Biology subjects

Zelic, M.

Publications and source records attributed to Zelic, M..

3 recordsLinked to original sources

bioRxiv2026

Love-thy-neighbor: Neural networks for tracking and lineage tracing in budding yeast

Tracking and lineage tracing are widely needed tasks in biological image analysis. For cells that grow and divide, tracking is challenging because cells change in number, shape, and size throughout a recording. As the time interval between images increases, it becomes more difficult to establish correspondences between cells across timepoints. Consequently, tracking has to be performed between consecutive or temporally close images, which leads to exponentially decreasing tracking accuracy and thus high sensitivity to error rates. For budding yeast, this challenge is further heightened by the similarity of cells in colonies, their dense packing, the asymmetric nature of cell divisions, and movement due to growth of the colony. A related task, lineage tracing, is similarly challenging without fluorescent markers due to multiple potential mother cells surrounding a new daughter cell. Here, we present neural networks for budding yeast tracking and lineage tracing, named LYN-track and LYN-trace, respectively. These methods leverage fine geometric features of cells and their neighborhoods. To train and test the algorithms, we recorded and annotated new budding and fission yeast microscopy movies (78,852 frame-to-frame tracklets, 2,512 images), which we make freely available. On these and existing datasets, our neural network-based methods demonstrate robust, above state-of-the-art performance. Both tools have been integrated into graphical user interfaces (GUIs), available on Github, and can be straightforwardly retrained with custom data if desired.

bioinformatics↗

bioRxiv2024

Glial state changes and neuroinflammatory RIPK1 signaling are a key feature of ALS pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes motor neuron loss in the brain and spinal cord. Neuroinflammation driven by activated microglia and astrocytes is prominent in ALS, but an understanding of cell state dynamics and which pathways contribute to the disease remains unclear. Single nucleus RNA sequencing of ALS spinal cords demonstrated striking changes in glial cell states, including increased expression of inflammatory and glial activation markers. Many of these signals converged on RIPK1 and the necroptotic cell death pathway. Activation of the necroptosis pathway in ALS spinal cords was confirmed in a large bulk RNA sequencing dataset and at the protein level. Blocking RIPK1 kinase activity delayed symptom onset and motor impairment and modulated glial responses in SOD1G93A mice. We used a human iPSC-derived motor neuron, astrocyte, and microglia tri-culture system to identify potential biomarkers secreted upon RIPK1 activation, inhibited pharmacologically in vitro, and modulated in the CSF of people with ALS treated with a RIPK1 inhibitor. These data reveal ALS-enriched glial populations associated with inflammation and suggest a deleterious role for neuroinflammatory signaling in ALS pathogenesis.

neuroscience↗

bioRxiv2021

Microglia ferroptosis is prevalent in neurodegenerative disease and regulated by SEC24B

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinsons Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS). One prominent feature of affected brain regions are iron-loaded microglia, but how iron overload influences microglia physiology and disease response is poorly understood. Here we show that microglia are highly susceptible to ferroptosis, an iron-dependent form of cell death. In a tri-culture of human iPSC-derived neurons, astrocytes, and microglia, under ferroptosis-inducing conditions, microglia undergo a drastic shift in cell state, with increased ferritin levels, disrupted glutathione homeostasis, and altered cytokine signaling. Similar ferroptosis-associated signature (FAS) microglia were uncovered in PD, and the signature was also found in a large cohort of PD patient blood samples, raising the possibility that ferroptosis can be identified clinically. We performed a genome-wide CRISPR screen which revealed a novel regulator of ferroptosis, the vesicle trafficking gene SEC24B. A small molecule screen also nominated several candidates which blocked ferroptosis, some of which are already in clinical use. These data suggest that ferroptosis sits at the interface of cell death and inflammation, and inhibition of this process in microglia and other brain cells may provide new ways for treating neurodegenerative disease.

neuroscience↗