Biology subjects

Niesman, I.

Publications and source records attributed to Niesman, I..

3 recordsLinked to original sources

bioRxiv2025

Integration of artificial intelligence and high-content screening enabled identification of drugs for long-term treatment of cerebral cavernous malformation disease

BackgroundAdults and children with cerebral cavernous malformations (CCMs) are at risk of experiencing lifelong complications such as hemorrhagic strokes, neurological deficits, and epileptic seizures. These complications can severely reduce quality of life. At present, there is no safe or effective therapeutic option for the long-term treatment of CCMs. MethodsUsing advanced artificial intelligence (AI) and machine learning models, powered by the Benevolent Platform, we aimed to identify therapeutic drug targets for CCM pathology (e.g., CCM1, CCM2, CCM3). An AI integrative approach utilized various data types from biomedical entities, including diseases, genes, tissues, and biological mechanisms, together with CCM transcriptomic experimental data. High-throughput drug screening of AI-selected FDA-approved medications, analyses of mitochondrial morphology, and studies on pharmacokinetics, pharmacodynamics, and toxicology were conducted in CCM animal models to identify drugs that could potentially be repurposed for the long-term treatment of CCM disease. ResultsAI predicted the AMPK (AMP-activated protein kinase) and mTOR (mammalian target of rapamycin) pathways as potential therapeutic targets that contribute to CCM pathology. High-content screening validation revealed that the FDA-approved drug metformin, which acts as an AMPK agonist and mTOR inhibitor, can reverse changes in cell-cell junction organization and increase KLF4 expression, a marker for CCM, in human CCM endothelial cells in cultured assays. In addition, pharmacodynamic markers of metformin were observed in CCM mouse models (Slco1c1-iCreERT2;Krit1fl/fl;Ptenfl/wt and Slco1c1-iCreERT2;Pdcd10fl/fl) including reduced S6 kinase or ribosomal protein phosphorylation, a marker of decrease mTOR signaling, and increased AMPK phosphorylation, a marker of AMPK activation, that corresponded to reduced lesion burden. Pharmacokinetic and toxicological studies in CCM animal models showed that that metformin penetrates the brain and long-term administration has a favorable safety profile. We also demonstrated that brain endothelial cells in chronic CCM mouse models exhibit increased levels of the inflammatory marker VCAM-1, which is associated with altered mitochondrial phenotypes, as observed by immunofluorescence, MITO-tagging, and electron microscopy analysis. Additionally, we discovered that metformin and a potent AMPK activator, PF-06409577, can reverse mitochondrial phenotypic changes in brain endothelial cells and reduce the elevation of VCAM-1 expression associated with chronic CCM disease. Therefore, metformin can provide cytoprotection and may reverse the CCM endothelial phenotype by activating AMPK. ConclusionsPredictions using AI technology and high-throughput drug screening, combined with pharmacokinetic, pharmacodynamic, and toxicological studies in CCM animal models, identified metformin as a promising drug candidate for repurposing for the long-term treatment of CCM disease. We propose that metformin enhances metabolic adaptation to brain vascular malformations by activating AMPK, which helps reverse mitochondrial fragmentation in brain endothelial cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/693036v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@17bfadforg.highwire.dtl.DTLVardef@936708org.highwire.dtl.DTLVardef@15171ceorg.highwire.dtl.DTLVardef@69029_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2024

Elasmobranchs Exhibit Species-Specific Epidermal Microbiomes Guided by Denticle Topography

Elasmobranch epidermal microbiomes are species-specific, yet microbial assembly and retainment drivers are mainly unknown. The contribution of host-derived factors in recruiting an associated microbiome is essential for understanding host-microbe interactions. Here, we focus on the physical aspect of the host skin in structuring microbial communities. Each species of elasmobranch exhibits unique denticle morphology, and we investigate whether microbial communities and functional pathways are correlated with the morphological features or follow the phylogeny of the three species. We extracted and sequenced the DNA from the epidermal microbial communities of three captive shark species: Horn (Heterodontus francisci), Leopard (Triakis semifasciata), and Swell shark (Cephaloscyllium ventriosum) and use electron microscopy to measure the dermal denticle features of each species. Our results outline species-specific microbial communities, as microbiome compositions vary at the phyla level; C. ventriosum hosted a higher relative abundance of Pseudomonadota and Bacillota, while H. francisci were associated with a higher prevalence of Euryarchaeota and Aquificae, and Bacteroidota and Crenarchaeota were ubiquitous with T. semifasciata. Functional pathways performed by each species respective microbiome were species-specific metabolic. Microbial genes associated with aminosugars and electron-accepting reactions were correlated with the distance between dermal denticles, whereas desiccation stress genes were only present when the dermal denticle overlapped. Microbial genes associated with Pyrimidines, chemotaxis and virulence followed the phylogeny of the sharks. Several microbial genera display associations that resemble host evolutionary lineage, while others had linear relationships with interdenticle distance. Therefore, denticle morphology was a selective influence for some microbes and functions in the microbiome contributing to the phylosymbiosis. ImportanceMicrobial communities form species-specific relationships with vertebrate hosts, but the drivers of these relationships remain an outstanding question. We explore the relationship between a physical feature of the host and the microbial community. A distinguishing feature of the subclass Elasmobranchii (sharks, rays, and skates), is the presence of dermal denticles on the skin. These structures protrude through the epidermis providing increased swimming efficiency for the host and an artificial model skin affect microbial recruitment and establishment of cultured microbes but has not been tested on natural microbiomes. Here, we show some naturally occurring microbial genera and functional attributes were correlated with dermal denticle features, suggesting they are one, but not only contributing factor in microbiome structure on benthic sharks.

microbiology↗

bioRxiv2020

Siamese cat tyrosinase has enhanced proteasome degradation and increased cellular aggregation

Siamese cats are a notable example of a temperature-sensitive partial albinism phenotype. The signature color-pointing pattern is the result of an amino acid substitution - G302R - in the cysteine-rich domain of feline tyrosinase. The precise mechanism for the loss of tyrosinase enzyme activity due to this mutation is unknown. ObjectiveWe have used a cellular biology approach to begin unravel relationships between feline coloration, behavior and increased risk for feline cognitive dysfunction syndrome. GFP-fusion constructs of wild type domestic short hair tyrosinase and Siamese (G302R) tyrosinase generated to study cellular trafficking, degradation and the propensity for cellular aggregation. Data DescriptionC-terminal GFP G302R expression has reduced Golgi localization, increased cytosolic fractions with reduced calnexin co-localization. N-terminal GFP constructs were retained in the ER, with little to no Golgi associated forms. C-terminal and N-terminal GFP G302R TYR is observed to have increased high molecular weight aggregation following proteasome inhibition.

cell biology↗