Biology subjects

Bergman, M.

Publications and source records attributed to Bergman, M..

5 recordsLinked to original sources

bioRxiv2026

A molecular circuit integrates environmental cues to coordinate the exit from developmental dormancy

Diapause is a reversible dormancy state that enables organisms to survive extreme environments. In annual killifishes, embryos use diapause to bridge seasonal drought, but how environmental cues are integrated to trigger exit remains unclear. Here, we combine model-based single-embryo transcriptomics with cross-clade small-molecule screening to define the molecular logic of diapause exit. In the African turquoise killifish (Nothobranchius furzeri), high-resolution profiling uncovered a temporal transcriptional cascade, while transcriptomic-clock analysis revealed reduced transcriptional noise during developmental reactivation. Transcriptome-guided drug-enrichment analysis nominated overlapping compounds across two annual killifish clades, leading to a targeted chemical screen that identified shared activators and inhibitors of diapause exit. Functional assays support a model in which HSP90 integrates temperature-dependent cues with steroid-hormone signaling. Together, these findings reveal shared molecular machinery that couples environmental sensing to developmental timing, aligns diapause exit with favorable conditions, and provides a powerful comparative framework for dissecting vertebrate dormancy control.

developmental biology↗

bioRxiv2026

Discovering Plastic-Binding Peptides with Favorable Affinity, Water Solubility, and Binding Specificity Through Deep Learning and Biophysical Modeling

Microplastic (MP) pollution, which is present in the ecosystem in vast quantities, adversely affects human health and the environment, making it imperative to develop methods for its mitigation. The challenge of detecting or capturing MPs could potentially be addressed using plastic-binding peptides (PBPs). The ideal PBP for MP remediation would not only bind strongly to plastic, but also have other properties such as high solubility in water or great binding specificity to a certain plastic. However, the scarcity or absence of known PBPs for common plastics along with the lack of methods that can discover PBPs with all of the desired properties precludes the development of peptide-based MP remediation strategies. In this study, we discovered short linear PBPs with high predicted water solubility and binding specificity by employing an in-silico discovery pipeline that combines deep learning and biophysical modeling. First, a long short-term memory (LSTM) network was trained on biophysical modeling data to predict peptide affinity to plastic. High affinity peptides were generated by pairing the trained LSTM with a Monte Carlo tree search (MCTS) algorithm. Molecular dynamics (MD) simulations showed that the PBPs discovered for polyethylene, the most common plastic, had 15% lower binding free energy than PBPs obtained using biophysical modeling alone. PBPs with both high affinity and high predicted solubility in water were found by including the CamSol solubility score in the MCTS peptide scoring function, increasing the average solubility score from 0.2 to 0.9, while only minimally decreasing affinity for polyethylene. The framework also discovered peptides with high binding specificity between polystyrene and polyethylene, two major constituents of MP pollution, using a competitive MCTS approach that optimized the difference in affinity between the two plastics. MD simulations showed that competitive MCTS increased the binding specificity of PBPs for polystyrene and identified peptides with relatively great preference for either of the two plastics. The framework can readily be applied to design PBPs for other types of plastic. Overall, the high-affinity PBPs with desirable properties discovered by marrying artificial intelligence and biophysics can be valuable for remediating MP pollution and protecting the health of humans and the environment.

biophysics↗

bioRxiv2024

The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes

Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes. While recent evidence suggests that inflammation, alongside mutation accumulation and cell death, may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here, by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish (N. furzeri), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly, mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also display reversal of telomere abnormalities and suppression of transposable elements, underscoring cGASs non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic instability syndromes.

genetics↗

bioRxiv2022

Genetic, clinical underpinnings of subtle early brain change along Alzheimer's dimensions

Alzheimers disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE {varepsilon}4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE {varepsilon}4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction - driven by genes different from APOE - which may collectively contribute to the early pathogenesis of AD.

bioengineering↗

bioRxiv2021

Heightened virulence of Yersinia is associated with decreased function of the YopJ protein

Despite the maintenance of YopP/J alleles throughout the human-pathogenic Yersinia lineage, the benefit of YopP/J-induced phagocyte death for Yersinia pathogenesis in animals is not obvious. To determine how sequence divergence of YopP/J has impacted Yersinia virulence, we examined protein polymorphisms in this Type III secreted effector protein across 17 Yersinia species, and tested the consequences of polymorphism in a murine model of sub-acute systemic yersiniosis. Our evolutionary analysis revealed that codon 177 has been subjected to positive selection - the Y. enterocolitica residue had been altered from a leucine to a phenylalanine in nearly all Y. pseudotuberculosis and Y. pestis strains examined. Despite being a minor change, as both leucine and phenylalanine have hydrophobic side chains, reversion of YopJF177 to the ancestral YopJL177 variant yielded a Y. pseudotuberculosis strain with enhanced cytotoxicity towards macrophages, consistent with previous findings. Surprisingly, expression of YopJF177L in the mildly attenuated ksgA- background rendered the strain completely avirulent in mice. Consistent with this hypothesis that YopJ activity indirectly relates to Yersinia pathogenesis in vivo, ksgA- strains lacking functional YopJ failed to kill macrophages but actually regained virulence in animals. Also, treatment with the anti-apoptosis drug suramin prevented YopJ-mediated macrophage cytotoxicity and enhanced Y. pseudotuberculosis virulence in vivo. Our results demonstrate that Yersinia-induced cell death is detrimental for bacterial pathogenesis in this animal model of illness, and indicate that positive selection has driven YopJ/P and Yersinia evolution towards diminished cytotoxicity and increased virulence, respectively.

microbiology↗