Biology subjects

Kral, A.

Publications and source records attributed to Kral, A..

5 recordsLinked to original sources

bioRxiv2025

Ovo, an Open-Source Ecosystem for De Novo Protein Design

The protein design field is rapidly advancing, with frequent emergence of new models and pipelines for designing de novo proteins with tailored properties and functions not found in nature. However, the current tool landscape is fragmented, tools are hard to install and deploy, and require significant computational expertise to integrate into end-to-end, scalable pipelines. A particular challenge is managing many sequences, structures, and metrics for downstream testing and retrospective analysis of input parameters. To address this need, we introduce Ovo, an open-source de novo protein design ecosystem that consolidates models, workflows, data management, and interactive visualization into a scalable, infrastructure-agnostic platform. Ovo features Nextflow-based workflow orchestration, a storage layer, and both command-line and graphical interfaces that democratize scaffold design, binder design and diversification, and validation workflows. Ovos novel ProteinQC module computes comprehensive sequence and structure descriptors, contextualizing designs against reference sets. Ovo plugins let the community add new workflows and user interfaces to accelerate adoption of emerging methods and facilitate community-driven benchmarking. Ovo lowers engineering barriers and demystifies the design process, allowing experts and non-technical users to design proteins at scale. With community-driven development, Ovo can accelerate de novo protein design and advance discovery in therapeutics and biotechnology.

bioinformatics↗

bioRxiv2025

MYC-Driven Activation of USP39 Enhances SRSF1 Stability and Promotes PDAC Progression

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy primarily driven by oncogenic KRAS signaling. The splicing factor SRSF1 plays a key oncogenic role in PDAC, where its tightly regulated expression constrains KRAS-driven signaling under normal conditions, while its upregulation promotes tumorigenesis. SRSF1 expression is regulated in part by proteostasis. However, the precise mechanisms remain unclear. Here, we identify USP39 as a deubiquitinase that interacts with SRSF1 in an RNA-independent manner and stabilizes it by reducing ubiquitination. USP39 expression is elevated in PDAC tumors and precancerous lesions, and correlates with poor patient survival. USP39 knockdown suppresses PDAC cell proliferation and migration, effects that are partially rescued by SRSF1 overexpression. Mechanistically, we show that MYC directly activates USP39 transcription via E-box motifs within its exon 1b promoter, linking MYC-driven transcriptional regulation to post- translational stabilization of SRSF1. Together, these findings define a MYC-USP39-SRSF1 regulatory axis that integrates transcriptional and post-translational mechanisms in PDAC and highlight USP39 as a potential therapeutic target.

cancer biology↗

bioRxiv2023

Hearing loss in juvenile rats leads to excessive play fighting and hyperactivity, mild cognitive deficits and altered neuronal activity in the prefrontal cortex

BackgroundIn children, hearing loss has been associated with hyperactivity, disturbed social interaction, and risk of cognitive disturbances. Mechanistic explanations of these relations sometimes involve language. To investigate the effect of hearing loss on behavioral deficits in the absence of language, we tested the impact of hearing loss in juvenile rats on motor, social, and cognitive behavior and on physiology of prefrontal cortex. MethodsHearing loss was induced in juvenile (postnatal day 14) male Sprague-Dawley rats by intracochlear injection of neomycin under general anaesthesia. Sham-operated and non-operated hearing rats served as controls. One week after surgery auditory brainstem response (ABR) measurements verified hearing loss or intact hearing in sham-operated and non-operated controls. All rats were then tested for locomotor activity (open field), coordination (Rotarod), and for social interaction during development in weeks 1, 2, 4, 8, 16, and 24 after surgery. From week 8 on, rats were trained and tested for spatial learning and memory (4-arm baited 8-arm radial maze test). In a final setting, neuronal activity was recorded in the medial prefrontal cortex (mPFC). ResultsIn the open field deafened rats moved faster and covered more distance than sham-operated and non-operated controls from week 8 on (both p<0.05). Deafened rats showed significantly more play fighting during development (p<0.05), whereas other aspects of social interaction, such as following, were not affected. Learning of the radial maze test was not impaired in deafened rats (p>0.05), but rats used less next-arm entries than other groups indicating impaired concept learning (p<0.05). In the mPFC neuronal firing rate was reduced and enhanced irregular firing was observed. Moreover, oscillatory activity was altered, both within the mPFC and in coherence of mPFC with the somatosensory cortex (p<0.05). ConclusionsHearing loss in juvenile rats leads to hyperactive behavior and pronounced play-fighting during development, suggesting a causal relationship between hearing loss and cognitive development. Altered neuronal activities in the mPFC after hearing loss support such effects on neuronal networks outside the central auditory system. This animal model provides evidence of developmental consequences of juvenile hearing loss on prefrontal cortex in absence of language as potential confounding factor.

animal behavior and cognition↗

bioRxiv2022

Stability of neural representations in the auditory midbrain across the lifespan despite age-related brainstem delays

The extent to which aging of the central auditory pathway impairs auditory perception in the elderly independent of peripheral cochlear decline is debated. To cause auditory deficits in normal hearing elderly, central aging needs to degrade neural sound representations at some point along the auditory pathway. However, inaccessible to psychophysical methods, the level of the auditory pathway at which aging starts to effectively degrade neural sound representations remains poorly differentiated. Here we tested how potential age-related changes in the auditory brainstem affect the stability of spatiotemporal multiunit complex speech-like sound representations in the auditory midbrain of old normal hearing CBA/J mice. Although brainstem conduction speed slowed down in old mice, the change was limited to the sub-millisecond range and only minimally affected temporal processing in the midbrain (i.e. gaps-in-noise sensitivity). Importantly, besides the small delay, multiunit complex temporal sound representations in the auditory midbrain did not differ between young and old mice. This shows that although small age-related neural effects in simple sound parameters in the lower brainstem may be present in aging they do not effectively deteriorate complex neural population representations at the level of the auditory midbrain when peripheral hearing remains normal. This result challenges the widespread belief of pure central auditory decline as an automatic consequence of aging. However, the stability of midbrain processing in aging emphasizes the role of undetected hidden peripheral damage and accumulating effects in higher cortical auditory-cognitive processing explaining perception deficits in normal hearing elderly.

neuroscience↗

bioRxiv2020

Deep sampling and pooled amplicon sequencing reveals hidden genic variation in heterogeneous rye accessions

Loss of genetic variation negatively impacts breeding efforts and food security. Genebanks house over 7 million accessions representing vast allelic diversity that is a resource for sustainable breeding. Discovery of DNA variations is an important step in the efficient use of these resources. While technologies have improved and costs dropped, it remains impractical to consider resequencing millions of accessions. Candidate genes are known for most agronomic traits, providing a list of high priority targets. Heterogeneity in seed stocks means that multiple samples from an accession need to be evaluated to recover available alleles. To address this we developed a pooled amplicon sequencing approach and applied it to the out-crossing cereal rye (Secale cereale). Ninety-five rye accessions of different improvement status and worldwide origin, each represented by a pooled sample comprising DNA of 96 individual plants, were evaluated for sequence variation in six target genes involved in seed quality, biotic and abiotic stress resistance. Seventy-four predicted deleterious variants were identified using multiple algorithms. Rare variants were recovered including those found only in a low percentage of seed. A large extent of within-population heterogeneity was revealed, providing an important point for consideration during rye germplasm conservation and utilization efforts. We conclude that this approach provides a rapid and flexible method for evaluating stock heterogeneity, probing allele diversity, and recovering previously hidden variation.

genomics↗