applied to aging mice, their effectiveness in prematurely aging mouse models such as PolgAD257A/D257A (PolgA) has not been completely explored. We demonstrated that frailty became evident in PolgA mice around 40 weeks, validated through body weight loss, reduced walking speed, decreased physical activity, and weaker grip strength. Moreover, we also identified sex differences in these mice with females exhibiting higher frailty compared to males. Frailty prevalence in PolgA mice at 40 weeks parallels that observed in naturally aging mice at 27 months and aging humans at 65-70 years. These findings contribute to understanding frailty onset and sex-specific patterns, emphasizing the significance of the PolgA mouse model in investigating aging and related disorders.

physiology↗

bioRxiv2022

Selective inhibition of goal-directed actions in the mesencephalic locomotor region

Dopamine enables purposive behavior and adjusts vigor as a function of the relative value of actions. In Parkinsons disease, dopamine neurons die and give rise to a series of motor and cognitive changes that interfere with the expression of volitional actions. Here we report a novel inhibitory input to dopamine neurons originated in the mesencephalic locomotor region that selectively blocks purposive behavior. GABAergic neurons of the pedunculopontine nucleus (PPN) synapse onto dopamine neurons of the substantia nigra and decrease dopamine release in the dorsal striatum. Activation of PPN neurons abolished exploratory locomotion and goal-directed actions while preserved other motor behaviors; furthermore, PPN caused a decrease in movement vigor and interrupted motor sequences presumably by modulating the immediate value of the learned action. Our results reveal an inhibitory mechanism in the midbrain that rapidly and reversibly adjusts the intrinsic value of ongoing actions.

neuroscience↗

bioRxiv2021

Simulations on the efficacy of radiotherapy with different time schemes of antiangiogenic therapy

The combination of radiotherapy and antiangiogenic agents has been suggested to be potent in tumor growth control compared to the application of antiangiogenic therapy or radiotherapy alone. Since radiotherapy is highly dependent on the oxygen level of the tumor area, antiangiogenic agents are utilized for the reoxygenation of tumor vasculature. We present a mathematical framework to investigate the efficacy of radiotherapy combined with antiangiogenic treatment. The framework consists of tumor cells, vasculature, and oxygenation levels evolving with time to mimic a tumor microenvironment. Non-linear partial differential equations (PDEs) are employed to simulate each component of the framework. Different treatment schemes are investigated to see the changes in tumor growth and oxygenation. To test combination schedules, radiation monotherapy, neoadjuvant, adjuvant, and concurrent cases are simulated. The efficiency of each therapy scheme on tumor growth control, the changes in tumor cell density, and oxygen levels shared by tumor cells are represented. The simulation results indicate that the application of radiotherapy after antiangiogenic treatment is more efficient in tumor growth control compared to other therapy schemes. The present study gives an insight into the possible interaction and timing of the combination of radiotherapy and antiangiogenic drug treatment.

cancer biology↗

bioRxiv2020

Chemotherapy response prediction with diffuser elapser network

In solid tumors, elevated fluid pressure and inadequate blood perfusion resulting from unbalanced angiogenesis are the prominent reasons for the ineffective drug delivery inside tumors. To normalize the heterogeneous and tortuous tumor vessel structure, antiangiogenic treatment is an effective approach. Additionally, the combined therapy of antiangiogenic agents and chemotherapy drugs has shown promising effects on enhanced drug delivery. However, the need to find the appropriate scheduling and dosages of the combination therapy is one of the main problems in anticancer therapy. Our study aims to generate a realistic response to the treatment schedule, making it possible for future works to use these patient-specific responses to decide on the optimal starting time and dosages of cytotoxic drug treatment. Our dataset is based on our previous in-silico model with a framework for the tumor microenvironment, consisting of a tumor layer, vasculature network, interstitial fluid pressure, and drug diffusion maps. In this regard, the chemotherapy response prediction problem is discussed in the study, putting forth a proof-of-concept for deep learning models to capture the tumor growth and drug response behaviors simultaneously. The proposed model utilizes multiple convolutional neural network submodels to predict future tumor microenvironment maps considering the effects of ongoing treatment. Since the model has the task of predicting future tumor microenvironment maps, we use two image quality evaluation metrics, which are structural similarity and peak signal-to-noise ratio, to evaluate model performance. We track tumor cell density values of ground truth and predicted tumor microenvironments. The model predicts tumor microenvironment maps seven days ahead with the average structural similarity score of 0.973 and the average peak signal ratio of 35.41 in the test set. It also predicts tumor cell density at the end day of 7 with the mean absolute percentage error of 2.292 {+/-} 1.820. Author summaryThe disorganized structure and leakiness of tumor vessels induce the inadequate blood supply and high fluid pressure within tumors. These features of the tumor microenvironment, identified as delivery barriers, lead to an insufficient amount of drugs to reach the interior parts of tumors. It is observed that the use of anti-vascular drugs makes the structure and function of the tumor vascular system more normal. Moreover, the combination of these drugs with cytotoxic agents provides favorable results with increased treatment response. But, it is also important to adjust the treatment schedule properly. In this regard, we build a deep learning model, designed to examine the tumor response with the ongoing treatment schedule. Our study suggests that deep learning models can be used to predict tumor growth and drug response in the scheduling of cytotoxic drugs.

systems biology↗